JP2010540541A - Methods and compounds for treating retinol-related diseases - Google Patents

Abstract

Compounds that reduce serum retinol levels are used to treat eye diseases associated with overproduction of waste products that accumulate over the course of the visual cycle. We describe methods, compounds, and compositions for treating, for example, macular degeneration and dystrophies, or alleviating symptoms associated with such eye diseases.
[Selection] Figure 1

Description

  This application claims the benefit of US Provisional Patent Application No. 60 / 975,765 (Title of Invention “Methods and Compounds for Treating Retinol-Related Disorders”, filed September 27, 2007). The entirety of which is incorporated herein by reference.

  The methods and compositions described herein provide retinol-related in a subject by modulating the activity or efficacy of serum retinol, retinol binding protein (RBP) and / or transthyretin (TTR) in the subject. Intended for treating disease.

  Retinoids are extremely important for maintaining normal growth, development, immunity, regeneration, vision, and other physiological processes. Conversely, abnormal production or action of retinoids correlates with signs of the disease process.

  For example, more than 100 million children in the world are deficient in vitamin A, causing blindness and death in these children. Excess vitamin A levels can also cause a variety of retinal diseases (including macular degeneration) in target organs and tissues such as the eye. Many types of diseases (commonly referred to as vitreous retinal diseases) can affect the vitreous and retina that are behind the eyes, including retinopathy, and macular degeneration and dystrophies . Macular degeneration is a group of eye diseases and is the leading cause of blindness in affected individuals over the age of 55 in the United States, affecting more than 10 million Americans. One study predicts a 6-fold increase in the number of new cases of macular degeneration over the next 10 years and has epidemic characteristics. Age-related macular degeneration or dystrophy is a particularly debilitating disease that causes a gradual loss of vision and ultimately severe damage to the central field.

  There are two general categories of age-related macular degeneration, dry and wet. Dry macular degeneration accounts for about 90% of all cases and is also known as atrophy, non-exudative, or drusenoid macular degeneration. In dry macular degeneration, drusen typically accumulates under RPE (retinal pigment epithelium) tissue in the retina. And if drusen interferes with photoreceptor function in the macula, blindness can occur. This form of macular degeneration gradually fades vision over the years.

  Wet macular degeneration accounts for about 10% of cases and is also known as choroidal neovascularization, subretinal neovascularization, exudative or discoidal degeneration. In wet macular degeneration, abnormal blood vessel growth can form under the macula; these blood vessels can leak blood and fluid into the macula and damage photoreceptor cells. Studies have shown that dry forms of macular degeneration can lead to wet forms of macular degeneration. Wet forms of macular degeneration can progress rapidly and cause severe damage to central vision.

  Presented herein are methods, compounds, and compositions for treating retinol-related diseases in a human subject or patient. Such diseases are macular degeneration, macular dystrophy, and retinal dystrophy, including dry macular degeneration, geographic atrophy, and / or photoreceptor degeneration. Also provided herein are methods, compounds, and compositions for treating hyperretinolemia (excess serum retinol levels) in a human subject or patient. Also provided herein are methods, compounds, and methods for lowering serum retinol, serum RBP (retinol binding protein), and / or serum TTR (transthyretin) levels in a human subject or patient, and It is a composition. Also provided herein are methods, compounds, and compositions for treating vitreous retinal disease such that the level of serum retinol in the patient's body is low. In certain embodiments, the vitreous retinal disease is macular degeneration, macular dystrophy, and retinal dystrophy. In certain embodiments, the vitreous retinal disease is dry macular degeneration, photoreceptor degeneration, geographic atrophy, macular dystrophy, diabetic retinopathy, wet macular degeneration, retinopathy of prematurity, and / or retinitis pigmentosa It is.

  One aspect is a medicament comprising a compound of formula (I) (Formula 1), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof, and a pharmaceutically acceptable excipient. It is a composition.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, sec-pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H or (Chemical Formula 2),
G is —OR ¹ , — (C ₁ -C ₆ ) alkyl, — (C ₁ -C ₆ ) alkyl-OR ¹ , halogen, —CO ₂ R ¹ , — (C ₁ -C ₆ ) alkyl-CO _{2. ^{R 1, NHR 1, - (}} C 1 -C 6) alkyl ^{-NHR 1, - (C = O} ) NHR 1, - (C 1 -C 6) alkyl ^{- (C = O) NHR 1} , -NHR 1 ( C═O) R ¹ , — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ,
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is a halogen. ]

  In one embodiment, the pharmaceutical composition is an oral pharmaceutical composition for systemic administration of a compound of formula (I).

  One embodiment is a compound having the structure of formula (II) (Formula 3), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof, and a pharmaceutically acceptable excipient: It is a pharmaceutical composition containing an agent.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H or (Chemical Formula 4),
G is —OR ¹ , — (C ₁ -C ₆ ) alkyl, — (C ₁ -C ₆ ) alkyl-OR ¹ , halogen, —CO ₂ R ¹ , — (C ₁ -C ₆ ) alkyl-CO _{2. ^{R 1, NHR 1, - (}} C 1 -C 6) alkyl ^{-NHR 1, - (C = O} ) NHR 1, - (C 1 -C 6) alkyl ^{- (C = O) NHR 1} , -NHR 1 ( C═O) R ¹ , or — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ,
R ¹ is H or (C ₁ -C ₆ ) alkyl. ]

  In one embodiment, the pharmaceutical composition is an oral pharmaceutical composition for systemic administration of a compound of formula (II).

Another embodiment is a pharmaceutical composition comprising a compound having the structure of formula (II), wherein A is O. An additional embodiment is a pharmaceutical composition comprising a compound having the structure of formula (II), wherein B is — (CH ₂ ) _n and n is 1-6, or — (C ₃ — C ₈₎ cycloalkyl. A further additional embodiment is a pharmaceutical composition comprising a compound having the structure of formula (II), wherein E is (C═O) —OR, carboxylic acid bioisostere, — (C═O) —NR. ¹ R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R. One embodiment is a pharmaceutical composition comprising a compound having the structure of Formula (II), A is O, is B - _(C 3 -C ₈₎ cycloalkyl, the E (C = O) -OR, and R is H. In additional embodiments, B is cyclohexyl and R is H. In a further additional embodiment, B is cyclopentyl and R is H. A further additional embodiment is a compound having the structure of A further additional embodiment is a compound having the structure of

  One embodiment is a pharmaceutical composition comprising a compound having the structure of formula (II), wherein R is (Formula 7).

  Another embodiment is a pharmaceutical composition comprising a compound having the structure of formula (II), wherein E is (C═O) —OR. An additional embodiment is a pharmaceutical composition comprising a compound having the structure of formula (II), wherein R is H. Further additional embodiments include 5- (2-tert-butyl-4-chlorophenoxy) -N- (4-hydroxyphenyl) pentanamide, 7- (2-tert-butyl-4-chlorophenoxy) -N -(4-hydroxyphenyl) heptanamide, 4- (5- (2-tert-butyl-4-chlorophenoxy) pentanamide) benzoic acid, 4- (3-((2-tert-butyl-4-chlorophenoxy) ) Methyl) cyclopentanamide) benzoic acid, 5- (2-tert-butyl-4-chlorophenoxy) pentanoic acid, 4- (2-tert-butyl-4-chlorophenoxy) butanoic acid, 2- (3- ( (2-tert-butyl-4-chlorophenoxy) methyl) cyclopentyl) acetic acid, 7- (2-tert-butyl-4-chlorophenoxy) heptanoic acid, 4- (5- (2-tert-butyl-4-methyl) Rophenoxy) pentanamide) benzamide, 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclohexanecarboxylic acid, 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclopentanecarboxylic acid 3-((2-tert-butyl-4-chlorophenylamino) methyl) cyclopentanamide, 4- (3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclopentanecarboxamide) benzoic acid, And a compound of formula (I) selected from the group consisting of 5- (2-tert-butyl-4-chlorophenylthio) pentanoic acid.

One embodiment is a pharmaceutical composition comprising a compound of formula (I) that inhibits the formation of a retinol-retinol binding protein-transthyretin complex, wherein the IC ₅₀ for the inhibition is less than about 5 μM. An additional embodiment is a pharmaceutical composition comprising a compound of formula (I), wherein the IC _{50 of} the inhibition is less than about 1 μM. Another embodiment is a pharmaceutical composition comprising a compound of formula (I) that inhibits cytochrome _P450 to less than about 50%. An additional embodiment is a pharmaceutical composition comprising a compound of formula (I) that inhibits cytochrome _P450 to less than about 10%. Another embodiment is a pharmaceutical composition comprising a compound of formula (I), wherein the compound of formula (I) is used for the treatment of vitreous retinal disease. An additional embodiment is a pharmaceutical composition comprising a compound of formula (I), wherein the vitreous retinal disease is dry macular degeneration, photoreceptor degeneration, geographic atrophy, macular dystrophy, diabetic Selected from the group consisting of retinopathy, wet macular degeneration, retinopathy of prematurity, and retinitis pigmentosa.

  One embodiment comprises a compound of formula (I) (Formula 8), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier. A pharmaceutical composition comprising.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C _{8) cycloalkenyl,} a hetero cycloalkenyl to _(C 3 -C _8),
D is isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, sec-pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, or optionally substituted heteroaryl;
X is a halogen. ]

  In one embodiment, the pharmaceutical composition is an oral pharmaceutical composition for systemic administration of a compound of formula (I).

  One embodiment is a compound having the structure of formula (II) (formula 9), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof and a pharmaceutically acceptable excipient. A pharmaceutical composition comprising an agent or carrier.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, or optionally substituted heteroaryl. ]

  In one embodiment, the pharmaceutical composition is an oral pharmaceutical composition for systemic administration of a compound of formula (II).

One embodiment is a compound having the structure of formula (II) (A is O, B is (C ₃ -C ₈ ) cycloalkyl, E is (C═O) —OR, and R is H), A pharmaceutical composition comprising an active metabolite, or a pharmaceutically acceptable prodrug, salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier. Additional embodiments include compounds having the structure of formula (II) (A is O, B is cyclohexyl, and R is H), active metabolites thereof, or pharmaceutically acceptable prodrugs, salts thereof Alternatively, it is a pharmaceutical composition comprising a solvate and a pharmaceutically acceptable excipient or carrier. A further additional embodiment is a compound having the structure of formula (II) (A is O, B is cyclopentyl, and R is H), an active metabolite thereof, or a pharmaceutically acceptable prodrug thereof, A pharmaceutical composition comprising a salt or solvate and a pharmaceutically acceptable excipient or carrier. Further additional embodiments include a compound having the structure: embedded image or an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof, and a pharmaceutically acceptable excipient. Or a pharmaceutical composition comprising a carrier. Other embodiments include a compound having the structure of embedded image or an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier. A pharmaceutical composition comprising

  Another embodiment is a pharmaceutical composition comprising a compound of formula (I), wherein the composition is included in an amount sufficient to modulate serum retinol or ocular tissue retinol levels or activity in a mammal.

  One embodiment requires dry macular degeneration, photoreceptor degeneration, geographic atrophy, macular dystrophy, diabetic retinopathy, wet macular degeneration, retinopathy of prematurity, or retinitis pigmentosa A method for treatment in a patient, wherein the patient is treated with a therapeutically effective amount of a compound of formula (I) (Chemical Formula 12), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvent thereof. A method comprising the step of administering a Japanese product.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ]

  In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  One embodiment requires dry macular degeneration, photoreceptor degeneration, geographic atrophy, macular dystrophy, diabetic retinopathy, wet macular degeneration, retinopathy of prematurity, and retinitis pigmentosa A method for treatment in a patient comprising the step of administering to the patient a therapeutically effective amount of a compound of formula (II) (formula 13), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvent thereof. It is a method comprising the step of administering a Japanese product.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]

  In one embodiment, a therapeutically effective amount of the compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  One embodiment is a method of treating vitreous retinal disease, comprising a therapeutically effective amount of a compound of formula (I) (Formula 14), an active metabolite thereof, or a pharmaceutically acceptable prodrug thereof, Administering a salt or solvate to the mammal.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl - _(C 3 -C ₈₎ cycloalkenyl, - the _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ]

  Here, the compound of formula (I) modulates the level or activity of retinol binding protein in mammals. In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  One embodiment is a method of treating a vitreous retinal disease, comprising a therapeutically effective amount of a compound of formula (II) (Formula 15), an active metabolite thereof, or a pharmaceutically acceptable prodrug thereof, Administering a salt or solvate to the mammal.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]

  Here, the compound of formula (I) modulates the level or activity of retinol binding protein in mammals. In one embodiment, a therapeutically effective amount of the compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  Another embodiment is a method of treating vitreous retinal disease comprising administering to a mammal a therapeutically effective amount of a compound of formula (I) or (II), wherein the retinol binding protein is RBP4. An additional embodiment is a method of treating vitreous retinal disease comprising administering to a mammal a therapeutically effective amount of a compound of formula (I) or (II), wherein the vitreous retinal disease is dry Macular degeneration, photoreceptor degeneration, geographic atrophy, macular dystrophy, diabetic retinopathy, wet macular degeneration, retinopathy of prematurity, and retinitis pigmentosa.

  One aspect is a method of reducing the level or activity of serum retinol binding protein or transthyretin in a mammal, comprising a therapeutically effective amount of a compound of formula (I) (Chem. 16), an active metabolite thereof, or a pharmaceutical thereof Administering a pharmaceutically acceptable prodrug, salt, or solvate to a mammal, wherein the compound of formula (I) (Chem. 16) increases the level or activity of serum retinol binding protein or transthyretin in the mammal. How to adjust.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl - _(C 3 -C ₈₎ cycloalkenyl, - the _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ]

  In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  One aspect is a method of reducing the level or activity of serum retinol binding protein or transthyretin in a mammal, comprising a therapeutically effective amount of a compound of formula (II) (formula 17), an active metabolite thereof, or a pharmaceutical thereof Of administering a pharmaceutically acceptable prodrug, salt or solvate, wherein the compound of formula (II) (Chem 17) modulates the level or activity of serum retinol binding protein or transthyretin in a mammal It is.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl - _(C 3 -C ₈₎ cycloalkenyl, - the _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]

  In one embodiment, a therapeutically effective amount of the compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  A further additional embodiment is a method of reducing the level or activity of serum retinol binding protein or transthyretin in a mammal comprising administering a therapeutically effective amount of a compound of formula (I) or (II). Provided, the serum retinol binding protein is RBP4. One embodiment is a method of reducing the level or activity of serum retinol binding protein or transthyretin in a mammal comprising the step of administering a therapeutically effective amount of a compound of formula (I) or (II), wherein The compound of (I) or (II) suppresses transcription of retinol binding protein or transthyretin in mammals. An additional embodiment is a method of reducing the level or activity of serum retinol binding protein or transthyretin in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or (II). The compounds of formula (I) or (II) inhibit the translation of retinol binding protein or transthyretin in mammals. Yet another embodiment is a method of reducing the level or activity of serum retinol binding protein or transthyretin in a mammal comprising administering a therapeutically effective amount of a compound of formula (I) or (II). The compound of formula (I) or (II) inhibits retinol binding to retinol binding protein. One embodiment is a method of reducing the level or activity of serum retinol binding protein or transthyretin in a mammal comprising the step of administering a therapeutically effective amount of a compound of formula (I) or (II), wherein The compound of (I) or (II) suppresses the binding of retinol binding protein to transthyretin. Another embodiment is a method of reducing serum retinol binding protein or transthyretin levels or activity in a mammal comprising administering a therapeutically effective amount of a compound of formula (I) or (II), Compounds of formula (I) or (II) increase the clearance of retinol binding protein or transthyretin in mammals.

  One aspect is a method of treating a retinol-related disease in a mammal, comprising a therapeutically effective amount of a compound of formula (I), or an active metabolite thereof, or a pharmaceutically acceptable prodrug thereof, A method comprising administering a salt or solvate to a mammal.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl - _(C 3 -C ₈₎ cycloalkenyl, - the _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ]

  In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  One embodiment is a method of treating a retinol-related disease in a mammal, comprising a therapeutically effective amount of a compound of formula (II) (Formula 19), an active metabolite thereof, or a pharmaceutically acceptable prodrug thereof. , A method comprising administering a salt or solvate to a mammal.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]

  In one embodiment, a therapeutically effective amount of the compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  Another embodiment is a method of treating a retinol-related disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) or (II), wherein the retinol-related disease comprises bone Proliferation, idiopathic intracranial hypertension, amyloidosis, Alzheimer's disease, and Alstrem-Harglen syndrome.

  One embodiment is a method for lowering serum retinol levels in a mammal having dry age-related macular degeneration, wherein the mammal comprises a therapeutically effective amount of a compound of formula (I) Comprising the step of administering an active metabolite, or a pharmaceutically acceptable prodrug, salt or solvate thereof, wherein the compound of formula (I) (Chemical Formula 20) directly affects the activity of the enzyme or protein in the visual cycle. It is a method that does not adjust to.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ]

  In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  One embodiment is a method for lowering serum retinol levels in a mammal having dry age-related macular degeneration, comprising a therapeutically effective amount of a compound of formula (II) (formula 21), an active metabolite thereof Or a pharmaceutically acceptable prodrug, salt or solvate thereof, wherein the compound of formula (II) (Chemical Formula 21) does not directly modulate the activity of the enzyme or protein in the visual cycle Is the method.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]

  In one embodiment, a therapeutically effective amount of the compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  Another embodiment is a method for lowering serum retinol levels in a mammal having dry age-related macular degeneration, comprising administering to the mammal a compound of formula (I) or (II), A method in which the compound of (I) or (II) does not directly inhibit or bind to the enzyme or protein directly in the visual cycle.

  Another embodiment is a method for lowering serum retinol levels in a mammal having dry age-related macular degeneration, comprising administering to the mammal a compound of formula (I) or (II), This is a method in which the compound (I) or (II) does not affect the rhodopsin regeneration rate.

  Yet another embodiment is a method for lowering serum retinol levels in a mammal having dry age-related macular degeneration, comprising administering to the mammal a compound of formula (I) or (II), This is a method in which the compound of formula (I) or (II) does not worsen the dark adaptation delay.

  A further additional embodiment is a method for lowering serum retinol levels in a mammal having dry age-related macular degeneration, comprising administering to the mammal a compound of formula (I) or (II) A compound of formula (I) or (II) is a method of limiting the spread of map-like atrophy or photoreceptor degeneration.

  One aspect is a method of treating hyperretinolemia, comprising a therapeutically effective amount of a compound of formula (I), an active metabolite thereof, or a pharmaceutically acceptable prodrug thereof. A method comprising administering a drug, salt or solvate.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ]

  In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  Another embodiment is a method of treating an excess retinol blood condition comprising a therapeutically effective amount of a compound of formula (II) (Chemical Formula 23), an active metabolite thereof, or a pharmaceutically acceptable prodrug thereof. Alternatively, the method comprises a step of administering a solvate.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]

  In one embodiment, a therapeutically effective amount of the compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  A further embodiment is a method of treating an excess retinol blood condition comprising administering to a mammal a therapeutically effective amount of a compound of formula (I) or (II), wherein the excess retinol blood condition is vitreous. It is a method related to retinal disease.

  Yet another embodiment is a method of treating an excess retinol blood condition comprising administering to a mammal a therapeutically effective amount of a compound of formula (I) or (II), wherein the excess retinol blood condition comprises: It is a method related to diabetes or Alzheimer's disease.

One aspect is a method of treating a retinol-related disease in a mammal, the mammal comprising an effective amount of a compound of formula (I) (Formula 24), an active metabolite thereof, or a pharmaceutically acceptable prodrug thereof, Administering a salt or solvate, wherein the compound of formula (I) inhibits the formation of a retinol-retinol binding protein-transthyretin complex and the IC ₅₀ inhibition is less than about 5 μM. .

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ]

  In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

One embodiment is a method of treating a retinol-related disease in a mammal, wherein the mammal is treated with an effective amount of a compound of formula (II) (Formula 25), an active metabolite thereof, or a pharmaceutically acceptable prodrug thereof. Administering a salt or solvate, wherein the compound of formula (II) inhibits the formation of a retinol-retinol binding protein-transthyretin complex and the IC ₅₀ inhibition is less than about 5 μM. is there.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl - _(C 3 -C ₈₎ cycloalkenyl, - the _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]

  In one embodiment, a therapeutically effective amount of the compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

One embodiment is a method of treating a retinol-related disease in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I) or (II), wherein the formula (I) or (II) A method wherein the compound inhibits the formation of a retinol-retinol binding protein-transthyretin complex and the IC ₅₀ inhibition is less than about 1 μM.

Another embodiment is a method of treating a retinol-related disease in a mammal comprising administering to the mammal an effective amount of a compound of formula (I) or (II), wherein the formula (I) or (II) Is a method in which the formation of a retinol-retinol binding protein-transthyretin complex is suppressed, and the compound of formula (I) or (II) further suppresses cytochrome _P450 to less than about 50%.

Another embodiment is a method of treating a retinol-related disease in a mammal comprising administering to the mammal an effective amount of a compound of formula (I) or (II), wherein the formula (I) or (II) Is a method in which the formation of a retinol-retinol binding protein-transthyretin complex is suppressed, and the compound of formula (I) or (II) further suppresses cytochrome _P450 to less than about 10%.

  One aspect is a method of treating type 1 or type 2 diabetes in a mammal, wherein the mammal is treated with a therapeutically effective amount of a compound of formula (I) (formula 26), an active metabolite thereof, or a pharmaceutically A method comprising administering an acceptable prodrug, salt or solvate, wherein the compound of formula (I) modulates the level or activity of retinol binding protein or transthyretin in a mammal.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ]

  In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  One embodiment is a method of treating type 1 or type 2 diabetes in a mammal, the mammal comprising an effective amount of a compound of formula (II) (Chemical Formula 27), an active metabolite thereof, or a pharmaceutically acceptable salt thereof. Wherein the compound of formula (II) modulates the level or activity of a retinol binding protein or transthyretin in a mammal comprising the step of administering a prodrug, salt or solvate.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]

  In one embodiment, a therapeutically effective amount of the compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  One aspect is a method of lowering serum retinol or ocular tissue retinol levels in a mammal, wherein the mammal is treated with a therapeutically effective amount of a compound of formula (I) (Formula 28), an active metabolite thereof, or a pharmaceutical thereof Administering an acceptable prodrug, salt or solvate.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ]

  In one embodiment, a therapeutically effective amount of a compound of formula (I) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  One embodiment is a method of lowering serum retinol or ocular tissue retinol levels in a mammal, wherein the mammal is treated with an effective amount of a compound of formula (II) (Chemical 29), an active metabolite thereof, or a pharmaceutically acceptable salt thereof. Administering a possible prodrug, salt or solvate.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]

  In one embodiment, a therapeutically effective amount of the compound of formula (II) is provided in the form of an oral pharmaceutical composition for systemic administration of the compound.

  One embodiment is a method of reducing the level of serum retinol or ocular tissue retinol in a mammal comprising administering to the mammal an effective amount of a compound of formula (I) or (II), wherein the mammal is a human Is the method.

  An additional embodiment is a method of lowering serum retinol or ocular tissue retinol levels in a mammal comprising administering to the mammal an effective amount of a compound of formula (I) or (II), wherein serum retinol or A method wherein the level of ocular tissue retinol is reduced by at least 20%.

  A further additional embodiment is a method of lowering serum retinol or ocular tissue retinol levels in a mammal comprising administering to the mammal an effective amount of a compound of formula (I) or (II), at least one Administering two additional agents, the additional agent comprising an inducer of nitric oxide production, an anti-inflammatory agent, a physiologically acceptable antioxidant, a physiologically acceptable mineral, A method selected from the group consisting of negatively charged phospholipids, carotenoids, statins, anti-angiogenic agents, matrix metalloprotease inhibitors, resveratrol and other trans-stilbene compounds, and 13-cis-retinoic acid.

  One aspect is a composition comprising a compound of formula (I) (Formula 30), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ but hetero cycloalkenyl, however, _- (C 2 _-C 7) heteroalkyl is a nitrogen atom, -C (= O) -, - S -, - S (= O) -, - S (= O) 2 -, - NR 1 (C = O) -, - (C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -O (C = O) NR ^1- , -NR ¹ (C = O) O-,- O (C═O) O—, —NR ¹ (C═O) NR ¹ —, — (C═O) O—, —O (C═O) — are not included,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; ^{, NR 1 - (C = O} ) -R, - (C 1 -C 7) alkyl - (C = O) -OR, - (C 1 -C 7) alkyl ^{- (C = O) -NR 1} R, C ₁ -C _{4 alkyl,} C 2 -C _{4 alkynyl,} C 3 -C _{6 cycloalkyl,} C 1 -C ₄ alkyl - _(C 3 -C ₆ cycloalkyl), aryl, heteroaryl, substituted heteroaryl, substituted aryl , Arylalkyl, —C (O) R ² , hydroxy- (C ₁ -C ₆ alkyl), areoxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, —O—C (O) NR ^{2 R 3, -NR 2 R 3} (C = O) OR 1, -SO 2 NR 2 R ³ except that heteroaryl does not contain a nitrogen atom,
R ² and R ³ are each independently selected from H, C ₁ -C ₆ alkyl, and C ₃ -C ₆ cycloalkyl;
R is H, optionally substituted aryl, or optionally substituted heteroaryl, provided that when B is —S—, R is not a pyrimidine and B is — (C ₂ -C ₇ ). R is not imidazole when alkyl,
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is a halogen,
However, E is not (Chemical Formula 31). ]

  One embodiment is a composition comprising a compound of formula (I) (Chemical Formula 32), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ but hetero cycloalkenyl, however, _- (C 2 _-C 7) heteroalkyl is a nitrogen atom, -C (= O) -, - S -, - S (= O) -, - S (= O) 2 -, - NR 1 (C = O) -, - (C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -O (C = O) NR ^1- , -NR ¹ (C = O) O-,- O (C═O) O—, —NR ¹ (C═O) NR ¹ —, — (C═O) O—, —O (C═O) — are not included,
D is tert-butyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; ^{, NR 1 - (C = O} ) -R, - (C 1 -C 7) alkyl - (C = O) -OR, - (C 1 -C 7) alkyl ^{- (C = O) -NR 1} R, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl- (C ₃ -C ₆ cycloalkyl), aryl, substituted aryl, arylalkyl, -C ( O) R ² , hydroxy- (C ₁ -C ₆ alkyl), areoxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, —O—C (O) NR ² R ³ , —NR ² R ³ (C═O) OR ¹ , —SO ₂ NR ² R ³ ,
R ² and R ³ are each independently selected from H, C ₁ -C ₆ alkyl, and C ₃ -C ₆ cycloalkyl;
R is H, optionally substituted aryl, or optionally substituted heteroaryl, provided that when B is —S—, R is not a pyrimidine and B is — (C ₂ -C ₇ ). R is not imidazole when alkyl,
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is Cl;
However, the compound of formula (I) is not a dimer. ]

  A pharmaceutical composition comprising a compound of formula (I) (Chemical Formula 33) and a pharmaceutically acceptable carrier or excipient.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ but hetero cycloalkenyl, however, _- (C 2 _-C 7) heteroalkyl is a nitrogen atom, -C (= O) -, - S -, - S (= O) -, - S (= O) 2 -, - NR 1 (C = O) -, - (C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -O (C = O) NR ^1- , -NR ¹ (C = O) O-,- O (C═O) O—, —NR ¹ (C═O) NR ¹ —, — (C═O) O—, —O (C═O) — are not included,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; ^{, NR 1 - (C = O} ) -R, - (C 1 -C 7) alkyl - (C = O) -OR, - (C 1 -C 7) alkyl ^{- (C = O) -NR 1} R, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl- (C ₃ -C ₆ cycloalkyl), aryl, substituted aryl, arylalkyl, -C ( O) R ² , hydroxy- (C ₁ -C ₆ alkyl), areoxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, —O—C (O) NR ² R ³ , —NR ² R ³ (C═O) OR ¹ , —SO ₂ NR ² R ³ ,
R ² and R ³ are each independently selected from H, C ₁ -C ₆ alkyl, and C ₃ -C ₆ cycloalkyl;
R is H, optionally substituted aryl, or optionally substituted heteroaryl, provided that when B is —S—, R is not a pyrimidine and B is — (C ₂ -C ₇ ). R is not imidazole when alkyl,
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is a halogen,
However, the compound of formula (I) is not a dimer. ]

  In one embodiment, the pharmaceutical compound is an oral pharmaceutical composition for systemic administration of a compound of formula (I).

In certain embodiments, E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O). ) —NR ¹ R, NR ¹ — (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O ) -NR < ¹ > R. Other embodiments are compositions wherein X is Cl and D is isopropyl, tert-butyl, or cyclopropyl. An additional embodiment is the composition where D is tert-butyl and X is Cl. An embodiment is the composition wherein B is — (CH ₂ ) _n and n is 1-6, or B is — (C ₃ -C ₈ ) cycloalkyl. An embodiment is a composition wherein A is O. Another embodiment is the composition wherein A is NH or S.

  An embodiment is a method for the treatment described herein, wherein a mammal is treated with a therapeutically effective amount of a compound of formula (I) (formula 34), an active metabolite thereof, or a pharmaceutically A method comprising administering an acceptable prodrug, salt or solvate.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ but hetero cycloalkenyl, however, _- (C 2 _-C 7) heteroalkyl is a nitrogen atom, -C (= O) -, - S -, - S (= O) -, - S (= O) 2 -, - NR 1 (C = O) -, - (C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -O (C = O) NR ^1- , -NR ¹ (C = O) O-,- O (C═O) O—, —NR ¹ (C═O) NR ¹ —, — (C═O) O—, —O (C═O) — are not included,
D is tert-butyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; ^{, NR 1 - (C = O} ) -R, - (C 1 -C 7) alkyl - (C = O) -OR, - (C 1 -C 7) alkyl ^{- (C = O) -NR 1} R, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl- (C ₃ -C ₆ cycloalkyl), aryl, substituted aryl, arylalkyl, -C ( O) R ² , hydroxy- (C ₁ -C ₆ alkyl), areoxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, —O—C (O) NR ² R ³ , —NR ² R ³ (C═O) OR ¹ , —SO ₂ NR ² R ³ ,
R ² and R ³ are each independently selected from H, C ₁ -C ₆ alkyl, and C ₃ -C ₆ cycloalkyl;
R is H, optionally substituted aryl, or optionally substituted heteroaryl, provided that when B is —S—, R is not a pyrimidine and B is — (C ₂ -C ₇ ). R is not imidazole when alkyl,
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is Cl;
However, the compound of formula (I) is not a dimer. ]

  One embodiment is a compound of formula (I) (Formula 35), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof.

[Wherein A is O;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ but hetero cycloalkenyl, however, _- (C 2 _-C 7) heteroalkyl is a nitrogen atom, -C (= O) -, - S -, - S (= O) -, - S (= O) 2 -, - NR 1 (C = O) -, - (C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -O (C = O) NR ^1- , -NR ¹ (C = O) O-,- O (C═O) O—, —NR ¹ (C═O) NR ¹ —, — (C═O) O—, —O (C═O) — are not included,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; ^{, NR 1 - (C = O} ) -R, - (C 1 -C 7) alkyl - (C = O) -OR, - (C 1 -C 7) alkyl ^{- (C = O) -NR 1} R, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl- (C ₃ -C ₆ cycloalkyl), aryl, substituted aryl, arylalkyl, -C ( O) R ² , hydroxy- (C ₁ -C ₆ alkyl), areoxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, —O—C (O) NR ² R ³ , —NR ² (C═O) OR ¹ , or —SO ₂ NR ² R ³ ,
R ² and R ³ are each independently selected from H, C ₁ -C ₆ alkyl, and C ₃ -C ₆ cycloalkyl;
R is H, — (C ₂ -C ₇ alkyl), optionally substituted aryl, or optionally substituted heteroaryl, provided that when B is —S—, R is not a pyrimidine; B is - _(C 2 -C ₇₎ R is not a imidazole time is alkyl,
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is a halogen. ]

Certain embodiments are compounds of formula (I) wherein B is — (CH ₂ ) _n and n is 1-6, or B is — (C ₃ -C ₈ ) cycloalkyl. In other embodiments, E is (C═O) —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R, — (C ₁ -C ₇ ) alkyl- (C═O) —. OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R. Additional embodiments are those compounds wherein D is isopropyl, tert-butyl, or cyclopropyl. In certain embodiments, X is Cl and D is tert-butyl.

  Another embodiment is a compound of formula (I) (Formula 36), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof.

[Wherein A is NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; ^{, NR 1 - (C = O} ) -R, - (C 1 -C 7) alkyl - (C = O) -OR, - (C 1 -C 7) alkyl ^{- (C = O) -NR 1} R, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl- (C ₃ -C ₆ cycloalkyl), aryl, substituted aryl, arylalkyl, -C ( O) R ² , hydroxy- (C ₁ -C ₆ alkyl), areoxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, —O—C (O) NR ² R ³ , —NR ² (C═O) OR ¹ , or —SO ₂ NR ² R ³ ,
R ² and R ³ are each independently selected from H, C ₁ -C ₆ alkyl, and C ₃ -C ₆ cycloalkyl;
R is H, — (C ₂ -C ₇ alkyl), optionally substituted aryl, or optionally substituted heteroaryl;
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is a halogen. ]

An embodiment is a compound of formula (I) wherein B is — (CH ₂ ) _n and n is 1-6, or B is — (C ₃ -C ₈ ) cycloalkyl. In other embodiments, E is (C═O) —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R, — (C ₁ -C ₇ ) alkyl- (C═O) —. oR, or - _(C 1 -C ₇₎ alkyl - a compound of (C = O) -NR ¹ R a is formula (I). An additional embodiment is a compound of formula (I) wherein D is isopropyl, tert-butyl, or cyclopropyl. In certain embodiments, X is Cl and D is tert-butyl.

  Other objects, properties, and advantages of the methods, compounds, and compositions described herein will become apparent from the following detailed description. It should be noted, however, that the detailed description and specific examples, while indicating specific embodiments, are merely illustrative examples.

The dose response relationship of the test compound is shown in comparison with fenretinide (HPR). The data show that the test compound (having a chemical structure consistent with Formula I) is about 7 times more potent than HPR in disrupting the RBP4-TTR interaction (each for IC ₅₀ = 0.1). IC ₅₀ = 0.7). HPLC analysis of serum retinol. Mice are treated with either DMSO or a compound having the structure of Formula I. Whole blood is collected from the tail vein and serum is prepared. Serum samples are analyzed by HPLC. Representative chromatographic outputs are shown for mice that received DMSO (panel A) and mice that received the test compound (panel B). The peak of retinol and its absorbance spectrum are shown in the small compartment. The steady state serum concentrations of retinol and test compound are shown. Mice are dosed daily with a dose of test compound having the structure of Formula I (20 mg / kg / day, intraperitoneally (i.p.) in DMSO). After 28 days of treatment, a blood sample is drawn and serum is prepared for HPLC analysis. A representative chromatogram is provided showing the presence of the test compound (detection at 280 nm, dashed line recording) and retinol (detection at 325 nm, solid line recording). Immunoblotting detection and densitometric quantification of RBP4. Western blot detection of RBP4 was performed in the sera of mice treated with either DMSO (upper panel, lanes 1-5) or test compounds having a structure consistent with Formula I (panel A, lanes 6-10). The The pixel density of the band indicated by lanes 1-5 of panel A is determined, and the average pixel density is 100%. The relative level of RBP4 in mice treated with the test compound is also determined by pixel densitometry. Data is shown in a histogram. 2 shows chromatographic separation and identification of toxic retinal fluorescent dye molecules. The fat-soluble component is extracted from the eye cup of abca4 null mutant mice (BL6 / 129, 6 months old). Eyecup extract is analyzed by HPLC using on-line absorbance (solid line) and fluorescence (dashed line) detection. The indicated fluorescent dye molecules (A2E precursor and A2E) are not present in age-matched wild-type mice. FIG. 3 shows genetic modification of RBP4 in abca4 mutant mice: effects on serum retinol, RBP4, and toxic retinal fluorophores. A strain of mice expressing heterozygous mutations in RBP4 and ABCA4 (RBP4 +/−, ABCA4 +/−) has been created, whereby the genetic reduction of RBP4 is associated with retinol, RBP4, and toxic retinal fluorophores within RPE. Determine if it is effective enough to reduce serum levels. Serum retinol concentrations in RBP4 +/−, ABCA4 +/− mice are reduced by more than 50% compared to mice with normal supplementation with RBP (RBP4 + / +, ABCA4 − / −). This degree of retinol reduction is comparable to that observed in HPR-treated RBP4 + / +, ABCA4 − / − mice (panel A). Serum retinol reduction correlates directly with RBP4 reduction as determined by immunoblot analysis. Panel B shows the identification of RBP4 in various mouse systems by Western blotting. Histological analysis is also performed. Tissue sections from RBP4 + / +, ABCA4 +/− mice (panel C), RBP4 +/−, ABCA4 +/− (panel D) and RBP4 + / +, ABCA4 + / + (panel E) were analyzed using fluorescence microscopy. Is done. From this analysis it is clear that lipofuscin fluorophore molecules (indicated by white arrows) are significantly reduced in mice with lower steady state levels of RBP4 and retinol. 2 shows the dose-response relationship of test compound to fenretinide (HPR). Data are shown for test compound (chemical name 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclohexanecarboxylic acid, and chemical name 3-((2-tert-butyl-4-chloro Test compound 3) with phenoxy) methyl) cyclopentanecarboxylic acid is shown to be effective in disrupting the RBP4-TTR interaction (IC ₅₀ = 0.25-0.70 μM). FIG. 5 shows cytochrome P450 inhibition profiles for test compounds and fenretinide (HPR). FIG. By screening six cytochrome P450 isozymes, test compound (test compound 2 is test compound 2 having the chemical name 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclohexanecarboxylic acid, and chemical The potential toxicity associated with the names 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclopentanecarboxylic acid 3) and HPR (2 μM present in the assay) is investigated. The data show that there is little inhibition of cytochrome P450 isozymes by the test compound. Shown is quantification of ocular retinoids after treatment with test compounds. ABCA4 − / − mice are dosed daily for 20 days with either ATRP (control) or ATRP + SIR-1047 (n = 3 mice / group). On the last day of dosing, all animals receive a small amount of [ ³ H] ATROL (0.32 pmol, 8 μCi) contained in 100 μl corn oil. The eyes are removed after 5 hours. As described in the method, one eye from each animal is used for retinoid analysis and the other eye is used for analysis of A2E and related fluorophores. The data shows a marked decrease in [ ³ H] ATROL uptake in animals treated with test compounds. Analysis of each retinoid type shows that the precursor substrate for visual chromophore biosynthesis (ATRE) and the direct precursor for A2E biosynthesis (AT-Ox) were significantly reduced. Figure 3 shows the effect of test compounds on the reduction of total fluorophore levels in ABCA4 − / − mice. Mice are treated as shown in FIG. 1 (top). At the end of the study, one eye from each animal is used to measure total fluorophore levels. Briefly, one whole eye is homogenized (homogenized) in 1 ml phosphate buffered saline (50 mM, Na ₂ HPO ₄ , 150 mM NaCl, pH 7.8). After homogenization, 1 ml of methanol is added and the sample is thoroughly mixed. The mixture is incubated for 5 minutes at room temperature and extracted twice with 2 ml of hexane. The extract is concentrated to ˜400 μl and used for fluorescence measurements. Corrected fluorescence spectra are obtained by operating in ratio mode using a Spex Fluorolog-3 fluorometer (Jobin Yvon Horiba, Edison, NJ). The sample is excited at 488 nm and the emission at 500-700 m is monitored. The data shows an overall decrease in the total fluorophore level of test compound treated mice. Figure 3 shows the effect of test compounds on the reduction of A2E and A2E precursor A2PE-H2 in ABCA4 − / − mice. Mice are treated as shown in FIG. 1 (top). At the end of the study, one eye from each animal is used to measure A2E and A2PE-H2. Briefly, one whole eye is homogenized in 1 ml phosphate buffered saline (50 mM, Na ₂ HPO ₄ , 150 mM NaCl, pH 7.8). After homogenization, 1 ml of methanol is added and the sample is thoroughly mixed. The mixture is incubated for 5 minutes at room temperature and extracted twice with 2 ml of hexane. The solvent is evaporated under a stream of nitrogen and the sample residue is returned to 200 μl isopropanol (IPA) and used for analysis by HPLC. The fluorescent dye molecules are equilibrated in the phospholipid mobile phase (hexane: IPA: ethanol: 25 mM phosphate buffer: acetic acid 485: 376: 100: 37.5: 0.275 v: v) at a flow rate of 1 ml / min. Separated into a Zorbax RX-Sil 5-μm column (250 × 4.6-mm). The data show that both A2E and its precursors were dramatically reduced in test compound treated mice compared to vehicle treated mice.

  Reference is now made to detailed embodiments of the methods and compositions described herein. Examples of embodiments are shown in the Examples section below.

  Interestingly, the compounds of formula (I) and (II) are used to provide benefits to patients suffering from or susceptible to various vitreous retinal diseases. Various types of vitreous retinal diseases include but are not limited to macular degeneration and dystrophies. For such patients, the compounds of formula (I) and (II) provide at least one of the benefits described below: reduction of serum retinol or RBP levels, modulation of transthyretin levels, drusen Reduced formation, reduced retinol-retinol binding protein complex formation, and reduced retinol binding protein-transthyretin complex formation. As used herein, RBP means protein RBP4.

  The use of compounds of formula (I) and (II) includes use as a prophylactic treatment of wet age-related macular degeneration. Furthermore, the compounds of formula (I) and (II) provide further therapeutic effect against wet age-related macular degeneration because of their further anti-angiogenic activity.

<Visual cycle>
The vertebrate retina contains two types of photoreceptor cells, rods and cones. The box is specialized in vision in a state where the amount of light is small. The cones are less sensitive, provide vision at high temporal and spatial resolution, and make color perception available. In daylight conditions, the rod response is saturated and vision is entirely provided by the cone. Both cell types contain structures called outer segments that contain layers of membranous discs. The reaction of visual transmission takes place on these disk surfaces. The first step in vision is photon absorption by opsin dye molecules (rhodopsin), which is involved in the isomerization of the chromophore from 11-cis to all-trans. Before regaining photosensitivity, the resulting all-trans-retinal needs to be converted back to 11-cis-retinal, which is a multiple enzyme that occurs in the retinal pigment epithelium, which is a monolayer of neighboring retinal cells. Made in the process.

<Macular or retinal degeneration and dystrophy>
Macular degeneration (also referred to as retinal degeneration) is an eye disease that contributes to exacerbation of the macular (located in the central location of the retina). About 85% to 90% of macular degeneration cases are of the “dry” (atrophic or non-angiogenic) type. In dry macular degeneration, retinal deterioration is involved in the formation of small yellow deposits known as drusen under the macula. Furthermore, the accumulation of lipofuscin in RPE causes photoreceptor degeneration and map-like atrophy. This phenomenon results in macular thinning and degeneration. The location and amount of thinning in the retina caused by drusen correlates directly with the amount of central vision loss. Degeneration of the retina covering drusen and the pigment epithelium layer of photoreceptors becomes atrophic and can cause a gradual decline in central vision. Ultimately, loss of retinal pigment epithelium and underlying photoreceptor cells results in map-like atrophy. Administering to a mammal at least one compound having a structure of formula (I) or (II) reduces or limits the spread of photoreceptor degeneration and / or map-like atrophy in the mammalian eye . By way of example only, administering a compound of formula (I) or (II) to a mammal is used to treat photoreceptor degeneration and / or geographic atrophy in the mammalian eye.

  The formation of new blood vessels in “wet” macular degeneration (ie, neovascularization) improves blood supply to retinal tissue, particularly directly under the macula. Underneath the macula is the part of the retina that is responsible for our vivid central vision. New blood vessels are easily damaged and sometimes rupture, causing bleeding and damage to surrounding tissues. Wet macular degeneration occurs in only about 10% of all retinal degeneration cases, but accounts for about 90% of macular degeneration-related blindness. Neovascularization results in a rapid loss of vision, resulting in scarring of the retinal tissue and bleeding in the eye. This scar tissue and blood creates a dark distorted area in the eye, sometimes resulting in legal blindness of the eye. Wet macular degeneration usually starts with distortion in the central region of vision and the straight line becomes wavy. Also, many people with macular degeneration report having blurred vision and blank spots (dark spots) in their visual area. Growth promoting proteins, called vascular endothelial growth factor, or VEGF, were targeted to cause proliferation of this abnormal blood vessel in the eye. This discovery has led to an active investigation of experimental agents that suppress or inhibit VEGF. Studies have shown that anti-VEGF drugs inhibit and prevent abnormal blood vessel growth. Such anti-VEGF drugs have low blood vessel growth in order to stop or inhibit VEGF stimulation. Such anti-VEGF agents either succeed in anti-angiogenesis or succeed in inhibiting the ability to induce subretinal vascular growth and vascular leakage. In one embodiment, administering at least one compound having a structure of formula (I) or (II) to a mammal reduces or limits the formation of wet age-related macular degeneration in the mammalian eye To do. By way of example only, administering a compound of formula (I) or (II) to a mammal is used to treat wet age-related macular degeneration in the mammalian eye. Similarly, compounds of formula (I) or (II) are used to treat choroidal neovascularization of the mammalian eye and abnormal angiogenesis directly under the macula. In one embodiment, such therapeutic benefits are derived from several effects: reduction of ocular retinol levels due to reduction of serum retinol; antiangiogenic activity, and / or suppression of geographic atrophy.

  Stargardt's disease is macular dystrophy that manifests as a recessive form of macular degeneration that occurs in childhood. (Eg, Allikmets et al., Science, 277: 1805-07 (1997); Lewis et al., Am. J. Hum. Genet., 64: 422-34 (1999); Stone et al., Nature Genetics, 20: 328-29 (1998); Allikmets, Am. J. Hum. Gen., 67: 793-799 (2000); Klevering, et al, Ophthalmology, 111: 546-553 (2004)). Stargardt disease is clinically characterized by progressive loss of central vision and progressive atrophy of RPE overlying the macula. Mutations in the human ABCA4 gene with respect to rim protein (RmP) are involved in Stargardt disease. Early in the course of the disease, patients show delayed dark adaptation, but otherwise show normal rod function. Histologically, Stargardt's disease is associated with the deposition of lipofuscin pigment granules in RPE cells.

  In addition, mutations in ABCA4 include recessive retinitis pigmentosa (see, for example, Cremers et al., Hum. Mol. Genet., 7: 355-62 (1998)), recessive cone-rod dystrophy (see the same book). ), And non-exudative age-related macular degeneration (Allikmets et al., Science, 277: 1805-07 (1997); Lewis et al., Am. J. Hum. Genet., 64: 422-34 (1999) For example). However, the prevalence of ABCA4 mutations in AMD remains uncertain. Stone et al., Nature Genetics, 20: 328-29 (1998); Allikmets, Am. J. Hum.Gen., 67: 793-799 (2000); Klevering, et al, Ophthalmology, 111: 546-553 ( (2004). Similar to Stargardt's disease, these diseases are associated with delayed rod dark adaptation. See Steinmetz et al., Brit. J. Ophthalm., 77: 549-54 (1993). Lipofuscin deposition in RPE cells has been reported in AMD (see Kliffen et al., Microsc. Res. Tech., 36: 106-22 (1997)), and in some cases of retinitis pigmentosa (Bergsma et al., Nature, 265). : 62-67 (1977)). Furthermore, the autosomal dominant form of Stargardt disease is caused by mutations in the ELOV4 gene (see Karan, et al., Proc. Natl. Acad. Sci. (2005)).

  In addition, there are several types of macular degeneration that affect infants, teenagers, or adults, commonly known as early onset or juvenile macular degeneration. Many of these types are hereditary and are considered as macular dystrophy rather than macular degeneration. Some examples of macular dystrophy include cone-rod dystrophy, corneal dystrophy, Fuchs dystrophy, sourceby macular dystrophy, best disease, juvenile retinal segregation, and Stargardt disease.

<Regulation of vitamin A level>
Vitamin A (all-trans retinol) is a cell nutrient necessary for life support, and since it cannot synthesize de novo, it must be taken from a dietary source. Vitamin A is a generic name that can refer to any compound having the biological activity of retinol (including binding activity). One retinol equivalent (RE) is the specific biological activity of 1 μg all-trans retinol (3.33 IU) or 6 μg (10 IU) beta carotene. Beta carotene, retinol, and retinal (vitamin A aldehyde) all have effective and reliable vitamin A activity. Each of these compounds is derived from carotene, a plant precursor molecule (one of a family of molecules known as carotenoids). Beta carotene is composed of two retinol molecules, and their aldehyde ends are linked. Beta carotene is also called the provitamin form of vitamin A.

  Ingested β-carotene is cleaved by β-carotene dioxygenase in the intestinal lumen to produce retinal. Retinal is esterified to palmitic acid by being reduced by retinaldehyde reductase, NADPH that requires the enzyme in the intestine.

  After digestion, retinol in the food material is transported to the liver that binds to lipid aggregates. See Bellovino et al., Mol. Aspects Med., 24: 411-20 (2003). Once in the liver, retinol forms a complex with retinol binding protein (RBP) and is then secreted into the blood circulation. Retinol-RBP holoprotein needs to bind to transthyretin (TTR) before it can be delivered to target tissues other than the liver (eg eyes) (Zanotti and Berni, Vitam. Horm., 69: 271- 95 (2004)). It is this second complex that allows retinol to remain in the blood circulation for an extended period of time. Binding to TTR promotes RBP release from hepatocytes and prevents renal filtration of the RBP-retinol complex. The retinol-RBP-TTR complex is delivered to the target tissue where it is taken up and utilized for various cellular processes. Delivery of retinol through the blood circulation to the cells by the RBP-TTR complex is a major route for cells and tissues to obtain retinol.

  Incorporation of retinol into the cell from the complex retinol-RBP-TTR type occurs by binding RBP to a cellular receptor on the target cell. This interaction is due to endocytosis of the RBP-receptor complex, followed by the release of retinol from the complex, or the binding of retinol to cellular retinol binding protein (CRBP), followed by cellular apoRBP plasma. Resulting in the release of. Other pathways consider alternative mechanisms for allowing retinol to enter the cell (including taking retinol alone into the cell). See Blomhoff (1994).

  The methods, compounds, and compositions described herein are useful for modulating vitamin A levels in a mammalian subject. In particular, regulation of vitamin A levels occurs by controlling the availability or activity of retinol binding protein (RBP) and transthyretin (TTR) in mammals. The methods, compounds, and compositions described herein provide modulation of RBP and TTR levels or activity in a mammalian subject, followed by modulation of vitamin A levels. An increase or decrease in vitamin A levels in a subject affects retinol availability in target organs and tissues. Thus, providing a means to modulate retinol or retinol derivative availability will correspondingly modulate pathologies caused by a lack or excess concentration of local retinol or retinol derivatives in target organs and tissues. . In addition, the therapeutic methods described herein are used to treat hyperretinolemia. In excessive retinol blood conditions, excessive levels of serum retinol cause vitreous retinal disease or symptoms associated with vitreous retinal disease (eg, lipofuscin or drusen formation).

  For example, A2E is the major fluorescent dye molecule of lipofuscin, formed in macular or retinal degeneration or dystrophies (age-related macular degeneration and Stargardt disease), which is a visual cycle retinoid, all-trans-retinaldehyde ( This is due to excessive production of A2E precursor. Thus, a reduction in vitamin A and all-trans-retinaldehyde in the retina is useful for reducing A2E and lipofuscin accumulation and for treating age-related macular degeneration.

  Modulators that inhibit the delivery of retinol to cells (eg, compounds of formulas (I) and (II)) bind retinol to apoRBP or holo RBP (RBP + retinol) and its transport protein (TTR). Retinol delivery to cells is inhibited by either blocking binding or by increasing renal excretion of RBP and TTR. This modulator is thus useful in reducing serum vitamin A levels and accumulation of retinol and its derivatives in target tissues such as the eye.

  Similarly, modulators that affect the availability of retinol transport protein, retinol binding protein (RBP), and transthyretin (TTR) include serum vitamin A levels, and retinol (eg, excess retinol blood condition) and its derivatives. Useful for reducing accumulation and physical expression in target tissues such as the eye. TTR, for example, has been shown to be a component of drusen constituents, meaning that TTR is directly involved in age-related macular degeneration (Mullins, RF, FASEB J. 14: 835 -846 (2000); Pfeffer BA, et al., Molecular Vision 10: 23-30 (2004)).

  Similar approaches to modulate RBP and / or TTR levels or activity in mammals are metabolic disorders such as type 1 or type 2 diabetes (obesity and / or non-obesity), IIH, bone related diseases such as ossification. It is expected to be used in the treatment of hyperplasia, protein misfolding and aggregation disorders such as systemic amyloidosis and Alzheimer's disease, and Alstrem-Harglen syndrome.

  Accordingly, one embodiment of the methods, compounds, and compositions described herein is by administering to a mammal a therapeutically effective amount of at least one compound of formula (I) or formula (II). Provide modulation of RBP or TTR levels or activity in mammals.

<Retinol binding protein (RBP) and transthyretin (TTR)>
Retinol binding protein, or RBP, is a single chain polypeptide and has a molecular weight of about 21 kD. RBP has been cloned and sequenced and its amino acid sequence has been determined. Colantuni et al., Nuc. Acids Res., 11: 7769-7776 (1983). The three-dimensional structure of RBP reveals a special hydrophobic pocket designed to bind and protect fat-soluble vitamin retinol. Newcomer et al., EMBO J., 3: 1451-1454 (1984). In in vitro experiments, cultured hepatocytes have been shown to synthesize and secrete RBP. Blaner, WS, Endocrine Rev., 10: 308-316 (1989). Subsequent experiments show that many cells contain mRNA for RBP, which means a broad distribution of RBP synthesis throughout the body. See Blaner (1989). Most of the RBP secreted by the liver contains retinol in a 1: 1 molar ratio, and retinol binding to RBP is necessary for normal RBP secretion.

  In cells, RBP binds tightly to retinol in the endoplasmic reticulum, where it is found at high concentrations. The binding of retinol to RBP initiates the transfer of retinal-RBP from the endoplasmic reticulum to the Golgi complex, after which retinol-RBP is secreted from the cell. RBP secreted from hepatocytes is also useful for the transfer of retinol from hepatocytes to stellate cells. In these stellate cells, retinol-RBP is secreted directly into plasma.

  In plasma, about 95% of plasma RBP is involved in transthyretin (TTR) at a 1: 1 mole / mole ratio. Here, substantially all plasma vitamin A is bound to RBP. TTR is a well-characterized plasma protein that is composed of four identical subunits and has a molecular weight of 54,980 daltons. The complete three-dimensional structure was elucidated by X-ray diffraction and revealed that a vast β-sheet was arranged tetrahedrally. Blake et al., J. Mol. Biol., 121: 339-356 (1978). The channel passes through the center of the tetramer containing two thyroxine binding sites. However, due to negative cooperativity, only one thyroxine molecule appears to normally bind to TTR. Complex formation of TTR with RBP-retinol is believed to reduce glomerular filtration of retinol, thereby increasing the half-life of retinol and RBP in plasma by about 3-fold.

<Modulation of RBP or TTR binding or clearance in a subject>
Retinol bound to RBP needs to form a complex with TTR before being transported into the bloodstream for delivery to the eye. It is this second complex that allows retinol to remain in the blood circulation for an extended period of time. In the absence of TTR, retinol-RBP complexes are rapidly excreted in the urine. Similarly, in the absence of RBP, retinol transport and cellular uptake in the bloodstream is reduced.

  Accordingly, other embodiments described herein may be of RBP or TTR for complex formation to retinol or retinol-RBP in the bloodstream by reducing the binding properties or clearance rate of RBP or TTR. It is to adjust the availability. As mentioned above, binding of TTR to RBP holoprotein reduces the clearance rate of RBP and retinol. Thus, by modulating either RBP or TTR availability or activity, retinol levels will be similarly modulated in subjects in need thereof.

  For example, antagonists of retinol binding to RBP are used in the methods, compounds, and compositions described herein. Retinol antagonists that bind to RBP include compounds of formula (I) or (II) that compete with the binding of retinol to RBP.

  As mentioned above, one means by which RBP binding to retinol is modulated is to competitively bind to compounds of formula (I) or (II). Accordingly, one embodiment of the methods and compositions described herein provides that RBP level or activity is increased by a compound having the structure of formula (I) (Chemical Formula 37), an active metabolite thereof, or a pharmaceutically acceptable salt thereof. Lowering with possible prodrugs, salts or solvates provides that the compound of formula (I) modulates RBP levels or activity.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl - _(C 3 -C ₈₎ cycloalkenyl, - the _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, or optionally substituted heteroaryl;
X is a halogen. ]

  Other embodiments of the methods and compositions disclosed herein provide that RBP levels or activity are measured by a compound having the structure of formula (II) (Chemical Formula 38), an active metabolite thereof, or a pharmaceutically acceptable salt thereof. The prodrug, salt or solvate is used to provide that the compound of formula (II) modulates RBP levels or activity.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl - _(C 3 -C ₈₎ cycloalkenyl, - the _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H or (Chemical Formula 39),
G is —OR ¹ , — (C ₁ -C ₆ ) alkyl, — (C ₁ -C ₆ ) alkyl-OR ¹ , halogen, —CO ₂ R ¹ , — (C ₁ -C ₆ ) alkyl-CO _{2. ^{R 1, NHR 1, - (}} C 1 -C 6) alkyl ^{-NHR 1, - (C = O} ) NHR 1, - (C 1 -C 6) alkyl ^{- (C = O) NHR 1} , -NHR 1 ( C═O) R ¹ , — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ,
R ¹ is H or (C ₁ -C ₆ ) alkyl. ]

<Detection of modulator activity>
In certain embodiments, the compounds and compositions described herein are also used in assays to detect perturbations in RBP or TTR availability using conventional means. For example, a subject is treated with any compound or composition described herein, and RBP or TTR levels are quantified using conventional assay techniques. See Sundaram, M., et al., Biochem. J. 362: 265-271 (2002). For example, a typical non-competitive sandwich assay is the assay described in US Pat. No. 4,486,530, which is incorporated herein by reference. In this method, a sandwich complex, such as an immune complex, is formed in the assay medium. The complex includes a binding member that binds to the specimen, the first antibody, or the specimen and the second antibody, or a binding member that binds to the specimen or the complex of the specimen and the first antibody, or a binding member. Subsequently, the sandwich complex is detected and related to the presence and / or amount of analyte in the sample. The sandwich complex is detected by its presence in the labeled complex. Here, either or both of the first antibody and the second antibody, or the binding member includes a label or a substituent capable of binding to the label. For example, the sample is plasma, blood, stool, tissue, mucus, tears, saliva, or urine, and is used, for example, to detect modulation of the clearance rate of RBP or TTR. For a more detailed discussion of this approach, see US Pat. Nos. Re29,169 and 4,474,878. This related disclosure is incorporated herein by reference.

  In a variation of the sandwich assay described above, a sample in a suitable medium is contacted with an analyte labeled antibody or binding member and incubated for a period of time. Thereafter, the medium is contacted with a carrier, and the second antibody or binding member for the specimen is bound to the carrier. After the incubation period, the carrier is separated from the medium and unbound reagents are removed by washing. The carrier or medium is examined for the presence of the label, which is related to the presence or amount of the analyte. For a more detailed discussion of this approach, see US Pat. No. 4,098,876. This related disclosure is incorporated herein by reference.

  In certain embodiments, the modulators disclosed herein are also used in in vitro assays to detect perturbations in RBP or TTR activity. For example, the modulator detects complex breakage by being added to a sample containing RBP, TTR and retinol. A component, such as RBP, TTR, retinol, or modulator is labeled to determine whether disruption of complex formation has occurred. For example, complex formation and subsequent disruption is detected and / or measured by conventional means such as the sandwich assay described above. Other detection systems are also used to detect modulation of RBP or TTR binding, including, for example, FRET detection of RBP-TTR-retinol complex formation. See US Provisional Patent Application No. 60 / 625,532 “Fluorescence Assay for Modulators of Retinol Binding”. This is incorporated herein by reference.

  In addition, other potential modulators (including but not limited to small molecules, polypeptides, nucleic acids, and antibodies) are also screened using the in vitro detection methods described above. For example, the methods and compositions described herein are used in conjunction with the teachings herein to screen small molecule libraries, nucleic acid libraries, peptide libraries, or antibody libraries. Methods for screening libraries (such as combinatorial libraries and other libraries described above) are described in, for example, US Pat. Nos. 5,591,646, 5,866,341, and 6,343, No. 257, incorporated herein by reference.

<In vivo detection of modulator activity>
In addition to the in vitro methods described above, in certain embodiments, the methods and compositions disclosed herein are used in conjunction with in vivo detection and / or quantification of modulator activity on TTR or RBP availability. For example, labeled TTR or RBP is injected into the subject, where the candidate modulator is added before, during, or after the injection of labeled TTR or RBP. The subject is a mammal, for example a human. However, other mammals such as primates, horses, dogs, sheep, goats, rabbits, mice, or rats are further examples. The biological sample is then removed from the subject and label detected to determine TTR or RBP availability. Biological samples include, but are not limited to, plasma, blood, urine, feces, mucus, tissue, tears, or saliva. Detection of the labeling reagent disclosed herein is carried out by using any conventional means depending on the nature of the label. Examples of devices for monitoring chemiluminescence, radioactive labels, and other labeled products can be found in US Pat. Nos. 4,618,485, 5,981,202, the related disclosures of which are incorporated by reference This is incorporated herein by reference.

<Excess retinol blood condition (hyperretinolemia)>
Retinol is a fat-soluble antioxidant vitamin. At the right level, retinol is important for vision and bone growth, but can be problematic when present in excess. Excess retinol blood condition is believed to be associated with illness and disease where elevated or abnormal levels of retinol are present in the blood. Diseases and disorders are type 1 and type 2 diabetes, hyperossification such as diffuse idiopathic osteoproliferative disorder (DISH), and vitreous retinal disease such as macular degeneration. The methods, compounds, and compositions described herein lower retinol levels in the blood and are used to treat such diseases and disorders. Also, the methods, compounds, and compositions presented herein are effective in reducing the availability of retinol in target organs and tissues such as the eye. By reducing the concentration of retinol in the blood, the availability of retinol in liver and other organs regulates the formation of retinol-retinol binding protein complex and / or retinol-retinol binding protein-transthyretin complex. can do. In one embodiment, a method of treating a patient suffering from an excess retinol blood condition comprises the step of administering a therapeutically effective amount of a compound of formula (I) or (II), of formula (I) or (II) The compound decreases the serum level or activity of retinol.

<Metabolic abnormality>
Metabolic abnormalities include type 1 and type 2 diabetes (obese and / or non-obese), which have also been associated with abnormal retinol levels.
・ Type 1 diabetes (insulin-dependent diabetes)
Type 1 diabetes is a severe form of diabetes. If left untreated, type 1 diabetes causes patient ketosis and rapid deterioration. About 10-20% of diabetic patients are classified as type 1 and mainly include young individuals. Non-obese adults also constitute type 1 diabetic patients, but there are fewer.

  Type 1 diabetes is a catabolic disorder in which there is virtually no circulating level of insulin and plasma glucagon levels are elevated. Type 1 diabetes is believed to have an autoimmune cause, possibly due to an infectious or toxic environmental disorder of the affected person's pancreatic B cells. In support of the theory of autoimmunity, insulin and autoantibodies to islet cells have been detected in patients with type 1 diabetes compared to non-diabetic individuals.

  Low levels of retinol have been observed to both reduce retinol binding protein (RBP) levels and increase urinary excretion of RBP, and have been correlated with type 1 diabetes in young people. See Basu, TK, et al. Am. J. Clin. Nutr. 50: 329-331 (1989); Durbey, SW et al., Diabetes Care 20: 84-89 (1997). Low levels of retinol and RBP occur with a concomitant decrease in zinc metabolism (a factor required for RBP synthesis in hepatocytes). See Cunningham, JJ, et al. Metabolism 42: 1558-1562 (1994). In contrast, tocopherol or vitamin E levels do not change in type 1 diabetic patients. See TK et al (1989).

  Low levels of retinol are observed despite increased vitamin A levels in liver storage cells. See Tuitoek PJ, et al. Br. J. Nutr. 75: 615-622 (1996). Studies showing the relationship between vitamin A status and insulin secretion show that treatment with insulin alone can reduce the level of vitamin A inhibition in type 1 diabetic subjects. Tuitoek, PJ et al., J. Clin. Biochem. Nutr. 19: 165-169 (1996). In contrast, dietary supplementation with vitamin A does not normalize the metabolic availability of vitamin A (ibid).

  These studies show the interaction between vitamin A and insulin control of glucose transport into muscle cells and adipocytes. Further studies have strengthened this interaction by showing that vitamin A is required for normal insulin secretion. See Chertow, BS, et al., J. Clin. Invest. 79: 163-169 (1987). Retinol has been shown to be required for insulin release from perfused islet cells deficient in vitamin A (ibid.). In vivo experiments showed that vitamin A deficient rats had impaired glucose-induced acute insulin release and only improved vitamin A excess (ibid). Vitamin A can exert its effect on insulin secretion through activation of transglutaminase activity in islet cells and insulin secreting cells (Driscoll HK, et al., Pancreas 15: 69-77 (1997)). Vitamin A is necessary for fetal islet development and prevention of impaired glucose tolerance in adults (see Matthews, KA et al., J. Nutr. 134: 1958-1963 (2004)). This further strengthens the role of vitamin A and retinol in controlling insulin release and blood glucose levels in diabetic patients. Presented herein are methods, compounds, and compositions for treating type 1 diabetes using compounds of formulas (I) and (II), wherein the level or activity of retinol and / or RBP is Adjusted.

・ Type 2 diabetes (non-insulin dependent diabetes)
Type 2 diabetes includes a mixed group of mild forms of diabetes. Type 2 diabetes usually develops in adults, but sometimes it can occur in young children.

  Type 2 diabetes classically exhibits insulin insensitivity in response to elevated plasma glucose levels. Up to 85% of type 2 diabetes is obese and is insensitive to endogenous insulin that correlates positively with the presence of fat distribution in the abdomen. The cause of insulin insensitivity is associated with a post-receptor deficiency in insulin action. This has to do with over-swelled cell depots (eg, swelled adipocytes and hypertrophic hepatocytes and muscle cells) and a reduced ability to remove nutrients from the blood circulation after a meal. Subsequent hyperinsulinism can also result in further downregulation of cellular insulin receptors. In addition, glucose transport proteins (eg GLUT4) are also down-regulated during continuous activation, resulting in exacerbation of the hyperglycemic state in the patient.

  In contrast to type 1 diabetes, type 2 diabetic patients selectively show elevated RBP levels, and normal to increased levels of retinol are observed. Sasaki, H et al., Am. J. Med. Sci. 310: 177-82 (1995); Basualdo CG, et al. J. Am Coll. Nutr. 16: 39-45 (1997); Abahausain, MA et al., Eur. J. Clin. Nutr. 53: 630-635 (1999). Retinoic acid (all-trans-RA and 13-cis RA) levels were also reduced in patients with type 2 diabetes. Yamakoshi, Y et al., Biol. Pharm. Bull 25: 1268-1271 (2002). Other vitamins (including vitamin E (tocopherol) and carotenoids) are unchanged in both the diabetic and control groups, as well as zinc, albumin and TTR levels (which affect vitamin A metabolism) It was similarly unchanged (ibid.).

  This selective increase in RBP levels in type 2 diabetes supports the role of RBP and vitamin A in insulin control of blood glucose levels when combined with selective RBP reduction in type 1 diabetes. Increased RBP levels have been attributed to increased insulin levels (hyperinsulinism) in diabetic patients. Basualdo et al. (1997). RBP levels have also been associated with the severity of hyperglycemia in patients (ibid). Retinoids have already been shown to increase insulin sensitivity in humans. See Hartmann, D. et al. Eur. J. Clin. Pharmacol. 42: 523-8 (1992). The inverse correlation between RBP levels and insulin sensitivity in type 1 and type 2 diabetic patients represents a therapeutic tool to control insulin sensitivity in mammalian subjects.

<Retinol binding protein 4 (RBP4)>
Retinol binding protein 4 (RBP4) is a protein secreted by adipocytes, and the role of vitamin A transport is recognized. Studies have shown that elevated levels of serum RBP4 help to indicate early onset of insulin resistance (a major cause of type 2 diabetes). See Kahn et al., 354 New Eng. J. Med. 2552-63 (2006). Mouse experiments also suggest that elevated RBP4 levels cause insulin resistance. Furthermore, serum RBP4 levels correlate with the magnitude of insulin resistance in non-obese and non-diabetic subjects with obese glucose intolerance or type 2 diabetes and a strong family history of type 2 diabetes . Elevation of serum RBP4 is associated with elements of the metabolic syndrome, which include body mass index, waist-to-hip ratio, increased serum triglyceride levels, and systolic blood pressure, and high-density lipoprotein Includes a reduction in cholesterol levels.

  The study suggests that the amount of RBP4 in the blood reflects the amount of fat surrounding the abdominal organ, indicating that RBP4 may be used as a biomarker for cardiovascular risk. As the level of RBP4 increases, the level of “intraperitoneal fat” associated with increased risk of heart disease and type 2 diabetes also increases. This is because increased “intraperitoneal fat” is associated with cardiovascular risk. Studies also show that RBP4 gene expression is increased in visceral adipose tissue (adipose tissue around internal organs) than subcutaneous adipose tissue. Thus, RPB4 levels are higher in people with “built-in” obesity than in people with subcutaneous obesity.

  Shown herein are compounds of formula (I) and (II) that lower excess serum levels of RBP4. One embodiment is a compound of formula (I) (formula 40), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof, wherein the compound of formula (I) is a compound of RBP4 It lowers serum levels.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C _{8) cycloalkenyl,} a hetero cycloalkenyl to _(C 3 -C _8),
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H or (Chemical Formula 41),
G is —OR ¹ , — (C ₁ -C ₆ ) alkyl, — (C ₁ -C ₆ ) alkyl-OR ¹ , halogen, —CO ₂ R ¹ , — (C ₁ -C ₆ ) alkyl-CO _{2. ^{R 1, NHR 1, - (}} C 1 -C 6) alkyl ^{-NHR 1, - (C = O} ) NHR 1, - (C 1 -C 6) alkyl ^{- (C = O) NHR 1} , -NHR 1 ( C═O) R ¹ , — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ,
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is a halogen. ]

  Another embodiment is a compound of formula (II) (formula 42), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof, wherein the compound of formula (II) is RBP4 Lowers serum levels.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H or (Chemical Formula 43),
G is —OR ¹ , — (C ₁ -C ₆ ) alkyl, — (C ₁ -C ₆ ) alkyl-OR ¹ , halogen, —CO ₂ R ¹ , — (C ₁ -C ₆ ) alkyl-CO _{2. ^{R 1, NHR 1, - (}} C 1 -C 6) alkyl ^{-NHR 1, - (C = O} ) NHR 1, - (C 1 -C 6) alkyl ^{- (C = O) NHR 1} , -NHR 1 ( C═O) R ¹ , or — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ,
R ¹ is H or (C ₁ -C ₆ ) alkyl. ]

  Yet another embodiment is a method of treating diabetes in a patient, wherein a therapeutically effective amount of a compound of formula (II) (formula 44), an active metabolite thereof, or a pharmaceutically acceptable prodrug thereof, A method comprising administering a salt or solvate to a patient, wherein administering a therapeutically effective amount of a compound of formula (I) reduces the level of RBP4.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl - _(C 3 -C ₈₎ cycloalkenyl, - the _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, or optionally substituted heteroaryl;
X is a halogen. ]

  Yet another embodiment is a method for treating a patient's eye disease (eg, macular degeneration), wherein the patient is administered a therapeutically effective amount of a compound of formula (I) or (II) With steps, the level of RBP4 is reduced. An additional embodiment is a method of lowering RBP4 in serum comprising administering a compound of formula (I) or (II). A further additional embodiment is a method of lowering RBP4 in tissue (eg, adipose tissue), comprising administering a compound of formula (I) or (II).

  One embodiment is a method of treating type 1 or type 2 diabetes in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or (II), wherein the therapeutic An effective amount of a compound of formula (I) or (II) modulates RBP4 in adipocytes. An additional embodiment is a method of treating type 1 or type 2 diabetes in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or (II), RBP4 levels decrease, as a decrease in RBP4 levels increases insulin sensitivity. Another embodiment is a method of treating type 1 or type 2 diabetes in a patient, wherein the patient is treated with a therapeutically effective amount of a compound of formula (II) (formula 45), an active metabolite thereof, or a The step of administering a pharmaceutically acceptable prodrug, salt or solvate comprises reducing the level of RBP4 such that decreasing RBP4 level increases insulin sensitivity.

[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl - _(C 3 -C ₈₎ cycloalkenyl, - the _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, or optionally substituted heteroaryl. ]

<Idiopathic intracranial hypertension (IIH)>
IIH (also known as pseudobrain tumor (PTC)) is a high-pressure state in the pericardial fluid and has no identifiable causative factor. This condition exists mostly in women of child-bearing age. The symptoms often begin or worsen during the weight gain period. Typical symptoms include headaches, pulse-synchronized tinnitus, and visual problems (papilledema), which can lead to severe and permanent vision loss in untreated cases.

  The etiology of IIH is unknown, but excess vitamin A levels are candidates. This is because the symptoms and signs of hypervitamin A are similar to those of IIH. Studies show that serum retinol levels are significantly higher in IIH patients than in the control group, although vitamin A intake or retinyl ester concentrations do not show significant differences in both groups. It is shown. See Jacobson, DM et al., Neurology, 54: 2192-3 (1999). Included herein are methods, compounds, and compositions for the treatment of IIH using compounds of formula (I) and (II).

(Bone-related disorders)
Hyperossification is a condition in which bone overgrowth occurs. This condition can lead to the formation of protruding masses from normal bone and is observed in many musculoskeletal disorders. Diffuse idiopathic osteoproliferation (DISH) is a form of hyperostosis and is characterized by fluidized calcification and vertebral ossification. Radiographic abnormalities in DISH patients are most commonly observed in the thoracic spine. This leads to the presence of a radiopaque barrier in the front of the spinal column. Ossification of the posterior longitudinal ligament (OPLL) is also associated with increased frequency in DISH patients, and is further associated with spinal cord injury resulting from hyperossification or spinal ligament ossification. Other disorders associated with patients with hyperossification or DISH include acute fractures and spinal false joints.

  The etiology of DISH and OPLL is currently unknown, but both disorders have been associated with high levels of serum retinol and RBP. See Kodama, T et al., In vivo 12: 339-344 (1998); Kilcoyne, RF, J. Am. Acad. Dermatol. 19: 212-216 (1988). This presents a possible role for vitamin A in the pathogenesis of DISH and OPLL. Other studies have shown the development of congenital functional RBP deficiency with abnormal retinol and RBP levels in patients with hyperossification. De Bandt, M., et al., J. Rheumatol. 22: 1395-8 (1995). Medical reports also report the development of hypervitamin A with osteoarthritis in elderly patients. See Romero, JB et al., Bull Hosp. Jt. Dis. 54: 169-174 (1996). Accordingly, the methods, compounds, and compositions described herein treat bone-related diseases (by way of example only, hyperostosis) using compounds of formula (I) and (II). Used for Here, the levels of serum retinol and RBP are regulated.

<Protein misfolding and aggregation disease>
Protein misfolding and aggregation have been associated with several diseases commonly known as amyloidosis, including Alzheimer's disease, Parkinson's disease, and systemic amyloidosis. These diseases occur with protein secondary structure misfolding, and soluble proteins usually form insoluble extracellular fiber deposits of β-sheet rich structure called amyloid fibrils, causing organ dysfunction. Twenty different fiber proteins (including transthyretin (TTR)) have been described in human amyloidosis, each with a different clinical picture.

  Wild-type TTR protein has been implicated in the development of senile systemic amyloidosis (a sporadic disorder resulting from the deposition of TTR fibers in heart tissue). In contrast, mutant TTR proteins are associated with familial amyloid polyneuropathy and cardiomyopathy, and this deposit primarily affects the peripheral and autonomic nervous systems and the heart. The causative mechanism of tissue selective deposition is currently unknown. In amyloidosis formation, TTR is associated with fibril formation in its monomeric form. Compounds that promote TTR tetramer stabilization (eg, the small molecules resveratrol and biarylamine) inhibit amyloid fibril formation in vitro. See Reixach, N. et al., PNAS 101: 2817-2822 (2004).

  Transthyretin is also involved in Alzheimer's disease, but in contrast to amyloid fibril formation in amyloidosis, TTR inhibits amyloid beta protein formation both in vitro and in vivo. See Schwartzman AL et al., Amyloid. 11: 1-9 (2004); Stein, TD and Johnson, JA, J. Neurosci. 22: 7380-7388 (2002). Vitamin A has also been shown to exhibit an anti-amyloidogenic effect and an amyloid-beta fibril stabilizing effect in vitro. See Ono, K., et al., Exp. Neurol. 189: 380-392 (2004).

<Cystic fibrosis>
Cystic fibrosis is a fatal genetic disease, and the major cause of this death is due to excessive lung inflammation associated with recurrent bacterial infection by Pseudomonas aeruginosa. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The production of this gene is an important chloride ion channel for making sweat, digestive juices, and mucus. The CGTR gene is located at the q31.2 locus on chromosome 7 and creates a protein that is 1,480 amino acids long. A common mutation, ΔF508, is a deletion of 3 nucleotides, resulting in a deletion of the amino acid phenylalanine at position 508 of the protein. Subsequently, ΔF508 creates a protein that does not fold normally and is degraded by the cell. The protein produced by the CFTR gene also acts as a chloride channel that connects the cytoplasm to the surrounding fluid. Mutations in the CFTR protein trap chloride ions extracellularly. The elimination of chloride ions into the cytoplasm attracts sodium ions, and this combination forms a salt that is heavily depleted in the sweat of individuals suffering from cystic fibrosis. One study shows that disturbances in CFTR protein produce dehydrated and viscous mucus by increasing sodium and chloride intake and increasing water reabsorption.

  The treatment of cystic fibrosis focuses on the treatment of lung injury caused by viscous mucus and infection. Antibiotics such as vancomycin and tobramycin are used when lung infection is reduced. Nasal steroids such as fluticasone have been used to reduce nasal inflammation. In other cases, sinus surgery is used to reduce nasal obstruction and limit further infection.

  Control of ceramide levels appears to be important for efficient clearance of bacteria from infected lungs. Shown herein is a method for treating cystic fibrosis comprising the step of administering a compound of formula (I) or (II), wherein the compound, through mediation of ceramide production, Help with load clearance. An embodiment is a method for treating a bacterial infection associated with cystic fibrosis, comprising administering a compound of formula (I) or formula (II). Here, the compound of formula (I) or formula (II) serves for the clearance of bacteria from the infected lung. In other embodiments, the bacteria are gram negative bacteria. In an additional embodiment, the Gram negative bacterium is Pseudomonas aeruginosa. Another embodiment is a method for treating cystic fibrosis comprising the step of administering a compound of formula (I) or formula (II), wherein the compound of formula (I) or (II) comprises: Corrects ceramide deficiency in cystic fibrosis-related organs. In additional other embodiments, the cystic fibrosis-related organ is the lung.

<Alstreem-Harglen syndrome>
Alstrem-Hullgren's syndrome (also known as Alstrem syndrome) is a rare autosomal recessive disorder that affects very young babies. Symptoms include blindness or severe visual loss in infancy associated with cone-rod dystrophy, hearing loss, onset of obesity within the first year of life, type 2 diabetes and severe insulin resistance, melanosis ( Development of skin black spots), hypergonadotropic hypogonadism, and thyroid deficits.

  The mutation associated with Alstrem syndrome is located in the 14.9 cM region of chromosome 2p. Collin, GB et al., Hum. Mol. Gen. 6: 213-219 (1997). There is currently no therapeutic treatment available for patients with Alstrem syndrome except to treat individual manifestations of the disease. One embodiment is a method, compound, and composition used in the treatment of Alstrem-Hullgren's syndrome, using a compound having the structure of formula (I) and (II).

<Definition>
An “alkoxy” group refers to a (alkyl) O— group, where alkyl is defined herein.

  An “alkyl” group refers to an aliphatic hydrocarbon. An alkyl moiety includes a “saturated alkyl” group, which means that it does not include any alkene or alkyne moiety. An alkyl moiety includes an “unsaturated alkyl” moiety, which means that it includes at least one alkene or alkyne moiety. An “alkene” moiety refers to a group composed of at least two carbon atoms and at least one carbon-carbon double bond. An “alkyne” moiety refers to a group composed of at least two carbon atoms and at least one carbon-carbon triple bond. Alkyl moieties include branched, straight chain, or cyclic, whether saturated or unsaturated.

An “alkyl” moiety is a moiety containing 1 to 10 carbon atoms (wherever a numerical range such as “1 to 10” means each integer within the given range: “1 to 10 carbon atoms” means an alkyl group consisting of up to 10 (including 10) carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. Also includes the presence of the unspecified term “alkyl”). An alkyl group can also be a “lower alkyl” having 1 to 5 carbon atoms. The alkyl group of the compounds described herein can be represented by “C ₁ -C ₄ alkyl” or similar designations. By way of example only, “C ₁ -C ₄ alkyl” has 1 to 4 carbon atoms in the alkyl chain, ie the alkyl chain is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec Selected from the group consisting of -butyl and t-butyl. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. It is not limited.

The term “alkenyl” refers to one of the alkyl groups, in which the first two atoms of the alkyl group form a double bond that is not part of an aromatic group. That is, an alkenyl group begins with the atoms -C (R) = CR, where R means the remainder of the alkenyl group and is the same or different. Example non-limiting of an alkenyl _{group, -CH = CH, -C (CH} 3) = CH, -CH = CCH 3, and _-C (CH 3) a = CCH _3. Alkenyl moieties include branched, straight chain, or cyclic (also known as “cycloalkenyl” groups in this case).

An “amide” is a chemical moiety having the formula —C (O) NHR or —NHC (O) R, where R is alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon), And a heteroalicyclic (bonded via a ring carbon). Amides include amino acid or peptide molecules attached to a compound of formula (I), thereby forming a prodrug. Any amine, hydroxyl or carboxyl side chain in the compounds described herein can be amidated. Procedures and specific groups to make such amides are, Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, seen references NY, 1999, etc., It is incorporated herein by reference.

  The term “aromatic” or “aryl” has at least one ring with a conjugated π-electron system and is a carbocyclic aryl (eg phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) group. An aromatic group containing both (eg pyridine). The term includes monocyclic or fused polycyclic (ie, sharing adjacent pairs of carbon atoms) groups. The term “carbocycle” means a compound containing one or more covalently bonded cyclic structures, and all the atoms forming the ring skeleton are carbon atoms. Thus, the term distinguishes carbocycles from heterocycles in which the ring skeleton contains at least one atom different from carbon.

  The term “cycloalkyl” means a monocyclic or polycyclic radical, includes only carbon and hydrogen, and includes saturated, partially unsaturated, or fully unsaturated. Cycloalkyl groups include groups having 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include the following moieties (Formula 46) and the like.

  The term “halo” or alternatively “halogen” is fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro, chloro and bromo.

  The terms “heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include optionally substituted alkyl, alkenyl, and alkynyl radicals, and include one or more backbone chain atoms selected from atoms other than carbon (eg, Oxygen, nitrogen, sulfur, phosphorus, or combinations thereof).

  The term “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the ring backbone atoms is a nitrogen atom. Polycyclic heteroaryl groups include fused or non-fused. Illustrative examples of heteroaryl groups include the following moieties (Formula 47) and the like.

  The term “moiety” means a specific section or functional group of a molecule. Chemical moieties are often recognized as chemical components that are incorporated into or attached to a molecule.

  The term “bond” or “single bond” means a chemical bond between two atoms or two moieties when the atoms are joined by a bond and is considered part of a larger substructure.

  The term “carboxylic acid bioisostere” means a moiety capable of substituting a carboxylic acid group. Bioisosteres involve the exchange of atoms or groups of atoms with other, roughly similar atoms or groups, and mimic the spatial arrangement, electronic properties, or other physicochemical properties of carboxylic acid groups. Maintain similar biological activity. Thus, for example, tetrazole, sulfonic acid, and sulfonamide are carboxylic acid bioisosteres.

  The term “optionally substituted” means that the group referred to is alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, One or more selected from thiocarbonyl, isocyanate, thiocyanate, isothiocyanate, nitro, perhaloalkyl, perfluoroalkyl, silyl, and amino (including mono- and di-substituted amino groups) and protected derivatives thereof Including individually independently substituted with additional groups. Examples of protecting groups can be found in Greene and Wuts et al.

  In certain embodiments, the compounds described herein possess one or more chiral centers, each center being in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as suitable mixtures thereof. Stereoisomers are obtained, for example, by separation of stereoisomers using a chiral chromatography column, if necessary.

  The methods and formulations described herein include N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of formula (I), as well as: Including the use of active metabolites of these compounds having the same type of activity. Under certain circumstances, the compounds exist as tautomers. All tautomers are included within the scope of the compounds described herein. In addition, the compounds described herein exist in unsolvated forms, as well as in solvated forms using pharmaceutically acceptable solvents (water, ethanol, etc.). The solvated forms of the compounds presented herein are also considered to be disclosed herein.

<Pharmaceutical composition>
Another aspect is a pharmaceutical composition comprising a compound of formula (I) or (II) and a pharmaceutically acceptable diluent, excipient or carrier.

  The term “pharmaceutical composition” means a mixture of a compound of formula (I) with other chemical components. Other chemical components are carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. The methods for administering the compounds are intravenous, oral, nebulized, parenteral, ophthalmic, pulmonary, and topical administration.

  The term “carrier” refers to a relatively non-toxic chemical or agent that facilitates the incorporation of a compound into cells or tissues.

  The term “diluent” means a chemical that is used to dilute a compound of interest prior to delivery. Diluents are also used to stabilize the compound. This is because the diluent provides a more stable environment. Salt dissolved in buffer (which also provides pH control or maintenance) is used as a diluent and includes but is not limited to phosphate buffered saline.

  The term “physiologically acceptable” means a substance that is non-toxic (eg, a carrier or diluent, etc.) without destroying the biological activity or properties of the compound.

  The term “pharmaceutically acceptable salt” means a form of a compound that does not cause significant inflammation to the organism to which the salt is administered and does not abrogate the biological activity or properties of the compound. In one example, a pharmaceutically acceptable salt is obtained by reacting a compound of formula (I) with an acid. Examples of the acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable salts are obtained by reacting a compound of formula (I) with a base to form a salt, for example ammonium salts, alkali metal salts (eg sodium or potassium salts) alkaline earths Metal salts (eg, calcium or magnesium salts), salts of organic bases (eg, dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine), and amino acids (eg, arginine, lysine, and the like) ) And salt.

  A compound “metabolite” disclosed herein is a derivative of a compound that is formed when the compound is metabolized. The term “active metabolite” means a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized” refers to the sum of actions (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes), by which certain substances are altered by the organism. Thus, enzymes can cause structural changes specific to the compound. For example, cytochrome P450 catalyzes a variety of oxidation and reduction reactions, whereas uridine diphosphate glucuronyltransferases can be used to convert aromatic alcohols, aliphatic alcohols, carboxylic acids, amines from activated glucuronic acid molecules. And catalyzing the transfer to free sulfhydryl groups. In addition, information on metabolites can be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).

  In certain embodiments, a metabolite of a compound disclosed herein comprises administering the compound to a host and analyzing a tissue sample from the host, or culturing the compound with hepatocytes in vitro and the resulting compound Are identified by either

  “Prodrug” means a drug that is converted into the parent drug in vivo. Prodrugs are useful in most cases. This is because, under certain circumstances, these prodrugs are easier to administer than the parent drug. In certain embodiments, the prodrug is biologically available, eg, by oral administration, while the parent drug is not available. For example, prodrugs have improved solubility in pharmaceutical compositions than the parent drug. An example is, but not limited to, a compound of formula (I) that is administered as an ester (“prodrug”), which facilitates delivery across cell membranes where water solubility adversely affects mobility; Thereafter, once it enters a cell in which water solubility is beneficial, it is metabolically hydrolyzed to a carboxylic acid (active substance). An additional example of a prodrug is a short peptide (polyamino acid) attached to an acidic group, where the peptide is metabolized to clearly show the active moiety.

  In certain embodiments, the compounds described herein are administered to a human patient per se or in the form of a pharmaceutical composition. In pharmaceutical compositions, the compounds are mixed with other active ingredients or with suitable carriers or excipients, as is the case with combination therapy. Techniques for formulation and administration of the compounds of this application can be found in “Remington: The Science and Practice of Pharmacy, 20th ed. (2000)”.

<Administration route>
Suitable routes of administration are, for example, oral, rectal, intravaginal, transmucosal, transdermal, pulmonary, or enteral administration;
Parenteral administration includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, or nasal administration.

  Alternatively, we often administer the compound locally rather than systemically (eg, injecting the compound directly into the organ), often in a storage or sustained release formulation. Liposomes will be selectively targeted and taken up by the organ. Further, for example, the drug is provided in the form of a rapid release formulation, a sustained release formulation, or an intermediate release formulation.

<Compound / Prescription>
For example, a pharmaceutical composition comprising a compound of formula (I) or (II) is manufactured by a method of mixing, dissolving, granulating, dragee-making, homogeneous mixing, emulsifying, encapsulating, encapsulating or compressing process.

  For example, a pharmaceutical composition is formulated in a conventional manner using one or more physiologically acceptable carriers. Physiologically acceptable carriers include excipients and auxiliaries to facilitate processing of the active compound into pharmaceutically used formulations. Proper formulation is dependent upon the route of administration chosen.

  In certain embodiments, the compound of formula (I) or (II) is administered in a variety of ways, including systemic administration, eg, oral or intravenous administration.

  Useful compositions also include solubilizers that aid in the solubility of the compound of formula (I) or (II). The term “solubilizing agent” generally includes agents that result in the formation of a micellar solution or true solution of the agent. In certain embodiments, certain acceptable nonionic surfactants (eg, polysorbate 80) are useful as solubilizers, as well as acceptable glycols, polyglycols (eg, polyethylene glycol 400) and glycol ethers. Also mentioned.

  Useful compositions also include one or more pH adjusting or buffering agents, which include acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; sodium hydroxide, sodium phosphate, Bases such as sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, and ammonium chloride. Such acids, bases, and buffers are included in amounts necessary to maintain the pH of the composition within an acceptable range.

  Useful compositions comprise one or more acceptable salts in an amount necessary to bring the osmotic pressure of the composition within an acceptable range. Such salts include sodium, potassium or ammonium cations and chlorides, citrates, ascorbates, borates, phosphates, bicarbonates, sulfates, thiosulfates, or bisulfites. Preferred salts are sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate.

  Other useful compositions also include one or more acceptable preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing materials such as merfen and thiomersal; stabilized chlorinated dioxides; and quaternary ammonium compounds such as benzalkonium chloride, cetylmethylammonium bromide, and cetylpyridinium chloride including.

  In certain embodiments, the aqueous suspension composition is packaged in a single dose, non-resealable container. Alternatively, multiple dose resealable containers may be used, in which case the composition typically includes a preservative.

  A pharmaceutical carrier for hydrophobic compounds of formula (I) or (II) is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. This co-solvent system comprises 10% ethanol, 10% polyethylene glycol 300, 10% polyethylene glycol 40 castor oil (PEG-40 castor oil) and a 70% aqueous solution. This co-solvent system dissolves hydrophobic compounds well and is itself less toxic when administered systemically. For example, the proportion of a co-solvent system varies significantly without destroying its solubility and toxicity characteristics. Further, for example, the identity of the co-solvent components varies: for example, other low toxicity non-polar surfactants are used in place of PEG-40 castor oil and the fraction size of polyethylene glycol 300 varies; In embodiments, other biocompatible polymers replace polyethylene glycol (eg, polyvinylpyrrolidone); and other sugars or polysaccharides can also be included in the aqueous solution.

  Alternatively, other delivery systems for hydrophobic pharmaceutical compounds are used. Liposomes and emulsions are examples of hydrophobic drug delivery vehicles or carriers. In certain embodiments, certain organic solvents such as N-methylpyrrolidone are also used, but usually at the expense of increased toxicity. In addition, the compounds are delivered using sustained release systems such as, for example, semi-permeable matrices of solid hydrophobic polymers containing therapeutic agents. Sustained release capsules release this compound from 2-3 weeks to 100 days, depending on their chemical nature. Depending on the chemical nature and biological stability of this therapeutic agent, additional strategies for protein stabilization are employed.

  All formulations described herein benefit from antioxidants, metal chelators, thiol-containing compounds, and other common stabilizers. Examples of such stabilizers include (a) about 0.5% to about 2% (w / v) glycerol, (b) about 0.1% to about 1% (w / v) methionine. (C) about 0.1% to about 2% (w / v) monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% (w / v) ) Ascorbic acid, (f) 0.003% to about 0.02% (w / v) polysorbate 80, (g) 0.001% to about 0.05% (w / v) polysorbate 20, ( h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrin, (l) pentosan polysulfate, and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) Including, but not limited to, combinations thereof.

  In certain embodiments, the compound of formula (I) or (II) is provided as a salt with a pharmaceutically compatible counterion. In certain embodiments, pharmaceutically compatible salts are formed with a number of acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free acid or base forms.

<Oral administration>
In certain embodiments, the pharmaceutical compositions described herein are provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration includes buccal, lingual, and sublingual administration. Suitable oral dosage forms are tablets, capsules, pills, troche, medicated drops, pastilles, oblate capsules, pills, medicated chewing gum, granules, bulk powders, foamed or non-foamed powders or granules, Including but not limited to solutions, emulsions, suspensions, solutions, wafers, sprays, elixirs, and syrups. In addition to the active ingredient, in certain embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable carriers or excipients. Such carriers or excipients include, but are not limited to, binders, extenders, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye transfer inhibitors, sweeteners, and flavors. .

  The binder or granulating agent provides adhesion to the tablet so that the tablet is not damaged after compression. Suitable binders or granulating agents include starches such as corn starch, potato starch, and pregelatinized starch (eg, starch 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic Gum, eg, acacia, alginic acid, alginate, Irish moss extract, panwar gum, gati gum, isapol shell mucus, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum , Larch arabogalactan, powdered tragacanth, and guar gum; cellulose such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium Um, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); microcrystalline cellulose, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL- PH-105 (FMC CORP., Marcus Hook, Pennsylvania); and mixtures thereof. Suitable bulking agents include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrate, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. In certain embodiments, the binder or filler is present from about 50 to about 99% by weight in the pharmaceutical compositions presented herein.

  Suitable diluents include, but are not limited to, calcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in effective amounts, impart properties to certain compressed tablets so that they can be disintegrated by chewing in the mouth. In certain embodiments, such compressed tablets are used as chewable tablets.

  Suitable disintegrants include agar; bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums such as guar gum and Veegum HV; citrus pulp; For example, croscarmellose; cross-linked polymer such as crospovidone; cross-linked starch; calcium carbonate; crystalline cellulose such as sodium starch glycolate; polacrilin potassium; starch such as corn starch, potato starch, tapioca starch, and pregelatinized starch Clays; alignments; and mixtures thereof; including but not limited to; The amount of disintegrant in the pharmaceutical compositions described herein will vary depending on the type of formulation. In certain embodiments, the pharmaceutical compositions described herein comprise about 0.5 to about 15% by weight, or about 1 to about 5% by weight of a disintegrant.

  Suitable lubricants include calcium stearate; magnesium stearate; mineral oil; light oil; glycerin; sorbitol; mannitol; glycols such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; Including, for example, peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lizard sprout; silica or silica gel, eg AEROSIL (Registered trademark) 200 (WR Grace Co., Baltimore, Maryland), CAB-O-SIL (registered trademark) (Cabot Co., Boston, Mass.), And mixtures thereof Not. In certain embodiments, the pharmaceutical compositions described herein comprise about 0.1 to 5% by weight of a lubricant.

  Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (Cabot Co., Boston, Mass.), And asbestos-free talc. Colorants include any approved and certified water soluble FD & C dyes, and water insoluble FD & C dyes (suspended in alumina white), lake pigments, and mixtures thereof. Lake pigments are combinations of heavy metals into hydrated oxides by absorption of water-soluble dyes, resulting in water-insoluble forms of the dyes. Perfumes include natural perfumes extracted from plants (eg fruits) and synthetic mixtures of compounds that produce a good taste (eg peppermint and methyl salicylic acid). Sweetening agents include sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifiers include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN®). 80), and triethanolamine oleate. Suspending and dispersing agents include sodium carboxymethylcellulose, pectin, tragacanth, bee gum, acacia, sodium carbomethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous solutions used in emulsions include mineral oil and cottonseed oil. Organic acids include citric acid and tartaric acid. The carbon dioxide source includes sodium bicarbonate and sodium carbonate.

  In certain embodiments, the pharmaceutical formulation used orally includes push-fit capsules made of gelatin, but by way of example only, soft and sealed made of gelatin and a plasticizer (eg, glycerol or sorbitol). Capsules; or hard gelatin capsules or tablets. In certain embodiments, the push-in capsule comprises an active ingredient, which includes a bulking agent (eg, lactose), a binder (eg, starch), and / or a lubricant (eg, talc or magnesium stearate) and Optionally included in admixture with a stabilizer. In certain embodiments, in soft capsules, the active compound is dissolved or suspended in a suitable solution (eg, fatty oil, liquid paraffin, or liquid polyethylene glycols). Further, in certain embodiments, a stabilizer is added. All formulations for oral administration should be in dosage forms suitable for such administration.

  In certain embodiments, for buccal or sublingual administration, the composition takes the form of a tablet, troche, or gel formulated in a conventional manner.

  It should be understood that in certain embodiments, multiple carriers and excipients perform several functions even in the same formulation.

  In certain embodiments, a pharmaceutical composition provided herein is a compressed tablet, a powder tablet, a chewable troche, a fast dissolving tablet, a multiple compressed tablet, or an enteric coated tablet, a sugar-coated or film-coated tablet Offered as. Enteric coated tablets are compressed tablets that protect the active ingredient from the acid environment of the stomach by being coated with a substance that is resistant to the action of gastric acid but dissolves or degrades in the intestine. Enteric coated tablets include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets that are wrapped with a sugar coating, and in certain embodiments are effective in masking undesirable tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered by a thin film or film of water-soluble material. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made in one or more compression cycles, including layered tablets, and press coated or dry coated tablets.

  In certain embodiments, tablet dosage forms are prepared from powdered, crystalline, or granular active ingredients, alone or in combination with one or more carriers or excipients described herein. The The carrier or excipient includes a binder, a disintegrant, a controlled release polymer, a lubricant, a diluent, and / or a colorant. Perfumes and sweeteners are particularly useful in the formulation of chewable tablets and troches.

  In one embodiment, the pharmaceutical compositions described herein are provided as soft or hard capsules, which are made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), are composed of two compartments, one of which slides over the other to completely enclose the active ingredient To do. Soft elastic capsules (SEC) are soft spherical shells (eg, gelatin shells) that are plasticized by the addition of glycerin, sorbitol, or similar polyols. In some embodiments, the soft gelatin shell prevents microbial growth by including a preservative. Suitable preservatives are as described herein and include methyl- and propyl-paraben and sorbic acid. In certain embodiments, the liquid, semi-solid, and solid dosage forms provided herein are encapsulated in a capsule form. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions are prepared and are described, for example, in US Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. In some embodiments, the capsule can be coated to modify or maintain the solubility of the active ingredient.

  In certain embodiments, the pharmaceutical compositions described herein are provided in liquid and semi-solid dosage forms and include emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout the other liquid and includes an oil-in-water type or a water-in-oil type. The emulsion includes a pharmaceutically acceptable water-insoluble liquid or solvent, an emulsifier, and a preservative. The suspension contains pharmaceutically acceptable suspending agents and preservatives. Aqueous alcohol solutions are pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes (the term “lower” is an alkyl having between 1 and 6 carbon atoms) and the like (for example, acetaldehyde diethyl Acetals); and water miscible solvents having one or more hydroxyl groups (eg, propylene glycol and ethanol). An elixir is a hydrous alcoholic solution that is transparent and sweet. Syrup is a concentrated aqueous solution of sugar (eg, sucrose) and also includes a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol is diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (eg, water) and conveniently measured and used for administration.

  Other useful liquid and semi-solid dosage forms include forms containing the active ingredients described herein, and dialkylated mono- or poly-alkylene glycols (1,2-dimethoxymethane, diglyme, triglyme, tetraglyme) , Polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 are estimated average molecular weights of polyethylene glycol), but are not limited thereto Not. These formulations in certain embodiments further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxy Examples include coumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium disulfite, thiodipropionic acid and its esters, and dithiocarbamate.

  In certain embodiments, the pharmaceutical compositions provided herein are pharmaceutical compositions for oral administration and are also provided in the form of liposomes, micelles, microspheres, or nanosystems. In certain embodiments, micelle dosage forms are prepared as described in US Pat. No. 6,350,458.

  In certain embodiments, the pharmaceutical compositions presented herein are returned to liquid dosage forms by being provided as non-foamed or foamable granules or powders. In certain embodiments, pharmaceutically acceptable carriers and excipients used in non-foamable granules or powders include diluents, sweeteners, and wetting agents. In certain embodiments, pharmaceutically acceptable carriers and excipients used in non-foamable granules or powders include an organic acid and a carbon dioxide source.

  In certain embodiments, coloring and perfume are used in all of the dosage forms described above.

  In certain embodiments, the pharmaceutical compositions described herein are formulated as modified release dosage forms including immediate or delayed-, sustained-, pulse-, controlled-, target-, and programmed release forms. The

<Parenteral administration>
In certain embodiments, the pharmaceutical compositions described herein are administered parenterally by infusion, infusion, or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

  In certain embodiments, the pharmaceutical compositions presented herein comprise any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and Prepared in a solid form suitable for solution or suspension in liquid prior to injection. In certain embodiments, such dosage forms are prepared according to conventional methods (see, eg, Remington: The Science and Practice of Pharmacy).

  In certain embodiments, a pharmaceutical composition intended for parenteral administration comprises one or more pharmaceutically acceptable carriers and excipients. Carriers and excipients include aqueous media, water-miscible media, water-insoluble media, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility promoters, isotonic agents, buffers, antioxidants, local These include, but are not limited to, anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickeners, pH adjusting agents, and inert gases. It is not limited.

  Suitable aqueous media include water, saline, saline, or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. It is not limited to these. Water-insoluble media include plant-derived fixed oils, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and coconut oil. Including but not limited to medium chain triglycerides and palm seed oil. Water miscible media are ethanol, 1,3-butanediol, liquid polyethylene glycol (eg, polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide. Including, but not limited to.

Suitable antibacterial or preservatives are phenol, cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride, benzethonium chloride, methyl- and propyl-paraben, and sorbine Including but not limited to acids. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those described herein and include bisulfite or sodium metabisulfite. Suitable local anesthetics include but are not limited to procaine hydrochloride. Suitable suspending and dispersing agents are those described herein and include sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers are those described herein and include polyoxyethylene sorbitan lauric acid monoester, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include but are not limited to cyclodextrins, which include α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfone butyl ether-β-cyclodextrin, and sulfone. Butyl ether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS)
including.

  In certain embodiments, the pharmaceutical compositions described herein are formulated for single or multiple dose administration. Single dose formulations are packaged in one ampule, vial, or syringe. Multiple dose parenteral formulations should contain antimicrobial agents in bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterilized.

  In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In other embodiments, the pharmaceutical composition is provided as a sterile dry solubilized product (including lyophilized powder and subcutaneous injection tablets) and reconstituted with the vehicle prior to use. In still other embodiments, the pharmaceutical composition is provided as a sterile suspension that can be used immediately. In still other embodiments, the pharmaceutical composition is provided as a sterile, dry, insoluble product and is reconstituted with media prior to use. In yet another embodiment, the pharmaceutical composition is provided as a sterile emulsion that can be used immediately.

  In certain embodiments, the pharmaceutical compositions described herein are formulated as immediate or modified release dosage forms, which are delayed-, sustained-, pulse-, controlled-, target-, and programmed release. Includes form.

  In certain embodiments, the pharmaceutical composition is formulated as a suspension, solid, semi-solid, or thixotropic solution for administration as an implantable long-acting drug. In one embodiment, the pharmaceutical composition provided herein is dispersed in a solid inner matrix that is insoluble in body fluids but by an outer polymeric membrane that allows diffusion through the active ingredient in the pharmaceutical composition. Surrounded.

  Suitable internal matrices are polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-acetic acid Vinyl copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymer (such as hydrogel of ester of acrylic acid and methacrylic acid), collagen, crosslinked polyvinyl alcohol, and crosslinked and partially hydrolyzed Polyvinyl acetate.

  Suitable outer polymer membranes include polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, poly Vinyl chloride and vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene, and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and Contains ethylene / vinyloxyethanol copolymer.

  In certain embodiments, for intravenous injection, the compound of formula (I) or (II) is formulated in an aqueous solution, preferably in a physiologically compatible buffer (Hank's solution, Ringer's solution, or physiological saline buffer). Is done. For transmucosal administration, penetrants appropriate to the barrier permeation are used in this formulation. For other parenteral injections, suitable formulations in certain embodiments include aqueous or non-aqueous solutions, preferably with a physiologically compatible buffer or excipient.

  The compounds in certain embodiments are formulated for parenteral administration by infusion (eg, bolus injection or continuous infusion). Injectable formulations in certain embodiments are presented in unit dosage form, eg, in ampoules or multiple dose containers, with preservatives added. The composition in certain embodiments takes the form of a suspension, solution or emulsion in an oily or aqueous medium and includes a formulation such as suspending, stabilizing and / or dispersing agents.

  Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds that are in a water-soluble form. Additionally, suspensions of the active compounds in certain embodiments are prepared as oily injection suspensions as needed. Suitable fat-soluble solvents or vehicles include fatty acids such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions contain, in certain embodiments, substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, this suspension also contains suitable stabilizers or agents that improve the solubility of the compounds to allow for the preparation of highly concentrated solutions.

  Alternatively, the active ingredient is in powder form for reconstitution with a suitable medium (eg, sterile pyrogen-free water) prior to use.

  The compound in certain embodiments is formulated as a rectal composition, such as a rectal gel, rectal foam, rectal aerosol, suppository or retention enemas (eg, cocoa butter or other). Conventional suppository bases such as glycerides).

  In addition to the formulations described above, the compound in certain embodiments is formulated as a depot preparation. Such long acting formulations are, in some embodiments, administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound is formulated with a suitable polymeric or hydrophobic material (eg, as an emulsion in an acceptable oil) or with an ion exchange resin, or as a poorly soluble derivative (eg, as a poorly soluble salt). The

  Injectable depot forms in certain embodiments are made by forming a microencapsulated matrix (also known as a microcapsule matrix) of a compound of formula (I) or (II) in a biodegradable polymer. Depending on the ratio of drug to polymer, and the nature of the particular polymer used, the rate of drug release is controlled. Depot injectable formulations in certain embodiments are prepared by entrapping the drug in liposomes or microemulsions. By way of example only, a depot near the posterior sclera is used as a mode of administration of a compound having the structural formula of formula (I) or (II). The sclera is a thin avascular layer and consists of a highly regular collagen network surrounding most vertebrate eyes. Since the sclera is avascular, it can be used as a natural storage repository (depot) from which the injected material is not rapidly removed nor lost from the eye. In certain embodiments, the formulation used to administer this compound to the scleral layer of the eye is applied to the sclera when injected through a cannula having a small diameter suitable for injection into the sclera layer. Any form suitable for Examples of injectable application forms are solutions, suspensions or colloidal suspensions.

<Topical administration>
In certain embodiments, the pharmaceutical compositions provided herein are administered topically to the skin, openings, or mucous membranes. As used herein, topical administration refers to skin (inner), conjunctiva, intracorneal, intraocular, intraocular, intraocular, transdermal, nasal, intravaginal, intraurethral, respiratory tract, and rectum. Including administration.

  In certain embodiments, the pharmaceutical compositions provided herein are formulated into any dosage form suitable for topical administration to obtain a local or systemic effect, the dosage form comprising an emulsion, solution, Suspension, cream, gel, hydrogel, ointment, spray, dressing, elixir, lotion, suspension, tincture, paste, foam, film, aerosol, detergent, spray, suppository, bandage Including transdermal patches. The topical formulations of pharmaceutical compositions provided herein also include liposomes, micelles, microspheres, nanospheres, or nanoparticles, and mixtures thereof, in certain embodiments.

  Other useful formulations for the administration of compounds having the structure of formula (I) or (II) use transdermal delivery devices (“patches”). Such transdermal patches in certain embodiments are used to perform continuous or discontinuous infusions of the compounds presented herein in controlled amounts. An example of the construction and use of a transdermal patch for the delivery of pharmaceuticals can be found in US Pat. Such patches in certain embodiments are constructed for continuous, pulsed, or on-demand delivery of pharmaceutical products. Further additionally, in certain embodiments, transdermal delivery of a compound of formula (I) or (II) is achieved by methods such as iontophoretic patches. Transdermal patches provide controlled delivery of this compound. In certain embodiments, the absorption rate is slowed by using a rate controlling membrane or by trapping the compound in a polymer matrix or gel. Conversely, in certain embodiments, absorption enhancers may be used to improve absorption. In certain embodiments, formulations suitable for transdermal administration are aqueous solutions of fat-soluble emulsions or buffers that exist as discrete patches or are dissolved and / or dispersed in polymers or adhesives.

  Pharmaceutically acceptable carriers and excipients suitably used in the topical formulations described herein include water soluble media, water miscible media, water insoluble media, antimicrobial agents against microbial growth or Preservatives, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, antiseptics Includes, but is not limited to, cryogens, lyoprotectants, thickeners, pH adjusters, and inert gases.

  In certain embodiments, the pharmaceutical composition is administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection, eg, POWDERJECT ™ (Chiron Corp, Emeryville, CA) ), And BIOJECT ™ (Bioject Medical Technologies Inc., Tualatin, Oregon).

  In certain embodiments, the pharmaceutical compositions described herein are provided in ointment, cream, and gel forms. Suitable ointment media are oleaginous or hydrocarbon media such as lard, benzoic lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifying media or absorption media such as hydrophilic petrolatum, hydroxystearic sulfate And water-removable media such as hydrophilic ointments; water-soluble ointment media (including variable molecular weight polyethylene glycols); water-in-oil (W / O) emulsions, or oil-in-water (O / W) Emulsion medium (including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid) that is any of the emulsions (see Remington: The Science and Practice of Pharmacy, supra). These media are emollients, but generally require the addition of antioxidants and preservatives.

  In certain embodiments, suitable cream bases are oil-in-water or water-in-oil. In certain embodiments, the cream medium is washable and includes an oil phase, an emulsifier, and an aqueous phase. The oil phase is also referred to as the “internal” phase and is generally composed of petrolatum and a fatty alcohol (such as cetyl or stearyl alcohol). The aqueous phase is usually, but not necessarily, larger than the oil phase and generally contains a humectant. Emulsifiers in cream formulations include nonionic, anionic, cationic, or amphoteric surfactants.

  Gels are semisolid and suspended systems. Single-phase gels contain organic polymers that are distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include cross-linked acrylic acid polymers such as carbomers carboxypolyalkylene (Carbopol®); hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl Alcohols; cellulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums such as tragacanth gum and xanthan gum; sodium alginate; and gelatin. In certain embodiments, a dispersant such as alcohol or glycerin is added to prepare a uniform gel, or the gelling agent is dispersed by trituration, mechanical mixing, and / or stirring.

  In certain embodiments, the pharmaceutical compositions described herein are suppositories, pessaries, bougies, poultices or pops, pastes, powders, dressings, creams, bandages, contraceptives, rectally, urethra, vaginally, around the vagina. It is administered in the form of a drug, ointment, solution, emulsion, suspension, tampon, gel, foam, spray, or enema. In certain embodiments, these dosage forms are manufactured using conventional processes described in Remington: The Science and Practice of Pharmacy, supra.

  Rectal, urethral, and intravaginal suppositories are solid materials for insertion into the body's opening, releasing the active ingredient in the opening by being solid at room temperature but dissolving or softening at body temperature . Pharmaceutically acceptable carriers used in rectal and vaginal suppositories are bases such as curing agents that, when formulated with a pharmaceutical composition described herein, provide a melting point near body temperature. Or a medium; and the antioxidants described herein (such as bisulfite and sodium metabisulfite). Suitable media are cocoa butter (cocoa butter), glycerin-gelatin, carbowax (polyethylene glycol), whale wax, paraffin, white and yellow wax, and suitable mixtures of mono-, di- and triglycerides of fatty acids, hydrogels For example, but not limited to, polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin. In some embodiments, various media combinations are used. Rectal and vaginal suppositories in certain embodiments are prepared by the compression method or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

  In certain embodiments, the pharmaceutical compositions provided herein are administered to the eye in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, solution powders, gels, ophthalmic inserts and implants. The

  In certain embodiments, the pharmaceutical compositions provided herein are administered intranasally or by inhalation into the respiratory tract. The pharmaceutical composition in certain embodiments is provided in an aerosol or solution form for delivery and is a compressed container, pump, spray, atomizer (such as a nebulizer for creating a mist mist using electrohydrodynamics), Or using a nebulizer alone or in combination with a suitable propellant (such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) . The pharmaceutical composition in certain embodiments is provided as a dry powder for insufflation alone or in combination with an inert carrier (lactose or phospholipid); and as a nasal spray. For nasal use, the powder in certain embodiments includes a bioadhesive (including chitosan or cyclodextrin).

  In certain embodiments, the use of solutions or suspensions in compressed containers, pumps, sprays, atomizers, or nebulizers for dispersion, stabilization, or sustained release of the active ingredients described herein. Ethanol, aqueous ethanol, or suitable alternatives are formulated to contain propellants as solvents; and / or surfactants such as sorbitan trioleate, oleic acid, or oligolactic acid.

  In certain embodiments, the pharmaceutical compositions described herein are micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Such sized particles may in certain embodiments be spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles. It is prepared using a pulverization method such as high-pressure homogenization or spray drying.

  In certain embodiments, capsules, blisters, and cartridges for use in inhalers or insufflators are powder mixtures of the pharmaceutical compositions described herein; suitable powder bases (such as lactose or starch) And a performance modifier (l-leucine, mannitol, or magnesium stearate). Lactose includes the anhydrous or monohydrate form. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. In certain embodiments, the pharmaceutical compositions described herein for inhalation / nasal administration further comprise a suitable fragrance (eg, menthol and levomenthol), or a sweetener (saccharin or saccharin sodium).

  In certain embodiments, the pharmaceutical compositions described herein for topical administration are formulated to have immediate or modified release, which is delayed-, sustained-, pulse-, controlled-, targeted -And including programmed release.

<Regulated release>
In certain embodiments, the pharmaceutical compositions described herein are formulated in a controlled release dosage form. As used herein, the term “modified release” means a dosage form in which the release rate or location of the active ingredient is different from that of the immediate dosage form when administered by the same route. Modified release dosage forms include delayed-, extended-, long-term-, sustained-, pulse-, controlled-, accelerated-, fast-, targeted-, programmed-release and include gastric retention dosage forms. Pharmaceutical compositions in modified release dosage forms are prepared using a variety of modified release devices and methods, including matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings , Microspheres, liposomes, and combinations thereof. In certain embodiments, the release rate of the active ingredient is adjusted by varying the particle size and polymorphism of the active ingredient.

  Examples of modified release are: U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; No. 5,354,556; No. 5,639,480; No. 5,733,566; No. 5,739,108; No. 5,891,474; No. 5,922,356; No. 5,972,891; No. 5,980,945; No. 5,993,855; No. 6,045,830; No. No. 6,197,350; No. 6,248,363; No. 6,264,970; No. 6,267,981; No. 6,376,461; No. 6,419,961; No. 6,589,548; No. 6,613,358; and No. 6,699,500.

<1. Matrix controlled release device>
The pharmaceutical compositions described herein are, in one embodiment, a modified release dosage form, such as a matrix controlled release device (eg, Takada et al in “Encyclopedia of Controlled Drug Delivery,” Vol. 2, Mathiowitz ed., Wiley, 1999).

  In certain embodiments, the pharmaceutical compositions described herein are in a modified release dosage form and are erodible matrix devices (water-swellable, erodable or soluble polymers, synthetic polymers and naturally The resulting polymer and derivatives (including polysaccharides and proteins) are used to formulate.

  Materials useful for forming an erodible matrix include chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenan, ghatti gum, guar gum, xanthan gum, and secrete. Starch, such as dextrin and maltodextrin; hydrocolloid, such as pectin; phospholipid, such as lecithin; alginate; propylene glycol alginate; gelatin; collagen; and cellulosic, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC) , Carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate (CA) , Cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropylmethylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropylmethylcellulose acetate trimellitate (HPMCAT), and ethylhydroxy Polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid ester; polyacrylamide; polyacrylic acid; a copolymer of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, New Jersey); poly (2-hydroxyethyl-methacrylate); polylactide; copolymer of L-glutamic acid and ethyl-L-glutamate; degradable milk -Glycolic acid copolymer; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives such as butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, methacrylic acid (2- Dimethylaminoethyl), and homopolymers and copolymers of methacrylic acid chloride (trimethylaminoethyl), but are not limited thereto.

  In a further embodiment, the pharmaceutical composition is formulated using a non-erodible matrix device. The active ingredient is dissolved or dispersed in an inert matrix and is released mainly by diffusion through the inert matrix after administration. Suitable materials for use as non-erodible matrix devices are insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate. -Methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl acetate, vinylidene chloride, ethylene, and vinyl chloride copolymer with propylene, ionomer Polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer , Polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, and; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linking And partially hydrolyzed polyvinyl acetate; and aliphatic compounds such as, but not limited to, carnauba wax, microcrystalline wax, and triglycerides.

  In a matrix controlled release system, for example, the type of polymer used, the viscosity of the polymer, the particle size of the polymer and / or active ingredient, the ratio of the active ingredient to the polymer, and other excipients or carriers in the composition Can control the desired release kinetics.

  The pharmaceutical compositions described herein are, in one embodiment, a modified release dosage form and are prepared by methods that include compression after direct compression, dry or wet granulation, compression after dissolution granulation.

<2. Osmotic pressure controlled release device>
The pharmaceutical compositions described herein are in controlled release dosage forms in certain embodiments, and include osmotic controlled release devices (1-chamber systems, 2-chamber systems, asymmetric membrane technology (AMT), and extruded core systems). (ECS)). In general, such devices have at least two elements: (a) a core containing the active ingredient; and (b) a semi-permeable membrane comprising at least one delivery port and encapsulating the core. Semipermeable membranes cause drug release by extrusion through the delivery port by controlling the inflow of water from the aqueous environment used to the core.

  In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent. An osmotic agent creates the motive force for transporting water from the environment of use to the core of the device. Water swellable hydrophilic polymers, one of the osmotic agents, are also referred to as “osmopolymers” and “hydrogels”, and are hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide ( PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic) acid, poly (methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA) ), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers (such as methyl methacrylate and vinyl acetate), hydrophilic polyurethanes with large PEO blocks, croscarmellose sodium, carrageenan, hydroxyethyl cellulose ( EC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), and carboxyethylcellulose (CEC), including sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate It is not limited to.

  Another type of osmotic agent is osmogen, which has the ability to absorb water, affecting the osmotic gradient across the barrier of the surrounding coating. Suitable osmogens are inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfate, lithium sulfate, potassium chloride, and sodium sulfate; For example, dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic salts such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, Including but not limited to sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

  Different dissolution rate osmotic agents in certain embodiments are employed to affect how quickly the active agent is first delivered from the dosage form. For example, saccharide amorphous (Mannogeme EZ (SPI Pharma, Lewis, Del.), Etc.) is used to provide more rapid delivery during the first few hours to quickly create the desired therapeutic effect and continue gradually By releasing the residual amount, the desired level of therapeutic or prophylactic effect is maintained over a long period of time. In this case, instead of the amount of active ingredient metabolized and excreted, the active ingredient is released at such a rate.

  The core in certain embodiments includes various other excipients and carriers as described herein to promote the efficiency of the dosage form or to promote stability or processing.

  Materials useful for forming semipermeable membranes include various grades of acrylic, vinyl, ether, polyamide, polyester, and cellulose derivatives, which are water permeable and water insoluble at physiologically relevant pH. And is susceptible to being rendered insoluble by chemical changes (such as crosslinking). Examples of suitable polymers that are useful for forming coatings include unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, propionic acid CA, cellulose nitrate, cellulose acetate butyrate (CAB), Ethyl carbamate CA, CAP, methyl carbamate CA, succinic acid CA, cellulose acetate trimellitate (CAT), dimethylaminoacetic acid CA, ethyl carbonate CA, chloroacetic acid CA, ethyl oxalate CA, methyl sulfonic acid CA, butyl sulfone Acid CA, p-toluenesulfonic acid CA, acetate agar, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, ethylene hydroxide-vinyl acetate, EC, PEG PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly (acrylic) acid and ester, and poly- (methacrylic) acid and ester and copolymer thereof, starch Dextran, dextrin, chitosan, collagen, gelatin, polyalkene, polyester, polysulfone, polyethersulfone, polystyrene, polyvinyl halide, polyvinyl ester and ether, natural wax and synthetic wax.

  The semipermeable membrane is in one embodiment a hydrophobic microporous membrane, the pores being substantially filled with gas and not wetted by an aqueous medium, but permeable to water vapor (US Pat. No. 5,798,119). Described in). Such a membrane that is hydrophobic but permeable to water vapor is typically composed of a hydrophobic polymer, such as polyalkene, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid. Derivatives, polyethers, polysulfones, polyether sulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

  The delivery port on the semipermeable membrane is formed in some embodiments by mechanical or laser drilling after coating. The delivery port, in certain embodiments, is formed in situ by erosion of a plug of water soluble material or by rupturing a thin portion of the membrane beyond a recess in the core. In addition, the delivery port is formed during the coating process and is disclosed in US Pat. Nos. 5,612,059 and 5,698,220 for the case of asymmetric membrane coating.

  The total amount and rate of release of the active ingredient is, in one embodiment, substantially adjusted by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of delivery ports.

  In certain embodiments, the pharmaceutical composition that is an osmotic controlled release dosage form further includes additional conventional excipients or carriers as described herein to enhance the efficiency or processing of the formulation. To do.

  In certain embodiments, osmotic controlled release dosage forms are prepared based on conventional methods and techniques (Remington: The Science and Practice of Pharmacy; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; see Verma et al., J. Controlled Release 2002, 79, 7-27).

  In certain embodiments, the pharmaceutical compositions described herein are prepared as an AMT controlled release dosage form comprising an asymmetric osmotic membrane that coats the core, the core comprising an active ingredient and other pharmaceutically acceptable Contains possible excipients or carriers. See U.S. Patent No. 5,612,059, and WO 2002/17918. In certain embodiments, AMT controlled release dosage forms are prepared using methods such as direct compression, dry granulation, wet granulation, and dip coating.

  In certain embodiments, the pharmaceutical compositions described herein are prepared as an ESC controlled release dosage form that includes an osmotic membrane that coats the core, the core comprising an active ingredient, hydroxyethyl cellulose, and other pharmaceuticals. Containing an acceptable excipient or carrier.

<3. Multi-particle controlled release device>
The pharmaceutical compositions described herein are in controlled release dosage forms in certain embodiments and are manufactured with multiparticulate controlled release devices. Multiparticulate controlled release devices include a large number of particles, granules, or pellets with diameters ranging from about 10 μm to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm. Such multiparticulates in certain embodiments are made by processes such as wet-, dry-granulation, extrusion / spheronization, roller compaction, dissolution-coagulation, and seed cores by spray coating. See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

  For administration by inhalation, the compound of formula (I) or (II) uses an appropriate propellant (eg, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). Conveniently delivered in the form of an aerosol spray from a compressed pack or nebulizer. In the case of a pressurized aerosol, the dosage unit in certain embodiments is determined by providing a valve to deliver a measured amount. Capsules and cartridges (eg, gelatin) for use in an inhaler or insufflator are formulated by containing a powder mixture of the compound and a suitable powder base such as lactose or starch.

<Treatment method, dose and combination therapy>
The term “mammal” refers to all mammals, including humans. Mammals include, by way of example, humans, non-human primates, cows, dogs, cats, goats, sheep, pigs, rabbit eyes, rats, mice, and rabbits.

  As used herein, the term “effective amount” means an amount of a compound that, when administered, alleviates some of one or more symptoms of the disease, disorder or disorder being treated.

  As used herein, the term “indirectly modulates” refers to an agent that reduces retinol levels in the mammal's eyes by lowering serum retinol levels in the mammal. Such a decrease in ocular retinol levels leads to modulation of visual cycle protein activity. This form of regulation (which occurs through a reduction in ocular serum retinol levels) is referred to herein as indirect regulation.

  In certain embodiments, a composition comprising a compound described herein is administered for prophylactic and / or therapeutic treatments. The term “therapy” is used to mean either prophylactic and / or therapeutic treatment. In therapeutic applications, the composition is administered to a patient already suffering from a disease, disorder, or disorder in an amount sufficient to cure or partially subside the symptoms of the disease, disorder, or disorder. The effective amount for this use depends on the severity and course of the illness, disorder or disease, previous treatment, patient health and responsiveness to the drug, and the judgment of the treating physician.

  In prophylactic applications, a composition comprising a compound described herein is administered to a patient susceptible to or at risk of a particular disease, disorder, or disease. Such an amount is defined as "prophylactically effective amount or dose." In this use, the exact amount will also depend on the patient's health, weight, etc.

  The term “enhance” or “enhance” means to increase or lengthen either the effectiveness or duration of the desired effect. Thus, with respect to improving the effect of a therapeutic agent, the term “enhancement” means increasing or prolonging the effect of another therapeutic agent on the system, either in effectiveness or duration. As used herein, “enhancing effective amount” means an amount sufficient to enhance the effect of the other therapeutic agent in the desired system. When used in patients, the amount effective for this use depends on the severity and course of the disease, disorder, or condition, previous treatment, patient health and responsiveness to the drug, and the judgment of the treating physician. To do.

  If the patient's disease does not improve, at the discretion of the physician, administration of the compound chronically (ie, a wide period of time including the lifetime of the patient's life) improves or controls the patient's disease or disease symptoms. Or given to limit.

  If the patient's condition does not improve, at the discretion of the physician, administration of the compound is stopped continuously or temporarily for a specified period of time (ie, a “drug holiday”).

  As the patient's disease improves, maintenance doses are administered as needed. Subsequently, in certain embodiments, the dosage or frequency of administration, or both, is reduced to a level at which the improved disease, disorder, or condition is retained, depending on the symptoms. In certain embodiments, the patient requires long-term intermittent treatment if any recurrence of symptoms occurs.

  The amount of a given drug that matches such an amount will vary depending on factors such as the particular compound, the condition and its severity, the identity of the subject or host in need of treatment (eg, weight), Determined according to the specific environment surrounding the case. A particular environment includes, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses used for adult human treatment typically range from about 0.02 to about 5000 mg per day. In other embodiments, doses used for adult human treatment range from about 1 to about 1500 mg per day. The desired dose is, in one embodiment, a single dose, or divided doses administered at the same time (or short period) or at appropriate intervals (eg, 2, 3, 4, or more sub-doses per day). Administration), also conveniently shown.

  In certain cases, administering at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate) in combination with other therapeutic agents. Is preferred. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein is inflammation, it is preferable to administer an anti-inflammatory agent in combination with the initial therapeutic agent. Alternatively, but by way of example only, the therapeutic efficacy of one of the compounds described herein is enhanced by administration of an adjuvant (ie, the adjuvant itself has minimal therapeutic utility, but other therapeutic agents. To improve overall therapeutic benefit to the patient). Alternatively, but by way of example only, the utility that a patient receives is one of the compounds described herein, along with other therapeutic agents that also have therapeutic utility (also including therapeutic modes of administration). Increased by administration. By way of example only, in the treatment of macular degeneration with respect to the administration of one of the compounds described herein, the increase in therapeutically useful outcomes has led patients to other therapeutic agents or methods for macular degeneration. Obtained by providing. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit that the patient receives is simply an additive or synergistic benefit of the two therapeutic agents.

  Shown herein is a combination therapy comprising using a compound of formula (I) or (II) with a modulator of serum retinol levels or activity. In one embodiment, the combination comprises a compound of formula (I) or (II) and a compound of formula (III) (formula 48), a metabolically active product thereof, or a pharmaceutically acceptable prodrug or solvate thereof. Including.

Wherein X ¹ is selected from the group consisting of NR ² , O, S, CHR ² ; R ¹ is (CHR ² ) _x -L ¹ -R ³ , and X is 0, 1, 2, or be a 3; ^{L 1} is a single bond or -C (O) -,; ^{R 2} _{is, H, (C 1 -C 4} ) _{alkyl, F, (C 1 -C 4} ) fluoroalkyl, (C ₁ -C ₄₎ alkoxy, -C (O) OH, -C (O) -NH 2, - (C 1 -C 4) _{alkylamine, -C (O) - (C} 1 -C 4) alkyl, - From the group consisting of C (O)-(C ₁ -C ₄ ) fluoroalkyl, —C (O)-(C ₁ -C ₄ ) alkylamine, and —C (O)-(C ₁ -C ₄ ) alkoxy. And R ³ is a moiety that is optionally substituted with H, or 1-3 independently selected substituents, wherein the substituents are ( C ₂ -C _{7) alkenyl, (C} 2 -C ₇₎ alkynyl, _{aryl, (C} 3 -C _{7) cycloalkyl,} are selected from _(C 5 -C ₇₎ cycloalkenyl, and a group consisting of heterocycle.

In other embodiments, the combination comprises a compound of formula (I) or (II) and a compound of formula (III), wherein the combination modulates serum retinol levels or activity. An additional embodiment is a combination comprising a compound of formula (I) or (II) and a compound of formula (III), wherein X ¹ is NR ² and R ² is H or (C ₁ -C ₄₎ alkyl. A further additional embodiment is a combination comprising a compound of formula (I) or (II) and a compound of formula (III), wherein x is 0. In another embodiment, the combination includes a compound of formula (I) or (II) and a compound of formula (III), x is 1 and L ¹ is —C (O) —. Yet another embodiment is a combination comprising a compound of formula (I) or (II) and a compound of formula (III), wherein R ³ is an optionally substituted heteroaryl. An additional embodiment is a combination comprising a compound of formula (I) or (II) and a compound of formula (III), wherein the compound of formula (III) is embedded image or an active metabolite thereof, or The pharmaceutically acceptable prodrug or solvate thereof.

  One embodiment is a combination comprising a compound of formula (I) or (II) and a compound of formula (III), wherein the compound of formula (III) is 4-hydroxyphenylretinamide.

  Specific and non-limiting examples of combination therapies include at least one compound of formula (I) or (II), a nitric oxide (NO) inducer, a statin, a negatively charged phospholipid, an antioxidant. Use with minerals, anti-inflammatory agents, anti-angiogenic agents, matrix metalloproteinase inhibitors, and carotenoids. In some instances, a suitable combination of agents falls within a multi-class range (although only an example, lutein is an antioxidant and a carotenoid). In addition, Formula (I) or (II) in certain embodiments is administered with an additional agent (which is by way of example but cyclosporin A) that may benefit the patient.

  Additionally, the compounds of formulas (I) and (II) in certain embodiments are used in combination with means to provide additive or synergistic utility to a patient, and by way of example only, in vitro rheopheresis. Use of rheopheresis (also known as membrane differential filtration), use of implantable micro telescopes, drusen laser photocoagulation, and microstimulation therapy.

  The use of antioxidants has been shown to benefit patients with macular degeneration and dystrophies. See, for example, Arch. Ophthalmol., 119: 1417-36 (2001); Sparrow, et al., J. Biol. Chem., 278: 18207-13 (2003). Examples of suitable antioxidants that can be used in combination with at least one compound having the structure of formula (I) or (II) include vitamin C, vitamin E, beta-carotene, and other carotenoids, coenzyme Q 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (also known as Tempol), lutein, butylated hydroxytoluene, resveratrol, trolox analog (PNU-83836-E) And bilberry extract.

  The use of certain minerals has also been shown to benefit patients with macular degeneration and dystrophies. For example, see Arch. Ophthalmol., 119: 1417-36 (2001). Examples of suitable minerals that may be used in combination with at least one compound having the structure of formula (I) or (II) include copper-containing minerals (eg, copper oxide (but by way of example)); zinc-containing minerals (For example, zinc oxide (only by way of example)); and selenium-containing compounds.

  The use of certain negatively charged phospholipids has also been shown to benefit patients with macular degeneration and dystrophies. See, for example, Shaban & Richter, Biol. Chem., 383: 537-45 (2002); Shaban, et al., Exp. Eye Res., 75: 99-108 (2002). Examples of suitable negatively charged phospholipids that can be used in combination with at least one compound having the structure of formula (I) or (II) include cardiolipin and phosphatidylglycerol. In certain embodiments, positively charged and / or neutral phospholipids may also benefit patients with macular degeneration and dystrophies when used in combination with compounds having the structure of formula (I) or (II) I will provide a.

  The use of certain carotenoids has been associated with maintaining the necessary photoprotection in photoreceptor cells. Carotenoids are naturally occurring yellow to red pigments of the terpenoid family that can be found in plants, algae, bacteria, and certain animals (eg, birds and shellfish). Carotenoids are a large class of molecules in which more than 600 naturally occurring carotenoids have been identified. Carotenoids include hydrocarbons (carotenes) and their oxidized alcohol derivatives (xanthophylls). These are actinioerythrol, astaxanthin, canthaxanthin, capsanthin, capsorubin, β-8′-apo-carotinal (apo-carotinal), β-12′-apo-carotinal, α-carotene, β-carotene , “Carotene” (a mixture of α-carotene and β-carotene), γ-carotene, β-cryptoxanthin, lutein, lycopene, biorelythrin, zeaxanthin, and esters of hydroxyl- or carboxyl-containing members thereof. Many carotenoids occur in nature in cis- and trans-isomer forms, while synthetic compounds are often racemic mixtures.

  In humans, the retina selectively accumulates two carotenoids: zeaxanthin and lutein. These two carotenoids are thought to help protect the retina. Because they are powerful antioxidants and absorb blue light. A quail study found that a group raised on carotenoid-deficient food had retinas with low levels of zeaxanthin and suffered severe photodamage (exhibited by a very large number of apoptotic photoreceptor cells) However, the group with high zeaxanthin concentration proved to have minimal damage. Examples of suitable carotenoids for combination with at least one compound having the structure of formula (I) include lutein and zeaxanthin, and any of the carotenoids described above.

  Suitable nitric oxide inducers include compounds that stimulate endogenous NO, compounds that increase the level of endogenous endothelium-derived relaxing factor (EDRF) in vivo, or compounds that are substrates for nitric oxide synthase. Such compounds include, for example, L-arginine, L-homoarginine, and N-hydroxy-L-arginine (nitrosated analogs and nitrosylated analogs thereof (eg, nitrosated L-arginine, nitrosylated L-arginine, Nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine, and nitrosylated L-homoarginine)), L-arginine and / or physiologically acceptable thereof Possible salt precursors (eg including citrulline, ornithine, glutamine, lysine, polypeptides comprising at least one of these amino acids), inhibitors of the enzyme arginase (eg N-hydroxy-L-arginine, and 2 ( S) -amino-6-boronohexanoic acid) and monoacid Substrates for oxide synthase, including cytokines, adenosine, bradykinin, calreticulin, bisacodyl, and phenolphthalein. EDRF is a vasorelaxant secreted by the endothelium and has been identified as nitric oxide or its closely related derivative (Palmer et al, Nature, 327: 524-526 (1987); Ignarro et al, Proc Natl. Acad. Sci. USA, 84: 9265-9269 (1987)).

  Statins act as lipid lowering agents and / or suitable nitric oxide inducers. Furthermore, a relationship between statin use and delayed onset or onset of macular degeneration has been demonstrated. G. McGwin, et al., British Journal of Ophthalmology, 87: 1121-25 (2003). Thus, statins can provide benefits to patients suffering from ocular diseases (eg, macular degeneration and dystrophies, and retinal dystrophy) when administered in combination with a compound of formula (I) or (II). Suitable statins are only examples, but rosuvastatin, pitivastatin, simvastatin, pravastatin, cerivastatin, mevastatin, verostatin, fluvastatin, compactin, lovastatin, dalvastatin, fluindostatin, atorvastatin, atorvastatin calcium (in atorvastatin hemi-calcium salt) And dihydrocompactin.

  In certain embodiments, suitable anti-inflammatory agents for use with compounds of formula (I) or (II) are by way of example only, but aspirin and other salicylates, cromolyn, nedocromil, theophylline, zileuton, zafirlukast, montelukast , Pranlukast, indomethacin, and lipoxygenase inhibitors; non-steroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen and naproxin); prednisone, dexamethasone, cyclooxygenase inhibitors (ie, COX such as Naproxen ™ or Celebrex ™) -1 and / or COX-2 inhibitors); statins (only by way of example, rosuvastatin, pitivastatin, simvastatin, pravastatin, cerivastatin, mevastatin, verosta) Tin, fluvastatin, compactin, lovastatin, dalvastatin, fluindostatin, atorvastatin, atorvastatin calcium (which is the hemi-calcium salt of atorvastatin), and dihydrocompactin); and isolated steroids.

In certain embodiments, a suitable matrix metalloprotease (MMP) inhibitor is administered in combination with a compound of formula (I) or (II) to treat an eye disease or condition associated with macular or retinal degeneration. MMP hydrolyzes most components of the extracellular matrix. These proteases play a central role in many biological processes such as normal tissue remodeling, embryonic development, wound healing, and angiogenesis. However, overexpression of MMP has been observed in many pathologies including macular degeneration. Many MMPs have been identified, most of which are multidomain zinc endopeptidases. Many metalloprotease inhibitors are known (see, for example, the review of MMP inhibitors by Whittaker M. et al, Chemical Reviews 99 (9): 2735-2776 (1999)). Representative examples of MMP inhibitors include metalloprotease tissue inhibitors (TIMP) (eg, TIMP-1, TIMP-2, TIMP-3, or TIMP-4), α ₂ -macroglobulin, tetracyclines (eg, tetracycline). , Minocycline, and doxycycline), hydroxamates (eg, BATIMASTAT, MARIMISTAT, and TROCAD), chelating agents (eg, EDTA, cysteine, acetylcysteine, D-penicillamine, and gold salts), synthetic MMP fragments, succinyl mercaptopurines, Contains phosphonamidates and hydroxamic acids. Examples of MMP inhibitors used in combination with a compound of formula (I) or (II) are but one example and include any of the above-mentioned inhibitors.

  The use of anti-angiogenic or anti-VEGF drugs has also been shown to provide benefits for patients with macular degeneration and dystrophies. Examples of suitable anti-angiogenic or anti-VEGF drugs that can be used in combination with at least one compound having the structure of formula (I) are Rhufab V2 (Lucentis ™), tryptophanyl-tRNA synthetase (TrpRS), Eye001 (anti-VEGF pegylated aptamer), squalamine, Retaane ™ 15 mg (Anecortab acetate for depot suspension; Alcon, Inc.), combretastatin A4 prodrug (CA4P), Macugen ™, Mifeprex (Trademark) (mifepristone-ru486), subtenon triamcinolone acetonide, intravitreal crystalline triamcinolone acetonide, purinomastert (AG3340-synthetic matrix metalloprotease inhibitor, Pfizer), fluocinolone acetonide (fluocinolone intraocular) Bausch & Lomb / Contro, including graft l Delivery Systems), VEGFR inhibitor (Sugen), and VEGF-Trap (Regeneron / Aventis). Resveratrol can be extracted from walnuts or red grapes and exhibits anti-angiogenic activity, and in certain embodiments is used as a second or additional agent for the combination therapy described herein. In addition, other trans-stilbene compounds are expected to show similar activity.

  In certain embodiments, other pharmaceutical treatments that have been used to alleviate visual impairment are used in combination with at least one compound of formula (I) or (II). Such treatments include: Visudyne®, PKC412, Endovion (NeuroSearch A / S), neurotrophic factors (eg, glial-derived neurotrophic factors and ciliary, used with non-thermal lasers Ophthalmic drug applications (echo therapy), including somatic neurotrophic factors), diatazem, dorzolamide, phototrop, 9-cis-retinal, and phospholine iodide or ecothiophosphate Or carbonic acid dehydrogenase inhibitors, AE-941 (AEterna Laboratories, INC.), Sirna-027 (Sirna Therapeutics, INC.), Pegaptanib (NeXstar Pharmaceuticals / Gilead Sciences), neurotrophin (only by way of example) NT-4 / 5, including Genentech), Cand5 (Acuity Pharmaceuticals), Ranibizumab (Genentech), INS-37217 (Inspire) Pharmaceuticals), integrin antagonists (including those from Jerini AG and Abbott Laboratories), EG-3306 (Ark Therapeutics LTD.), BDM-E (BioDiem LTD.), Thalidomide (eg, used by EntreMed, INC.) , Cardiotrophin-1 (Genentech), 2-methoxyestradiol (Allergan / Oculex), DL-8234 (Toray Industries), NTC-200 (Neurotech), tetrathiomolybdate (University of Michigan), LYN-002 ( Lynkeus Biotech), microalgal compounds (Aquasearch / Albany, MeraPharmaceuticals), D-9120 (Celltech Group plc), ATX-S10 (Hamamatsu Photonics), TGF-beta2 (Genzyme / Celtrix), tyrosine kinase inhibitors (Allergan, SUGEN, Pfizer), NX-278-L (NeXstar Pharmaceuticals / Gilead Sciences), Opt-24 (OPTIS France SA), retinal ganglion neuroprotective agent (Cogent Neurosciences), N-Ni Ropirazoru derivatives (Texas A & M University System), KP-102 (Krenitsky Pharmaceuticals), and including cyclosporin A, but not limited to. See U.S. Patent Application Publication No. 20040092435.

  In any case, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order in certain embodiments. Or even at the same time. When administered simultaneously, the plurality of therapeutic agents in certain embodiments may be in a single and integrated form or in multiple forms (either by way of example only, but a single pill or two separate pills). Provided. One of the therapeutic agents in certain embodiments can be given in multiple doses, or both can be given as multiple doses. If not administered simultaneously, the timing between multiple doses varies from greater than 0 weeks to less than 4 weeks. Furthermore, combination methods, compositions and formulations are not limited to the use of only two agents; we envision the use of multiple therapeutic combinations. By way of example only, a compound having the structure of formula (I) or (II) is provided with at least one antioxidant and at least one negatively charged phospholipid; or alternatively, formula (I) or ( The compound having the structure of II) is provided with at least one antioxidant and at least one inducer of nitric oxide production; or alternatively, the compound having the structure of formula (I) or (II) is Provided with at least one inducer of nitric oxide production and at least one negatively charged phospholipid;

  Further, the compounds of formula (I) or (II) in certain embodiments are used in combination with procedures that provide an additive or synergistic benefit to the patient. Procedures to reduce visual impairment include "limited retinal movement", photodynamic therapy (but by way of example, receptor-targeted PDT, Bristol-Myers Squibb, Co .; porfimer sodium for infusion with PDT; verteporfin (QLT INC.); Rostaporfin with PDT (Miravent Medical Technologies); Talaporfin sodium with PDT (including Nippon Petroleum; Motexafine lutetium (Pharmacyclics, Inc.)), antisense oligonucleotide (only one example) Including products tested by Novagali Pharma SA and ISIS-13650 (Isis Pharmaceuticals), laser photocoagulation therapy, drusen laser therapy, macular hole surgery, macular transfer surgery, miniature implantable telescope, phi-motion vessels Phi-Motion Angiography (Micro Laser Therapy and Nutrition Vascular Treatment (Feeder Ve) also known as ssel treatment), proton therapy, microstimulation therapy, retinal detachment and vitreous surgery, scleral buckle, submacular surgery, transpupillary hyperthermia, photosystem I therapy, RNA interference ( Use of RNAi), in vitro rheopheresis (also known as membrane fractionation filtration and rhetherapy), microchip transplantation, stem cell therapy, gene replacement therapy, ribozyme gene therapy (gene therapy for hypoxia response elements ( Oxford Biomedica); Lentipak (Genetix); including PDEF gene therapy (GenVec), photoreceptor / retinal cell transplant (implantable retinal epithelial cells (Diacrin, Inc.); retinal cell graft (CELL Genesys, Inc.). )), As well as acupuncture.

  Additional combinations used to benefit an individual include using genetic testing to determine whether the individual is a carrier of a mutated gene that correlates with a particular eye disease. By way of example only, deficiencies in the human ABCA4 gene are thought to be associated with five different retinal phenotypes, including Stargardt disease, cone-rod dystrophy, age-related macular degeneration, and retinitis pigmentosa. For example, Allikmets et al., Science, 277: 1805-07 (1997); Lewis et al., Am. J. Hum. Genet., 64: 422-34 (1999); Stone et al., Nature Genetics, 20 : 328-29 (1998); Allikmets, Am. J. Hum. Gen., 67: 793-799 (2000); Klevering, et al, Ophthalmology, 111: 546-553 (2004). Furthermore, the autosomal dominant form of Stargardt disease is caused by mutations in the ELOV4 gene. See Karan, et al., Proc. Natl. Acad. Sci. (2005). Patients with any of these mutations are expected to find therapeutic and / or prophylactic benefits in the methods described herein.

  Further, in certain embodiments, a compound of formula (I) or (II) that results in a decrease in serum retinol levels, or other agent, together with an agent that treats or reduces side effects caused by retinol reduction (previous, moderate) Or means later). Such side effects include dry skin and dry eyes. Thus, an agent that reduces or treats either dry skin or dry eyes, in certain embodiments, is administered with Formula (I) or (II) or other agents that reduce serum retinol levels.

<Example>
The following examples provide example methods for the synthesis of compounds of formula (I) or (II). These examples are for illustrative purposes only and are not intended to limit the scope of the claims set forth herein.

<Analytical LC / MS method>:
Method A:
Instrument: Waters UPLC / MS with UV detector (220 nM) and MS detector (ESI)
HPLC column: Waters Acquity BEH C18, 1.7 μm 2.1 mm x 50 mm
HPLC gradient: 0.6 mL / min, 95: 5 20 mM ammonium formate buffer in 1.5 min (pH 7.4 with ammonium hydroxide): acetonitrile to 20:80 ammonium formate buffer: acetonitrile , Maintained for 1.3 minutes.

Method B:
Instrument: Waters LC / MS with DAD detector (220 and 254 nM) and MS detector (ESI)
HPLC column: Merck LiChroCART 30-4 Purospher STAR RP-18, with end cap, 3 μm 4.6 mm × 50 mm
HPLC gradient: 1.5 mL / min, 95: 5 20 mM ammonium formate buffer in 2.5 minutes (pH 7.4 with ammonium hydroxide): acetonitrile to 5:95 ammonium formate buffer: acetonitrile , Maintained for 1.8 minutes.

Method C:
Instrument: Waters Alliance with UV detector (220 nM) and MS detector (ESI)
HPLC column: Waters XTerra MS C18, 5 μm 4.6 mm x 50 mm
HPLC gradient: 2 mL / min from 95: 5 water + 5% formic acid: acetonitrile + 5% formic acid in 0.5 min and 5:95 aqueous: organic in 5 min and maintained for 0.5 min.

<Example 1: Synthesis of 5- (2-tert-butyl-4-chlorophenoxy) pentanoic acid>

Methyl 5-bromovaleric acid (1.52 mL, 2.09 g, 10.7 mmol), 2-tert-butyl-4-chloro-phenyl (2.4 g, 13 mmol) and potassium carbonate (1.4 g, 10.1 mmol) Is suspended in dry DMF (10 ml) and stirred at 120 ° C. for 2 hours. To the resulting mixture, water is added (80 ml) and extracted with ethyl acetate (3 × 20 mL). The organic layer was washed twice with 10% sodium hydroxide (2 × 20 ml), washed with water (1 × 20 ml), dried over sodium sulfate and evaporated under vacuum. 3.46 g (quantity) of crude 1a is provided and used in the next step without the need for additional purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.21 (d, J = 2.6 Hz, 1H), 7.10 (dd, J = 8.6, 2.6 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 3.97 (t, J = 5.8 Hz, 2H), 2.46 (t, J = 6.9 Hz, 2H), 1.84-1.94 (m, 4H), 1.36 (s, 9H).

A mixture of 1a (3.46 g) and 10% sodium hydroxide (10 ml) in dioxane (50 ml) is stirred overnight at room temperature. Dioxane is removed under vacuum. The remaining mixture is diluted with water and extracted with ethyl acetate (2 × 20 ml). The pH of the aqueous layer is adjusted to 4 with concentrated hydrochloric acid and extracted with chloroform (1 × 20 ml). The combined organic layers were dried over sodium sulfate and evaporated under vacuum. The product was triturated with hexane to yield 1.87 g (61% calculated from methyl 5-bromovaleric acid) of white crystals 1-1. mp. 95.4-96.4 ℃, ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.21 (d, J = 2.6 Hz, 1H), 7.10 (dd, J = 8.6, 2.6 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 3.97 (t, J = 5.8 Hz, 2H), 2.46 (t, J = 6.9 Hz, 2H), 1.84-1.94 (m, 4H), 1.36 (s, 9H).

  The following compounds are prepared by the above procedure using 2-tert-butyl-4-chlorophenol and a suitable methanesulfonyl ester.

  The following compounds are prepared according to the above procedure using 2-tert-butyl-4-chlorophenol, using a suitable bromoester and cesium carbonate as a base for the first step and lithium hydroxide for the second step. Is done.

<Example 2: Synthesis of 5- (2-tert-butyl-4-chlorophenoxy) -N- (4-hydroxyphenyl) pentanamide>

  A mixture of 1-1 (0.3 g, 1.05 mmol) and carbonyldiimidazole (0.18 g, 1.11 mmol) is stirred in dichloroethane (2.5 ml) for 30 minutes. Then 4-aminophenol (0.136 g, 1.25 mmol) and N, N-diisopropylethylamine (220 μL, 1.25 mmol) are added. The resulting solution is stirred for an additional 4 hours. The solvent is evaporated and the remaining mixture is diluted with 20 ml of ether and washed with 1M hydrochloric acid (1 × 20 ml). The organic layer is dried over sodium sulfate and the solvent is evaporated. The product is triturated with diisopropyl ether to yield 2-1 (6 mg, 25%).

<Example 3: Synthesis of 4- (5- (2-tert-butyl-4-chlorophenoxy) pentanamide) benzoic acid>

  A mixture of 1-1 (0.25 g, 0.88 mmol) and oxalyl chloride (0.12 g, 0.95 mmol) in dichloroethane (5 ml) is stirred for 48 hours at room temperature. The solvent is removed under vacuum and the residue is dissolved in dichloroethane. To this solution is added methyl 4-aminobenzoate (0.146 g, 0.96 mmol) and N, N-diisopropylethylamine (350 μL, 2.0 mmol) and stirred at room temperature overnight. The mixture is washed with 20 mL 10% hydrochloric acid. The organic acid is dried over sodium sulfate and the solvent is removed in vacuo to yield 0.25 g (69%) of 3-1. LCMS: Method A, Rt: 1.85 min, M + H = 418.

  The following compounds are prepared using the procedure described above and use either oxalyl chloride or thionyl chloride.

<Example 4: Synthesis of methyl 3- (3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclopentane-carboxamido) cyclohexanecarboxylic acid>

  A solution of 1-2 (0.109 g, 0.354 mmol), N-hydroxybenzotriazole (0.053 g, 0.35 mmol), and EDC HCl (0.067 g, 0.35 mmol) in dry DMF was stirred at room temperature for 40 minutes. And then methyl 3-aminocyclohexanecarboxylate hydrochloride (0.075 g, 0.385 mmol) and triethylamine (54 μL, 0.385 mmol) were added and stirring continued for 4 hours. The reaction mixture is diluted with 5% sodium bicarbonate (20 ml) and extracted with dichloromethane (3 × 20 ml). The combined organic layers are washed with 10% hydrochloric acid (1 × 20 ml), brine (2 × 20 ml) and dried over sodium sulfate. The solvent is removed under vacuum and the oily residue is purified by flash chromatography on Kieselgel 60H using chloroform as the eluent to yield 0.1 g (63%) of 4-1 as a pale yellow oil. LCMS: Method A, Rt: 1.98 min, M + H = 450.

  The following compounds are prepared using the above procedure and using the appropriate amine.

<Example 5: Synthesis of 4- (5- (2-tert-butyl-4-chlorophenoxy) pentanamide) benzoic acid>

A mixture of 3-1 (0.25 g, 0.59 mmol) and sodium hydroxide (1M, 3 mL) is stirred overnight at room temperature. The pH is adjusted to 4 with 1M hydrochloric acid. The solution is extracted with 20 ml of dichloromethane. The organic layer is dried over sodium sulfate and the solution is removed under vacuum to yield 5-1 (0.2 g, 83%). LCMS: Method B, Rt: 2.08 min, M + H ₂ O = 421.

  The following compounds are prepared using the above procedure and using the appropriate ester.

  The following compounds are prepared from the appropriate ester using the procedure described above. Heat at 50 ° C. during the hydrolysis step.

Example 6 Synthesis of N- (4- (2-tert-butyl-4-chlorophenoxy) butyl) -4-hydroxy-3- (morpholinomethyl) -benzamide

  To a solution of Boc-4-aminobutanol (5.07 g, 26.8 mmol) and triethylamine (7.5 mL, 53.6 mol) in dichloroethane (60 ml) was added methanesulfonyl chloride (2.3 mL, 29.5 mmol) at 0 ° C. Is added. After the addition is complete, the mixture is stirred for an additional 10 minutes. The reaction mixture is washed with 30 ml of chilled saturated sodium bicarbonate and the organic layer is dried over magnesium sulfate. The solvent is evaporated to produce 9.9 g crude 6a as a yellow oil. This crude product is used in the next step.

  To a mixture of 2-tert-butyl-4-chlorophenol (4.0 g, 21.7 mmol) and potassium carbonate (6.0 g, 43.4 mol) in dry DMF (40 mL) was added 24a (9 .9 g, mmol) is added as droplets at 60 ° C. The resulting mixture is stirred at 60 ° C. overnight. The mixture is poured into water and extracted with 20 mL of ethyl acetate. The organic layer is dried over sodium sulfate and the solvent is removed under vacuum. The crude product (8.3 g) is purified by column chromatography using hexane / dichloromethane (1: 1) followed by gradient elution with dichloromethane to yield 2.41 g (31%) of 6b.

  A mixture of 6b (2.41 g, 6.8 mmol) and HCl in dioxane (15 ml, 6.5 M) is stirred overnight. The mixture is evaporated and the residue is recrystallized from a mixture of diethyl ether and ethyl acetate to yield 1.41 g (81%) of 6c.

  4- (2-tert-butyl-4-chloro-phenoxy) -butylamine hydrochloride (0.102 g, 0.35 mmol), 4-hydroxy-3-morpholin-4-ylmethyl-benzoic acid (0.091 g) in dry DMF , 0.385 mmol), triethylamine (54 μL, 0.385 mmol), N-hydroxybenzotriazole (0.059 g, 0.385 mmol), EDC HCl (0.074 g, 0.385 mmol) was stirred for 3 hours at room temperature. Is done. 20 mL of 5% sodium bicarbonate solution is added and the reaction is extracted with dichloromethane (3 × 20 mL). The combined organic layers are washed with 10% hydrochloric acid (1 × 20 mL), brine (2 × 20 mL) and dried over sodium sulfate. The solvent is removed in vacuo and the residue is triturated with a mixture of diethyl ether and ethyl acetate. The crude product is purified by flash chromatography (Kieselgel 60H) using chloroform: methanol (10: 3) as eluent. Product: 0.070 g (42%) 6-1. LCMS: Method A, Rt: 1.80 min, M + H = 475).

  The following compounds are prepared with the appropriate acid by the above procedure.

<Example 7: Synthesis of 4- (4- (2-tert-butyl-4-chlorophenoxy) butylcarbamoyl) benzoic acid>

  6c (0.117 g, 0.40 mmol), terephthalic acid mono-tert-butyl ester (0.098 g, 0.44 mmol), triethylamine (62 μL, 0.44 mmol), N-hydroxybenzotriazole (5 mL) in dry DMF (5 mL) A mixture of 0.067 g, 0.44 mmol) and EDC HCl (0.084 g, 0.44 mmol) is stirred for 1 hour at room temperature. 5% sodium bicarbonate solution is added (20 mL) and the mixture is extracted with dichloromethane (3 × 20 mL). The combined organic layers are extracted with 10% hydrochloric acid (1 × 20 ml), brine (2 × 20 mL) and dried over sodium sulfate. The solvent is removed under vacuum to produce 0.246 g of crude 7a.

  Ester 7a is dissolved in 5 mL dioxane. 4 ml of 6.5M hydrogen chloride in dioxane are added and the mixture is stirred for 24 hours at room temperature. The reaction mixture is poured into water and extracted with dichloromethane (2 × 20 mL). The combined organic layers are washed with water (1 × 20 mL), dried over sodium sulfate and the solvent is evaporated. Product 7-1 is crystallized from ether / hexane, filtered and washed several times with ether / hexane, yielding 0.127 (59%) of white crystals 25-1. LCMS: Method A, Rt: 1.36 min, M + H = 404.

  The following compounds are made by the above procedure.

<Example 8>
The following compounds are made by the procedures described herein.

  The following examples provide example methods for testing the utility and safety of compounds of formula (I) or (II). These examples are for illustrative purposes only and are not intended to limit the scope of the claims set forth herein.

<Mouse and rat studies>
The optimal amount of a compound of formula (I) or (II) to inhibit A2E formation in abca4 ^{− / −} mice is determined using standard dose escalation studies. High-throughput in vitro assays that detect modulators that inhibit RBP-TTR interaction have been developed to determine the dose range to use. The drug concentration causing 50% inhibition (IC ₅₀ value) of the RBP-TTR interaction is calculated from the data. In these experiments, fenretinide was taken as a positive control, which is known as a potent inhibitor of RBP-TTR interaction. Representative data from a typical dose-response experiment is shown in FIG. Illustrative in vivo procedures using compounds having the structure of formula (I) or (II) are shown below.

  The effect of the compound of formula (I) or (II) on all-trans-retinal in the retina from light-adapted mice is determined at doses encompassing human therapeutic doses. This method involves treating the mouse with a single morning intraperitoneal administration. In certain embodiments, increased infusion frequency is necessary to keep all-trans-retinal levels in the retina much lower throughout the day.

(ABCA4 knockout mouse)
ABCA4 encodes the rim protein (RmP), which is an ATP-binding cassette (ABC) transporter in the outer disc of rod and cone photoreceptors. The transport substrate for RmP is not known. Mice made to have a knockout mutation in the abca4 gene (see Weng et al., Cell, 98: 13-23 (1999)) are useful for studying RmP function and demonstrate the effectiveness of candidate substances in vivo. It is also useful for screening with. These animals clearly exhibit a complex eye phenotype: (i) slow photoreceptor degeneration, (ii) delayed recovery of rod sensitivity after exposure, (iii) in photoreceptor outer segments after photobleaching increased atRAL and decreased atROL, (iv) elevated phosphatidylethanolamine (PE) structurally in the outer segment, and (v) accumulation of lipofuscin in RPE cells. See Weng et al., Cell, 98: 13-23 (1999).

The rate of photoreceptor denaturation is monitored by two approaches in treated and untreated wild-type and abca4 ^{− / −} mice. One is the study of mice at different times by ERG analysis, taken from clinical diagnostic procedures. See Weng et al., Cell, 98: 13-23 (1999). An electrode is placed on the corneal surface of an anesthetized mouse and the electrical response to the flash is recorded from the retina. The amplitude of the α wave is the result of light-induced hyperpolarization of the photoreceptor and is a sensitivity indicator for photoreceptor degeneration. See Kedzierski et al., Invest. Ophthalmol. Vis. Sci., 38: 498-509 (1997). ERG is performed on live animals. In certain embodiments, the same mouse is analyzed repeatedly during the time course study. A definitive technique for quantifying photoreceptor degeneration is histological analysis of retinal sections. The number of photoreceptors remaining in the retina at each time point is determined by counting the rows of photoreceptor nuclei in the outer granule layer.

(Tissue extraction)
The eye samples are thawed on ice to 1 ml PBS (pH 7.2) and homogenized by hand using a Dual glass-glass homogenizer. The sample is further homogenized after the addition of 1 ml chloroform / methanol (2: 1, v / v). The sample is transferred to a borosilicate tube and the lipid is extracted into 4 ml of chloroform. The organic extract is washed with 3 ml of water, after which the sample is centrifuged at 3000 × g for 10 minutes. The chloroform phase is gently moved and the aqueous phase is re-extracted with another 4 ml of chloroform. After centrifugation, the chloroform phase is combined and the sample is dried under nitrogen gas. The sample residue is resuspended in 200 μl 2-propanol and analyzed by HPLC as described below.

(HPLC analysis)
Chromatographic separation is performed on an Agilent Zorbax Rx-Sil column (5 μm, 4.6 × 250 mm) using an Agilent 1100 series liquid chromatograph equipped with fluorescence and diode array detectors. The mobile phase is delivered at a desired rate in a defined amount per minute. Sample peak identification is done by comparison with authentic reference duration and absorbance spectra. Data is reported as the fluorescence peak (L.U.) obtained from the fluorescence detector.

  Administration of the compound of formula (I) or (II) to the experimental group of mice and DMSO alone to the control group of mice are performed and the accumulation of A2E is analyzed. Experimental groups receive about 2.5 to about 20 mg / kg of the compound of formula (I) or (II) per day in about 10 to about 25 μl of DMSO. If no effect is seen at the highest dose of about 50 mg / kg, a higher dose is tested. Control groups are injected with 10-25 μl of DMSO alone. Mice are given either experimental or control material by intraperitoneal (i.p.) infusion and are administered during the chronic dosage regimen.

abca4 ^{− / −} mice To analyze the accumulation of A2E in RPE, 2.5 to 20 mg / kg of compound of formula (I) or (II) per day was applied to 2 month old abca4 ^{− / −} mice. It is given by intraperitoneal administration. After a period of time, experimental and control mice are killed and APE levels of RPE are measured by HPLC.

<Example 9: Effect of test compound on rod cell death or rod dysfunction>

  Administration of the compound of formula (I) or (II) to the experimental group of mice and DMSO alone to the mouse control group were carried out, and the effect of the test compound on rod cell death or rod dysfunction was carried out. And analyzed. Experimental groups are given about 2.5 to about 20 mg / kg of the compound of formula (I) or (II) per day in about 10 to about 25 μl of DMSO. If no effect is seen at the highest dose of about 50 mg / kg, a higher dose is tested. Control groups are injected with 10-25 μl of DMSO alone. Mice are administered either experimental or control material by intraperitoneal (i.p.) injection at various experimental time points. Alternatively, mice are implanted with a pump that delivers experimental or control material at a rate of about 0.25 μl / hour for various experimental times.

  Mice treated with about 2.5 to about 20 mg / kg of compound of formula (I) or (II) per day for about 8 weeks can be monitored by monitoring ERG recordings and performing retinal histological diagnosis. The effect of the compound of formula (I) or (II) on rod cell death or rod dysfunction is analyzed.

<Example 10 Inspection for protection from light damage>
The following study is from Sieving, PA, et al, Proc. Natl. Acad. Sci., 98: 1835-40 (2001). For chronic exposure light studies, 7 week old Sprague-Dawley male albino rats are housed in 5 lux fluorescent white light in a 12:12 hour light / dark cycle. About 20 to about 50 mg / kg of a compound of formula (I) or (II) in 0.18 ml DMSO is administered intraperitoneally (ip) to chronic rats three times daily for 8 weeks. Controls receive 0.18 ml DMSO by intraperitoneal (ip) injection. Rats are killed 2 days after the final injection. If no effect is seen at the highest dose of about 50 mg / kg, a higher dose is tested.

  For acute exposure light studies, rats are dark-adapted overnight and about 20 to about 50 mg / kg of test compound in 0.18 ml DMSO is injected once intraperitoneally (ip) under a dark red light, It is maintained for 1 hour in the dark before being exposed to decolorizing light before ERG measurement. Rats are exposed to 2000 lux fluorescent white light for 48 hours. An ERG is recorded after 7 days and a histological diagnosis is performed immediately thereafter.

  Rats are euthanized and eyes are removed. The outer granule layer thickness and rod outer cell number (ROS) length are measured every 200 μm across both hemispheres. The numbers are then averaged to obtain a measurement of cell changes throughout the retina. ERGs are recorded from chronic rats at 4 and 8 weeks of treatment. In acute rodents, rod recovery from depigmented light is followed by dark-adapted ERGs using stimuli that do not elicit cone contributions. Cone recovery is monitored using light-adapted ERGs. Prior to ERG, animals are made with a dark red light and anesthetized. The pupil is dilated and ERG is recorded simultaneously from both eyes using a gold wire corneal loop.

<Example 11: Combination therapy including fenretinide>
Mice and / or rats are tested in the manner described in Examples 8 and 9, except that two more arms are used. In one additional arm, groups of mice and / or rats are treated with increasing doses of fenretinide from 5 mg / kg per day to 50 mg / kg per day. In the second additional arm, groups of mice and / or rats are treated with a combination of 20 mg / kg test compound per day and increasing doses of fenretinide from 5 mg / kg per day to 50 mg / kg per day. The The benefits of combination therapy are analyzed as described in Examples 8 and 9.

Example 12: Efficacy of test compound on accumulation of lipofuscin (and / or A2E) in abca4 null mutant mice: phase I-dose response and effect on serum retinol>
By the effect of compounds of formula (I) or (II) on serum retinal reduction in animal and human subjects, we explore the possibility that a reduction in lipofuscin and the toxic bis-retinoid conjugate A2E can also be realized. Became. The principle for this approach depends on two independent strains of scientific evidence: 1) reduction of the vitamin A concentration in the eye via inhibition of a known visual cycle enzyme (11-cis retinol dehydrogenase) It produces a marked decrease in A2E; 2) animals maintained on a vitamin A deficient diet show a dramatic decrease in lipofuscin accumulation. Therefore, the purpose of this example is to test the effects of compounds of formula (I) or (II) in animal models that show a huge accumulation of lipofuscin and A2E in the eye tissue of abca4 null mutant mice. .

  The initial study begins by examining the effect of a compound of formula (I) or (II) on serum retinol. Animals are divided into groups and given either DMSO or about 20 mg / kg of a compound of formula (I) or (II) for at least 14 days. At the end of the study period, blood is collected from the animals, serum is prepared, and acetonitrile extracts of serum are analyzed by reverse phase LC / MS. Perform UV-visible spectrum and mass / charge analysis to confirm the identity of the elution peak. Representative chromatographic data showing serum retinol levels in mice treated with either DMSO or a compound having the structure of formula (I) is shown in FIG. Also, the steady-state serum concentration of the test compound (structure consistent with chemical formula (I)) is determined by HPLC (see FIG. 3). Furthermore, the level of RBP4 in serum is quantified by immunoblotting (see FIG. 4).

  Administering an agent (s) that lowers serum retinol levels in a patient without modulating at least one enzyme in the visual cycle provides treatment for macular and / or retinal dystrophy or related symptoms To do. Assays as described herein, in certain embodiments, to further select agents having this effect (agents selected from compounds having a structure of formula (I) or (II) to be selected). used.

Example 13: Efficacy of test compounds against accumulation of lipofuscin (and / or A2E) in abca4 null mutant mice: chronic treatment of phase II-abca4 null mutant mice>
Studies are conducted to evaluate the effect of compounds of formula (I) or (II) on the reduction of A2E and A2E precursors in abca4 null mutant mice. Compounds of formula (I) or (II) are administered daily in DMSO (about 20 mg / kg, ip) to abca4 null mutant mice (BL6 / 129, 2 months old) for at least 28 days. Age / strain matched control mice receive DMSO vehicle only. Mice are sampled at day 0, 14, and 28 (n = 3 per group), their eyes are removed, and chloroform soluble components (lipids, retinoids and lipid-retinoid complexes) are extracted. Mice are sacrificed by cervical dislocation, their eyes are removed and individually snap frozen in cryovials. The sample extract is then analyzed by HPLC with on-line fluorescence detection. A representative chromatographic output record obtained from the eyecup extract of abca4 null mutant mice is shown in FIG. Similar studies are conducted to ascertain the effect of treatment with compounds of formula (I) or (II) on electroretinography and morphological phenotypes.

<Example 14: Combination therapy including test compound and statin>
Mice and / or rats are tested in the manner described in Examples 8 and 9, except that two more arms are used. In one further arm, groups of mice and / or rats are treated with an optimal dose of the appropriate statin based on weight, eg: Lipitor® (atorvastatin), Mevacor® (lovastatin), Pravachol ® (pravastatin sodium), Zocor ™ (simvastatin), Leschol (fluvastatin sodium), and the like. In the second further arm, the group of mice and / or rats is combined with about 20 mg / kg of the compound of formula (I) or (II) per day and the increasing dose of statin used in the previous step. Be treated with. Recommended human doses of such statins are, for example, about 10 to about 80 mg / day for Lipitor® (atorvastatin), about 10 to about 80 mg / day for Mevacor® (lovastatin), Pravachol® ) (Pravastatin sodium) from about 10 to about 40 mg / day, Zocor ™ (simvastatin) from about 5 to about 80 mg / day, and Leschol (fluvastatin sodium) from about 20 to about 80 mg / day. The dose of statins for mouse and / or rat subjects should be determined based on weight. The benefits of combination therapy are analyzed as described in Examples 8 and 9.

<Example 15: Combination therapy including test compound, vitamin, and mineral>
Mice and / or rats are tested in the manner described in Example 13 and selected vitamins and minerals are used. Administration of a compound of formula (I) or (II) with vitamins and minerals is administered either orally or parenterally in an amount effective to inhibit the progression or recurrence of macular degeneration. The The test amount is initially about a compound of formula (I) or (II) in the range of about 20 mg / kg per day, about 100 to about 1000 mg of vitamin C, about 100 to about 600 mg of vitamin E, about 10,000. From about 40,000 IU of vitamin A, about 50 to about 200 mg of zinc, and about 1 to about 5 mg of copper, performed for 15 to 20 weeks. The benefits of combination therapy are analyzed as described in Examples 8 and 9.

<Example 16: Analysis of serum retinol depending on test compound concentration>

  ABCA4 null mutant mice were given daily doses of compounds of formula (I) or (II) in DMSO (i.p.) for 28 days (n = 4 mice per dose group). At the end of the study period, a blood sample is taken and serum is prepared. After acetonitrile precipitation of serum proteins, the concentration of retinol and the compound of formula (I) or (II) is measured from the soluble phase by LC / MS. The identity of the eluted compound was confirmed by UV-visible absorption spectroscopy and co-elution of sample peaks with true standards (see FIG. 2).

<Example 17: Identification of a compound that binds to TTR and / or inhibits gene expression of TTR>
Purified TTR polypeptide containing glutathione-S-transferase protein and adsorbed on a glutathione derivatized well of a 96-well microtiter plate is converted into a test compound from a small molecule library in a physiological buffer solution at pH 7.0. Contact with. Purified TTR polypeptides have been disclosed as prior art. See U.S. Patent Application No. 20020160394. This is incorporated herein by reference. The test compound in certain embodiments includes a fluorescent tag. Samples are incubated for 5 minutes to 1 hour. Control samples are cultured in the absence of test compound.

  Buffer containing the test compound is washed from the well. Binding of the test compound to the TTR polypeptide is detected by fluorescence measurement of the contents of the well. A test compound that increases fluorescence in the well by at least 15% compared to the fluorescence of a well in which the test compound is not cultured is identified as a compound that binds to the TTR polypeptide.

  In certain embodiments, the identified test compound is administered to a culture of human cells transfected with a TTR expression construct and incubated at 37 ° C. for 10 to 45 minutes. Untransfected cultures of allogeneic cells are cultured for the same time without the test compound and serve as negative controls.

RNA is then isolated from the two cultures as described in Chirgwin et al., Biochem. 18, 5294-99, 1979. Northern blots are prepared using 20-30 μg total RNA and hybridized with a ³² P-labeled TTR-specific probe. Probes for detecting TTR mRNA transcription have been previously described. A test compound that decreases the TTR-specific signal compared to the signal obtained in the absence of the test compound is identified as an inhibitor of TTR gene expression.

<Example 18: Identification of a compound that binds to RBP and / or inhibits RBP gene expression>
Purified apo RBP is contacted with a test compound from a small molecule library in a physiological buffer solution at pH 7.0. Purified apo RBP has been disclosed as prior art. See U.S. Patent Application No. 200301197715. This is incorporated herein by reference. The test compound in certain embodiments includes a fluorescent tag. Samples are incubated for 5 minutes to 1 hour. Control samples are cultured in the absence of test compound. In some embodiments, a competition assay in the presence of holo RBP (RBP complexed with retinol) is also performed.

  A buffer solution containing the test compound is washed from the well. Binding of the test compound to the apo RBP is detected by fluorescence measurement of the contents of the well. A test compound that increases the fluorescence in the well by at least 15% compared to the fluorescence of the well in which the test compound is not cultured is identified as a compound that binds to apoRBP.

  The identified test compound is administered to a culture of human cells transfected with an RBP expression construct and incubated at 37 ° C. for 10 to 45 minutes. Untransfected cultures of allogeneic cells are cultured for the same time without the test compound and serve as negative controls.

RNA is then isolated from the two cultures as described in Chirgwin et al., Biochem. 18, 5294-99, 1979. Northern blots are prepared with about 20 to about 30 μg of total RNA and hybridized with a ³² P-labeled RBP-specific probe. A test compound that decreases the RBP-specific signal compared to the signal obtained in the absence of the test compound is identified as an inhibitor of RBP gene expression.

Example 19: Further Analysis of Test Compound Effect on Serum Retinol, Eyecup Retinoid, and A2E Levels
(Treatment of the compound of formula (I) or (II))
Compounds of formula (I) or (II) are administered daily (about 1.5 to about 15 μg / μl in 25 μl DMSO intraperitoneally (ip)) to abca4 − / − mice for 28 days. The mice are 1-2 months of age at the start of the study and are either pigmented (129 / SV) or albino (BALB / c) strains. Mice were housed under 12-hour light / dark (30-50 lux) during the treatment period and before death due to cervical dislocation, in addition to ketamine (about 200 mg / kg) xylazine (about 10 mg / kg). Anesthetized by intraperitoneal (ip) injection.

(Analysis of serum retinol)
Whole blood is collected from the tail vein of mice treated with test compound 18 hours after the last dose of test compound (ie day 28). Serum is obtained from whole blood after centrifugation at 1,500 × g for 10 minutes. Serum proteins are precipitated by the addition of an equal volume of ice-cold acetonitrile and centrifugation (10,000 × g, 10 minutes). Aliquots (aliquots) are removed from the soluble phase and analyzed by HPLC using an Agilent 1100 series capillary liquid chromatography equipped with a diode array detector. Chromatography is performed as described above.

(Extraction and analysis of retinoid and A2E)
Steady state levels of retinoid and A2E in the eyecup of ABCA4 − / − mice are determined after daily administration (28 days) of compounds of formula (I) or (II). Mice are sacrificed, eyes are removed, and the back of each eye is used for extraction of retinol or A2E. Techniques and HPLC analysis techniques used to extract retinoids and A2E from eye tissue have been disclosed. For example, Mata NL, Weng J, Travis GH.Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration.Proc Natl Acad Sci US A. 2000; 97: 7154-7159; Weng J, et al .; Cell. 1999; 98: 13-23; Mata NL, et al .; Invest. Ophthalmol. Visual Sci. 2001; 42: 1685-1690. All samples are analyzed by HPLC using absorbance and fluorescence detection. In these analyses, a column thermostat is used to maintain the solvent and column temperature at 40 ° C. The identity of the compounds shown is confirmed by on-line spectral analysis and by co-elution with true criteria.

(Correlation between serum retinol, ocular retinoid, and A2E)
The data collected shows a direct correlation between the reduction of serum retinol and the reduction of retinoid and A2E levels in the mammalian eye cup. In particular, serum retinol reduction follows both ocular retinoid levels and ocular A2E levels in a dose-dependent manner. For example, a decrease in mammalian serum retinol levels by a compound of formula (I) or (II) indicates that the decrease in serum retinol affects the level of substances associated with retinopathy and retinal degeneration / dystrophy (eg, A2E) Is shown. Thus, agents that cause serum retinol reduction as described herein are also used, in certain embodiments, to reduce A2E and retinoid levels in the eye, and further to lipofuscin-based retinal diseases (eg, , Retinopathy, and macular degeneration / dystrophy).

<Example 20: Verification of RBP as a therapeutic target for inhibiting accumulation of A2E>
Investigations of non-pharmaceutical approaches to reduce lipofuscin fluorophore molecules will be conducted to validate therapeutic approaches based on reduced RBP levels in patients. In this study, RBP protein levels will be reduced by genetic manipulation. Two new strains of mice expressing heterozygous mutations in retinol binding protein (RBP4) are created. The first line has heterozygous mutations only at the RBP locus (RBP +/−); the second line has heterozygous mutations at both the ABCA4 and RBP4 loci (RBP4 +/−, ABCA4 +/−). RBP +/− mice are wild type at the ABCA4 locus and therefore do not accumulate excessive amounts of A2E fluorophore molecules. However, ABCA4 +/− mice accumulate A2E fluorophore molecules at a level of about 50% of the amount observed in ABCA4 − / − (null homozygous) mice. The immediate question is whether reducing RBP expression in RBP4 +/−, ABCA4 +/− mice affects the accumulation of toxic retinal fluorophores (eg, A2E). FIG. 6 (Panel A) shows a dramatic decrease (> 50%) in serum retinol in RBP4 +/−, ABCA4 +/− mice compared to RBP4 + / +, ABCA4 − / − mice. The degree of retinol reduction in RBP4 +/−, ABCA4 +/− mice is comparable to the degree of retinol reduction observed in RBP4 + / +, ABCA4 − / − mice administered HPR for 28 days. Immunoblot analysis of RBP4 levels in the sera of these mice is consistent with the retinol data (Figure 6, Panel B).

The levels of A2E and precursor fluorophore molecules (A2PE and A2PE-H ₂ ) in mice with genetically reduced RBP4 expression (RBP4 +/−, ABCA4 +/−) were monitored monthly over 3 months, and RBP4 + / +, Compared to fluorophore levels in ABCA4 +/− mice. Overall, RBP4 +/−, ABCA4 +/− mice reduce their total fluorophore molecule levels by ˜70% compared to the levels present in ABCA4 +/− (panels D and C, respectively). In fact, the measured fluorophore levels in RBP4 +/−, ABCA4 +/− mice are close to those observed in the wild type (compare panels D and E). These data demonstrate that RBP is effective as a therapeutic target for reducing the level of fluorophore molecules in the eye. In addition, these data indicate that the drug or method inhibits RBP transcription or translation in the patient, and (a) reduces serum retinol levels in the patient, and (b) retinol-related described herein. Shows that it provides a therapeutic benefit in the disease. Furthermore, agents or methods that improve the clearance of RBP in patients also produce such effects and benefits.

<Example 21: Quantification of ocular retinoid>
ABCA4 − / − mice are administered either ATRP (control) or ATRP + test compound daily for 20 days (n = 3 mice / group). On the last day of dosing, a trace amount of [ ³ H] ATROL (0.32 pmol, 8 μCi) in 100 μl corn oil is administered to all animals. The eyes are removed after 5 hours. As shown in the method, one eye from each animal is used for retinoid analysis and the other eye is used for analysis of A2E and related fluorophores. The data shows a significant decrease in [ ³ H] ATROL uptake in animals treated with test compounds (FIG. 9). Analysis of each retinoid type indicates that the precursor substrate for visual chromophore biosynthesis (ATRE) and the direct precursor for A2E biosynthesis (AT-Ox) were significantly reduced.

<Example 22: Effect of test compound on reduction of overall fluorescent dye molecule level>
Effect of test compound on reduction of total fluorophore levels in ABCA4 − / − mice. Mice are treated as described in Example 13 above. At the end of the study, one eye from each animal is used to measure the overall fluorophore level. Briefly, one whole eye is homogenized in 1 ml phosphate buffered saline (50 mM Na ₂ HPO ₄ , 150 mM NaCl, pH 7.8). After homogenization, 1 ml of methanol is added and the sample is thoroughly mixed. The mixture is incubated for 5 minutes at room temperature and extracted twice with 2 ml of hexane. The extract is concentrated to ˜400 μl and used for fluorescence measurements. Corrected fluorescence spectra are obtained by operating in ratio mode using a Spex Fluorolog-3 fluorometer (Jobin Yvon Horiba, Edison, NJ). The sample is excited at 488 nm and the emission at 500-700 m is monitored. The data shows an overall decrease in the total fluorophore level of mice treated with the test compound (FIG. 10).

Example 23: Effect of test compound on reduction of A2E and A2E precursors
Mice are treated as described in Example 13 above. At the end of the study, one eye from each animal is used to measure A2E and A2PE-H2. Briefly, one whole eye is homogenized in 1 ml phosphate buffered saline (50 mM Na ₂ HPO ₄ , 150 mM NaCl, pH 7.8). After homogenization, 1 ml of methanol is added and the sample is thoroughly mixed. The mixture is incubated for 5 minutes at room temperature and extracted twice with 2 ml of hexane. The solvent is evaporated under a stream of nitrogen and the sample residue is returned to 200 μl isopropanol (IPA) and used for analysis by HPLC. The fluorescent dye molecules are equilibrated in the phospholipid mobile phase (hexane: IPA: ethanol: 25 mM phosphate buffer: acetic acid 485: 376: 100: 37.5: 0.275 v: v) at a flow rate of 1 ml / min. Separated into a Zorbax RX-Sil 5-μm column (250 × 4.6-mm). The data shows that both A2E and its precursor were dramatically reduced in mice treated with the test compound compared to vehicle-treated mice (FIG. 11).

(Human research)
(Detection of macular or retinal degeneration)
Identification of abnormal blood vessels in the eye is performed using, for example, an angiogram. This identification helps to determine which patients are candidates for the use of candidate substances or other therapeutic methods that delay or prevent further vision loss. Angiograms are useful for follow-up of treatment and are also useful for future assessment of any new blood vessel growth.

  Fluorescein angiography (fluorescein angiography, fluorescein angioscope) is a technique for visualizing the choroid and corneal circulation on the back of the eye. Fluorescein dye is injected intravenously, after which multi-frame photography (angiography), ophthalmoscopic evaluation (vascular endoscopy), or Heidelberg retinal angiography (confocal laser scanning system) is performed. In addition, the retina is examined by OCT and a high-resolution cross-sectional image of the retina is obtained in a non-invasive manner. Fluorescein angiograms are used to assess a wide range of retinal and choroidal diseases through analysis of the potential for leaks or damage to blood vessels delivered to the retina. It has also been used to assess optic nerve and iris abnormalities (Berkow et al., Am. J. Ophthalmol. 97: 143-7 (1984).

  Similarly, angiograms using indocyanine green are used to visualize circulation on the back of the eye. Here, fluorescein is more effective in studying retinal circulation, and indocyanine is better in observing deeper choroidal vascular layers. The use of indocyanine angiography is useful when no neovascularization is observed with fluorescein dye alone.

  Appropriate human doses for compounds having the structure of formula (I) will be determined using standard dose-step studies.

Example 24: Clinical trial to test the effectiveness of a test compound to treat macular degeneration>
As a preliminary test, all human patients will undergo routine ophthalmic examinations including fluorescein angiography, visual acuity measurements, electrophysiological parameters, and biochemical and rheological parameters. The patient criteria tested were as follows: visual acuity between 20/160 and 20/32 in at least one eye, drusen, areolar atrophy, pigment clumping, pigment epithelium Signs of AMD such as detachment or subretinal neovascularization. Pregnant patients or actively breastfeeding infants are excluded from this study. Other exclusion criteria include those who have already had vitrectomy or other AMD surgical intervention, severe scarring, and severe concurrent eye disease (uncontrolled glaucoma).

  Groups of patients diagnosed as macular degeneration or having progressive formation of A2E, lipofuscin, or drusen in the eyes are divided into control and experimental groups. Compounds of formula (I) or (II) are administered daily to the experimental group. Placebo is administered to the control group on the same dosing schedule as the test compound was administered to the experimental group.

The compound of formula (I) or (II), or placebo is administered to the patient orally or parenterally in an amount effective to inhibit the progression or recurrence of macular degeneration. Effective doses range from about 1 to about 4000 mg / m ² up to 3 times a day.

  One method of measuring the progression of macular degeneration in the control and experimental groups is optimal corrected vision as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) chart (Lighthouse, Long Island, NY), row evaluation and forced selection Method (Ferris et al. Am J Ophthalmol, 94: 97-98 (1982)). Visual acuity is recorded in logMAR. A change in one line in the ETDRS chart corresponds to 0.1 logMAR. Further exemplary methods for measuring the progression of macular degeneration in both control and experimental groups include visual field examinations, which include Humphrey visual field examinations, microfield examinations (eg, using Micro Perimeter MP-1 from NIDEK) , And measurement / monitoring of autofluorescence of specific compounds in the patient's eye.

  Additional methods for measuring the progression of macular degeneration in both control and experimental groups include fundus photography, observation of autofluorescence changes over time using Heidelberg retinal angiography (or alternatively, M. Hammer, et al. Ophthalmologe 2004 Apr. 7 (Technology described in [Epub ahead of patent]), and follow-up after the examination, fluorescein angiograms should be obtained at baseline, 3, 6, 9, and 12 months Including. The evidence for morphological changes are: (a) drusen size, characteristics, and distribution; (b) progression and development of choroidal neovascularization; (c) other interval fundus changes or abnormalities; d) reading speed and / or reading vision; (e) dark spot size; or (f) changes in size and number of geographic atrophy lesions. In addition, the Amsler Grid Test and the color vision test are performed as necessary.

  To statistically assess visual improvement during drug administration, the investigator uses an ETDRS (LogMAR) chart and standardized refraction and vision protocols. Assessment of mean ETDRS (LogMAR) Best Corrected Visual Acuity (BCVA) from baseline via spaced post-procedure visits available to help measure statistical visual improvement.

  Mean change from baseline in visual acuity of ETDRS (LogMAR) via available post-treatment visits to assess ANOVA (intergroup analysis of variance) between control and experimental groups Are compared to repeated measures analysis with unstructured covariance using SAS / STAT Software (SAS Institutes Inc, Cary, NC) using two groups of ANOVA.

  Serum retinol levels are assessed as follows: After acetonitrile precipitation of serum proteins, the retinol concentration is determined from the soluble phase by LC / MS. Alternatively, serum retinol levels are assessed as described in Driskell et al., J Chromatogr, 1982, 231, 439-444 or Futterman et al., Invest. Ophthalmol Vis Sci, 1975, 14, 125.

  Toxicity assessment after study initiation includes testing every 3 months for the next year, testing every 4 months for the following year, and testing every 6 months thereafter. Plasma levels of test compounds and their metabolites, serum retinol, and / or RBP are also evaluated during these visits. Toxicity assessment includes patients using compounds of formula (I) or (II) and patients in the control group.

Example 25 Non-retinoid modulator activity against RBP-TTR and CYP ₄₅₀

Table 1 shows the IC ₅₀ value and the analysis result of cytochrome P ₄₅₀ inhibition of typical compounds having the structures of the chemical formulas (I) and (II).

Example 26: Efficacy test of compound of formula (I) or (II) for A2E production
The same protocol design, including the pre-examination, administration, dose and toxicity assessment protocol described in Example 24, for the compounds of formula (I) or (II) for reducing or limiting the production of A2E in the patient's eye It was also used to test efficacy.

  Methods for measuring or monitoring the formation of A2E include measuring and / or monitoring the autofluorescence of specific compounds in the patient's eyes, visual acuity and visual field examinations (only by way of example, including microfield examination methods) ), Reading speed and / or reading vision test, measurement of the size and number of dark spots and / or geographic atrophy lesions, as described in Example 23. The statistical analysis described in Example 23 is employed.

Example 27: Efficacy test of compound of formula (I) or (II) for reducing lipofuscin production>
Efficacy of compounds of formula (I) or (II) for reducing or limiting lipofuscin production in the patient's eye, including the same protocol design described in Example 24, including the pre-test, administration, dose and toxicity assessment protocol It was also used to test sex. The statistical analysis described in Example 24 is employed.

  Tests used as surrogate markers for the usefulness of certain treatments include the use of visual acuity and visual field examination (including but not limited to micro field examination), reading speed and / or reading visual acuity test, dark spot And / or measuring the size and number of geographic atrophy lesions, and measuring and / or monitoring the autofluorescence of certain compounds in the patient's eyes, as described in Example 24.

<Example 28: Utility test of compound of formula (I) or (II) for reducing drusen production>
The same protocol design, including the pre-examination, administration, dose and toxicity assessment protocol described in Example 24, is of formula (I) or (II) for reducing or limiting drusen production or formation in the patient's eye. It is also used to test the effectiveness of a compound. The statistical analysis described in Example 24 is employed.

  A method to measure the progressive formation of drusen in both control and experimental groups is to obtain fluorescein angiograms at baseline, 3, 6, 9, and 12 months in fundus photography and follow-up after examination. Including doing. The evidence for morphological changes is (a) drusen size, characteristics, and distribution; (b) progression and development of choroidal neovascularization; and (c) other interval fundus changes or abnormalities. is there. Tests used as surrogate markers for the usefulness of certain treatments include the use of visual acuity and visual field examination (including but not limited to micro field examination), reading speed and / or reading visual acuity test, dark spot And / or measuring the size and number of geographic atrophy lesions, and measuring and / or monitoring the autofluorescence of certain compounds in the patient's eyes, as described in Example 23.

<Example 29: Genetic test for macular dystrophy>
Defects in the human ABCA4 gene are thought to be associated with five distinct retinal phenotypes, including Stargardt disease, cone-rod dystrophy, age-related macular degeneration (both dry and wet), and retinitis pigmentosa Yes. For example, Allikmets et al., Science, 277: 1805-07 (1997); Lewis et al., Am. J. Hum. Genet., 64: 422-34 (1999); Stone et al., Nature Genetics, 20 : 328-29 (1998); Allikmets, Am. J. Hum. Gen., 67: 793-799 (2000); Klevering, et al, Ophthalmology, 111: 546-553 (2004). Furthermore, the autosomal dominant form of Stargardt disease is caused by mutations in the ELOV4 gene. See Karan, et al., Proc. Natl. Acad. Sci. (2005). The patient is diagnosed as having Stargardt disease by any of the assays in the examples below,
A direct sequencing mutation detection strategy associated with sequencing all exons of ABCA4 or ELOV4 and its adjacent introns for sequence mutations;
-Genomic Southern analysis;
-A microarray assay comprising all known ABCA4 or ELOV4 variants; and-liquid chromatography tandem mass spectrometry with immunocytochemical analysis and Western analysis using antibodies.

  Fundus imaging, fluorescein angiography, and laser scanning system ophthalmoscopic imaging are methods for predicting and / or confirming a diagnosis, along with the patient and his or her family's medical history.

<Example 30: Formulation>
Example 30a: Oral composition
To prepare a pharmaceutical composition for oral delivery, 100 mg of compound of either formula (I) or formula (II) is mixed with 750 mg of starch. The mixture is placed in an oral dosage unit form suitable for oral administration, eg for hard gelatin capsules.

(Example 30b: parenteral composition)
To prepare a parenteral pharmaceutical composition suitable for administration by injection, 100 mg of a water-soluble salt of a compound of either formula (I) or formula (II) is dissolved in DMSO and then 10 ml of 0.9% Mix with sterile saline. The mixture is placed in a dosage unit form suitable for administration by injection.

Example 30c: Sublingual (hard lozenge composition)
To prepare a pharmaceutical composition for buccal delivery such as a hard troche, 100 mg of compound of either formula (I) or formula (II) is added to 420 mg powdered sugar, 1.6 ml light corn syrup; Mix with 4 ml distilled water and 0.42 ml mint extract. The mixture is gently mixed and poured into a mold to form a lozenge suitable for buccal administration.

Example 30d: Inhalation composition
To prepare a pharmaceutical composition for inhalation delivery, 20 mg of compound of either formula (I) or formula (II) is mixed with 50 mg anhydrous citric acid and 100 ml 0.9% sodium chloride solution. The mixture is placed in an inhalation delivery unit such as a nebulizer that is suitable for inhalation administration.

Example 30e: Rectal gel composition
To prepare a pharmaceutical composition for rectal delivery, 100 mg of compound of either formula (I) or formula (II) is added to 2.5 g methylcellulose (1500 mPa), 100 mg methylparapen, 5 g glycerin, and 100 mL purified water. Mixed with. The resulting gel mixture is then placed in a rectal delivery unit such as a syringe suitable for rectal administration.

Example 30f: Topical gel composition
To prepare a pharmaceutical topical gel composition, 100 mg of compound of either formula (I) or formula (II) is 1.75 g hydroxypropylcellulose, 10 mL propylene glycol, 10 mL isopropyl myristate, and 100 mL purification. Mixed with alcohol USP. The resulting gel mixture is placed in a container such as a tube that is suitable for topical administration.

(Example 30g: eye drop solution composition)
To prepare a pharmaceutical ophthalmic solution composition, 100 mg of compound of either formula (I) or formula (II) is mixed with 0.9 g NaCl in 100 mL purified water and filtered using a 0.2 micron filter. The The resulting isotonic solution is then incorporated into an ophthalmic delivery unit such as an eye drop container suitable for ocular administration.

  The examples and embodiments described herein are for illustrative purposes only and the various improvements or modifications presented are within the spirit and scope of the invention and are within the scope of the appended claims. Is included.

Claims (74)

A pharmaceutical composition comprising a compound of formula (I) (Formula 1), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof, and a pharmaceutically acceptable excipient.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H or (Chemical Formula 2),
G is —OR ¹ , — (C ₁ -C ₆ ) alkyl, — (C ₁ -C ₆ ) alkyl-OR ¹ , halogen, —CO ₂ R ¹ , — (C ₁ -C ₆ ) alkyl-CO _{2. ^{R 1, NHR 1, - (}} C 1 -C 6) alkyl ^{-NHR 1, - (C = O} ) NHR 1, - (C 1 -C 6) alkyl ^{- (C = O) NHR 1} , -NHR 1 ( C═O) R ¹ , or — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ,
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is a halogen. ] The pharmaceutical composition according to claim 1, comprising a compound having the structure of the chemical formula (II) (Chemical formula 3), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof. .
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H or (Chemical Formula 4),
G is —OR ¹ , — (C ₁ -C ₆ ) alkyl, — (C ₁ -C ₆ ) alkyl-OR ¹ , halogen, —CO ₂ R ¹ , — (C ₁ -C ₆ ) alkyl-CO _{2. ^{R 1, NHR 1, - (}} C 1 -C 6) alkyl ^{-NHR 1, - (C = O} ) NHR 1, - (C 1 -C 6) alkyl ^{- (C = O) NHR 1} , -NHR 1 ( C═O) R ¹ , or — (C ₁ -C ₆ ) alkyl-NHR ¹ (C═O) R ¹ ,
R ¹ is H or (C ₁ -C ₆ ) alkyl. ]   The pharmaceutical composition according to claim 2, wherein A is O. Wherein B is, - _{(CH 2)} a _n and n is 1-6, or - _(C 3 -C ₈₎ according to claim 3 pharmaceutical composition, wherein the cycloalkyl. E is (C═O) —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — ( The pharmaceutical composition according to claim 4, which is C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R. 6. The pharmaceutical composition according to claim 5, wherein R is (Chemical formula 5).
  The pharmaceutical composition according to claim 4, wherein E is (C═O) —OR.   The pharmaceutical composition according to claim 7, wherein R is H.   5- (2-tert-butyl-4-chlorophenoxy) -N- (4-hydroxyphenyl) pentanamide, 7- (2-tert-butyl-4-chlorophenoxy) -N- (4-hydroxyphenyl) heptane Amido, 4- (5- (2-tert-butyl-4-chlorophenoxy) pentanamide) benzoic acid, 4- (3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclopentanamide) benzoic acid Acid, 5- (2-tert-butyl-4-chlorophenoxy) pentanoic acid, 4- (2-tert-butyl-4-chlorophenoxy) butanoic acid, 2- (3-((2-tert-butyl-4 -Chlorophenoxy) methyl) cyclopentyl) acetic acid, 7- (2-tert-butyl-4-chlorophenoxy) heptanoic acid, 4- (5- (2-tert-butyl-4-chlorophenoxy) pentaneami ) Benzamide, 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclohexanecarboxylic acid, 3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclopentanecarboxylic acid, 3-(( 2-tert-butyl-4-chlorophenylamino) methyl) cyclopentanamide, 4- (3-((2-tert-butyl-4-chlorophenoxy) methyl) cyclopentanecarboxamido) benzoic acid, and 5- (2 2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is selected from the group consisting of -tert-butyl-4-chlorophenylthio) pentanoic acid. The pharmaceutical composition according to claim 1, which suppresses the formation of a retinol-retinol binding protein-transthyretin complex and has an IC ₅₀ of the inhibition of less than about 5 µM. 11. The pharmaceutical composition of claim 10, wherein the inhibition IC ₅₀ is less than about 1 μM. The pharmaceutical composition of claim 1, wherein cytochrome P ₄₅₀ is suppressed to less than about 50%. 13. The pharmaceutical composition of claim 12, wherein cytochrome _P450 is suppressed to less than about 10%.   The pharmaceutical composition according to claim 1, wherein the compound of formula (I) is used for the treatment of vitreous retinal disease.   The vitreous retinal disease is composed of dry macular degeneration, photoreceptor degeneration, maple atrophy, macular dystrophy, diabetic retinopathy, wet macular degeneration, retinopathy of prematurity, and retinitis pigmentosa The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is selected from: A compound of formula (I) (Formula 6), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof;
A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, or optionally substituted heteroaryl;
X is a halogen. ] A compound having the structure of formula (II) (formula 7), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof;
17. A pharmaceutical composition according to claim 16, comprising a pharmaceutically acceptable excipient or carrier.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, or optionally substituted heteroaryl. ]   17. The pharmaceutical composition according to claim 16, wherein the composition is included in an amount effective enough to reduce the level or activity of serum retinol or ocular tissue retinol in a mammal. A vitreous retina comprising the step of administering to a mammal a therapeutically effective amount of a compound of formula (I) (Formula 8), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof. How to treat a disease.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ] Administering to a mammal a therapeutically effective amount of a compound of formula (II) (formula 9), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof. The method of claim 19.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ] The compound modulates the level or activity of retinol binding protein in a mammal;
The method according to claim 19 or 20, wherein the retinol-binding protein is RBP4.   The vitreous retinal disease is selected from dry macular degeneration, photoreceptor degeneration, geographic atrophy, macular dystrophy, diabetic retinopathy, wet macular degeneration, retinopathy of prematurity, or retinitis pigmentosa 20. The method of claim 19, wherein: A method of reducing the level or activity of serum retinol binding protein or transthyretin in a mammal, comprising:
Administering to a mammal a therapeutically effective amount of a compound of formula (I) (Formula 10), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof,
A method wherein the compound of formula (I) (Formula 10) modulates the level or activity of serum retinol binding protein or transthyretin in a mammal.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ] Administering a therapeutically effective amount of a compound of formula (II) (formula 11), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof,
24. The method of claim 23, wherein the compound of formula (II) (Formula 11) modulates the level or activity of serum retinol binding protein or transthyretin in a mammal.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]   24. The method of claim 23, wherein the serum retinol binding protein is RBP4.   24. The method of claim 23, wherein the compound of formula (I) inhibits transcription of retinol binding protein or transthyretin in mammals.   24. The method of claim 23, wherein the compound of formula (I) inhibits translation of retinol binding protein or transthyretin in a mammal.   24. The method of claim 23, wherein the compound of formula (I) inhibits retinol binding to retinol binding protein.   24. The method of claim 23, wherein the compound of formula (I) inhibits retinol binding protein binding to transthyretin.   24. The method of claim 23, wherein the compound of formula (I) increases clearance of retinol binding protein or transthyretin in the mammal. A method of treating a retinol-related disease in a mammal, comprising:
Administering to a mammal a therapeutically effective amount of a compound of formula (I) (Chemical Formula 12), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof. And how to.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ] 32. The method of claim 31, comprising administering a therapeutically effective amount of a compound of formula (II) (Formula 13), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof. .
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]   32. The method of claim 31, wherein the retinol-related disease is osteoproliferation, idiopathic intracranial hypertension, amyloidosis, Alzheimer's disease, and Alstrem-Harglen syndrome. A method for lowering serum retinol levels in a mammal having dry age-related macular degeneration, comprising:
Administering to the mammal a compound of formula (I) (Formula 14), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof,
A method wherein the compound of formula (I) (Chem. 14) does not directly modulate the activity of an enzyme or protein in the visual cycle.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ] Administering a therapeutically effective amount of a compound of formula (II) (Formula 15), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof,
35. The method of claim 34, wherein the compound of formula (II) (Chemical 15) does not directly modulate the activity of an enzyme or protein in the visual cycle.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]   35. The method of claim 34, wherein the compound of formula (I) does not directly inhibit or bind directly to the enzyme or protein in the visual cycle.   35. The method of claim 34, wherein the compound of formula (I) does not affect rhodopsin regeneration.   35. The method of claim 34, wherein the compound of formula (I) does not substantially exacerbate dark adaptation delay.   35. The method of claim 34, wherein the compound of formula (I) limits the spread of maple atrophy, dark spots, dark spots or autofluorescent rings around lesions or photoreceptor degeneration. A method of treating hyperretinolemia, comprising administering a compound of formula (I), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof A method comprising the steps.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ] 41. The method comprising administering a therapeutically effective amount of a compound of formula (II) (Formula 17), an active metabolite thereof, or a pharmaceutically acceptable prodrug or solvate thereof. The method described.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]   41. The method of claim 40, wherein the excess retinol blood condition is associated with vitreous retinal disease.   41. The method of claim 40, wherein the excess retinol blood condition is associated with diabetes or Alzheimer's disease. A method of treating a retinol-related disease in a mammal, comprising:
Administering to said mammal an effective amount of a compound of formula (I) (Formula 18), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof,
The compound of formula (I) suppresses the formation of a retinol-retinol binding protein-transthyretin complex;
IC ₅₀ inhibition is less than about 5 μM.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ] Administering a therapeutically effective amount of a compound of formula (II) (Formula 19), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof,
The compound of formula (II) suppresses the formation of a retinol-retinol binding protein-transthyretin complex,
IC ₅₀ inhibition method of claim 44, wherein less than about 5 [mu] M.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ] The _{IC 50} inhibition The method of claim 44, wherein less than about 1 [mu] M. 45. The method of claim 44, wherein the compound of formula (I) further inhibits cytochrome _P450 to less than about 50%. 48. The method of claim 47, wherein the compound of formula (I) further inhibits cytochrome _P450 to less than about 10%. A method of treating type 1 or type 2 diabetes in a mammal, comprising:
Administering to said mammal a therapeutically effective amount of a compound of formula (I) (Formula 20), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof,
A method wherein the compound of formula (I) modulates the level or activity of retinol binding protein or transthyretin in a mammal.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ] Administering to said mammal an effective amount of a compound of formula (II) (Formula 21), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof,
50. The method of claim 49, wherein the compound of formula (II) modulates the level or activity of retinol binding protein or transthyretin in the mammal.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ] A method of reducing the level of serum retinol or ocular tissue retinol in a mammal, comprising:
Administering to said mammal a therapeutically effective amount of a compound of formula (I) (Formula 22), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof. Feature method.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl;
X is a halogen. ] Administering to the mammal an effective amount of a compound of formula (II) (Chemical Formula 23), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof. 52. The method of claim 51.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; , NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ R And
R is H, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl. ]   52. The method of claim 51, wherein the mammal is a human.   52. The method of claim 51, wherein the level of serum retinol or ocular tissue retinol is reduced by at least 20%.   Administering at least one additional agent, the additional agent comprising an inducer of nitric oxide production, an anti-inflammatory agent, a physiologically acceptable antioxidant, a physiologically acceptable Selected from the group consisting of minerals, negatively charged phospholipids, carotenoids, statins, anti-angiogenic agents, matrix metalloprotease inhibitors, resveratrol and other trans-stilbene compounds, and 13-cis-retinoic acid 52. The method of claim 51. A composition comprising a compound of formula (I) (Formula 24), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof.
[Wherein A is O, NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ but hetero cycloalkenyl, however, _- (C 2 _-C 7) heteroalkyl is a nitrogen atom, -C (= O) -, - S -, - S (= O) -, - S (= O) 2 -, - NR 1 (C = O) -, - (C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -O (C = O) NR ^1- , -NR ¹ (C = O) O-,- O (C═O) O—, —NR ¹ (C═O) NR ¹ —, — (C═O) O—, or —O (C═O) — are not included,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; ^{, NR 1 - (C = O} ) -R, - (C 1 -C 7) alkyl - (C = O) -OR, - (C 1 -C 7) alkyl ^{- (C = O) -NR 1} R, C ₁ -C _{4 alkyl,} C 2 -C _{4 alkynyl,} C 3 -C _{6 cycloalkyl,} C 1 -C ₄ alkyl - _(C 3 -C ₆ cycloalkyl), aryl, substituted aryl, arylalkyl, -C ( O) R ² , hydroxy- (C ₁ -C ₆ alkyl), areoxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, —O—C (O) NR ² R ³ , —NR ² R ³ (C═O) OR ¹ , or —SO ₂ NR ² R ³ ,
R ² and R ³ are each independently selected from H, C ₁ -C ₆ alkyl, and C ₃ -C ₆ cycloalkyl;
R is H, optionally substituted aryl, or optionally substituted heteroaryl, provided that when B is —S—, R is not a pyrimidine and B is — (C ₂ -C ₇ ). R is not imidazole when alkyl,
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is a halogen,
However, the compound of formula (I) is not a dimer. ] E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ^1. R, NR ^1- (C═O) —R, — (C ₁ -C ₇ ) alkyl- (C═O) —OR, or — (C ₁ -C ₇ ) alkyl- (C═O) —NR ¹ 57. The composition of claim 56, wherein R. X is Cl;
57. The composition of claim 56, wherein D is isopropyl, tert-butyl, or cyclopropyl.   57. The composition of claim 56, wherein A is O. Wherein B is, - _{(CH 2)} a _n and the n is 1-6, or - _(C 3 -C ₈₎ The composition of claim 56, wherein the cycloalkyl.   57. A pharmaceutical composition comprising a compound according to claim 56 and a pharmaceutically acceptable carrier or excipient.   59. A method for treating vitreous retinal disease comprising administering to a mammal a therapeutically effective amount of the composition of claim 56. A compound of formula (I) (Formula 25), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof.
[Wherein A is O;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ but hetero cycloalkenyl, however, _- (C 2 _-C 7) heteroalkyl is a nitrogen atom, -C (= O) -, - S -, - S (= O) -, - S (= O) 2 -, - NR 1 (C = O) -, - (C = O) NR ^1- , S (= O) ₂ NR ^1- , -NR ¹ S (= O) ₂ , -O (C = O) NR ^1- , -NR ¹ (C = O) O-,- O (C═O) O—, —NR ¹ (C═O) NR ¹ —, — (C═O) O—, or —O (C═O) — are not included,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; ^{, NR 1 - (C = O} ) -R, - (C 1 -C 7) alkyl - (C = O) -OR, - (C 1 -C 7) alkyl ^{- (C = O) -NR 1} R, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl- (C ₃ -C ₆ cycloalkyl), aryl, substituted aryl, arylalkyl, -C ( O) R ² , hydroxy- (C ₁ -C ₆ alkyl), areoxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, —O—C (O) NR ² R ³ , —NR ² (C═O) OR ¹ , or —SO ₂ NR ² R ³ ,
R ² and R ³ are each independently selected from H, C ₁ -C ₆ alkyl, and C ₃ -C ₆ cycloalkyl;
R is H, — (C ₂ -C ₇ alkyl), optionally substituted aryl, or optionally substituted heteroaryl, provided that when B is —S—, R is not a pyrimidine; B is - _(C 2 -C ₇₎ R is not a imidazole time is alkyl,
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is a halogen. ] Wherein B is, - _{(CH 2) n} and said n is 1-6, or - _(C 3 -C ₈₎ A compound according to claim 63, wherein the cycloalkyl. Wherein E is, (C = O) -OR, carboxylic acid ^{bioisostere, - (C = O) -NR} 1 R, - (C 1 -C 7) alkyl - (C = O) -OR, or - ( C ₁ -C ₇₎ alkyl - (C = O) -NR ¹ 64. a compound according to characterized in that the R.   66. The compound of claim 65, wherein E is (C = O) -OR.   68. The compound of claim 66, wherein D is isopropyl, tert-butyl, or cyclopropyl.   68. The compound of claim 67, wherein X is Cl and D is tert-butyl. A compound of formula (I) (Formula 26), an active metabolite thereof, or a pharmaceutically acceptable prodrug, salt or solvate thereof.
[Wherein A is NH or S;
Of B, a single bond, - _(C 2 -C ₇₎ alkyl, - _(C 2 -C ₇₎ alkenyl, - _(C 3 -C ₈₎ cycloalkyl, - _(C 2 -C ₇₎ heteroalkyl, - _(C 3 -C ₈₎ heterocycloalkyl, - _(C 3 -C ₈₎ cycloalkenyl, or - to _(C 3 -C ₈₎ a hetero cycloalkenyl,
D is isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, or methylenecyclopentyl;
E is (C═O) —OR, —O— (C═O) —R, — (C═O) —R, —OR, carboxylic acid bioisostere, — (C═O) —NR ¹ R; ^{, NR 1 - (C = O} ) -R, - (C 1 -C 7) alkyl - (C = O) -OR, - (C 1 -C 7) alkyl ^{- (C = O) -NR 1} R, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl- (C ₃ -C ₆ cycloalkyl), aryl, substituted aryl, arylalkyl, -C ( O) R ² , hydroxy- (C ₁ -C ₆ alkyl), areoxy, halo, C ₁ -C ₆ -haloalkyl, cyano, hydroxy, nitro, —O—C (O) NR ² R ³ , —NR ² (C═O) OR ¹ , or —SO ₂ NR ² R ³ ,
R ² and R ³ are each independently selected from H, C ₁ -C ₆ alkyl, and C ₃ -C ₆ cycloalkyl;
R is H, — (C ₂ -C ₇ alkyl), optionally substituted aryl, or optionally substituted heteroaryl;
R ¹ is H or (C ₁ -C ₆ ) alkyl;
X is a halogen. ] Wherein B is, - _{(CH 2)} a _n and the n is 1-6, or - _(C 3 -C ₈₎ A compound according to claim 69, wherein the cycloalkyl. Wherein E is, (C = O) -OR, carboxylic acid ^{bioisostere, - (C = O) -NR} 1 R, - (C 1 -C 7) alkyl - (C = O) -OR, or - ( C ₁ -C ₇₎ alkyl - (C = O) -NR ¹ compound of claim 70, wherein it is a R.   72. The compound of claim 71, wherein E is (C = O) -OR.   73. The compound of claim 72, wherein D is isopropyl, tert-butyl, or cyclopropyl.   74. The compound of claim 73, wherein X is Cl and D is tert-butyl.