CN101245043B - Aza-heterocyclic compounds used to treat neurological disorders and hair loss - Google Patents
Aza-heterocyclic compounds used to treat neurological disorders and hair loss Download PDFInfo
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Abstract
This invention relates to novel N-heterocyclic carboxylic acids and carboxylic acid isosteres represented by formula (I), their preparation and use for treating neurological disorders including physically damaged nerves and neurodegenerative diseases, and for treating alopecia and promoting hair growth. In said formula, n is 1-3; X is either O or S; R1 is selected from the group consisting of C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, aryl, heteroaryl, carboncycle, or heterocycle; D is a bond, or a C1-C10 straight or branched chain alkyl, C2-C10 alkenyl or C2-C10 alkynyl; R is as defined in the application.
Description
The application is to be on December 3rd, 1998 applying date, and application number is the dividing an application of patent application of 98814099.3 (PCT international application no PCT/US98/25573).
Related application
The application be by the people such as Hamilton be called " carboxylic acid of N-heterogeneous ring compound and carboxylic acid isostere " in the name of on June 3rd, 1998 application, application number is 60/087,788 U.S. Patent application and be called the part continuation application that " carboxylic acid of N-heterogeneous ring compound and carboxylic acid isostere ", application number are 60/101,077 U.S. Patent application in the name of on September 18th, 1998 application by people such as Hamilton.
Background of invention
1. invention field
The present invention relates to carboxylic acid and the carboxylic acid isostere of new N-heterogeneous ring compound, it prepares, and comprises physical damnification neural and neurodegenerative disease and the application in hair growth and promotion hair growth in the neurologic disease for the treatment of.
2. Description of Related Art
Have been found that the immunosuppressor of pmol concentration such as FK506 and Wyeth-Ayerst Laboratories can stimulate the spinous process wart in the PC12 cell and be called the Sensory neurone of back root neural section cell (DRGs).Lyons etc., Proc.of Natl.Acad.Sci., 91 volumes in 1994,3191-3195 page or leaf.In all animals test, FK506 shows the stimulating neuronal regeneration after the face nerve damage and causes functional rehabilitation in the animal of sciaticnerve lesions.
There are several overall neurotrophic factors of specific neurone that affect in the central nervous system to determine.For example, supposed that Alzheimer's is minimizing or the loss that comes from nerve growth factor (NGF).Suggestion is treated the person with Alzheimer's disease with the survival of the neural population that improves degeneration with exogenesis nerve growth factor or other neurotrophin such as brain derived nerve factor (BDNF), neuroglia neural factor, eyelash neurotrophic factor and NT-3 thus.
Owing to the conveying of large protein neuralward aims of systems and the difficulty of biological availability have hindered the clinical application of these protein in various neural morbid state.On the contrary, have the immune suppressant drug less of neurotrophic activity, and have good biological availability and specificity.But when long-term taking, immunosuppressor shows many potential severe side effect, comprise weakening that nephrotoxicity such as glomerulus filter and irreversible interstitial fibers sex change (Kopp etc., 1991, J.Am.Soc.Nephrol.1:162); Neurological deficit such as unconscious tremble or unspecific cerebellum angina such as non-localized headache (De Groen etc., 1987, N.Engl.J.Med.317:861); And hypertension and complication thereof (Kahan etc., 1989, N.Engl.J.Med.321:1725).
Therefore need to can be used for the micromolecular compound that neurotrophic effect is provided and can be used for treating neurodegenerative disorders.
Trichomadesis may have multiple situation.These situations comprise male pattern alopecia, senile alopecia, alopecia areata, the disease of following basic skin lesion or tumour and system disorders such as nutrition disorder and endocrine regulation.The reason that produces trichomadesis is very complicated, but it is unusual to be attributable in some cases age, inherited genetic factors, male hormone activation, the leiphemia that is delivered to hair follicle and scalp.
Immunosuppressive drug FK506, Wyeth-Ayerst Laboratories and S-Neoral are well-known as effective T cell special immune inhibitor, and very effective to prevention transplant rejection after the organ transplantation.FK506 (Yamamoto etc., J.Invest.Dermatol.1994,102,160-164; Jiang etc., J.Invest.Dermatol.1995,104,523-525) and S-Neoral (Iwabuchi etc., J.Dermatol.Sci.1995,9, topical application 64-69) but non-ly orally rely on the mode stimulating hair growth with dosage and have been reported.A kind of trichomadesis of form, spot takes off, and known is relevant with autoimmune activity; Therefore expectation proof topical application immunomodulatory compounds can be effective to treating such alopecia.The hair growth hormesis of FK506 is the theme (Honbo etc., EP 0 423 714 A2) that covers the international monopoly that is used for stimulating hair growth of FK506 and dependency structure thereof.The people such as Honbo disclose relatively large tricyclic compound, and its immunosuppressive effect is known, as the purposes of hair revitalizing agent.
The hair growth of FK506 and related reagent and recovery effects be open (Goulet etc., USP5,258,389 in many United States Patent (USP)s; Luly etc., USP5,457,111; Goulet etc., USP5,532,248; Goulet etc., USP5,189,042; Ok etc., USP5,208,241; Rupprecht etc., USP5,284,840; And Organ etc., USP5,284,877).The compound that the claimed FK506 of these patents is relevant.Although the method that they do not have claimed hair to recover, they disclose the known application of FK506 for hair growth.Be similar to FK506 (and in the people's such as Honbo patent desired variation range), desired compound is all relatively large in these patents.And these patents of quoting are all relevant with the immunomodulatory compounds that is used for the autoimmunity relative disease, and wherein the effect of FK506 is well-known.
Some other United States Patent (USP) discloses for the S-Neoral of hair recovery and purposes (Hauer etc., USP5,342,625 of related compound; Eberle, USP5,284,826; With Hewitt etc., USP4,996,193).These patents are also relevant with the compound that is used for the treatment of autoimmune disorders, and quoted for the S-Neoral of hair growth and the known application of related immune Inhibitor.
But defined immunosuppressive compounds Immunosuppression system and show other toxic side effect.Therefore need to can be used as the micromolecular compound that hair recovers compound.
Summary of the invention
The present invention relates to can be used for treating neurodegenerative disorders and break away from the disorderly wonderful discovery that contains carboxylic acid or carboxylic acid isostere N-heterogeneous ring compound partly with hair growth and relevant hair.Therefore a kind of acid moieties of the 2-carbon potential that new the containing of one class be connected to the N-heterocyclic ring or a kind of compound of its isostere are provided.Regeneration and the wart of these compounds energy stimulating neuronals, thus can be used for treating neurologic disease and neurodegenerative disease.These compounds can also promote hair growth, thereby can be used for treating the trichomadesis disease.The favourable feature of the compounds of this invention be they do not produce any obvious immunosuppressive activity and/or right and wrong immunosuppressant.
The compound that a kind of preferred embodiment of the present invention is general formula (I) or the acceptable salt of its pharmacology, ester or solvate:
Wherein
N is 1-3;
X is O or S;
R
1Be selected from by C
1-C
9Straight or branched alkyl, C
2-C
9In the group that straight or branched alkenyl, aryl, heteroaryl, carbocyclic ring or heterocycle form;
D is a key or C
1-C
10Straight or branched alkyl, C
2-C
10Alkenyl or C
2-C
10Alkynyl group;
R
2Isostere for carboxylic acid or carboxylic acid; With
Wherein the isostere of said alkyl, alkenyl, alkynyl group, aryl, heteroaryl, carbocyclic ring, heterocycle or carboxylic acid is optionally by one or more R that are selected from
3Replace with the substituting group of Z, wherein
R
3With Z be hydrogen, hydroxyl, halogen, haloalkyl, thiocarbonyl, alkoxyl group, alkenyloxy, alkyl-aryloxy, aryloxy, alkoxy aryl, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylthio, alkylsulfonyl, C independently
1-C
6Straight or branched alkyl, C
2-C
6Straight or branched alkenyl or alkynyl group, aryl, aralkyl, heteroaryl, carbocyclic ring, heterocycle or CO
2R
7R wherein
7Be hydrogen or C
1-C
9Straight or branched alkyl or C
2-C
9The straight or branched alkenyl;
Its precondition is:
Work as n=1, D is a key, and R
2During for COOH,
R
1Not C
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
5-C
7Cycloalkyl, C
5-C
7Cycloalkenyl group, anilino, 2-(3,4-dichlorophenyl) ethyl, hydroxyl, oxyethyl group, benzyl or Ar
1, Ar wherein
1Be 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 1-pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl, wherein said alkyl, alkenyl, cycloalkyl, cycloalkenyl group or Ar
1Optionally be selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C by one or more
1-C
9Straight or branched alkyl, C
2-C
9Straight or branched alkenyl, C
1-C
4Alkoxyl group, C
2-C
4Substituting group in alkene oxygen base, phenoxy group, benzyloxy, COOH and the amino group that forms replaces;
Further condition is:
Work as n=1, D is a key, R
2Be carboxylic acid isostere-CONZ (R
3), Z is hydrogen or C
1-C
6Alkyl, R
3Be phenyl or C
2-C
6Straight or branched alkyl or alkenyl, wherein said alkyl be unsubstituted or in its one or more positions with the Ar that defines later
2, C
3-C
8Cycloalkyl, with methyl or C
2-C
6Cycloalkyl, C that straight or branched alkyl or alkenyl connect
1-C
4Alkyl ester or Ar
3Replace Ar wherein
3Be selected from the group that is formed by 2-indyl, 3-indyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl and have 1-3 and be independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl, C
2-C
6Straight or branched alkenyl, C
1-C
4Alkoxyl group, C
2-C
4Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group that forms; Wherein said alkyl ester is optionally replaced by phenyl; Perhaps R
3Be following fragment:
R wherein
4Be selected from by by C
3-C
8The straight or branched C that the cycloalkyl selectivity replaces
1-C
8Alkyl, benzyl or the Ar that defines later
2In the group that forms, R wherein
2Be COOZ or CONR
6, R wherein
6Be selected from by hydrogen, C
1-C
6Straight or branched alkyl and C
2-C
6In the group that the straight or branched alkenyl forms, R wherein
5Be selected from by phenyl, benzyl, C
1-C
6Straight or branched alkyl and C
2-C
6In the group that the straight or branched alkenyl forms, wherein said alkyl or alkenyl are optionally replaced by phenyl; The time,
R
1Not C
1-C
9Straight or branched alkyl, C
2-C
9The thienyl of straight or branched alkenyl, replacement or C
1-C
4Alkoxyl group, wherein said alkyl or alkenyl on its one or more regioselectivities ground by C
3-C
8Cycloalkyl, C
5-C
7Cycloalkenyl group or Ar
2Replace Ar wherein
2Define such as the back, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl group can be optionally by C
1-C
4Alkyl, C
1-C
4Alkenyl or hydroxyl replace, wherein said Ar
2For 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or phenyl and have 1-3 and be selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C
1-C
6Straight or branched alkyl, C
2-C
6Straight or branched alkenyl, C
1-C
4Alkoxyl group, C
2-C
4Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group that forms;
Further condition is:
Work as n=1, X is O, and D is a key, and R
2For-CONH
2The time,
R
1Not methyl, ethyl, sec.-propyl, isobutyl-, isopentyl, 4-methyl amyl, indyl, phenyl or hydroxyphenyl;
Further condition is:
Work as n=1, X is O, and D is a key, and R
2During for cyano group,
R
1It or not methyl;
Further condition is:
Work as n=2, X is O, and D is a key, R
2Be CONZ (R
3), and R
1During for oxyethyl group,
R
3Or Z is not the phenyl that halogen replaces;
Further condition is:
Work as n=2, X is O, and D is a key, R
2Be CONZ (R
3), and R
1During for the thienyl that replaces or tetrahydro-pyran oxy or methoxyl group,
R
3Or Z is not the C that replaces with ethyl
1-C
4Alkyl ester;
Further condition is:
Work as n=2, X is O, and D is a key, R
2Be CONZ (R
3), and R
1During oxyethyl group,
R
3Or Z is not the 4-chloro-phenyl-;
Further condition is:
Work as n=2, X is O, and D is a key, R
2Be CONZ (R
3), and R
1During for cyclohexyl,
R
3Or Z is not ethyl or propyl group with phenyl substituted;
Further condition is:
When D is CH
2The time,
R
2Be not-OMe ,-NHMe or replace-the NH cyclohexyl;
Further condition is:
When D is CH
2, R
2During for-OH,
R
1Not phenyl or pyrrolidine carbinol;
Further condition is:
Work as n=2, X is O, and D is a key, and R
2During for COOH,
R
1Not methyl, the tertiary butyl, 1,1-dimethyl-2-methyl-propyl group, 1, the C that 1-dimethyl-propyl group, methoxyl group, oxyethyl group, phenyl, tetrahydro-pyran oxy replace
4-C
6Alkyl, 1-methyl isophthalic acid-methoxyamide, 1-methylcyclohexyl, 3-iodophenyl, 3-methyl ester-cyclopentyl, 1,1-dimethyl-6-phenyl-hexyl-3,5-dioxy base or trimethoxyphenyl.
Preferred embodiment of the present invention is R
2For containing the CH that is in any chemically stable oxidation state
2, O, S or N carbocyclic ring or the heterocycle of any combination, wherein its one or more regioselectivities ground of the atom of any said ring structure is by R
3Replace.
Particularly preferred embodiment of the present invention is R wherein
2Be selected from following group:
Wherein its one or more positions of the atom of said ring structure can be optionally by R
3Replace.
The preferred embodiment of another kind of the present invention is R wherein
2Be selected from by-COOH ,-SO
3H ,-SO
2HNR
3,-PO
2(R
3)
2,-CN ,-PO
3(R
3)
2,-OR
3,-SR
3,-NHCOR
3,-N (R
3)
2,-CON (R
3)
2,-CONH (O) R
3,-CONHNHSO
2R
3,-COHNSO
2R
3, and-CONR
3In the group that CN forms.
Preferred embodiment of the present invention is: (2S)-and 1-(1,2-dioxy-3,3-dimethyl amyl group)-2-hydroxymethyl pyrrolidine; (2S)-1-(1,2-dioxy-3,3-3,5-dimethylphenyl)-2-tetramethyleneimine tetrazolium; (2S)-1-(1,2-dioxy-3,3-dimethyl amyl group)-2-tetramethyleneimine carbon nitrile; (2S)-1-(1,2-dioxy-3,3-dimethyl amyl group)-2-aminocarboxyl piperidines.
The preferred embodiment of another kind of the present invention is that general formula (I) compound that contains significant quantity and pharmacology are fit to or a kind of pharmaceutical composition of pharmacology acceptable carrier.As neurotrophic compositions, the neurotrophic factor that is different from general formula (I) also can use or otherwise be included in the said composition.
The preferred embodiment of another kind of the present invention is the method that promotes mammiferous neuron regeneration and growth, and the method comprises to Mammals takes the carboxylic acid of N-heterocycle of significant quantity or the isostere of carboxylic acid.
The preferred embodiment of another kind of the present invention is the method for the neurologic disease for the treatment of animal, the method comprises to animal takes the carboxylic acid of N-heterocycle of significant quantity or the isostere of carboxylic acid, with the growth that stimulates impaired periphery nerve or promote neuron regeneration.
The preferred embodiment of another kind of the present invention is the neurodegenerative method of prevention animal, and the method comprises to animal takes the carboxylic acid of N-heterocycle of significant quantity or the isostere of carboxylic acid.
The preferred embodiment of another kind of the present invention is alopecia or the trichogenous method for the treatment of animal, and the method comprises to animal takes the carboxylic acid of N-heterocycle of significant quantity or the isostere of carboxylic acid.
Brief description of drawings
Fig. 1 is the photo that shaving is used for hair regeneration test C57 Black 6 mouse before.
Fig. 2 is for processing the photo of the mouse after 6 weeks with vehicle.Fig. 2 shows that only being less than the hair that 3% shaving area newly grown when using vehicle (controlled trial) covers.
Fig. 3 is bar graph, the relative hair growth when describing with N-heterocyclic carboxylic acid or carboxylic acid isostere according to the mouse of the amount treatment shaving of every milliliter of 1 micromole's per week 3 times.Hair growth is estimated after 14 days in treatment.
Detailed description of the present invention
Definition
" alkyl " refers to contain the side chain of carbonatoms of appointment or the saturated hydrocarbon chain of straight chain.For example, C
1-C
6Straight or branched alkyl hydrocarbon chain contains 1-6 carbon atom, includes but not limited to substituting group such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, n-pentyl, n-hexyl etc.Be also included within and in the scope of the present invention be, " alkyl " can refer to that also any carbon atom of said alkyl wherein is optionally by O, NH, S or SO
2The hydrocarbon chain that substitutes.For example, the carbon 2 of n-pentyl can substitute with O and form the propoxy-methyl.
" alkenyl " refers to contain the side chain of carbonatoms of appointment or the aliphatic unsaturated hydrocarbon of straight chain.For example, C
2-C
6Straight or branched alkenyl hydrocarbon chain contains 2-6 the carbon atom with at least one two key, includes but not limited to substituting group such as vinyl, propenyl, pseudoallyl, butenyl, isobutenyl, uncle's butenyl, positive pentenyl, n-hexylene base etc.Be also included within and in the scope of the present invention be, " alkenyl " can refer to that also any carbon atom of said alkenyl wherein is optionally by O, NH, S or SO
2The aliphatic unsaturated hydrocarbon that substitutes.For example, the carbon 2 of 4-pentenyl can substitute with O and form (2-propylene) oxygen ylmethyl.
" alkoxyl group " refers to group-OR, and wherein R locates defined alkyl for this reason.Preferably R is the saturated hydrocarbon chain that contains 1-6 carbon atom of side chain or straight chain.
Term " carbocyclic ring " refers to organic loop section that ring skeleton wherein only is comprised of carbon atom, one or morely is selected from the heteroatoms of nitrogen, oxygen or sulphur and can contains or organic loop section of carbon atoms not and term " heterocycle " refers to that wherein ring skeleton contains.
Therefore, term " carbocyclic ring " refers to contain the isocyclic part that specifies number carbon atom.So term " C
3-C
8Cycloalkyl " refer to that wherein three to eight carbon atoms form three, four, five, six, seven or the organic ring substituents of octatomic ring, comprise, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group." carbocyclic ring " used herein also can refer to condense formation, for example, and the cyclic rings system of two or more of two rings, three rings or other similar bridging substituting group (such as adamantyl).
" aryl " refers to the aromatic carbon cyclic group, and this aromatic carbon cyclic group has single ring such as phenyl ring; A plurality of rings such as phenylbenzene; Or wherein at least one ring is a plurality of rings of aromatic nucleus such as naphthyl, 1,2,3,4-tetralyl, anthryl or phenanthryl, and they can be for not replacing or replacing with one or more previously defined substituting groups.The substituting group that is connected to the phenyl ring part of the aryl moiety in general formula (I) compound can be connected to ortho-, meta-or p-position direction.
The example of the typical aryl moiety that is included in the scope of the present invention can include, but not limited to following groups:
" aralkyl " refers to alkyl or alkene (alkenyl) chain with aryl, heteroaryl, carbocyclic ring or heterocyclic substituted, perhaps also can be one or more aryl, heteroaryl, carbocyclic ring or the heterocycle that replaces with alkyl or alkenyl, i.e. the Ar ＇ that the alkyl of ＇ Ar replacement/alkenyl ＇ or ＇ alkyl/alkenyl replace.
" heterocycle " refers to have single ring, a plurality of ring or a plurality of condensed ring, and has at least one heteroatoms such as nitrogen, oxygen or sulphur, saturated, unsaturated or fragrant carbon ring group at least one ring therein." heteroaryl " refers to that wherein at least one ring is the heterocycle of aromatic nucleus.Any heterocyclic radical or heteroaryl can be unsubstituted, are perhaps optionally replaced by one or more previously defined groups.And the heteroaryl moieties of two-or three-ring can contain at least one all or part of saturated ring.
Those skilled in the art will appreciate that these heterocyclic moieties can exist with the form of a plurality of isomer, all these isomer all comprise in the present invention.For example, the 1,3,5-triazines part can become 1,2,4-triazine group by isomery.This positional isomers is contemplated within the scope of the present invention.Similarly, this heterocyclic radical or heteroaryl can be bonded on the other parts of the compounds of this invention.Be connected to point on these other parts and can not be interpreted as restriction to protection domain of the present invention.Therefore, for instance, the pyridyl part can be bonded on other group by 2-, 3-or the 4-position of pyridyl.All these configurations all are considered to be in protection scope of the present invention.
The heterocyclic radical that is included in the scope of the present invention or the example of heteroaryl moieties can include, but not limited to following groups:
" halogen " refers at least a in fluorine, chlorine, bromine or the iodine part.
Term " the acceptable salt of pharmacology, ester or solvate " refers to have desirable pharmacologically active and is not salt, ester or solvate unwelcome, target compound at biology and other side.This salt, ester, or solvate can be with inorganic or organic acid formation, such as acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, fumarate, the glucose enanthate, gluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromide, hydriodide, 2-hydroxyethanesulfonic acid salt, lactic acid salt, maleate, mesylate, naphthoate, the 2-naphthalenesulfonate, nicotinate, oxalate, vitriol, thiocyanate-, tosylate and undecylate.Basic salt, ester or solvate comprise ammonium salt, an alkali metal salt such as lithium, sodium and sylvite, and alkaline earth salt such as calcium and magnesium salts, with the salt of organic bases such as dicyclohexylamine, N-methyl D-glycosamine, and with the salt of amino acid such as arginine, Methionin etc.In addition, the group that contains basic nitrogen can be quaternized with these reagent, as: 1) muriate of low-carbon alkyl halogenide such as methyl, ethyl, propyl group and butyl, bromide and iodide; 2) vitriol of dialkyl sulfate such as dimethyl, diethyl, dibutyl and diamyl; 3) chain alkyl such as decyl, dodecyl, tetradecyl and the octadecyl that replace with one or more halogens such as chlorine, bromine and iodine; With 4) aryl or aralkyl halogenide such as benzyl and phenethyl bromide compound etc.
Compound of the present invention can have at least one asymmetric center, thereby can be with the form of the mixture of steric isomer or with the independently form preparation of enantiomer or diastereomer.Independent steric isomer can use a kind of opticity parent material, and the fractionation of the racemize by splitting intermediate in the synthetic a certain suitable stage or non-racemic mixture or the compound by general formula (I) obtains.Be appreciated that independent steric isomer and the mixture of steric isomer (racemize or non-racemize) all comprise within the scope of the invention.S-steric isomer on 1 atom of general formula I is most preferred embodiment of the present invention.
" steric isomer " refers to only different isomer on the spatial disposition mode of atom.
" isomer " refers to have identical molecular formula and comprises that cyclic isomers is such as the different compound of (different) indoles and other circular part isomeric forms.
" enantiomer " refers to that a pair of is the steric isomer of mirror image that can not be overlapping each other.
" diastereomer " refers to not be each other the steric isomer of mirror image.
" racemic mixture " refers to the mixture of the independent enantiomer of umbers such as containing." non-racemic mixture " refers to contain the independent enantiomer that do not wait umber or the mixture of steric isomer.
But " isostere " refers to have different molecular formula the different compounds that show identical or similar character.For example tetrazolium is a kind of isostere of carboxylic acid, although because they have diverse molecular formula, and the character of tetrazolium imitation carboxylic acid.Tetrazolium is a kind of in many isosteres that may substitute carboxylic acid.Other isostere that belongs to carboxylic acid of the present invention comprises-COOH ,-SO
3H ,-SO
2HNR
3,-PO
2(R
3)
2,-CN ,-PO
3(R
3)
2,-OR
3,-SR
3,-NHCOR
3,-N (R
3)
2,-CON (R
3)
2,-CONH (O) R
3,-CONHNHSO
2R
3,-COHNSO
2R
3, and-CONR
3CN.
In addition, the isostere of carboxylic acid can comprise the carbocyclic ring of 5-7 unit and contain the CH that is in any chemically stable oxidation state
2, O, S or N the heterocycle of any combination, wherein any atom in the said ring structure can optionally be substituted in one or more positions.Lower array structure is the example that belongs to the indefiniteness of preferred carbocyclic ring of the present invention and heterocycle isostere.
Wherein the atom on the said ring structure can be optionally at one or more position R
3Replace.Compound of the present invention still kept the character of carboxylic acid isostere when the present invention expectation joined in the isostere of carboxylic acid when chemical substituting group.
The present invention's expectation is worked as the isostere of carboxylic acid with being selected from R
3One or more part selectivity when replacing, this replacement can not be eliminated the carboxylic acid isostere character of the compounds of this invention.The present invention also expects if one or more R
3Substituting group will destroy the carboxylic acid isostere character of the compounds of this invention, the so one or more R on carbocyclic ring or heterocyclic carboxylic acid isostere
3Substituent displacement will be not keep or with the carboxylic acid isostere character of the compounds of this invention be that one or more atoms place of one carries out.
The carboxylic acid isostere of other that does not exemplify especially in this manual or describe is also included among the present invention.
Should be understood that when chemical substituting group is designated, selected chemical substituting group will form sufficiently stable compound.
Term used herein " prevention neurodegeneration " comprises when taking these compounds simultaneously, inhibition or prevention are diagnosed as the neurodegenerative ability of suffering from neurodegenerative disease or having the patient of the new neurodegenerative disease danger of development recently, and the further neurodegenerative ability of patient that suppresses or prevent to have suffered or had the neurodegenerative disease symptom.
Term used herein " treatment " has covered animal especially people's disease and/or any treatment of state, comprising:
(i) prevention may suffer from but also not be diagnosed as the generation of disease or state;
(ii) suppress disease and/or state, namely stop its development; Or
(iii) palliate a disease and/or state, even disease and/or state disappear.
Be example with compound of Formula I, the naming system of the compounds of this invention is such as following description.
A kind of compound, particularly general formula I of the present invention, wherein n is that 1, X is O, D is a key, R
1Be 1,1-dimethyl propyl, R
2For-CN, its called after (2S)-1-(1,2-dioxy-3,3-dimethyl amyl group)-2-tetramethyleneimine carbon nitrile.
" alopecia " refers to that hair growth deficiency and hair partly or entirely come off, and comprise to indefiniteness masculine sex character alopecia (male pattern alopecia), toxic alopecia, senile alopecia, bunch property alopecia, alopecia areata and trichotillomania.When the growth cycle of hair multilated, produce alopecia.Modal phenomenon is owing to hyperplasia is ended to cause hair growth or anagen phase to shorten.This will cause beginning too early of catagen phase, and cause a large amount of hairs to be arranged in stage telogen thereupon, during hair follicle separate trichomadesis from the capsule head of skin.Alopecia has multiple cause of disease, comprises the secondary action of inherited genetic factors, age, region and systemic disease, febrile state, stress, hormone problem and medicine etc.
" growth cycle of hair " refers to the life cycle of hair follicle, comprises three phases:
(1) anagen phase is active hair vegetative period, as hair of scalp, can continue about 3 to 5 years;
(2) catagen phase for growth stops and the hair follicle atrophy phase, as hair of scalp, can continue for 1 to two week; With
(3) stage telogen, in the later stage for hair separates gradually and comes off at last, as hair of scalp, can continue about 3 to 4 months.
The hair follicle of general 80-90% is in anagen phase, is less than 1% hair follicle and is in catagen phase, and remaining hair follicle is in stage telogen.The diameter of hair is even in stage telogen, has slightly microspheric colourless root.In anagen phase, hair has large coloured bulb at its root on the contrary.
The growth that " promotion hair growth " refers to keep, bring out, stimulate, accelerate or recover hair.
" hair growth " refers to:
(i) the animal alopecia that prevention may alopecia; And/or
(ii) suppress, delay or reduce alopecia; And/or
(iii) promote hair growth; And/or
(iv) anagen phase that prolongs hair cycle; And/or
(v) make it be grown to terminal hair the hair conversion.Terminal hair is thick coloured long hair, and wherein the bulb of hair follicle is buried in skin.On the contrary, hair be thin, thin, without the bob of color, wherein the bulb of hair follicle is positioned at the upper layer of skin.When developing along with alopecia, hair becomes the hair type by tip type.
Term used herein " neurotrophy " includes but not limited to ability and/or the prevention of stimulating neuronal regeneration or growth or treats neurodegenerative ability.
Term " nonimmune inhibition " refers to that compound of the present invention can not cause immune response when comparing with control sample such as FK506 or cyclosporin A.Measuring immunosuppressant test knows for those of ordinary skills.Specific and the infinite example of the test of knowing comprises PMA and OKT3 test, wherein uses mitogen to stimulate the hyperplasia of the peripheral blood lymphocytes of human body (PBC).Compound is added into the ability that suppresses this hyperplasia to estimate it in this pilot system.
Compound of the present invention
The isostere compounds that the present invention relates to carboxylic acid or carboxylic acid is neurotrophic and the surprising discovery of energy hair growth.Thereby provide a class novel compound.A favourable feature of the compounds of this invention is that they do not produce any obvious immunosuppressive activity.
Preferred compound of the present invention contains other isostere surrogate of carboxylic moiety and carboxylic moiety, and the some of them example exemplifies in front.If there is not different explanations, other isostere surrogate known by the technical staff in medical chemistry field is included in protection scope of the present invention.
Compound of the present invention can periodically be given, and for example, be in the various peripheral neuropathies relevant with neurodegeneration and the patient of europathology disorder and take, treating neurologic disease, or owing to other reason is wished stimulating neuronal regeneration and growth.Compound of the present invention takes to treat various mammiferous neurologic diseases also can for human Mammals in addition.
New compound of the present invention has good neurotrophic activity degree.This activity promotes neuron regeneration for stimulating the neurone that damages, and the prevention neurodegeneration all is useful with treating the various known neurologic diseases relevant with neuronal degeneration and peripheral neuropathy.Medicable neurologic disease includes but not limited to: trigeminal neuralgia, glossopharyngeal neuralgia, bell's palsy, myasthenia gravis, muscular dystrophy, amyotrophic lateral sclerosis, progressive myatrophy, carrying out property oblongata sex-controlled inheritance myatrophy, hernia, ruptured or prolapsed invertebrate disk syndromes, cervical spondylosis, panizza's plexuses is disorderly, thoracic outlet destruction syndromes, the neuropathy of peripheral neuropathy as being caused by lead, dapsone, tick, prophyria or Gullain-Barre syndrome, Alzheimer's, and Parkinson's disease.
The application of above-mentioned and the compounds of this invention and take relevant discussion and also be applicable to pharmaceutical composition of the present invention.
Term used herein " pharmacology acceptable carrier " refers to any carrier, thinner, vehicle, suspension agent, lubricant, auxiliary agent, vehicle, transmission system, emulsifying agent, disintegrating agent, absorption agent, sanitas, tensio-active agent, tinting material, seasonings or sweeting agent.
For these purposes, compound of the present invention can take, suck that spraying is taken, take the part, rectum is taken, nose take, buccally is taken, vagina is taken or take by the reservoir of implantation to contain conventional oral, the non-enteron aisle of atoxic pharmacology acceptable carrier, auxiliary agent or vectorial dosage form.Injection or the input technology of the non-enteron aisle of term used herein comprises subcutaneous, intravenous, intramuscular, endoperitoneal, intravaginal, intraventricular, intrasternal and encephalic.
For oral, compound of the present invention can provide with any suitable dosage form well known in the art.For example, can use conventional equipment well known in the art and technology that composition is made tablet, pulvis, granula, bead, masticable lozenge, capsule, liquor, aqeous suspension or solution or similar dosage form.Tablet form preferably.Tablet can contain carrier such as lactose and W-Gum, and/or lubricant such as Magnesium Stearate.Capsule can contain the thinner that comprises lactose and dried corn starch.Aqeous suspension can contain emulsification and the suspension agent of being combined with activeconstituents.
When preparation was combined with the dosage form of composition of the present invention, this compound also can be mixed with conventional vehicle such as tackiness agent, comprises the starch of gelatin, pregelatinized etc.; Lubricant such as hydrogenated vegetable oil, stearic acid etc.; Thinner such as lactose, seminose and sucrose; Disintegrating agent such as carboxymethyl cellulose and primojel; Suspension agent such as Povidone, polyvinyl alcohol etc.; Absorption agent such as silicon-dioxide; Sanitas such as methyl p-hydroxybenzoate, propylparaben and Sodium Benzoate; Tensio-active agent such as sodium lauryl sulphate, tween 80 etc.; Tinting material such as F.D.﹠amp; C. dyestuff or color lake etc.; Seasonings; And sweeting agent.
The technology that component of the present invention and method also can use control to discharge.Therefore, for example, the compounds of this invention can join control release within the time of a couple of days in the hydrophobic polymeric matrix.The film that this control discharges is well known in the art.Particularly preferably be transdermal delivery system.Other can be used for the example that generally is used for the polymkeric substance of this purpose of the present invention comprise can external application or in nondegradable vinyl-vinyl acetate copolymer and the degradable lactic acid-ethanol copolymer used.Some hydrogel also can use such as poly-(methacrylic acid hydroxyethyl ester) or poly-(vinyl alcohol), but in order to shorten deenergized period, should use other polymkeric substance delivery systme those delivery systmes as mentioned above.
For the central nervous system target effective is treated, the compounds of this invention should be easy to penetrate blood brain barrier when take the periphery.The compound that can not penetrate blood brain barrier can be taken effectively by the suitable transmission system that approach in the ventricle or other are suitable for being administered into brain.
The compounds of this invention can be taken with the form of sterile injectable preparation such as sterile injectable aqueous or oily suspension.These suspension can use suitable dispersion agent or wetting agent and suspension agent to prepare according to technology well known in the art.Sterile injectable preparation also can be at the nontoxic acceptable thinner of non-enteron aisle or solution or the suspension in the solvent, such as the solution in 1,3 butylene glycol.Operable in acceptable vehicle and solvent is water, Ringer's solution isotonic sodium chlorrde solution.In addition, aseptic expressed oil is conventional solvent or the suspension vehicle of using.For this reason, the expressed oil of any gentleness be can use, synthetic list or two glyceryl ester comprised.Lipid acid such as oleic acid and its glyceride derivative comprise sweet oil and Semen Ricini oil, and particularly the ethylating variant of its polyoxy can be used for the preparation of injectable formulation.These oil solutions or suspension also can contain long-chain alcohol thinner or dispersion agent.
The compounds of this invention also can be taken by rectum with the form of suppository.These compositions can prepare by medicament is mixed with a kind of suitable non-irritating excipient, and this vehicle is solid at room temperature, and is liquid under rectal temperature, thereby will melt at internal rectum and discharge medicament.This material comprises Oleum Cocois, beeswax and polyoxyethylene glycol.
The compounds of this invention also can topical, is particularly treating in the situation of accessible position or organ by topical application, comprises the neurologic disease of eye, skin or enteron aisle lower end.Can prepare easily suitable topical formulations to each this position.
Topical application for eyes or eye usefulness; the compounds of this invention can be mixed with and wait the stroke-physiological saline solution of oozing to regulate the micronize suspension of pH; perhaps preferably be mixed with waiting stroke-physiological saline solution of oozing to regulate the solution of pH, wherein contain or do not contain sanitas such as benzyl alkylammonium muriate.Perhaps for eye usefulness, this compound also can be formulated in ointment such as the vaseline.
Topical application for skin, the compounds of this invention can be formulated in a kind of suitable, contain in the ointment that is dispersed or dissolved in this compound in a kind of mixture for example, this mixture contains one or more following materials: mineral oil, petrosio, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Perhaps, this compound also can be formulated in a kind of suitable, contain in the lotion or emulsifiable paste that is dispersed or dissolved in this active compound in a kind of mixture for example, this mixture contains one or more following materials: mineral oil, sorbitan monostearate, polysorbate60, hexadecyl ester type waxes, cetearyl alcohol (cetearyl) alcohol, 2-Standamul G, phenylcarbinol and water.
Take for the lower intestine part, can adopt enteron aisle suppository formulations (seing above face) or suitable enema agent.
The dosage level that can use when the above-mentioned disease for the treatment of is the extremely approximately 10000mg active compound component order of magnitude of about 0.1mg, is preferably about 0.1mg to about 1000mg level.The amount that can be combined with solid support material with the activeconstituents of preparation unitary agent form changes according to treatment target and concrete mode of administration.Be typically, the appropriate dose that the effect of external dosage is taken the patient provides the guidance of usefulness.The research of animal model also is helpful.The method of determining the appropriate dose level is well known in the art.
But should be appreciated that, any concrete patient's given dose level depends on various changing factors, the activity, age, body weight, healthy state, sex, diet, medicine time, excretion rate, medicine that comprises used specific compound in conjunction with and the severity of the specified disease for the treatment of and take mode.
For effective hair growth or promotion hair growth, the compound that uses in the inventive method and pharmaceutical composition must can be easy to act on target site.For this purpose, compound preferably topical in skin.
In order to be locally applied to skin, the compounds of this invention can be formulated in a kind of suitable, contain in the ointment that is dispersed or dissolved in this compound in a kind of mixture for example, this mixture contains one or more following materials: mineral oil, petrosio, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Perhaps, this compound also can be formulated in a kind of suitable, contain in the lotion or emulsifiable paste that is dispersed or dissolved in this active compound in a kind of mixture for example, this mixture contains one or more following materials: mineral oil, sorbitan monostearate, polysorbate60, hexadecyl ester type waxes, cetostearyl alcohol, 2-Standamul G, phenylcarbinol and water.
The compounds of this invention can use with other hair revitalizing agent.The given dose level of other hair revitalizing agent depends on the validity of foregoing factor and medicine combination.Other route of administration of knowing in the pharmaceutical field also belongs to the scope of the invention.
The specific embodiment of the compounds of this invention is listed among Table I, II and the III.The present invention expects to use compound among following Table I, II and the III to use in composition and the method for the neurologic disease that is used for preventing and/or treating animal, with in the alopecia that is used for the treatment of animal and trichogenous composition and method, use and all other purposes of advising in this manual.
Table I
D is singly-bound and R
2Be COOH,
| Sequence number | X | n | R 1 |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 | O O O O O O O O O O O O O O O O O O O O O O O | 1 2 1 3 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 3 1 2 3 | 3,4,5-trimethylphenyl 3,4,5-trimethylphenyl tertiary butyl tertiary butyl cyclopentyl cyclopentyl cyclopentyl cyclohexyl ring hexyl cyclohexyl ring heptyl suberyl suberyl 2-thienyl 2-thienyl 2-thienyl 2-furyl 2-furyl 2-furyl phenyl 1,1-dimethyl amyl group 1,1-dimethyl hexyl ethyl |
[0161]Table II
| Sequence number | X | n | R 1 | D | R 2 |
| 24 | S | 1 | 1,1-dimethyl propyl | CH 2 | COOH |
| 25 | S | 1 | 1,1-dimethyl propyl | Singly-bound | COOH |
| 26 | O | 1 | 1,1-dimethyl propyl | CH 2 | OH |
| 27 | O | 1 | 1,1-dimethyl propyl | Singly-bound | SO 3H |
| 28 | O | 1 | 1,1-dimethyl propyl | CH 2 | CN |
| 29 | O | 1 | 1,1-dimethyl propyl | Singly-bound | CN |
| 30 | O | 1 | 1,1-dimethyl propyl | Singly-bound | Tetrazyl |
| 31 | S | 1 | Phenyl | (CH 2) 2 | COOH |
| 32 | S | 1 | Phenyl | (CH 2) 3 | COOH |
| 33 | S | 2 | Phenyl | CH 2 | COOH |
| 34 | O | 1 | 1,1-dimethyl propyl | Singly-bound | CONH 2 |
| 35 | O | 2 | 1,1-dimethyl propyl | Singly-bound | CONH 3 |
| 36 | S | 2 | The 2-furyl | Singly-bound | PO 3H 2 |
| 37 | O | 2 | Propyl group | (CH 2) 2 | COOH |
| 38 | O | 1 | Propyl group | (CH 2) 3 | COOH |
| 39 | O | 1 | The tertiary butyl | (CH 2) 4 | COOH |
| 40 | O | 1 | Methyl | (CH 2) 5 | COOH |
| 41 | O | 2 | Phenyl | (CH 2) 6 | COOH |
| 42 | O | 2 | 3,4,5-trimethoxyphenyl | CH 2 | COOH |
| 43 | O | 2 | 3,4,5-trimethoxyphenyl | CH 2 | Tetrazyl |
[0164]Table III
| Sequence number | n | X | D | R 2 | R 1 |
| 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 | 1 1 2 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 1 2 1 1 1 1 1 2 2 2 2 1 1 1 1 | S O O O O O O O O O O O S O O O O O O O O O O O O O O O O O O O O | Singly-bound singly-bound singly-bound singly-bound singly-bound CH 2Singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound CH 2 (CH 2) 2 (CH 2) 3 (CH 2) 4 | COOH COOH COOH tetrazolium SO 3H COOH SO 2HNMe CN PO 3H 2 COOH COOH COOH COOH COOH PO 2HEt PO 3H propyl group PO 3(Et) 2OMe OEt propoxy-butoxy pentyloxy hexyloxy SMe SEt rosickyite base butylthio NHCOMe NHCOEt N (Me) 2 N(Me)Et CON(Me) 2 CONHMe | Phenyl α-methylbenzyl 4-methyl-benzyl benzyl α-methylbenzyl 4-methyl-benzyl benzyl α-methylbenzyl 4-methyl-benzyl benzyl α-methylbenzyl 4-methyl-benzyl 3,4,5 Three methyl Benzene chlorine hexyl sec.-propyl ethyl-methyl tertiary butyl n-pentyl n-hexyl cyclohexyl ring amyl group n-heptyl n-octyl n-nonyl 2-indyl 2-furyl 2-thiazolyl 2-thienyl 2-pyridyl 1,1-dimethyl propyl 1,1-dimethyl propyl 1, the 1-dimethyl propyl |
[0167]
| Sequence number | n | X | D | R 2 | R 1 |
| 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 | 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 1 1 3 3 3 1 2 1 1 1 1 1 1 1 1 1 1 | O O O O O O O O O O O O S O O O O O O O O S S O O O O O O O O O O O O O O O O O O | (CH 2) 5 (CH 2) 6Singly-bound singly-bound singly-bound CH 2Singly-bound singly-bound CH 2 (CH 2) 2 (CH 2) 3 (CH 2) 4 (CH 2) 5 (CH 2) 6 (CH 2) 7 (CH 2) 8 (CH 2) 9 (CH 2) 10 C 2H 22-OH, Et crotyl sec.-propyl tertiary butyl 2-nitro hexyl (CH 2) 2 (CH 2) 3Singly-bound singly-bound singly-bound singly-bound singly-bound singly-bound (CH 2) 2 (CH 2) 3 (CH 2) 4 (CH 2) 5 (CH 2) 6 (CH 2) 7 (CH 2) 8 (CH 2) 9 C 2H 2 | CONHEt CONH propyl group CONH (O) Me CONH (O) Et CONH (O) propyl group COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH COOH CN CN CONHNHSO 2Me CONHNHSO 2Et CONHSO 2Me CONHNHSO 2Et CON(Me)CN CON(Et)CN COOH COOH COOH COOH COOH COOH COOH COOH COOH | 1,1-dimethyl propyl 1,1-dimethyl propyl benzyl Alpha-Methyl phenyl 4-aminomethyl phenyl benzyl Alpha-Methyl phenyl 4-aminomethyl phenyl 1,1-dimethyl propyl 1,1-dimethylbutyl 1,1-dimethyl amyl group 1,1-dimethyl hexyl 1, the 1-dimethyl ethyl sec.-propyl tertiary butyl 1,1-dimethyl propyl benzyl 1,1-dimethyl propyl cyclohexyl methyl 1,1-dimethyl propyl 1,1-dimethyl propyl 1,1-dimethyl propyl phenyl 1,1-dimethyl propyl 1,1-dimethyl propyl 1,1-dimethyl propyl benzyl Alpha-Methyl phenyl 4-methyl phenyl phenyl Alpha-Methyl phenyl 4-aminomethyl phenyl methylethyl n-propyl tertiary butyl amyl group hexyl heptyl octyl group cyclohexyl |
[0168]Sequence number n X D R
2R
1
118 2 O singly-bounds
1,1-dimethyl propyl
119 1 O singly-bounds
1,1-dimethyl propyl
120 1 O singly-bounds
1,1-dimethyl propyl
121 1 O singly-bounds
1,1-dimethyl propyl
122 1 O singly-bounds
1,1-dimethyl propyl
123 1 O singly-bounds
1,1-dimethyl propyl
124 1 O singly-bounds
1,1-dimethyl propyl
125 1 O singly-bounds
1,1-dimethyl propyl
Sequence number n X D R
2R
1
126 1 O singly-bounds
1,1-dimethyl propyl
127 1 O singly-bounds
1,1-dimethyl propyl
128 1 O singly-bounds
1,1-dimethyl propyl
129 1 O singly-bounds
1,1-dimethyl propyl
130 1 O singly-bounds
1,1-dimethyl propyl
131 1 O singly-bounds
1,1-dimethyl propyl
132 1 O singly-bounds
1,1-dimethyl propyl
133 1 O singly-bounds
1,1-dimethyl propyl
Sequence number n X D R
2R
1
134 1 O singly-bounds
1,1-dimethyl propyl
135 1 O singly-bounds
1,1-dimethyl propyl
136 1 O singly-bounds
1,1-dimethyl propyl
137 1 O singly-bound COOH 1, the 1-dimethyl propyl
138 2 O singly-bound COOH 1, the 1-dimethyl propyl
The specific embodiment of the present invention also comprises compound 139:
Compound 139
In addition carboxylic acid and the isostere claimed or N-heterogeneous ring compound as a comparison of the present invention that also show obvious neurotrophy and hair growth effect are listed in the following Table IV:
Table IV
| Compound | n | D | R 2 | L | R 1 |
| A/137 | 1 | Singly-bound | COOH | 1,2-dioxoethyl | 1,1-dimethyl propyl |
| B/138 | 2 | Singly-bound | COOH | 1,2-dioxoethyl | 1,1-dimethyl propyl |
| C | 1 | Singly-bound | COOH | SO 2 | Benzyl |
| D/26 | 1 | CH 2 | OH | 1,2-dioxoethyl | 1,1-dimethyl propyl |
| E/30 | 1 | Singly-bound | Tetrazolium | 1,2-dioxoethyl | 1,1-dimethyl propyl |
| F/29 | 1 | Singly-bound | -CN | 1,2-dioxoethyl | 1,1-dimethyl propyl |
| G/35 | 2 | Singly-bound | CONH 2 | 1,2-dioxoethyl | 1,1-dimethyl propyl |
| Wherein Y and Z are carbon to compd A-G. | |||||
| H | 1 | Singly-bound | COOH | 1,2-dioxoethyl | 1,1-dimethyl propyl |
| I | 1 | Singly-bound | COOH | 1,2-dioxoethyl | 1,1-dimethyl propyl |
| To compound H, Z is S; To Compound I, Y is S. |
Pharmaceutical composition of the present invention
The present invention relates to a kind of pharmaceutical composition, said composition contains:
(i) the isostere compounds of a kind of N-heterocyclic carboxylic acid of significant quantity or carboxylic acid; With
(ii) a kind of pharmacology acceptable carrier.
The present invention also relates to a kind of pharmaceutical composition, said composition contains:
(i) a kind of neurodegenerative disease that is used for the treatment of animal of significant quantity, neurologic disease and nerve injury or the N-heterocyclic carboxylic acid of promotion nerve growth or the isostere compounds of carboxylic acid; With
(ii) a kind of pharmacology acceptable carrier.
The present invention also relates to a kind of pharmaceutical composition, said composition contains:
(i) the isostere compounds of a kind of alopecia that is used for the treatment of animal of significant quantity or trichogenous N-heterocyclic carboxylic acid or carboxylic acid; With
(ii) a kind of pharmacology acceptable carrier.
The compounds of this invention can use with other neurotrophic agents, such as neurotrophic growth factor, brain derived growth factor, glial derived growth factor, CNTF, insulin-like growth factor and its active truncated derivative, acidic fibroblast growth factor, alkaline fiber cell growth factor, platelet derived growth factor, NT-3 and neurotrophin 4/5.The dosage level of other neurotrophy medicament depends on the neurotrophy effect of above-mentioned factor and medicine combination.
Method of the present invention
The present invention relates to the listed any compound of Table I, II, III and IV and the application of specifically described other compound in medicine preparation herein, this medicine is used for the treatment of disease such as the peripheral neuropathy that caused by physical damnification or morbid state, brain physical damnification, spinal cord physical damnification, apoplexy, Alzheimer's, Parkinson's disease and the amyotrophic lateral sclerosis relevant with brain injury.The present invention also relates to be used for the treatment of the application of the isostere compounds of the carboxylic acid of above-mentioned neuropathy, neurologic disease and nerve injury and carboxylic acid.
The present invention also relates to treat alopecia or the trichogenous method of animal, the method comprises to said animal uses the N-heterocyclic carboxylic acid of significant quantity or the isostere of carboxylic acid.The present invention also relates to the compounds of this invention and composition for the preparation of the treatment alopecia of animal or the application in the trichogenous medicine.
The inventive method be specially adapted to treat male pattern alopecia, senile alopecia, bunch property alopecia, because the alopecia that skin lesion or tumour cause, because the alopecia that cancer is levied alopecia that treatment as chemotherapy and radiotherapy cause and caused owing to system disorders such as nutrition disorder and endocrine regulation.
But should be appreciated that, the given dose level of any particular patient depends on various changing factors, comprises specified disease or disorderly severity and the administering mode of activity, age, body weight, healthy state, sex, diet, medicine time, excretion rate, medicine combination and the treatment of used specific compound.
The parkinsonian MPTP model of mouse
The dopaminergic neuronic MPTP infringement of mouse is as parkinsonian animal model.4 weeks, large male CD1 white mouse carried out 5 days taking medicine with the MPTP of 30mg/kg.The compounds of this invention (4mg/kg), perhaps vehicle is carried out 5 days subcutaneous administration with MPTP, and is ending to carry out after MPTP processes 5 days use again.Carrying out the MPTP processing after 18 days, kill this animal, and cutting striatum and homogenate.With the anti-tyrosine hydroxylase of 1g sagging and crown brain section is carried out immunostaining, with the dopaminergic neuronic survival of quantitative assay and recovery.When processing this animal with MPTP and vehicle, with a large amount of losses that do not have prejudicial animal to compare to observe functional dopaminergic end.In another record, after bringing out infringement, only takes MPTP test compound.Therefore, processing animal after 5 days with MPTP, passed through again other 3 days, treat at the 8th day beginning oral pharmaceutical.Animal once a day, was treated 5 days altogether with the compounds of this invention (0.4mg/kg) oral administration.The kill animals and analyzing as mentioned above at the 18th day.
Table V provides the dopaminergic neuronic recovery percentage ratio in first (parallel taking) example in the animal of having accepted carboxylic acid of the present invention or carboxylic acid isostere compounds.
Following Table V has shown the obvious neuron regeneration effect of carboxylic acid of the present invention or carboxylic acid isostere respective compound, neurotrophy ability when having described the carboxylic acid isostere as a class shows that the undermined animal capable of having accepted carboxylic acid or carboxylic acid isostere compounds produces the dopaminergic neuronic obvious recovery that TH-pollutes.
Table V-MPTP neurodegeneration model
Recovery rate %
Compd A 26.7%
Compd B ND
Compound C 24.4%
Compound D 23.2%
Compd E 19.6%
Compound F 17-hydroxy-corticosterone 34.1%
Compound G 46.5%
Compound H 14.0%
Compound I ND
The percentage ratio of the striatal neural distribution density in the brain section, the dopaminergic neurone of its deixis have been measured with anti-tyrosine hydroxylase Immunoglobulin quantitation.Only with the vehicle pre-treatment and during processing the striatal neural distribution density of oral vectorial animal be 23%, show not have normally prejudicial striatum.With the MPTP pre-treatment and during processing the striatal neural distribution density of oral vectorial animal be reduced to 5%, show that MPTP has brought out infringement.Surprisingly, with the MPTP pre-treatment and during processing the striatal neural distribution density of the animal of oral 0.4mg/kg the compounds of this invention increase 8-13%, showing after having brought out the MPTP infringement has substantial neuron regeneration.
The following examples are the descriptions to the preferred embodiments of the disclosure, but can not be interpreted as limitation of the invention.The molecular weight of all polymkeric substance all is weight-average molecular weight.Except as otherwise noted, all percentage ratio weight percentage and its total amount of all being based on the preparation of last transmission system or preparation equals 100 % by weight.
Embodiment
The compounds of this invention can prepare by the various synthetic orders that adopted existing chemistry to shift.A kind of common path such as the response path I of the compounds of this invention describe.N-glyoxylyl proline derivative can be by L-PROLINE methyl ester and the reaction of methyl oxalyl chloride are prepared, shown in response path I.The oxamate of gained can react with multiple carbon nucleophile, obtains for compound of the present invention.
Response path I
Embodiment 1 (compound 137)
(2S)-1-(3,3-dimethyl-1,2-dioxy amyl group)-pyrrolidine 2 carboxylic acid ester synthesis
A.
(2S)-1-(1,2-dioxy-2-methoxy ethyl)-pyrrolidine 2 carboxylic acid ester synthesis
The solution of L-PROLINE methyl ester hydrochloride (3.08g, 18.60mmol) in the methylene dichloride of drying is cooled to 0 ℃ also to be processed with triethylamine (3.92g, 38.74mmol, 2.1 equivalents).The slurries that form are splashed into the solution of methyl oxalyl chloride (3.20g, 26.12mmol) in methylene dichloride (45ml) wherein after 15 minutes in stirring under the nitrogen atmosphere.The gained mixture was stirred 1.5 hours under 0 ℃.After the solids removed by filtration, organic phase is washed with water, with dried over mgso and concentrated.With thick resistates purifying on silicagel column, wherein use 50% ethyl acetate/cyclohexane solution wash-out, obtain the product of 3.52g (88%) blush oil.Mixture for suitable-derotation acid amides rotational isomer; The data of trans rotational isomer have been provided.
1H NMR (CDCl
3): δ 1.93 (dm, 2H); (2.17 m, 2H); (3.62 m, 2H); (3.71 s, 3H); 3.79,3.84 (s, 3H are altogether); (4.86 dd, 1H, J=8.4,3.3).
B.
(2S)-1-(1,2-dioxy-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid methyl esters synthetic
With (2S)-1-(1,2-dioxy-2-methoxy ethyl)-pyrrolidine 2 carboxylic acid methyl esters (2.35g, 10.90mmol) solution in 30 milliliters of tetrahydrofuran (THF)s (THF) is cooled to-78 ℃, and with 1 of 14.2 milliliters of 1.0M, the THF solution-treated of 1-dimethyl propyl magnesium chloride.The gained uniform mixture, is poured into mixture in the saturated ammonium chloride (100ml), and uses ethyl acetate extraction after 3 hours-78 ℃ of stirrings.With organic phase wash with water, dry and concentrated, with the roughage purifying on silicagel column that obtains after the desolventizing, wherein use 25% ethyl acetate/cyclohexane solution wash-out, obtain 2.10g (75%) oxamate water white oil.
1H NMR (CDCl
3): δ 0.88 (t, 3H); 1.22,1.26 (s, 3H each); (1.75 dm, 2H); (1.87-2.10 m, 3H); (2.23 m, 1H); (3.54 m, 2H); (3.76 s, 3H); (4.52 dm, 1H, J=8.4,3.4).
C.
(2S)-synthetic (compound 137) of 1-(1,2-dioxy-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid
LiOH (15ml) and the methyl alcohol (50ml) of (2S)-1-(1,2-dioxy-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid methyl esters (2.10g, 8.23mmol), 1 N were stirred 30 minutes under 0 ℃, and at room temperature spend the night.Be 1 with the hcl acidifying of 1N to pH with this mixture, dilute with water is with 100 milliliters of dichloromethane extractions.Organic extract with salt water washing and concentrated, is obtained the snow-white solid that 1.73g (87%) need not be further purified.
1H NMR (CDCl
3): δ 0.87 (t, 3H); 1.22,1.25 (s, 3H each); (1.77 dm, 2H); (2.02 m, 2H); (2.17 m, 1H); (2.25 m, 1H); (3.53 dd, 2H, J=10.4,7.3); (4.55 ddm, 1H, J=8.6,4.1).
Response path II
The compounds of this invention that contains bridged ring can adopt above-mentioned synthesis path to synthesize by the substrate replacement that will contain the N-heterocycle structure with the corresponding substrate that contains the bridged ring structure.
Embodiment 2
(2S)-1-(1,2-dioxy-3,3-dimethyl amyl group)-2-tetramethyleneimine carbonyl acid amides synthetic(compound 34)
-10 ℃ and stir under with isobutyl chlorocarbonate (20mmol, 2.7ml) join and contain (2S)-1-(1,2-dioxy-3,3-dimethyl amyl group)-solution of pyrrolidine 2 carboxylic acid (4.89g, 20mmol) (obtaining from embodiment 1) and 50 milliliters of methylene dichloride.Be added dropwise to ammonia (20mmol, the 2M ethanolic soln of 10ml) after 5 minutes.After 30 minutes, reactant is warmed to room temperature-10 ℃ of stirrings.With this mixture dilute with water, and with 200 milliliters of dichloromethane extractions.Organic extract is concentrated and be further purified with silica gel, obtain 4.0g white solid product (productive rate 81.8%).
1H NMR (CDCl
3): δ 0.91 (t, 3H, J=7.5); 1.28 (s, 6H, each); (1.63-1.84 m, 2H); (1.95-2.22 m, 3H); (2.46 m, 1H); (3.55-3.67 m, 2H); (4.67 t, 1H, J=7.8); (5.51-5.53 br, 1H, NH); (6.80 br, 1H, NH).
Embodiment 3
(2S)-1-(1,2-dioxy-3,3-dimethyl amyl group)-2-tetramethyleneimine carbon nitrile synthetic(compound 29)
Under 0 ℃, in the solution that is formed by 0.465 milliliter of DMF (6mmol) and 10 milliliters of acetonitriles, add 0.48 milliliter of (5.5mmol) oxalyl chloride.Produce immediately white precipitate and be attended by gas and overflow.After reaction is finished, to wherein add by 1.2g (5mmol) (2S)-solution of 1-(1,2-dioxy-3,3-dimethyl amyl group)-2-tetramethyleneimine carbonyl acid amides (obtaining from embodiment 2) and 2.5 milliliters of acetonitriles compositions.When mixture becomes homogeneous, add 0.9 milliliter of (11mmol) pyridine.After 5 minutes, with this mixture dilute with water, and with 200 milliliters of dichloromethane extractions.Organic phase is concentrated and be further purified with silica gel, obtain 0.8g white solid product (productive rate 72%).
1H NMR(CDCl
3)：δ0.37(t，3H，J＝7.5)；1.22(s，3H)；1.24(s，3H)；1.80(m，2H)；2.03-2.23(m，4H)；3.55(m，2H)；4.73(m，1H)。
Embodiment 4
(2S)-1-(1,2-dioxy-3,3-dimethyl amyl group)-2-tetramethyleneimine tetrazolium synthetic(compound 30)
Will be by (2S)-1-(1,2-dioxy-3,3-dimethyl amyl group)-2-tetramethyleneimine carbon nitrile (222mg, 1mmol) (obtaining from embodiment 3), NaN
3(81mg, 1.3mmol), NH
4The mixture of Cl (70mg, 1.3mmol) and 3 milliliters of DMF compositions stirred 16 hours at 130 ℃.Mixture is concentrated and be further purified with silica gel, obtain 200mg white solid product (productive rate 75.5%).
1H NMR(CDCl
3)：δ0.88(t，3H，J＝7.5)；1.22(s，6H)；1.68(m，2H)；2.05-2.36(m，3H)；2.85(m，1H)；3.54(m，1H)；3.75(m，1H)；5.40(m，1H)。
Embodiment 5
Carry out external hair growth test with C57 Black 6 mouse
Hair restorability with C57 Black 6 mouse checking N-heterocyclic carboxylic acid or carboxylic acid isostere.With reference to Fig. 1 and Fig. 2 of accompanying drawing, C57 Black 6 mouse large near 7 weeks go out the hair that wherein all existence are removed in about 2 inches * 2 inches zone in its buttocks shaving.Note not making following skin layer to produce otch or cause scratch.Pinkish skin shows that this animal is in the regrowth growth phase.With reference to Fig. 2, every group of 4 mouse are processed (Fig. 2) by the propylene glycol vehicle of topical application 20%, perhaps process with the nerve immunity fkbp ligand body that is dissolved in this vehicle.This animal per 48 hours is processed (altogether using 3 times) with vehicle or neuroimmunophilin ligand in 5 days the course for the treatment of, allow hair growth continue for 6 week.The percentage ratio quantitative assay hair growth that the hair of newly being grown by its shaving zone in during this period covers.
Fig. 2 show the animal of processing with vehicle only have a small amount of spot or bunch hair growth, only be less than the hair of 3% shaving zone newly being grown and cover.
On the contrary, it is the animal that compd A (137), compd B (138) and compound G (35) processed for 2 weeks that Fig. 3 shows with N-heterocyclic carboxylic acid compound, show theatrical hair growth, two kinds of compounds wherein have the hair of newly being grown greater than 25% shaving zone to cover in all animals.
Fig. 3 shows the corresponding hair growth situation of processing C57 Black 6 mouse of rear 14 days shaving with one of three N-heterocyclic carboxylic acids or carboxylic acid isostere.Mouse is gone out 2 inches * 2 inches zone in its back shaving remove wherein all hairs.Note not making following skin layer to produce otch or cause scratch.Be that the antimony that every milliliter of 1 micromolar compound carefully is applied in mouse (every group of 5 mouse) is scraped the zone with concentration, per week is used 3 times.Estimate its hair growth situation in after the drug treating 14 days of beginning.The phase In Grade of assessing hair growth is as follows:
0=is growth not;
1=begins to have the growth of Xiao Cong;
2=is coated with＜and 25% antimony scrapes the hair growth of area;
3=is coated with＞and 25% antimony scrapes area but is lower than the hair growth that 50% antimony is scraped area;
4=is coated with＞and 50% antimony scrapes area but is lower than the hair growth that 75% antimony is scraped area;
5=antimony is scraped completely hair growth of area.
Embodiment 6
Preparation contains the lotion of following composition.
| (％) | |
| 95% ethanol | 80.0 |
| The isostere of N-heterocyclic carboxylic acid or carboxylic acid | 10.0 |
| The alpha-tocopherol acetic ester | 0.01 |
| The oxyethane of hardened castor oil (40 moles) adducts | 0.5 |
| Purified water | 9.0 |
| Spices and dyestuff | In right amount |
In 95% ethanol, oxyethane (40 moles) adducts, spices and the dyestuff of alpha-tocopherol acetic ester, hardened castor oil.The gained mixture is stirred and dissolving, and purified water is joined in this mixture, obtain transparent liquid lotion.
5 milliliters of these lotions can be used once or secondary at the position that obvious bald head or alopecia are arranged every day.
Embodiment 7
Preparation contains the lotion of following composition.
| (％) | |
| 95% ethanol | 80.0 |
| The isostere of N-heterocyclic carboxylic acid or carboxylic acid | 0.005 |
| Hinokitiol | 0.01 |
| The oxyethane of hardened castor oil (40 moles) adducts | 0.5 |
| Purified water | 19.0 |
| Spices and dyestuff | In right amount |
Add isostere, the Hinokitiol of N-heterocyclic carboxylic acid or carboxylic acid, oxyethane (40 moles) adducts, spices and the dyestuff of hardened castor oil in 95% the ethanol.With gained mixture stirring and dissolving, and purified water joined in this mixture, obtain transparent liquid lotion.
This lotion can be sprayed once to four times at the position that obvious bald head or alopecia are arranged every day.
Embodiment 8
Prepare mutually a kind of emulsion from the A phase with following composition with B.
| (A phase) | (％) |
| Spermaceti | 0.5 |
| Hexadecanol | 2.0 |
| Vaseline | 5.0 |
| Squalane | 10.0 |
| Polyoxyethylene (10 moles) monostearate | 2.0 |
| Dehydrated sorbitol mono-fatty acid ester | 1.0 |
| The isostere of N-heterocyclic carboxylic acid or carboxylic acid | 0.01 |
| (B phase) | ％ |
| Glycerine | 10.0 |
| Purified water | 69.0 |
| Spices, dyestuff and sanitas | In right amount |
[0281]With A phase and B heat fused and remain on 80 ℃ respectively mutually.Then two-phase is mixed also under agitation being cooled to normal temperature, obtain a kind of emulsion.
This emulsion can be sprayed once to four times at the position with obvious bald head or alopecia every day.
Embodiment 9
Prepare mutually a kind of emulsifiable paste from the A phase with following composition with B.
| (A phase) | (％) |
| Liquid Paraffin | 5.0 |
| Cetostearyl alcohol | 5.5 |
| Vaseline | 5.5 |
| Zerol | 33.0 |
| Polyoxyethylene (20 moles) 2-octyl group lauryl ether | 3.0 |
| Propylparaben | 0.3 |
| (B phase) | ％ |
| The isostere of N-heterocyclic carboxylic acid or carboxylic acid | 0.8 |
| Glycerine | 7.0 |
| Dipropylene glycol | 20.0 |
| Macrogol 4000 | 5.0 |
| Hexamethyl phosphoric acid sodium | 0.005 |
| Purified water | 44.895 |
With A heat phase fusing and remain on 70 ℃.With B be added to A mutually in and mixture stirred, obtain a kind of emulsion.Then this emulsion cooling is obtained a kind of emulsifiable paste
This emulsifiable paste can be used once to four times at the position that obvious bald head or alopecia are arranged every day.
Embodiment 10
Preparation contains a kind of liquid of following composition.
| (％) | |
| The polyoxyethylene butyl ether | 20.0 |
| Ethanol | 50.0 |
| The isostere of N-heterocyclic carboxylic acid or carboxylic acid | 0.001 |
| Propylene glycol | 5.0 |
| Polyoxyethylene hardened castor oil derivative (80 moles of adductss of oxyethane) | 0.4 |
| Spices | In right amount |
| Purified water | In right amount |
The isostere and the spices that add polyoxyethylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, N-heterocyclic carboxylic acid or carboxylic acid in the ethanol.The gained mixture is stirred, and purified water is joined in this mixture, obtain a kind of liquid.
This liquid can be used once to four times at the position with obvious bald head or alopecia every day.
Embodiment 11
Preparation contains a kind of shampoo of following composition.
| (％) | |
| Sodium lauryl sulphate | 5.0 |
| The dodecyl sulphate triethanol ammonium | 5.0 |
| Trimethyl-glycine dodecyl dimethyl Glycinates | 6.0 |
| Unister E 275 | 2.0 |
| Polyoxyethylene glycol | 5.0 |
| The isostere of N-heterocyclic carboxylic acid or carboxylic acid | 5.0 |
| Ethanol | 2.0 |
| Spices | 0.3 |
| Purified water | 69.7 |
[0296]In the 69.7g purified water, add the 5.0g sodium lauryl sulphate, 5.0g dodecyl sulphate triethanol ammonium, 6.0g trimethyl-glycine dodecyl dimethyl Glycinates.Then add isostere, 5.0g polyoxyethylene glycol and the 2.0g Unister E 275 of 5.0g N-heterocyclic carboxylic acid or carboxylic acid in the 2.0g ethanol, obtain a kind of mixture, then stir, and add 0.3g spices.With the gained mixture heating up, then cooling obtains a kind of shampoo.
This shampoo can be used for hair washing once a day or secondary.
Embodiment 12
A patient suffers from the senile alopecia disease.Use the isostere of N-heterocyclic carboxylic acid or carboxylic acid can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth of expecting afterwards in treatment increases.
Embodiment 13
A patient suffers from the male pattern alopecia disease.Execute the isostere of N-heterocyclic carboxylic acid or carboxylic acid can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth of expecting afterwards in treatment increases.
Embodiment 14
A patient suffers from bunch property alopecia.Use the isostere of N-heterocyclic carboxylic acid or carboxylic acid can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth of expecting afterwards in treatment increases.
Embodiment 15
A patient suffers from the epilation that is caused by skin injury.Use the isostere of N-heterocyclic carboxylic acid or carboxylic acid can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth of expecting afterwards in treatment increases.
Embodiment 16
A patient suffers from the epilation that is caused by tumour.Use the isostere of N-heterocyclic carboxylic acid or carboxylic acid can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth of expecting afterwards in treatment increases.
Embodiment 17
Patient suffers from the epilation that is caused by system disorders such as nutrition disorder or endocrine regulation.Use the isostere of N-heterocyclic carboxylic acid or carboxylic acid can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth of expecting afterwards in treatment increases.
Embodiment 18
A patient suffers from the epilation that is caused by chemotherapy.Use the isostere of N-heterocyclic carboxylic acid or carboxylic acid can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth of expecting afterwards in treatment increases.
Embodiment 19
A patient suffers from the epilation that is caused by radiotherapy.Use the isostere of N-heterocyclic carboxylic acid or carboxylic acid can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth of expecting afterwards in treatment increases.
Embodiment 20
A patient suffers from neurodegenerative disease.Use carboxylic acid or the carboxylic acid isostere of N-heterocycle for this patient, or contain the pharmaceutical composition of this compound.The situation that is contemplated that this patient improves or recovers.
Embodiment 21
The disease of neurotic of patient.Use carboxylic acid or the carboxylic acid isostere of N-heterocycle for this patient, or contain the pharmaceutical composition of this compound.The situation that is contemplated that this patient improves or recovers.
Embodiment 22
A patient suffers stroke.Use carboxylic acid or the carboxylic acid isostere of N-heterocycle for this patient, or contain the pharmaceutical composition of this compound.The situation that is contemplated that this patient improves or recovers.
Embodiment 23
A patient suffers from Parkinson's disease.Use carboxylic acid or the carboxylic acid isostere of N-heterocycle for this patient, or contain the pharmaceutical composition of this compound.The situation that is contemplated that this patient improves or recovers.
Embodiment 24
A patient suffers from Alzheimer's.Use carboxylic acid or the carboxylic acid isostere of N-heterocycle for this patient, or contain the pharmaceutical composition of this compound.The situation that is contemplated that this patient improves or recovers.
Embodiment 25
A patient suffers from peripheral neuropathy.Use carboxylic acid or the carboxylic acid isostere of N-heterocycle for this patient, or contain the pharmaceutical composition of this compound.The situation that is contemplated that this patient improves or recovers.
Embodiment 26
A patient suffers from amyotrophic lateral sclerosis.Use carboxylic acid or the carboxylic acid isostere of N-heterocycle for this patient, or contain the pharmaceutical composition of this compound.The situation that is contemplated that this patient improves or recovers.
Embodiment 27
A patient suffers from Spinal injury.Use carboxylic acid or the carboxylic acid isostere of N-heterocycle for this patient, or contain the pharmaceutical composition of this compound.The situation that is contemplated that this patient improves or recovers.
Embodiment 28
A patient has the danger of suffering from neurodegenerative disease or neurologic disease.Prophylactically use carboxylic acid or the carboxylic acid isostere of N-heterocycle for this patient, or contain the pharmaceutical composition of this compound.Compare with those patients that do not carry out pretreat, be contemplated that to prevent some or all of these diseases or disorderly generation, perhaps its situation has obtained obvious improvement or recovery.
The present invention is described, and clearly, the present invention can have the variation of various ways.This variation can not be regarded as a departure from spirit of the present invention and protection domain, and all these improvement all are included within the following claim scope.
Claims (2)
1. pharmaceutical composition, it contains:
(i) (2S)-the acceptable salt of pharmacology of 1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid or this compound; With
(ii) pharmaceutically acceptable carrier.
2. (2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-application of the acceptable salt of pharmacology of pyrrolidine 2 carboxylic acid or this compound, it is for the preparation of the medicine of the alopecia for the treatment of animal, or the application of the acceptable salt of pharmacology of this compound, it is for the preparation of trichogenous medicine.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8778898P | 1998-06-03 | 1998-06-03 | |
| US60/087,788 | 1998-06-03 | ||
| US10107798P | 1998-09-18 | 1998-09-18 | |
| US60/101,077 | 1998-09-18 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB988140993A Division CN100351230C (en) | 1998-06-03 | 1998-12-03 | Urea of N-heterocyclic carboxylic acid or the isostere of carboxylic acid and aminocarboxylic acid ester |
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| Publication Number | Publication Date |
|---|---|
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| CN 200710180921 Expired - Fee Related CN101245043B (en) | 1998-06-03 | 1998-12-03 | Aza-heterocyclic compounds used to treat neurological disorders and hair loss |
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| ZA (1) | ZA9811063B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5330993A (en) * | 1990-07-02 | 1994-07-19 | Vertex Pharmaceuticals, Inc. | Immunosuppressive compounds |
| US5614547A (en) * | 1995-06-07 | 1997-03-25 | Guilford Pharmaceuticals Inc. | Small molecule inhibitors of rotamase enzyme |
| WO1997031898A1 (en) * | 1996-02-28 | 1997-09-04 | Ariad Gene Therapeutics, Inc. | Synthetic derivatives of rapamycin as multimerizing agents for chimeric proteins with immunophilin-derived domains |
-
1998
- 1998-12-03 ZA ZA9811063A patent/ZA9811063B/en unknown
- 1998-12-03 CN CN 200710180921 patent/CN101245043B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5330993A (en) * | 1990-07-02 | 1994-07-19 | Vertex Pharmaceuticals, Inc. | Immunosuppressive compounds |
| US5614547A (en) * | 1995-06-07 | 1997-03-25 | Guilford Pharmaceuticals Inc. | Small molecule inhibitors of rotamase enzyme |
| WO1997031898A1 (en) * | 1996-02-28 | 1997-09-04 | Ariad Gene Therapeutics, Inc. | Synthetic derivatives of rapamycin as multimerizing agents for chimeric proteins with immunophilin-derived domains |
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| CN101245043A (en) | 2008-08-20 |
| ZA9811063B (en) | 2000-07-07 |
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