WO2004043471A1 - Antipruritic drug - Google Patents
Antipruritic drug Download PDFInfo
- Publication number
- WO2004043471A1 WO2004043471A1 PCT/JP2003/014446 JP0314446W WO2004043471A1 WO 2004043471 A1 WO2004043471 A1 WO 2004043471A1 JP 0314446 W JP0314446 W JP 0314446W WO 2004043471 A1 WO2004043471 A1 WO 2004043471A1
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- WO
- WIPO (PCT)
- Prior art keywords
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- optionally substituted
- substituted
- hydroxyl
- alkyl
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- 239000003908 antipruritic agent Substances 0.000 title description 13
- 208000024891 symptom Diseases 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 27
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- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 229940079593 drug Drugs 0.000 claims abstract description 20
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- 125000000217 alkyl group Chemical group 0.000 claims description 59
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- 230000001823 pruritic effect Effects 0.000 claims description 26
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 24
- 125000005843 halogen group Chemical group 0.000 claims description 22
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- REOJLIXKJWXUGB-UHFFFAOYSA-N mofebutazone Chemical group O=C1C(CCCC)C(=O)NN1C1=CC=CC=C1 REOJLIXKJWXUGB-UHFFFAOYSA-N 0.000 description 1
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- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
- A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/559—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing hetero atoms other than oxygen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
Definitions
- the present invention relates to an agent for preventing or treating pruritic symptoms (hereinafter, also referred to as an antipruritic), and particularly to an antipruritic agent which is effective in relieving pruritus caused by atopic symptoms.
- an antipruritic an agent for preventing or treating pruritic symptoms
- an antipruritic agent which is effective in relieving pruritus caused by atopic symptoms.
- drugs such as topical steroids, immunosuppressants, antihistamines, and antiallergic drugs have been used for pruritic symptoms.
- steroids and immunosuppressants has been limited due to the side effects of long-term use, and antihistamines and antiallergic agents have not been sufficiently satisfactory in terms of therapeutic effect.
- antipruritic agents was based on the administration of itch-inducing substances such as histamine and serotonin into the skin of animals to measure the pruritic behavior.In recent years, the onset of pruritus due to pruritic symptoms such as atopic dermatitis has been observed. However, it has been reported that the reaction is not simply due to histamine etc. released from mast cells (J. Dermatological Science 25, 20-28,
- An object of the present invention is to provide a novel drug for preventing or treating pruritic symptoms, in particular, a drug for preventing and treating atopic diseases.
- the present inventors have studied using the evaluation method described below to achieve the above object. As a result, it was found that certain prostaglandins have few side effects and have an antipruritic effect, especially pruritus associated with atopic symptoms. And found that the present invention was effectively suppressed, and completed the present invention.
- X represents a hydrogen atom, a methylene group, a hydroxyl group, an oxo group, an optionally substituted d- 5 alkoxy group or —S (0) nl Rs,
- ⁇ is an ethylene group, an optionally substituted vinylene group, an ethynylene group or
- Ri represents a hydrogen atom, a hydroxyl group or substituted with may be d- alkoxy group
- R2 is an alkyl group optionally d-io be substituted, an optionally substituted C 2 - 10 of an alkenyl group, substituted which may be C 2 - 10 alkynyl group, one (CH 2) wQ or formula
- R3 represents a hydrogen atom or an optionally substituted d.5 alkyl group
- R3 forms a cycloalkyl group optionally Cs-io be connexion substitutions with R 2 and adjacent carbon atoms,
- R represents a hydroxyl group or an optionally substituted d- 5 alkoxy group
- R5 is a hydroxyl group, an optionally substituted dw alkoxy group, optionally substituted C 2 - 10 Arukeniruokishi group, optionally substituted C 2 - 10 Arukiniruokishi group, optionally substituted C 3 - 10 A cycloalkyloxy group, an optionally substituted aryloxy group, an optionally substituted aryl group, an optionally substituted d-10 alkyl group,
- Each R6a and RSb is alkyl of Cno optionally substituted, optionally substituted C 2 - alkenyl group 1 (), optionally substituted C 2 - 10 alkynyl group may be substitution C 3 _ 10 represents a cycloalkyl group or 1 (CH 2 ) w ′ —Q, R 7 represents an optionally substituted C ⁇ o alkyl group or an optionally substituted aryl group,
- R8 represents an optionally substituted d. 5 alkyl group
- R9 is alkyl group optionally Cno be substituted, an optionally substituted C 2 - 10 of an alkenyl group, an optionally substituted C 2 - 10 alkynyl group, or,
- a and A ' are the same or different, an ethylene group, an optionally substituted Piniren group, Echiniren group, allene group, an optionally substituted phenylene group, cycloalkylene group optionally C _ 7 be substituted
- B and B are the same or different and each represents an oxygen atom or S ( ⁇ ) groups represented by n 2, m represents an integer of 0 to 2, n, n 1 and n 2 are the same or different 0 Represents an integer from 2 to 2, w represents an integer from 0 to 5, w 'represents an integer from 1 to 5, p, Q, r and t represent the same or different integers from 0 to 4 ( However, when E is a hydroxyl group and X is a hydrogen atom, and when both E and X are hydroxyl groups, and the compounds in the following table are excluded).
- E and X are each different JP2003 / 014446
- a prostaglandin derivative, or a pharmaceutically acceptable salt or hydrate thereof which is an oxo or hydroxyl group, or a methylene group or a hydroxyl group, respectively, as an active ingredient.
- a prostaglandin derivative of the formula [1] wherein E is an oxo or methylene group and X is a hydroxyl group, a pharmaceutically acceptable salt thereof or a hydrate thereof is effective. It is intended to provide a drug for preventing or treating the above-mentioned pruritic symptoms as a component.
- a prostaglandin derivative wherein G is —COR 5 and Y is a vinylene group or an edylene group in the formula [1], a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof.
- a drug for preventing or treating the above-mentioned pruritic symptoms comprising the hydrate as an active ingredient.
- a prostaglandin derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof is administered to a mammal in an amount effective for prevention or treatment of the symptoms. And a method for preventing or treating pruritic symptoms.
- FIG. 1 shows dermatitis scores observed over time for 4 weeks after drug administration.
- FIG. 2 shows the dermatitis score observed 4 weeks after drug administration.
- the present invention is characterized in that a prostaglandin derivative represented by the formula [1] is used as an active ingredient.
- the “prostaglandin derivative, pharmaceutically acceptable salt thereof” further includes all isomers (geometric isomers, optical isomers).
- “Pharmaceutically acceptable salt” here means, for example, sodium, potassium, etc. With alkaline metals, salts with alkaline earth metals such as calcium and magnesium, ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanol Salts with amines, tromethamine, lysine, tetraalkylammonium, tris (hydroxymethyl) aminomethane, salts with mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, Salts with organic acids such as maleic acid, maleic sulfonic acid, and benzene sulfonic acid.
- the terms used in the present invention are defined below
- Halogen atom means a fluorine, chlorine, bromine or iodine atom.
- aryl group examples include a phenyl group and a naphthyl group.
- the substituted aryl group of the “optionally substituted aryl group” includes, for example, a hydroxyl group, a halogen atom, an alkyl group of, an alkyl group of d substituted with a halogen atom, a nitro group, a cyano group, ( :. 5 alkoxy group, d is substituted with a halogen atom 5 alkoxy, phenyl group, phenoxy group, 1 or 2 C optionally substituted amino group with an alkyl group, C 2 - 5 ⁇ Alkylcarbonyl group and
- C 2 - 5 alkylcarbonyl group Ariru groups substituted on 1 ⁇ in selected from the group consisting of Amino group substituted by, preferably, a hydroxyl group, a halogen atom, d - s alkyl group, triflate Ruo b methyl , A nitro group, a cyano group, an alkoxy group, a phenyl group, a phenoxy group and an acetylamino group.
- substituted aryl group examples include a phenyl group, a tolyl group, a mesityl group, a cumenyl group and a xylyl group.
- the " ⁇ 5 alkyl group” represents a linear or branched ⁇ alkyl group having 1 to 5 carbon atoms, such as methyl, Echiru group, a propyl group, an isopropyl group, blanking butyl group, sec Examples thereof include a monobutyl group, a tert-butyl group, a pentyl group, and a tert-pentyl group.
- the substituted C-L- 5 alkyl group of the ⁇ optionally substituted d- 5 alkyl group '' is, for example, d substituted with one or more selected from the group consisting of a hydroxyl group and an octagen atom -Means an alkyl group of 5 .
- G is an alkyl group of which has been d-5-substituted
- alkyl group substituted by a halogen atom d-5 is preferred.
- R8 is a substituted d- 5 alkyl group
- an alkyl group substituted with a hydroxyl group is preferred.
- Examples of the d-5 alkyl group substituted with a hydroxyl group include a hydroxymethyl group,
- Examples thereof include a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, and a 5-hydroxypentyl group.
- Examples of the d-5 alkyl group substituted by a halogen atom include a dichloromethyl group, a trifluoromethyl group, a pentafluoroethyl group, and a 1,3-dibromopropyl group.
- D. 5 alkoxy group and represents a linear or branched alkoxy group having 1 to 5 carbon atoms, such as methoxy group, ethoxy group, propoxy group, iso epoxy group, a butoxy group, sec —Butoxy group, tert-butoxy group and pentyloxy group, and methoxy group and ethoxy group are preferred.
- the substituted ds alkoxy group of the "optionally substituted ⁇ 5 alkoxy group" is, for example, a d- 5 alkoxy group substituted by one or more selected from the group consisting of a hydroxyl group and an octagen atom Means
- Vinyl group means a cis or trans vinylene group.
- the substituted vinylene group in the “optionally substituted vinylene group” means a vinylene group substituted with one or more selected from the group consisting of a halogen atom and a d-5 alkyl group.
- alkoxy group means a linear or branched alkoxy group having 1 to 10 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy. Groups, tert-butoxy group, pentoxy group, tert-pentyloxy group, 5-methylhexyloxy group, octyloxy group, decyloxy group and the like.
- the substituted d-io alkoxy group of the "optionally substituted C ⁇ o alkoxy group” is, for example, a d-io substituted with at least one selected from the group consisting of a hydroxyl group and a halogen atom. It means an alkoxy group.
- Alkyl group refers to a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl. Group, tert-butyl group, pentyl group, tert-pentyl group, isohexyl group, heptyl group, octyl group, decyl group and the like.
- the substituted dw alkyl group in the "optionally substituted C ⁇ o alkyl group” means, for example, a Cno alkyl group substituted with one or more selected from the group consisting of a hydroxyl group and a nodogen atom. I do.
- the "C 2. 1 () alkenyl group” means a group having one or more double bonds at any position of the straight-chain or branched alkyl group having 2 to 10 carbon atoms Examples thereof include a vinyl group, an aryl group, a 1-propenyl group, an isopropenyl group, a 3-butenyl group, a 1,3-butenyl group, and a 7-octenyl group.
- C 2 is substituted - "10 alkenyl group optionally substituted C 2" - 10 Aruke two Le group, for example, substituted with one or more members selected from the group consisting of hydroxyl group and ⁇ androgenic atoms means 10 alkenyl - C 2.
- C 2. 10 alkynyl group means a group having one or more triple bonds at any position of the straight-chain or branched alkyl group having 2 to 10 carbon atoms, for example, E Examples thereof include a chel group, a 2-propenyl group, a 2-pentynyl group, and a 41-year-old cutinyl group.
- Optionally substituted C 2 - 10 alkynyl group C 2 is substituted - with 10 Arukini Le group, for example, C substituted with one or more members selected from the group consisting of hydroxyl group and eight androgenic atoms 2 - means a 10 alkynyl group.
- Examples of - "C 3 cycloalkyl group 10" may include a cyclopropyl group, Shikuropuchi group, cyclopentyl group, cyclohexyl group, heptyl group cycloalkyl, and cyclononyl groups.
- Optionally substituted C 3 - 10 cycloalkyl group C 3 is substituted - 10 Sik of The alkyl group is, for example, C 5 substituted with at least one selected from the group consisting of C 5 alkyl groups which may be substituted with a halogen atom, hydroxyl group and halogen atom.
- the ". C 2 10 Arukeniruokishi group” a linear or branched alkenyl group having a carbon number of 2 to 10 - O-has a structure composed of, for example Ariruoki sheet group And a propenyloxy group, a 1-isopropenyloxy group, a 3-butenyloxy group, a 1,3-butenyloxy group, a 7-octenyloxy group, and the like.
- Optionally substituted C 2 - 10 Arukeniruokishi group C 2 is substituted - with 10 ⁇ Rukeniruokishi group, for example, substituted with a hydroxyl group and from selected Ru 1 or more group consisting of halogen atoms means 10 Arukeniruokishi group - C 2 was.
- C 2 10 Arukiniruokishi group have a straight or branched configuration alkynyl groups and in which one ⁇ - was combined C2-10, such as 2-propyl Examples include a niloxy group, a 2-pentynyloxy group, and a 4-octynyloxy group.
- Rukiniruokishi group e.g., hydroxyl and eight androgenic than selected Ru 1 or more group consisting of atoms - the "optionally substituted C 2 - 10 Arukiniruokishi group" C 2 which is substituted means 10 Arukiniruokishi group - C 2 which it is.
- C 3 10 cycloalkyl O alkoxy group includes a cycloalkyl group c 3 10.
- the compound has a complex form, and examples thereof include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and a cyclononyloxy group.
- C 3 is substituted - with 10 cycloalkyl O alkoxy group, for example, an alkyl group of which has been or d-5 substituted with a halogen atom , Substituted with one or more selected from the group consisting of a hydroxyl group and an octylogen atom Has been C 3 - 10 means a cycloalkyl O alkoxy group.
- aryloxy group examples include a phenoxy group and a naphthoxy group.
- the substituted aryloxy group of the "optionally substituted aryloxy group” is a hydroxyl group, a halogen atom, an alkyl group of ds, an alkyl group of d- 5 substituted with a halogen atom, a nitro group, a cyano group.
- substituted aryloxy group examples include a bromophenoxy group, a chlorophenoxy group, a tolyloxy group, a cumenyloxy group, and a methoxyphenoxy group.
- cycloalkylene C 3 _ 7 may include cyclopropylene group, cyclobutylene group, cyclopentylene group, cyclohexylene group, a etc. heptylene cyclohexylene.
- alkyl groups may be substituted with a halogen atom, a hydroxyl group, and eight androgenic atoms means one or more substituted c 3 _ 7 of consequent opening alkylene group selected from the group consisting of.
- Q may be substituted C 3 - as example for a cycloalkyl group 10, cyclopropylmethyl group, cyclobutyl E methyl group, consequent opening Penchirumechiru group, a cycloalkyl Examples include a hexylmethyl group, a cycloheptylmethyl group, a cyclononylbutyl group, and a 41-fluorocyclohexylmethyl group.
- Q is an aryloxy group which may be substituted Examples thereof include a phenoxymethyl group, a phenoxypropyl group, a chlorophenoxyethyl group, a methoxyphenoxymethyl group, a trioxymethyl group and the like.
- R2 is an (CH 2) w- Q
- Q is C 3 - 10 cycloalkyl group or ⁇ Li
- Ruokishi groups are preferred.
- R6a and R6b are come as an (CH 2) w- Q, Q is C 3 - preferably a cycloalkyl group 10.
- R8 is a d-5 alkyl group which may be substituted
- an alkyl group substituted by a hydroxyl group is preferable.
- prostaglandin derivative represented by the formula [1] as the active ingredient of the present invention are described below.
- E and X are preferably respectively different oxo or hydroxyl groups, or differently different methylene groups or hydroxyl groups, and more preferably E is an oxo or methylene group and X is a hydroxyl group.
- Y is preferably an ethylene group, an optionally substituted vinylene group, or an ethynylene group, and more preferably a vinylene group or an ethynylene group.
- R 5 is preferably a hydroxyl group, an alkoxy group, or —NHS O2R 7 .
- Z preferably one (CH 2) P A (CH 2) qA, (CH 2) r first and one (CH 2) p A (CH 2) q B (CH 2) a r scratch.
- R9 is preferably an optionally substituted ( ⁇ alkyl group, more preferably a Ci-s alkyl group.
- the prostaglandin derivative serving as the active ingredient of the present invention includes known compounds disclosed in the following publications. Patent No. 2503047, Patent No. 2571250, Patent No. 2641622, Patent No. 2677779, Patent No.
- Typical compounds of the formula (1) according to the present invention include the following compounds.
- Table 1 shows the prostaglandin where Z is a group represented by the formulas (CH 2 ) p A (CH 2 ) qA and (CH 2 ) r , and the formula (CH 2 ) p A (CH 2 ) q B ( The prostaglandin represented by CH 2 ) r is shown in Table 2, the prostaglandin represented by the formula (CH 2 ) P B (CH 2 ) q B '(CH 2 ) r is shown in Table 3, and the formula (CH 2) pB '(CH 2) q a' (CH 2) illustrating the prostaglandins represented by r in Table 4.
- Table 1 shows the prostaglandin where Z is a group represented by the formulas (CH 2 ) p A (CH 2 ) qA and (CH 2 ) r , and the formula (CH 2 ) p A (CH 2 ) q B ( The prostaglandin represented by CH 2
- Z-CH CH: cispinylene group
- Z-C bond between Z and the adjacent 5-membered ring carbon atom
- E-C or X-C Bond between E or X and the adjacent 5-membered carbon
- ⁇ -G Bond between Y and the adjacent 5-membered carbon
- R1-C bond between R1 and adjacent carbon atom
- E-GH GH: transpinylene group
- Z-CH CH: cis vinylene group
- Z-G Bond between Z and adjacent 5-membered ring carbon atom
- E-CorX-C Bond between E or X and the adjacent 5-membered carbon
- Y-C Bond between Y and adjacent 5-membered ring carbon atom
- Z-CH CH: cis vinylene group
- Z-G Bond between Z and adjacent 5-membered ring carbon atom
- E-GorX- G bond between E or X and the adjacent 5-membered carbon
- Y-C bond between Y and an adjacent 5-membered ring carbon atom
- R1-C Bond between R1 and adjacent carbon atom
- Z-G Bond between Z and adjacent 5-membered ring carbon atom
- E-G or X-G bond between E or X and the adjacent 5-membered carbon
- Y-C Bond between Y and adjacent 5-membered ring carbon atom
- R1-C Bond between R1 and adjacent carbon atom
- E-CH GH: trans vinylene group
- Gyc5 cyclopentyl group
- Z-C Bond between Z and adjacent 5-membered carbon atom
- E-G or X_G Bond between E or X and the adjacent 5-membered carbon
- Y-C Bond between Y and the adjacent 5-membered ring carbon atom
- R1- G bond between m and adjacent carbon atom
- E-CH GH: trans vinylene group
- Z-G Bond between Z and adjacent 5-membered ring carbon atom
- E-G or X-G Bond between E or X and the adjacent 5-membered carbon
- Y-G bond between Y and an adjacent 5-membered ring carbon atom
- the antipruritic agent of the present invention is not particularly limited as long as it reduces or eliminates pruritus, and is particularly effective for pruritus due to atopy (antigen-specific immunoreaction via IgE antibody). From this point, the antipruritic agent of the present invention includes a drug for preventing or treating atopic symptoms.
- the “pruritic condition” refers to a condition having localized or generalized itching and associated inflammation on the skin and mucous membranes. Examples include scabies, juniper measles, eczema, xeroderma (xeroderma senile, sebum deficient eczema, etc.), psoriasis, cutaneous pruritus and prurigo.
- atopic symptom refers to a symptom having localized or generalized itching caused by atopy and inflammation related thereto on the skin and mucous membranes, that is, a pruritic symptom caused by atopy.
- atopic symptom refers to a symptom having localized or generalized itching caused by atopy and inflammation related thereto on the skin and mucous membranes, that is, a pruritic symptom caused by atopy.
- Examples include atopic dermatitis and atopic conjunctivitis.
- atopic dermatitis refers to a disease in which pruritus eczema is the main lesion that repeats exacerbation and remission, and occurs in individuals with an atopic predisposition (a predisposition to produce IgE antibodies).
- atopic dermatitis refers to a disease in which pruritus eczema is the main lesion that repeats exacerbation and remission, and occurs in individuals with an atopic predisposition (a predisposition to produce IgE antibodies).
- the dose of the active ingredient in the antipruritic agent of the present invention can be appropriately increased or decreased according to the patient's body weight, age, sex, etc., but is usually 1 ng to 10 mg per administration, preferably 0.1 to 1.0. It can be administered once to several times a day.
- the antipruritic agent of the present invention can also be used in combination with an antihistamine (eg, diphenhydramine, carbinoxamine, chlorpheniramine, ranitidine, a salt thereof, etc.) as an active ingredient.
- an antihistamine eg, diphenhydramine, carbinoxamine, chlorpheniramine, ranitidine, a salt thereof, etc.
- the antipruritic agent of the present invention can be prepared as a pharmaceutical composition using carriers, excipients, and other additives commonly used in the formulation of the active ingredient.
- carriers and excipients for pharmaceuticals for example, water, ethanol, lactose, microcrystalline cellulose, liquid paraffin, hydrogenated oil, honey, squalane, stearyl alcohol, ethylene glycol and the like are commonly used. You can give something.
- additives examples include disintegrants (starch, etc.), binders ⁇ hydroxypropylcellulose, low-substituted hydroxypropylsulose ⁇ , lubricants (talc, glyceryl stearate, etc.), antioxidants, preservatives ( Paraben), Cotin Agents (gelatin, hydroxypropylcellulose, etc.), coloring agents, flavoring agents, whitening agents (sodium ellagate, etc.), surfactants (such as sorbitan fatty acid esters), plasticizers, humectants (glycerin, propylene glycol) , Polyethylene dalicol, haluronic acid, etc.).
- the antipruritic agent of the present invention is in the form of tablets, granules, powders, capsules, liquids, gels, plasters, ointments, creams, patches, aerosols, etc. (Including eye drops and nasal drops).
- Preferred dosage forms include external preparations because they can be directly administered to the affected area, are easy to administer, and reduce the possibility of systemic side effects.
- the "external preparation” includes a liquid preparation for external use, an aerosol, a powder for external use, an ointment, a cream, a gel, a plaster, a patch and the like.
- drug concentration (%) means w / v%.
- Magnets are implanted in both feet of a 20-week-old NC / Nga mouse (purchased from SLC) weighing about 30 g and developing atopic dermatitis, and the movement of the feet is sensed by detecting the magnetic force. Manufactured). Of the pulling actions, those with 1.5 seconds or more were regarded as pruritic actions, and the number of times was continuously measured. Because of the diurnal rhythm of pruritus behavior, the daily pruritus rhythm of each animal was measured 24 hours from the day before the test, and then each drug dissolved in 100% ethanol was applied to the back skin at a rate of 0.2 ml / mouse.
- the pruritic behavior for 24 hours was measured and the number of pruritic behavior before and after drug administration was compared.
- the pruritus suppression rate was calculated from the total number of pruritus 24 hours before and after drug application, and is shown in Table 5. The significant difference test was performed using a paired t'test for the number of pruritus before and after drug application in each animal of each drug concentration application group.
- Itching suppression rate (%) (itch number before application / itch number after application) xlOOZ number of itching before application
- mice After living together for 2 weeks, the purchased mice were removed and reared in separate cages at 8 per cage until the start of the test. Immediately before the start of drug application, the mice were sorted so that the Zhao flame scores of each cage became equal, and the mice were reared at 4 mice per cage.
- Drug administration Compound 3 (0.01%) and compound 16 (solubilized in 99.5% ethanol, 99.5% ethanol) in the back skin of 20-week-old NC mice that developed skin inflammation by living with NC mice that developed skin inflammation 0.01%) was applied 200 times each once a day for 4 weeks using a micropip. The untreated group received no treatment. Each group was tested with 8 animals per group.
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Abstract
A drug which contains as an active ingredient a prostaglandin derivative represented by the following formula, a pharmaceutically acceptable salt thereof, or a hydrate of either. The drug is reduced in side effects and has an antipruritic effect. It can effectively diminish the itchiness accompanying, in particular, atopic symptom.
Description
明細書 鎮痒剤 本発明は、 搔痒性症状の予防または治療用薬剤 （以下、 鎮痒剤ともいう） に関 し、 特にアトピー症状による搔痒感の解消に効果がある鎮痒剤に関する。 背景技術 TECHNICAL FIELD The present invention relates to an agent for preventing or treating pruritic symptoms (hereinafter, also referred to as an antipruritic), and particularly to an antipruritic agent which is effective in relieving pruritus caused by atopic symptoms. Background art
近年、 アトピー性皮膚炎、 アトピー性結膜炎、 老人性乾皮膚症などの搔痒性症 状の患者数が急激に増加してきている。 これらの疾患は原因不明の強い痒み感を 有し、 また搔痒行動 （引つ搔き行動） により粘膜または皮膚に炎症が発生するも のと考えられている。 したがって、 これらの症状の解消には搔痒感を解消するこ とが非常に重要である。 In recent years, the number of patients with pruritic symptoms such as atopic dermatitis, atopic conjunctivitis, and senile xerosis has rapidly increased. These diseases have a strong itching sensation of unknown cause, and it is thought that pruritic behavior (pulling behavior) causes inflammation of mucous membranes or skin. Therefore, it is very important to eliminate pruritus to eliminate these symptoms.
従来、 搔痒性症状に対しては、 外用ステロイド剤、 免疫抑制剤、 抗ヒスタミン 剤、 抗アレルギー剤などの薬剤が使用されている。 しかし、 ステロイド剤および 免疫抑制剤は長期連用による副作用からその使用が制限されており、 抗ヒスタミ ン剤、抗アレルギー剤は、治療効果の点で十分満足のいくものが得られていない。 また、 これまで鎮痒剤 の評価は、 ヒスタミン、セロトニン等の痒み惹起物質を 動物の皮膚内に投与し搔痒行動を測定していたが、 近年アトピー性皮膚炎などの 搔痒性症状による痒みの発症は、 単なる肥満細胞から放出されるヒスタミン等に よる反応ではないと報告されている （J. Dermatological Science 25, 20-28, Conventionally, drugs such as topical steroids, immunosuppressants, antihistamines, and antiallergic drugs have been used for pruritic symptoms. However, the use of steroids and immunosuppressants has been limited due to the side effects of long-term use, and antihistamines and antiallergic agents have not been sufficiently satisfactory in terms of therapeutic effect. In the past, the evaluation of antipruritic agents was based on the administration of itch-inducing substances such as histamine and serotonin into the skin of animals to measure the pruritic behavior.In recent years, the onset of pruritus due to pruritic symptoms such as atopic dermatitis has been observed. However, it has been reported that the reaction is not simply due to histamine etc. released from mast cells (J. Dermatological Science 25, 20-28,
2001)。 2001).
したがって、 ァトピー性皮膚炎などの搔痒性症状の予防及び治療に対して新た な作用機序に基づく鎮痒剤の開発が望まれている。 Therefore, development of an antipruritic agent based on a new mechanism of action for prevention and treatment of pruritic symptoms such as atopic dermatitis is desired.
一方、 プロスタグランジン類が痒み惹起成分であるという報告はなされている が鎮痒剤としての使用は知られていない (J. Am. Acad. Dermatol. 7, 28-32, On the other hand, it has been reported that prostaglandins are itch-inducing components, but their use as antipruritic agents is not known (J. Am. Acad. Dermatol. 7, 28-32,
2002)。 発明の開示
本発明は、 新規な搔痒性症状の予防または治療用薬剤、 特にアトピー性疾患予 防及び治療用薬剤を提供することを目的とする。 2002). Disclosure of the invention An object of the present invention is to provide a novel drug for preventing or treating pruritic symptoms, in particular, a drug for preventing and treating atopic diseases.
本発明者らは、 上記目的を達成するために、 後述の評価方法を用いて検討した 結果、 ある種のプロスタグランジン類が副作用が少なく止痒効果を有すること、 特にアトピー症状に伴う搔痒感を効果的に抑制することを見出し、 本発明を完成 した。 The present inventors have studied using the evaluation method described below to achieve the above object. As a result, it was found that certain prostaglandins have few side effects and have an antipruritic effect, especially pruritus associated with atopic symptoms. And found that the present invention was effectively suppressed, and completed the present invention.
すなわち、 本発明の 1態様によると、 That is, according to one embodiment of the present invention,
式 [1] Equation [1]
Gは水素原子、 ハロゲン原子、 ニトロ基、 シァノ基、 水酸基、 置換されてもよい ァリール基、 置換されてもよい アルキル基、 一 （CH2) w— Q、 一 CH = NR4、 一 COR5、 一〇R6a、 一 NHR6a、 — NR6aR6b、 G is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, an optionally substituted aryl group, an optionally substituted alkyl group, one (CH 2 ) w—Q, one CH = NR4, one COR5, one 〇R6a, one NHR6a, — NR6aR6b,
-NHSO2R7または一 S(〇)nR を示し、 -NHSO2R 7 or one S (〇) n R,
Xは水素原子、 メチレン基、 水酸基、 ォキソ、 置換されてもよい d-5 のアルコ キシ基または—S(0)nlRs を示し、 X represents a hydrogen atom, a methylene group, a hydroxyl group, an oxo group, an optionally substituted d- 5 alkoxy group or —S (0) nl Rs,
γはエチレン基、 置換されてもよいビニレン基、 ェチニレン基または γ is an ethylene group, an optionally substituted vinylene group, an ethynylene group or
-OCH2- を示し、 -OCH 2-
Zは式 Z is the expression
― (CH2) PA (CH2) qB (CH2) r一、 ― (CH 2 ) P A (CH 2 ) q B (CH 2 ) r
一 (CH2) PA (CH2) qA， (CH2) r一、 One (CH 2 ) P A (CH 2 ) qA, (CH 2 ) r one,
一 (CH2) PB (CH2) qB' (CH2) r- または One (CH 2 ) P B (CH 2 ) q B '(CH 2 ) r -or
一 (CH2) PB， (CH2) qA， (CH2) r一
で表される基を示し、 (CH 2 ) P B, (CH 2 ) q A, (CH 2 ) r Represents a group represented by
Ri は水素原子、 水酸基または置換されてもよい d- のアルコキシ基を示し、 R2 は置換されてもよい d-io のアルキル基、 置換されてもよい C2-10 のアル ケニル基、 置換されてもよい C2-10 のアルキニル基、 一 （CH2) w-Q または式 Ri represents a hydrogen atom, a hydroxyl group or substituted with may be d- alkoxy group, R2 is an alkyl group optionally d-io be substituted, an optionally substituted C 2 - 10 of an alkenyl group, substituted which may be C 2 - 10 alkynyl group, one (CH 2) wQ or formula
R3は水素原子または置換されてもよい d.5アルキル基を示すか、 R3 represents a hydrogen atom or an optionally substituted d.5 alkyl group,
または R3が Ri と一緒になつてォキソまたは =NR4を示すか、 Or R3 together with Ri indicates oxo or = NR 4 ,
または R3が R2および隣接する炭素原子と一緒になつて置換されてもよい Cs-ioのシクロアルキル基を形成し、 Or R3 forms a cycloalkyl group optionally Cs-io be connexion substitutions with R 2 and adjacent carbon atoms,
R4は水酸基または置換されてもよい d-5 アルコキシ基を示し、 R represents a hydroxyl group or an optionally substituted d- 5 alkoxy group,
R5は水酸基、置換されてもよい d-wアルコキシ基、置換されてもよい C2-10 アルケニルォキシ基、置換されてもよい C2-10 アルキニルォキシ基、置換されて もよい C3-10 のシクロアルキルォキシ基、 置換されてもよいァリ一ルォキシ基、 置換されてもよいァリール基、 置換されてもよい d- 10 アルキル基、 R5 is a hydroxyl group, an optionally substituted dw alkoxy group, optionally substituted C 2 - 10 Arukeniruokishi group, optionally substituted C 2 - 10 Arukiniruokishi group, optionally substituted C 3 - 10 A cycloalkyloxy group, an optionally substituted aryloxy group, an optionally substituted aryl group, an optionally substituted d-10 alkyl group,
— NHR6a、 -NR6aR6b または— NHS02R7 を示し、 — NHR6a, -NR6aR6b or — NHS0 2 R7,
R6aおよび RSb はそれぞれ、 置換されてもよい Cno のアルキル基、 置換され てもよい C2-1() のアルケニル基、 置換されてもよい C2-10 のアルキニル基、 置 換されてもよい C3_10のシクロアルキル基または一 （CH2) w' — Qを示し、 R7 は置換されてもよい C^o のアルキル基または置換されてもよいァリール 基を示し、 Each R6a and RSb is alkyl of Cno optionally substituted, optionally substituted C 2 - alkenyl group 1 (), optionally substituted C 2 - 10 alkynyl group may be substitution C 3 _ 10 represents a cycloalkyl group or 1 (CH 2 ) w ′ —Q, R 7 represents an optionally substituted C ^ o alkyl group or an optionally substituted aryl group,
R8 は置換されてもよい d.5 アルキル基を示し、 R8 represents an optionally substituted d. 5 alkyl group,
R9 は置換されてもよい Cno のアルキル基、 置換されてもよい C2-10 のアル ケニル基、 置換されてもよい C2-10 のアルキニル基、 または、 R9 is alkyl group optionally Cno be substituted, an optionally substituted C 2 - 10 of an alkenyl group, an optionally substituted C 2 - 10 alkynyl group, or,
一 (CH2) w— Qを示し、
Qは置換されてもよい C 3 - 1 0 のシクロアルキル基または置換されてもよいァリ 一ルォキシ基を示し、 は単結合または二重結合を示し、 One (CH 2 ) w—shows Q, Q is optionally substituted C 3 - 1 indicates 0 cycloalkyl group or an optionally substituted § Li one Ruokishi group also, represents a single bond or a double bond,
Aおよび A'は同一または異なって、 エチレン基、 置換されてもよいピニレン基、 ェチニレン基、 アレン基、 置換されてもよいフエ二レン基、 置換されてもよい C _7のシクロアルキレン基 A and A 'are the same or different, an ethylene group, an optionally substituted Piniren group, Echiniren group, allene group, an optionally substituted phenylene group, cycloalkylene group optionally C _ 7 be substituted
Bおよび B，は同一または異なって、酸素原子または S (〇)n 2で表される基を示し、 mは 0〜2の整数を示し、 n、 n 1および n 2は同一または異なって 0〜 2の整 数を示し、 wは 0〜5の整数を示し、 w' は 1〜5の整数を示し、 p、 Q、 rお よび tは同一または異なって 0〜4の整数を示す （ただし、 Eが水酸基であり、 かつ、 Xが水素原子である場合、 及び E及び Xの両方が水酸基である場合、 並び に下記表の化合物を除く）。 ]で表されるプロスタグランジン誘導体、 その製薬学 的に許容される塩またはその水和物を有効成分とする搔痒性症状の予防または治 療用薬剤を提供する。 B and B, are the same or different and each represents an oxygen atom or S (〇) groups represented by n 2, m represents an integer of 0 to 2, n, n 1 and n 2 are the same or different 0 Represents an integer from 2 to 2, w represents an integer from 0 to 5, w 'represents an integer from 1 to 5, p, Q, r and t represent the same or different integers from 0 to 4 ( However, when E is a hydroxyl group and X is a hydrogen atom, and when both E and X are hydroxyl groups, and the compounds in the following table are excluded). A prostaglandin derivative represented by the formula [I], or a pharmaceutically acceptable salt or hydrate thereof, as an active ingredient.
本発明の他の態様によると、 式 [1]において Eおよび Xは、 それぞれ異なって
JP2003/014446 According to another embodiment of the present invention, in formula [1], E and X are each different JP2003 / 014446
ォキソまたは水酸基であるか、 または、 それぞれ異なってメチレン基または水酸 基であるプロスタグランジン誘導体、 その製薬学的に許容される塩またはその水 和物を有効成分とする上記の搔痒性症状の予防または治療用薬剤を提供する。 本発明の他の態様によると、 式 [ 1 ]において Eがォキソまたはメチレン基であ り、 Xが水酸基であるプロスタグランジン誘導体、 その製薬学的に許容される塩 またはその水和物を有効成分とする上記の搔痒性症状の予防または治療用薬剤を 提供する。 A prostaglandin derivative, or a pharmaceutically acceptable salt or hydrate thereof, which is an oxo or hydroxyl group, or a methylene group or a hydroxyl group, respectively, as an active ingredient. Provide a prophylactic or therapeutic agent. According to another embodiment of the present invention, a prostaglandin derivative of the formula [1] wherein E is an oxo or methylene group and X is a hydroxyl group, a pharmaceutically acceptable salt thereof or a hydrate thereof is effective. It is intended to provide a drug for preventing or treating the above-mentioned pruritic symptoms as a component.
本発明の他の態様によると、 式 [ 1 ]において Gが— C O R5 であり、 Yがビニ レン基またはエヂ二レン基であるプロスタグランジン誘導体、 その製薬学的に許 容される塩またはその水和物を有効成分とする上記の搔痒性症状の予防または治 療用薬剤を提供する。 According to another embodiment of the present invention, a prostaglandin derivative wherein G is —COR 5 and Y is a vinylene group or an edylene group in the formula [1], a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof. There is provided a drug for preventing or treating the above-mentioned pruritic symptoms, comprising the hydrate as an active ingredient.
本発明の他の態様によると、 搔痒性症状の予防または治療剤の製造における、 上記いずれかのプロスタグランジン誘導体、 その製薬学的に許容される塩または その水和物の使用を提供する。 According to another aspect of the present invention, there is provided the use of any of the above prostaglandin derivatives, pharmaceutically acceptable salts or hydrates thereof in the manufacture of a prophylactic or therapeutic agent for pruritic symptoms.
本発明の他の態様によると、 症状の予防または治療に有効である量の上記いず れかのプロスタグランジン誘導体、 その製薬学的に許容される塩またはその水和 物を哺乳動物に投与することを含む搔痒性症状の予防または治療方法を提供する。 図面の簡単な説明 According to another aspect of the present invention, a prostaglandin derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof is administered to a mammal in an amount effective for prevention or treatment of the symptoms. And a method for preventing or treating pruritic symptoms. BRIEF DESCRIPTION OF THE FIGURES
図 1は、 薬物投与後 4週間経時的に観察した皮膚炎スコアを示す。 FIG. 1 shows dermatitis scores observed over time for 4 weeks after drug administration.
図 2は、 薬物投与後 4週間目に観察した皮膚炎スコアを示す。 発明を実施するための最良の形態 FIG. 2 shows the dermatitis score observed 4 weeks after drug administration. BEST MODE FOR CARRYING OUT THE INVENTION
以下、 本発明の鎮痒剤について説明する。 Hereinafter, the antipruritic agent of the present invention will be described.
本発明は、 式 [ 1 ]で表されるプロスタグランジン誘導体を有効成分とすること を特徴とする。 The present invention is characterized in that a prostaglandin derivative represented by the formula [1] is used as an active ingredient.
ここで、 「プロスタグランジン誘導体、その製薬学的に許容される塩」 とは、 さ らに、 全ての異性体 （幾何異性体、 光学異性体） を包含する。 · ここで、 「製薬学的に許容される塩」 とは、例えば、 ナトリウム、 カリウムなど
のアルカリ金属との塩、 カルシウム、 マグネシウムなどのアルカリ土類金属との 塩、 アンモニア、 メチルァミン、 ジメチルァミン、 シクロペンチルァミン、 ベン ジルァミン、 ピぺリジン、 モノエタノールァミン、 ジエタノールァミン、 モノメ チルモノエタノールァミン、 トロメタミン、 リジン、 テトラアルキルアンモニゥ ム、 トリス （ヒドロキシメチル） ァミノメタンなどとの塩、 硫酸、 塩酸、 リン酸 などの鉱酸との塩、 酢酸、 シユウ酸、 乳酸、 酒石酸、 フマール酸、 マレイン酸、 メ夕ンスルホン酸、 ベンゼンスルホン酸などの有機酸との塩などである。 本発明において使用される用語が以下に定義される。 Here, the “prostaglandin derivative, pharmaceutically acceptable salt thereof” further includes all isomers (geometric isomers, optical isomers). · “Pharmaceutically acceptable salt” here means, for example, sodium, potassium, etc. With alkaline metals, salts with alkaline earth metals such as calcium and magnesium, ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanol Salts with amines, tromethamine, lysine, tetraalkylammonium, tris (hydroxymethyl) aminomethane, salts with mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, Salts with organic acids such as maleic acid, maleic sulfonic acid, and benzene sulfonic acid. The terms used in the present invention are defined below.
「ハロゲン原子」 とは、 フッ素原子、 塩素原子、 臭素原子またはヨウ素原子を 意味する。 “Halogen atom” means a fluorine, chlorine, bromine or iodine atom.
「ァリール基」 の例としては、 フエニル基、 ナフチル基などを挙げることがで さる。 Examples of the "aryl group" include a phenyl group and a naphthyl group.
「置換されてもよいァリール基」 の置換されたァリール基とは、 例えば、 水酸 基、 ハロゲン原子、 のアルキル基、 ハロゲン原子で置換された d のァ ルキル基、 ニトロ基、 シァノ基、 （： 5 のアルコキシ基、 ハロゲン原子で置換さ れた d .5 のアルコキシ基、 フエニル基、 フエノキシ基、 1または 2個の C のアルキル基で置換されてもよいアミノ基、 C 2— 5のァルキルカルボニル基及びThe substituted aryl group of the “optionally substituted aryl group” includes, for example, a hydroxyl group, a halogen atom, an alkyl group of, an alkyl group of d substituted with a halogen atom, a nitro group, a cyano group, ( :. 5 alkoxy group, d is substituted with a halogen atom 5 alkoxy, phenyl group, phenoxy group, 1 or 2 C optionally substituted amino group with an alkyl group, C 2 - 5 § Alkylcarbonyl group and
C 2— 5のアルキルカルボニル基で置換されたァミノ基からなる群より選ばれる 1 偭以上で置換されたァリール基、 好ましくは、 水酸基、 ハロゲン原子、 d - s の アルキル基、 トリフルォロメチル基、 ニトロ基、 シァノ基、 のアルコキシ 基、 フエニル基、 フエノキシ基及びァセチルァミノ基からなる群より選ばれる 1 個以上で置換されたァリ一ル基を意味する。 C 2 - 5 alkylcarbonyl group Ariru groups substituted on 1偭以in selected from the group consisting of Amino group substituted by, preferably, a hydroxyl group, a halogen atom, d - s alkyl group, triflate Ruo b methyl , A nitro group, a cyano group, an alkoxy group, a phenyl group, a phenoxy group and an acetylamino group.
「置換されたァリール基」 の例としては、 クロ口フエ二ル基、 トリル基、 メシ チル基、 クメニル基、 キシリル基などを挙げることができる。 Examples of the “substituted aryl group” include a phenyl group, a tolyl group, a mesityl group, a cumenyl group and a xylyl group.
「〇 5 のアルキル基」 とは、 炭素原子数 1〜5の直鎖状または分枝鎖状のァ ルキル基を示し、 例えばメチル基、 ェチル基、 プロピル基、 イソプロピル基、 ブ チル基、 s e c一ブチル基、 t e r t—ブチル基、 ペンチル基、 t e r t—ペン チル基などを挙げることができる。
「置換されてもよい d-5 のアルキル基」 の置換された C;L-5 のアルキル基と は、例えば、水酸基及び八ロゲン原子からなる群より選ばれる 1個 以上で置換さ れた d-5 のアルキル基を意味する。 Gが置換された d-5 のアルキル基である 場合、 ハロゲン原子で置換された d-5 のアルキル基が好ましい。 R8が置換さ れた d-5 のアルキル基であるとき、 水酸基で置換された のアルキル基が 好ましい。 The "〇 5 alkyl group" represents a linear or branched § alkyl group having 1 to 5 carbon atoms, such as methyl, Echiru group, a propyl group, an isopropyl group, blanking butyl group, sec Examples thereof include a monobutyl group, a tert-butyl group, a pentyl group, and a tert-pentyl group. The substituted C-L- 5 alkyl group of the `` optionally substituted d- 5 alkyl group '' is, for example, d substituted with one or more selected from the group consisting of a hydroxyl group and an octagen atom -Means an alkyl group of 5 . When G is an alkyl group of which has been d-5-substituted, alkyl group substituted by a halogen atom d-5 is preferred. When R8 is a substituted d- 5 alkyl group, an alkyl group substituted with a hydroxyl group is preferred.
水酸基で置換された d-5 のアルキル基の例としては、 ヒドロキシメチル基、 Examples of the d-5 alkyl group substituted with a hydroxyl group include a hydroxymethyl group,
1ーヒドロキシェチル基、 2—ヒドロキシェチル基、 2—ヒドロキシプロピル基、 3—ヒドロキシプロピル基、 2， 3—ジヒドロキシプロピル基、 5—ヒドロキシ ペンチル基などを挙げることができる。 Examples thereof include a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, and a 5-hydroxypentyl group.
ハロゲン原子で置換された d-5 のアルキル基の例としては、 ジクロロメチル 基、 トリフルォロメチル基、 ペンタフルォロェチル基、 1, 3—ジブロモプロピ ル基などを挙げることができる。 Examples of the d-5 alkyl group substituted by a halogen atom include a dichloromethyl group, a trifluoromethyl group, a pentafluoroethyl group, and a 1,3-dibromopropyl group.
「d.5 のアルコキシ基」 とは、 炭素原子数 1〜5の直鎖状または分枝鎖状の アルコキシ基を示し、 例えばメトキシ基、 エトキシ基、 プロポキシ基、 イソプロ ポキシ基、 ブトキシ基、 s e c—ブトキシ基、 t e r t—ブトキシ基、 ペンチル ォキシ基を挙げられ、 好ましくはメトキシ基、 エトキシ基である。 "D. 5 alkoxy group" and represents a linear or branched alkoxy group having 1 to 5 carbon atoms, such as methoxy group, ethoxy group, propoxy group, iso epoxy group, a butoxy group, sec —Butoxy group, tert-butoxy group and pentyloxy group, and methoxy group and ethoxy group are preferred.
「置換されてもよい < 5 のアルコキシ基」 の置換された d-s のアルコキシ 基とは、例えば、水酸基及び八ロゲン原子からなる群より選ばれる 1個 以上で置 換された d- 5 のアルコキシ基を意味する。 The substituted ds alkoxy group of the "optionally substituted < 5 alkoxy group" is, for example, a d- 5 alkoxy group substituted by one or more selected from the group consisting of a hydroxyl group and an octagen atom Means
「ビニレン基」 とは、 シスまたはトランスのビニレン基を意味する。 “Vinylene group” means a cis or trans vinylene group.
「置換されてもよいビニレン基」 の置換されたビニレン基とは、 ハロゲン原子 および d-5 アルキル基からなる群より選ばれる 1個以上で置換されたビニレン 基を意味する。 The substituted vinylene group in the “optionally substituted vinylene group” means a vinylene group substituted with one or more selected from the group consisting of a halogen atom and a d-5 alkyl group.
のアルコキシ基」 とは、 炭素原子数 1〜1 0の直鎖状または分枝鎖状 のアルコキシ基を示し、 例えばメトキシ基、 エトキシ基、 プロポキシ基、 イソプ 口ポキシ基、 ブトキシ基、 s e c一ブトキシ基、 t e r t—ブトキシ基、 ペンチ ルォキシ基、 t e r t—ペンチルォキシ基、 5—メチルへキシルォキシ基、 ォク チルォキシ基、 デシルォキシ基などを挙げることができる。
「置換されてもよい C^o のアルコキシ基」 の置換された d-io のアルコキ シ基とは、 例えば、 水酸基及びハロゲン原子からなる群より選ばれる 1個以上で 置換された d-io のアルコキシ基を意味する。 The term "alkoxy group" means a linear or branched alkoxy group having 1 to 10 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy. Groups, tert-butoxy group, pentoxy group, tert-pentyloxy group, 5-methylhexyloxy group, octyloxy group, decyloxy group and the like. The substituted d-io alkoxy group of the "optionally substituted C ^ o alkoxy group" is, for example, a d-io substituted with at least one selected from the group consisting of a hydroxyl group and a halogen atom. It means an alkoxy group.
「じ ^ のアルキル基」 とは、 炭素原子数 1~10の直鎖状または分枝鎖状の アルキル基を示し、 例えばメチル基、 ェチル基、 プロピル基、 イソプロピル基、 ブチル基、 s e c—プチル基、 t e r t—ブチル基、 ペンチル基、 t e r t—べ ンチル基、 イソへキシル基、 ヘプチル基、 ォクチル基、 デシル基などを挙げるこ とができる。 “Alkyl group” refers to a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl. Group, tert-butyl group, pentyl group, tert-pentyl group, isohexyl group, heptyl group, octyl group, decyl group and the like.
「置換されてもよい C^o のアルキル基」 の置換された d-w のアルキル基 とは、 例えば、 水酸基及びノヽロゲン原子からなる群より選ばれる 1個以上で置換 された Cnoのアルキル基を意味する。 The substituted dw alkyl group in the "optionally substituted C ^ o alkyl group" means, for example, a Cno alkyl group substituted with one or more selected from the group consisting of a hydroxyl group and a nodogen atom. I do.
「C2.1() のアルケニル基」 とは、炭素原子数 2〜10の直鎖状または分枝鎖状 のアルキル基の任意の位置に 1個以上の二重結合を有する基を意味し、 例えばビ ニル基、ァリル基、 1一プロぺニル基、イソプロぺニル基、 3—ブテニル基、 1， 3—ブタジェニル基、 7—ォクテニル基などを挙げることができる。 The "C 2. 1 () alkenyl group" means a group having one or more double bonds at any position of the straight-chain or branched alkyl group having 2 to 10 carbon atoms Examples thereof include a vinyl group, an aryl group, a 1-propenyl group, an isopropenyl group, a 3-butenyl group, a 1,3-butenyl group, and a 7-octenyl group.
「置換されてもよい C2-10 のアルケニル基」 の置換された C2-10 のァルケ二 ル基とは、 例えば、 水酸基及び Λロゲン原子からなる群より選ばれる 1個以上で 置換された C2-10 のアルケニル基を意味する。 C 2 is substituted - "10 alkenyl group optionally substituted C 2" - 10 Aruke two Le group, for example, substituted with one or more members selected from the group consisting of hydroxyl group and Λ androgenic atoms means 10 alkenyl - C 2.
「C2.10 のアルキニル基」 とは、 炭素原子数 2〜10の直鎖状または分枝鎖状 のアルキル基の任意の位置に 1個以上の三重結合を有する基を意味し、 例えばェ チェル基、 2—プロピエル基、 2—ペンチニル基、 4一才クチニル基などを挙げ ることができる。 The "C 2. 10 alkynyl group" means a group having one or more triple bonds at any position of the straight-chain or branched alkyl group having 2 to 10 carbon atoms, for example, E Examples thereof include a chel group, a 2-propenyl group, a 2-pentynyl group, and a 41-year-old cutinyl group.
「置換されてもよい C2-10 のアルキニル基」 の置換された C2-10 のアルキニ ル基とは、 例えば、 水酸基及び八ロゲン原子からなる群より選ばれる 1個以上で 置換された C2-10 のアルキニル基を意味する。 "Optionally substituted C 2 - 10 alkynyl group" C 2 is substituted - with 10 Arukini Le group, for example, C substituted with one or more members selected from the group consisting of hydroxyl group and eight androgenic atoms 2 - means a 10 alkynyl group.
「C3-10 のシクロアルキル基」 の例としては、 シクロプロピル基、 シクロプチ ル基、 シクロペンチル基、 シクロへキシル基、 シクロへプチル基、 シクロノニル 基などを挙げることができる。 Examples of - "C 3 cycloalkyl group 10" may include a cyclopropyl group, Shikuropuchi group, cyclopentyl group, cyclohexyl group, heptyl group cycloalkyl, and cyclononyl groups.
「置換されてもよい C3-10 のシクロアルキル基」 の置換された C3-10 のシク
口アルキル基とは、 例えば、 ハロゲン原子で置換されてもよい Cい 5 のアルキル 基、 水酸基及びハロゲン原子からなる群より選ばれる 1個以上で置換された C"Optionally substituted C 3 - 10 cycloalkyl group" C 3 is substituted - 10 Sik of The alkyl group is, for example, C 5 substituted with at least one selected from the group consisting of C 5 alkyl groups which may be substituted with a halogen atom, hydroxyl group and halogen atom.
3- 1 0のシクロアルキル基を意味する。 Means 3 1 0 cycloalkyl group.
「置換された C3-10のシクロアルキル基」 の例としては、 4一フルォロシクロ へキシル基、 4, 4ージフルォロシクロへキシル基、 4—メトキシシクロへキシ ル基、 2—メチルシクロへキシル基、 4—トリフルォロメチルシクロへキシル基 などを挙げることができる。 Examples of - "C 3 substituted cycloalkyl group of 10", 4 hexyl group one Furuoroshikuro, 4, 4-difluoromethyl O b cyclohexyl group, 4-methoxy cycloheteroalkyl alkoxy group, the 2-methylcyclohexane A xyl group, a 4-trifluoromethylcyclohexyl group, and the like.
「C2.10 のアルケニルォキシ基」 とは、 炭素原子数 2〜10の直鎖状または分 枝鎖状のアルケニル基と— O—が複合した形態を有しており、 例えばァリルォキ シ基、 プロぺニルォキシ基、 1一イソプロぺニルォキシ基、 3—ブテニルォキシ 基、 1, 3—ブタジェニルォキシ基、 7—ォクテニルォキシ基などを挙げること ができる。 The ". C 2 10 Arukeniruokishi group", a linear or branched alkenyl group having a carbon number of 2 to 10 - O-has a structure composed of, for example Ariruoki sheet group And a propenyloxy group, a 1-isopropenyloxy group, a 3-butenyloxy group, a 1,3-butenyloxy group, a 7-octenyloxy group, and the like.
「置換されてもよい C2-10 のアルケニルォキシ基」 の置換された C2— 10 のァ ルケニルォキシ基とは、 例えば、 水酸基及びハロゲン原子からなる群より選ばれ る 1個以上で置換された C2- 10のアルケニルォキシ基を意味する。 "Optionally substituted C 2 - 10 Arukeniruokishi group" C 2 is substituted - with 10 § Rukeniruokishi group, for example, substituted with a hydroxyl group and from selected Ru 1 or more group consisting of halogen atoms means 10 Arukeniruokishi group - C 2 was.
「C2-10 のアルキニルォキシ基」 とは、 炭素原子数 2〜10の直鎖状または分 枝鎖状のアルキニル基と一〇—が複合した形態を有しており、 例えば 2—プロピ ニルォキシ基、 2—ペンチニルォキシ基、 4—ォクチニルォキシ基などを挙げる ことができる。 The - "C 2 10 Arukiniruokishi group" have a straight or branched configuration alkynyl groups and in which one 〇- was combined C2-10, such as 2-propyl Examples include a niloxy group, a 2-pentynyloxy group, and a 4-octynyloxy group.
「置換されてもよい C2-10 のアルキニルォキシ基」 の置換された C2-10 のァ ルキニルォキシ基とは、 例えば、 水酸基及び八ロゲン原子からなる群より選ばれ る 1個以上で置換された C2-10のアルキニルォキシ基を意味する。 Substituted with a 10 § Rukiniruokishi group, e.g., hydroxyl and eight androgenic than selected Ru 1 or more group consisting of atoms - the "optionally substituted C 2 - 10 Arukiniruokishi group" C 2 which is substituted means 10 Arukiniruokishi group - C 2 which it is.
「C3-10 のシクロアルキルォキシ基」 とは、 c3.10 のシクロアルキル基と—And - "C 3 10 cycloalkyl O alkoxy group" includes a cycloalkyl group c 3 10. -
〇一が複合した形態を有しており、 例えば、 シクロプロピルォキシ基、 シクロブ チルォキシ基、 シクロペンチルォキシ基、 シクロへキシルォキシ基、 シクロヘプ チルォキシ基、 シク口ノニルォキシ基などを挙げることができる。 The compound has a complex form, and examples thereof include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and a cyclononyloxy group.
「置換されてもよい C3-10 のシクロアルキルォキシ基」 の置換された C3-10 のシクロアルキルォキシ基とは、例えば、ハロゲン原子で置換されてもよい d- 5 のアルキル基、 水酸基及び八ロゲン原子からなる群より選ばれる 1個以上で置換
された C3-10 のシクロアルキルォキシ基を意味する。 "Optionally substituted C 3 - 10 cycloalkyl O alkoxy group" C 3 is substituted - with 10 cycloalkyl O alkoxy group, for example, an alkyl group of which has been or d-5 substituted with a halogen atom , Substituted with one or more selected from the group consisting of a hydroxyl group and an octylogen atom Has been C 3 - 10 means a cycloalkyl O alkoxy group.
「ァリールォキシ基」 の例としては、 フエノキシ基、 ナフトキシ基などを挙げ ることができる。 Examples of the "aryloxy group" include a phenoxy group and a naphthoxy group.
「置換されてもよぃァリールォキシ基」 の置換されたァリ一ルォキシ基とは、 水酸基、 ハロゲン原子、 d-s のアルキル基、 ハロゲン原子で置換された d-5 のアルキル基、 ニトロ基、 シァノ基、 のアルコキシ基、 ハロゲン原子で置 換された d-s のアルコキシ基、 フエニル基、 フエノキシ基、 1または 2個の C 1-5 のアルキル基で置換されてもよいアミノ基、 C2_5のアルキル力ルポニル基 及び C2_5のアルキルカルポニル基で置換されたァミノ基からなる群より選ばれ る 1個以上で置換されたァリールォキシ基、好ましくは、水酸基、ハロゲン原子、The substituted aryloxy group of the "optionally substituted aryloxy group" is a hydroxyl group, a halogen atom, an alkyl group of ds, an alkyl group of d- 5 substituted with a halogen atom, a nitro group, a cyano group. , an alkoxy group, an alkoxy group of ds which are substitution with a halogen atom, phenyl group, phenoxy group, one or two alkyl groups optionally substituted amino group of the C 1-5, alkyl of C 2 _ 5 force Ruponiru group and C 2 _ 5 alkyl Cal Poni Le group Ariruokishi group substituted with from selected Ru 1 or more group consisting of amino group substituted by, preferably, a hydroxyl group, a halogen atom,
Cl-5 のアルキル基、 トリフルォロメチル基、 ニトロ基、 シァノ基、 d-5 のァ ルコキシ基、 フエニル基、 フエノキシ基及びァセチルァミノ基からなる群より選 ばれる 1個以上で置換されたァリール基を意味する。 An aryl group substituted with one or more selected from the group consisting of an alkyl group of Cl-5, trifluoromethyl group, nitro group, cyano group, alkoxy group of d- 5 , phenyl group, phenoxy group and acetylamino group. Means
「置換されたァリールォキシ基」 の例としては、 ブロモフエノキシ基、 クロ口 フエノキシ基、 トリルォキシ基、 クメニルォキシ基、 メトキシフエノキシ基など を挙げることができる。 Examples of the “substituted aryloxy group” include a bromophenoxy group, a chlorophenoxy group, a tolyloxy group, a cumenyloxy group, and a methoxyphenoxy group.
「C3_7のシクロアルキレン基」 の例としては、 シクロプロピレン基、 シクロ ブチレン基、 シクロペンチレン基、 シクロへキシレン基、 シクロへプチレン基な どを挙げることができる。 Examples of "cycloalkylene C 3 _ 7" may include cyclopropylene group, cyclobutylene group, cyclopentylene group, cyclohexylene group, a etc. heptylene cyclohexylene.
「置換されてもよい C3_7のシクロアルキレン基」の置換された C3_7のシクロ アルキレン基とは、 ハロゲン原子で置換されてもよい のアルキル基、 水酸 基及び八ロゲン原子からなる群より選ばれる 1個以上で置換された c3_7のシク 口アルキレン基を意味する。 The substituted cycloalkyl alkylene C 3 _ 7 of "cycloalkylene group optionally C 3 _ 7 be substituted", alkyl groups may be substituted with a halogen atom, a hydroxyl group, and eight androgenic atoms means one or more substituted c 3 _ 7 of consequent opening alkylene group selected from the group consisting of.
一 (CH2) w— Qにおいて、 Qが置換されてもよい C3-10 のシクロアルキル 基の場合の例としては、 シクロプロピルメチル基、 シクロブチルェチル基、 シク 口ペンチルメチル基、 シクロへキシルメチル基、 シクロへプチルメチル基、 シク 口ノニルブチル基、 4一フルォロシク口へキシルメチル基などを挙げることがで さる。 In one (CH 2) w- Q, Q may be substituted C 3 - as example for a cycloalkyl group 10, cyclopropylmethyl group, cyclobutyl E methyl group, consequent opening Penchirumechiru group, a cycloalkyl Examples include a hexylmethyl group, a cycloheptylmethyl group, a cyclononylbutyl group, and a 41-fluorocyclohexylmethyl group.
一 (CH2) w— Qにおいて、 Qが置換されてもよいァリールォキシ基の場合
の例としては、 フエノキシメチル基、 フエノキシプロピル基、 クロロフエノキシ ェチル基、 メトキシフエノキシメチル基、 トリルォキシメチル基などを挙げるこ とができる。 I (CH 2 ) w— In Q, when Q is an aryloxy group which may be substituted Examples thereof include a phenoxymethyl group, a phenoxypropyl group, a chlorophenoxyethyl group, a methoxyphenoxymethyl group, a trioxymethyl group and the like.
R2が一 （CH2) w— Qであるとき、 Qは C3-10 のシクロアルキル基または ァリ一ルォキシ基が好ましい。 R6a および R6b が一 （CH2) w— Qであると き、 Qは C3-10 のシクロアルキル基が好ましい。 When R2 is an (CH 2) w- Q, Q is C 3 - 10 cycloalkyl group or § Li one Ruokishi groups are preferred. R6a and R6b are come as an (CH 2) w- Q, Q is C 3 - preferably a cycloalkyl group 10.
R8は置換されてもよい d-5 アルキル基である場合、水酸基で置換された のアルキル基が好ましい。 When R8 is a d-5 alkyl group which may be substituted, an alkyl group substituted by a hydroxyl group is preferable.
本発明の有効成分となる式 [1]のプロスタグランジン誘導体の他の好ましい態 様を以下にあげる。 Other preferred embodiments of the prostaglandin derivative represented by the formula [1] as the active ingredient of the present invention are described below.
Eおよび Xは、 好ましくは、 それぞれ異なってォキソまたは水酸基であるか、 または、 それぞれ異なってメチレン基または水酸基であり、 さらに好ましくは、 Eがォキソまたはメチレン基であり、 Xが水酸基である。 E and X are preferably respectively different oxo or hydroxyl groups, or differently different methylene groups or hydroxyl groups, and more preferably E is an oxo or methylene group and X is a hydroxyl group.
Yは、 好ましくはエチレン基、 置換されてもよいビニレン基、 ェチニレン基で あるが、 より好ましくはビニレン基またはェチニレン基である。 Y is preferably an ethylene group, an optionally substituted vinylene group, or an ethynylene group, and more preferably a vinylene group or an ethynylene group.
Yがビニレン基である場合、 トランスでもシスでも好ましい。 When Y is a vinylene group, trans or cis is preferred.
Gは、 好ましくはシァノ基、 _CH = NR4、 -COR5 であり、 より好まし くは— COR5である。 ここで、 R 5は水酸基、 アルコキシ基、 — NHS O2R7であるのが好ましい。 G is preferably a cyano group, —CH = NR4, —COR5, more preferably —COR5. Here, R 5 is preferably a hydroxyl group, an alkoxy group, or —NHS O2R 7 .
Zは、 好ましくは、 一 （CH2) PA (CH2) qA， (CH2) r一及び一 （CH2) p A (CH2) qB (CH2) r一である。 Z preferably one (CH 2) P A (CH 2) qA, (CH 2) r first and one (CH 2) p A (CH 2) q B (CH 2) a r scratch.
Zがー （CH2) p A (CH2) qA， (CH2) r一であるとき、 好ましくは、 A 及び A，は、同一又は異なって、— CH2CH2— 、 一 CH-CH—、 一 C≡C一、 — CH=C = CH—であるか、 又は A及び A'のいずれかが、 2, 5— C4H2〇、 2, 5— C4H2Sであって、 他が _CH2CH2— であ る 。 When Z is-(CH 2 ) p A (CH 2 ) qA, (CH 2 ) r , preferably, A and A are the same or different and are —CH 2 CH 2 —, one CH-CH —, One C≡C one, — CH = C = CH—, or one of A and A ′ is 2, 5—C 4 H 2 〇, 2, 5—C 4 H 2 S And the other is _CH 2 CH 2 —.
Zがー （CH2) p A (CH2) qB (CH2) r—であるとき、 Aがー CH2CH 2— であ り 、 Bが〇または Sであるのが好ましい。 When it is, A gar CH 2 CH 2 - - Z Gar (CH 2) p A (CH 2) q B (CH 2) r der Ri, B is preferably a 〇 or S.
R9は、 好ましくは、 置換されてもよい（ ^ のアルキル基であり、 さらに好 ましくは、 Ci-sのアルキル基である。
本発明の有効成分となるプロスタグランジン誘導体は以下の公報に開示された 公知化合物を含む。 特許第 2503047号、 特許第 2571250号、 特許第 2641622号、 特許第 2677779、 特許第 3316050号、 W094 /27962、 W〇 98/34916、 WO 00/54809、 WO 00/61 550、 WO 01/19789, 特開昭 52-83524号、 特開昭 53- 15 342号、 特開昭 53— 21147号、 特開昭 54— 141751号、 特開昭 5 5- 133354号、 特開昭 58 -4762号、 特開昭 58— 29710号、 特 開昭 59— 134746号、 特開昭 63— 122663号、 特開昭 63— 122 665号、 特開平 5— 58992号、 特開平 5— 1 17230号、 特開平 5— 2 94924号、 特開平 6— 107626号、 特開平 6— 1 16233、 特開平 7 一 25847号、 特開平 7— 233145号、 特開平 7— 238068号、 特開 平 7— 285930号、 特開平 8— 310956号、 特開平 10— 168056 号、 特開平 10— 175948号、 特開平 11一 12249号、 特開平 11— 1 93268号、 特開平 11一 322709号、 特開 2000— 1472号、 特開 2000— 128858号、 特開 2000— 302751号、 特開 2001— 0 55375号、特開 2001— 316357号、特開 2002— 161082号、 特公平 6— 51678号、 特公平 6— 62559号、 特公平 6— 88966号、 特公平 7— 116134号。 R9 is preferably an optionally substituted (^ alkyl group, more preferably a Ci-s alkyl group. The prostaglandin derivative serving as the active ingredient of the present invention includes known compounds disclosed in the following publications. Patent No. 2503047, Patent No. 2571250, Patent No. 2641622, Patent No. 2677779, Patent No. 3316050, W094 / 27962, W〇98 / 34916, WO 00/54809, WO 00/61 550, WO 01/19789, JP-A-52-83524, JP-A-53-15342, JP-A-53-21147, JP-A-54-141751, JP-A-55-133354, JP-A-58-4762, JP-A-58-29710, JP-A-59-134746, JP-A-63-122663, JP-A-63-122665, JP-A-5-58992, JP-A-5-117230, JP-A-5-117230 5-2 94924, JP-A-6-107626, JP-A-6-116233, JP-A-7-125847, JP-A-7-233145, JP-A-7-238068, JP-A-7-285930, Kaihei 8-310956, JP 10-168056, JP 10-175948, JP 11-12249, JP 11-1 93268, JP 11-322709, JP 2000-1472, Open 2000-128858, JP 2000-302751, JP 2001-0553 No. 75, JP-A-2001-316357, JP-A-2002-161082, Japanese Patent Publication No. 6-51678, Japanese Patent Publication No. 6-62559, Japanese Patent Publication No. 6-88966, and Japanese Patent Publication No. 7-116134.
本発明に係る代表的な式 （1) の化合物としては下記の化合物をあげることが できる。 Zが式 (CH2) p A (CH2) qA， (CH2) r で表される基であるプロ ス夕グランジンを表 1に、 式 （CH2) p A (CH2) qB (CH2) rで表される プロスタグランジンを表 2に、 式 （CH2) PB (CH2) qB' (CH2) r で表されるプロスタグランジンを表 3に、式（CH2) pB' (CH2) qA' (CH2) rで表されるプロスタグランジンを表 4に示す。
表 1 Typical compounds of the formula (1) according to the present invention include the following compounds. Table 1 shows the prostaglandin where Z is a group represented by the formulas (CH 2 ) p A (CH 2 ) qA and (CH 2 ) r , and the formula (CH 2 ) p A (CH 2 ) q B ( The prostaglandin represented by CH 2 ) r is shown in Table 2, the prostaglandin represented by the formula (CH 2 ) P B (CH 2 ) q B '(CH 2 ) r is shown in Table 3, and the formula (CH 2) pB '(CH 2) q a' (CH 2) illustrating the prostaglandins represented by r in Table 4. table 1
E-CH=CH：トランスビニレン基 E-CH = CH: trans vinylene group
Z-CH=CH：シスピニレン基 Z-CH = CH: cispinylene group
Ms:メタンスルホニル基 Ms: methanesulfonyl group
Z - C:Zと隣接した 5員環炭素原子との結合 Z-C: bond between Z and the adjacent 5-membered ring carbon atom
E-C or X - C:Eまたは Xとそれぞれ隣接した 5員環炭素との結合 丫- G:Yと隣接した 5員環炭素原子との結合 E-C or X-C: Bond between E or X and the adjacent 5-membered carbon 丫-G: Bond between Y and the adjacent 5-membered carbon
R1-C:R1と隣接した炭素原子との結合 R1-C: bond between R1 and adjacent carbon atom
Me:メチル基
Me: methyl group
表 1つづき Table 1 continued
E-GH=GH:トランスピニレン基 E-GH = GH: transpinylene group
Z-CH=CH：シスビニレン基 Z-CH = CH: cis vinylene group
Z-G:Zと隣接した 5員環炭素原子との結合 Z-G: Bond between Z and adjacent 5-membered ring carbon atom
E- CorX- C:Eまたは Xとそれぞれ隣接した 5員環炭素との結合 E-CorX-C: Bond between E or X and the adjacent 5-membered carbon
Y-C:Yと隣接した 5員環炭素原子との結合Y-C: Bond between Y and adjacent 5-membered ring carbon atom
1 -C： R1と隣接した炭素原子との結合
1 -C: Bond between R1 and adjacent carbon atom
表 1つづき Table 1 continued
E-CH=CH：トランスビニレン基 E-CH = CH: trans vinylene group
Z-CH=CH：シスビニレン基 Z-CH = CH: cis vinylene group
2.5-C4H20： J jL 2.5-C4H20: J jL
o o
2.5-C4H2S: え V 2.5-C4H2S: Huh V
Ms:メタンスルホニル基 Ms: methanesulfonyl group
Z-G:Zと隣接した 5員環炭素原子との結合 Z-G: Bond between Z and adjacent 5-membered ring carbon atom
E-GorX- G:Eまたは Xとそれぞれ隣接した 5員環炭素との結合 E-GorX- G: bond between E or X and the adjacent 5-membered carbon
Y - C:Yと隣接した 5員環炭素原子との結合 Y-C: bond between Y and an adjacent 5-membered ring carbon atom
R1- C:R1と隣接した炭素原子との結合
R1-C: Bond between R1 and adjacent carbon atom
表 2 Table 2
E-GH=CH：トランスビニレン基 E-GH = CH: trans vinylene group
cyc6：シクロへキシル基 cyc6: cyclohexyl group
Ms :メタンスルホニル基 Ms: methanesulfonyl group
Z - G :Zと隣接した 5員環炭素原子との結合 Z-G: Bond between Z and adjacent 5-membered ring carbon atom
E-G or X-G:Eまたは Xとそれぞれ隣接した 5員環炭素との結合 E-G or X-G: bond between E or X and the adjacent 5-membered carbon
Y-C:Yと隣接した 5員環炭素原子との結合 Y-C: Bond between Y and adjacent 5-membered ring carbon atom
R1-C： R1と隣接した炭素原子との結合
R1-C: Bond between R1 and adjacent carbon atom
表 3 Table 3
E-CH=GH：トランスビニレン基 E-CH = GH: trans vinylene group
Gyc5:シクロペンチル基 Gyc5: cyclopentyl group
cyc6：シクロへキシル基 cyc6: cyclohexyl group
cyc6m:シクロへキシルメチル基 cyc6m: cyclohexylmethyl group
Gyc7:シクロへプチル基 G yc7: cycloheptyl group
Z-C： Zと隣接した 5員環炭素原子との結合 Z-C: Bond between Z and adjacent 5-membered carbon atom
E-G or X_G:Eまたは Xとそれぞれ隣接した 5員環炭素との結合 E-G or X_G: Bond between E or X and the adjacent 5-membered carbon
Y-C： Yと隣接した 5員環炭素原子との結合 Y-C: Bond between Y and the adjacent 5-membered ring carbon atom
R1- G:mと隣接した炭素原子との結合
R1- G: bond between m and adjacent carbon atom
表 4 Table 4
E- CH=GH :トランスビニレン基 E-CH = GH: trans vinylene group
Gyc5:シクロペンチル基 G yc5: cyclopentyl group
cyc6 :シクロへキシル基 cyc6: cyclohexyl group
cyc6m：シクロへキシルメチル基 cyc6m: cyclohexylmethyl group
Z-G :Zと隣接した 5員環炭素原子との結合 Z-G: Bond between Z and adjacent 5-membered ring carbon atom
E- G or X-G:Eまたは Xとそれぞれ隣接した 5員環炭素との結合 E-G or X-G: Bond between E or X and the adjacent 5-membered carbon
Y - G:Yと隣接した 5員環炭素原子との結合Y-G: bond between Y and an adjacent 5-membered ring carbon atom
1 - C： R1と隣接した炭素原子との結合
1-C: Bond between R1 and adjacent carbon atom
本発明の鎮痒剤は、 搔痒感を軽減'解消するものであれば限定はないが、 特 にアトピー （I g E抗体を介した抗原特異的免疫反応） による痒みに有効であ る。 この点から本発明の鎮痒剤 は、アトピー症状の予防または治療用薬剤を包 含するものである。 The antipruritic agent of the present invention is not particularly limited as long as it reduces or eliminates pruritus, and is particularly effective for pruritus due to atopy (antigen-specific immunoreaction via IgE antibody). From this point, the antipruritic agent of the present invention includes a drug for preventing or treating atopic symptoms.
なお、 本発明において 「搔痒性症状」 とは、 限局性ないし汎発性のかゆみ及 びそれに関連する炎症を皮膚及び粘膜に有する症状をいう。 例えば、 疥癬、 蓴 麻疹、湿疹、乾皮症（老人性乾皮症、皮脂欠乏性湿疹など)、乾癬、皮膚搔痒症、 痒疹があげられる。 In the present invention, the “pruritic condition” refers to a condition having localized or generalized itching and associated inflammation on the skin and mucous membranes. Examples include scabies, juniper measles, eczema, xeroderma (xeroderma senile, sebum deficient eczema, etc.), psoriasis, cutaneous pruritus and prurigo.
本発明において 「アトピー症状」 とは、 アトピーが原因でおこる限局性ない し汎発性のかゆみ及びそれに関連する炎症を皮膚及び粘膜に有する症状、 すな わちアトピーが原因でおこる搔痒性症状をいう。 例えば、 アトピー性皮膚炎お よびァトピ一性結膜炎があげられる。 In the present invention, the term "atopic symptom" refers to a symptom having localized or generalized itching caused by atopy and inflammation related thereto on the skin and mucous membranes, that is, a pruritic symptom caused by atopy. Say. Examples include atopic dermatitis and atopic conjunctivitis.
本発明において 「アトピー性皮膚炎」 とは、 増悪 ·寛解を繰り返す、 搔痒の ある湿疹を主病変とする疾患をいい、 アトピー素因 （I g E抗体を産生しやす い素因） の個体に発生しやすい。 In the present invention, the term “atopic dermatitis” refers to a disease in which pruritus eczema is the main lesion that repeats exacerbation and remission, and occurs in individuals with an atopic predisposition (a predisposition to produce IgE antibodies). Cheap.
本発明の鎮痒剤における有効成分の投与量は患者の体重、 年齢、 性別等によ り適宜増減できるが、 通常 1回投与あたり 1 n g〜l O m g、 好ましくは 0 . ：!〜 1 0 0 であり 1日に 1回〜数回投与できる。 The dose of the active ingredient in the antipruritic agent of the present invention can be appropriately increased or decreased according to the patient's body weight, age, sex, etc., but is usually 1 ng to 10 mg per administration, preferably 0.1 to 1.0. It can be administered once to several times a day.
また、 本発明の鎮痒剤は、 有効成分として抗ヒスタミン剤 （例えば、 ジフエ ンヒドラミン、 カルビノキサミン、 クロルフエ二ラミン、 ラニチジン、 それら の塩など） も組み合わせて用いることができる。 The antipruritic agent of the present invention can also be used in combination with an antihistamine (eg, diphenhydramine, carbinoxamine, chlorpheniramine, ranitidine, a salt thereof, etc.) as an active ingredient.
本発明の鎮痒剤は、 有効成分に通常の製剤化に用いられる担体、 賦形剤、 そ の他の添加剤を用いて医薬組成物として調製することができる。 The antipruritic agent of the present invention can be prepared as a pharmaceutical composition using carriers, excipients, and other additives commonly used in the formulation of the active ingredient.
製剤用の担体ゃ賦形剤としては、 例えば、 水、 エタノール、 乳糖、 微晶性セ ルロース、 流動パラフィン、 硬化油、 蜜蠟、 スクヮラン、 ステアリルアルコ一 ル、 エチレングリコ一ルなどやその他常用されるものをあげることができる。 添加剤としては、 例えば、 崩壊剤 （デンプンなど)、 結合剤 {ヒドロキシプロ ピルセルロース、 低置換ヒドロキシプロピルゼルロース }、 滑沢剤 （タルク、 ス テアリン酸グリセリンなど）、 抗酸化剤、 保存剤 （パラベンなど)、 コーティン
グ剤 （ゼラチン、 ヒドロキシプロピルセルロースなど）、 着色料、 矯味矯臭剤、 美白剤（ェラグ酸ナトリウムなど）、界面活性剤（ソルビ夕ン脂肪酸エステルな ど）、 可塑剤、 保湿剤 （グリセリン、 プロピレングリコール、 ポリエチレンダリ コール、 ヒャルロン酸など） などの通常使用される成分があげられる。 As carriers and excipients for pharmaceuticals, for example, water, ethanol, lactose, microcrystalline cellulose, liquid paraffin, hydrogenated oil, honey, squalane, stearyl alcohol, ethylene glycol and the like are commonly used. You can give something. Examples of additives include disintegrants (starch, etc.), binders {hydroxypropylcellulose, low-substituted hydroxypropylselulose}, lubricants (talc, glyceryl stearate, etc.), antioxidants, preservatives ( Paraben), Cotin Agents (gelatin, hydroxypropylcellulose, etc.), coloring agents, flavoring agents, whitening agents (sodium ellagate, etc.), surfactants (such as sorbitan fatty acid esters), plasticizers, humectants (glycerin, propylene glycol) , Polyethylene dalicol, haluronic acid, etc.).
本発明の鎮痒剤は、 錠剤、 顆粒剤、 散剤、 カプセル剤、 液剤、 ゲル剤、 硬膏 剤、 軟膏剤、 クリーム剤、 貼付剤、 エアゾール剤などの剤形で、 内服剤、 注射 剤、 外用剤 （点眼剤、 点鼻剤を含む） などとして投与することができる。 The antipruritic agent of the present invention is in the form of tablets, granules, powders, capsules, liquids, gels, plasters, ointments, creams, patches, aerosols, etc. (Including eye drops and nasal drops).
好ましい剤形としては、 患部に直接投与できる点、 投与が容易な点、 全身副 作用発生の可能性が低減する点などから外用剤があげられる。 Preferred dosage forms include external preparations because they can be directly administered to the affected area, are easy to administer, and reduce the possibility of systemic side effects.
ここで 「外用剤」 とは、 外用液剤、 エアゾール剤、 外用散剤、 軟膏剤、 クリ ーム剤、 ゲル剤、 硬膏剤、 貼付剤などがあげられる。 Here, the "external preparation" includes a liquid preparation for external use, an aerosol, a powder for external use, an ointment, a cream, a gel, a plaster, a patch and the like.
本発明を以下の実施例および試験例によってさらに詳しく説明するが、 本発 明の範囲はこれに限定されない。 本発明の記載に基づき種々の変更、 修飾が当 業者には可能であり、 これらの変更、 修飾も本発明に含まれる。 実施例 The present invention will be described in more detail with reference to the following Examples and Test Examples, but the scope of the present invention is not limited thereto. Various changes and modifications can be made by those skilled in the art based on the description of the present invention, and these changes and modifications are also included in the present invention. Example
以下実施例および試験例により、 本発明をさらに詳細に説明する。 Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples.
なお、 特に断らない限り薬剤の濃度 (%) は、 w/ v %を意味する。
Unless otherwise specified, drug concentration (%) means w / v%.
実施例 1 Example 1
下記成分を抨量し均一に混合した後、 精製水とエタノールの下記容量を加え After weighing the following components and mixing uniformly, add the following volumes of purified water and ethanol
1 0 0 0 m 1の液剤を得た。 A solution of 100 000 ml was obtained.
化合物 1 6 0 . 1 g Compound 160.1 g
エタノール 2 0 0 m l Ethanol 200 ml
精製水 8 0 0 m l 試験例 1 ： NCマウス自発搔痒行動に対する作用 800 ml of purified water Test Example 1: Effect on spontaneous pruritic behavior of NC mice
自然発症的にアトピー性皮膚炎様の皮膚疾患を発症する NC/Ngaマウスを用 いた実験で、 多くのプロスタグランジン類が自然発症的に惹起される搔痒行動 を効果的に抑制することができることがわかった。 In experiments using NC / Nga mice that spontaneously develop atopic dermatitis-like skin disease, many prostaglandins can effectively suppress the pruritus behavior spontaneously induced I understood.
薬剤塗布前後 2 4時間の各動物個体における搔痒回数について対応のある検 定を行い、 0 . 5 %以下の危険率で有意差のあるものを 「有効」 と判定したと ころ、 以下のプロスタグランジン類で優れた効果が確認された。 A paired test was performed on the number of pruritus in each animal 24 hours before and after drug application, and a significant difference with a risk factor of 0.5% or less was judged to be “effective”. Excellent effects were confirmed with gins.
(実験方法） (experimental method)
体重約 30 gの 20週齢のァトピ一性皮膚炎を発症した NC/Ngaマウス （購入 元 S L C) の両足に磁石を植え込み、 その磁力感知により、 足の動きを搔痒測 定システム （ニューロサイエンス社製） により測定した。 引つ搔き行為の内、 1.5秒以上のものを搔痒行動としてその回数を継続的に測定した。 搔痒行動に は日内リズムがあるため、 試験前日から 24時間の各動物個体の日内搔痒リズ ムを測定後、 100%エタノールに溶解した各薬物を 0.2 ml/mouseの割合で背部 皮膚に塗布した。 その後 24時間の搔痒行動を測定し薬物投与前後の搔痒行動 数を比較した。 実験データは、 薬物塗布前後 24時間の総搔痒回数から搔痒抑 制率を算出し表 5に示した。 有意差検定は、 各薬物濃度塗布群の個々動物にお ける薬物塗布前後の搔痒回数について対応のある t検定 (paired t'test)を用い て処理した。 Magnets are implanted in both feet of a 20-week-old NC / Nga mouse (purchased from SLC) weighing about 30 g and developing atopic dermatitis, and the movement of the feet is sensed by detecting the magnetic force. Manufactured). Of the pulling actions, those with 1.5 seconds or more were regarded as pruritic actions, and the number of times was continuously measured. Because of the diurnal rhythm of pruritus behavior, the daily pruritus rhythm of each animal was measured 24 hours from the day before the test, and then each drug dissolved in 100% ethanol was applied to the back skin at a rate of 0.2 ml / mouse. Then, the pruritic behavior for 24 hours was measured and the number of pruritic behavior before and after drug administration was compared. For the experimental data, the pruritus suppression rate was calculated from the total number of pruritus 24 hours before and after drug application, and is shown in Table 5. The significant difference test was performed using a paired t'test for the number of pruritus before and after drug application in each animal of each drug concentration application group.
搔痒抑制率 （％) = (塗布前搔痒回数一塗布後搔痒回数） xlOOZ塗布前搔痒回 数 Itching suppression rate (%) = (itch number before application / itch number after application) xlOOZ number of itching before application
(実験結果）
結果を表 5に示した。 (Experimental result) Table 5 shows the results.
表 5 化合物 No 濃度（％) 阻害 ％ ¾思 化合物 1 0.1 55.2 ** Table 5 Compound No. Concentration (%) Inhibition% Compound 1 0.1 55.2 **
0.01 45.8 0.01 45.8
化合物 3 0.01 55.7 ** Compound 3 0.01 55.7 **
0.00001 54.3 ** 化合物 6 0.01 43.0 ** 0.00001 54.3 ** Compound 6 0.01 43.0 **
0.001 43.1 ** 0.001 43.1 **
0.0001 38.3 氺 化合物 1 3 0.01 48.8 ** 0.0001 38.3 化合物 Compound 1 3 0.01 48.8 **
0.00001 36.1 ** 化合物 1 6 0.01 40.9 氺: 1« 0.00001 36.1 ** Compound 1 6 0.01 40.9 氺: 1 «
0.00001 34.0 氺
0.00001 34.0 氺
表 5続き Table 5 continued
*： P<0.05> **： P<0.01、 ***： Pく 0.005
試験例 2 ： NCマウス皮膚炎症モデルに対する作用 *: P <0.05> **: P <0.01, ***: P less 0.005 Test example 2: Effect on NC mouse skin inflammation model
(実験方法） (experimental method)
動物： 4週齢の SPF NCマウス （雄性） を日本 SLC より購入し、 入荷後 直ちに皮膚炎を発症した雄性 NC マウス （20週齢以上） と 2週間以下のよう な状態で同居させ搔痒行動を誘発させた。 Animals: 4-week-old SPF NC mice (male) were purchased from Japan SLC, and immediately after arrival, coexisted with male NC mice (20 weeks or older) that developed dermatitis for 2 weeks or less, and exhibited pruritic behavior. Triggered.
1ケージ当たり皮膚炎発症マウス及び皮膚炎未発症マウス各 4匹ずつをおが屑ケ一 ジ （34 X 17 X 39 cm) に同居させ、 室温 23±3 °C、 55±15 %、 照明 12 時間 （am 7:00 - pm 19:00) に設定された動物舎において飼育した。 Dermatitis onset mice and non-dermatitis onset mice per cage were allowed to live together in a sawdust cage (34 x 17 x 39 cm) at room temperature of 23 ± 3 ° C, 55 ± 15%, and 12 hours of illumination ( am 7:00-pm 19:00).
2週間同居後、 購入したマウスを取り出し、 別ケージに 1ケージ当たり 8匹で試験 開始まで飼育した。薬剤塗布開始直前にそれぞれのケージの趙炎スコアが均等にな るようにマウスを振り分け、 1ケージ当たり 4匹で個育した。 After living together for 2 weeks, the purchased mice were removed and reared in separate cages at 8 per cage until the start of the test. Immediately before the start of drug application, the mice were sorted so that the Zhao flame scores of each cage became equal, and the mice were reared at 4 mice per cage.
薬物投与：皮膚炎症を発症した NC マウスと同居により皮膚炎症を発症し た 20週齢の NC マウス背部皮膚に 99.5% エタノール、 99.5% エタノール に可溶化した化合物 3 (0.01%) 及び化合物 1 6 (0.01%) をマイクロピぺッ トを用いてそれぞれ 200 1ずつ、 1日 1回、 4週間連続塗布した。 なお、 無 処置群は何も処置を施さなかった。 各群とも 1群あたり 8匹で試験した。 Drug administration: Compound 3 (0.01%) and compound 16 (solubilized in 99.5% ethanol, 99.5% ethanol) in the back skin of 20-week-old NC mice that developed skin inflammation by living with NC mice that developed skin inflammation 0.01%) was applied 200 times each once a day for 4 weeks using a micropip. The untreated group received no treatment. Each group was tested with 8 animals per group.
皮膚炎症状の観察： 1回/週、 皮膚炎症状の観察及び測定を行った。 毛並み、 脱毛、 出血、痂皮形成の 4項目について、それぞれ無症状： 0， 軽度： 1， 中度： 2, 重度： 3 にスコア化 （合計の最小： 0， 合計の最大： 12) した。 Observation of skin inflammation: Once / week, observation and measurement of skin inflammation were performed. The four items of fur, alopecia, bleeding, and crust formation were scored as asymptomatic: 0, mild: 1, moderate: 2, severe: 3, respectively (minimum total: 0, maximum total: 12).
(実験結果） (Experimental result)
皮膚炎症状の観察結果を図 1および 2に示した。 The results of observation of skin inflammation are shown in FIGS.
薬剤塗布 4週間後において、 化合物 3および 1 6は、 溶媒塗布群に比較し、 皮 膚炎スコアを有意に抑制した。
産業上の利用可能性 Four weeks after drug application, Compounds 3 and 16 significantly reduced the dermatitis score as compared to the vehicle-applied group. Industrial applicability
本発明により、 搔痒性症状に対して皮膚炎などの炎症を惹起させる痒みを特 異的に抑制することができ、 特にァトピー症状に有効である薬剤の提供が可能 になった。
INDUSTRIAL APPLICABILITY According to the present invention, itching which can specifically suppress pruritic symptoms causing inflammation such as dermatitis can be provided, and a drug which is particularly effective for atopic symptoms can be provided.
Claims
1. 式 [1] 1. Equation [1]
Gは水素原子、 ハロゲン原子、 ニトロ基、 シァノ基、 水酸基、 置換されてもよ ぃァリール基、 置換されてもよい (^_5アルキル基、 ― （CH2) w— Q、 一 CH = NR4、 一 C〇R5、 — OR6a、 一 NHR6a、 一 NR6aR6b、 G is a hydrogen atom, a halogen atom, a nitro group, Shiano group, a hydroxyl group, it may also be substituted I Ariru group, an optionally substituted (^ _ 5 alkyl group, - (CH 2) w- Q , one CH = NR4 , One C〇R5, — OR6a, one NHR6a, one NR6aR6b,
一 NHS〇2 R7 または一 S(〇)n R6a を示し、 One NHS〇 2 R7 or one S (〇) n R6a
Xは水素原子、 メチレン基、 水酸基、 ォキソ、 置換されてもよい のアル コキシ基または一 S(0)nlR8を示し、 X represents a hydrogen atom, a methylene group, a hydroxyl group, an oxo group, an optionally substituted alkoxy group or one S (0) nl R 8 ,
Yはエチレン基、 置換されてもよいビニレン基、 ェチニレン基または Y is an ethylene group, an optionally substituted vinylene group, an ethynylene group or
一 OCH2— を示し、 OCH 2 — indicates
Zは式 Z is the expression
一 (CH2) p A (CH2) qB (CH2) r一、 One (CH 2 ) p A (CH 2 ) q B (CH 2 ) r one,
一 (CH2) p A (CH2) qA， (CH2) r一、 One (CH 2 ) p A (CH 2 ) q A, (CH 2 ) r one,
一 (CH2) PB (CH2) qB' (CH2) r一 One (CH 2 ) P B (CH 2 ) qB '(CH 2 ) r one
または Or
一 (CH2) pB' (CH2) qA， (CH2) r- で表される基を示し、 I represents a group represented by (CH 2 ) pB ′ (CH 2 ) qA, (CH 2 ) r- ,
Riは水素原子、水酸基または置換されてもよい C^oのアルコキシ基を示し、 R2 は置換されてもよい d- のアルキル基、 置換されてもよい C2-10 のァ ルケニル基、 置換されてもよい C2.10 のアルキニル基、 一 （CH2) w-Q または式
で表される基を示し、 Ri represents an alkoxy group of a hydrogen atom, a hydroxyl group or an optionally substituted C ^ o be, R2 is substituted with may be d- alkyl group, optionally substituted C 2 - 10 of § alkenyl groups, substituted good C 2 also. 10 alkynyl group, one (CH 2) wQ or formula Represents a group represented by
R3は水素原子または置換されてもよい d-5アルキル基を示すか、 または R3が Ri と一緒になつてォキソまたは =NR4を示すか、 Or R3 denotes a connexion Okiso or = NR 4 such represents hydrogen atom or substituted by may be d-5 alkyl group, or R3 is with Ri,
または R3 が R2 および隣接する炭素原子と一緒になつて置換されてもよい COr R3 is which may be connexion substitutions with R 2 and the adjacent carbon atom C
3-10のシクロアルキル基を形成し、 Forming a 3-10 cycloalkyl group,
R4は水酸基または置換されてもよい d-5 アルコキシ基を示し、 R4 represents a hydroxyl group or an optionally substituted d-5 alkoxy group,
R5 は水酸基、 置換されてもよい C^o アルコキシ基、 置換されてもよい CR 5 is a hydroxyl group, an optionally substituted C ^ o alkoxy group, an optionally substituted C
2-10 アルケニルォキシ基、 置換されてもよい C2.1() アルキニルォキシ基、 置 換されてもよい C3-10 のシクロアルキルォキシ基、置換されてもよいァリール ォキシ基、置換されてもよいァリール基、置換されてもよい C i - i 0 アルキル基、 — NHR6a、 -NR6aR6b または一 NHS〇2 R7 を示し、 . 2-10 Arukeniruokishi group, optionally substituted C 2 1 () Arukiniruokishi group, substitution which may be C 3 - 10 cycloalkyl O alkoxy group, may be substituted Ariru Okishi group, optionally substituted Ariru group, optionally substituted C i - i 0 alkyl group, - NHR6a, indicates -NR6aR6b or single NHS_〇 2 R7,
R6aおよび R6bはそれぞれ、置換されてもよい のアルキル基、置換さ れてもよい C2-io のアルケニル基、置換されてもよい C2.10 のアルキニル基、 置換されてもよい C3_10のシクロアルキル基または一 （CH2) w' — Qを示 し、 R6a and R 6 b are each of which may be substituted alkyl groups, optionally substituted C 2 -io alkenyl group, optionally substituted C 2 .10 alkynyl group, optionally substituted C 3 to 10 cycloalkyl groups or one (CH 2 ) w ′ — Q,
R7 は置換されてもよい のアルキル基または置換されてもよいァリ一 レ ¾を示し、 R7 represents an optionally substituted alkyl group or an optionally substituted aryl group;
R8は置換されてもよい d.5アルキル基を示し、 R8 represents an optionally substituted d. 5 alkyl group,
R9 は置換されてもよい C^o のアルキル基、 置換されてもよい C2-10 のァ ルケニル基、 置換されてもよい C2-10 のアルキニル基、 または、 R9 is alkyl group optionally C ^ o be substituted, an optionally substituted C 2 - 10 of § alkenyl group, an optionally substituted C 2 - 10 alkynyl group, or,
一 (CH2) w— Qを示し、 One (CH 2 ) w—shows Q,
Qは置換されてもよい C3-10 のシクロアルキル基または置換されてもよいァ リールォキシ基を示し、 は単結合または二重結合を示し、
Aおよび A'は同一または異なって、エチレン基、置換されてもよいビニレン基、 ェチニレン基、 アレン基、 置換されてもよいフエ二レン基、 置換されてもよい C 3 _7のシクロアルキレン基 Q is optionally substituted C 3 be - shows a 10 cycloalkyl group or an optionally substituted § Riruokishi group, represents a single bond or a double bond, A and A 'are the same or different, an ethylene group, an optionally substituted vinylene group, Echiniren group, allene group, an optionally substituted phenylene group, cycloalkylene group C 3 _ 7 may be substituted
Bおよび B'は同一または異なって、酸素原子または S (〇)n 2で表される基を示 し、 B and B 'are the same or different, indicates an oxygen atom or S (〇) groups represented by n 2,
mは 0〜2の整数を示し、 n、 n 1および n 2は同一または異なって 0〜2の 整数を示し、 wは 0〜5の整数を示し、 w' は 1〜 5の整数を示し、 p、 Q、 rおよび tは同一または異なって 0〜4の整数を示す （ただし、 Eが水酸基で あり、 かつ、 Xが水素原子である場合、 及び E及び Xの両方が水酸基である場 合、 並びに下記表の化合物を除く）。 ]で表されるプロスタグランジン誘導体、 その製薬学的に許容される塩またはその水和物を有効成分とする搔痒性症状の 予防または治療用薬剤。 m represents an integer of 0 to 2, n, n1, and n2 are the same or different and represent an integer of 0 to 2, w represents an integer of 0 to 5, w 'represents an integer of 1 to 5 , P, Q, r and t are the same or different and each represent an integer of 0 to 4 (provided that E is a hydroxyl group and X is a hydrogen atom, and that both E and X are hydroxyl groups) And excluding the compounds in the table below). And a pharmaceutically acceptable salt or hydrate thereof as an active ingredient for preventing or treating pruritus.
2. 式 [1]において Eおよび Xは、 それぞれ異なってォキソまたは水酸基で あるか、 または、 それぞれ異なってメチレン基または水酸基であるプロスタグ ランジン誘導体、 その製薬学的に許容される塩またはその水和物を有効成分と する請求項 1記載の搔痒性症状の予防または治療用薬剤。 2. In the formula [1], E and X each represent a different oxo or hydroxyl group, or a different methylene group or a different hydroxyl group, a prostaglandin derivative, a pharmaceutically acceptable salt thereof, or a hydration thereof. 2. The medicament for preventing or treating pruritic symptoms according to claim 1, which comprises a substance as an active ingredient.
3. 式 [1]において Eがォキソまたはメチレン基であり、 Xが水酸基である
プロスタグランジン誘導体、 その製薬学的に許容される塩またはその水和物を 有効成分とする請求項 1記載の搔痒性症状の予防または治療用薬剤。 3. In formula [1], E is an oxo or methylene group and X is a hydroxyl group 2. The prophylactic or therapeutic agent for pruritic symptoms according to claim 1, comprising a prostaglandin derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.
4. 式 [1]において、 Gが— COR5 (R5は、 請求項 1で定義した通りであ る）であり、 Yがビニレン基またはェチニレン基であるプロスタグランジン誘導 体、 その製薬学的に許容される塩またはその水和物を有効成分とする請求項 2 または 3記載の搔痒性症状の予防または治療用薬剤。 4. In the formula [1], a prostaglandin derivative wherein G is —CO 5 (R 5 is as defined in claim 1) and Y is a vinylene group or an ethynylene group; 4. The medicament for preventing or treating pruritic symptoms according to claim 2 or 3, comprising a chemically acceptable salt or a hydrate thereof as an active ingredient.
5. 搔痒性症状がァ卜ピー症状である請求項 1〜 4のいずれか 1項に記載の 薬剤。 5. The drug according to any one of claims 1 to 4, wherein the pruritic symptom is an atopic symptom.
6. アトピー症状が、 アトピー性皮膚炎またはアトピー性結膜炎である請求 項 5に記載の薬剤。 6. The drug according to claim 5, wherein the atopic symptom is atopic dermatitis or atopic conjunctivitis.
7. 外用剤である請求項 1〜 6のいずれか 1項に記載の薬剤。 7. The drug according to any one of claims 1 to 6, which is an external preparation.
8. 症状の予防または治療に有効である量の式 [1]のプロスタグランジン誘 導体、 その製薬学的に許容される塩またはその水和物を哺乳動物に投与するこ とを含む搔痒性症状の予防または治療方法。 8. Pruritic comprising administering to a mammal an amount of a prostaglandin derivative of Formula [1], a pharmaceutically acceptable salt or a hydrate thereof, that is effective in preventing or treating the symptoms. How to prevent or treat symptoms.
式 [1] Equation [1]
[式中、 Eは水酸基、 メチレン基、 ォキソまたは 二 NR4を示し、 [In the formula, E represents a hydroxyl group, a methylene group, oxo or diNR4,
Gは水素原子、 ハロゲン原子、 ニトロ基、 シァノ基、 水酸基、 置換されてもよ ぃァリール基、 置換されてもよい — 5アルキル基、 一 （CH2) w— Q、
一 CH = NR4、 一 C〇R5、 — OR — NHR6a、 一 NR6aR6b、 — NHS〇2 R7 または一S(〇)n R6a を示し、 G is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, an optionally substituted aryl group, an optionally substituted — 5 alkyl group, one (CH 2 ) w — Q, One CH = NR4, one C〇R5, — OR — NHR6a, one NR6aR6b, — NHS〇 2 R7 or one S (〇) n R6a,
Xは水素原子、 メチレン基、 水酸基、 ォキソ、 置換されてもよい のアル コキシ基または一 S(〇)n l R8 を示し、 X represents a hydrogen atom, a methylene group, a hydroxyl group, Okiso, substituted for may be alkoxy group or a S a (〇) nl R8,
Yはエチレン基、 置換されてもよいビニレン基、 ェチニレン基または Y is an ethylene group, an optionally substituted vinylene group, an ethynylene group or
-OCH2- を示し、 -OCH 2-
Zは式 Z is the expression
一 (CH2) PA (CH2) qB (CH2) r一、 One (CH 2 ) P A (CH 2 ) q B (CH 2 ) r
― (CH2) p A (CH2) qA' (CH2) r一、 ― (CH 2 ) p A (CH 2 ) qA '(CH 2 ) r
一 (CH2) PB (CH2) qB， (CH2) r一 One (CH 2 ) P B (CH 2 ) qB, (CH 2 ) r one
または Or
一 (CH2) PB， (CH2) qA， (CH2) r一 (CH 2 ) P B, (CH 2 ) q A, (CH 2 ) r
で表される基を示し、 Represents a group represented by
Ri は水素原子、水酸基または置換されてもよい のアルコキシ基を示し、 R2 は置換されてもよい d.w のアルキル基、 置換されてもよい C2.10 のァ ルケニル基、 置換されてもよい C2-10のアルキニル基、 一 （CH2) w-Q または式 Ri represents a hydrogen atom, a hydroxyl group or an optionally substituted alkoxy group, R2 is an alkyl group optionally dw substituted, optionally C 2 may be substituted. 10 § alkenyl groups, optionally substituted C 2 - 10 alkynyl group, one (CH 2) wQ or formula
R3は水素原子または置換されてもよい d-5アルキル基を示すか、 R3 represents a hydrogen atom or an optionally substituted d- 5 alkyl group,
または R3が Ri と一緒になつてォキソまたは =NR4を示すか、 Or R3 together with Ri indicates oxo or = NR 4 ,
または R3 が R2 および隣接する炭素原子と一緒になつて置換されてもよい COr R3 is which may be connexion substitutions with R 2 and the adjacent carbon atom C
3-10 のシクロアルキル基を形成し、 Forming 3-10 cycloalkyl groups,
R4は水酸基または置換されてもよい d-5 アルコキシ基を示し、 R represents a hydroxyl group or an optionally substituted d- 5 alkoxy group,
R5 は水酸基、 置換されてもよい d- アルコキシ基、 置換されてもよい CR 5 is a hydroxyl group, an optionally substituted d-alkoxy group, an optionally substituted C
2-10 アルケニルォキシ基、 置換されてもよい C2-1() アルキニルォキシ基、 置
換されてもよい C3-10 のシクロアルキルォキシ基、置換されてもよいァリール ォキシ基、置換されてもよいァリール基、置換されてもよい Ci-wアルキル基、2-10 Arukeniruokishi group, optionally substituted C 2 - 1 () Arukiniruokishi group, location Conversion which may be C 3 - 10 cycloalkyl O alkoxy group, may be substituted Ariru Okishi group, an optionally substituted Ariru group, an optionally substituted Ci-w-alkyl group,
— NHR6a、 — NR6aR6b または一 NHS〇2 R7 を示し、 - NHR6a, - indicates NR6aR6b or single NHS_〇 2 R7,
R6aおよび RSbはそれぞれ、置換されてもよい Cno のアルキル基、置換さ れてもよい C2-10 のアルケニル基、置換されてもよい C2-1() のアルキニル基、 置換されてもよい 。のシクロアルキル基または一 （CH2) w' 一 Qを示 し、 Each R6a and RSb is alkyl group optionally Cno be substituted, an optionally substituted C 2 - 10 alkenyl group, optionally substituted C 2 - 1 () alkynyl groups may be substituted . A cycloalkyl group or one (CH 2 ) w ′ one Q,
R7 は置換されてもよい のアルキル基または置換されてもよいァリー ル基を示し、 R7 represents an optionally substituted alkyl group or an optionally substituted aryl group;
R8は置換されてもよい d- 5 アルキル基を示し、 R8 represents an optionally substituted d-5 alkyl group,
R9 は置換されてもよい C^o のアルキル基、 置換されてもよい C2-10 のァ ルケニル基、 置換されてもよい C2-10のアルキニル基、 または、 R9 is alkyl group optionally C ^ o be substituted, an optionally substituted C 2 - 10 of § alkenyl group, an optionally substituted C 2 - 10 alkynyl group, or,
一 (CH2) w— Qを示し、 One (CH 2 ) w—shows Q,
Qは置換されてもよい C3-10 のシクロアルキル基または置換されてもよいァ リールォキシ基を示し、 は単結合または二重結合を示し、 Q is optionally substituted C 3 be - shows a 10 cycloalkyl group or an optionally substituted § Riruokishi group, represents a single bond or a double bond,
Aおよび A，は同一または異なって、エチレン基、置換されてもよいビニレン基、 ェチニレン基、 アレン基、 置換されてもよいフエ二レン基、 置換されてもよい C3_7のシクロアルキレン基 A and A, are the same or different, an ethylene group, an optionally substituted vinylene group, Echiniren group, allene group, an optionally substituted phenylene group, cycloalkylene group C 3 _ 7 may be substituted
Bおよび B，は同一または異なって、酸素原子または S(〇)n2で表される基を示 し、 B and B are the same or different and each represent an oxygen atom or a group represented by S (〇) n2 ;
mは 0〜2の整数を示し、 n、 n 1および n 2は同一または異なって 0〜2の 整数を示し、 wは 0〜5の整数を示し、 w， は 1〜 5の整数を示し、 p、 d、
rおよび tは同一または異なって 0 4の整数を示す （ただし、 Eが水酸基で あり、 かつ、 Xが水素原子である場合、 及び E及び Xの両方が水酸基である場 合、 並びに下記表の化合物を除く）。 ] m represents an integer of 0 to 2, n, n 1 and n 2 are the same or different and represent an integer of 0 to 2, w represents an integer of 0 to 5, w, represents an integer of 1 to 5 , P, d, r and t are the same or different and each represent an integer of 04 (provided that E is a hydroxyl group and X is a hydrogen atom, and that both E and X are hydroxyl groups; Excluding compounds). ]
9. 搔痒性症状の予防または治療剤の製造における、 式 [1]のプロス夕ダラ ンジン誘導体、 その製薬学的に許容される塩またはその水和物の使用。 9. Use of the prossudarandin derivative of the formula [1], a pharmaceutically acceptable salt thereof or a hydrate thereof in the manufacture of a prophylactic or therapeutic agent for pruritic symptoms.
式 [1] Equation [1]
[式中、 Eは水酸基、 メチレン基、 ォキソまたは =NR4を示し、 [Wherein E represents a hydroxyl group, a methylene group, oxo or = NR 4
Gは水素原子、 ハロゲン原子、 ニトロ基、 シァノ基、 水酸基、 置換されてもよ ぃァリール基、 置換されてもよい アルキノレ基、 一 (CH2) w— Q、G represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, an optionally substituted aryl group, an optionally substituted alkynole group, one (CH 2 ) w—Q,
— CH = NR4、 — COR5、 一 OR6a、 一 NHR6a、 一 NR6aR6b、 — NHS02 R7 または一S(〇)nR6a を示し、 — CH = NR4, — COR5, one OR6a, one NHR6a, one NR6aR6b, — NHS0 2 R7 or one S (〇) n R6a,
Xは水素原子、 メチレン基、 7K酸基、 ォキソ、 置換されてもよい d- 5 のアル コキシ基または一 S(0)nlR8 を示し、 X represents a hydrogen atom, a methylene group, a 7K acid group, an oxo group, an optionally substituted d-5 alkoxy group or 1S (0) nlR 8 ,
γはエチレン基、 置換されてもよいビニレン基、 ェチニレン基または γ is an ethylene group, an optionally substituted vinylene group, an ethynylene group or
-OCH2- を示し、 -OCH 2-
Zは式 Z is the expression
一 (CH2) p A (CH2) qB (CH2) r一、 One (CH 2 ) p A (CH 2 ) q B (CH 2 ) r one,
一 (CH2) p A (CH2) qA， (CH2) r―、 One (CH 2 ) p A (CH 2 ) qA, (CH 2 ) r ―,
一 (CH2) PB (CH2) qB， (CH2) r—
または One (CH 2 ) P B (CH 2 ) q B, (CH 2 ) r — Or
- (CH2) PB， (CH2) qA， (CH2) r - で表される基を示し、 -Represents a group represented by (CH 2 ) P B, (CH 2 ) q A, (CH 2 ) r-
Ri は水素原子、水酸基または置換されてもよい C^o のアルコキシ基を示し、 R2 は置換されてもよい（：ぃ のアルキル基、 置換されてもよい C2-10 のァ ルケニル基、 置換されてもよい C2-10 のアルキニル基、 一 （CH2) w-Q または式 Ri represents an alkoxy group of a hydrogen atom, a hydroxyl group or an optionally substituted C ^ o, R2 is an optionally substituted (: I alkyl, optionally substituted C 2 - 10 of § alkenyl group, a substituted which may be C 2 - 10 alkynyl group, one (CH 2) wQ or formula
R3 は水素原子または置換されてもよい アルキル基を示すか、 R 3 represents a hydrogen atom or an optionally substituted alkyl group,
または R3が Ri と一緒になつてォキソまたは =NR4を示すか、 Or R3 together with Ri indicates oxo or = NR 4 ,
または R3 が R2 および隣接する炭素原子と一緒になつて置換されてもよい C 3 - 1 0 のシクロアルキル基を形成し、 Or R3 is R 2 and the adjacent may be a connexion replaced together with the carbon atom to C 3 - to form a cycloalkyl group of 1 0,
R4は水酸基または置換されてもよい C]L - 5 アルコキシ基を示し、 R4 represents a hydroxyl group or an optionally substituted C] L- 5 alkoxy group,
R5 は水酸基、 置換されてもよい アルコキシ基、 置換されてもよい CR5 is a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted C
2-10 アルケニルォキシ基、 置換されてもよい C2.1() アルキニルォキシ基、 置 換されてもよい C3-10 のシクロアルキルォキシ基、置換されてもよいァリール ォキシ基、置換されてもよいァリール基、置換されてもよい C^o アルキル基、 — NHR6a、 -NR6aR6b または一 NHS〇2 R7 を示し、 . 2-10 Arukeniruokishi group, optionally substituted C 2 1 () Arukiniruokishi group, substitution which may be C 3 - 10 cycloalkyl O alkoxy group, may be substituted Ariru Okishi group, An optionally substituted aryl group, an optionally substituted C ^ o alkyl group, — NHR6a, -NR6aR6b or one NHS〇 2 R7,
R6aおよび Rebはそれぞれ、置換されてもよい C^o のアルキル基、置換さ れてもよい C2-1()のアルケニル基、置換されてもよい C2-1() のアルキニル基、 置換されてもよい Cg— i。のシクロアルキル基または— （CH2) w' 一 Qを示 し、 Each R6a and Reb is an alkyl group optionally C ^ o be substituted, an optionally substituted C 2 - 1 () alkenyl groups, optionally substituted C 2 - alkynyl group 1 (), substituted Cg—i may be done. Represents a cycloalkyl group or — (CH 2 ) w′-Q,
R7 は置換されてもよい のアルキル基または置換されてもよいァリー ル基を示し、 R7 represents an optionally substituted alkyl group or an optionally substituted aryl group;
R8 は置換されてもよい アルキル基を示し、
R9 は置換されてもよい d- W のアルキル基、 置換されてもよい C2-10 のァ ルケニル基、 置換されてもよい C2-10 のアルキニル基、 または、 R 8 represents an alkyl group which may be substituted, R9 is an alkyl group of which may be substituted also d-W, optionally substituted C 2 -10 of § alkenyl group, an optionally substituted C 2 - 10 alkynyl group, or,
一 (CH2) w— Qを示し、 One (CH 2 ) w—shows Q,
Qは置換されてもよい C3-10 のシクロアルキル基または置換されてもよいァ リールォキシ基を示し、 は単結合または二重結合を示し、 Q is optionally substituted C 3 be - shows a 10 cycloalkyl group or an optionally substituted § Riruokishi group, represents a single bond or a double bond,
Aおよび A'は同一または異なって、エチレン基、置換されてもよいビニレン基、 ェチニレン基、 アレン基、 置換されてもよいフエ二レン基、 置換されてもよい C。一 7のシクロアルキレン基 A and A ′ are the same or different and are an ethylene group, an optionally substituted vinylene group, an ethynylene group, an arene group, an optionally substituted phenylene group, and an optionally substituted C. One 7 cycloalkylene group
Bおよび B'は同一または異なって、酸素原子または S(〇)n2で表される基を示 mは 0〜2の整数を示し、 n、 n 1および n 2は同一または異なって 0〜 2の 整数を示し、 wは 0〜5の整数を示し、 w' は 1〜 5の整数を示し、 p、 Q、 rおよび tは同一または異なって 0〜4の整数を示す （ただし、 Eが水酸基で あり、 かつ、 Xが水素原子である場合、 及び E及び Xの両方が水酸基である場 合、 並びに下記表の化合物を除く）。 ] B and B ′ are the same or different and represent an oxygen atom or a group represented by S (〇) n2 , m represents an integer of 0 to 2, n, n1 and n2 are the same or different and represent 0 to 2 Represents an integer of 0, w represents an integer of 0 to 5, w 'represents an integer of 1 to 5, p, Q, r and t are the same or different and represent an integer of 0 to 4 (where E is A hydroxyl group and when X is a hydrogen atom, and when both E and X are hydroxyl groups, and the compounds in the following table). ]
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2004551230A JP4477504B2 (en) | 2002-11-13 | 2003-11-13 | Antipruritic |
| AU2003301900A AU2003301900A1 (en) | 2002-11-13 | 2003-11-13 | Antipruritic drug |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002329980 | 2002-11-13 | ||
| JP2002-329980 | 2002-11-13 |
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| Publication Number | Publication Date |
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| WO2004043471A1 true WO2004043471A1 (en) | 2004-05-27 |
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ID=32310586
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2003/014446 WO2004043471A1 (en) | 2002-11-13 | 2003-11-13 | Antipruritic drug |
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|---|---|
| JP (1) | JP4477504B2 (en) |
| AU (1) | AU2003301900A1 (en) |
| WO (1) | WO2004043471A1 (en) |
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- 2003-11-13 AU AU2003301900A patent/AU2003301900A1/en not_active Abandoned
- 2003-11-13 WO PCT/JP2003/014446 patent/WO2004043471A1/en active Application Filing
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Also Published As
| Publication number | Publication date |
|---|---|
| JP4477504B2 (en) | 2010-06-09 |
| JPWO2004043471A1 (en) | 2006-03-09 |
| AU2003301900A1 (en) | 2004-06-03 |
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