WO2001010439A1 - Antagonistes d'amine cyclique ccr3 - Google Patents
Antagonistes d'amine cyclique ccr3 Download PDFInfo
- Publication number
- WO2001010439A1 WO2001010439A1 PCT/JP2000/005260 JP0005260W WO0110439A1 WO 2001010439 A1 WO2001010439 A1 WO 2001010439A1 JP 0005260 W JP0005260 W JP 0005260W WO 0110439 A1 WO0110439 A1 WO 0110439A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- alkyl
- amino
- phenyl
- aromatic heterocyclic
- Prior art date
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
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- 210000000130 stem cell Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000006203 subcutaneous dosage form Substances 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003458 sulfonic acid derivatives Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- KIVCWXSGPCIKQE-UHFFFAOYSA-N tert-butyl n-[1-[(4-chlorophenyl)methyl]pyrrolidin-3-yl]carbamate Chemical compound C1C(NC(=O)OC(C)(C)C)CCN1CC1=CC=C(Cl)C=C1 KIVCWXSGPCIKQE-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical group C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940093609 tricaprylin Drugs 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- JLYXXMFPNIAWKQ-UHFFFAOYSA-N γ Benzene hexachloride Chemical compound ClC1C(Cl)C(Cl)C(Cl)C(Cl)C1Cl JLYXXMFPNIAWKQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- 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
Definitions
- the present invention relates to allergic diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis, measles, contact dermatitis, and allergic conjunctivitis, and inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
- allergic diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis, measles, contact dermatitis, and allergic conjunctivitis
- inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.
- Eosinophilia eosinophilic gastroenteritis, eosinophilic enteropathy, eosinophilic fasciitis, eosinophilic granuloma, eosinophilic pustular folliculitis, eosinophilic pneumonia , And diseases in which eosinophils, basophils, activated T cells, etc.
- the present invention relates to a CCR3 antagonist that is expected to be effective as a therapeutic and / or prophylactic agent for AIDS (AIDS: acquired immunodeficiency syndrome) caused by infection with human immunodeficiency virus (AIDS).
- AIDS acquired immunodeficiency syndrome
- Eotaxin has been identified as a specific chemotactic factor that causes this eosinophil accumulation / migration (eg, Jose, PJ, et al., J. Exp. Med., 1994, 179, 881; Garcia-Zepda, EA). et al., Nature Med., 1996, 2, 449; Ponath, PD et al., J. Clin. Invest., 1996, 97, 604; Kitaura, M. et al., J. Biol. Chem., 1996, 271, 7725, etc.).
- eotaxin binds to the CCR3 receptor expressed on eosinophils and exerts an effect.
- eotaxin-1 and RAN TES (Regulated upon activation normal T-cell expressed and secreted)
- MCP-2 abbreviation for monocyte chemoaf.tractant protein-2
- MCP-3 abbreviation for monocyte chemoattractant protein-3
- MCP-4 abbreviation of monocyte chemoat tractant protein-4
- eotaxin has an effect of promoting the release of eosinophils and their progenitor cells from the bone marrow into the blood (eg, Paliraman, RT et al., Blood, 1998, 91 , 2 240).
- eotaxin and CCR3 play important roles in allergic diseases such as bronchial asthma.
- suppression of eosinophil infiltration by an anti-eotaxin antibody in a mouse asthma model see Gonzalo, J. -A. Et al., J. Clin. Invest., 1996, 98, 2332
- Inhibition of eosinophil infiltration by anti-eotaxin antiserum in mice (Teixeira,. M. et al., J. Clin. Invest., 1997, 100, 1657) Suppresses the formation of eosinophils (see Ruth, JH et a J. Immunol., 1998, 161, 4276).
- eotaxin is a disease that can be assumed to be deeply involved in the progression of eosinophils by accumulating and activating eosinophils at the lesion site via CCR3.
- allergic diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis, juniper, contact dermatitis, and allergic conjunctivitis; inflammatory bowel diseases such as ulcerative colitis and Crohn's disease; Eosinophilia, eosinophilic gastroenteritis, eosinophilic enteropathy, eosinophilic fasciitis, eosinophilic granuloma, eosinophilic pustular folliculitis, eosinophilic pneumonia, It is strongly suggested that it is deeply involved in the onset, progress, and maintenance of eosinophilic leukemia.
- the CCR3 receptor is expressed not only on eosinophils but also on basophils and Th2 lymphocytes, and eotaxin causes an increase in intracellular calcium ion concentration and cell migration of these cells Therefore, eotaxin and CCR3 are involved in the onset, progression and maintenance of diseases involving these cells, such as allergic diseases, by accumulating and activating these cells.
- eotaxin and CCR3 are involved in the onset, progression and maintenance of diseases involving these cells, such as allergic diseases, by accumulating and activating these cells.
- HIV-1 human immunodeficiency virus-1
- CCR3 antagonists are used for HIV-1 (AIDS) caused by HIV virus infection.
- Acquired immunodeficiency syndrome is also considered to be useful as a therapeutic or prophylactic agent (eg, et al., Choe, H. et al., Cell, 19).
- a xanthene-one-strength lupoxamide derivative see W09804554
- a piperazine or piperidine derivative see EP903349; W00029377; W00031033; W00035449; WO0035451; drawings 35452; W00035453; W00035454; W00035876; W00035877
- Lysine derivatives see WO0031032
- feniralanine derivatives see W09955324; W09955330; W00004003; WOOO27800; WOO027835; see W00027843
- other low molecular compounds see W09802151
- an object of the present invention is to provide a low molecular weight compound having an activity of inhibiting binding of a CCR3 ligand such as eotaxin to CCR3 on a target cell.
- a further object of the present invention is to use a CCR3 antagonist to treat and / or prevent a disease in which binding of a CCR3 ligand such as eotaxin to CCR3 on target cells is one of the causes. Is to provide the law.
- a cyclic amine derivative having an arylalkyl group, a pharmaceutically acceptable to alkyl adduct thereof, or a pharmaceutically acceptable acid adduct thereof is eotaxin or the like.
- eotaxin a pharmaceutically acceptable to alkyl adduct thereof
- a pharmaceutically acceptable acid adduct thereof is eotaxin or the like.
- the present invention was completed.
- Ingredient alkyl adduct, agents are provided with CCR 3 antagonism. -(CH 2 ) p- • (CH 2 ) q -GR e I)
- R 1 represents a phenyl group, C 3 - ⁇ 8 cycloalkyl group or an acid atom as base hetero atom, a sulfur atom, and or aromatic heterocyclic group having 3 1 nitrogen atom
- the phenyl group or the aromatic heterocyclic group in R 1 is condensed with a benzene ring or an aromatic heterocyclic group having 1 to 3 oxygen, sulfur, and / or nitrogen atoms as a hetero atom to form a condensed ring may also be further off
- Eniru group represented by R 1, 0 3 ⁇ 8 cycloalkyl group, aromatic heterocyclic group or a fused ring is any number of halogen atoms, hydroxy groups, Shiano group, a nitro group, carboxyl group, Karubamo I group, one C 6 alkyl group, C 3 - ⁇ 8 cycloalkyl group,.
- R 2 represents a hydrogen atom, a Ct—C 6 alkyl group, a C 2 —C 7 alkoxycarbonyl group, a hydroxy group, or a phenyl group, and the Ci—Ce alkyl group or the phenyl group in R 2 is optional.
- j represents an integer of 0-2.
- k represents an integer of 0-2.
- n an integer of 2-4.
- n 0 or 1.
- R 3 is a hydrogen atom, or (one or two phenyl groups which may be substituted by any of the same or different halogen atoms, a hydroxy group, a d-C 6 alkyl group, or a Ci-Ce alkoxy group) ) Represents a C ⁇ C 6 alkyl group which may be substituted by
- R 4 and R 5 are the same or different, a hydrogen atom, hydroxy group, phenyl group, or a C, - represents a C 6 alkyl group, C i one C 6 alkyl group in R 4 and R 5, any number of halogen atom, hydroxy group, Shiano group, a nitro group, a force Rupokishiru group, forces Rubamoiru group, a mercapto group, Guanijino group, C 3 - ⁇ 8 cycloalkyl group, CI- C 6 alkoxy group, CI- Ce alkylthio group, (any number A halogen atom, a hydroxy group, a Ci—Ce alkyl group, a —C 6 alkoxy group, or a phenyl group which may be substituted by a benzyloxy group), a phenoxy group, a benzyloxy group, a benzyloxycarbonyl group, a C 2 _C 7 alkanoyl group
- P represents 0 or 1.
- Q represents 0 or 1.
- G is one CO—, one S0 2 —, one CO— ⁇ one, one NR 7 _CO—, one CO— NR 7 —, — NH—CO—NH—, — NH—CS—NH—, one NR 7 - S0 2 -, one S_ ⁇ 2 - NR 7 -, - NH- CO- 0-, or - ⁇ - CO- NH- represents a group represented by.
- R 7 is either a hydrogen atom or a C 6 alkyl group, or scale 7 1 5 a Together they may form a C 2 -C 5 alkylene group.
- R 6 is a phenyl group, a C 3 — ⁇ 8 cycloalkyl group, a C 3 — ⁇ 6 cycloalkenyl group
- a benzyl group, or an aromatic heterocyclic group having 1-3 oxygen atoms, sulfur atoms, and / or nitrogen atoms as hetero atoms and is a phenyl group, a benzyl group, or an aromatic heterocyclic group represented by R 6 above.
- the ring group may form a condensed ring by condensing with a benzene ring or an aromatic heterocyclic group having 1 to 3 oxygen atoms, sulfur atoms, and / or nitrogen atoms as hetero atoms.
- phenyl group in the 6, C 3 - C 8 consequent opening alkyl group, C 3 - ⁇ 6 cycloalkenyl group, a benzyl group, aromatic heterocyclic group, or condensed ring may be any number of halogen atoms, hydroxy group, a mercapto group , Shiano group, a nitro group, a thiocyanato group, a carboxyl group, a force Rubamoiru group, triflate Ruo Russia methyl, CI- Ce alkyl group, C 3 - ⁇ 8 cycloalkyl group, ⁇ 2 - Flip 6 Arukeniru group, C i-C 6 alkoxy group, C 3 - Ji 8 cycloalkyl O alkoxy group, CI- C 6 Arukiruchio group, CI- C 3 alkylenedioxy O alkoxy group, phenyl group, phenoxy group, Fueniruamino group, Benzyl, benzoyl,
- the compound represented by the above formula (I) is a CCR3 receptor such as eotaxin. It has an activity of inhibiting the binding of a target ligand to a target cell, and an activity of inhibiting the physiological action of a CCR3 ligand such as eotaxin on a target cell. That is, the compound represented by the above formula (I) is a CCR3 antagonist.
- R 1 is phenyl group, C 3 - Ji 8 cycloalkyl group or to an oxygen atom as a hetero atom, a sulfur atom, and Roh or aromatic heterocyclic group 1 one three have a nitrogen atom
- R 1 represents a phenyl group or an aromatic heterocyclic group represented by R 1 by condensing with a benzene ring or an aromatic heterocyclic group having 113 oxygen atoms, sulfur atoms, and / or nitrogen atoms as hetero atoms.
- phenyl groups represented by R 1, C 3 - ⁇ 8 cycloalkyl group, aromatic heterocyclic group or a fused ring is any number of halogen atoms, hydroxy groups, Shiano group, nitro group, Karupoki sill group, forces Rubamoiru group, CI- C 6 alkyl group, C 3 - 0 8 cycloalkyl group, C 2 -C 6 alkenyl group, CI- C 6 alkoxy groups, one C 6 alkylthio group, C 3 — C 5 alkylene group, C 2 —C 4 alkyleneoxy group, 1 C 3 alkylenedioxy group, phenyl group, phenoxy group, phenylthio group, benzyl group, benzyloxy group, benzoylamino group, C 2 — C 7 Arukanoiru groups, C 2 - C 7 Arukokikarubo alkenyl groups, C 2 -C 7 alkan
- C 3. 8 cycloalkyl group refers for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl cyclohexane, which cyclic alkyl group of Shikurookuchiru group, the preferred embodiment Examples include a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group.
- Examples of the "aromatic heterocyclic group having 1 to 3 oxygen atoms, sulfur atoms, and Z or nitrogen atoms as hetero atoms" in R 1 include, for example, phenyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, and isoxazolyl , Thiazolyl, i It means an aromatic heterocyclic group such as a sothiazolyl, pyridyl, pyrimidinyl, triazinyl, triazolyl, oxadiazolyl (furazanyl), thiadiazolyl group, and preferable examples thereof include chenyl, furyl, pyrrolyl, isoxazolyl, and pyridyl group. No.
- the “fused ring” in R 1 means that the phenyl group or the aromatic heterocyclic group is a benzene ring or an aromatic heterocyclic group having 113 oxygen atoms, sulfur atoms, and / or nitrogen atoms as hetero atoms.
- a bicyclic aromatic heterocyclic group formed by condensing at any possible position preferred examples of which are naphthyl, indolyl, benzofuranyl, benzochenyl, quinolyl, benzimidazolyl, benzozo Examples include xazolyl, benzotriazolyl, benzoxazodiazolyl (benzofurazanyl), and benzothiadiazolyl groups.
- R 1 is particularly preferably a phenyl group, a phenyl group, a pyrazolyl group, an isooxazolyl group, a benzofuranyl group, or an indolyl group.
- C i -C 6 alkyl group as a substituent of R 1 includes, for example, methyl, ethyl, n-propyl, n-butyl, —pentyl, / 7-hexyl, 73-heptyl, ⁇ -octyl, isopropyl, Isopuchiru, sec- heptyl, i er - butyl, Isopenchi Le, hexyl neopentyl, Ieri- pentyl, iso, 2-methylpentyl, 1 - a C i one C 6 such Eterubuchiru groups linear or branched It means an alkyl group, and preferable specific examples thereof include a methyl, ethyl, propyl, and isopropyl group.
- C 2 —C 6 alkenyl group as a substituent of R 1 includes, for example, vinyl, aryl, 1-probenyl, 2-butenyl, 3-butenyl, 2-methyl-1-probenyl, 4 —C 2 —C 6 straight-chain or branched alkenyl group such as —pentenyl, 5-hexenyl, 4-methyl-3-pentenyl group; preferable examples of which are vinyl group and 2-methyl- And a 1-propenyl group.
- the “Ci—C 6 alkoxy group” as a substituent of R 1 means a group consisting of the aforementioned CL—C 6 alkyl group and an oxy group, and preferable examples thereof include a methoxy group and an ethoxy group. And the like.
- the one C 6 alkylthio group "as a substituent of R 1, means a group consisting of the CI- C 6 alkyl group and Chio group, as its preferred embodiments, a methylthio group, etc.
- C 5 alkylene radical C 3 for example, trimethylene, Te Toramechiren, C 3, such as pentamethylene, and 1-methyltrimethylene group - as a substituent for R 1 a divalent alkylene group of C 5
- preferred specific examples thereof include a trimethylene group and a tetramethylene group.
- the “C 2 —C 4 alkyleneoxy group” as a substituent of R 1 includes, for example, ethyleneoxy (one CH 2 CH 2 ), trimethyleneoxy (—CH 2 CH 2 CH 2 ) , Te tiger methylene O carboxymethyl (one CH 2 CH 2 CH 2 CH 2 0-), 1, 1 over dimethylethylene Okishi - such as (CH 2 C (CH 3) 2 0-) groups, C 2 - to C 4 It means a group consisting of a divalent alkylene group and an oxy group, and preferable specific examples thereof include an ethyleneoxy group and a trimethyleneoxy group.
- R 1 as "Ci one C 3 alkylenedioxy O alkoxy group"
- methylene di Okishi an OCH 2 0-
- Echirenjiokishi an OCH 2 CH 2 0-
- Bok Rimechire Njiokishi an OCH 2 CH 2 CH 20 —
- propylene dioxy one OCH 2 CH (CH 3 ) 0 —) group, etc.
- methylene di Okishi an OCH 2 0-
- Echirenjiokishi an OCH 2 CH 2 0-
- Bok Rimechire Njiokishi an OCH 2 CH 2 CH 20 —
- propylene dioxy one OCH 2 CH (CH 3 ) 0 —) group, etc.
- Preferred examples thereof include a methylenedioxy group and an ethylenedioxy group.
- C 2 —C 7 alkanoyl group as a substituent of R 1 includes, for example, acetyl, propanoyl, butanol, pentanoyl, hexanoyl, heptanyl, isobutylyl, 3-methylbutanoyl, 2-methylbutynoyl, vivaloyl, A C 2 -C 7 linear or branched alkanoyl group such as 4-methylpentanoyl, 3,3-dimethylbutanoyl and 5-methylhexanoyl is preferred. And a tyl group. '
- the “C 2 —C 7 alkoxycarbonyl group” as a substituent of R 1 means a group consisting of the aforementioned C 6 alkoxy group and a carbonyl group, and preferable specific examples thereof include a methoxycarbonyl group and an ethoxy group. And a carbonyl group.
- R 1 - and “C 2 C 7 alkanoyloxy noisy Ruo alkoxy group” the C 2 - C 7 7 means Rukanoiru group and Okishi comprising a group group, Asechi as the preferred embodiment Roxy group and the like.
- C 2 —C 7 alkanoylamino group as a substituent of R 1 means a group consisting of the C 2 —C 7 alkanoyl group and an amino group, and preferable specific examples thereof include: Acetylamino group and the like.
- C 2 —C 7 alkyl rubamoyl group as a substituent of R 1 means a group consisting of the d—C 6 alkyl group and a rubamoyl group, and preferable specific examples thereof include N— Examples include a methylcarbamoyl group and an N-ethylcarbamoyl group.
- C 4 C 9 N-cycloalkyl force Rubamoiru group refers to a pre-Symbol C 3 - ⁇ 8 comprising a cycloalkyl group and Karubamo Le group group, the preferred specific Examples include an N-cyclopentylcarbamoyl group, an N-cyclohexylcarbamoyl group, and the like.
- R 1 - and C 6 alkylsulfonyl group "means a group consisting of the d-C 6 7 alkyl group and a sulfonyl group, as its preferred embodiments, such as methylcarbamoyl Rusuruhoniru group No.
- C 3 —C 8 (alkoxycarbonyl) methyl group as a substituent of R 1 means a group consisting of the aforementioned C 2 —C 7 alkoxycarbonyl group and a methyl group. Methoxycarbonylmethyl group, ethoxycarbonylmethyl group and the like.
- the “mono (C, —C 6 alkyl) amino group” as the substituent of R 1 means an amino group substituted by the above-mentioned Ci—C 6 alkyl group, and a preferred specific example thereof is methylamino. And an ethylamino group.
- “Di (Ci—C 6 alkyl) amino group” as a substituent of R 1 means an amino group substituted by the same or different two of the aforementioned mono C 6 alkyl groups, and preferred specific examples thereof. Examples thereof include a dimethylamino group, a getylamino group, an ethyl-TV-methylamino group, and the like.
- a halogen atom a hydroxy group, d-C 6 alkyl group, CI- C 6 alkoxy groups, C i one C 6 alkylthio group, a Mechirenjiokishi group, and N- phenylene carbamoyl group.
- phenyl group in R 1, C 3 - ⁇ 8 cycloalkyl group, aromatic heterocyclic group, or a substituent of the fused ring is further optionally halogen atoms, hydroxy group, amino group, triflate Ruo Russia methyl group, It may be substituted by a C 6 alkyl group or a C i -C 6 alkoxy group.
- a halogen atom CI- C 6 alkyl group, beauty d-C 6 alkoxy group Oyo, phenyl group in the R 1, C 3 - Ji 8 cycloalkyl group, aromatic heterocyclic group or the condensed ring, It is the same as that defined for the substituent, and the same group can be mentioned as a preferable specific example.
- R 2 represents a hydrogen atom, —C 6 alkyl group, C 2 —C 7 alkoxycarbonyl group, hydroxy group, or phenyl group, and d—C 6 alkyl in R 2 group or phenyl group, any number of halogen atoms, hydroxy group, may be substituted by d-C 6 alkyl group or CI- Ce alkoxy group.
- R 2 is not a hydroxy group.
- R C i-C 6 in 2 alkyl and C 2 - C 7 alkoxy force Ruponiru group phenyl group in R 1, ⁇ 3 _ Ji 8 cycloalkyl group, aromatic heterocyclic group, or for a substituent fused ring
- substituents on the aromatic heterocyclic group or the condensed ring are the same as those defined above, and the same examples can be mentioned as preferred specific examples.
- R 2 particularly preferably represents a hydrogen atom.
- j represents an integer of 0-2. j is particularly preferably 0.
- k represents an integer of 0-2, and m represents an integer of 2-4.
- 2-substituted piperidine when k is 0 and m is 3, and when k is 1 and is 2.
- Particularly preferred are a 3-substituted pyrrolidine when k is 1 and m is 2 and a 4-substituted piberidine when k is 2 and m is 2.
- n 0 or 1.
- R 3 is a hydrogen atom, or even if each is substituted by any of the same or different halogen atoms, a hydroxy group, a C 6 alkyl group, or a Ci—C 6 alkoxy group. Represents a Ci—Ce alkyl group which may be substituted by 1 or 2 phenyl groups.
- the one C 6 alkyl group for R 3 is the same as defined for the substituent for the phenyl group, C 3 -C 8 cycloalkyl group, aromatic heterocyclic group, or fused ring in R 1 , Preferred specific examples include a methyl group, an ethyl group, and a propyl group.
- a halogen atom as a substituent of a phenyl group as a substituent of a C i -C 6 alkyl group in R 3 , a Ci-Ce alkyl group, and a C 6 alkoxy group are respectively a phenyl group in the aforementioned R 1 , C 3 - Ji 8 cycloalkyl group are the same as those defined for the substituents of the aromatic heterocyclic group or condensed Gowa, may be the same examples as a preferred embodiment.
- R 3 is particularly preferably a hydrogen atom or an unsubstituted Ci—Ce alkyl group.
- R 4 and R 5 are the same or different and each represent a hydrogen atom, a hydroxyl group, a phenyl group, or a C 1 -C 6 alkyl group
- the Ci—C 6 alkyl in R 4 and R 5 group can be any halogen atoms, hydroxy groups, Shiano group, a nitro group, a carboxyl group, a force Rubamoiru group, a mercapto group, Guanijino group, C 3 - Ji 8 cyclo alkyl group, d-C 6 alkoxy group, ⁇ 1 - 6 alkirchio group, (any halogen atom, hydroxy group, Ci—Ce alkyl group, 1 C 6 alkoxy group, or phenyl group optionally substituted by benzyloxy group), phenoxy group, Benzyloxy, benzyloxycarbonyl, C 2 —C 7 alkanoyl, C 2 —C 7 alkoxycarbonyl, C
- Ci—Ce alkyl group for R 4 and R 5 is the same as defined for the phenyl group, C 3 -C 8 cycloalkyl group, aromatic heterocyclic group, or fused ring substituent in R 1 above.
- the same example can be cited as a preferred specific example.
- 3-6 membered cyclic hydrocarbon comprising R 4 , R 5 and adjacent carbon atoms
- R 4 , R 5 and adjacent carbon atoms include cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.
- a hydrogen atom and a Ci—C 6 alkyl group, R 4 and R 5 can be cited as particularly preferred examples.
- G is — C ⁇ —, — S ⁇ 2 —, — C ⁇ -1 0—, —NR 7 — CO—, one C ⁇ -1 NR 7 —, one NH— CO— NH— one NH- CS- NH- one NR 7 - S_ ⁇ 2 - one S0 2 - represents a one NH- CO- O-, or one hundred and one C_ ⁇ group represented one NH- - NR 7 .
- R 7 represents a hydrogen atom or a Ci—Ce alkyl group, or R 7 may be combined with R 5 to form a C 2 —C 5 alkylene group.
- -CO- the force Ruponiru group, one S0 2 - a sulfonyl group, - CS- means respectively Ji Sairyoku Lupo two Le group.
- Particularly preferred examples of G include, for example, groups represented by 1 NR 7 —C ⁇ — and 1 NH—CO—NH—.
- R 7 a hydrogen atom can be mentioned as a particularly preferred example.
- R 6 is phenyl group, C 3 - 0 8 cycloalkyl group, C 3 - C 6 cycloalkenyl group, a benzyl group, or to an oxygen atom as a hetero atom, a sulfur atom, and or nitrogen atom
- R 6 represents an aromatic heterocyclic group having one to three
- the phenyl group, benzyl group, or aromatic heterocyclic group in R 6 is an oxygen atom, a sulfur atom, and / or a benzene ring or a hetero atom. It may be condensed with an aromatic heterocyclic group having 113 nitrogen atoms to form a condensed ring.
- the phenyl group for R 6 and C 3 —. 8 cycloalkyl group, C 3 ⁇ 6 cycloalkenyl group, benzyl group, aromatic heterocyclic group, or fused ring may be any halogen atom, hydroxy group, mercapto group, cyano group, nitro group, thiocyanato group , a carboxyl group, a force Rubamoiru group, triflate Ruo Russia methyl, Ci one C 6 alkyl group, C 3 - Ji 8 cycloalkyl group, C 2 - C 6 alkenyl group, CI- Ce alkoxy groups, C 3 - ⁇ 8 cycloalkyl Alkyloxy group, I C 6 alkylthio group, Ci—C 3 alkylenedioxy group, phenyl group, phenoxy group
- R 6 an oxygen atom as a hetero atom, a sulfur atom, and or nitrogen atom a one having three aromatic heterocyclic group, and a condensed ring, defined for the R 1
- the "C 3 Ji 8 cycloalkenyl group" for example, cyclobutenyl, cyclo pentenyl, cyclohexenyl, means a cyclic alkenyl group such as heptenyl cycloalkyl, and Shikurookuparu group, as its preferred embodiment is , 1-cyclopentenyl group, 1-cyclohexenyl group and the like.
- a phenyl group, a furyl group, a phenyl group, an indolyl group, and a benzofurazadyl group can be mentioned as particularly preferred examples.
- C 6 alkyl group C 2 - C 6 alkenyl group, CI- C 6 alkoxy group, C - C 6 alkylthio group, C t-C 3 alkylenedioxy O alkoxy group, ⁇ 2 - ⁇ 7 Arukanoiru group, C 2 -C 7 alkoxy Carbonyl group, C 2 —C 7 alkanoyloxy group, C 2 —C 7 alkylamino group, C 2 —C 7 N-alkyl rubamoyl group, 1 C 6 alkylsulfonyl group, mono (Ci— C 6 alkyl) amino group, and di (Ci one C 6 alkyl) amino group, phenyl group in the R 1, C 3 - Ji 8 cycloalkyl group, aromatic heterocyclic group, or with respect to a substituting group of fused ring, It is the same as the one defined and prefers the same example for each It may be mentioned as such examples.
- the C 3 - C 8 means a cycloalkyl group and Okishi comprising a group group, as its preferred embodiments, Examples thereof include a cyclopropyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.
- N, N-di (d—C 6 alkyl) sulfamoyl group as a substituent of R 6 means a sulfamoyl group substituted by two identical or different C! -C 6 alkyl groups.
- Preferable specific examples thereof include, for example, an N, N-dimethylsulfamoyl group, an N, N-dimethylsulfamoyl group, and a TV-ethyl-TV-methylsulfamoyl group.
- C 2 —C 7 (alkoxycarbonyl) amino group as a substituent of R 6 means a group consisting of the aforementioned C 2 —C 7 alkoxycarbonyl group and an amino group, and a preferred specific example thereof is Is, for example, a methoxycarbonylamino group, an ethoxycarbonylamino group and the like.
- the “Ci—C 6 (alkylsulfonyl) amino group” as the substituent for R 6 means a group consisting of the aforementioned C i-C 6 alkylsulfonyl group and an amino group, and preferable specific examples thereof include: (Methylsulfonyl) amino group and the like.
- “Bis (Ci-Cealkylsulfonyl) amino group” as a substituent of R 6 means an amino group substituted by two same or different Ci-Cealkylsulfonyl groups. Specific examples include a bis (methylsulfonyl) amino group.
- phenyl group, C 3 - ⁇ 8 cycloalkyl group, C 3 in the R 6 - The C 8 sik Roarukeniru group, a benzyl group, aromatic heterocyclic group, or condensed ring substituent, a halogen atom, a mercapto group , nitro group, triflate Ruo Russia methyl, CI- C 6 alkyl le group, - C 6 alkoxy group, phenyl group, Benjiruokishi group, Hue Nils sulfinyl group, C 2 - C 7 Arukanoiru groups, C 2 - C 7 alkanol Preferred examples include an ilamino group and an amino group.
- halogen atom a nitro group, a trifluoromethyl group, a C 6 alkyl group, a C 6 alkoxy group, a phenylsulfinyl group, and an amino group.
- phenyl groups in R 6, C - C s cycloalkyl groups, C - ⁇ 8 cycloalkyl Alkenyl group, a benzyl group, aromatic heterocyclic group, or a substituent of the fused ring, a halogen atom further Ren go, Shiano group, hydroxy group, amino group, triflate Ruo Russia methyl, CI- C 6 alkyl group, It may be replaced by a Ci—Ce alkoxy group, a Ci—C 6 alkylthio group, a mono (Ci—C 6 alkyl) amino group, or a di (Ci—C 6 alkyl) amino group.
- the C 6 alkyl group, Ci—C 6 alkoxy group, mono C 6 alkylthio group, mono (Ci—C 6 alkyl) amino group, and di (Ci—C 6 alkyl) amino group are the phenyl group in R 1 , 3 - ⁇ 8 cycloalkyl group, aromatic heterocyclic group, or is the same as defined for the substituents of the fused ring include the same examples as a preferred embodiment, respectively.
- the compound represented by the above formula (I), its pharmaceutically acceptable acid adduct, or its pharmaceutically acceptable C 1 -C 6 alkyl adduct has a therapeutically effective amount in a pharmaceutically acceptable amount.
- the present invention provides a pharmaceutical composition together with a carrier and / or a diluent to inhibit binding of a CCR3 ligand such as eotaxin of the present invention to CCR3 on a target cell, or a CCR3 such as eotaxin. It can be used as a drug having an effect of inhibiting the physiological action of a ligand on a target cell, or as a therapeutic or preventive agent for a disease in which CCR3 is considered to be involved.
- the cyclic amine derivative represented by the above formula (I), a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable —C 6 alkyl adduct is orally or It can be administered parenterally, such as intravenously, subcutaneously, intramuscularly, transdermally, or rectally.
- Examples of the dosage form for oral administration include tablets, pills, granules, powders, solutions, suspensions, capsules and the like.
- excipients such as lactose, starch, and microcrystalline cellulose
- binders such as carboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone
- disintegrants such as sodium alginate, sodium bicarbonate, and sodium lauryl sulfate; And can be formed by an ordinary method.
- pills, powders, and granules can be formed by an ordinary method using the above-mentioned excipients and the like.
- Solutions and suspensions can be prepared in the usual manner using, for example, glycerin esters such as tricaprylin and triacetin, and alcohols such as ethanol. Therefore, it is molded.
- Capsules are formed by filling granules, powders, liquids, or the like, into capsules such as gelatin.
- Subcutaneous, intramuscular and intravenous dosage forms include injections in the form of aqueous or non-aqueous solutions.
- aqueous solution for example, physiological saline is used.
- non-aqueous solution for example, propylene glycol, polyethylene glycol, olive oil, ethyl oleate and the like are used, and if necessary, a preservative and a stabilizer are added.
- the injection is sterilized by appropriate filtration through a bacteria-retaining filter and treatment with a bactericide.
- the dosage form for transdermal administration includes, for example, ointments and creams.
- Ointments include oils and fats such as castor oil and olive oil, or vaseline, and creams include fatty oils.
- emulsifier such as diethylene glycol-sorbitan monofatty acid ester.
- suppositories such as gelatin soft capsules are used.
- the dosage of the cyclic amine derivative of the present invention, the pharmaceutically acceptable acid adduct thereof, or the pharmaceutically acceptable mono-C 6 alkyl adduct may vary depending on the type of disease, administration route, age and sex of the patient, It usually varies from 1 to 50 OmgZ days per adult, depending on the severity of the disease.
- cyclic amine derivative of the above formula (I) include compounds containing each substituent shown in the following Table i. 1-1.221.
- “chirality” means “absolute configuration”, that is, the absolute configuration of the asymmetric carbon on the ring of the cyclic amine.
- “R” means that the asymmetric carbon atom on the ring of the cyclic amine has the absolute configuration of R
- “S” means that the asymmetric carbon atom has the absolute configuration of S
- “one” is racemic. Or that the compound has no asymmetric carbon atom on the cyclic amine.
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Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00950006A EP1201239A4 (en) | 1999-08-04 | 2000-08-04 | CYCLIC AMINES AS CCR3 ANTAGONISTS |
CA002378499A CA2378499A1 (en) | 1999-08-04 | 2000-08-04 | Cyclic amine ccr3 antagonists |
AU63193/00A AU779610B2 (en) | 1999-08-04 | 2000-08-04 | Cyclic amine CCR3 antagonists |
US10/031,698 US7576117B1 (en) | 1999-08-04 | 2000-08-04 | Cyclic amine CCR3 antagonist |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP11/220864 | 1999-08-04 | ||
JP22086499 | 1999-08-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001010439A1 true WO2001010439A1 (fr) | 2001-02-15 |
Family
ID=16757751
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2000/005260 WO2001010439A1 (fr) | 1999-08-04 | 2000-08-04 | Antagonistes d'amine cyclique ccr3 |
Country Status (7)
Country | Link |
---|---|
US (1) | US7576117B1 (ja) |
EP (1) | EP1201239A4 (ja) |
KR (1) | KR100667645B1 (ja) |
CN (1) | CN1192773C (ja) |
AU (1) | AU779610B2 (ja) |
CA (1) | CA2378499A1 (ja) |
WO (1) | WO2001010439A1 (ja) |
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WO2003087089A1 (fr) * | 2002-04-16 | 2003-10-23 | Teijin Limited | Derives de piperidine possedant un antagonisme de ccr3 |
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Also Published As
Publication number | Publication date |
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EP1201239A4 (en) | 2004-12-08 |
CA2378499A1 (en) | 2001-02-15 |
KR100667645B1 (ko) | 2007-02-28 |
AU779610B2 (en) | 2005-02-03 |
KR20020015722A (ko) | 2002-02-28 |
CN1376063A (zh) | 2002-10-23 |
US7576117B1 (en) | 2009-08-18 |
CN1192773C (zh) | 2005-03-16 |
EP1201239A1 (en) | 2002-05-02 |
AU6319300A (en) | 2001-03-05 |
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