WO2003072545A1 - Compose d'amine cyclique et medicament inhibiteur de ccr3 contenant ce compose comme principe actif - Google Patents

Compose d'amine cyclique et medicament inhibiteur de ccr3 contenant ce compose comme principe actif Download PDF

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WO2003072545A1
WO2003072545A1 PCT/JP2003/002227 JP0302227W WO03072545A1 WO 2003072545 A1 WO2003072545 A1 WO 2003072545A1 JP 0302227 W JP0302227 W JP 0302227W WO 03072545 A1 WO03072545 A1 WO 03072545A1
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alkyl
substituted
methyl
added
group
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PCT/JP2003/002227
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English (en)
Japanese (ja)
Inventor
Takayuki Imaoka
Kuniaki Kawamura
Masayuki Kaneko
Hideki Kozono
Koichiro Morihira
Hirokazu Kubota
Tatsuaki Morokata
Masanobu Kaneeda
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Toray Industries, Inc.
Yamanouchi Pharmaceutical Co., Ltd.
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Priority to AU2003211397A priority Critical patent/AU2003211397A1/en
Priority to JP2003571251A priority patent/JPWO2003072545A1/ja
Publication of WO2003072545A1 publication Critical patent/WO2003072545A1/fr

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    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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    • A61K31/4164—1,3-Diazoles
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • 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

Definitions

  • the present invention relates to a cyclic amine compound or a pharmaceutically acceptable salt thereof, and a medicament containing these as an active ingredient, particularly a CCR3 inhibitor.
  • MBP major basic prot ein
  • ECP eosinophil cationic protein
  • EDN eosi hito derived neuroto xin
  • EPO eosinophil peroxidase
  • Eosinophils accumulated in the inflamed area play an important role in the development of the above-mentioned inflammatory diseases by releasing such granule proteins. Therefore, drugs that suppress tissue accumulation of eosinophils are It is thought to contribute to the treatment of such diseases.
  • Steroidal anti-inflammatory drugs are clinically used as effective therapeutic agents for many chronic inflammatory diseases, including eosinophilic inflammatory diseases, and are known to strongly suppress eosinophil tissue accumulation. I have. However, various side effects such as adrenal atrophy, growth inhibition, weakening of connective tissue due to inhibition of collagen synthesis, etc., and problems such as a gradual increase in the amount used due to the acquisition of resistance have been pointed out with steroids. The development of eosinophil accumulation inhibitors with few side effects is desired.
  • chemokines proteinaceous mediators
  • Leukocytes express a chemokine receptor on their cell surface, and the binding of the chemokine to the receptor induces a leukocyte migration reaction—a mediae overnight release reaction.
  • eosinophils mainly express CCR3 as a chemokine receptor (for example, "The European Respiratory Journal", (Denmark), 1996, Vol. 9, p.2454—2460; “See The Journal of Clinical Investigation” (USA), 1997, Vol. 99, pp. 926—936), and its ligands.
  • RANTES, MCP-3, MCP-4, and eotaxin have been reported to be produced at high levels from the respiratory epithelium in human asthma (see, for example, "The Journal of Clinical Medicine, (The Journal of Clinical Investigation) ">
  • CCR3 is considered to be an effective target in controlling eosinophilic inflammation (eg, "Nature Reviews. Immunology” '(UK), 2001, (See Volume 1, p.108-116.)
  • TCR type 2 helper T (Th2) cells which control airway inflammation, also express CCR3, CCR4, CXC4, and CCR8.
  • CCR5 and CXCR3 are expressed in T helper type 1 (Thl) cells that act in the direction of suppressing Th2 cell response (see, for example, "The Journal of Experimental Medicine”).
  • CCR3 inhibitors are thought to be effective in controlling inflammatory diseases.
  • CCR5 is expressed on Till cells and macrophages, but few reports suggest the involvement of the ligand in the inflammatory disease and the importance of CCR5. It is easily speculated that CCR3 inhibitors are a better choice than CCR5 inhibitors.
  • a piperazine, piperidine or pyrrolidine derivative for example, International Publication No. 00Z10439; pamphlet of International Publication No. 00Z143333); No. 0/310, 32, but the structure is different from the compound of the present invention.
  • R 1 is such as alkyl (which may have a substituent such as Ariru group)
  • R 2 is hydrogen, alkyl, etc.
  • R 3 is alkyl, cycloalkyl , NR 4 3 ⁇ 4 46 etc.
  • R 4, R 5, R 6, R 7 is hydrogen, alkyl, etc.
  • R 45 is hydrogen or the like
  • R 46 is a halogen as Ariru like (substituent, hydroxy, NR 28 R 29, C ( 0) NR 39 R 40, C0 2 R 42, alkyl, alkoxy, full Eniru, phenylalanine alkoxy, Heteroariru may have a hetero ⁇ reel alkoxy, etc.)
  • m, p represents 0 to 2. More See the official gazette.
  • cyclic amine compound represented by the general formula (1) of the present invention is included in the compound represented by the following general formula described in a document published after the filing date of the priority application of the present application,
  • the following compounds are known to have CCR3 antagonism (for example, see WO 02/183335).
  • X is - C0_, - S0 2 -, etc.
  • D is a monocyclic or bicyclic Ariru
  • n represents shows the 0-2.
  • the problem to be solved by the present invention is to provide a medicament capable of preventing and treating inflammatory diseases caused by leukocyte accumulation such as lymphocytes, eosinophils and basophils by finding a CCR3 inhibitor. Is to do.
  • the present inventors have conducted intensive studies and found that the cyclic amine compound represented by the general formula (1) shows a strong inhibitory activity against CCR3, and that, in an asthma model using an animal, It has been found that the cyclic amine compound represented by the formula (1) exhibits excellent effects. Furthermore, in an oral absorption test using an animal, the cyclic amine compound represented by the general formula (1) was found to exhibit excellent bioavailability, thereby completing the present invention. I came to.
  • the present invention includes the following inventions
  • A is a group selected from the group consisting of an aryl group, a heterocyclic group, and a cycloalkyl group, and has at least one substituent X and at least one substituent Y. May be
  • Substituent X is substituted with 0H (6 alkyl, (0- (C 2 substituted by 0H - 6 alkyl)) _ 6 alkyl substituted with, - substituted with C00H (6 alkyl, - C00 ( (V 6 alkyl) _ 6 alkyl substituted by, - alkyl substituted by C0Nh 2, - CON (CH alkyl) _ 6 alkyl substituted by 2, - substituted with NHCiHCni alkyl) (alkyl, ( 0 _ 6 alkyl substituted with (substituted (C6 alkyl) by C00H), - substituted with (0 (COOO e alkyl) by substitution have been c 6 alkyl)) (6 alkyl, (o- ((o-(substituted by alkyl) (alkyl)) _ 6 alkyl substituted with, 0- ((0- C w alkyl substituted by alkyl)), o -
  • Substituent Y is halogen, alkyl, 0H, methoxy, selected from the group consisting of CN and CF 3.
  • a pharmaceutical composition comprising, as an active ingredient, the cyclic amine compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof.
  • a CCR3 inhibitor comprising, as an active ingredient, the cyclic amine compound or the pharmaceutically acceptable salt thereof according to any of (1) to (3).
  • a therapeutic drug for an inflammatory disease comprising as an active ingredient the cyclic amine compound or the pharmaceutically acceptable salt thereof according to any of (1) to (3).
  • a therapeutic drug for a disease derived from inflammatory cell infiltration comprising as an active ingredient the cyclic amine compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (3).
  • a therapeutic agent for a disease derived from eosinophil infiltration comprising as an active ingredient the cyclic amine compound or the pharmaceutically acceptable salt thereof according to any one of (1) to (3) as described above.
  • the cyclic amine compound of the present invention is represented by the above formula 1.
  • the aryl group represented by A represents an aryl group having 6 to 14 carbon atoms, preferably a monocyclic or bicyclic aryl having 6 to 10 carbon atoms, and more preferably a phenyl group.
  • the heterocyclic group represented by A is a 4- to 14-membered monocyclic to tricyclic heterocyclic group having 1 to 4 heteroatoms selected from 0, S and N, and a saturated ring. , An aromatic ring, and a partially hydrogenated ring group thereof.
  • the heterocyclic group is preferably an unsaturated heterocyclic group, more preferably pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, benzimidazolyl, pyrazolyl, indolyl, and indazolyl.
  • the cycloalkyl group represented by A represents, for example, a cyclic alkyl group having 3 to 10 carbon atoms, preferably 5 to 8 carbon atoms, more preferably cyclohexyl, cycloheptyl and cyclooctyl.
  • halogen represents F, CL Br and I.
  • alkyl may be linear or branched, as a "_ 6 alkyl", for example methyl, E chill, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, I Sopenchiru, neopentyl, Hexyl and the like, "[;! _ 3 alkyl” is an alkyl group having 1 to 3 carbon atoms of the above-mentioned "CH alkyl”, and "C M alkyl” is the above-mentioned "(V 6 alkyl) .
  • an alkyl group having 2 to 6 carbon atoms - the term "C 2 3 alkyl” rc, _ 6 alkyl “of, refers to an alkyl group having 2 to 3 carbon atoms" (: Bok 6 alkyl " Preferably ( 3 alkyl, more preferably methyl.
  • Halogen-substituted ( 3 alkyl) '' is one or more halogen, preferably F-substituted ( 3 alkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, and the like, Preferably, it is trifluoromethyl.
  • the aryl group, heterocyclic group and cycloalkyl group represented by A may have at least one substituent X and may further have at least one substituent Y.
  • Substituent X is substituted with 0H (6 alkyl, (0 (as substitution with C 2 _ 6 alkyl)) substituted with 0H (6 alkyl, - CH alkyl substituted with C00H, - C00 O 6 alkyl) in replacement alkyl, - C0Nh alkyl substituted with 2, - C0N O 3 alkyl) 2 in replacement has been _ 6 alkyl, - NHC0 0 3 alkyl) alkyl substituted with, (0 - substituted with (substituted with (alkyl) C00H) (6 alkyl, ( ⁇ - ⁇ ⁇ alkyl) C H alkyl substituted with)) CH alkyl substituted with, (0- ((0- (V 6 alkyl) Has been (6 alkyl)) C M alkyl substituted with 0 - in substituted with ((0 _ 6 alkyl) (alkyl), o- ((substituted with o- halogen
  • substituent X '_ 6 alkyl substituted with 0H " is preferably cyclohexyl hydroxy methylation, hydroxy E chill, hydroxypropyl, hydroxybutyl, hydroxy pentyl, hydroxy.
  • Substituent X as the "(0- (C 2 _ 6 alkyl substituted with 0H)) _ 6 alkyl mud substituted with carboxymethyl-butoxymethyl, hydroxypentyl Ruo carboxymethyl, carboxymethyl Ruokishimechiru to hydroxy, hydroxyethoxy E chill, Hydroxypropoxyshetyl, hydroxybutoxyl, hydroxypentyloxethyl, hydroxyhexoxyl, hydroxyethoxypropyl, hydroxypropoxypropyl
  • Hydroxybutyl pill hydroxyhexyloxy Roxypropoxybutyl, hydroxybutoxybutyl, hydroxyhexyloxybutyl, hydroxypropoxypentyl, hydroxybutoxypentyl,
  • alkyl substituted with —COO Os alkyl) as the substituent X is preferably methoxycarbonylmethyl, methoxycarbonylmethyl, propoxycarbonylmethyl, butoxycarbonylmethyl, pentyloxycarbonylmethyl, hexyl Oxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, propoxylponylethyl, butoxycarbonylethyl, pentyloxycarbonylethyl, hexyloxycarbonylethyl, methoxycarbonylpropyl, ethoxycarbonylpropyl, propoxycarbonylpropyl, butoxy Xycarbonylpropyl, pentyloxycarbonylpropyl, hexyloxycarbonylpropyl, methoxycarbonylbutyl, ethoxycarbonylbutyl, Ropoxycarbonylbutyl, butoxycarbonylbutyl, pentyl
  • substituent X "- substituted with C0Nh 2 (6 alkyl” is preferably cyclohexyl are Karubamo Irumechiru force Rubamoiruechiru force Luba moil propyl, force Rubamoirubuchiru force Luba moil pentyl, to force Rubamoiru.
  • “-C0N ((V 3 alkyl) 2 -substituted ( 6 alkyl)” as a substituent X is preferably ⁇ dimethylcarbamoylmethyl, getylcarbamoylmethyl, dipropyl-capable rubamoylmethyl, dimethylcarbamoylethyl, dimethylcarbamoyl Ethyl, dipropyl carbamoyl propyl, dimethyl carbamoyl propyl, getyl carbamoyl propyl, dipropyl rubamoyl propyl, dimethyl carbamoyl butyl, getyl carbamoyl butyl, dipropyl carb amoyl butyl, dimethyl dimethyl carbamoyl pentyl, dipropyl carbamo getyl carbamoyl hexyl Dipropyl potash is rubamoylhexyl.
  • substituents x "- _ 6 alkyl substituted with dish co 3 alkyl)" refers preferably ⁇ is ⁇ cetyl aminomethyl, propionylaminomethyl, Petit Lil aminomethyl, ⁇ cetyl aminoethyl, Propionylaminoethyl, butyrylaminoethyl, acetylaminopropyl, propionylaminopropyl, propylylaminopropyl, acetylaminobutyl, propionylaminobutyl, petyrylaminobutyl, acetylaminopentyl, propionylamino Pentyl, butyrylaminopentyl, acetylaminohexyl, propionylaminohexyl, and butyrylaminohexyl.
  • substituent X '(0 (_ 6 alkyl Le substituted with substituted (alkyl)) in C00H "preferably carboxymethyl methoxymethyl, carboxymethyl ethoxymethyl, force Lupo carboxymethyl Provo carboxymethyl, carboxyethyl butoxy Methyl, carboxypentyloxymethyl, carboxyhexyloxymethyl, carboxymethoxyethyl, carbyl, carboxypentyloxethyl, carboxyhexyloxyshetyl, carboxymethoxypropyl, carboxyethoxy Propyl, carboxypropoxypropyl, carboxybutoxypropyl, carboxypentyloxypropyl, carboxyhexyloxypropyl, carboxymethoxybutyl, carboxyethoxybutyl, carboxypropoxybutyl, carboxybutoxybutyl, Rupoxypentyloxybutyl, carboxyhexyloxybutyl, carboxyl, carboxyptoxy
  • the “_ 6 alkyl substituted with (0- (CH alkyl substituted with (OC B alkyl))” as the substituent X is preferably methoxymethoxymethyl, methoxyethoxymethyl, methoxypropoxymethyl. , Methoxybutoxymethyl, methoxypentyloxymethyl, methoxyhexyloxymethyl, methoxymethoxyl, methoxyethoxyl, methoxypropoxyl, methoxybutoxyl, methoxypentoxyl, methoxyl Xyloxyshethyl, methoxymethoxypropyl, methoxyethoxypropyl, methoxypropoxypropyl, methoxybutoxypropyl, methoxypentyloxypropyl, methoxyhexyloxypropyl, methoxymethoxybutyl, methoxyethoxybutyl, methoxypro Boxybutyl, methoxybutoxybutyl, methoxypentyloxybuty
  • Methoxypropoxypentyl methoxybutoxypentyl, methoxypentyloxypentyl, methoxyhexyloxypentyl, methoxymethoxyhexyl
  • substituent X '0- ((OC H alkyl) substituted with (alkyl) "is rather preferably the methoxymethoxy, E Bok Kishimetokishi, Purobokishime Bok alkoxy, Butokishime Bok alkoxy, pliers Ruo carboxymethyl methoxy, to Xyloxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyshethoxy, pentyloxyshethoxy, hexyloxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, pentyloxypropoxy, hexyl Oxypropoxy, methoxybutoxy, X toxic butoxy, propoxybutoxy, butoxybutoxy, pentyloxybutoxy, hexyloxybutoxy, methoxypentyloxy, ethoxypentyloxy, propoxypentyloxy Butoxypentyloxy, pent
  • substituent X is preferably trifluoromethoxymethoxy, trifluoromethoxymethoxy, trifluoromethoxypropyl, Methoxy, trifluoromethoxybutoxy, trifluoromethoxypentyloxy and trifluoromethoxyhexyloxy.
  • substituent X '0- (C 2 _ 6 alkyl substituted with OH) is preferably Kishiruokishi is hydroxy Shietokishi, hydroxy Provo, hydroxy butoxy, hydroxypentyl Okishi, the hydroxy.
  • substituent X '0- ((0- (C 2 _ 6 alkyl substituted with 0H)) CH substituted by; al kill) "preferably hydroxyethoxy methoxy, hydroxy Provo Kishime Bok, hydroxy Butoxymethoxy, hydroxypentyloxymethoxy, hydroxypoxyethoxy, hydroxybutoxyethoxy, hydroxypentyloxyethoxy, hydroxyhexylethoxyethoxy, hydroxyethoxypropoxy, hydroxypropoxypropoxy, hydroxybutoxypropoxy, hydroxy. Hydroxypropoxy, hydroxyhexyloxypropoxy, hydroxyethoxybutoxy, hydroxypropoxybutoxy, hydroxybutoxybutoxybutoxy
  • substituent X '0- N (C substituted by 0H 2 - 3 alkyl) CH alkyl Le substituted by 2) "preferably bis (hydroxymethyl E chill) amino methoxy, bis (hydroxypropyl) Aminomethoxy, bis (hydroxyethyl) aminoethoxy, bis (hydroxypropyl) aminoethoxy, bis (hydroxyethyl) aminopropoxy, bis (hydroxypropyl) aminopropoxy, bis (hydroxyethyl) aminobutoxy, bis (hydroxy) Propyl) aminobutoxy, bis (hydroxyethyl) aminopentyloxy, bis (hydroxypropyl) aminopentyloxy, bis (hydroxyethyl) aminohexyloxy, and bis (hydroxypropyl) aminohexyloxy.
  • 0-(_ 6 alkyl substituted with CN) as the substituent X is preferably a cyanome / 02227 Toxi, cyanoethoxy, cyanopropoxy, cyanobutoxy, cyanopentyloxy, cyanohexyloxy.
  • “0-(_ 6 alkyl substituted with an oxo group)” as the substituent X is preferably methoxy substituted with an oxo group, ethoxy substituted with an oxo group, propoxy substituted with an oxo group, or oxo.
  • substituent X "0_ (substituted with C00H (6 alkyl)" is preferably Kishiruokishi is carbo Kishimetokishi, Cal Po ethoxy, Cal Po carboxymethyl Provo carboxymethyl force Rupokishibutoki shea, carboxypentyl Ruo alkoxy, to carboxy.
  • “0-(_ 6 alkyl substituted with C0NH 2 )” as the substituent X is preferably rubamoylmethoxy, rubamoylethoxy, Ruptoxy, carbamoylpentyloxy, carbamoylhexyloxy, “alkyl substituted with 0-0 ⁇ ” as the substituent X is preferably sulfamoylmethoxy, sulfamoylethoxy, sulfamoylpropoxy. , Suroxy.
  • substituent X is preferably dimethylcarbamoylmethoxy, getylcarbamoylmethoxy, dimethylcarbamoylmethoxy, dimethylcarbamoylethoxy.
  • 0-CH (C 2 alkyl substituted with 0H) 2 as the substituent X is preferably bis (hydroxymethyl) methoxy, bis (hydroxyethyl) methoxy.
  • substituent X examples include, in particular, lipoxymethyl, lipoxyxetil, lipoxypoxy pill, carboxybutyl, carboxypentyl, carboxyhexyl, lipamoyl methyl, lipamoylethyl, lipamoylpropyl, lipamoylbutyl, lipamoylpentyl, Powerbamoylhexyl, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, pentyloxymethoxy, hexoxymethoxy, methoxyxoxy, ethoxyethoxy, propoxyethoxy, butoxyxoxy, pentyloxyx Ethoxy, hexoxyloxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, pentyloxypropoxy, hexoxypropoxy, Toki Shipu Bok alkoxy, E WINCH Kishibu Bok alkoxy, Puropok
  • Substituent Y is a halogen, (3 alkyl, 0H, methoxy barrel selected from the group consisting of CN and CF 3. Substituents if group there are two or more Y, these are as substituent Y which be the same or different Halogen is preferably F, C1 ( 3 alkyl as substituent Y is preferably methyl, tyl, propyl.
  • Specific compounds of the present invention include, for example, the compounds shown in Table 1.
  • reaction conditions are appropriately selected from those described below.
  • Equation 1 becomes Equation 2
  • the amount of 4-ditrophenylchloroformate-phenylphenylformate used in the first step of the present production method is not particularly limited, but is usually about 1 to 5 equivalents to the formula 2.
  • the amount of the base used in the first step, such as sodium hydrogencarbonate and tertiary amine, is not particularly limited, but is usually 1 to 4 parts by weight of 4-nitrophenyl chloroformate to phenyl chloroformate. Equivalent to about 20 equivalents.
  • the amount of the tertiary amine used in the second step is not particularly limited, but is usually about 1 to 20 equivalents to the formula 2.
  • the reaction temperature of the first-stage formula 2 with 4-nitrophenyl chloroformate-phenyl chloroformate is not particularly limited, but is about 0 ° C. to room temperature, and the reaction temperature of the second step is 4-nitrophenyl chloroformate.
  • the temperature is usually about 0 ° C. to 50 ° C., and in the case of phenyl chloroformate, it is about room temperature to about the heating reflux temperature.
  • a base such as sodium bicarbonate or tertiary amamine
  • substituted arylamine substituted heterocyclic amine
  • substituted cyclopentylamine substituted cyclohexylamine
  • substituted cycloheptylamine substituted After reacting the corresponding amine, such as cyclooctylamine, with 4-ditrophenyl chloroformate, phenyl chloroformate, etc.
  • first step in the presence of tertiary amines, such as triethylamine, diisopropylethylamine, DBU, or It can also be produced by reacting with Formula 2 in the absence (second stage).
  • tertiary amines such as triethylamine, diisopropylethylamine, DBU, or It can also be produced by reacting with Formula 2 in the absence (second stage).
  • the amount of 4-nitrophenyl chloroformate used in the first step of the present production method is not particularly limited, but is usually, substituted arylamine, substituted heterocyclic amine, substituted cyclopentylamine, substituted cyclohexylamine, It is about 1 to 5 equivalents to the substituted cycloheptylamine and the substituted cyclooctylamine.
  • the amount of the base such as sodium hydrogencarbonate and tertiary amine used in the first step of the present production method is not particularly limited, but is usually 1 to 20 equivalents based on 4-nitrophenyl chloroformate and phenyl chloroformate. It is about.
  • the amount of the tertiary amine used in the second step is not particularly limited, but is usually a substituted arylamine, a substituted heterocyclic amine, a substituted cyclopentylamine, a substituted cyclohexylamine, a substituted cycloheptylamine, a substituted cyclooctyl. It is about 1 to 20 equivalents to the amine.
  • Amines such as substituted arylamines, substituted heterocyclic amines, substituted cyclopentylamines, substituted cyclohexylamines, substituted cycloheptylamines, substituted cyclooctylamines, etc. in the first step, and chloroformate 4-nitrophenyl chloroformate
  • the reaction temperature with phenyl is not particularly limited, but is about 0 ° C. to room temperature.
  • the reaction temperature of the second step is usually about 0 ° C. to 50 ° C. for 4-nitrophenyl chloroformate. In the case of chloroformate, the temperature is from room temperature to the heating reflux temperature.
  • formula 2 is converted to dichloromethane, chloroform, tetrahydrofuran, and acetonitrile.
  • solvents such as ril, usually 0.5 to 2.0 equivalents of diphosgene, triphosgene, 1,1-potassyldiimidazole, 1, tricarponylbisbenzotriazole, N, N-disuccinimide
  • zircarbonate, bis (4-nitrophenyl carbonate), etc. substituted arylamine, substituted heterocyclicamine, substituted cyclopentylamine, substituted cyclohexylamine, substituted cycloheptylamine, substituted cyclooctyl It can also be produced by reacting with a corresponding amine such as an amine.
  • the ratio (mol ratio) of Formula 2 to the substituted arylamine, substituted heterocyclicamine, substituted cyclopentylamine, substituted cyclohexylamine, substituted cycloheptylamine, or substituted cyclooctylamine is not particularly limited, but is usually
  • the reaction is performed at a temperature of about 0 ° (about 50 ° C) for about 1 to 24 hours.
  • the corresponding amines such as substituted arylamine, substituted heterocyclicamine, substituted cyclopentylamine, substituted cyclohexylamine, substituted cycloheptylamine, substituted cyclooctylamine, and the like can be dissolved in a solvent such as dichloromethane, chloroform, tetrahydrofuran, and acetonitrile.
  • a solvent such as dichloromethane, chloroform, tetrahydrofuran, and acetonitrile.
  • diphosgene, triphosgene, 1,1-potassyldiimidazole, 1,1-carbonylbisbenzotriazole, N, N-disuccinimidyl , Bis (4-nitrophenol-one), etc. and then reacting with formula 2.
  • the ratio (molar ratio) between the substituted arylamine, the substituted heterocyclic amine, the substituted cyclopentylamine, the substituted cyclohexylamine, the substituted cycloheptylamine, the substituted cyclooctylamine and the formula 2 is not particularly limited. : 1 to 1: 2. Usually, the reaction is carried out at 0 ° (at a temperature of about 50) for about 1 to 24 hours.
  • substituted arylalkyl carboxylic acid substituted heterocyclic carboxylic acid, and substituted cyclopentyl carboxyl.
  • first stage It can also be produced by reacting sodium azide, diphenylphosphoryl azide and the like (second step), heating the resulting azide to form an isocyanate, and then reacting with isocyanate 2 (third step).
  • first stage of the manufacturing method The amount of ethyl chloroformate used for the above is not particularly limited, but is usually a substituted aryl carboxylic acid, a substituted heterocyclic carboxylic acid, a substituted cyclopentyl carboxylic acid, a substituted cyclohexyl carboxylic acid, a substituted cycloheptyl carboxylic acid, It is about 1 to 2 equivalents to cyclooctylcarboxylic acid.
  • the amount of the base such as tertiary amine used in the first step of the present production method is not particularly limited, but is usually about 1 equivalent to 20 equivalents to ethyl chloroformate.
  • the amount of sodium azide and diphenylphosphoryl azide used in the second step is not particularly limited, but is usually a substituted aryl alcohol, a substituted heterocyclic carboxylic acid, a substituted cyclopentyl carboxylic acid, a substituted cycle hexyl carboxylic acid. It is about 1 to 10 equivalents to the substituted cycloheptyl carboxylic acid and the substituted cyclooctyl carboxylic acid.
  • the amount of Formula 2 used in the third step is not particularly limited, but is usually a substituted aryl carboxylic acid, a substituted heterocyclic carboxylic acid, a substituted cyclopentyl carboxylic acid, a substituted cyclohexyl carboxylic acid, a substituted cyclo heptyl carboxylic acid. It is about 1 to 5 equivalents to the acid and substituted cyclooctylcarboxylic acid.
  • Step 1 Reaction of substituted aryl carboxylic acid, substituted heterocyclic carboxylic acid, substituted cyclopentyl carboxylic acid, substituted cyclohexyl carboxylic acid, substituted cycloheptyl carboxylic acid, substituted cyclooctyl carboxylic acid with ethyl chloroformate
  • the temperature is not particularly limited, but is about 0 ° C to room temperature.
  • the reaction temperature of the second step with sodium azide and diphenylphosphoryl azide is usually about 0 ° C to room temperature
  • the reaction temperature of the isocyanate-forming reaction is usually from room temperature to about 150 ° C.
  • Formula 1 can also be produced by the following steps.
  • Step 1 is a step of producing urea. After reacting formula 3 with 4-ditrophenyl chloroformate or phenyl chloroformate in a solvent such as acetonitrile-dichloromethane in the presence of a base such as sodium bicarbonate or tertiary amine (first step), triethylamine ⁇ Substituted arylamine, substituted heterocyclicamine, substituted cyclopentylamine, substituted cyclohexylamine, substituted cycloheptylamine, substituted cyclooctylamine in the presence or absence of a tertiary amine such as diisopropylethylamine or DBU It can be produced by reacting with the corresponding amine (step 2).
  • the amount of 4-ditrophenylchloroformate-chloroformate used in the first step of the production method is not particularly limited, but is usually about 1 to 5 equivalents to the formula 3.
  • the amount of the base such as sodium bicarbonate tertiary amine used in the first step is not particularly limited, but is usually about 1 to 20 equivalents to 4-nitrophenyl chloroformate to phenyl chloroformate.
  • the amount of the tertiary amine used in the second step is not particularly limited, but is usually about 1 to 20 equivalents based on the formula 3.
  • the reaction temperature of the first-stage formula 3 with 4-nitrophenyl chloroformate-phenylphenyl chloroformate is not particularly limited, but is about 0 ° C.
  • the reaction temperature of the second step is the reaction temperature of 4_nitrophenyl chloroformate.
  • the temperature is usually about 0 ° C. to 50 ° C., and in the case of phenyl chloroformate, it is about room temperature to about the heating reflux temperature.
  • Step 2 is a step of removing a protecting group for a nitrogen atom.
  • the removal method is described in the above-mentioned rProtective Groups in Organic Synthesis (third edition). What is necessary is just to carry out suitably according to these reaction conditions.
  • Step 3 is a step of condensing Formula 5 and Formula 6.
  • Reaction of Formula 5 with Formula 6 in a solvent such as acetonitrile, dimethylformamide, or dichloromethane in the presence of a tertiary amine such as triethylamine diisopropylethylamine or a base such as carbon dioxide or sodium bicarbonate.
  • a tertiary amine such as triethylamine diisopropylethylamine or a base such as carbon dioxide or sodium bicarbonate.
  • the mixing ratio (molar ratio) of Formula 5 and Formula 6 is not particularly limited. However, it is usually about 3: 1 to 1: 3, and the amount of the tertiary amine or base is not particularly limited, but is usually about 1 to 20 equivalents to the formula 5.
  • Formula 2 can be manufactured by the following steps.
  • P 2 represents a protecting group for a nitrogen atom.
  • P 2 in the above formula represents a protecting group for a nitrogen atom, and the type of the protecting group and the method of introducing it are described in, for example, “Protective Group in Greene and Wuts”. Organic Synthes is (3rd edition) ". What is necessary is just to carry out suitably according to these reaction conditions.
  • Step 1 is a step of condensing Formula 7 and Formula 6.
  • Reaction of Formula 7 with Formula 6 in a solvent such as acetonitrile, dimethylformamide, or dichloromethane in the presence of a tertiary amine such as triethylamine / diisopropylethylamine, or a base such as carbon dioxide or sodium bicarbonate.
  • a tertiary amine such as triethylamine / diisopropylethylamine
  • a base such as carbon dioxide or sodium bicarbonate. It can be manufactured by Although the reaction of the formulas 7 and 6 is not particularly limited, it can be usually performed by reacting at a temperature of about 0T to about 80T for about 1 hour to 24 hours.
  • the mixing ratio (molar ratio) of Formula 7 and Formula 6 is not particularly limited, but is usually about 3: 1 to 1: 3, and the amounts of tertiary amine and base are not particularly limited. It is about 1 to 20 equivalents to the formula 7.
  • Step 2 is a step of removing the protective group P 2 of the nitrogen atoms. The removal method is described in the above-mentioned “Protective Groups in 0 rganic Synthes is (3rd edition).” The method may be appropriately performed according to these reaction conditions.
  • the reaction product obtained by each of the above production methods is isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate.
  • the salt can be produced by subjecting the salt to a usual salt-forming treatment. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various column chromatography.
  • optical isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers.
  • the optical isomers can be separated by a general optical resolution method, for example, fractional crystallization or chromatography. Further, the optical isomer can also be produced using a suitable optically active compound as a raw material.
  • Pharmaceutically acceptable salts of the compound represented by Formula 1 include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, boric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, tartaric acid, and succinic acid. Acid addition salts with organic acids such as malic acid, lactic acid, cunic acid, malonic acid, benzoic acid, paratoluenesulfonic acid, and methylsulfonic acid; amino acids such as lysine, glycine, phenylalanine, asparagine, and glutamic acid; And the like. Furthermore, the present invention also includes various hydrates and solvates of the compound of the present invention (Formula 1) and salts thereof.
  • the cyclic amine compound represented by the formula 1 or a pharmaceutically acceptable salt thereof inhibits the action of chemokines mediated by CCR3, as specifically shown in Examples below.
  • the cyclic amine compound of the present invention or a pharmaceutically acceptable salt thereof can be used for various allergic diseases represented by asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, and chronic sinuses involving CCR3.
  • Inflammation ulcerative colitis, Crohn's disease, pulmonary aspergillosis, Cyaug-Strauss syndrome, eosinophilia, parasitic infections, self-immune disease, rheumatoid arthritis, nephritis, arteriosclerosis, virus It is useful as a preventive and therapeutic agent for inflammatory diseases such as infectious diseases, bacterial infections, hepatitis, and chronic lung disease.
  • diseases derived from inflammatory cell infiltration specifically, asthma and allergic rhinitis , Allergic unilateral conjunctivitis, various allergic diseases represented by atopic dermatitis, chronic sinusitis, ulcerative colitis, Crohn's disease, autoimmune disease, rheumatoid arthritis, Flame, arterial sclerosis, viral infection, bacterial infection, hepatitis, chronic lung disease, prevention of such eosinophilia, are useful as therapeutic agents.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is represented by a disease derived from eosinophil infiltration, specifically, asthma, allergic rhinitis, allergic conjunctivitis, and atopic dermatitis.
  • a disease derived from eosinophil infiltration specifically, asthma, allergic rhinitis, allergic conjunctivitis, and atopic dermatitis.
  • As a preventive and therapeutic agent for various allergic diseases chronic sinusitis, ulcerative colitis, Crohn's disease, eosinophilia, etc. More useful.
  • it can be used as a prophylactic and therapeutic agent for various diseases involving chemokine via CCR3.
  • the inflammatory disease referred to in the present invention refers to a disease in which invasion or injury of a tissue induced as a result of an excessive self-defense reaction causes the onset of symptoms.
  • the disease derived from inflammatory cell infiltration referred to in the present invention refers to a disease derived from inflammatory cell infiltration among inflammatory diseases, for example, neutrophil, eosinophil, basophil, mast cell It is a disease in which invasion or injury of the tissue is induced as a result of excessive infiltration or accumulation of lymphocytes, macrophages, etc. into the local area.
  • the disease derived from eosinophil infiltration as referred to in the present invention particularly refers to a disease derived from eosinophil infiltration among diseases derived from inflammatory cell infiltration, and a part of inflammatory cells excessively accumulated. It is a disease when is an eosinophil.
  • the cyclic amine compound of the present invention or a pharmaceutically acceptable salt thereof is a compound that is particularly excellent in an inhibitory effect on inflammatory cell infiltration.
  • the cyclic amine compound of the present invention inhibits the infiltration of inflammatory cells into the lung using the ovalbumin-induced mouse asthma model.
  • Examples 43 and 44 are shown. Compared with the number of inflammatory cell infiltration in animals to which PBS was administered, the number of inflammatory cell infiltration in animals to which the compound of Example 18 which is the cyclic amine compound of the present invention was administered was reduced to half or less.
  • the cyclic amine compound represented by the general formula (1) is included in the claims of International Publication No. 01 Z878339, but is not specifically disclosed. For example,
  • the cyclic amine compound of the present invention or a pharmaceutically acceptable salt thereof is a compound having excellent oral absorbability especially in mammals.
  • the results of an oral absorption evaluation test of the cyclic amine compound of the present invention are shown in Example 45.
  • the bioavailability of the compound of Example 10 which is the cyclic amine compound of the present invention is as high as 19%, and the excellent oral absorbability of the cyclic amine compound of the present invention is excellent in this example. You can confirm.
  • the compound represented by the formula 1 or a pharmaceutically acceptable salt thereof is directly used as a powder.
  • dosage forms for administration include tablets, powders, pills, capsules, granules, syrups, solutions, injections, emulsions, suspensions, suppositories, and the like.
  • dosage form is produced by a method known per se and contains various carriers usually used in the field of pharmaceuticals. Examples include excipients, lubricants, binders, disintegrants in solid preparations, solvents, dissolution aids, suspending agents, soothing agents and the like in liquid preparations. If necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used.
  • Excipients include, for example, lactose, D-mannitol, starch, sucrose, corn starch, crystalline cellulose, light caffeic anhydride, and the like.
  • Lubricants include, for example, magnesium stearate, calcium stearate, talc, colloidal silicic acid and the like.
  • the binder include crystalline cellulose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethylcellulose.
  • Disintegrators include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylsuccinate sodium, L-hydroxypropylcellulose, and the like.
  • the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.
  • dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalcodium chloride, benzethonium chloride, glyceryl monostearate, and polyvinyl alcohol, Polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcell And hydrophilic polymers such as loin.
  • examples of the tonicity agent include glucose, sodium chloride, D-sorbitol, D-mannitol and the like.
  • buffer examples include buffers such as phosphate, acetate, carbonate, and citrate.
  • Examples of the soothing agent include benzyl alcohol and the like.
  • Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid and the like.
  • the cyclic amine compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a medicine.
  • it can be used as a CCR3 inhibitor, specifically as a prophylactic and therapeutic agent for inflammatory diseases, and particularly preferably used for diseases derived from inflammatory cell infiltration, and for eosinophil infiltration. It can be more preferably used for diseases of origin.
  • the effective dose and frequency of administration of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof will vary depending on the dosage form, the age and weight of the patient, the nature or severity of the condition to be treated, but is usually adult 1 to 1000 mg, preferably 1 to 300 mg, can be administered once or several times a day.
  • Each of the above-mentioned dosage forms may contain or be used in combination with other active ingredients for treatment as long as undesired interaction is not caused by compounding with the compound represented by the formula 1 or a salt thereof.
  • active ingredients for example, steroids, non-steroidal anti-inflammatory drugs, lipoxygenase inhibitors, leukotriene antagonists, bronchodilators, tropoxane synthesis inhibitors, tropoxan antagonists, histamine antagonists, histamine release inhibitors, platelet activating factor (PAF) Antagonists, serotonin antagonists, adenosine receptor antagonists, adrenaline i3 stimulants, immunosuppressants, immunomodulators and the like.
  • PAF platelet activating factor
  • Triethylamine (4.2 ml) and benzyl bromide (3.6 ml) were added to a solution of 6-hydroxypicolinic acid (2.8 g) in ethyl acetate (30 ml), and the mixture was heated under reflux for 3 hours.
  • An aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate. Dried and concentrated. The obtained solid was washed with ethyl acetate (2.56 g).
  • Methyl 3-aminophenoxyacetic acid was synthesized in the same manner as in Reference Example 7, using 3-ditrophenol as a raw material.
  • 3-nitrophenoxyacetic acid methyl ester (220 mg) obtained in the same manner as in Reference Example 3 was dissolved in methanol (5 ml), and sodium borohydride (100 mg) was added. For 15 minutes. The solvent was distilled off, and the residue was washed with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (2 ml), sodium hydride (43 mg) and methyl iodide (0.067 ml) were added, and the mixture was stirred at room temperature. The reaction solution was washed with water and extracted with ethyl acetate.
  • Methyl (4-amino-2-methoxycarbonylmethoxyphenoxy) acetate was synthesized using 3,4-dihydroxynitrobenzene as a raw material and in the same manner as in Reference Example 7.
  • Example 1 Using 3_ (tert-butyldimethylsilanyloxymethyl) phenylamine instead of 3- [2- (tert-butyldimethylsilanyloxy) ethoxy] pyridine-2-ylamine as a raw material, Using the same method as in 4, convert l-i (R) -l _ [(6-fluoronaphthalene-2-ylyl) methyl] pyrrolidine-3-yl 3 [3- (hydroxymethyl) phenyl] ⁇ rea Synthesized.
  • N- (4-aminobenzyl) acetamide was obtained in the same manner as in Example 11.
  • L) methyl] pyrrolidine-3-yl 1-reido) benzyl] acetamide was synthesized.
  • the reaction solution was concentrated, the residue was dissolved in ethanol (15 ml), 10% palladium carbon (containing 50% water, 19 mg) was added, and the mixture was stirred overnight under a hydrogen atmosphere. The palladium carbon was filtered off, and the filtrate was concentrated. . The residue was purified by silica gel column chromatography (ethyl acetate) to give tri- [2- (tert-butyldimethylsilanyloxy) ethyl] -1H-benzoimidazole-5-ylamine (134 mg).
  • a solution was prepared by adding the fluorescent indicator fura-2 AM (Dohjin Chemical Laboratory Co., Ltd.) to an RPMI 1640 medium containing 1% fetal bovine serum to a final concentration of 5 ⁇ M.
  • B300-19 cells (Cell 27, 381-390, 1981) transformed with human CCR3 were suspended at 7 cells / ml.
  • Test compounds were added one minute before you added Mouse eotaxin, by measuring the impact with respect to the increase of by mouse eotaxin [Ca 2+] i, CCR3 inhibitory activity IC 5Q values of the test compound (mouse eo taxin (A concentration that suppresses the increase of [Ca 2+ ] i by 50% caused by the addition of). Table 3 shows the inhibitory activities of typical compounds.
  • Example 43 Inhibitory effect on inflammatory cell infiltration into lung using ovalbumin-induced mouse asthma model 1
  • the inhibitory effect of the compound of the present invention on inflammatory cell infiltration into the lung in a mouse asthma model using ovalbumin (0VA) as an antigen was evaluated.
  • mice After purchasing female BALB / c mice at the age of 6 weeks, they were pre-bred for 1 week before use in the experiments. The mice were sensitized on day 1 and day 14 by intraperitoneal administration of 0.2 ml of a mixture containing 20 ovalbumin (0VA) and 2 mg of aluminum hydroxide. On the 28th day, an aerosol generated by an ultrasonic nebulizer (NE_U12, OMRON, Kyoto, Japan) supplemented with 20 xg / ml OVA-PBS was inhaled for 20 minutes to induce an asthmatic response (induced group). . In the non-induced group, only PBS was inhaled for 20 minutes (non-induced group).
  • NE_U12 ultrasonic nebulizer
  • the alveolar lavage solution was transferred to a plastic tube, centrifuged, and the supernatant was removed.
  • the cells were then reconstituted with 1 ml of Hank's balanced salt solution (Invitrogen, Tokyo, Japan). Suspended in water. The total number of leukocytes contained in this cell suspension was measured using a multi-item automatic blood cell counter (Toa Medical Co., Ltd., Hyogo, Japan).
  • inflammatory cell infiltration into the lungs is eosinophils, and the average of the total leukocyte (resident cell) count in the uninduced group measured as described above is subtracted from the total leukocyte count in each individual.
  • the inflammatory cell infiltration number was calculated by subtraction.
  • % of Control (the value when the control group was taken as 100) was calculated by dividing the number of inflammatory cell infiltration of each individual by the average value of the number of inflammatory cell infiltration in the control group. Table 4 shows the values of Control for representative compounds.
  • the inhibitory effect of the compound of the present invention on inflammatory cell infiltration into the lung in a mouse asthma model using ovalbumin (0VA) as an antigen was evaluated.
  • mice After purchasing female BALB / c mice at the age of 6 weeks, they were pre-bred for 1 week before use in the experiments. The mice were sensitized on day 1 and day 14 by intraperitoneal administration of 0.2 ml of a mixture containing 20 ovalbumin (0VA) and 2 mg of aluminum hydroxide. Day 28 On the 29th and 29th days, an aerosol generated by an ultrasonic nebulizer (NE- ⁇ 12, OMRON, Kyoto, Japan) supplemented with 20 zg / ml OVA-PBS was inhaled for 20 minutes to induce an asthma reaction ( Trigger group). In the non-induced group, only PBS was inhaled for 20 minutes (non-induced group).
  • an ultrasonic nebulizer NE- ⁇ 12, OMRON, Kyoto, Japan
  • a solvent containing no compound of the present invention or a drug solution containing the compound of the present invention was administered before inhaling OVA-PBS.
  • the administration was carried out continuously from the 27th to 30th day from the start of the test by implanting two Osmotic Pumps (manufactured by Alzet) filled with the compound solution of the present invention subcutaneously in the back.
  • two pumps filled only with the solvent were implanted subcutaneously in the back.
  • Twenty-four hours after induction the animals were exsanguinated and killed under ether anesthesia, tracheal force was introduced, and the alveolar cavity was washed four times with 0.7 ml of physiological saline to collect cells. .
  • the alveolar cavity washing solution was transferred to a plastic tube, centrifuged, the supernatant was removed, and the cells were suspended in 1 ml of Hank's balanced salt solution (Invitrogen Corporation, Tokyo, Japan). The total number of leukocytes contained in the cell suspension was measured using a multi-item automatic blood cell counter (Toa Medical Co., Ltd., Hyogo, Japan).
  • the activity of the compound of the present invention was measured in the same manner as in Example 43, except that asthma induction by inhalation of 20 g / ml of OVA-PBS was performed on days 28 and 29.
  • the number of inflammatory cell infiltration was calculated by the same method as in Example 43, and the number of inflammatory cell infiltration of each individual was divided by the average value of the number of inflammatory cell infiltration in the control group to obtain% of Cont. rol (value when the control group is set to 100) was calculated.
  • Table 5 shows typical compounds and numerical values (% of Control Compound 9) of compounds (compound 9) included in the claims of International Publication No. 01/87983 9 but not specifically disclosed. ) showed that.
  • the compound of this example was found to have a superior effect of inhibiting infiltration of inflammatory cells as compared to Compound 9.
  • Example 45 Evaluation of oral absorption in monkeys After the test drug was administered to cynomolgus monkeys (intravenous administration: 0.5 mg / kg, oral administration: 1. Omg / kg), plasma was collected over time. After the collected plasma was pretreated with tert-butyl methyl ether, the test drug concentration in the plasma was measured by LC-MS / MS, and the area under the plasma concentration time curve (AUC) was calculated. By dividing the AUC after oral administration by the AUC after intravenous administration, bioavailability, an indicator of oral absorbability, was determined. Table 6 shows the values of the bioavailability calculated from the plasma concentration when the compound of Example 10 which is the cyclic amine compound of the present invention was administered.
  • the compounds of the present invention are useful as active ingredients in pharmaceutical preparations.
  • it has a CCR3 antagonistic activity i, so it is useful as a prophylactic and therapeutic agent for inflammatory diseases and the like. It is more useful as
  • the compound of the present invention is a compound having excellent oral absorption in mammals and a compound having excellent drug efficacy even when administered orally.

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Abstract

L'invention concerne un composé d'amine cyclique représenté par la formule générale (1) : [ dans laquelle A représente un groupe sélectionné dans le groupe constitué par des composés aryles, des groupes hétérocycliques substitués ainsi que des cycloalkyles substitués, comporte au moins un substituant X, et peut contenir au moins un substituant Y (le substituant X étant choisi dans le groupe constitué par HO-(C1-6 alkyle), HO-(C2-6 alkyl)-O-(C1-6 alkyle), HOOC-(C1-6 alkyle), (C1-6 alkyl)-OCO-(C1-6 alkyle), NH2CO-(C1-6 alkyle), C1-3 alkyl)2NCO-(C1-6 alkyle), (C1-3 alkyl)- CONH-(C1-6 alkyle), HOOC-( C1-6 alkyle), etc., le substituant A étant choisi dans le groupe constitué par halogéno, C1-3 alkyle, OH, méthoxy, CN, et CF3)], ou un sel pharmaceutiquement acceptable de ce composé.
PCT/JP2003/002227 2002-02-27 2003-02-27 Compose d'amine cyclique et medicament inhibiteur de ccr3 contenant ce compose comme principe actif WO2003072545A1 (fr)

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AU2003211397A AU2003211397A1 (en) 2002-02-27 2003-02-27 Cyclic amine compound and ccr3 inhibitory drug containing the same as active ingredient
JP2003571251A JPWO2003072545A1 (ja) 2002-02-27 2003-02-27 環状アミン化合物及びそれを有効成分とするｃｃｒ３阻害薬

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004078101A2 (fr) * 2003-03-08 2004-09-16 Glaxo Group Limited Derives d'uree
US7514562B2 (en) 2003-03-07 2009-04-07 Glaxo Group Limited Urea derivatives and their use as vanilloid receptor antagonists in the treatment of pain
US7528151B2 (en) 2003-03-06 2009-05-05 Glaxo Group Limited Heterocyclic urea derivatives for the treatment of pain

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001028987A1 (fr) * 1999-10-15 2001-04-26 Du Pont Pharmaceuticals Company Amines benzyle cycloalkyle comme modulateurs de l'activite du recepteur de la chimiokine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001028987A1 (fr) * 1999-10-15 2001-04-26 Du Pont Pharmaceuticals Company Amines benzyle cycloalkyle comme modulateurs de l'activite du recepteur de la chimiokine

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7528151B2 (en) 2003-03-06 2009-05-05 Glaxo Group Limited Heterocyclic urea derivatives for the treatment of pain
US7514562B2 (en) 2003-03-07 2009-04-07 Glaxo Group Limited Urea derivatives and their use as vanilloid receptor antagonists in the treatment of pain
WO2004078101A2 (fr) * 2003-03-08 2004-09-16 Glaxo Group Limited Derives d'uree
WO2004078101A3 (fr) * 2003-03-08 2005-02-17 Glaxo Group Ltd Derives d'uree
US7528150B2 (en) 2003-03-08 2009-05-05 Glaxo Group Limited Urea derivatives having vanilloid receptor antagonist activity

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JPWO2003072545A1 (ja) 2005-06-16

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