EP1453825A1 - N-ureido-piperidines utilises comme antagonistes viii du recepteur ccr3 - Google Patents

N-ureido-piperidines utilises comme antagonistes viii du recepteur ccr3

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Publication number
EP1453825A1
EP1453825A1 EP02787796A EP02787796A EP1453825A1 EP 1453825 A1 EP1453825 A1 EP 1453825A1 EP 02787796 A EP02787796 A EP 02787796A EP 02787796 A EP02787796 A EP 02787796A EP 1453825 A1 EP1453825 A1 EP 1453825A1
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EP
European Patent Office
Prior art keywords
alkyl
chlorobenzyl
piperidin
mmol
cyclopentyl
Prior art date
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Application number
EP02787796A
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German (de)
English (en)
Inventor
Daisy Joe Du Bois
Denis John Kertesz
Eric Brian Sjogren
David Bernard Smith
Beihan Wang
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F Hoffmann La Roche AG
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F Hoffmann La Roche AG
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Publication of EP1453825A1 publication Critical patent/EP1453825A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • N-UREIDO-PIPERIDINES AS ANTAGONISTS VI II FOR CCR-3 RECEPTOR
  • This invention relates to piperidine derivatives that are CCR-3 receptor antagonists, pharmaceutical compositions containing them, their use, and methods for preparing them.
  • Tissue eosinophilia is a feature of a number of pathological conditions such as asthma, rhinitis, eczema and parasitic infections (see Bousquet, J. et al., N. Eng. J. Med. 323: 1033-1039 (1990) and Kay, A. B. and Corrigan, C. J., Br. Med. Bull. 48:51-64 (1992)).
  • asthma eosinophil accumulation and activation are associated with damage to bronchial epithelium and hyperresponsiveness to constrictor mediators.
  • Chemokines such as RANTES, eotaxin and MCP-3 are known to activate eosinophils (see Baggiolini, M. and Dahinden, C.
  • Glucocorticoids such as dexamethasone, methprednisolone and hydrocortisone have been used for treating many eosinophil-related disorders, including bronchial asthma (R. P. Schleimer et al., Am. Rev. Respir. Dis., 141, 559 (1990)).
  • the glucocorticoids are believed to inhibit IL-5 and IL-3 mediated eosinophil survival in these diseases.
  • prolonged use of glucocorticoids can lead to side effects such as glaucoma, osteoporosis and growth retardation in the patients (see Hanania, N. A. et al., J. Allergy and Clin. Immunol., Vol.
  • the CCR-3 receptor was identified as a major chemokine receptor that eosinophils use for their response to eotaxin, RANTES and MCP-3.
  • CCR-3 bound eotaxin, RANTES and MCP-3 conferred chemotactic responses on these cells to eotaxin, RANTES and MCP-3 (see Ponath, P. D. et al., J. Exp. Med. 183, 2437-2448 (1996)).
  • the CCR-3 receptor is expressed on the surface of eosinophils, T-cells (subtype Th-2), basophils and mast cells and is highly selective for eotaxin.
  • blocking the ability of the CCR-3 receptor to bind RANTES, MCP-3 and eotaxin and thereby preventing the recruitment of eosinophils should provide for the treatment of eosinophil-mediated inflammatory diseases.
  • the present invention concerns novel piperidine derivatives which are capable of inhibiting the binding of eotaxin to the CCR-3 receptor and thereby provide a means of combating eosinophil induced diseases, such as asthma.
  • this invention provides a compound of Formula (I):
  • R 1 is (C r C 2 )alkylene
  • R is optionally substituted phenyl
  • R is hydrogen, alkyl, acyl, aryl, or arylalkyl;
  • ring A is a cycloalkyl, heterocyclyl, or optionally substituted phenyl;
  • R a is hydrogen, alkyl, acyl, aryl, arylalkyl, alkoxycarbonyl, or benzyloxycarbonyl;
  • X is absent, -(CR'R")O-, -(CR'R")S-,-(CR > R")NR b - or alkylene;
  • R' and R" are independently hydrogen or alkyl, and R is hydrogen or alkyl
  • R 4 is aryl or heteroaryl
  • R 5 is hydrogen or alkyl
  • R 1 is -CH 2 -
  • R is phenyl
  • R 3 is hydrogen
  • R 5 is hydrogen
  • A is phenyl
  • prodrugs individual isomers, ramecic and non-racemic mixtures of isomers, and pharmaceutically acceptable salts thereof.
  • R'-R 5 , A, L, and X are as defined in (i).
  • R'-R 5 , A, L, and X are as defined in (i).
  • R 3 , R 4 , A, L, and X are as defined in (i).
  • this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • this invention provides processes disclosed herein for preparing compounds of Formula (I).
  • this invention provides novel intermediates disclosed herein that are useful for preparing compounds of Formula (I).
  • this invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in medical therapy or diagnosis (e.g. for treating asthma).
  • this invention provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament useful for treating a disease in a mammal treatable by administration of a CCR-3 receptor antagonist (e.g. asthma).
  • a CCR-3 receptor antagonist e.g. asthma
  • Acyl means a radical -C(O)R, where R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl wherein alkyl, cycloalkyl, cycloalkylalkyl, and phenylalkyl are as defined herein.
  • Representative examples include, but are not limited to formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl.
  • Acylalkyl means a radical -alkylene-C(O)R where R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkyl-alkyl, optionally substituted phenyl, benzyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino.
  • Representative examples include methylcarbonyl- methyl, 2-(ethoxycarbonyl)ethyl, 2-(methoxycarbonyl)ethyl, 2-carboxyethyl.
  • Acylamino means a radical -NR'C(O)R, where R' is hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl wherein alkyl, cycloalkyl, cycloalkylalkyl, and phenylalkyl are as defined herein.
  • Representative examples include, but are not limited to formylamino, acetylamino, cylcohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino.
  • Alkoxy means a radical -OR where R is an alkyl as defined herein e.g., methoxy, efhoxy, propoxy, butoxy.
  • Alkoxycarbonyl means a radical -C(O)-R where R is alkoxy as defined herein.
  • Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, n-butyl, j ' so-butyl, tert-butyl, pentyl.
  • Alkylamino or “Monoalkylamino” means a radical -NHR where R represents an alkyl, cycloalkyl or cycloalkyl-alkyl group as defined herein. Representative examples include, but are not limited to methylamino, ethylamino, isopropylamino, cyclohexylamino.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-mefhylpropylene, butylene, pentylene.
  • Alkynyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl.
  • Alkylsulfonyl means a radical -S(O) 2 R where R is an alkyl, cycloalkyl or cycloalkylalkyl group as defined herein, e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, cyclohexylsulfonyl.
  • Alkylsulfinyl means a radical -S(O)R where R is an alkyl, cycloalkyl or cycloalkylalkyl group as defined herein e.g., methylsulfinyl, efhylsulfinyl, propylsulfinyl, butylsulfinyl, cyclohexylsulfinyl.
  • Alkylthio means a radical -SR where R is an alkyl as defined above e.g., methylthio, ethylthio, propylthio, butylthio.
  • Aryl means a monocyclic or bicyclic aromatic hydrocarbon radical of preferably 6 to 10 ring atoms which is optionally substituted with one or more substituents, preferably one, two or three, substituents preferably selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, -SO 2 NR'R" (where R' and R" are independently hydrogen or alkyl), alkoxy, haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halo, nitro, cyano, mercapto, methylenedioxy or ethylenedioxy. More specifically the term aryl includes, but is not limited to, phenyl, chlorophenyl, fluorophenyl, methoxyphenyl, 1-
  • Allene means a divalent aryl group as defined above.
  • Arylalkyl refers to an alkyl radical as defined herein in which one of the hydrogen atoms of the alkyl group is replaced with an aryl group.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan- l-yl, naphthylmethyl, 2-naphthylethan-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl.
  • Aryloxy means a radical -O-R where R is an aryl group as defined herein.
  • Cycloalkyl refers to a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons e.g., cyclopropyl, cyclobutyl, cyclohexyl, 4-methylcyclohexyl. x y x V
  • Cycloalkyl-alkyl means a radical -R R where R is an alkylene group and R is cycloalkyl group as defined herein, e.g., cyclohexylmefhyl.
  • Dialkylamino means a radical -NRR' where R and R' independently represent an alkyl, cycloalkyl, or cycloalkylalkyl group as defined herein. Representative examples include, but are not limited to dimethylamino, me hylethylamino, di( l-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl) (propyl)amino, (cyclohexylmethyl)(mefhyl)amino, (cyclohexylmethyl)(ethyl)amino.
  • Halo means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro.
  • Haloalkyl means alkyl substituted with one or more same or different halo atoms, e.g., -CH 2 ⁇ , -CF 3 , -CH 2 CF 3) -CH 2 CC1 3 .
  • Heteroaryl means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring.
  • the heteroaryl ring is optionally substituted independently with one or more substituents, preferably one or two substituents, selected from alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, -SO 2 NR'R" (where R' and R" are independently hydrogen or alkyl), alkoxy, haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halo, nitro, cyano, mercapto, methylenedioxy, ethylenedioxy or optionally substituted phenyl.
  • substituents preferably one or two substituents, selected from alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino, alkylamino, dialkylamino, al
  • heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, 5-(3,4-dimethoxyphenyl)-pyrimidin-2-yl, 5-(4- methoxyphenyl)-pyrimidin-2-yl, 5-(3,4-methylenedioxyphenyl)-pyrimidin-2-yl, benzofuranyl, tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl, benzimidazolyl, benzisoxazolyl, triazo
  • Heteroarylene means a divalent heteroaryl group as defined above.
  • Heteroarylalkyl means an alkyl radical as defined herein in which one of the hydrogen atoms of the alkyl group is replaced with a heteroaryl group.
  • Heteroalkyl means an alkyl radical as defined herein wherein one, two or three hydrogen atoms have been replaced with a substituent independently selected from the group consisting of -OR d , -NR R c , and -S(O) n R (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein R d is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R and R c are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; when n is 0, R d is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamin
  • Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-l-hydroxymethylefhyl, 2,3-dihydroxypropyl, 1-hydroxymethyl ethyl, 3- hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-l-mefhylpropyl, 2-aminoethyl, 3- aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl.
  • Heterocyclyl means a saturated or unsaturated non-aromatic cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from NR X ⁇ wherein each R x is independently hydrogen, alkyl, acyl, alkylsulfonyl, aminosulfonyl, (alkylamino)sulfonyl, (dialkylamino)sulfonyl, carbamoyl, (alkylamino)carbonyl, (dialkylamino)carbonyl, (carbamoyl)alkyl, (alkylamino)carbonylalkyl, or dialkylaminocarbonylalkyl ⁇ , O, or S(O) n (where n is an integer from 0 to 2), the remaining ring atoms being C.
  • the heterocyclyl ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, haloalkyl, heteroalkyl, halo, nitro, cyanoalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, arylalkyl, -(X) n - C(O)R (where X is O or NR ⁇ n is 0 or 1, R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino or optionally substituted phenyl, and R' is hydrogen or alkyl), -alkylene-C(O)R (where R is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino or optionally substituted phenyl) or -S(O) n R (where n is an integer from 0 to 2, and
  • heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3- yl, 3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1 -oxide, thiomorpholino-l,l-dioxide,tetrahydrothiophenyl-S,S-dioxide, pyrrolinyl, imidazolinyl, and the derivatives thereof.
  • “Hydroxyalkyl” means an alkyl radical as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group.
  • Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, l-(hydroxymethyl)-2- mefhylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 2- hydroxy-1-hydroxymethylethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and l-(hydroxymethyl)-2-hydroxyethyl. Accordingly, as used herein, the term "hydroxyalkyl" is used to define a subset of heteroalkyl groups.
  • Leaving group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or a group capable of being displaced by a nucleophile and includes halo (such as chloro, bromo, and iodo), alkanesulfonyloxy, arenesulfonyloxy, alkylcarbonyloxy (e.g., acetoxy), arylcarbonyloxy, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy), methoxy, N,O- dimethylhydroxylamino.
  • halo such as chloro, bromo, and iodo
  • alkanesulfonyloxy arenesulfonyloxy
  • alkylcarbonyloxy e.g., acetoxy
  • arylcarbonyloxy mesyloxy, tosyloxy, trifluorome
  • Optionally substituted phenyl means a phenyl group which is optionally substituted with one or more substituents, preferably one, two or three, substituents preferably selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl, acylamino, amino, alkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl, -SO 2 NR'R" (where R' and R" are independently hydrogen or alkyl), alkoxy, haloalkoxy, alkoxycarbonyl, carbamoyl, hydroxy, halo, nitro, cyano, mercapto, methylenedioxy or ethylenedioxy.
  • substituents preferably one, two or three, substituents preferably selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, acyl,
  • the term includes, but is not limited to, phenyl, chlorophenyl, fluorophenyl, bromophenyl, methylphenyl, ethylphenyl, methoxyphenyl, cyanophenyl, 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-methylphenyl, 3-chloro-4-fluorophenyl or 3,4-dichlorophenyl and the derivatives thereof.
  • aryl group optionally mono- or di-substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the aryl group is mono- or disubstituted with an alkyl group and situations where the aryl group is not substituted with the alkyl group.
  • “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a "pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • “Pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid
  • Phenylalkyl refers to an alkyl radical as defined herein in which one of the hydrogen atoms of the alkyl radical has been replaced by an optionally substituted phenyl.
  • Protecting group refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in T.W. Green and P.G. Futs, Protective Groups in Organic Chemistry, (Wiley, 2 nd ed. 1991) and Harrison and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (John Wiley and Sons, 1971-1996).
  • Representative amino protecting groups include, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), ter -butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC).
  • hydroxy protecting groups include those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
  • Treating" or “treatment” of a disease includes: (1) preventing the disease, i.e., causing the clinical symptoms of the disease not to develop in a mammal that maybe exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • a therapeutically effective amount means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • Prodrugs means any compound which releases an active parent drug according to Formula I in vivo when such a prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of Formula I are prepared by modifying functional groups present in the compound of Formula I in such a way that the modifications maybe cleaved in vivo to release the parent compound.
  • Prodrugs include compounds of Formula I wherein a hydroxy, amino, or sulfhydryl group in a compound of Formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimefhylaminocarbonyl) of hydroxy functional groups in compounds of Formula I.
  • esters e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., N,N-dimefhylaminocarbonyl
  • isomers Compounds that have the same molecular Formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992). The nomenclature used in this application is generally based on the IUPAC recommendations.
  • a compound of Formula (I) wherein Ri is methylene; R 2 is 4-chlorophenyl; L is C( O)NH; X is absent; A is cyclopentyl; R 3 is hydrogen; and R is 2-quinolyl (Compound 1 in Table 1), is named ( ⁇ )- trans- l- ⁇ 2-[4-(4-chlorobenzyl)piperidin-l-yl]cyclopentyl ⁇ -3-quinolin-2-yl-urea.
  • a preferred compound of the invention is a compound of Formula (I) wherein R 1 is methylene.
  • One aspect of the invention relates to compounds of Formula (I) where ring A is cycloalkyl, heterocyclyl or substituted phenyl.
  • Another preferred compound of the invention are compounds of Formula (I) wherein ring A is cyclopentyl. Compounds where ring A is cyclopentyl are bind unexpectedly potently to the CCR-3 receptor.
  • Other preferred compounds of the invention are compounds of Formula (I) wherein ring A is heterocyclyl (particularly tetrahydropyranyl, S,S-dioxo-tetrahydothiophenyl, tetrahydrothiophenyl or pyrrolidinyl) or compounds of Formula (I) wherein ring A is substituted phenyl.
  • a preferred compound of the invention is a compound of Formula (I) wherein R 2 is phenyl ring substituted with one, or two substituents selected from alkyl, alkoxy, haloalkyl, halo, cyano or nitro; preferably methyl, ethyl, methoxy, trifluoromefhyl, chloro, fluoro or bromo; most preferably 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4- difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-methylphenyl, 3- chloro-4-fluorophenyl or 3,4-dichlorophenyl. Particularly preferred are 4-chlorophenyl or 3,4-dichlorophenyl.
  • a preferred compound of the invention is a compound of Formula (I) wherein R 3 is hydrogen or methyl, preferably hydrogen.
  • a preferred compound of the invention is a compound of Formula (I) wherein X is absent, methylene, 1,2-ethanediyl, 1,3-propanediyl, or 1,4-butanediyl.
  • a preferred compound of the invention is a compound of Formula (I) wherein R is optionally substituted phenyl, optionally substituted heteroaryl wherein the heteroaryl ring is indolyl, thienyl, quinolinyl, substituted pyrimidin-2-yl, e.g. (5-(3,4- dimethoxyphenyl)pyrimidin-2-yl, 5-(3,4-methylenedioxy)-pyrimidin-2-yl or 5-(4- methoxyphenyl)pyrimidin-2-yl) or 1,8-naphthyridinyl.
  • R is optionally substituted phenyl, optionally substituted heteroaryl wherein the heteroaryl ring is indolyl, thienyl, quinolinyl, substituted pyrimidin-2-yl, e.g. (5-(3,4- dimethoxyphenyl)pyrimidin-2-yl, 5-(3,4-methylenedioxy)-pyrimidin-2-
  • R 4 is selected from 3,4- dichlorophenyl, 3,4,5-trimethoxyphenyl, 4-methanesulfonyl-phenyl, 3- methanesulfonylphenyl, 4-methoxynaphthalen-2-yl, 5-(3,4-dimethoxyphenyl)pyrimidin- 2-yl, phenyl, 3-fluorophenyl, 4-ethylphenyl, 3 -methoxyphenyl, 2,4-difluorophenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-fluorophenyl, 2-fluorophenyl, 4- carboxamidophenyl, 4-acetylphenyl, 4-nitrophenyl, 2-methylphenyl, 2-chloro-4- fluorophenyl, 3,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,3-dichlorophenyl,
  • R 4 being trimethoxyphenyl, e.g 3,4,5-trimethoxyphenyl, 4-acetyl-phenyl, 4-carboxamido-phenyl and 4-methanesulfonyl-phenyl.
  • X is -CH 2 S-, -CH 2 O-, -CH 2 CH 2 - and R 4 is heteroaryl, preferably optionally substituted pyrimidinyl, pyrazolyl or thienyl.
  • Particularly preferred are compounds where X is -CH 2 S- and R 4 is 5-(3,4-dimethoxyphenyl)- pyrimidin-2-yl, 5-(3,4-methylenedioxyphenyl)-pyrimidin-2-yl, 5-(4- methoxyphenyl)pyrimidin-2-yl
  • a specific compound of Formula (I) is a compound of Formula (II):
  • R'-R 5 , A, L, and X have any of the values described herein.
  • a specific compound of Formula (I) is a compound of Formula (III):
  • a specific compound of Formula (I) is a compound of formula (IV):
  • R , R , A, L, and X have any of the values described herein.
  • a specific compound of Formula (I) is a compound of formula (V):
  • a specific compound of Formula (I) is a compound of formula (VI):
  • a specific compound of Formula (I) is a compound of formula (VII):
  • a specific compound of Formula (I) is a compound of formula (VIII):
  • R x is hydrogen, alkyl, acyl, alkylsulfonyl, aminosulfonyl, (alkylamino)sulfonyl, (dialkylamino)sulfonyl, carbamoyl, (alkylamino)carbonyl, (dialkylamino)carbonyl, (carbamoyl)alkyl, (alkylamino)carbonylalkyl, or dialkylaminocarbonylalkyl.
  • a specific compound of Formula (I) is a compound of formula (IX):
  • a specific compound of Formula (I) is a compound of formula (X):
  • a particularly preferred compound of the invention is:
  • the compounds of the invention are CCR-3 receptor antagonists and inhibit eosinophil recruitment by CCR-3 chemokines such as RANTES, eotaxin, MCP-2, MCP-3 and MCP-4.
  • CCR-3 chemokines such as RANTES, eotaxin, MCP-2, MCP-3 and MCP-4.
  • Compounds of this invention and compositions containing them are useful in the treatment of eosiniphil-induced diseases such as inflammatory or allergic diseases and including respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., chronic eosinophilic pneumonia); inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis); and psoriasis and inflammatory dermatoses such as dermatitis and eczema.
  • respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis
  • the CCR-3 antagonistic activity of the compounds of this invention can be measured by in vitro assays such as ligand binding and chemotaxis assays as described in more detail in Examples 45, 46, and 47. In vivo activity was assayed in the Ovalbumin induced Asthma in Balb/c Mice Model as described in more detail in Example 48.
  • the compounds of this invention can be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • the actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
  • Therapeutically effective amounts of compounds of Formula (I) may range from approximately 0.01-20 mg per kilogram body weight of the recipient per day; preferably about 0.1-10 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 7 mg to 0.7 g per day.
  • compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, transdermal, inhalation (e.g., intranasal or oral inhalation) or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes e.g., oral, transdermal, inhalation (e.g., intranasal or oral inhalation) or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
  • routes e.g., oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, liposomes, elixirs, or any other appropriate compositions.
  • Another preferred manner for administering compounds of this invention is inhalation. This is an effective means for delivering a therapeutic agent directly to the respiratory tract for the treatment of diseases such as asthma and other
  • the choice of formulation depends on various factors such as the mode of drug administration and the bioavailability of the drug substance.
  • the compound can be formulated as liquid solutions or suspensions, aerosol propellants or dry powder and loaded into a suitable dispenser for administration.
  • suitable dispenser for administration There are three types of pharmaceutical inhalation devices--nebulizer inhalers, metered-dose inhalers (MDI) and dry powder inhalers (DPI).
  • MDI metered-dose inhalers
  • DPI dry powder inhalers
  • Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which has been formulated in a liquid form) to spray as a mist which is carried into the patient's respiratory tract.
  • MDI's typically have the formulation packaged with a compressed gas.
  • the device Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent.
  • DPI's administer therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device.
  • the therapeutic agent In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient, such as lactose.
  • a measured amount of the therapeutic is stored in a capsule form and is dispensed to the patient with each actuation.
  • pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
  • compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I).
  • excipient maybe any solid, liquid, semi- solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of this invention in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the drug and the lipids are dissolved in a suitable organic solvent e.g. tert-butanol, cyclohexane (1% ethanol).
  • a suitable organic solvent e.g. tert-butanol, cyclohexane (1% ethanol).
  • the solution is lyopholized and the lipid mixture is suspended in an aqueous buffer and allowed to form a liposome. If necessary, the liposome size can be reduced by sonification.
  • a suitable organic solvent e.g. tert-butanol, cyclohexane (1% ethanol).
  • the level of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1-80 wt %.
  • Representative pharmaceutical formulations containing a compound of Formula (I) are described in
  • the compounds of the present invention can be prepared in a number of ways known to one skilled in the art. Preferred methods include, but are not limited to, the general synthetic procedures described below.
  • the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Enika Chemie, or Sigma (St. Louis, Mo., USA), Maybridge (Dist: Ryan Scientific, P.O. Box 6496, Columbia, S.C. 92960), Bionet Research Ltd., (Cornwall PL32 9QZ, UK), Menai Organics Ltd., (Gwynedd, N. Wales, UK), Butt Park Ltd., (Dist.
  • the starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography. Such materials may be characterized using conventional means, including physical constants and spectral data.
  • Compounds of Formula (I) are generally prepared from the precursor amine of Formula (la) as shown below.
  • Schemes 1-5 show methods of preparing compounds of Formula la having different rings A. Specific exemplification is provided for R -R being 4-chlorobenzyl in Preparations 1-6. Preparation of analogous compounds where R and R vary within the full scope of this invention may be readily prepared by one of skill in the art in light of this specification and incorporated references.
  • a 0.2-0.3 M solution of the amino alcohol (1 equiv) in CH 2 C1 2 at 0 °C is treated successively with Et 3 N (2 equiv) and MeSO 2 Cl (2 equiv), stirred at 0 °C for 1-2 hours, and partitioned between CH 2 CI2 and 10-15% NH 4 OH.
  • the aqueous phase is extracted with CH 2 CI 2 and the extracts are dried and concentrated.
  • a 0.13M solution of the residue in 2.5:1 dioxane:28-30 wt % NH 4 OH is stirred at 70-80 °C for 2.5-18 hours, allowed to cool to room temperature, and concentrated.
  • R 2 NH 4-(4-C lorobenzyl)piperidine
  • Schemes 6 and 7 show preparation of compounds of Formula la where ring A is substituted.
  • Scheme 6 shows preparation of compounds of Formula la with a substituted cyclopentyl ring A.
  • NR 2 4-( 4 -chlorobenzyl)p ⁇ per ⁇ d ⁇ nyl
  • Schemes 8 and 9 show methods of converting compounds of Formula (la) to compounds of Formula (I) where L and A are varied.
  • a 0.1-0.6 M solution of the amine (1 equiv) in CH 2 C1 2 or CH 2 C1 2 and DMF at 0-20 °C is treated with the specified isocyanate (1.1-2 equiv), stirred for 0.5-1.5 hours, and partitioned between CH 2 C1 2 and saturated NaHCO 3 .
  • the aqueous phase is extracted with CH 2 CI 2 and the extracts are dried and concentrated.
  • the crude urea is purified by column chromatography or preparative TLC or used in the next step without further purification.
  • a solution of the free base in CH 2 CI2 is treated with 1 N HCI in Et 2 ⁇ and concentrated to give the hydrochloride salt.
  • a 0.1-0.4 M solution of the amine (1 equiv) and the specified carboxylic acid (1.2-1.5 equiv) in CH 2 CI 2 at 0 °C is treated successively with 1-hydroxybenzotriazole hydrate (HOBt) (0.2-0.5 equiv) and l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (DEC) (1.3-2 equiv), stirred at 0-20 °C for 2-72 hours, and partitioned between CH 2 C1 2 and saturated NaHCO 3 .
  • the aqueous phase is extracted with CH 2 CI 2 and the extracts are dried and concentrated.
  • the crude amide is purified by column chromatography and/or preparative TLC.
  • a 0.1-0.4 M solution of the amine (1 equiv) and the specified carboxylic acid (1.2-1.5 equiv) in CH 2 C1 2 at 0 °C is treated successively with 1-hydroxybenzotriazole hydrate (HOBt) (0.2-0.5 equiv) and l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (DEC) (1.3-2 equiv), stirred at 0-20 C for 2-72 hours, and partitioned between CH 2 C1 2 and saturated NaHCO 3 .
  • the aqueous phase is extracted with CH 2 C1 2 and the extracts are dried and concentrated.
  • the crude amide is purified by column chromatography and/or preparative TLC.
  • a solution of the free base in CH 2 C1 2 is treated with 1 N HCI in Et 2 O and concentrated to provide the hydrochloride salt.
  • Mass spectral analyses were accomplished using electrospray ionization.
  • Analytical reverse-phase HPLC was performed on Shimadzu system equipped with a diode array spectrometer (range 190-300 nm; Hewlett Packard).
  • the stationary phase was a Zorbax SB-Phenyl Rapid Resolution column (4.6 mm x 50 mm; Hewlett Packard), mobile phase A was 0.1% trifluoroacetic acid, and mobile phase B was CH 3 CN.
  • a flow rate of 2.5 ml/min with a linear gradient of 20-55% B in 5 min and then 55-20% B in 5 min was employed.
  • Other physical and analytical data were obtained by the physical and analytical chemistry group at Roche Bioscience.
  • Step A Preparation of ( ⁇ )-tr ⁇ ns-2-[4-(4-chlorobenzyI)piperidin-l-yl1- cyclohexanol
  • Step B Preparation of ( ⁇ )-t ⁇ ms-2-f4-(4-chIorobenzyl)piperidin-l-yl1- cyclohexylamine
  • Step A Preparation of ( ⁇ )-tmHS-2-[4-(4-chlorobenzyl)piperidin-l-yl1- cyclopentanol
  • Step B Preparation of ( ⁇ )-fmns-2-[4-(4-chlorobenzyl)piperidin-l-yl1- cyclopentylamine
  • Step A Preparation of ( ⁇ )-tr ns-4-nitro-benzenesulfonic acid 2-azido-cyclopentyl ester
  • Step B Preparation of ( ⁇ )- ⁇ s-l-(2-azido-cyclopentyl)-4-(4-chlorobenzyl)-piperidine
  • Step C Preparation of ( ⁇ )-ris-2-[4-(4-chlorobenzyl)piperidin-l-yI]- cyclopentylamine
  • Step A Preparation of ( ⁇ )-fmns-4-nitro-benzenesulfonic acid 2-azido-cyclohexyl ester
  • Step B Preparation of ( ⁇ )- ⁇ ' s- l-(2-azido-cyclohexyI)-4-(4-chlorobenzyl)-piperidine
  • Step C Preparation of ( ⁇ )-ris-2-f4-(4-chlorobenzyl)piperidm-l-yl1-cyclohexylamine
  • Step A Preparation of ( ⁇ )-2-[4-(4-chlorobenzyl)piperidin-l-yl]-cyclobutanone
  • Step B Preparation of ( ⁇ )-2-[4-(4-chlorobenzyl)piperidin-l-yl]-cyclobutanone O-methyl-oxime
  • Step C Preparation of ( ⁇ )-rrans-2-[4-(4-chlorobenzyl)piperidin-l-yl1- cyclobutylamine
  • the aqueous phase was extracted with EtOAc and the extracts were washed with brine, dried (Na 2 SO 4 ) and concentrated.
  • a solution of the residue in MeOH (30 ml) and 1 N HCI (3 ml) was stirred at 50 °C for 1 hour and at 75 °C for 5 hours, allowed to cool to room temperature, and concentrated.
  • the residue was partitioned between CH 2 C1 2 and 1 N NaOH, the aqueous phase was extracted with CH 2 CI 2 and the extracts were dried and concentrated.
  • Step A Preparation of 4-(4-Chloro-benzylidene)-piperidine-l-carboxylic acid fert-butyl ester
  • the phosphorium salt (lOg) was taken up in THF and placed in an ice bath.
  • the KHMDS (42ml) was added slowly, the ice bath was removed, and the reaction was stirred for 45 minutes at room temperature.
  • the reaction solution was then cooled to -78°C and the ketone (4.2g) was added slowly.
  • the reaction was stirred for 30 minutes, the cooling bath was removed, and the reaction was stirred overnight at room temperature.
  • the reaction solution was poured into a saturated NH 4 C1 (100ml) solution, the layers were separated, the aqueous layer was washed twice with EtOAc, the organic layers were combined, dried (MgSO 4 ), and concentrated to ⁇ 40ml.
  • the solution was diluted with hexane and filtered to remove the majority of the Ph PO. Chromatography of the crude product with 20:1-10:1 hexane:EtOAc gave the product as a colorless oil (4.7g).
  • Step B Preparation of 4-(4-Chloro-benzyl)-piperidine-l-carboxylic acid tert-butyl ester
  • the protected piperidine ( lOg) was dissolved in EtOAc ( 100ml), the Pt ⁇ 2 was added, and the mixture was stirred rapidly under H 2 for 3 hours. The mixture was filtered through celite and concentrated. The crude product was taken up in hot hexane, filtered and allowed to crystallize. The product was recrystallized with hot hexane to yield the clean product (8.0g). Additional product was isolated form the mother liquor.
  • Step A Preparation of ( ⁇ )-tr ⁇ n5-4-[4-(4-chlorobenzyl)piperidin-l-yl]-tetrahydro- furan-3-ol
  • Step B Preparation of (+)-trflns-4-[4-(4-chlorobenzyl)piperidin-l-yl]-tetrahydro- furan-3-ylamine
  • Example 6 Preparation of ( ⁇ )-l- ⁇ (ii?,2 ⁇ ,4S)-2-[4-(4-chlorobenzyl)piperidin-l-yl]- 4-hydroxy-cyclopentyl ⁇ -3-(3 ) 4,5-trimethoxyphenyl)urea.
  • Step A Preparation of ( ⁇ )-(l#,2#,4#)-4-(te ⁇ bu1yl-dimethyIsilanyloxy)- 2-[4-(4-chIorobenzyl)piperidin-l-yll-cyclopentanol
  • Step B Preparation of ( ⁇ )-(lfl,2/ ⁇ S)-4-(tert-butyl-dimethylsilanyloxy)- 2-[4-(4-chlorobenzyI)piperidin-l-yl]-cyclopentylamine
  • Step C Preparation of ( ⁇ )-l- ⁇ (l ⁇ ,2 ⁇ ,4S)-4-(tert-butyl-dimethylsilanyloxy)- 2-f4-(4-chlorobenzyl)piperidin-l-yl1-cvclopentyll-3-(3,4,5-trimethoxyphenyl)urea
  • Example 7 Preparation of ( ⁇ )-l- ⁇ (li?,2i?,4S)-2-[4-(4-chlorobenzyl)piperidin-l-yl]- 4-hydroxycyclopentyl ⁇ -3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
  • Example 8 Preparation of ( ⁇ )-l- ⁇ (l. ,2JR,4S)-2-[4-(4-chlorobenzy ⁇ )piperidin-l-yl]- 4-hydroxyrnethyl-cyclopentyl ⁇ -3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
  • Step A Preparation of ( ⁇ )-( lfl,2R,4i -4-(terf-butyl-dimethylsilanyloxymethyl)-
  • Step B Preparation of ( ⁇ )-(U ⁇ ,2i ,4S)-4-(tert-butyl-dimethylsilanyloxymethyl)- 2-[4-(4-chlorobenzyl)piperidin-l-yl]-cyclopentylamine
  • Step C Preparation of ( ⁇ )-l- ⁇ (l ⁇ ,2i ⁇ ,4S)-4-(tert-butyl-dimethylsilanyloxymethyl)- 2-[4-(4-chlorobenzyl)piperidin-l-yl]-cyclopentyl ⁇ -3-(3 > 4,5-trimethoxyphenyl)urea
  • Example 9 Preparation of ( ⁇ )-frans-l- ⁇ 4-[4-(4-chlorobenzy ⁇ )piperidin-l-yl]- pyrr olidin- 3 -yl ⁇ - 3 - ( 3 ,4, 5-trimethoxyphenyl) urea dihydr ochloride .
  • Step A Preparation of ( ⁇ )-frflns-3-[4-(4-chlorobenzyl)piperidin-l-yl]-4-hydroxy- pyrrolidine-1 -carboxylic acid t ⁇ rr-butyl ester
  • Step B Preparation of ( ⁇ )-t ⁇ 5-3-amino-4-[4-(4-chlorobenzyl)piperidin-l-yl]- pyrrolidine-1 -carboxylic acid tert-butyl ester
  • Step C Preparation of ( ⁇ )-tr ⁇ s-3-[4-(4-chlorobenzyl)piperidin-l-yl1- 4-[3-(3,4,5-trimethoxyphenyl)ureido1-pyrrolidine-l-carboxylic acid tert-butyl ester
  • Example 10 Preparation of ( ⁇ )-cis-l- ⁇ 2-[4-(4-chlorobenzyl)piperidin-l-yl]-cyclopentyl ⁇ - 3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
  • Example 11 Preparation of ( ⁇ )-cis-N- ⁇ 2- [4- (4-chlorobenzyl)piperidin-l-yl]-cyclopentyl ⁇ - 4-methanesulfonyl-benzamide hydrochloride.
  • Example 12 Preparation of ( ⁇ )-tr ⁇ «s-l- ⁇ l-acetyl-4-[4-(4-chlorobenzyl)piperidin-l-yl]- pyrrolidin-3-yl ⁇ -3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
  • Example 13 Preparation of ( ⁇ )-ris-l- ⁇ 2-[4-(4-chlorobenzyl)piperidin-l-yl]- cyclohexyl ⁇ -3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
  • Example 14 Preparation of ( ⁇ )-cis-N- ⁇ 2-[4-(4-chlorobenzyl)piperidin-l-yl]- cyclohexyl ⁇ -4-methanesulfonyl-benzamide hydrochloride.
  • Example 15 Preparation of ( ⁇ )-trans-l- ⁇ 4-[4-(4-chlorobenzyl)piperidin-l-yl]- l-methanesulfonyl-pyrrolidin-3-yl ⁇ -3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
  • Example 16 Preparation of ( ⁇ )-trans-3-[4-(4-chlorobenzyl)piperidin-l-yl]- 4-[3-(3,4,5-trimethoxyphenyl)-ureido]-pyrroridine-l-sulfonic acid dimethylamide hydrochloride.
  • Example 19 Preparation of ( ⁇ )-l- ⁇ (li?,2/?,4S)-2-[4-(4-chlorobenzyl)piperidin-l-yl]- 4-methoxymethyl-cyclopentyl ⁇ -3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
  • Example 20 Preparation of ( ⁇ )-l- ⁇ (ljR,2 ⁇ ,4S)-2-[4-(4-chlorobenzyl)piperidin-l-yl]- 4-methoxy-cyclopentyl ⁇ -3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
  • Example 21 Preparation of ( ⁇ )-tr ⁇ ns-2- ⁇ 3-[4-(4-chlorobenzyl)piperidin-l-yl]- 4-[3-(3,4 ) 5-trimethoxyphenyl)-ureido]-pyrrolidin-l-yl ⁇ -acetamide dihydrochloride.
  • Example 22 Preparation of (+)-tr «s-l- ⁇ 2-[4-(4-chlorobenzyl)piperidin-l-yl]- cyclopentyl ⁇ -3-(4-methoxy-naphthalen-2-yl)urea.
  • Example 23 Preparation of ( ⁇ )-tr ⁇ «s-l- ⁇ 4-[4-(4-chlorobenzyl)piperidin-l-yl]- l-(2-methanesulfonyl-ethyl)-pyrrolidin-3-yl ⁇ -3-(3,4,5-trimethoxyphenyl)urea dihydrochloride.
  • Example 24 Preparation of ( ⁇ )-trans-l- ⁇ 2-[4-(4-chlorobenzyl)piperidin-l-yl]- cyclopentyl ⁇ -3-[2-(3,4,5-trimethoxyphenyl)-ethyl]urea hydrochloride.
  • Example 25 Preparation of ( ⁇ )-tr ns-3-[4-(4-chlorobenzyl)piperidin-l-yl]- 4-[3-(3,4,5-trimethoxyphenyl)-ureido]-pyrrolidine-l-sulfonic acid amide hydrochloride.
  • Example 27 Preparation of ( ⁇ )-tr ⁇ «s-l- ⁇ 4-[4-(4-chlorobenzyl)piperidin-l-yl]-l.l-dioxo- tetrahydro-l ⁇ 6 -thiophen-3-yl ⁇ -3-(3,4,5-trimethoxyphenyl)urea hydrochloride
  • Step A Preparation of ( ⁇ )-tmns- ⁇ 4-[4-(4-chlorobenzyl)piperidin-l-yl]-l.l-dioxo- tetrah dro-l ⁇ -thiophen-3-yU-carbamic acid ethyl ester
  • Step B Preparation of ( ⁇ )-trflns-4- 4-(4-chlorobenzyl)piperidin-l-yl]-l.l-dioxo- tetrahydro- l ⁇ -thiophen-3-ylamine
  • Example 28 Preparation of ( ⁇ )-tr ⁇ ns-3- ⁇ 3-[4-(4-chlorobenzyl)piperidin-l-y ⁇ ]- 4-[3-(3,4,5-trimethoxyphenyl)-ureido]-pyrrolidin-l-yl ⁇ -3-oxo-propinoic acid.
  • Example 29 Preparation of ( ⁇ )-trans-l- ⁇ 2-[4-(4-chlorobenzyl)piperidin-l-yl]- cyclobutyl ⁇ -3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
  • Example 31 Preparation of ( ⁇ )-c ⁇ ' s-l- ⁇ 2-[4-(4-chlorobenzyl)piperidin-l-yl]-cyclobutyl ⁇ - 3-(3,4,5-trimethoxyphenyl)urea hydrochloride.
  • Example 32 The following compound was prepared using General Procedure C, with the appropriate amine and isocyanate.
  • Example 33 The following compounds were prepared using General Procedure E, with the appropriate amine and carboxylic acid.
  • Example 34 The following compounds were prepared following General Procedure F, using the appropriate amine and carboxylic acid. ( ⁇ )- ⁇ s-N- ⁇ 2-[4-(4-Chlorobenzyl)piperidin-l-yl]-cyclopentyl ⁇ -
  • Example 35 The following compounds were prepared following General Procedure G, using the appropriate amine and sulfonyl chloride.
  • Example 36 The following compounds were prepared following General Procedure H, using the appropriate amine and acid chloride.
  • Example 37 The following compounds were prepared following General Procedure I, using the appropriate amine and carboxylic acid.
  • Example 38 The following compounds were prepared following General Procedure J, using the appropriate amine and isocyanate. ( ⁇ )-trans-l- ⁇ 2-[4-(4-Chlorobenzyl)piperidin-l-yl]-cyclopentyl ⁇ -
  • Example 39 The following compounds were prepared following General Procedure K, using the appropriate amine and isocyanate.
  • Example 40 The following compounds were prepared following General Procedure L, using the appropriate aniline and Phoxime resin. ( ⁇ )-trans-l- ⁇ 2-[4-(4-Chlorobenzyl)piperidin-l-yl]-cyclopentyl ⁇ -
  • Example 41 The following compounds were prepared following General Procedure M, using the appropriate aniline.
  • Example 42 The following compounds were prepared following General Procedure N, using the appropriate thioisocyanate.
  • Example 43 The following compounds were prepared following General Procedure O, using the appropriate succinimide.
  • the following ingredients are mixed to form a suspension for oral administration.
  • Veegum K (Vanderbilt Co.) 1.0 g
  • the CCR-3 antagonistic activity of the compounds of the invention was determined by their ability to inhibit the binding of l I eotaxin to CCR-3 LI.2 transfectant cells (see Ponath, P. D. et al., J. Exp. Med., Vol. 183, 2437-2448, (1996)).
  • the assay was performed in Costar 96-well polypropylene round bottom plates. Test compounds were dissolved in DMSO and then diluted with binding buffer (50 mM HEPES, 1 mM CaCl.sub.2, 5 mM MgCl 2 , 0.5% bovine serum albumin (BSA), 0.02% sodium azide, pH 7.24) such that the final DMSO concentration was 2%. 25 ⁇ l of the test solution or only buffer with DMSO (control samples) was added to each well, followed by the addition of 25 ⁇ l of 125 I-eotaxin (100 pmol) (NEX314, New England Nuclear, Boston, Mass.) and 1.5 x 10 5 of the CCR-3 LI.2 transfected cells in 25 ⁇ l binding buffer. The final reaction volume was 75 ⁇ l.
  • binding buffer 50 mM HEPES, 1 mM CaCl.sub.2, 5 mM MgCl 2 , 0.5% bovine serum albumin (BSA), 0.02% sodium azide, pH
  • the reaction was terminated by filtering the reaction mixture through polyethylenimine treated Packard Unifilter GF/C filter plate (Packard, Chicago, 111.).
  • the filters were washed four times with ice cold wash buffer containing 10 mm HEPES and 0.5M sodium chloride (pH 7.2) and dried at 65°C. for approximately 10 minutes. 25 ⁇ l/well of Microscint-20® scintillation fluid (Packard) was added and the radioactivity retained on the filters was determined by using the Packard TopCount ® .
  • the CCR-3 antagonistic activity of the compounds of this invention can be determined by measuring the inhibition of eotaxin mediated chemotaxis of the CCR-3 Ll.2 transfectant cells, using a slight modification of the method described in Ponath, P. D. et al., J. Clin. Invest. 97: 604-612 (1996). The assay is performed in a 24-well chemotaxis plate (Costar Corp., Cambridge, Mass.). CCR-3 Ll.2 transfectant cells are grown in culture medium containing RPMI 1640, 10% Hyclone ® fetal calf serum, 55 mM 2- mercaptoethanol and Geneticin 418 (0.8 mg/ml).
  • the transfected cells are treated with n-butyric acid at a final concentration of 5 mM/lxlO cells/ml, isolated and resuspended at lxlO 7 cells/ml in assay medium containing equal parts of RPMI 1640 and Medium 199 (M 199) with 0.5% bovine serum albumin.
  • the plate is incubated at 37 °C. After 4 hours, the inserts are removed from the chambers and the cells that have migrated to the bottom chamber are counted by pipetting out 500 ⁇ l of the cell suspension from the lower chamber to 1.2 ml Cluster tubes (Costar) and counting them on a FACS for 30 seconds.
  • Cluster tubes Costar
  • Endothelial cells are cultured on 6.5 mm diameter Biocoat.RTM. Transwell tissue culture inserts (Costar Corp., Cambridge, Mass.) with a 3.0 ⁇ M pore size.
  • Culture media for ECV 304 cells consists of M199, 10% Fetal Calf Serum, L-glutamine and antibiotics.
  • Assay media consists of equal parts RPMI 1640 and M199, with 0.5% BSA. 24 hours before the assay 2xl0 5 ECV 304 cells are plated on each insert of the 24-well chemotaxis plate and incubated at 37 X. 20 nM of eotaxin diluted in assay medium is added to the bottom chamber. The final volume in bottom chamber is 600 ⁇ l.
  • the endothelial coated tissue culture inserts are inserted into each well. 10 eosinophil cells suspended in 100 ⁇ l assay buffer are added to the top chamber. Test compounds dissolved in DMSO are added to both top and bottom chambers such that the final DMSO volume in each well was 0.5%. T he assay is performed against two sets of controls. The positive control contains cells in the top chamber and eotaxin in the lower chamber. The negative control contains cells in the top chamber and only assay buffer in the lower chamber. The plates are incubated at 37 °C. in 5% CO 2 /95% air for 1-1.5 hours.
  • the cells that migrate to the bottom chamber are counted using flow cytometry.
  • 500 ⁇ l of the cell suspension from the lower chamber are placed in a tube, and relative cell counts are obtained by acquiring events for a set time period of 30 seconds.
  • Example 48 Inhibition of Eosinophil Influx Into the Lungs of Ovalbumin Sensitized Balb/c Mice by CCR-3 Antagonist-In Vivo Assay
  • the ability of the compounds of the invention to inhibit leukocyte infiltration into the lungs can be determined by measuring the inhibition of eosinophil accumulation into the bronchioalveolar lavage (BAL) fluid of Ovalbumin (OA)-sensitized balb/c mice after antigen challenge by aerosol.
  • BAL bronchioalveolar lavage
  • OA Ovalbumin
  • male balb/c mice weighing 20-25g are sensitized with OA (10 ⁇ g in 0.2 ml aluminum hydroxide solution) intraperitoneally on days 1 and 14. After a week, the mice are divided into ten groups. Test compound or only vehicle (control group) or anti-eotaxin antibody (positive control group) is administered either intraperitoneally, subcutaneously or orally.
  • mice After 1 hour, the mice are placed in a Plexiglass box and exposed to OA aerosol generated by a PARISTAR.TM. nebulizer (PARI, Richmond, Va.) for 20 minutes. Mice which have not been sensitized or challenged are included as a negative control. After 24 or 72 hours, the mice are anesthetized (urethane, approx. 1 g/kg, i.p.), a tracheal cannula (PE 60 tubing) is inserted and the lungs are lavaged four times with 0.3 ml PBS. The BAL fluid is transferred into plastic tubes and kept on ice. Total leukocytes in a 20 ⁇ l aliquot of the BAL fluid is determined by Coulter Counter .TM. (Coulter, Miami, Fla.). Differential leukocyte counts are made on Cytospin.TM. preparations which have been stained with a modified Wright's stain (DiffQuick.TM.) by light microscopy using standard morphological criteria.

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Abstract

La présente invention concerne des composés représentés par la formule (I). Dans cette formule R1 R5, A, L, et X sont définis dans les spécifications. Ces composés conviennent comme antagonistes du récepteur CCR-3 et, par conséquent, ils peuvent être utilisés pour le traitement des maladies induites par le récepteur CCR-3.
EP02787796A 2001-11-30 2002-11-25 N-ureido-piperidines utilises comme antagonistes viii du recepteur ccr3 Withdrawn EP1453825A1 (fr)

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CA2502178A1 (fr) * 2002-10-30 2004-05-21 Merck & Co., Inc. Modulateurs d'heteroarylpiperidine de l'activite des recepteurs de la chimiokine
IN2006CH00378A (en) * 2003-06-30 2007-05-11 Sumitomo Chemical Co Asymmetric urea compound and process for producing asymmetric compound by asymmetric conjugate addition reaction with the same as catalyst
WO2005058805A1 (fr) * 2003-12-17 2005-06-30 Sumitomo Chemical Company, Limited Procede de production de compose amine optiquement actif
US7635698B2 (en) 2004-12-29 2009-12-22 Millennium Pharmaceuticals, Inc. Compounds useful as chemokine receptor antagonists
WO2006071875A1 (fr) 2004-12-29 2006-07-06 Millennium Pharmaceuticals, Inc. Composes utilises comme antagonistes des recepteurs de la chemokine
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Title
J.F. BUNNETT ET AL.: "The ortho: para ratio in activation of aromatic nucleophilic substitution by the nitro group", J. AM. CHEM. SOC., vol. 77, 1955, pages 5051 - 5055 *
See also references of WO03045937A1 *

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