WO2003068759A1 - Anti-inflammatoires a base de derives piperazine - Google Patents

Anti-inflammatoires a base de derives piperazine Download PDF

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Publication number
WO2003068759A1
WO2003068759A1 PCT/GB2003/000583 GB0300583W WO03068759A1 WO 2003068759 A1 WO2003068759 A1 WO 2003068759A1 GB 0300583 W GB0300583 W GB 0300583W WO 03068759 A1 WO03068759 A1 WO 03068759A1
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compound
formula
unsubstituted
substituted
solution
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PCT/GB2003/000583
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Michael Dennis Dowle
Colin David Eldred
Martin Redpath Johnson
Tracy Jane Redfern
John Edward Robinson
Naimisha Trivedi
Victoria Weller
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Glaxo Group Limited
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Priority to JP2003567889A priority Critical patent/JP2005528342A/ja
Priority to EP03739556A priority patent/EP1480959A1/fr
Priority to AU2003245703A priority patent/AU2003245703A1/en
Publication of WO2003068759A1 publication Critical patent/WO2003068759A1/fr

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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/42—One nitrogen atom
    • C07D251/44—One nitrogen atom with halogen atoms attached to the two other ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds, processes for their preparation, pharmaceutical formulations containing them and their use in therapy.
  • Inflammation is a primary response to tissue injury or microbial invasion and is characterised by leukocyte adhesion to the endothelium, diapedesis and activation within the tissue.
  • Leukocyte activation can result in the generation of toxic oxygen species (such as superoxide anion), and the release of granule products (such as peroxidases and proteases).
  • Circulating leukocytes include neutrophils, eosinophiis, basophils, monocytes and lymphocytes.
  • Different forms of inflammation involve different types of infiltrating leukocytes, the particular profile being regulated by the profile of adhesion molecule, cytokine and chemotactic factor expression within the tissue.
  • leukocytes The primary function of leukocytes is to defend the host from invading organisms, such as bacteria and parasites. Once a tissue is injured or infected, a series of events occurs which causes the local recruitment of leukocytes from the circulation into the affected tissue. Leukocyte recruitment is controlled to allow for the orderly destruction and phagocytosis of foreign or dead cells, followed by tissue repair and resolution of the inflammatory infiltrate. However in chronic inflammatory states, recruitment is often inappropriate, resolution is not adequately controlled and the inflammatory reaction causes tissue destruction.
  • bronchial inflammation which is characteristic of asthma represents a specialised form of cell-mediated immunity, in which cytokine products, such as IL-4 and IL-5 released by T-helper 2 (Th2) lymphocytes, orchestrate the accumulation and activation of granulocytes, in particular eosinophiis and to a lesser extent basophils.
  • Th2 T-helper 2
  • eosinophiis Through the release of cytotoxic basic proteins, pro-inflammatory mediators and oxygen radicals, eosinophiis generate mucosal damage and initiate mechanisms that underlie bronchial hyperreactivity. Therefore, blocking the recruitment and activation of Th2 cells and eosinophiis is likely to have anti-inflammatory properties in asthma.
  • eosinophiis have been implicated in other disease types such as rhinitis, eczema, irritable bowel syndrome and parasitic infections.
  • Chemokines are a large family of small proteins which are involved in trafficking and recruitment of leukocytes (for review see Luster, New Eng. J. Med., 338, 436-445 (1998)). They are released by a wide variety of cells and act to attract and activate various cell types, including eosinophiis, basophils, neutrophils, macrophages, T and B lymphocytes. There are two major families of chemokines, CXC- ( ⁇ ) and CC- ( ⁇ ) chemokines, classified according to the spacing of two conserved cysteine residues near to the amino terminus of the chemokine proteins.
  • Chemokines bind to specific cell surface receptors belonging to the family of G-protein-coupled seven transmembrane-domain proteins (for review see Luster, 1998). Activation of chemokine receptors results in, amongst other responses, an increase in intracellular calcium, changes in cell shape, increased expression of cellular adhesion molecules, degranulation and promotion of cell migration (chemotaxis).
  • CCR-3 CC-chemokine receptor-3
  • RANTES RANTES
  • MCP-3 and MCP-4 are known to recruit and activate eosinophiis.
  • eotaxin and eotaxin-2 which specifically bind to CCR-3.
  • the localization and function of CCR-3 chemokines indicate that they play a central role in the development of allergic diseases such as asthma.
  • CCR- 3 is specifically expressed on all the major cell types involved in inflammatory allergic responses.
  • Chemokines that act at CCR-3 are generated in response to inflammatory stimuli and act to recruit these cell types to sites of inflammation, where they cause their activation (e.g. Griffiths et al., J. Exp. Med., 179, 881 -887 (1994), Lloyd et al., J. Exp. Med., 191 , 265-273 (2000)).
  • anti-CCR-3 monoclonal antibodies completely inhibit eotaxin interaction with eosinophiis (Heath, H. et al., J. Clin. Invest.
  • chemokines and their receptors also play a role in infectious disease.
  • Mammalian cytomegaloviruses, herpes viruses and pox viruses express chemokine receptor homologues, which can be activated by human CC chemokines such as RANTES and MCP-3 receptors (for review see Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748, 1997).
  • human chemokine receptors such as CXCR-4, CCR-5 and CCR-3, can act as co-receptors for the infection of mammalian cells by microbes such as human immunodeficiency viruses (HIV).
  • chemokine receptor antagonists including CCR-3 antagonists, may be useful in blocking infection of CCR-3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.
  • WO 01/24786 discloses certain aryl and heteroaryl derivatives for treating diabetes.
  • WO 00/69830 discloses certain diazacyclic compounds, and libraries containing them, for biological screening.
  • WO 00/18767 discloses certain piperazine derivatives as dopamine D4 receptor antagonists.
  • United States Patent 6,031 ,097 and WO 99/21848 discloses certain aminoisoquinoline derivatives as dopamine receptor ligands.
  • WO 99/06384 discloses piperazine derivatives useful for the treatment of neuromuscular dysfunction of the lower urinary tract.
  • WO 98/56771 discloses certain piperazine derivatives as anti- inflammatory agents.
  • WO 97/47601 discloses certain fused heterocyclic compounds as dopamine D-receptor blocking agents.
  • WO 96/39386 discloses certain piperidine derivatives as neurokinin antagonists.
  • WO 96/02534 (Byk Gulden Lomberg Chemische Fabrik GmbH) discloses certain piperazine thiopyridines useful for controlling helicobacter bacteria.
  • WO 95/32196 (Merck Sharp & Dohme Limited) discloses certain piperazine, piperidine, and tetrahydropyridine derivatives as 5-HT1 D-alpha antagonists.
  • United States Patent 5,389,635 (E.I. Du Pont de Nemours and Company) discloses certain substituted imadazoles as angiotensin-ll antagonists.
  • European Patent Application publication number 0 306 440 (Schering Aktiengesellschaft) discloses certain imidazole derivatives as cardiovascular agents.
  • CCR-3 antagonists A novel group of compounds has now been found which are CCR-3 antagonists. These compounds block the migration/chemotaxis of eosinophiis and thus possess anti-inflammatory properties. These compounds are therefore of potential therapeutic benefit, especially in providing protection from eosinophil, basophil and Th2-cell-induced tissue damage in diseases where such cell types are implicated, particularly allergic diseases, including but not limited to bronchial asthma, allergic rhinitis and atopic dermatitis.
  • R 1 represents substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
  • R 2 represents hydrogen, C ⁇ . 6 alkyl, C 2 . 6 alkenyl, or C 3 . 8 cycloalkyl
  • X and Y each independently represent a bond or -(CH 2 ) a -, with the proviso that X and Y do not both represent a bond; a represents 1 or 2; R 3 represents C 1-6 alkyl, C 2 . 6 alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, C 3 . 8 cycloalkyl, -CO 2 R 7 , or -CONR 7 R 8 wherein said C -6 alkyl, C 2 . 6 alkenyl, and C 3 .
  • cycloalkyl groups may independently be either unsubstituted or substituted by one or more groups selected from -NHSO 2 R 7 , -OCOR 7 , -OR 7 , -NR 7 R 8 , -NR 7 COR 8 , - NR 7 CO 2 R 8 , -CO 2 R 7 , -CONR 7 R 8 , -NHCONR 7 R 8 ,
  • n represents an integer from 0 to 2;
  • R 4 and R 5 each independently represent hydrogen, C h alky!, -CO 2 R 9 ,
  • R 6 represents unsubstituted or substituted aryl or unsubstituted or substituted heteroaryl
  • R 7 and R 8 each independently represent hydrogen, aryl, heteroaryl, d. 6 alkyl, or C 3-8 cycloalkyl; wherein said C ⁇ . 6 alkyl, or C 3 . 8 cycloalkyl groups may be either unsubstituted or substituted by one or more of -OR 12 , -NR 12 R 13 , -CO 2 R 12 , - CONR 12 R 13 , -NHCONR 12 R 13 , or aryl; alternatively R 7 and R 8 together represent a group -(CH 2 ) b -Z-(CH 2 ) c -; b represents an integer from 0 to 4; c represents an integer from 0 to 4; b + c is 3, 4, or 5;
  • R 9 , R 10 , and R 11 may each independently represent hydrogen or Ci_ 6 alkyl
  • R 12 and R 13 may each independently represent hydrogen or alkyl, wherein said C 1-6 alkyl group may be either unsubstituted or substituted by
  • R 14 represents hydrogen or C 1-6 alkyl
  • X 1 represents oxygen, -NR 10 , or sulphur
  • X 2 represents CH 2 , oxygen, -NR 10 , or sulphur; with the provisos that; when moiety (K) is linked to the residue of the compound of formula (I) through an X 1 group, then X 1 represents N, and when moiety (K) is linked to the residue of the compound of formula (I) through an X 2 group, then X 2 represents N or CH; m 1 represents an integer from 1 to 3, m 2 represents an integer from 1 to 3, provided that m 1 +m z is in the range from 3 to 5; and wherein the moiety of formula (K) may be either unsubstituted or substituted by one or more of C ⁇ alkyl, -CONR 12 R 13 , -CO 2 R 12 , or oxo;
  • Z represents oxygen, -NR 12 , sulphur, or a methylene group, which methylene group may be either unsubstituted or substituted by a -CO 2 R 7 or -CONR 7 R 8 group; and salts and solvates thereof; with the proviso that N-[1-methyl-2-(4-benzylpiperazino)ethyl]aniline is excluded.
  • R 1 represents substituted heteroaryl
  • suitable substituents include C 1-6 alkyl, halo, nitro, aryl, and amino.
  • R 3 represents substituted C ⁇ alkyl
  • suitable substituents include Ci. 6 alkoxy; hydroxy; d-ealkylthio; Ci-ealkoxycarbonyl; d. 6 alkoxycarbonylamino; amino; unsubstituted aryl or aryl substituted with d. 6 alkoxy, amino, Ci- 6 alkylcarbonylamino, perhaloCi ⁇ alkylcarbonylamino, d.
  • R 3 represents substituted C 2-6 alkenyl
  • suitable substituents include d. 6 alkoxycarbonyl.
  • suitable substituents include halo.
  • R 7 or R 8 represent substituted d. 6 alkyl
  • suitable substituents include C ⁇ . 6 alkoxycarbonyl, d-ealkoxy, unsubstituted or substituted aryl, hydroxy, hydroxyd- ⁇ alkoxy, aminocarbonyl, and carboxy.
  • R 12 or R 13 represent substituted C h alky!
  • suitable substituents include hydroxy.
  • Suitable substituents for K include d. 6 alkoxycarbonyl, carboxy, and aminocarbonyl.
  • Suitable substituents for Z include Ci-ealkoxycarbonyl and carboxy.
  • R 1 is unsubstituted or substituted heteroaryl. More suitably, R 1 is unsubstituted or substituted benzoxazolyl, unsubstituted or substituted thienopyrimidinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazolopyrimidinyl, unsubstituted or substituted benzimidazolyl, unsubstituted or substituted triazinyl, or unsubstituted or substituted quinoxolinyl.
  • R is unsubstituted benzoxazolyl or benzoxazolyl substituted with C ⁇ _ 6 alkyl for example methyl, halo, nitro, or unsubstituted aryl for example phenyl; thienopyrimidinyl substituted with d.
  • R 1 is unsubstituted benzoxazolyl or benzoxazolyl substituted with C 1-6 alkyl for example methyl, halo, nitro, or unsubstituted aryl for example phenyl.
  • R 1 is unsubstituted benzoxazolyl.
  • R 2 is hydrogen, or d. 6 alkyl for example methyl.
  • R 2 is hydrogen
  • R 3 is unsubstituted or substituted d ⁇ alkyl, C 3 _scycloalkyl, - CO 2 R 7 , -CONR 7 R 8 , or unsubstituted or substituted C 2 ⁇ alkenyl.
  • R 3 is unsubstituted alkyl for example /so-propyl or /so-butyl; alkyl substituted with -OR 7 , -S(O) n R 7 , -CO 2 R 7 , -NR 7 CO 2 R 8 , -NR 7 R 8 , -CONR 7 R 8 , - OCOR 7 , -NHCOR 7 , -NR 7 SO 2 R 8 , -O(CO)NR 7 R 8 , -NHCONR 7 R 8 , or unsubstituted or substituted heteroaryl; unsubstituted or substituted aryl; unsubstituted cycloalkyl; alkenyl substituted with -CO 2 R 7 ; or -CONR 7 R 8 .
  • R 3 is selected from the group consisting of -CH(CH 3 ) 2 ⁇ - CH 2 CH(CH 3 ) 2 , -cyclohexyl, -(CH 2 ) 3 CH 3 , -CH 2 OtBu, -CH(CH 3 )OtBu, -CO 2 Et, - (CH 2 ) 2 OH, -(CH 2 ) 2 SMe, -CH 2 CO 2 tBu, -CH 2 CO 2 iBu, -(CH 2 ) 3 OH, - (CH 2 ) 3 NHCO 2 tBu, -(CH 2 ) 2 CO 2 tBu, -(CH 2 ) 4 OH, -(CH 2 ) 4 NHCO 2 tBu, -(CH 2 ) 5 NH 2 , - CH 2 Ph, -CH 2 (4-OtBu)Ph, -CH 2 (4-NH 2 )Ph, -CH 2 (4-NHCOMe)Ph, -
  • R 3 is selected from the group consisting of - (CH 2 ) 2 CO 2 H, -CH 2 (4-OH)Ph, -CH 2 (4-imidazolyl), -(CH 2 ) 2 CO(4-morpholinyl), - (CH 2 ) 2 CONMe 2 , -(CH 2 ) 2 CONHCH 2 CONH 2 .
  • R 3 is -(CH 2 ) 2 CO 2 H.
  • R 4 is hydrogen or -CONR 7 R 8 .
  • R 4 is hydrogen
  • R 5 is hydrogen, d. 6 alkyl for example methyl, or -CONR 7 R 8 for example amido.
  • R 5 is hydrogen.
  • R 6 is unsubstituted or substituted aryl, for example phenyl.
  • R 6 is phenyl substituted with halo.
  • R 6 is phenyl substituted with chloro or fluoro.
  • R 6 is phenyl substituted with chloro. Most preferably, R 6 is dichlorophenyl, especially 3,4-dichlorophenyl.
  • R 7 is unsubstituted or substituted d. 6 alkyl, hydrogen, or unsubstituted or substituted aryl.
  • R 8 is unsubstituted or substituted C 1-6 alkyl, hydrogen, or unsubstituted or substituted aryl.
  • R 7 and R 8 together represent a group -(CH 2 ) b -Z-(CH 2 ) c -.
  • b is 0 or 2 and c is 2 or 3, provided that when b is 0 then Z is unsubstituted or substituted methylene.
  • Preferred compounds of the invention are those of Examples 58, 59, 62, 84, 93, and 94; most preferably Example 58. There exists a preferred subgroup of compounds of formula (I) being of formula (I 1 )
  • R 1 is unsubstituted benzoxazolyl or benzoxazolyl substituted with d- 6 alkyl for example methyl, halo, nitro, or unsubstituted aryl for example phenyl; thienopyrimidinyl substituted with d-ealkyl for example methyl; unsubstituted benzimidazolyl or benzimidazolyl substituted with halo for example chloro, or methyl; unsubstituted quinoxalinyl or quinoxalinyl substituted with nitro; pyrazolopyrimidinyl substituted with C 1-6 alkyl for example methyl; pyrimidinyl substituted with one or more of amino or halo for example chloro; or triazinyl substituted with halo for example chloro;
  • R 2 is hydrogen, or C h alky! for example methyl;
  • R 3 is unsubstituted alkyl for example /so-propyl or /so-butyl; alkyl substituted with -OR 7' , -S(O) n R , -CO 2 R 7' , -NR 7 CO 2 R 8' , -NR 7 R 8' , -CONR 7 R 8' , - OCOR 7' , -NHCOR 7' , -NR 7' SO 2 R 8' , -O(CO)NR 7 R 8' , -NHCONR 7 R 8' , unsubstituted or substituted aryl, or unsubstituted or substituted heteroaryl; unsubstituted or substituted aryl; unsubstituted cycloalkyl; alkenyl substituted with -CO 2 R 7 ; or - CONR r R 8' ;
  • R 4' is hydrogen or -CONR 7 R 8' ;
  • R 5' is hydrogen, C h alky! for example methyl, or -CONR 7 R 8 for example -CONH 2 ;
  • R 6 is phenyl substituted with chloro or fluoro
  • R 7 is unsubstituted or substituted C ⁇ -6 alkyl, hydrogen, or unsubstituted or substituted aryl
  • R 8 is unsubstituted or substituted d. 6 alkyl, hydrogen, or unsubstituted or substituted aryl, or;
  • R 7' and R 8' together represent a group -(CH 2 ) b -Z-(CH 2 ) c -; b is 0 or 2 and c is 2 or 3, provided that when b is 0 then Z is unsubstituted or substituted methylene, and ; X and Y are as defined for formula (I) herein; and salts and solvates thereof.
  • R 1 " is unsubstituted benzoxazolyl or benzoxazolyl substituted with d. 6 alkyl for example methyl, halo, nitro, or unsubstituted aryl for example phenyl;
  • R 2' is hydrogen;
  • R 3" is selected from the group consisting of -CH(CH 3 ) 2, -CH 2 CH(CH 3 ) 2 , - cyclohexyl, -(CH 2 ) 3 CH 3 , -CH 2 ⁇ tBu, -CH(CH 3 )OtBu, -CO 2 Et, -(CH 2 ) 2 OH, - (CH 2 ) 2 SMe, -CH 2 CO 2 tBu, -CH 2 CO 2 iBu, -(CH 2 ) 3 OH, -(CH 2 ) 3 NHCO 2 tBu - (CH 2 ) 2 C0 2 tBu, -(CH 2 ) 4 OH, -(CH 2 ) 4 NHCO 2 tBu, -(CH 2 ) 5 NH 2, -CH 2 Ph, -CH 2 (4- OtBu)Ph, -CH 2 (4-NH 2 )Ph, -CH 2 (4-NHCOMe)Ph, -CH 2 (4
  • R 5 is hydrogen
  • R 6 is phenyl substituted with chloro
  • R 7" is unsubstituted or substituted C ⁇ alkyl, hydrogen, or unsubstituted or substituted aryl;
  • R 8" is unsubstituted or substituted d. 6 alkyl, hydrogen, or unsubstituted or substituted aryl, or;
  • R 7" and R 8" together represent a group -(CH 2 ) -Z-(CH 2 ) c -; b is 0 or 2 and c is 2 or 3, provided that when b is 0 then Z is unsubstituted or substituted methylene, and;
  • X and Y are as defined for formula (I) herein; and salts and solvates thereof.
  • Suitable salts of the compounds of formula (I) include physiologically acceptable salts and salts which may not be physiologically acceptable but may be useful in the preparation of compounds of formula (I) and physiologically acceptable salts thereof.
  • acid addition salts may be derived from inorganic or organic acids, for example hydrochlorides, hydrobromides, sulphates, phosphates, acetates, benzoates, citrates, succinates, lactates, tartrates, fumarates, maleates, 1 -hydroxy-2-naphthoates, pamoates, methanesulphonates, formates or trifluoroacetates.
  • solvates include hydrates.
  • Certain of the compounds of formula (I) may contain chiral atoms and/or multiple bonds, and hence may exist in one or more stereoisomeric forms.
  • the present invention encompasses all of the stereoisomers of the compounds of formula (I), including geometric isomers and optical isomers, whether as individual stereoisomers or as mixtures thereof including racemic modifications.
  • a compound of formula (I) is in the form of a single enantiomer or diastereoisomer.
  • R 3 is derived from a corresponding D-amino acid.
  • Certain of the compounds of formula (I) may exist in one of several tautomeric forms. It will be understood that the present invention encompasses all of the tautomers of the compounds of formula (I) whether as individual tautomers or as mixtures thereof.
  • references to 'aryl' include references to monocyclic carbocyclic aromatic rings, for example phenyl, and bicyclic carbocyclic aromatic rings, for example naphthyl.
  • references to 'heteroaryl' include references to mono- and bicyclic heterocyclic aromatic rings containing 1-4 heteroatoms selected from nitrogen, oxygen and sulphur.
  • monocyclic heterocyclic aromatic rings include pyrimidinyl, imidazolyl, triazinyl, and tetrazolyl.
  • bicyclic heterocyclic aromatic rings include benzoxazolyl, thienopyrimidinyl, pyrazolopyrimidinyl, benzimidazolyl, and quinoxolinyl.
  • Suitable substituents for any aryl or heteroaryl group include alkyl, halo, nitro, amino, alkoxy, alkylcarbonylamino, perhaloalkylcarbonylamino, alkylsulphonyl, hydroxy, alkoxycarbonyl, alkylsulphonylamino, aminocarbonyl, and carboxy.
  • references to alkyl include references to both straight chain and branched chain aliphatic isomers of the corresponding alkyl, suitably containing up to six carbon atoms. It will be appreciated that references to alkenyl and alkylene shall be interpreted similarly.
  • Suitable substituents for any alkyl, alkenyl, or cycloalkyl group include alkoxy, hydroxy, alkylthio, alkoxycarbonyl, alkoxycarbonylamino, amino, aryl, carboxy, aralkylaminocarbonyl, heteroaryl, cycloalkylaminocarbonyl, heterocyclylcarbonyl, mono- and di-alkylaminocarbonyl, mono- and di- (hydroxyalkyl)aminocarbonyl, aminocarbonyl, alkoxycarbonylalkylaminocarbonyl, alkoxyalkylaminocarbonyl, hydroxyalkoxyalkylaminocarbonyl, aminocarbonylalkylaminocarbonyl, alkoxycarbonylalkoxy, aminocarbonylalkoxy, mono- or di-aralkylamino, mono-or di-alkylamino, alkylcarbonyloxy, alkylcarbonylamino, alkylsulphony
  • Examples of group J include pyrrolidinyl, piperidinyl, and morpholinyl.
  • References to C 3 - 8 cycloalkyl include references to alicyclic isomers thereof i.e. moieties consisting of cycloalkyl groups substituted by alkyl groups, which moieties contain 3-8 carbon atoms.
  • halogen or halo
  • heterocyclyl include non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur. Each ring suitably has from 4 to 7, preferably
  • heterocyclyl examples include piperidinyl, morpholinyl, and pyrrolidinyl.
  • Suitable substituents for any heterocyclyl group include aminocarbonyl, alkoxycarbonyl, and carboxy.
  • Processes (a) to (g) according to the invention for preparing a compound of formula (I) which processes comprise: Process (a): Reacting a compound of formula (II)
  • R 2 , R 3 , R 4 , R 5 , R 6 , X and Y are as defined in formula (I) above, with a compound of formula R 1 -L 1 , wherein R 1 is as defined in formula (I) above, and L 1 represents a leaving group, suitably a halogen atom, such as chlorine, and optionally removing any necessary protecting group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , X and Y are as defined above, with a compound of formula (IV)
  • R 6 is as defined above and L 2 represents a leaving group, suitably a halogen atom, such as bromine, and optionally removing any necessary protecting group.
  • R 1 , R 2 , R 3 and X are as defined in formula (I), with a compound of formula (VI)
  • R 4 , R 5 and R 6 are as defined in formula (I), followed by reduction of the resultant intermediate in situ, and optionally removing any necessary protecting group.
  • R 2 , R 3 , R 4 , R 5 , R 6 , X and Y are as defined in formula (I) above, with a compound of formula (VII)
  • R 1 , R 3 , R 4 , R 5 , R 6 , X and Y are as defined in formula (I) above, with a compound of formula R 2a -L 3 , wherein R 2a is C ⁇ _ 6 alkyl or C 3 - ⁇ cycloalkyl, and L 3 represents a leaving group, suitably a halogen atom such as iodine, and optionally removing any necessary protecting group.
  • Process (a) may be performed in the presence of a suitable base eg. diisopropylethylamine under suitable conditions, eg. heating under reflux in a suitable solvent, eg. isopropanol.
  • a suitable base eg. diisopropylethylamine under suitable conditions, eg. heating under reflux in a suitable solvent, eg. isopropanol.
  • Process (b) may be performed in the presence of a suitable base, eg. diisopropylethylamine in a suitable solvent eg. dichloromethane under suitable conditions, eg. ambient temperature.
  • a suitable base eg. diisopropylethylamine
  • a suitable solvent eg. dichloromethane
  • Process (c) may be performed in the presence of a suitable solvent, eg. dichloromethane containing glacial acetic acid followed by the addition of a suitable reducing agent, eg. sodium triacetoxyborohydride.
  • a suitable solvent eg. dichloromethane containing glacial acetic acid
  • a suitable reducing agent eg. sodium triacetoxyborohydride.
  • Process (d) may be performed in the presence of a suitable solvent eg. xylene under suitable conditions, eg. heating at 140 9 C.
  • a suitable solvent eg. xylene under suitable conditions, eg. heating at 140 9 C.
  • Process (e) may be performed in the presence of a suitable solvent eg. dimethylformamide and suitable reagents eg. sodium hydride and an alkyl halide, eg. methyl iodide at a suitable temperature, eg. ambient temperature.
  • a suitable solvent eg. dimethylformamide
  • suitable reagents eg. sodium hydride and an alkyl halide, eg. methyl iodide
  • a suitable temperature eg. ambient temperature.
  • Process (f) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, reductive alkylation, "Wittig” olefin synthesis, acylation, sulphonylation, esterification, urea formation, hydrolysis or aromatic substitution.
  • protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 1991).
  • Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g. benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g.
  • benzyl which may be removed by hydrolysis or hydrogenolysis as appropriate.
  • suitable amine protecting groups include trifluoroacetyl (-COCF 3 ) which may be removed by base catalysed hydrolysis, or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
  • Suitable hydroxyl and carboxylate protecting groups include alkyl (e.g. methyl or t-butyl), acetal (e.g. acetonide) and acyl (e.g. acetyl or benzoyl) which may be removed by hydrolysis, and arylalkyl (e.g. benzyl) which may be removed by catalytic hydrogenolysis.
  • Step (i) comprises the use of suitable reagents for amide formation, eg. O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), dimethylformamide and diisopropylethylamine at a suitable temperature, eg. at ambient temperature.
  • suitable temperature eg. at ambient temperature.
  • the free amine group of formula (VIM) is preferably protected eg. by 9-fluorenylmethoxycarbonyl (fmoc) or t-butoxycarbonyl (boc).
  • Step (ii) comprises the use of suitable reducing agents, eg. borane- tetrahydrofuran complex, at a suitable temperature, eg. 65 Q C.
  • Step (i) typically comprises reaction in the presence of a suitable reducing agent, eg. sodium triacetoxyborohydride, in a suitable solvent, eg. dichloromethane, containing glacial acetic acid.
  • a suitable reducing agent eg. sodium triacetoxyborohydride
  • a suitable solvent eg. dichloromethane
  • step (X) is preferably protected eg. by 9-fluorenylmethoxycarbonyl (fmoc) or t- butoxycarbonyl (boc). Where compounds of formula (X) are protected, completion of step (i) will typically comprise a deprotection reaction, as hereinbefore described.
  • R , R 2 , R 3 , R 4 , R 5 , X and Y are as defined above, L 4 represents a leaving group, suitably a methanesulphonyloxy group or a halogen atom such as bromine, and L 5 represents a leaving group, suitably a halogen atom such as chlorine.
  • Step (i) typically comprises the use of a suitable solvent, eg. tetrahydrofuran and a suitable base, eg. diisopropyl ethylamine, under suitable reaction conditions, eg. heating under reflux.
  • a suitable solvent eg. tetrahydrofuran and a suitable base
  • eg. diisopropyl ethylamine eg. diisopropyl ethylamine
  • suitable reaction conditions eg. heating under reflux.
  • the free amine group of formula (X) is preferably protected eg. by t-butoxycarbonyl. Where compounds of formula (X) are protected, completion of step (i) will typically comprise a deprotection reaction, as hereinbefore described.
  • Step (ii) may typically be performed in the presence of a suitable base eg. diisopropylethylamine in suitable conditions, eg. heating under reflux in a suitable solvent eg. /so-propyl alcohol.
  • a suitable base eg. diisopropylethylamine
  • suitable conditions eg. heating under reflux in a suitable solvent eg. /so-propyl alcohol.
  • R 1 , R 2 , R 3 and X are as defined in formula (I) above, and L 6 represents a leaving group, suitably a halogen atom such as chlorine.
  • Step (i) typically comprises the use of a suitable solvent, eg. isopropanol, and a suitable base, eg. diisopropylethylamine, under suitable conditions, eg. heating at reflux.
  • Step (ii) typically comprises a Swern oxidation reaction (K. Omura and D.
  • R 4 , R 5 and R 6 are as defined in formula (I) above and L 3 represents a leaving group, suitably a halogen atom such as chlorine.
  • Step (i) typically comprises the use of a suitable base, eg. sodium bicarbonate in the presence of a suitable solvent, eg. ethanol, under suitable conditions, eg. heating at reflux.
  • a suitable base eg. sodium bicarbonate
  • a suitable solvent eg. ethanol
  • One of the free amine groups on compounds of formula (XI) may be protected eg. by a suitable amine protecting group as described above.
  • a CCR-3 competition binding SPA was used to assess the affinity of novel compounds for CCR-3.
  • Membranes prepared from K562 cells stably expressing CCR-3 (2.5 ⁇ g/well) were mixed with 0.25mg/well wheat-germ agglutinin SPA beads (Amersham) and incubated in binding buffer (HEPES 50 mM, CaCI 2 1 mM, MgCI 2 5 mM, 0.5% BSA) at 4°C for 1.5 hr.
  • Eosinophiis were purified from human peripheral blood by standard CD16 cell depletion using a Miltenyi cell separation column and a magnetic Super Macs magnet as previously described (Motegi & Kita, 1998; J. Immunology. 161 :4340-6). Cells were re-suspended in RPMI 1640/10% FCS solution and incubated with calcein-AM (Molecular Probes) at 37°C for 30 mins. Following incubation, the eosinophiis were centrifuged at 400g for 5 min and re- suspended in RPMI/FCS at 2.2 million/ml.
  • the compounds of the Examples were tested in the CCR-3 binding and/or eosinophil chemotaxis assays (assays (a) and (b) respectively).
  • the compounds of the Examples tested in the CCR-3 binding assay possessed pldo values in the range 5-8.
  • the compounds of the Examples tested in the CCR-3 eosinophil chemotaxis assay possessed fpKi values in the range 5.5-7.5.
  • Examples of disease states in which the compounds of the invention have potentially beneficial anti-inflammatory effects include diseases of the respiratory tract such as bronchitis (including chronic bronchitis), asthma
  • COPD chronic obstructive pulmonary disease
  • intestinal inflammatory diseases including inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) and intestinal inflammatory diseases secondary to radiation exposure or allergen exposure.
  • compounds of the invention may be used to treat nephritis; skin diseases such as psoriasis, eczema, allergic dermatitis and hypersensitivity reactions; and diseases of the central nervous system which have an inflammatory component (eg. Alzheimer's disease, meningitis, multiple sclerosis), HIV and AIDS dementia.
  • skin diseases such as psoriasis, eczema, allergic dermatitis and hypersensitivity reactions
  • diseases of the central nervous system which have an inflammatory component (eg. Alzheimer's disease, meningitis, multiple sclerosis), HIV and AIDS dementia.
  • Compounds of the present invention may also be of use in the treatment of nasal polyposis, conjunctivitis or pruritis. Further examples of disease states in which compounds of the invention have potentially beneficial effects include cardiovascular conditions such as atherosclerosis, peripheral vascular disease and idiopathic hypereosinophilic syndrome. Compounds of the invention may be useful as immunosuppressive agents and so have use in the treatment of auto-immune diseases such as allograft tissue rejection after transplantation, rheumatoid arthritis and diabetes.
  • Compounds of the invention may also be useful in inhibiting metastasis.
  • a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with inflammatory conditions, eg. asthma or rhinitis.
  • a method for the treatment of a human or animal subject with an inflammatory condition eg. asthma or rhinitis, which method comprises administering an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.
  • the compounds according to the invention may be formulated for administration in any convenient way.
  • a pharmaceutical composition comprising a compound of formula (I), or a physiologically acceptable salt or solvate thereof, and optionally one or more physiologically acceptable diluents or carriers.
  • a process for preparing such a pharmaceutical formulation which comprises admixing the compound of formula (I) or a physiologically acceptable salt or solvate thereof with one or more physiologically acceptable diluents or carriers.
  • the compounds according to the invention may, for example, be formulated for oral, inhaled, intranasal, buccal, parenteral or rectal administration, preferably for oral administration.
  • Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize- starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p.- hydroxybenzoates or sorbic acid.
  • the preparations may also contain buffer salts, flavouring, colouring and/or sweeten
  • the compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multidose containers with an added preservative.
  • the compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or tonicity adjusting agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • the dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.
  • the compounds and pharmaceutical compositions according to the invention may also be used in combination with other therapeutic agents, for example antihistaminic agents, anticholinergic agents, anti-inflammatory agents such as corticosteroids, e.g. fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide; or non-steroidal anti-inflammatory drugs (NSAIDs) eg.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • beta adrenergic agents such as salmeterol, salbutamol, formoterol, fenoterol or terbutaline and salts thereof; or antiinfective agents e.g. antibiotic agents and antiviral agents.
  • Compounds of the invention may conveniently be administered in amounts of, for example, 0.001 to 500mg/kg body weight, preferably 0.01 to 500mg/kg body weight, more preferably 0.01 to 10Omg/kg body weight, and at any appropriate frequency e.g. 1 to 4 times daily.
  • the precise dosing regimen will of course depend on factors such as the therapeutic indication, the age and condition of the patient, and the particular route of administration chosen.
  • This system used a 3 ⁇ m ABZ+PLUS (3.3cm x 4.6mm internal diameter) column, eluting with solvents: (A) - 0.1% v/v formic acid + 0.077% w/v ammonium acetate in water; and (B) - 95:5 acetonitrile:water + 0.05% v/v formic acid, at a flow rate of 3 ml per minute.
  • the following gradient protocol was used: 100% (A) for 0.7mins; (A)+(B) mixtures, gradient profile 0 - 100% (B) over 3.5mins; hold at 100% (B) for 1.1 mins; return to 100% (A) over 0.2mins.
  • Example 12 The starting material for Example 12 may be prepared according to Descriptions 1 -3 below. Description 1
  • the starting material for Example 26 may be prepared according to Descriptions 4-7 below.
  • Description 6 The compound of Description 5 (0.72g) was dissolved in dichloromethane (15ml) and the resulting solution was treated with 1 -[(3,4- dichlorophenyl)methyl]piperazine [CAS 55513-17-2] (0.39g), sodium triacetoxyborohydride (0.68g) and glacial acetic acid (0.23ml). The resulting suspension was stirred at room temperature for 2 days. The mixture was diluted with dichloromethane (30ml) and washed with saturated sodium bicarbonate solution (2x20ml). The aqueous layer was extracted with dichloromethane (20ml) and the combined organics were washed with brine (20ml), dried (MgSO 4 ) and concentrated in vacuo.
  • the starting material for Example 17 may be prepared according to Descriptions 8-10 below.
  • Example 18 The starting material for Example 18 may be prepared according to Descriptions 10 11 -13 below.
  • Description 13 5 A solution of the compound of Description 12 (0.6g) in tetrahydrofuran (10ml) was treated with a 1.0M solution of borane/THF complex in THF (15ml) and the resulting mixture was heated at reflux for 18h. The cooled mixture was quenched by addition of methanol (50ml). The resultant solution was stirred for 18h at room temperature then concentrated in vacuo to give the title compound (0.48g) as a 0 colourless oil.
  • LC-MS (System A): Rt 0.92min.
  • the starting material for Example 19 may be prepared according to Descriptions 15 14 to 16 below.
  • the starting material for Example 21 may be made according to Descriptions 17- 25 22 below.
  • the starting material for Example 22 may be prepared according to Descriptions 23-26 below.
  • the starting material for Example 27 may be prepared according to Descriptions 27-30 below.
  • Example 28 The starting material for Example 28 may be prepared according to Descriptions 31 -34 below.
  • Description 33 A solution of the compound of Description 32 (1.2g) in tetrahydrofuran (20ml) was treated with a 1.OM solution of borane/THF complex in THF (12.2ml) and the resulting mixture was heated at 65°C for 12 hours. The cooled mixture was quenched with methanol (10ml). 2M hydrochloric acid (20ml) was added and the mixture was stirred for 1 hour then neutralised with solid sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, dried (MgSO ) and concentrated in vacuo.
  • Description 36 A mixture of the compound of Description 35 (1.07g) and O-(7-azabenzotriazol- 1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ("HATU", 1.07g) in anhydrous dimethylformamide (10ml) was left standing at room temperature for 5min. The resulting solution was then treated with 1 -[(3,4-dichlorophenyl)methyl] piperazine [CAS 55513-17-2] (0.9g) and diisopropylethylamine (1.72ml). The resulting mixture was left standing at room temperature for 3 days. The solvent was removed in vacuo.
  • HATU O-(7-azabenzotriazol- 1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the starting material for Example 31 may be prepared according to Descriptions 39-41 below.
  • the starting material for Example 32 may be prepared according to Description 42 below.
  • N- ⁇ -Fmoc-N-im-trityl-D-histidine [CAS 135610-90-1] was converted, in four steps using Synthetic Method B, into the [imidazole N-(triphenylmethyl)] protected analogue of Example 62.
  • This intermediate (0.095g) was treated with a mixture of trifluoroacetic acid (1 ml) and dichloromethane (0.5ml). The mixture was left to stand overnight then concentrated in vacuo. The residue was partitioned between dichloromethane (5ml) and saturated aqueous sodium bicarbonate (5ml). The organic phase was washed with brine (5ml), dried (MgSO ) and concentrated in vacuo. Autoprep. HPLC purification gave the title compound
  • Example 63 The starting material for Example 63 may be prepared according to Descriptions 43-45 below.
  • Equal ica 1ml) portions of a mixture of the compound of Description 47 (0.28g) and diisopropylethylamine (0.2ml) in dichloromethane(9ml) were dispensed into 9 scintillation vials and each was treated with the appropriate amine 1 , followed by a solution of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ["HATU", 1 ml from a stock solution of 0.24g in dimethylformamide (9ml)].
  • the starting material for Example 65 may be prepared according to Descriptions 46-47 below.
  • Synthetic Method V incorporates examples of a variety of methods that were used to interconvert compounds of formula (I), by chemical modification of R 3 [process (g)].
  • Example 58 prepared from fmoc-D-glu(OtBu)-OH [CAS 104091 - 08-9] using Synthetic Methods C and R) (0.050g) in acetonitrile, followed immediately by the addition of O-(7-azabenzotriazol-1-yl)-N,N,N 1 ,N 1 - tetramethyluronium hexafluorophosphate ("HATU", 0.050g). The reaction mixture was stirred for 2.5h then left to stand overnight. The solvent was removed in vacuo.
  • Example 25 prepared from (4-hydroxybutyl)glycine [CAS 305-77-1] using Synthetic Method F) (0.038g), triphenylphosphine (0.028g) and glacial acetic acid (0.007g) in tetrahydrofuran (2ml) was stirred for 2min. Diisopropylazodicarboxylate (0.020g) was added and the reaction mixture was stirred for 4h. More glacial acetic acid (0.01 Og) was added and stirring was continued for 3h. The reaction mixture was left to stand overnight then concentrated in vacuo.
  • Example 57 prepared from fmoc-D-lys(boc)-OH [CAS 92122-45-7] using Synthetic Methods C and R ) (0.05g) in dichloromethane (5ml) was treated with methanesulphonyl chloride (0.008ml) and triethylamine (0.014ml) and the resulting solution was stirred at room temperature for 5h.
  • Example 108 A solution of the compound of Description 48 (0.027g), glacial acetic acid (0.015g) and N-methyl glycine tert-butyl ester [CAS 5616-81-9] (0.020g) in dichloromethane (3.7ml) was stirred for 10min. Sodium triacetoxyborohydride (60mg) was added and stirring was continued for 1.5h. The reaction mixture was left to stand overnight. Sodium bicarbonate (1.0M, 5ml) was added, with stirring. After stirring for 5 min the mixture was partitioned between water (5ml) and dichloromethane (10ml). The aqueous phase was separated and extracted with dichloromethane (10ml).
  • Example 108 The starting material for Example 108 may be prepared according to Description 48 below.
  • Example 57 prepared from fmoc-D-lys(boc)-OH [CAS 92122-45-7] using Synthetic Methods C and R) (0.037g) in dichloromethane (2ml) was treated with 4-nitrophenyl chloroformate (0.032g) and triethylamine (0.026ml). After 1h, 2.0M methylamine in THF (0.2ml) was added and the reaction mixture was left overnight. The reaction mixture was partitioned between dichloromethane (30ml) and saturated sodium bicarbonate (30ml). The organic phase was separated and washed further with saturated sodium bicarbonate (6 x 30ml), dried (MgSO 4 ) and concentrated in vacuo.
  • Example 57 prepared from fmoc-D-lys(boc)-OH [CAS 92122-45-7] using Synthetic Methods C and R ) (0.021 g) in propan-2-ol (2ml) was treated with 2-chlorobenzoxazole [CAS 102-47-6] (0.006ml) and diisopropylethylamine (0.008ml) and the resulting solution was heated under reflux for 18h. The solution was concentrated in vacuo.
  • Example 111 The starting material for Example 111 may be prepared according to Descriptions 49-53 below.
  • Example 129 The starting materials for Example 129 may be prepared according to Descriptions 54-56 below.
  • Example 133 The starting material for Example 133 may be prepared according to Descriptions 57-63 below.
  • Example 134 The starting material for Example 134 may be prepared according to Descriptions 64-68 below.

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Abstract

La présente invention concerne des composés représentés par la formule générale (I), ou certains de leurs sels et solvats. Dans cette formule, les groupes R1 à R6, X, et Y sont tels que définis dans la description. Antagonistes des CCR-3, ces composés trouvent des utilisations thérapeutiques.
PCT/GB2003/000583 2002-02-12 2003-02-10 Anti-inflammatoires a base de derives piperazine WO2003068759A1 (fr)

Priority Applications (3)

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JP2003567889A JP2005528342A (ja) 2002-02-12 2003-02-10 抗炎症剤としてのピペラジン誘導体
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WO2004089922A2 (fr) * 1998-06-30 2004-10-21 Neuromed Technologies, Inc. Inhibiteurs des canaux calciques comprenant du benzhydryle espace de la piperazine
WO2005040129A2 (fr) * 2003-10-24 2005-05-06 F. Hoffmann-La Roche Ag Antagonistes du recepteur ccr3
US6943168B2 (en) 1998-06-30 2005-09-13 Neuromed Technologies Inc. Calcium channel inhibitors comprising benzhydril spaced from piperazine
US6949554B2 (en) 1998-06-30 2005-09-27 Neuromed Technologies Inc. Calcium channel blockers comprising two benzhydril moieties
US7186726B2 (en) 1998-06-30 2007-03-06 Neuromed Pharmaceuticals Ltd. Preferentially substituted calcium channel blockers
WO2008123582A1 (fr) 2007-04-04 2008-10-16 Kowa Company, Ltd. Composé de tétrahydroisoquinoline
CN108912116A (zh) * 2018-08-15 2018-11-30 翟学旭 一种含氮杂环类衍生物及其在视网膜疾病中的应用

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Publication number Priority date Publication date Assignee Title
US7064128B2 (en) 1998-06-30 2006-06-20 Neuromed Technologies, Inc. Preferentially substituted calcium channel blockers
WO2004089922A3 (fr) * 1998-06-30 2005-03-24 Neuromed Tech Inc Inhibiteurs des canaux calciques comprenant du benzhydryle espace de la piperazine
US7186726B2 (en) 1998-06-30 2007-03-06 Neuromed Pharmaceuticals Ltd. Preferentially substituted calcium channel blockers
WO2004089922A2 (fr) * 1998-06-30 2004-10-21 Neuromed Technologies, Inc. Inhibiteurs des canaux calciques comprenant du benzhydryle espace de la piperazine
US6943168B2 (en) 1998-06-30 2005-09-13 Neuromed Technologies Inc. Calcium channel inhibitors comprising benzhydril spaced from piperazine
US6949554B2 (en) 1998-06-30 2005-09-27 Neuromed Technologies Inc. Calcium channel blockers comprising two benzhydril moieties
US6951862B2 (en) 1998-06-30 2005-10-04 Neuromed Technologies, Inc. Calcium channel blockers comprising two benzhydril moieties
WO2005040129A3 (fr) * 2003-10-24 2005-06-23 Hoffmann La Roche Antagonistes du recepteur ccr3
WO2005040129A2 (fr) * 2003-10-24 2005-05-06 F. Hoffmann-La Roche Ag Antagonistes du recepteur ccr3
JP2007509095A (ja) * 2003-10-24 2007-04-12 エフ．ホフマン−ラ　ロシュ　アーゲー Ｃｃｒ３受容体アンタゴニスト
WO2008123582A1 (fr) 2007-04-04 2008-10-16 Kowa Company, Ltd. Composé de tétrahydroisoquinoline
US8273766B2 (en) 2007-04-04 2012-09-25 Kowa Company, Ltd. Tetrahydroisoquinoline compound
CN108912116A (zh) * 2018-08-15 2018-11-30 翟学旭 一种含氮杂环类衍生物及其在视网膜疾病中的应用

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