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WO1999054321A1 - Diamines substituees et leur utilisation en tant qu'inhibiteurs d'adhesion cellulaire - Google Patents

Diamines substituees et leur utilisation en tant qu'inhibiteurs d'adhesion cellulaire Download PDF

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Publication number
WO1999054321A1
WO1999054321A1 PCT/GB1999/001230 GB9901230W WO9954321A1 WO 1999054321 A1 WO1999054321 A1 WO 1999054321A1 GB 9901230 W GB9901230 W GB 9901230W WO 9954321 A1 WO9954321 A1 WO 9954321A1
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WIPO (PCT)
Prior art keywords
compound
ureido
methoxy
phenyl
acid
Prior art date
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PCT/GB1999/001230
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English (en)
Inventor
Clive Mccarthy
Neil Victor Harris
Andrew David Morley
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Aventis Pharma Limited
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Publication date
Priority claimed from GBGB9808431.2A external-priority patent/GB9808431D0/en
Priority claimed from GBGB9811417.6A external-priority patent/GB9811417D0/en
Application filed by Aventis Pharma Limited filed Critical Aventis Pharma Limited
Priority to AU37164/99A priority Critical patent/AU3716499A/en
Publication of WO1999054321A1 publication Critical patent/WO1999054321A1/fr

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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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    • 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
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    • C07D211/36—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07C2601/14—The ring being saturated

Definitions

  • This invention is directed to substituted diamines, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states capable of being modulated by the inhibition of cell adhesion.
  • Cell adhesion is a process by which cells associate with each other, migrate towards a specific target or localise within the extra-cellular matrix.
  • Many of the cell-cell and cell-extracellular matrix interactions are mediated by protein ligands (e.g. fibronectin, VCAM-1 and vitronectin) and their integrin receptors [e.g. ⁇ l (VLA-5), o4 ⁇ l (VLA-4) and ⁇ V ⁇ 3], Recent studies have shown these interactions to play an important part in many physiological (e.g. embryonic development and wound healing) and pathological conditions (e.g. tumour-cell invasion and metastasis, inflammation, atherosclerosis and autoimmune disease).
  • protein ligands e.g. fibronectin, VCAM-1 and vitronectin
  • integrin receptors e.g. ⁇ l (VLA-5), o4 ⁇ l (VLA-4) and ⁇ V ⁇ 3
  • proteins serve as ligands for integrin receptors.
  • the proteins recognised by integrins fall into one of three classes: extracellular matrix proteins, plasma proteins and cell surface proteins.
  • Extracellular matrix proteins such as collagen fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to a number of integrins.
  • Many of the adhesive proteins also circulate in plasma and bind to activated blood cells. Additional components in plasma that are ligands for integrins include fibrinogen and factor X.
  • Ig-like cell adhesion molecule Ig-like cell adhesion molecule
  • VCAM-1 vascular cell adhesion molecule
  • Integrins are heterodimeric cell surface receptors consisting of two subunits called ⁇ and ⁇ . There are at least fifteen different ⁇ -subunits ( ⁇ l- ⁇ 9, ⁇ -L, -M, ⁇ -X, ⁇ -IIb, cc-V and oc-E) and at least seven different ⁇ ( ⁇ l- ⁇ 7) subunits.
  • the integrin family can be subdivided into classes based on the ⁇ subunits, which can be associated with one or more ⁇ -subunits. The most widely distributed integrins belong to the ⁇ l class, also known as the very late antigens (VLA).
  • the second class of integrins are leukocyte specific receptors and consist of one of three ⁇ -subunits ( ⁇ -L, ⁇ -M or ⁇ -X) complexed with the ⁇ 2 protein.
  • the present invention principally relates to agents which modulate the interaction of the ligand VCAM-1 with its integrin receptor ⁇ 4 ⁇ l (VLA-4), which is expressed on numerous hematopoietic cells and established cell lines, including hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, thymocytes and eosinophils.
  • VLA-4 integrin receptor ⁇ 4 ⁇ l
  • the integrin ⁇ 4 ⁇ l mediates both cell-cell and cell-matrix interactions.
  • Cells expressing ⁇ 4 ⁇ l bind to the carboxy-terminal cell binding domain (CS-1) of the extracellular matrix protein fibronectin, to the cytokine-inducible endothelial cell surface protein VCAM-1, and to each other to promote homotypic aggregation.
  • CS-1 carboxy-terminal cell binding domain
  • VCAM-1 cytokine-inducible endothelial cell surface protein
  • the expression of VCAM-1 by endothelial cells is upregulated by proinflammatory cytokines such as INF- ⁇ , TNF- ⁇ , IL-l ⁇ and IL-4.
  • ⁇ 4 ⁇ l mediated cell adhesion is important in numerous physiological processes, including T-cell proliferation, B-cell localisation to germinal centres, and adhesion of activated T-cells and eosinophils to endothelial cells.
  • Evidence for the involvement of VLA-4 VCAM-1 interaction in various disease processes such as melanoma cell division in metastasis, T-cell infiltration of synovia] membranes in rheumatoid arthritis, autoimmune diabetes, collitis and leukocyte penetration of the blood-brain barrier in experimental autoimmune encephalomyelitis, atherosclerosis, peripheral vascular disease, cardiovascular disease and multiple sclerosis, has been accumulated by investigating the role of the peptide CS-1 (the variable region of fibronectin to which ⁇ 4 ⁇ l binds via the sequence Leu-Asp-Val) and antibodies specific for VLA-4 or
  • VCAM-1 in various in vitro and in vivo experimental models of inflammation.
  • CS-1 in a Streptococcal cell wall-induced experimental model of arthritis in rats, intravenous administration of CS-1 at the initiation of arthritis suppresses both acute and chronic inflammation (S.M.Wahl et al., J.Clin.Invest., 1994, 94, pages 655-662).
  • oxazalone- sensitised model of inflammation contact hypersensitivity response
  • mice intravenous administration of anti- ⁇ 4 specific monoclonal antibodies significantly inhibited (50-60% reduction in the ear swelling response) the efferent response (P.L.Chisholm et al. J. Immunol., 1993, 23, pages 682-688).
  • the present invention is directed to compounds of general formula (I):
  • R! represents a group selected from :
  • R ⁇ represents hydrogen or lower alkyl
  • R ⁇ is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, .heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl;
  • R" is an alkylene chain
  • R' is an alkylene chain, an alkenylene chain, or an alkynylene chain
  • R° is an acidic functional group (or corresponding protected derivative), aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocycloalkyl, -ZR 9 or -NY* ⁇ 2.
  • R" is alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
  • R1" is a hydrogen atom or a lower alkyl group; R is hydrogen or R 9 ;
  • Ar is phenylene or heteroaryldiyl
  • Ar 2 is phenylene, cycloalkylene, heterocycloalkylene or heteroaryldiyl
  • L 1 represents C2-6 a lkylene or - (CH) — A — (CH) - ; or
  • R the group -N(R 2 )-Ll- represents N (CH) - ;
  • the group -N(R 2 )-Ll-N(R 3 )- represents — N ;
  • L 2 represents an alkylene, alkenylene, alkynylene, cycloalkenylene, cycloalkylene or heterocycloalkylene linkage, each optionally substituted by alkyl, alkenyl, alkynyl, aryl, carboxy (or an acid bioisostere), cyano, cycloalkenyl, cycloalkyl, heteroaryl, heterocycloalkyl, oxo,
  • L" is a direct bond, an alkenylene or alkynylene chain, or a -Z-, -SO-, -SO2-, -NR*"- linkage;
  • Y 3 and Y 4 are independently hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl;
  • Z represents an oxygen or sulphur atom; b is zero or when w is at least 1 then b may also represent 1; m is zero or 1; n is an integer 2 to 4; p is zero or an integer 1 to 3; q is zero or an integer 1 to 4; r is an integer 2 to 5; and q+r is 2 to 7; s is an integer 1 to 3; t is an integer 2 or 3; and s+t is 3 or 5; v is 0, 1 or 2; w is zero or an integer 1 to 3; x is an integer 1 to 3; and b+w+x is 1 to 5; y is zero or an integer 1 to 3; and their prodrugs, and pharmaceutically acceptable salts and solvates (e.g.
  • Patient includes both human and other mammals.
  • Acid bioisostere means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986,21,p283 "Bioisosterism In Drug Design”; Yun, Hwahak Sekye, 1993,33,p576-579 "Application Of Bioisosterism To New Drug Design”; Zhao, Huaxue Tongbao, 1995,p34-38 "Bioisosteric Replacement And Development Of Lead Compounds In Drug Design”; Graham, Theochem, 1995,343,p 105-109 "Theoretical Studies Applied To Drug Design:ab initio Electronic Distributions In Bioisosteres”).
  • Acidic functional group means a group with an acidic hydrogen within it.
  • the “corresponding protected derivatives” are those where the acidic hydrogen atom has been replaced with a suitable protecting group.
  • suitable protecting groups see T.W. Green and P.G.M.Wuts in "Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.
  • Exemplary acidic functional groups include carboxyl (and acid bioisosteres), hydroxy, mercapto and imidazole.
  • Exemplary protected derivatives include esters of carboxy groups, ethers of hydroxy groups, thioethers of mercapto groups and N-benzyl derivatives of imidazoles.
  • “Acyl” means an H-CO- or alkyl-CO- group in which the alkyl group is as described herein.
  • acylamino is an acyl-NH- group wherein acyl is as defined herein.
  • Alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear chain; here a linear alkenyl chain.
  • “Lower alkenyl” means about 2 to about 4 carbon atoms in the chain which may be straight or branched.
  • alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.
  • alkenylene means an aliphatic bivalent radical derived from a straight or branched C2-6alkenyl group.
  • alkenylene radicals include vinylene and propylene.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as described herein.
  • exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
  • Alkoxy carbonyl means an alkyl-O-CO- group in which the alkyl group is as described herein.
  • exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
  • Alkyl means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain optionally substituted by one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms.
  • “Lower alkyl” as a group or part of a lower alkoxy group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 4 carbon atoms in the chain.
  • Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.
  • Alkylene means an aliphatic bivalent radical derived from a straight or branched C j .galkyl group.
  • exemplary alkylene radicals include ethylene, ethylene and trimethylene.
  • Alkylenedioxy means an -O-alkyl-O- group in which the alkyl group is as defined above.
  • Exemplary alkylenedioxy groups include methylenedioxy and ethylenedioxy.
  • Alkylsulphinyl means an alkyl-SO- group in which the alkyl group is as previously described.
  • Preferred alkylsulphinyl groups are those in which the alkyl group is Cj ⁇ alkyl.
  • Alkylsulphonyl means an alkyl-S ⁇ 2- group in which the alkyl group is as previously described.
  • Preferred alkylsulphonyl groups are those in which the alkyl group is Cj.4a.kyl.
  • Preferred alkylsulphonylcarbamoyl groups are those in which the alkyl group is C _4alkyl.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • exemplary alkylthio groups include methylthio, ethylthio, isopropylthio and heptylthio.
  • Alkynyl means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl.
  • Alkynylene means an aliphatic bivalent radical derived from a C2.6 ⁇ alkynyl group.
  • alkenylene radicals include ethynylene and propynylene.
  • Aroyl means an aryl-CO- group in which the aryl group is as described herein.
  • Exemplary aroyl groups include benzoyl and 1- and 2-naphthoyl.
  • Aroylamino is an aroyl-NH- group wherein aroyl is as previously defined.
  • Aryl as a group or part of a group denotes: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted partially saturated multicyclic aromatic carbocyclic moiety in which an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring.
  • Aryl groups may be substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent" includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulphinyl, alkylsulphonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsuiphinyi, arylsulphonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, Y 6 Y 7 N-, Y 6 Y 7 NCO-, Y 6 Y 7 NS0 2
  • Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyl moieties are as previously described.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a Cj.4a.kyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
  • Arylalkyloxy means an arylalkyl-O- group in which the arylalkyl groups is as previously described.
  • exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthaIenemethoxy.
  • Arylalkyloxycarbonyl means an arylalkyl-O-CO- group in which the arylalkyl groups is as previously described.
  • An exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.
  • Arylalkylthio means an arylalkyl-S- group in which the arylalkyl group is as previously described.
  • An exemplary arylalkylthio group is benzylthio.
  • Arylalkynyl means an aryl-alkynyl- group in which the aryl and alkynyl moieties are as previously described.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • Exemplary aryloxy groups include optionally substituted phenoxy and naphthoxy.
  • Aryloxycarbonyl means an aryl-O-CO- group in which the aryl group is as previously described.
  • exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
  • Arylsulphinyl means an aryl-SO- group in which the aryl group is as previously described.
  • Arylsulphonyl means an aryl-SO2- group in which the aryl group is as previously described.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • exemplary arylthio groups include phenylthio and naphthylthio.
  • Azaheteroaryl means an aromatic carbocyclic moiety of about 5 to about 10 ring members in which one of the ring members is nitrogen and the other ring members are chosen from carbon, oxygen, sulphur, or nitrogen.
  • Examples of azaheteroaryl groups include pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl, and benzimidazolyl.
  • Cycloalkenylene means a bivalent radical derived from an unsaturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring.
  • exemplary cycloalkenylene radicals include cyclopentenylene and cyclohexenylene.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • Cycloalkenylalkyl means a cycloalkenyl-alkyl- group in which the cycloalkenyl and alkyl moieties are as previously described.
  • Cycloalkylalkenyl means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as previously described. -1
  • Cycloalkyl means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms optionally substituted by oxo.
  • Exemplary monocyclic cycloalkyl rings include C3_gcycloaIkyI rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described.
  • Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • Cycloalkylalkenyl means a cycloalkyl-alkenyl- group in which the cycloalkyl and alkenyl moieties are as previously described.
  • Cycloalkylalkynyl means a cycloalkyl-alkynyl- group in which the cycloalkyl and alkynyl moieties are as previously described.
  • Cycloalkylene means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 3 to about 10 carbon atoms by removing a hydrogen atom from each of two different carbon atoms of the ring.
  • Exemplary cycloalkylene radicals include cyclopentylene and cyclohexylene.
  • Halo or halogen means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
  • Heteroaroyl means a heteroaryl-CO- group in which the heteroaryl group is as described herein.
  • exemplary groups include pyridylcarbonyl.
  • Heteroaroylamino means a heteroaroyl-NH- group in which the heteroaryl moiety are as previously described.
  • Heteroaryl as a group or part of a group denotes: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur (examples of such groups include benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups, optionally substituted by one or more aryl group substituents
  • heteroaryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure
  • substituents include one or more "aryl group substituents" as defined above. When R or R 4 contains an optionally substituted heteroaryl group this may particularly represent an optionally substituted "azaheteroaryl" group.
  • Heteroarylalkenyl means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl moieties are as previously described.
  • Heteroarylalkynyl means a heteroaryl-alkynyl- group in which the heteroaryl and alkynyl moieties are as previously described.
  • Heteroarylalkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C j _4alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
  • Heteroarylalkyloxy means an heteroarylalkyl-O- group in which the heteroarylalkyl group is as previously described.
  • exemplary heteroaryloxy groups include optionally substituted pyridylmethoxy.
  • Heteroaryldiyl means a bivalent radical derived from an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members in which one or more of the ring members is/are element(s) other than carbon, for example nitrogen, oxygen or sulphur., and optionally substituted by one or more aryl group substituents as defined above.
  • Ar* is a heteroaryldiyl radical this may particularly represent an optionally substituted pyridindiyl or an optionally substituted benzoxazoldiyl.
  • Heteroaryloxy means an heteroaryl-O- group in which the heteroaryl group is as previously described.
  • exemplary heteroaryloxy groups include optionally substituted pyridyloxy.
  • Heterocycloalkyl means: (i) a cycloalkyl group of about 3 to 7 ring members which contains one or more heteroatoms selected from O, S or NY ⁇ (where Y° is hydrogen, alkyl, arylalkyl, and - 13-
  • aryl (ii) an optionally substituted partially saturated multicyclic heterocarbocyclic moiety in which an aryl (or heteroaryl ring) and a heterocycloalkyl group are fused together to form a cyclic structure
  • examples of such groups include chromanyl, dihydrobenzofuranyl, indolinyl and pyrindolinyl groups.
  • Heterocycloalkylalkyl means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • Heterocycloalkylene means a bivalent radical derived from a saturated monocyclic hydrocarbon of about 5 to about 7 atoms, which contains one or more heteroatoms selected from
  • O, S or NY° (where Y° is hydrogen, alkyl, arylalkyl, and aryl) and is optionally substituted by oxo, by removing a hydrogen atom from each of two different carbon atoms of the ring, or when
  • NY° is NH by removing a hydrogen atom from one carbon atom of the ring and a hydrogen atom from the NH, or when the ring contains two NY° heteroatoms and NY° is NH by removing a hydrogen atom from both nitrogen atoms.
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyl groups contain Cj.4alkyl for example hydroxymethyl and 2-hydroxyethyl.
  • M ⁇ 6 ⁇ 7N-" means a substituted or unsubstituted amino group, wherein Y" and Y 7 are as previously described.
  • exemplary groups include amino (H2N-), methylamino, ethylmethylamino, dimethylamino and diethylamino.
  • YY 7 NCO- means a substituted or unsubstituted carbamoyl group, wherein Y*> and Y 7 are as previously described.
  • exemplary groups are carbamoyl (H2NCO-) and dimethylcarbamoyl
  • YY 7 NS ⁇ 2- means a substituted or unsubstituted sulphamoyl group, wherein Y ⁇ and Y 7 are as previously described.
  • exemplary groups are sulphamoyl (H2NSO2-) and dimethylsulphamoyl (Me2NS ⁇ 2-).
  • Phenylene means an optionally substituted bivalent radical derived from a phenyl group. Suitable substituents include one or more "aryl group substituents" as defined above, particularly halogen, methyl or methoxy. -14-
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula (I), including N-oxides thereof.
  • an ester of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • an ester of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of formula (I) containing a hydroxy group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesuiphonates, cyclohexylsulphamates and quinates.
  • esters of compounds of formula (I) containing a hydroxy group may be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 1989, 32 , page 2503-2507, and include substituted (aminomethyl)-benzoates, for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyI)-benzoates, and (4-alkyIpiperazin-l-yI)benzoates, e.g. 3- or 4-(4-alkylpiperazin-l-yl)benzoates.
  • substituted (aminomethyl)-benzoates for example dialkylamino-methylbenzoates in which the two alkyl groups may be joined together and/or
  • base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form.
  • the bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the cations.
  • Pharmaceutically acceptable salts including those derived from alkali and alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
  • bases sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glu
  • Some of the compounds of the present invention are basic, and such compounds are useful in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt thereof.
  • Acid addition salts are a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form.
  • the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not vitiated by side effects ascribable to the anions.
  • compositions are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures.
  • Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, e.g.
  • hydrochlorides and hydrobromides sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methane-sulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
  • R5 is arylalkyl (the aryl ring of which is optionally substituted) or heteroarylalkyl (the heteroaryl ring of which is optionally substituted).
  • Ar is optionally substituted phenylene, such as optionally substituted m- or /7-phenyIene, preferably optionally substituted p-phenylene, more preferably a 3-substituted /7-phenylene (preferred optional substituents include C _4alkyl and Cj_4alkoxy, especially methyl and methoxy), or Ar ⁇ is an optionally substituted heteroaryldiyl, such as optionally substituted pyridinediyl, preferably an optionally substituted p-pyridinediyl (preferred optional substituents include C j _4alkyl and C .4alkoxy, especially methyl and methoxy), more preferably a pyridine-2,5-diyl which is substituted in the 4- or 6-position with a methyl or methoxy group,
  • R 5 is an optionally substituted aryl group such as 2-substituted or 3-substituted phenyl, and is preferably 2- or 3-methyl(or methoxy)phenyI
  • R ⁇ is an optionally substituted heteroaryl group, such as optionally substituted pyridyl, and is preferably 3-methyl-2-pyridyI.
  • Ar ⁇ is an optionally substituted phenylene, such as optionally substituted m- or 7-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene (preferred optional substituents include Cj.4alkyl and Cj.4alkoxy, especially methyl and methoxy), or
  • Ar* is an optionally substituted heteroaryldiyl, such as optionally substituted pyridinediyl, preferably an optionally substituted p-pyridinediyl
  • R ⁇ is an optionally substituted aryl group such as 2-substituted or 3-substituted phenyl, and is preferably 2- or 3-methyl(or methoxy)phenyl, or R ⁇ is an optionally substituted heteroaryl group, such as optionally substituted pyridyl, and is preferably 3-methyl-2-pyridyl.
  • R 2 may particularly represent hydrogen.
  • R 2 may also particularly represent C j _4alkyl (e.g. methyl).
  • R 3 may particularly represent hydrogen. - 17-
  • R 3 may also particularly represent C _4alkyl (e.g. methyl).
  • R 4 may particularly represent hydrogen.
  • R 4 may also particularly represent C j .4alkyl (e.g. methyl).
  • R 4 may also particularly represent C _4alkyl substituted by aryl, especially arylmethyl or arylethyl.
  • aryl groups include phenyl optionally substituted by one or more "aryl group substituents", for example alkylphenyl, alkoxyphenyl, dialkoxyphenyl, piperonyl, halophenyl, dialkylaminophenyl, trifluoromethyl and methanesulphonylphenyl, especially dialkoxyphenyl such as 3,4-dimethoxyphenyl.
  • R 4 may also particularly represent C j _4alkyl substituted by heteroaryl, especially azaheteroaryl.
  • exemplary heteroaryl groups include optionally substituted indolyl, imidazolyl, pyridyl and furyl.
  • R 4 especially represents 3-(imidazol-l-yI)-propyl.
  • R 4 may also particularly represent C .4alkyl substituted by -NY ⁇ Y 2 .
  • Exemplary -NY ⁇ Y 2 groups include acylamino, aryl(alkylamino) and 5-7 membered cyclic amines such as morpholine, piperidine, pyrrolidine and 2-oxo-pyrrolidine.
  • R 4 especially represents 3-(2-oxo-pyrrolidin-l-yI)-propyl or 3-(N-methyl-N-phenyl-amino)propyl.
  • R 4 may also particularly represent C _4alkyl substituted by cycloalkyl.
  • exemplary cycloalkyl groups include cyclohexyl and cyclopentyl.
  • R 4 may also particularly represent Cj_4alkyl substituted by alkoxy.
  • R 4 may also particularly represent C j _4alkyl substituted by halo.
  • R 4 may also particularly represent lower alkenyl (e.g. allyl).
  • L* may particularly represent a straight chain C2-6 lkylene, especially ethylene and trimethylene.
  • L* may also particularly represent -Ar 2 -, especially where Ar 2 is cycloalkylene (particularly (cyclohexylene).
  • ⁇ may also particularly represent a -CH2-Ar 2 -CH2- linkage, especially where Ar 2 is arylene (particularly phenylene).
  • the group -Ll-N(R 3 )- may also particularly represent - (CH 2 ) N , preferably
  • the group -N(R 2 )-Ll-N(R 3 )- may also particularly represent — N , preferably
  • L 2 may particularly represent a straight or branched Cj_4alkylene linkage.
  • Exemplary C _4alkylene linkages include methylene, ethylene, trimethylene, -CH2-CH(CH3)-, -CH(CH3)-CH2- and tetramethylene.
  • Y may particularly represent carboxy.
  • Y may also particularly represent an acid bioisostere.
  • n may particularly represent zero.
  • n may also particularly represent 1.
  • a particular group of compounds of the invention are compounds of formula (Ia):-
  • R 2 , R 3 , R 4 , L*, L 2 and Y are as hereinbefore defined, RU is hydrogen, halogen, lower alkyl or lower alkoxy, R* 2 is a direct bond or an alkylene chain, X*, X 2 and X 3 independently represent N or CR ⁇ 3 (where R* 3 is hydrogen, halogen, lower alkyl or lower alkoxy), and
  • aryl groups include phenyl optionally substituted by one or more "aryl group substituents", for example alkylphenyl, alkoxyphenyl, dialkoxyphenyl, piperonyl, halophenyl, dialkylaminophenyl, trifluoromethyl and methanesulphonylphenyl, especially dialkoxyphenyl such as 3,4-dimethoxyphenyI.
  • R 4 represents alkyl substituted by heteroaryl, especially azaheteroaryl, are also preferred.
  • exemplary heteroaryl groups include optionally substituted indolyl, imidazolyl, pyridyl and furyl.
  • Compounds of formula (la) in which R 4 represents 3-(imidazoI-l-yl)-propyl are especially preferred.
  • R 4 represents C _ alkyl substituted by -NY ⁇ Y 2
  • exemplary -NY*Y 2 groups include acylamino, aryl(alkylamino) and 5-7 membered cyclic amines such as morpholine, piperidine, pyrrolidine and 2-oxo-pyrrolidine.
  • Compounds of formula (la) in which R 4 represents 3-(2-oxo-pyrrolidin-l-yl)-propyl are especially preferred.
  • R 4 represents Cj_4alkyl substituted by cycloalkyl
  • exemplary cycloalkyl groups include cyclohexyl and cyclopentyl.
  • N N preferably 1,4-piperazindiyl or 1,4-homopiperazindiyl, are also
  • Cj_4alkylene linkages include methylene, ethylene, trimethylene, -CH 2 -CH(CH 3 )-, -CH(CH 3 )-CH 2 - and tetramethylene.
  • a preferred group of compounds of the invention are compounds of formula (la) in which:- R 2 is hydrogen or C j _4alkyl (e.g. methyl) and R 3 is hydrogen or C .4a.kyl (e.g. methyl); R 4 is hydrogen, C j _4alkyl substituted by aryl (especially 4-dimethylaminophenyl-C j _2aIkyl and
  • L 1 is a straight C2.6alkylene chain (especially ethylene), cycloalkylene (especially cyclohexylene); or the
  • group -N(R 2 )-Ll-N(R 3 )- represents — N (especially 1,4-piperazindiyl or
  • L 2 is a straight or branched Cj ⁇ alkylene chain (especially -CH2-, -CH 2 CH 2 -, -CH 2 CH 2 CH2-, -CH(CH 3 )CH 2 -), or a Cj.4alkylene chain substituted by
  • R 11 is hydrogen;
  • R 12 is a bond or a straight C j .4alkylene chain (especially methylene);
  • X* represents CR* 3 (especially C-methyl);
  • X 2 represents CR* 3 (especially C-methoxy);
  • X 3 represents CH;
  • R 2 , R 3 , L*, L 2 and Y are as hereinbefore defined, R ⁇ is hydrogen, halogen, lower alkyl or lower alkoxy, R* 2 is a direct bond or an alkylene chain, X*, X 2 and X 3 independently represent N or CR 3 (where R* is hydrogen, halogen, lower alkyl or lower alkoxy), and
  • C j_4alkylene linkages include methylene, ethylene, trimethylene, -CH 2 -CH(CH 3 )-, -CH(CH 3 )-CH 2 - and tetramethylene.
  • a preferred group of compounds of the invention are compounds of formula (lb) in which:- R 2 is hydrogen; R 3 is hydrogen or Cj_4alkyl (e.g. methyl); ⁇ 7 is a straight C2-6alkylene chain
  • N -N(R 2 )-L1-N(R 3 )- represents N ⁇ N- especially 1,4-piperazindiyl or
  • L 2 is a straight or branched Cj_4alkylene chain (especially -CH2-, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 -), or a Cj.
  • Preferred compounds of the invention include: - ⁇ [(4- ⁇ [3-methoxy-4-(3-(2-methylphenyl)ureido)-phenyl]-acetyl ⁇ -homopiperazin-l-yl)-carbonyl]- [3-(2-oxo-pyrrolidin-l-yl)-propyl]-amino ⁇ -propionic acid, Compound A; 3- ⁇ [(4- ⁇ [3-methoxy-4-(3-(2-methylphenyl)ureido)-phenyI]-acetyl ⁇ -homopiperazin-l-yl)-carbonyl]- amino ⁇ -butanoic acid, Compound BJ; -50-
  • the compounds of the invention exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders.
  • the present invention thus provides, according to a further aspect, compounds of the invention and compositions containing compounds of the invention for use in therapy.
  • the present invention provides compounds of the invention and compositions containing compounds of the invention for use in the treatment of a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of ⁇ 4 ⁇ l mediated cell adhesion.
  • compounds of the present invention are useful in the treatment of inflammatory diseases, for example joint inflammation, including arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis.
  • the compounds are useful in the treatment of acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, collitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, multiple sclerosis, asthma, psoriasis restenosis, myocarditis, inflammatory bowel disease and melanoma cell division in metastasis.
  • a special embodiment of the therapeutic methods of the present invention is the treating of asthma.
  • Another special embodiment of the therapeutic methods of the present invention is the treating of joint inflammation.
  • Another special embodiment of the therapeutic methods of the present invention is the treating of inflammatory bowel disease.
  • Effective amount is meant to describe an amount of compound of the present invention effective in inhibiting the interaction of the ligand VCAM-1 to its integrin receptor VLA -4 ( ⁇ 4 ⁇ l), and thus producing the desired therapeutic effect.
  • references herein to treatment should be understood to include prophylactic therapy as well as treatment of established conditions. -52-
  • the present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of the invention in association with a pharmaceutically acceptable carrier or excipient.
  • Compounds of the invention may be administered by any suitable means.
  • compounds of the present invention may generally be administered parenterally, topically, rectally, orally or by inhalation, especially by the oral route.
  • compositions according to the invention may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients.
  • the adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents.
  • the compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and can contain one or more agents chosen from the group comprising sweeteners, flavourings, colourings, or stabilisers in order to obtain pharmaceutically acceptable preparations.
  • excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used for preparing tablets.
  • lactose and high molecular weight polyethylene glycols When aqueous suspensions are used they can contain emulsifying agents or agents which facilitate suspension.
  • Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
  • emulsions, suspensions or solutions of the products according to the invention in vegetable oil for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, are used.
  • vegetable oil for example sesame oil, groundnut oil or olive oil
  • aqueous-organic solutions such as water and propylene glycol
  • injectable organic esters such as ethyl oleate
  • sterile aqueous solutions of the pharmaceutically acceptable salts are used.
  • the solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection.
  • aqueous solutions also comprising solutions of the salts in pure distilled water, may be used for intravenous administration with the proviso that their pH is suitably adjusted, that they are judiciously buffered and rendered isotonic with a sufficient quantity of glucose or sodium chloride and that they are sterilised by heating, irradiation or microfiltration.
  • gels water or alcohol based
  • creams or ointments containing compounds of the invention may be used.
  • Compounds of the invention may also be incorporated in a gel or matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier.
  • inhalation compounds of the invention may be dissolved or suspended in a suitable carrier for use in a nebuliser or a suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for use in a dry powder inhaler.
  • Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of the invention.
  • the percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time.
  • the dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation, from about 0.01 to about 100, preferably 0.1 to 70, more especially 0.5 to 10, mg kg body weight per day by oral administration, and from about 0.001 to about 10, preferably 0.01 to 1, mg/kg body weight per day by intravenous administration. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
  • the compounds according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. Of course, for some patients, it will be necessary to prescribe not more than one or two doses per day.
  • compounds of formula (I) wherein R , R 2 , R 3 , R 4 , L*, L 2 and m are as hereinbefore defined, and Y is carboxy may be prepared by hydrolysis of esters of formula (I), wherein R , R 2 , R 3 , R 4 , L*, L 2 and m are as hereinbefore defined, and Y is -CO2R ⁇ (in which
  • R!5 is alkyl, alkenyl, aryl or arylalkyl).
  • the hydrolysis may conveniently be carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, e.g. lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate, in the presence of an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol, at a temperature from about ambient to about reflux.
  • a base such as an alkali metal hydroxide, e.g. lithium hydroxide, or an alkali metal carbonate, e.g. potassium carbonate
  • organic solvents such as dioxan, tetrahydrofuran or methanol
  • the hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of an aqueous/inert organic solvent mixture, using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50°C to about 80°C.
  • an inorganic acid such as hydrochloric acid
  • an aqueous/inert organic solvent mixture using organic solvents such as dioxan or tetrahydrofuran, at a temperature from about 50°C to about 80°C.
  • compounds of formula (I) wherein R*, R 2 , R 3 , R 4 , ⁇ 7, L 2 and m are as hereinbefore defined, and Y is carboxy
  • Y is carboxy
  • a suitable metal catalyst e.g. platinum or palladium optionally supported on an inert carrier such as carbon, preferably in a solvent such -55-
  • R5-L 4 -A ⁇ *-R 7 - and R ⁇ , R 7 , L 4 and Ar* are as hereinbefore defined] may be prepared by coupling of an acid with an amine to give an amide bond using standard peptide coupling procedures as described hereinafter.
  • Resin 3 in which R 2 , R 3 ,R 4 and L* are as defined hereinbefore.
  • R ⁇ 7 is a suitable amino protecting group (such as 9-fluorenylmethoxycarbonyl) and n is as hereinbefore defined, in the presence of 0-(7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate and diisopropylethylamine in dimethylformamide, at room temperature to give Resin 4 wherein R 7 and L 2 are as hereinbefore defined: -58-
  • Resin 4 wherein R 7 and L 2 are as hereinbefore defined, may then be deprotected, for example by treating with piperidine in dimethylformamide, at room temperature, to give Resin 5 wherein L 2 is as hereinbefore defined:
  • Resin 5 wherein L 2 is as hereinbefore defined may then be treated with an alkyl or aryl-chloroformate, such as 4-nitrophenylchloroformate, in an inert solvent, such as tetrahydrofuran or dichloromethane, or a mixture of inert solvents, followed by reaction with an amine of formula (III) wherein R 2 , R 3 and L are as hereinbefore defined, in the presence of triethylamine, in an inert solvent such as -59-
  • RI 7 is as hereinbefore defined
  • R*° is a suitable carboxylic acid protecting group, such as tertiary butyl
  • L 7 represents an alkylene linkage, to give resin 8 wherein R 7 , R*8 and L 7 are as hereinbefore defined:
  • Resin 8 wherein R 7 , R and L 7 are as hereinbefore defined, may then be deprotected, for example by treating with piperidine in dimethylformamide, at room temperature, to give Resin 9 wherein R ⁇ and L 7 are as hereinbefore defined: -61-
  • Resin 9 wherein R ⁇ and L 7 are as hereinbefore defined, may then be treated with an alkyl or aryl-chloroformate, followed by reaction with an amine of formula (III) wherein R 2 , R 3 and L* are as hereinbefore defined, as described hereinabove, to give resin 10 wherein R 2 , R 3 , R 8, L and L are as hereinbefore defined.
  • compounds of the invention may be prepared by interconversion of other compounds of the invention.
  • a carbodiimide for example dicyclohexylcarbodiimide
  • an inert solvent such as dichloromethane or tetrahydrofuran
  • the coupling may also be carried out using l-hydroxybenzotriazole and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide in dichloromethane at room temperature.
  • the preparation may also be carried out using an O-protected hydroxylamine such as 0-(trimethylsilyl)hydroxylamine,
  • compounds of formula (I) containing sulphoxide linkages may be prepared by the oxidation of corresponding compounds containing -S- linkages.
  • the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature, or alternatively by means of potassium hydrogen peroxomonosulphate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0°C and room temperature.
  • a peroxyacid e.g. 3-chloroperbenzoic acid
  • an inert solvent e.g. dichloromethane
  • potassium hydrogen peroxomonosulphate in a medium such as aqueous methanol, buffered to about pH5, at temperatures between about 0°C and room temperature.
  • This latter method is preferred for compounds containing an acid-labile group.
  • compounds of formula (I) containing sulphone linkages may be prepared by the oxidation of corresponding compounds containing -S- or sulphoxide linkages.
  • the oxidation may conveniently be carried out by means of reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferably in an inert solvent, e.g. dichloromethane, preferably at or near room temperature.
  • a peroxyacid e.g. 3-chloroperbenzoic acid
  • an inert solvent e.g. dichloromethane
  • compounds of the present invention may contain asymmetric centres. These asymmetric centres may independently be in either the R or S configuration. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometrical isomerism. It is to be understood that the present invention includes individual geometrical isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) hereinabove. Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallisation techniques, or they are separately prepared from the appropriate isomers of their intermediates.
  • acid addition salts of the compounds of this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods.
  • the acid addition salts of the compounds of this invention may be prepared either by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • the acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods.
  • parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • parent compounds of the invention can be regenerated from their base addition salts by the application or adaptation of known methods.
  • parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, e.g. hydrochloric acid.
  • Hydrates of compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallisation from an aqueous/organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol.
  • base addition salts of the compounds of this invention may be prepared by reaction of the free acid with the appropriate base, by the application or adaptation of known methods.
  • the base addition salts of the compounds of this invention may be prepared either by dissolving the free acid in water or -69-
  • aqueous alcohol solution or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and base in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • the starting materials and intermediates may be prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
  • Esters of formula (I), wherein R 1 , R 2 , R 3 , R 4 , L 1 and L 2 are as hereinbefore defined, Y is a -CO2R ⁇ group (in which R ⁇ is as hereinbefore defined) and m is 1 may be prepared by standard reactions, such as acylation, aikylation or sulphonylation, from compounds of formula
  • esters of formula (I) where R* represents R ⁇ -L 3 - (in which R5 is as hereinbefore defined and L 3 is a direct bond) may be prepared using R ⁇ -X 4 (in which R ⁇ is as hereinbefore defined and X 4 is a halogen atom) as the alkylating agent.
  • esters of formula (I) where R* represents R ⁇ -L 3 - (in which R ⁇ is as hereinbefore defined and L 3 is a -SO2- linkage) may be prepared using R ⁇ -SO2Cl (in which R ⁇ is as hereinbefore defined) as the sulphonylating agent.
  • Esters of formula (I), wherein R R 2 , R 3 , L* and L 2 are as hereinbefore defined, Y is a -CO2R group (in which R ⁇ is as hereinbefore defined ) and m is zero, may be prepared by reaction of compounds of formula (3):-
  • R $ and L 2 are as hereinbefore defined and X ⁇ is a leaving group such as an alkyl or aryl sulphonate (for example methanesulphonate or 4-methylphenylsulphonate), or a halogen atom.
  • X ⁇ is a leaving group such as an alkyl or aryl sulphonate (for example methanesulphonate or 4-methylphenylsulphonate), or a halogen atom.
  • Compounds of formula (3) wherein R*, R 2 , R 3 and i - are as hereinbefore defined, may be prepared by standard reactions, such as acylation, peptide coupling, reductive animation, alkylation and sulphonylation, from diamines of formula (III), wherein R 2 , R 3 and ⁇ 7 are as defined hereinbefore.
  • Rl is as hereinbefore defined and X" is bromo or chloro, as the acylating agent.
  • R5, L", L 4 and Ar* are as hereinbefore defined and R" is for example methylene
  • R" is for example methylene
  • Rl-X 4 in which R* contains a -R"- linkage and X 4 is a halogen atom
  • R* represents R 5 -L 3 -, R 5 -L -R 7 -L 5 -, R 5 -L 4 -Ar*-L 3 - or R 5 -L -Ar!-R 7 -L 5 -
  • R 5 , R 7 , L 4 and Ar* are as hereinbefore defined and L 3 or L ⁇ is a -SO2- linkage
  • R 5 -SO 2 CI R 5 -L 4 -R 7 -SO 2 Cl, R 5 -L 4 -Ar 1 -SO 2 Cl or RS-L ⁇ Ar ⁇ -R 7 - SO 2 Cl respectively as the sulphonylating agent.
  • Esters of formula (I), wherein R*, R 2 , R 3 , R 4 , L* and L 2 are as hereinbefore defined, Y is a -CO2R group and m is zero, may also be prepared by standard acylation, peptide coupling, reductive animation, alkylation and sulphonylation reactions, from compounds of formula (6):-
  • esters of formula (I) where R* contains a -R *- linkage may be prepared using R ⁇ -X 4 (in which R* contains a -R"- linkage and X 4 is a halogen atom) as the alkylating agent.
  • esters of formula (I), where R* represents R ⁇ -L 3 -, R ⁇ -L 4 -R 7 -L ⁇ -, R ⁇ -L 4 -Arl-L 3 - or R -L 4 -Arl-R 7 -L5- may be prepared using R 5 -SO 2 Cl, R 5 -L 4 -R 7 -S0 2 C1, R 5 -L 4 -Ar 1 -SO 2 CI or R ⁇ -L 4 -Ar ⁇ -R 7 -SO2Cl respectively as the sulphonylating agent.
  • the present invention is further Exemplified but not limited by the following illustrative Examples and Reference Examples.
  • Mass spectra were recorded using total loop electrospray technique[MS(ES)]. Mass spectra [MS(ES)] for compounds A to DB were determined using a Micromass Platform II mass spectrometer fitted with an Electrospray source and an HPllOO liquid chromatograph (5 micron Hypersil Elite C18 HPLC column operated under gradient elution conditions with a mixture of acetonitrile and water plus 0.1 % trifluoroacetic acid as the mobile phase [0-3 minutes 20% acetonitrile; 3-15 minutes ramp up to 80% acetonitrile; 15 minutes to end of run 80% acetonitrile, flow rate 0.3ml/minute and using evaporative light scattering (ELS) for detection].
  • ELS evaporative light scattering
  • Mass spectra [MS(ES)] for Compounds KT to LQ were determined using a Finnigan TSQ700 mass spectrometer, Hypersil Elite C18 5micron column (4.6mm i.d. x 150mm) operated under gradient elution conditions (0-2 minutes 95:5, A:B then 2-12min 95:5 to 5:95% A:B, solvent A is a mixture of water 0.1%trifluoroacetic acid and solvent B is a mixture of acetonitrile and 0.1% trifluoroacetic acid ) and using UV detection at 220nm.
  • Mass spectra [MS(ES)] for Compounds DC to EZ, FA to JH, LG and MH to NJ were determined using inline ELS and Diode Array detection, a Phenomenex Luna 3 ⁇ C18 (2) 30x4.6mm column and gradient elution with a flow rate of 2ml/minute and mixtures of (A) 0.1 % trifluoroacetic acid in water and (B) 0.1% trifluoroacetic acid in acetonitrile, v/v (0 minutes, 95:5, A:B; 0.5 minutes, 95;5, A:B; 4.5 minutes, 5:95, A:B; 5.0 minutes, 95:5, A:B; 5.5 minutes, 95:5).
  • Mass spectra [MS(ES)] for Compounds LJ, LK and LL were determined using by ESI-LC-MS using gradient elution conditions: 0.00 minutes, 9:1, A:B; 9.50 minutes 5:95. A:B; 14.5 minutes 5:95, A:B; 19.5 minutes 9:1, A:B; 21.5 minutes 9:1, A:B (where A is 0.01% ammonium acetate and water and B is 0.01% ammonium acetate and methanol).
  • HPLC High Pressure Liquid Chromatography
  • Step 1 A suspension of Wang resin (15g , Advanced ChemTech) in dichloromethane (200ml) was treated with diisopropylethylamine (9ml) then with acryloyl chloride (4.5ml). The mixture was kept at ambient temperature for 3 hours with occasional agitation. The resin was filtered and then washed three times with 50ml portions each of dichloromethane, tetrahydrofuran, dimethylformamide, tetrahydrofuran and dichloromethane, and then dried under vacuum.
  • Step 2 The acrylate-loaded Wang resin from Step 1 (l.Og, 0.83mmol/g loading) was swelled with dimethylformamide (15ml) and then treated with l-(3-aminopropyl)-2-pyrrolidinone (1.2ml). The mixture was shaken gently for 18 hours. The resin was drained and then washed three times with dimethylformamide, three times with tetrahydrofuran three times with dichloromethane then sucked dry.
  • Step 3 The resin from Step 2 was swelled in dichloromethane (20ml), then treated with diisopropylethylamine (1.44ml) and treated with triphosgene (0.74g). There was a slight exotherm and some evolution of gas. The mixture was gently agitated for 2 hours, then washed four times with dichloromethane and then sucked dry. A solution of homopiperazine (0.83g) and pyridine (0.67ml) in dichloromethane (15ml) was added to the resin and the mixture was gently agitated for 2 hours. The resin was then drained, washed thoroughly with five portions of dichloromethane and then dried under vacuum.
  • Step 4 The resin from Step 3 was treated with a solution of 3-methoxy-4-[3-(2- methylphenyl)ureido]phenylacetic acid (0.52g, prepared as described in Example 52B of
  • 1,1,3,3-tetramethyIuronium hexafluorophosphate (0.63g) and diisopropylethylamine (0.87ml) in dimethylformamide (20ml). After standing at room temperature for 18 hours the mixture was drained and the resin was washed three times with dimethylformamide, then three times with tetrahydrofuran, then three times with dichloromethane and then dried under vacuum.
  • Step 5 The resin from Step 4 was treated with a mixture of trifluoroacetic acid and dichloromethane (15ml , 1:1, v/v). After 1 hour, the resin was drained and then washed twice with a mixture of trifluoracetic acid and dichloromethane (5ml, 1:1, v/v). The combined filtrate and washings was evaporated to dryness.
  • Step 2 The resin from Step 1 (900mg, 0.79mmol/g loading) was placed in a flask and treated with 20% piperidine in dimethylformamide (20ml). The mixture was shaken for 2 minutes and drained. This process was repeated twice and then the resin was washed three times with 20ml portions of dimethylformamide, tetrahydrofuran and then a mixture of dichloromethane and tetrahydrofuran (1:1 v/v).
  • Step 3 The resin from Step 2 was swelled in a mixture of dichloromethane and tetrahydrofuran (20ml, 1:1, v/v) and then treated successively with diisopropylethylamine (1.23ml) and then 4-nitrophenylchloroformate. The mixture was gently agitated for 1 hour, then washed four times with a mixture of dichloromethane and tetrahydrofuran (1:1, v/v) and then sucked dry.
  • Step 4 The resin from Step 3 was treated with a solution of 3-methoxy-4-[3-(2- methylphenyl)ureido]phenylacetic acid (1.24g, prepared as described in Example 52B of International Patent Application Publication No. WO 96/22966), O-(7-azabenzotriazol-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (1.19g) and diisopropylethylamine (1.65ml) in dimethylformamide (10ml). After gentle agitation for 3.5 hours the resin was drained, then washed three times with dimethylformamide, methanol, tetrahydrofuran and then dichloromethane, and then dried under vacuum.
  • 3-methoxy-4-[3-(2- methylphenyl)ureido]phenylacetic acid (1.24g, prepared as described in Example 52B of International Patent Application Publication No. WO 96/22966
  • Step 5 The resin from Step 4 was treated with a mixture of trifluoroacetic acid and dichloromethane (15ml, 1:1, v/v) and allowed to stand for 1 hour with occasional agitation. The resin was drained, washed twice with a mixture of trifluoracetic acid and dichloromethane (5ml, 1:1, v/v) and the combined filtrates evaporated to dryness. The residue was triturated with diethyl ether to give 3- ⁇ r(4-(r3-methoxy-4-(2-methylphenylureido)-phenyl1-acetyl ⁇ - homopiperazin-l-yl)-carbonvn-amino>-butanoic acid (Compound BJ) as a light brown solid

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Abstract

La présente invention concerne des composés physiologiquement actifs de formule générale (I) dans laquelle R1 représente R?5-L3-, R5-L4-R6-, R5-L4-R7-L5-, R5-L4-Ar1-L3, R5-L4-Ar1-L6-R6- ou R5-L4-Ar1-R7-L5-; R2¿ représente l'hydrogène ou un alkyle inférieur; R3 et R4 représentent indépendamment l'hydrogène ou un groupe pris dans alkyle, alcényle et alkynyl, chacun pouvant être substitués par un ou plusieurs atomes ou groupes choisis dans halo, oxo, R8, -C(=O)-R9, -NH-C(=O)-R9 ou -C(=O)NY?1Y2; ou R3 et R1¿ ensemble peuvent représenter -(CH¿2?)n- ou-C(=O)-CH=CH-; L?1¿ représente C¿2-6? alkylène ou (II); ou le groupe -L?1-N(R3¿)- représente (III); ou le groupe -N(R2)-L1- représente (IV); ou le groupe N(R?2)-L1-N(R3¿) représente (V); L2 représente une liaison alkylène, alkénylène, alkynylène, cycloalkénylène, cycloalkylène ou hétérocycloalkylène, chacune éventuellement substituée par alkyle, alcényle, alkynyle, aryle, carboxy (ou un acide bioisostère), cyano, cycloalcényle, cycloalkyle, hétéroaryle, hétérocycloalkyle, oxo, -C(=O)R9, -C(=O)OR9, -C(=O)NY?1Y2 ou NY1Y2¿, ou par alkyle substitué lui-même par aryle, carboxy (ou acide un bioisostère), cyano, hétéroaryle, hétérocycloalkyle, hydroxy, mercapto, -C(=O)R9, C(=O)OR9, C(=O)NY?1Y2, -OR9¿, S(O)¿vR?9, -NHC(=O)Oalkyle, -NY?1Y2, -NR10¿C(=Z)-NY3Y4 ou -NH-C(=NH)NH¿2?; ou le groupe -N(R?4)-L2¿ représente (VI); Y est carboxy (ou un acide bioisostère) ou -C(=O)-NY1Y2; et m est zéro ou 1. L'invention concerne également les promédicaments ainsi que les sels et solvats pharmaceutiquement acceptables de ces composés et de leurs promédicaments. Ces composés possèdent des propriétés pharmaceutiques précieuses, en particulier l'aptitude à réguler l'interaction de VCAM-1 et de la fibronectine avec l'intégrine VLA-4(α4β1).
PCT/GB1999/001230 1998-04-21 1999-04-21 Diamines substituees et leur utilisation en tant qu'inhibiteurs d'adhesion cellulaire WO1999054321A1 (fr)

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AU37164/99A AU3716499A (en) 1998-04-21 1999-04-21 Substituted diamines and their use as cell adhesion inhibitors

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GBGB9808431.2A GB9808431D0 (en) 1998-04-21 1998-04-21 Chemical compounds
GB9808431.2 1998-04-21
GB9811417.6 1998-05-28
GBGB9811417.6A GB9811417D0 (en) 1998-05-28 1998-05-28 Chemical compounds
US10413998P 1998-10-14 1998-10-14
US10423898P 1998-10-14 1998-10-14
US60/104,238 1998-10-14
US60/104,139 1998-10-14

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WO2000039103A1 (fr) * 1998-12-23 2000-07-06 Aventis Pharma Limited Dihydro-benzo(1,4)oxazines et tetrahydroquinoxalines
WO2001000206A1 (fr) * 1999-06-30 2001-01-04 Daiichi Pharmaceutical Co., Ltd. Composes inhibiteurs de vla-4
JP2002088070A (ja) * 2000-09-18 2002-03-27 Mitsubishi Rayon Co Ltd 新規ピペラジノン誘導体およびその製造方法
WO2002046146A1 (fr) * 2000-12-05 2002-06-13 Kyorin Pharmaceutical Co., Ltd. Derives d'acide carboxylique substitues
WO2002036553A3 (fr) * 2000-11-04 2003-03-13 Aventis Pharma Ltd Acides alcanoiqies substitues
US6548533B2 (en) 1999-05-05 2003-04-15 Aventis Pharma Limited Ureido substituted pyrrolidines
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6680333B2 (en) 2001-03-10 2004-01-20 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, their preparation, their use and pharmaceutical preparations comprising them
US6756378B2 (en) 1999-06-30 2004-06-29 Pharmacopeia Drug Discovery, Inc. VLA-4 inhibitor compounds
US6962937B2 (en) 2001-08-01 2005-11-08 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, their preparation and their use
US6984651B2 (en) 2000-06-21 2006-01-10 Bristol-Myers Squibb Pharma, Company Piperidine amides as modulators of chemokine receptor activity
WO2008093737A1 (fr) 2007-01-31 2008-08-07 Dainippon Sumitomo Pharma Co., Ltd. Dérivé d'amide
WO2008112022A1 (fr) * 2007-03-13 2008-09-18 Arete Therapeutics, Inc. Inhibiteurs de l'époxyde hydrolase soluble
US7754737B2 (en) 2004-10-07 2010-07-13 Vitae Pharmaceuticals, Inc. Diaminoalkane aspartic protease inhibitors
WO2010150840A1 (fr) 2009-06-24 2010-12-29 大日本住友製薬株式会社 Dérivé amino cyclique n-substitué
US8198453B2 (en) 2006-09-18 2012-06-12 Vitae Pharmaceuticals, Inc. Piperidine renin inhibitors
US8372978B2 (en) 2009-08-06 2013-02-12 Vitae Pharmaceuticals, Inc. Salts of methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-2-(methylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate
US8487108B2 (en) 2005-11-14 2013-07-16 Vitae Pharmaceuticals, Inc. Piperidinyl carbamate intermediates for the synthesis of aspartic protease inhibitors
US12258324B2 (en) * 2018-05-16 2025-03-25 Lin Bioscience Pty Ltd. Fatty acid analogues and methods of use

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000039103A1 (fr) * 1998-12-23 2000-07-06 Aventis Pharma Limited Dihydro-benzo(1,4)oxazines et tetrahydroquinoxalines
US6632814B1 (en) 1998-12-23 2003-10-14 Aventis Pharma Ltd. Dihydro-benzo(1,4)oxazines
US6548533B2 (en) 1999-05-05 2003-04-15 Aventis Pharma Limited Ureido substituted pyrrolidines
US6756378B2 (en) 1999-06-30 2004-06-29 Pharmacopeia Drug Discovery, Inc. VLA-4 inhibitor compounds
WO2001000206A1 (fr) * 1999-06-30 2001-01-04 Daiichi Pharmaceutical Co., Ltd. Composes inhibiteurs de vla-4
US7179819B2 (en) 1999-06-30 2007-02-20 Daiichi Pharmaceutical Co., Ltd. VLA-4 inhibitor compounds
JP2003503350A (ja) * 1999-06-30 2003-01-28 第一製薬株式会社 Ｖｌａ−４インヒビター化合物
US6903128B2 (en) 1999-12-28 2005-06-07 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6668527B2 (en) 1999-12-28 2003-12-30 Pfizer Inc. Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6984651B2 (en) 2000-06-21 2006-01-10 Bristol-Myers Squibb Pharma, Company Piperidine amides as modulators of chemokine receptor activity
US6949546B2 (en) 2000-06-30 2005-09-27 Bristol-Myers Squibb Pharma Company N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
US6627629B2 (en) 2000-06-30 2003-09-30 Bristol-Myers Squibb Pharma N-ureidoheterocycloalkyl-piperidines as modulators of chemokine receptor activity
JP2002088070A (ja) * 2000-09-18 2002-03-27 Mitsubishi Rayon Co Ltd 新規ピペラジノン誘導体およびその製造方法
WO2002036553A3 (fr) * 2000-11-04 2003-03-13 Aventis Pharma Ltd Acides alcanoiqies substitues
WO2002046146A1 (fr) * 2000-12-05 2002-06-13 Kyorin Pharmaceutical Co., Ltd. Derives d'acide carboxylique substitues
US6680333B2 (en) 2001-03-10 2004-01-20 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, their preparation, their use and pharmaceutical preparations comprising them
US6962937B2 (en) 2001-08-01 2005-11-08 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, their preparation and their use
US7754737B2 (en) 2004-10-07 2010-07-13 Vitae Pharmaceuticals, Inc. Diaminoalkane aspartic protease inhibitors
US8455521B2 (en) 2004-10-07 2013-06-04 Vitae Pharmaceuticals, Inc. Diaminoalkane aspartic protease inhibitors
US8487108B2 (en) 2005-11-14 2013-07-16 Vitae Pharmaceuticals, Inc. Piperidinyl carbamate intermediates for the synthesis of aspartic protease inhibitors
US8198453B2 (en) 2006-09-18 2012-06-12 Vitae Pharmaceuticals, Inc. Piperidine renin inhibitors
US8580823B2 (en) 2006-09-18 2013-11-12 Vitae Pharmaceuticals, Inc. Piperidine renin inhibitors
WO2008093737A1 (fr) 2007-01-31 2008-08-07 Dainippon Sumitomo Pharma Co., Ltd. Dérivé d'amide
WO2008112022A1 (fr) * 2007-03-13 2008-09-18 Arete Therapeutics, Inc. Inhibiteurs de l'époxyde hydrolase soluble
WO2010150840A1 (fr) 2009-06-24 2010-12-29 大日本住友製薬株式会社 Dérivé amino cyclique n-substitué
US8372978B2 (en) 2009-08-06 2013-02-12 Vitae Pharmaceuticals, Inc. Salts of methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-2-(methylamino)-3-((R)-tetrahydro-2H-pyran-3-yl)propylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate
US12258324B2 (en) * 2018-05-16 2025-03-25 Lin Bioscience Pty Ltd. Fatty acid analogues and methods of use

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