WO2000020396A1 - Derives d'acide phenylalcanoique comme inhibiteurs d'integrines alpha-4 - Google Patents

Derives d'acide phenylalcanoique comme inhibiteurs d'integrines alpha-4 Download PDF

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Publication number
WO2000020396A1
WO2000020396A1 PCT/GB1999/003243 GB9903243W WO0020396A1 WO 2000020396 A1 WO2000020396 A1 WO 2000020396A1 GB 9903243 W GB9903243 W GB 9903243W WO 0020396 A1 WO0020396 A1 WO 0020396A1
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group
optionally substituted
alk
groups
atom
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PCT/GB1999/003243
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English (en)
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Graham John Warrellow
John Robert Porter
Sarah Catherine Archibald
John Clifford Head
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Celltech Therapeutics Limited
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Priority to EP99947708A priority Critical patent/EP1117646A1/fr
Priority to JP2000574513A priority patent/JP2002526533A/ja
Priority to AU61083/99A priority patent/AU6108399A/en
Publication of WO2000020396A1 publication Critical patent/WO2000020396A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/60—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 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated

Definitions

  • This invention relates to a series of phenylalkanoic acid derivatives, to 5 compositions containing them, to processes for their preparation, and to their use in medicine.
  • the adhesion molecules have been sub-divided into different groups on the basis of their structure.
  • One family of adhesion molecules which is believed to play a particularly important role in regulating immune and inflammatory responses is the integrin family.
  • This family of cell surface glycoproteins has a typical non-covalently linked heterodimer structure.
  • VLA 25 consists of the integrin alpha 4 chain associated with the integrin beta 1 chain, but is also widely referred to as Very Late Antigen 4 or VLA4. Not all of the potential pairings of integrin alpha and beta chains have yet been observed in nature and the integrin family has been subdivided into a number of subgroups based on the pairings that have been recognised
  • LAD Leukocyte Adhesion Deficiency
  • ⁇ 4 ⁇ 1 One particular integrin subgroup of interest involves the ⁇ 4 chain which can pair with two different beta chains ⁇ 1 and ⁇ 7 [Sonnenberg, A. ibid].
  • the ⁇ 4 ⁇ 1 pairing occurs on many circulating leukocytes (for example lymphocytes, monocytes and eosinophils) although it is absent or only present at low levels on circulating neutrophils.
  • ⁇ 4 ⁇ 1 binds to an adhesion molecule (Vascular Cell Adhesion Molecule-1 also known as VCAM-1 ) frequently up-regulated on endothelial cells at sites of inflammation [Osborne, L. Cell, 62, 3, (1990)].
  • VCAM-1 an adhesion molecule
  • the molecule has also been shown to bind to at least three sites in the matrix molecule fibronectin [Humphries, M. J. et al. Ciba Foundation Symposium, 189. 177, (1995)]. Based on data obtained with monoclonal antibodies in animal models it is believed that the interaction between ⁇ 4 ⁇ 1 and ligands on other cells and the extracellular matrix plays an important role in leukocyte migration and activation [Yednock, T. A et al. Nature, 3Jj6, 63, (1992); Podolsky, D. K. et al. J. Clin. Invest. 92, 373, (1993); Abraham, W. M. sLal- J- Clin. Invest. 92, 776, (1994)].
  • LPAM-1 [Holzmann, B and Weissman, I. EMBO J. 8, 1735, (1989)] and like ⁇ 4 ⁇ 1 , binds to VCAM-1 and fibronectin.
  • ⁇ 4 ⁇ 7 binds to an adhesion molecule believed to be involved in the homing of leukocytes to mucosal tissue termed MAdCAM-1 [Berlin, C. et al. Cell, 74, 185, (1993)].
  • MAdCAM-1 adhesion molecule believed to be involved in the homing of leukocytes to mucosal tissue termed MAdCAM-1 [Berlin, C. et al. Cell, 74, 185, (1993)].
  • MAdCAM-1 adhesion molecule believed to be involved in the homing of leukocytes to mucosal tissue
  • the interaction between ⁇ 4 ⁇ 7 and MAdCAM-1 may also be important at sites of inflammation outside of mucosal tissue [Yang, X-D.
  • Regions of the peptide sequence recognised by ⁇ 4 ⁇ 1 and ⁇ 4 ⁇ 7 when they bind to their ligands have been identified.
  • ⁇ 4 ⁇ 1 seems to recognise LDV, IDA or REDV peptide sequences in fibronectin and a QIDSP sequence in VCAM-1 [Humphries, M. J. et al. ibid] whilst ⁇ 4 ⁇ 7 recognises a LDT sequence in MAdCAM-1 [Briskin, M. J. et al. J. Immunol. 156. 719, (1996)].
  • inhibitors of these interactions being designed from modifications of these short peptide sequences [Cardarelli, P. M. et al J. Biol. Chem. 269.
  • alpha 4 subgroup of integrins are predominantly expressed on leukocytes their inhibition can be expected to be beneficial in a number of immune or inflammatory disease states.
  • the ubiquitous distribution and wide range of functions performed by other members of the integrin family it is very important to be able to identify selective inhibitors of the alpha 4 subgroup.
  • Ar 1 is an aromatic or heteroaromatic group
  • R 1 , R 2 , R 3 , R 4 and R 5 which may be the same or different is each an atom or group -L 2 (Alk 3 )tL 3 (R ) u in which L 2 and L 3 which may be the same or different is each a covalent bond or a linker atom or group, t is zero or the integer 1 , u is an integer 1 , 2 or 3,
  • Alk 3 is an aliphatic or heteroaliphatic chain and
  • R 7 is a hydrogen or halogen atom or a group selected from alkyl, -OR 8 [where R 8 is a hydrogen atom or an optionally substituted alkyl group], -SR 8 , -NR 8 R 9 [where R 9 is as just defined for R 8 and may be the same or different], -NO 2 , -CN, -C0 2 R 8 , -SO 3 H, -S(O)R 8 , -SO 2 R
  • R 10 is a hydrogen atom or an optionally substituted alkyl group] -N(R 8 )CSN(R 9 )(R 10 ) or -N(R 8 )SO 2 N(R 9 )(R 10 );
  • Alk 1 is an optionally substituted aliphatic or heteroaliphatic chain
  • L 1 is a covalent bond or a linker atom or group
  • Alk 2 is a straight or branched alkylene chain; m is zero or an integer 1 ;
  • R 6 is a hydrogen atom or a methyl group; r is zero or the integer 1 ;
  • R is a carboxylic acid (-CO H) or a derivative thereof;
  • R a is a hydrogen atom or a methyl group
  • A is an optionally substituted aliphatic, heteroaliphatic, cycloaliphatic, polycycloaliphatic, heterocycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group; and the salts, solvates, hydrates and N-oxides thereof.
  • compounds of formula (1 ) may have one or more chiral centres, and exist as enantiomers or diastereomers.
  • the invention is to be understood to extend to all such enantiomers, diastereomers and mixtures thereof, including racemates.
  • Formula (1 ) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
  • derivatives of the carboxylic acid group R include carboxylic acid esters and amides. Particular esters and amides include -CO 2 Alk 5 and -CONR 8 R 9 groups as described herein.
  • substituents R , R 2 and R 3 in compounds of the invention may be positioned on any available carbon atom, or, when present, nitrogen atom in the aromatic or heteroaromatic group represented by Ar 1 .
  • Alk 1 and/or the group A is present in compounds of formula (1) as an optionally substituted aliphatic chain it may be an optionally substituted Ci-io aliphatic chain.
  • Particular examples include optionally substituted straight or branched chain C ⁇ -6 alkyl, C 2 -6 alkenyl, or C 2 - ⁇ alkynyl chains.
  • Heteroaliphatic chains represented by Alk 1 and/or the group A include the aliphatic chains just described but with each chain additionally containing one, two, three or four heteroatoms or heteroatom-containing groups.
  • Particular heteroatoms or groups include atoms or groups L 4 where L 4 is as defined above for L 1 when L 1 is a linker atom or group.
  • Each L 4 atom or group may interrupt the aliphatic chain, or may be positioned at its terminal carbon atom to connect the chain to an adjoining atom or group.
  • Particular examples of aliphatic chains represented by Alk 1 and/or the group A include optionally substituted -CH 2 -, -CH 2 CH 2 -, -CH(CH3)-, -C(CH 3 )2-, -(CH 2 ) 2 CH 2 - -CH(CH 3 )CH 2 -, -(CH 2 ) 3 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -C(CH 3 ) 2 CH 2 -, -(CH 2 ) 4 CH 2 -, -(CH 2 ) 5 CH 2 -, -CHCH-, -CHCHCH 2 -, -CH 2 CHCH-, -CHCHCHCH 2 CH 2 -, -CH 2 CHCHCH 2 -, -(CH 2 ) 2 CHCH-, -CC-, -CCCH 2 -, -CH 2 CC-, -CCCH 2 CH 2 -
  • each of said chains may be optionally interrupted by one or two atoms and/or groups L 4 to form an optionally substituted heteroaliphatic chain.
  • Particular examples include optionally substituted -L 4 CH 2 -, -CH 2 L 4 CH 2 -, -L 4 (CH 2 ) 2 -, -CH 2 L (CH 2 ) 2 -, - (CH 2 ) 2 L 4 CH 2 -, -L 4 (CH 2 ) 3 - and -(CH 2 ) 2 L 4 (CH 2 ) 2 - chains.
  • the optional substituents which may be present on aliphatic or heteroaliphatic chains represented by Alk 1 include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or Ci- ⁇ alkoxy, e.g. methoxy or ethoxy, thiol, d- ⁇ alkylthio e.g. methylthio or ethylthio, amino or substituted amino groups.
  • Substituted amino groups include -NHR 12 and -N(R 12 ) 2 groups where R 12 is an optionally substituted straight or branched alkyl group as defined below for R 1 1 .
  • substituted chains represented by Alk 1 include those specific chains just described substituted by one, two, or three halogen atoms such as fluorine atoms, for example chains of the type -CH(CF 3 )-, -C(CF 3 ) 2 - -CH 2 CH(CF 3 )- -CH 2 C(CF 3 ) 2 -, -CH(CF 3 )- and -C(CF 3 ) 2 CH 2 .
  • Alk 2 in the compounds of the invention may be for example a straight or branched C -
  • L 1 , L 2 and/or L 3 When in the compounds of formula (1 ) L 1 , L 2 and/or L 3 is present as a linker atom or group it may be any divalent linking atom or group. Particular examples include -O- or -S- atoms or -C(O)-, -C(O)O-, -OC(O)-, -C(S)-, -S(O)-, -S(O) 2 -, -N(R 1 1 )- [where R 1 1 is a hydrogen atom or an optionally substituted alkyl group], -CON(R 1 1 )-, -OC(O)N(R 1 1 )-, -CSN(R 11 )-, -N(R 11 )CO- -N(R 11 )C(O)O-, -N(R 11 )CS-, -S(O) 2 N(R 1 )-, -N(R 11 )S(O) 2
  • linker group contains two R 11 substituents, these may be the same or different.
  • R 7 , R 8 , R 9 , R 10 and/or R 1 1 in the compounds of formula (1 ) is an alkyl group it may be a straight or branched C ⁇ -6alkyl group, e.g. a C-
  • Optional substituents which may be present on such groups include for example one, two or three substituents which may be the same or different selected from halogen atoms, for example fluorine, chlorine, bromine or iodine atoms, or hydroxy or C ⁇ -6alkoxy e.g. methoxy or ethoxy groups.
  • Alk 3 is present in the compounds of formula (1 ) as an aliphatic or heteroaliphatic chain it may be for example any of the above-mentioned C ⁇ - ⁇ oaliphatic or heteroaliphatic chains described for Alk 1 .
  • Halogen atoms represented by R 7 in compounds of the invention include fluorine, chlorine, bromine, or iodine atoms.
  • Examples of the substituents represented by R 1 , R 2 , R 3 , R 4 and R 5 in compounds of formula (1 ) include atoms or groups -L 2 Alk 3 L 3 R 7 , -L 2 Alk 3 R 7 , -L 2 R 7 and -Alk 3 R 7 wherein L 2 , Alk 3 , L 3 and R 7 are as defined above.
  • substituents include -L 2 CH 2 L 3 R 7 , -L 2 CH(CH 3 )L 3 R 7 , -L 2 CH(CH 2 ) 2 L 3 R 7 , -L 2 CH 2 R 7 , -L 2 CH(CH 3 )R 7 , -L 2 (CH 2 ) 2 R 7 , -CH 2 R 7 , -CH(CH 3 )R 7 , (CH 2 ) 2 R 7 and -R 7 groups.
  • each of R 1 , R 2 , R 3 , R 4 and R 5 in compounds of the invention may be for example a hydrogen atom, a halogen atom, e.g. a fluorine, chlorine, bromine or iodine atom, or a C-i- ⁇ alkyl, e.g. methyl, ethyl, n-propyl, i- propyl, n-butyl or t-butyl, Ci- ⁇ alkylamino, e.g. methylamino or ethylamino, C-
  • Ci- ⁇ alkylthio e.g. methylthio or ethylthio, carboxyCi- ⁇ alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxy- propylthio
  • Ci- ⁇ alkoxy e.g. methoxy or ethoxy, hydroxyCi- ⁇ alkoxy, e.g. 2- hydroxyethoxy
  • haloC-i- ⁇ alkyl e.g. trifluoromethyl, haloCi- ⁇ alkoxy, e.g. trifluoromethoxy
  • Ci- ⁇ alkylamino e.g.
  • methylamino or ethylamino amino (-NH 2 ), aminoCi- ⁇ alkyl, e.g. aminomethyl or aminoethyl, Ci- ⁇ dialkylamino, e.g. dimethylamino or diethylamino, Ci- ⁇ alkylaminoCi- ⁇ alkyl, e.g. ethylaminoethyl, C-
  • sulphonyl e.g. thiomethyl or thioethyl, sulphonyl (-SO 3 H), Ci- ⁇ alkylsulphinyl e.g. methylsulphinyl, C-i- ⁇ alkylsulphonyl, e.g. methylsulphonyl aminosulphonyl (-SO 2 NH 2 ), C-
  • -6alkylaminocarbonyl e.g. methylaminocarbonyl or ethylaminocarbonyl
  • C-i- ⁇ dialkylamino- carbonyl e.g. dimethylaminocarbonyl or diethylaminocarbonyl
  • aminoCi- ⁇ alkylaminocarbonyl e.g. aminoethylaminocarbonyl
  • Ci-6dialkylaminoC ⁇ - ⁇ alkylaminocarbonyl e.g.
  • diethylaminoethylaminocarbonyl amino- carbonylamino
  • Ci- ⁇ alkylaminocarbonylamino e.g. methylaminocarbonyl- amino or ethylaminocarbonylamino
  • Ci- ⁇ dialkylaminocarbonyiamino e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino
  • -6alkylamino e.g. methylaminocarbonyimethyl- amino, aminothiocarbonylamino
  • Ci- ⁇ alkylaminothiocarbonylamino e.g.
  • ⁇ dialkylaminothiocarbonylamino e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino
  • Ci- ⁇ aikylaminothiocarbonylCi- ⁇ alkyl- amino e.g. ethylaminothiocarbonylmethylamino
  • C-i- ⁇ alkylsulphonylamino e.g. methylsulphonylamino or ethylsulphonylamino
  • Ci- ⁇ dialkylsulphonyl- amino e.g.
  • dimethylsulphonylamino or diethylsulphonylamino aminosulphonyiamino (-NHSO 2 NH 2 ), C i- ⁇ alkylaminosuiphonylamino, e.g. methylaminosulphonylamino or ethyl-aminosulphonylamino, C-i- edialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, d- ⁇ alkanoylamino, e.g. acetylamino, aminoCi- ⁇ alkanoylamino e.g.
  • - ⁇ alkanoylamino e.g. dimethylaminoacetylamino
  • Ci- ⁇ alkanoylaminoCi - ealkyt e.g. acetylaminomethyl
  • C ⁇ -6alkanoylaminoC ⁇ -6alkylamino e.g. acetamidoethylamino
  • Ci- ⁇ alkoxycarbonylamino e.g. methoxycarbonyl- amino, ethoxycarbonylamino or t-butoxycarbonylamino group.
  • Optionally substituted cycloaliphatic groups represented by the group A in compounds of the invention include optionally substituted C3-10 cycloaliphatic groups. Particular examples include optionally substituted C 3 - ⁇ o cycloalkyl, e.g. C3.7 cycloalkyl or C3-10 cycloalkenyl, e.g C 3 -7 cycloalkenylgroups.
  • Optionally substituted heterocycloaliphatic groups represented by the group A include optionally substituted C 3 - ⁇ oheterocycloaliphatic groups.
  • Particular examples include optionally substituted C 3 -ioheterocycloaikyl, e.g. C 3 -7 heterocycloalkyl, or C3-ioheterocycloalkenyl, e.g. C 3 -7 hetercycloalkenyl groups, each of said groups containing one, two, three or four heteroatoms or heteroatom-containing groups L 4 as defined above.
  • Optionally substituted polycycloaliphatic groups represented by the group A include optionally substitued C7-10 bi- or tricycloalkyl or C7- ⁇ rjbi- or tricycloalkenyl groups.
  • Optionally substituted polyheterocycloaliphatic groups represented by the group A include the optionally substituted polycycloalkyl groups just described, but with each group additionally containing one, two, three or four L 4 atoms or groups.
  • cycloaliphatic, polycycloaliphatic, heterocycloaliphatic and polyheterocycloaliphatic groups represented by the group A include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1 -yl, 2-cyclopenten-1 -yl, 3- cyclopenten-1-yl, adamantyl, norbomyl, norbomenyl, tetrahydrofuranyl, pyrroline, e.g.
  • the optional substituents which may be present . on the R 1 and R 6 cycloaliphatic, polycycloaliphatic, heterocycloaliphatic or polyheterocycloaliphatic groups represented by the group A include one, two, three or more substituents each selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C-i- ⁇ alkyl, e.g. methyl or ethyl, haloCi- ⁇ alkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, optionally substituted by hydroxyl, e.g.
  • halogen atoms e.g. fluorine, chlorine, bromine or iodine atoms
  • C-i- ⁇ alkyl e.g. methyl or ethyl
  • haloCi- ⁇ alkyl e.g. halomethyl or
  • C ⁇ -C(OH)(CF 3 ) 2 C ⁇ - ⁇ alkoxy, e.g. methoxy or ethoxy, haloC-i- ⁇ alkoxy, e.g. halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, thiol, Ci- ⁇ alkylthio e.g.
  • R 12 is a -OH, -SH, -N(R 11 a ) 2 , -CN, -CO 2 R 11a , -NO 2 , -CON(R 1 a ) 2 , -CSN(R 11a ) 2 , -COR 1a , -CSN(R 11a ) 2 , -N(R 11 a )COR 1 a , -N(R 11 a )CSR 11 a , -SO 2 N(R 11 a ) 2 , -N(R 11a )SO 2 R 11 a , -N(R 11 a )CON(R 11 a ) 2 , -N(R 11 a )CSN(R 1 a ) or -
  • each nitrogen atom may be optionally substituted by a group -(L 5 ) p (Alk 6 ) q R 15 in which L 5 is -C(O)-, -C(O)O-, -C(S)-, -S(O) 2 -, -CON(R 1 1 )-, -CSN(R 11 )-, -SON(R 11 )- or SO 2 N(R 11 )-; p is zero or an integer 1; Alk 6 is an optionally substituted aliphatic or heteroaliphatic chain; q is zero or an integer 1 ; and R 1 5 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group.
  • Optionally substituted aliphatic or heteroaliphatic chains represented by Alk 6 include those optionally substituted chains described above for Alk 1 .
  • Cycloaliphatic, heterocycloaliphatic, polycycloaliphatic or polyheterocycloaliphatic groups represented by R 15 include those groups just described for the group A.
  • Optional substituents which may be present on these groups include those described above in relation to Alk 1 aliphatic and heteroaliphatic chains.
  • Aromatic groups represented by the group Ar 1 and/or A in compounds of the invention include for example monocyclic or bicyclic fused ring C6-1 2 aromatic groups, such as phenyl, 1 - or 2-naphthyl, 1- or 2- tetrahydronaphthyl, indanyl or indenyl groups.
  • Aromatic groups represented by the group A may be optionally substituted by one, two, three or more R 13 atoms or groups as defined below.
  • Heteroaromatic groups represented by the group Ar 1 and/or A in the compounds of formula (1 ) include for example C1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups.
  • Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • Bicyclic heteroaromatic groups include for example eight- to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
  • heteroaromatic groups of these types include pyrrolyl, furyl, thienyl, imidazolyl, N-C-i- ⁇ alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,3,4-thiadiazole, pyridyl, pyrimidinyl, pyhdazinyl, pyrazinyl, 1 ,3,5-triazinyl, ,2,4-triazinyl, 1 ,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, benzo
  • Optional substituents which may be present on the aromatic or heteroaromatic groups represented by the group A include one, two, three or more substituents, each selected from an atom or group R 13 in which R 13 is -R 13a or -Alk (R 13a ) m , where R 13a is a halogen atom, or an amino (- NH 2 ), substituted amino, nitro, cyano, amidino, hydroxyl (-OH), substituted hydroxyl, formyl, carboxyl (-CO 2 H), esterified carboxyl, thiol (-SH), substituted thiol, -COR 14 [where R 14 is an -Alk 3 (R 13a ) m ⁇ aryl or heteroaryl group], -CSR 14 , -SO 3 H, -SO 2 R 14 -SO 2 NH 2 , -SO 2 NHR 1 4 SO 2 N(R 1 ) 2 , -CONH2, -CSNH 2 , -CON
  • ⁇ alkenylene or C 2 -6alkynylene chain optionally interrupted by one, two or three -O- or -S- atoms or -S(O) n [where n is an integer 1 or 2] or -N(R 15 )- groups [where R 15 is a hydrogen atom or C-i- ⁇ aikyl, e.g. methyl or ethyl group]; and m is zero or an integer 1 , 2 or 3. It will be appreciated that when two R 11 or R 14 groups are present in one of the above substituents, the R 11 or R 14 groups may be the same or different.
  • m is an integer 1 , 2 or 3, it is to be understood that the substituent or substituents R 13a may be present on any suitable carbon atom in -Alk 4 . Where more than one R 13a substituent is present these may be the same or different and may be present on the same or different atom in -Alk 4 . Clearly, when m is zero and no substituent R 13a is present the alkylene, alkenylene or alkynylene chain represented by Alk 4 becomes an alkyl, alkenyl or alkynyl group.
  • R 13a is a substituted amino group it may be for example a group -NHR 14 [where R 14 is as defined above] or a group -N(R 14 ) 2 wherein each R 14 group is the same or different.
  • R 13a is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
  • Esterified carboxyl groups represented by the group R 3a include groups of formula -CO 2 Alk 5 wherein Alk 5 is a straight or branched, optionally substituted C-i-salkyl group such as a methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl or t-butyl group; a C6-i 2 arylC ⁇ -8al yl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6- ⁇ 2 aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6- ⁇ 2 aryloxyCi-8alkyl group such as an optionally substituted phenyloxymethyl, phenyloxy
  • Alk 4 When Alk 4 is present in or as a substituent it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butyiene, s- butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3- butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three -O- or -S-, atoms or -S(O)-, -S(O) 2 - or -N(R 12 )- groups.
  • Aryl or heteroaryl groups represented by the groups R 13a or R 1 include mono- or bicyclic optionally substituted C ⁇ -1 2 aromatic or C-
  • the aromatic and heteroaromatic groups may be attached to the remainder of the compound of formula (1 ) by any carbon or hetero e.g. nitrogen atom as appropriate.
  • each may be for example an optionally substituted pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinyl group.
  • Het 2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group.
  • Optional substituents which may be present on -NHet 1 or -Het 2 include those R 7 substituents described above.
  • Particularly useful atoms or groups represented by R 13 include fluorine, chlorine, bromine or iodine atoms, or Ci- ⁇ alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, or thienyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolidinyl, piperadinyl, Ci-ealkylamino, e.g.
  • Ci- ⁇ hydroxyalkyl e.g. hydroxymethyl or hydroxyethyl, carboxyC-i- ⁇ alkyl, e.g. carboxyethyl, C -i- ⁇ alkylthio e.g. methylthio or ethylthio, carboxyCi - ⁇ alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxy- propylthio, Ci- ⁇ alkoxy, e.g. methoxy, ethoxy or propoxy, hydroxyC-i . ⁇ alkoxy, e.g.
  • 2-hydroxyethoxy optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, Cs ⁇ cycloalkoxy, e.g. cyclopentyloxy, haloC-i- ⁇ alkyl, e.g. trifluoromethyl, haloCi- ⁇ alkoxy, e.g. trifluoromethoxy, Ci- ⁇ alkylamino, e.g. methylamino or ethylamino, optionally substituted CQ. ⁇ 2 arylC ⁇ -6alkylamino e.g. benzylamino, amino (-NH 2 ), aminoCi .
  • ⁇ alkylamino e.g. aminomethylamino, aminoethylamino or aminopropyl- amino, aminoC-i- ⁇ alkyl, e.g. aminomethyl or aminoethyl, C-i- ⁇ dialkylamino, e.g. dimethylamino or diethylamino, C ⁇ -6alkylaminoC ⁇ -6alkyl, e.g. ethylaminoethyl, C ⁇ -6dialkylaminoC ⁇ -6alkyl, e.g. diethylaminoethyl, aminoCi- ⁇ alkoxy, e.g. aminoethoxy, C ⁇ -6alkylaminoC ⁇ -6alkoxy, e.g.
  • -6alkoxy e.g. dimethylamino- ethoxy, diethylaminoethoxy, diisopropylaminoethoxy, or dimethylamino- propoxy
  • hydroxyCi- ⁇ alkylamino e.g. hydroxym ethylamino or hydroxyethyl - amino
  • Hef NCi- ⁇ alkylamino e.g. morpholinopropylamino or piperidinyl- ethyiamino
  • imido such as phthalimido or naphthalimido, e.g.
  • methylaminosuiphonyl or ethylaminosulphonyl C ⁇ - 6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylamino- sulphonyl, phenylaminosulphonyl, carboxamido (-CONH 2 ), Ci- ⁇ alkyl- aminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C ⁇ - 6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylamino- carbonyl, aminoC-
  • aminoethylaminocarbonyl C ⁇ -6dialkylaminoC ⁇ -6alkylaminocarbonyl, e.g. diethylaminoethylamino- carbonyl, aminocarbonylamino, Ci- ⁇ alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, Ci- ⁇ dialkylamino- carbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonyl- amino, C i-6alkylaminocabonylC-
  • C-i- ⁇ alkyl- sulphonylamino e.g. methylsulphonylamino or ethylsulphonylamino
  • C ⁇ .6dialkylsulphonylamino e.g. dimethyisulphonylamino or diethyl- sulphonylamino
  • Ci- ⁇ dialkyl- aminosulphonylamino e.g. dimethylaminosulphonylamino or diethylamino- sulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonylC-i-ealkylamino, optionally substituted phenylamino- sulphonylamino
  • Ci- ⁇ alkanoylamino e.g. acetylamino, aminoCi- ⁇ alkanoylamino e.g.
  • aminoacetylamino C-i-edialkylaminoCi-eaikanoyl- amino, e.g. dimethylaminoacetylamino, C-i- ⁇ alkanoylaminoCi- ⁇ alkyl, e.g. acetylaminom ethyl, Ci- ⁇ alkanoylaminoCi- ⁇ alkylamino, e.g. acetamido- ethylamino, Ci- ⁇ alkoxycarbonylamino, e.g.
  • two R 13 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C-i- ⁇ alkylenedioxy group such as methylenedioxy or ethylenedioxy.
  • a cyclic group such as a cyclic ether, e.g. a C-i- ⁇ alkylenedioxy group such as methylenedioxy or ethylenedioxy.
  • R 13 substituents need not necessarily be the same atoms and/or groups.
  • the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group represented by Ar 2 .
  • Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
  • Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
  • Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, pipe ⁇ dine, dimethylamine or diethylamine salts.
  • Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
  • the group Ar 1 is preferably a phenyl or monocyclic heteroaromatic group.
  • Particularly useful groups of this type are five- or six-membered heteroaromatic groups as described previously, especially five- or six-membered heteroaromatic groups containing one or two heteroatoms selected from oxygen, sulphur or nitrogen atoms. Nitrogen-containing groups are especially useful, particularly pyridyl or pyrimidinyl groups.
  • R 1 , R 2 and R 3 attached to these Ar 1 groups may each be a hydrogen atom or one of the other atoms or groups generally and particularly described above in relation to R 1 , R 2 and R 3 .
  • Particularly useful atoms or groups include halogen atoms or alkyl, -OR 8 , -SR 8 , NR 8 R 9 , -NO 2 or -CN groups as described above in relation to the compounds of formula (1).
  • a particularly useful group of compounds according to the invention has the formula (2):
  • R 1 and R 2 which may be the same or different is each an atom or group -L 2 (Alk 3 )tL 3 (R 7 ) u in which L 2 , Alk 3 , t, L 3 , R 7 and u are as defined for formula (1 ) provided that R 1 and R 2 are not both hydrogen atoms;
  • Alk 1 , Alk 2 , m, r, L 1 , R 4 , R 5 , R 6 , R a , A and R are as defined for formula (1); and the salts, solvates, hydrates and N-oxides thereof.
  • R 1 and R 2 in compounds of formula (2) and in general in compounds of formula (1 ) is each preferably as particularly described above for compounds of formula (1 ), other than a hydrogen atom.
  • Particularly useful R 1 and R 2 substituents include halogen atoms, especially fluorine or chlorine atoms, or methyl, halomethyl, especially -CF 3 , -CHF 2 or -CH 2 F, methoxy or halomethoxy, especially -OCF 3 , -OCHF 2 or -OCH 2 F groups.
  • R 3 in compounds of the invention is in particular a hydrogen atom.
  • R in the compounds of formulae (1 ) and (2) is preferably a -CO 2 H group.
  • the aliphatic chain represented by Alk 1 in compounds of formulae (1) and (2) is preferably a -CH 2 - chain.
  • m is preferably 1 and Alk 2 is preferably -CH 2 -.
  • R 4 and R 5 in the compounds of formulae (1) and (2) may be the same or different and is each preferably a hydrogen or halogen atom or an alkyl, alkoxy, hydroxy, nitro, cyano or -NR 8 R 9 group.
  • R 6 and R a in the compounds of formulae (1 ) and (2) is each preferably a hydrogen atom.
  • the group A may especially be an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group as defined herein.
  • Particularly useful groups of this type include optionally substituted C5-7heterocycloaliphatic, especially optionally substituted pyrrolidinyl or thiazolidinyl, optionally substituted phenyl and optionally substituted C 5.7heteroaromatic, especially optionally substituted pyridyl groups.
  • Optional substituents on these groups include in particular R 13 atoms or groups where the group is an aromatic or heteroaromatic group and -(L 5 ) p (Alk 6 ) q R 15 groups as described earlier where the group is a nitrogen-containing heterocycloaliphatic group such as a pyrrolidinyl or thiazolidinyl group.
  • Especially useful A groups include optionally sustituted phenyl or pyridyl groups.
  • R 13 substituents in compounds of the invention include a halogen atom, especially fluorine or chlorine, optionally substituted morpholinyl, optionally substituted thiomorpholinyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted piperazinyl, thioC-i- ⁇ alkyl, especially thiomethyl, thioethyl or thiopropyi, optionally substituted thiobenzyl, haloC-i- ⁇ alkyl, especially trifluoromethyl, C ⁇ -6alkyloxy, especially methoxy, ethoxy or propoxy, optionally substituted benzyloxy, haloCi - ⁇ alkoxy, especially trifluoromethoxy and difluoromethoxy, C-i - ⁇ alkylamino, especially propylamino, C ⁇ - ⁇ dialkylamino, especially dimethylamino or diethylamino, optionally substituted C6
  • alkyisulphinyl C-i- ⁇ alkylsulphonyl, C-i- ⁇ alkylaminosulphonyoyl, C ⁇ - ⁇ dialkylam inosulphonyl, C i - ⁇ alkylam ino-carbonyl and C-
  • Particularly useful -(L 5 ) p (Alk 6 )qR 15 groups include those in which L 5 is a -CO- group. Alk 6 in these groups is preferably present (i.e. q is preferably an integer 1) and in particular is a -CH 2 -chain.
  • R 15 is a hydrogen atom or an optionally substituted aromatic or heteroaromatic group, especially an optionally substituted phenyl, pyridyl or imidazolyl group are particularly preferred.
  • Particularly useful optional substituents on these groups include those R 13 groups just mentioned.
  • Particularly useful compounds according to the invention include:
  • Compounds according to the invention are potent and selective inhibitors of ⁇ 4 integrins.
  • the ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.
  • the compounds are of use in modulating cell adhesion and in particular are of use in the prophylaxis and treatment of diseases or disorders involving inflammation in which the extravasation of leukocytes plays a role and the invention extends to such a use and to the use of the compounds for the manufacture of a medicament for treating such diseases or disorders.
  • Diseases or disorders of this type include inflammatory arthritis such as rheumatoid arthritis vasculitis or polydermatomyositis, multiple sclerosis, allograft rejection, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
  • the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1 ) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives.
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • compositions for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions for buccal administration may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for formula (1 ) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • suitable propellant e.g. dichlorodifluoromethane, trichloro- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • daily dosages may range from around 100ng/kg to 100mg/kg e.g. around 0.01mg/kg to 40mg/kg body weight for oral or buccal administration, from around 10ng/kg to 50mg/kg body weight for parenteral administration and around 0.05mg to around 1000mg e.g. around 0.5mg to around 1000mg for nasal administration or administration by inhalation or insufflation.
  • the compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter.
  • the symbols R 1 -R 6 , Ar 1 , L 1 , Alk 1 , Alk 2 , m, r, A, R a and R when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1 ) unless otherwise indicated.
  • reactive functional groups for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W.
  • a compound of formula (1) in which R is a -CO 2 H group may be obtained by hydrolysis of an ester of formula (3):
  • R b is an alkyl group, for example a Ci- ⁇ alkyI group as described above.
  • the hydrolysis may be performed using either an acid or a base depending on the nature of R , for example an organic acid such as trifluoroacetic acid or an inorganic base such as lithium or potassium hydroxide optionally in an aqueous organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran or dioxane or an alcohol, e.g. methanol at around ambient temperature. Where desired, mixtures of such solvents may be used.
  • Esters of formula (3) may be prepared by coupling an acid of formula (4):
  • Active derivatives of acids of formula (4) include anhydrides, esters and halides and may be obtained by standard procedures and may be obtained by standard procedures, for example as described in the Examples hereinafter.
  • the coupling reaction may be performed using standard conditions for reactions of this type.
  • the reaction may be carried out with an active derivative of the acid of formula (4) in the presence of a base, e.g. an organic base such as an amine, e.g. triethylamine or N,N- diisopropylethylamine, or a cyclic amine, such as N-methylmorpholine, or a hydride, such as sodium hydride in an inert organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, an ether, e.g. a cyclic ether such as tetrahydrofuran or a halogenated hydrocarbon, such as dichloromethane, at a low temperature, e.g. around -30°C to around ambient temperature.
  • a base e.g. an organic base such as an amine, e.g. triethylamine or N,N- diisopropylethy
  • the reaction may additionally be performed in the presence of a condensing agent, for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,N'-dicyclo- hexylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxy- benzotriazole.
  • a condensing agent for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,N'-dicyclo- hexylcarbodiimide
  • a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxy- benzotriazole.
  • the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to reaction with the amine ANHR
  • the acids of formula (4) may be obtained from simpler, known compounds by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions as described below and in the Examples hereinafter.
  • Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of formulae (1 ) and (2) where appropriate functional groups exist in these compounds.
  • a number of the intermediate amines ANHR a for use in the coupling reaction described above are known, others can be derived therefrom using these standard synthetic methods.
  • compounds of the invention and intermediates thereto may be prepared by alkylation, arylation or heteroarylation.
  • compounds containing a -L 1 H, -L 2 H, or -L 3 H group may be treated with an alkylating agent:
  • a leaving atom or group such as a halogen atom, e.g. a fluorine, bromine, iodine or chlorine atom or a sulphonyloxy group
  • R 7a is an alkyl group.
  • the reaction may be carried out in the presence of a base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran.
  • a base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride
  • a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran.
  • compounds containing a -L 1 H, -L 2 H or -L 3 H group as defined above may be functionalised by acylation or thioacylation, for example by reaction with one of the alkylating agents just described but in which X 2 is replaced by a -C(O)X 3 , C(S)X 3 , -N(R 8 )COX 3 or -N(R 8 )C(S)X 3 group in which X 3 is a leaving atom or group as described for X 2 .
  • the reaction may be performed in the presence of a base, such as a hydride, e.g. sodium hydride or an amine, e.g.
  • a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or carbon tetrachloride or an amide, e.g. dimethylformamide, at for example ambient temperature.
  • a halogenated hydrocarbon e.g. dichloromethane or carbon tetrachloride
  • an amide e.g. dimethylformamide
  • the acylation or thioacylation may be carried out under the same conditions with an acid or thioacid (for example one of the alkylating agents described above in which X 2 is replaced by a -CO 2 H or -COSH group) in the presence of a condensing agent, for example a diimide such as 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide or N,N'-dicyclohexylcarbodi- imide, advantageously in the presence of a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxybenzotriazole.
  • the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to the desired acylation reaction
  • compounds may be obtained by sulphonylation of a compound containing an -OH group by reaction with one of the above alkylating agents but in which X 2 is replaced by a -S(O)Hal or -SO 2 Hal group in which Hal is a halogen atom such as chlorine atom] in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
  • a base for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
  • compounds containing a -L 1 H, -L 2 H or -L 3 H group as defined above may be coupled with one of the alkylation agents just described but in which X 2 is replaced by an -OH group in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl, diisopropyl- or dimethylazodicarboxylate.
  • ester groups -CO 2 R 8 or -CO 2 Alk 5 in the compounds may be converted to the corresponding acid [-CO 2 H] by acid- or base- catalysed hydrolysis depending on the nature of the groups R 8 or Alk 5 .
  • Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
  • an organic or inorganic acid e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
  • -OR 8 or -OR 14 groups [where R 8 or R 14 each represents an alkyl group such as methyl group] in compounds of formula (1) may be cleaved to the corresponding alcohol -OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around -78°C.
  • a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around -78°C.
  • Alcohol [-OH] groups may also be obtained by hydrogenation of a corresponding -OCH 2 R 14 group (where R 14 is an aryl group) using a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature.
  • a metal catalyst for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature.
  • -OH groups may be generated from the corresponding ester [-CO 2 Alk 5 or CO 2 R 8 ] or aldehyde [-CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
  • alcohol -OH groups in the compounds may be converted to a corresponding -OR 8 group by coupling with a reagent R 8 OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
  • a phosphine e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
  • Aminosulphonyiamino [-NHSO 2 NH 2 ] groups in the compounds may be obtained, in another example, by reaction of a corresponding amine [-NH 2 ] with sulphamide in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
  • amine (-NH 2 ) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
  • a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e
  • amine [-NH 2 ] groups in compounds of formula (1) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
  • a nitro [-NO 2 ] group may be reduced to an amine [- NH 2 ], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
  • a metal catalyst for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol
  • an acid such as hydrochloric acid
  • Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around -78° C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent.
  • a base for example a lithium base such as n-butyl or t-butyl lithium
  • a solvent such as tetrahydrofuran
  • an electrophile to introduce a desired substituent.
  • a formyl group may be introduced by using dimethylformamide as the electrophile
  • a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
  • sulphur atoms in the compounds may be oxidised to the corresponding sulphoxide or sulphone using an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
  • an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid
  • an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane
  • N-oxides of compounds of formula (1 ) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
  • an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid
  • an elevated temperature for example around 70°C to 80°C
  • a peracid such as peracetic acid in a solvent, e.g. dichloromethane
  • Salts of compounds of formula (1 ) may be prepared by reaction of a compound of formula (1) with an appropriate base in a suit able solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
  • a suit able solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
  • diastereomeric derivatives e.g. salts
  • diastereomeric derivatives may be produced by reaction of a mixture of enantiomers of formula (1 ) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (1 ) may be separated using chiral High Performance Liquid Chromatography.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • Diethyl malonate (7.41 g, 46.3mmol) was added to a slurry of NaH (60% oil dispersion, 2.04g, 50.9mmol) in THF (200ml) and stirred for 15 min, before adding a solution of 4-nitrobenzyl bromide (10. Og, 46.3mmol) in THF (100ml) by can nuisancea.
  • the reaction was stirred for 3h at room temperature then quenched by the addition of water (100ml).
  • the aqueous layer was separated and extracted with Et 2 O (200ml).
  • the combined organic layers were washed with brine (200ml), dried (MgSO4 ) and the solvent evaporated in vacuo to give an off-white solid.
  • Tin (II) chloride 28.8g, 0.128mmol was added to a solution of Intermediate 6 (7.54g, 25.6mmol) in EtOH (150ml) and the reaction stirred for 72h at room temperature. The solvent was removed in vacuo and the residue was treated with 35% aqueous KOH (100ml), stirred for 30min and partitioned between EtOAc (200ml) and water (100ml). The organic layer was washed with brine, dried (MgSO4) and the solvent evaporated in vacuo to give an oil. Trituration with Et 2 O/hexane (1 :1, 50ml) gave the title compound (2.86g, 42%) as an off white solid.
  • LiOH.H 2 O 120mg, 2.9mmol was added to a solution of the compound of Example 1 (0.98g, 1.9mmol) in THF (10ml) and water (5ml) and the reaction stirred at room temperature for 1.5h, then acidified to pH1 with 10% hydrochloric acid and extracted with DCM (2 x 25ml). The combined organic layers were dried (MgSO4) and the solvent evaporated in vacuo to give a white foam that was triturated with DCM/Et 2 O to give the title compound as a white solid (0.52 ⁇ . 54%).
  • the following assays can be used to demonstrate the potency and selectivity of the compounds according to the invention.
  • ⁇ Inte ⁇ rin-dependent JY cell adhesion to MAdCAM-l ⁇ This assay was performed in the same manner as the ot4 ⁇ assay except that MAdCAM-lg (150ng/ml) was used in place of 2d VCAM-lg and a sub- line of the ⁇ -lympho blastoid cell-line JY was used in place of Jurkat cells. The IC50 value for each test compound was determined as described in the ot4 ⁇ integrin assay. ctt ⁇ Inte ⁇ rin-dependent K562 cell adhesion to fibronectin
  • 96 well tissue culture plates were coated with human plasma fibronectin (Sigma F0895) at 5 ⁇ g/ml in phosphate-buffered saline (PBS) for 2 hr at 37°C.
  • the plates were washed (3x in PBS) and then blocked for 1h in 100 ⁇ l PBS/1 % BSA at room temperature on a rocking platform.
  • the blocked plates were washed (3x in PBS) and the assay then performed at 37°C in a total volume of 200 ⁇ l containing 2.5x 10 5 K562 cells, phorbol- 12-myristate-13-acetate at 10ng/ml, and in the presence or absence of titrated test compounds. Incubation time was 30 minutes.
  • Each plate was fixed and stained as described in the ct4 ⁇ assay above.
  • 96 well tissue culture plates were coated with RPM I 1640/10% FCS for 2h at 37° C.
  • 2 x 10 5 freshly isolated human venous polymorphonuclear neutrophils (PMN) were added to the wells in a total volume of 200 ⁇ l in the presence of 10ng/ml phorbol-12-myristate-13-acetate, and in the presence or absence of test compounds, and incubated for 20min at 37° C followed by 30min at room temperature.
  • PMN human venous polymorphonuclear neutrophils
  • TMB tetramethyl benzidine
  • Human platelet aggregation was assessed using impedance aggregation on the Chronolog Whole Blood Lumiaggregometer.
  • Human platelet-rich plasma (PRP) was obtained by spinning fresh human venous blood anticoagulated with 0.38% (v/v) tri-sodium citrate at 220xg for 10 min and diluted to a cell density of 6 x 10 8 /ml in autologous plasma.
  • Cuvettes contained equal volumes of PRP and filtered Tyrode's buffer (g/liter: NaCI 8.0; MgCI 2 .H 2 O 0.427; CaCI 2 0.2; KCI 0.2; D-giucose 1.0; NaHCO 3 1.0; NaHPO4.2H 2 O 0.065). Aggregation was monitored following addition of 2.5 ⁇ M ADP (Sigma) in the presence or absence of inhibitors.
  • the preferred compounds of the invention generally have IC50 values in the ot4 ⁇ and ⁇ 4 ⁇ 7 assays of 1 ⁇ M and below.
  • the same compounds had IC50 values of 50 ⁇ M and above thus demonstrating the potency and selectivity of their action against 0:4 integrins.

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Abstract

L'invention concerne des dérivés d'acide phénylalcanoïque représentés par la formule (1) dans laquelle: Ar1 représente un groupe aromatique ou hétéroaromatique; L1 représente une liaison covalente ou un atome ou un groupe de liaison; A représente un groupe aliphatique, hétéroaliphatique, cycloaliphatique, polycycloaliphatique, hétérocycloaliphatique, polyhétérocycloaliphatique, aromatique ou hétéroaromatique éventuellement substitué; R représente un acide carboxylique (-CO¿2?H) ou un dérivé de ce dernier. L'invention concerne également les sels, solvates, hydrates et N-oxydes de ces composés. Les composés sont capables d'inhiber la liaison d'intégrines alpha-4 avec leurs ligands et s'utilisent pour la prophylaxie et le traitement de troubles immunitaires ou inflammatoires.
PCT/GB1999/003243 1998-10-01 1999-09-30 Derives d'acide phenylalcanoique comme inhibiteurs d'integrines alpha-4 WO2000020396A1 (fr)

Priority Applications (3)

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EP99947708A EP1117646A1 (fr) 1998-10-01 1999-09-30 Derives d'acide phenylalcanoique comme inhibiteurs d'integrines alpha-4
JP2000574513A JP2002526533A (ja) 1998-10-01 1999-09-30 アルファ４インテグリンインヒビターとしてのフェニルアルカン酸誘導体
AU61083/99A AU6108399A (en) 1998-10-01 1999-09-30 Phenylalkanoic acid derivatives as inhibitors of alpha4 integrins

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GBGB9821406.7A GB9821406D0 (en) 1998-10-01 1998-10-01 Chemical compounds

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001092233A1 (fr) * 2000-05-30 2001-12-06 Celltech R & D Limited Derives de isoquinoline-1-yl 3-substitue
WO2002008222A2 (fr) * 2000-07-21 2002-01-31 Elan Pharmaceuticals, Inc. Derives de heteroaryle-beta-alanine en tant qu'inhibiteurs d'alpha-4-integrine
WO2002020522A1 (fr) * 2000-09-06 2002-03-14 Celltech R & D Limited Dérivés bicycliques de l'énamide, inhibiteurs de l'intégrine
US6369229B1 (en) 1998-06-03 2002-04-09 Celltech Therapeutics, Limited Pyridylalanine derivatives
US6555562B1 (en) 1998-02-26 2003-04-29 Celltech R&D Limited Phenylalanine derivatives
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
US6960597B2 (en) 2000-06-30 2005-11-01 Orth-Mcneil Pharmaceutical, Inc. Aza-bridged-bicyclic amino acid derivatives as α4 integrin antagonists
WO2015136468A1 (fr) 2014-03-13 2015-09-17 Prothena Biosciences Limited Polythérapie pour la sclérose en plaques

Citations (2)

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Publication number Priority date Publication date Assignee Title
DE2837264A1 (de) * 1977-08-25 1979-03-01 Shionogi & Co 7 beta -arylmalonamido-7 alpha -methoxy-3-thiadiazolylthio-1-oxadethiacephalosporine, ihre ester und salze, sowie verfahren zu deren herstellung
WO1993009795A1 (fr) * 1991-11-22 1993-05-27 Yeda Research And Development Co. Ltd. Succedanes non peptidiques de la sequence arg-gly-asp, et compositions pharmaceutiques les contenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2837264A1 (de) * 1977-08-25 1979-03-01 Shionogi & Co 7 beta -arylmalonamido-7 alpha -methoxy-3-thiadiazolylthio-1-oxadethiacephalosporine, ihre ester und salze, sowie verfahren zu deren herstellung
WO1993009795A1 (fr) * 1991-11-22 1993-05-27 Yeda Research And Development Co. Ltd. Succedanes non peptidiques de la sequence arg-gly-asp, et compositions pharmaceutiques les contenant

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6555562B1 (en) 1998-02-26 2003-04-29 Celltech R&D Limited Phenylalanine derivatives
US6369229B1 (en) 1998-06-03 2002-04-09 Celltech Therapeutics, Limited Pyridylalanine derivatives
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
WO2001092233A1 (fr) * 2000-05-30 2001-12-06 Celltech R & D Limited Derives de isoquinoline-1-yl 3-substitue
US6960597B2 (en) 2000-06-30 2005-11-01 Orth-Mcneil Pharmaceutical, Inc. Aza-bridged-bicyclic amino acid derivatives as α4 integrin antagonists
WO2002008222A3 (fr) * 2000-07-21 2002-06-13 Elan Pharm Inc Derives de heteroaryle-beta-alanine en tant qu'inhibiteurs d'alpha-4-integrine
WO2002008222A2 (fr) * 2000-07-21 2002-01-31 Elan Pharmaceuticals, Inc. Derives de heteroaryle-beta-alanine en tant qu'inhibiteurs d'alpha-4-integrine
US7015216B2 (en) 2000-07-21 2006-03-21 Elan Pharmaceuticals, Inc. Heteroaryl-β-alanine derivatives as alpha 4 integrin inhibitors
WO2002020522A1 (fr) * 2000-09-06 2002-03-14 Celltech R & D Limited Dérivés bicycliques de l'énamide, inhibiteurs de l'intégrine
US6603041B2 (en) 2000-09-06 2003-08-05 Celltech R & D Limited Bicyclic enamide derivatives
WO2015136468A1 (fr) 2014-03-13 2015-09-17 Prothena Biosciences Limited Polythérapie pour la sclérose en plaques

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JP2002526533A (ja) 2002-08-20
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AU6108399A (en) 2000-04-26

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