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WO1999006436A1 - Composes de benzyle inhibant une adhesion de leucocytes regulee par vla-4 - Google Patents

Composes de benzyle inhibant une adhesion de leucocytes regulee par vla-4 Download PDF

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Publication number
WO1999006436A1
WO1999006436A1 PCT/US1998/015327 US9815327W WO9906436A1 WO 1999006436 A1 WO1999006436 A1 WO 1999006436A1 US 9815327 W US9815327 W US 9815327W WO 9906436 A1 WO9906436 A1 WO 9906436A1
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WO
WIPO (PCT)
Prior art keywords
phenylalanine
prolyl
sulfonyl
toluene
substimted
Prior art date
Application number
PCT/US1998/015327
Other languages
English (en)
Inventor
Eugene D. Thorsett
Christopher M. Semko
Michael A. Pleiss
Louis John Lombardo
Andrei W. Konradi
Francine S. Grant
Darren B. Dressen
Michael S. Dappen
Original Assignee
Elan Pharmaceuticals, Inc.
American Home Products Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Elan Pharmaceuticals, Inc., American Home Products Corporation filed Critical Elan Pharmaceuticals, Inc.
Priority to BR9811573-1A priority Critical patent/BR9811573A/pt
Priority to KR1020007000993A priority patent/KR20010022413A/ko
Priority to JP2000505191A priority patent/JP2001512138A/ja
Priority to IL13363598A priority patent/IL133635A0/xx
Priority to AU85851/98A priority patent/AU8585198A/en
Priority to HU0002680A priority patent/HUP0002680A3/hu
Priority to CA002291473A priority patent/CA2291473A1/fr
Priority to EP98937054A priority patent/EP1001975A1/fr
Publication of WO1999006436A1 publication Critical patent/WO1999006436A1/fr
Priority to NO20000414A priority patent/NO20000414L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • This invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4.
  • VLA-4 (also referred to as ⁇ 4 ⁇ l integrin and CD49d/CD29), first identified by Hemler and Takada 1 , is a member of the ⁇ l integrin family of cell surface receptors, each of which comprises two subunits, an ⁇ chain and a ⁇ chain.
  • VLA-4 contains an ⁇ 4 chain and a ⁇ l chain.
  • VLA-4 for example, binds to fibronectin.
  • VLA-4 is unique among ⁇ j integrins in that it also binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed on cytokine-activated human umbilical vein endothelial cells in culture. Distinct epitopes of VLA-4 are responsible for the fibronectin and VCAM-1 binding activities, and each activity has been shown to be inhibited independently. 2
  • Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a number of inflammatory responses.
  • activated vascular endothelial cells express molecules that are adhesive for leukocytes.
  • the mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release chemical mediators to combat infection.
  • adhesion receptors of the immune system see, for example, Springer 3 and Osborn 4 .
  • Inflammatory brain disorders such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of central nervous system disorders in which the endothelium/leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue.
  • EAE experimental autoimmune encephalomyelitis
  • MS multiple sclerosis
  • M multiple sclerosis
  • meningitis are examples of central nervous system disorders in which the endothelium/leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue.
  • BBB blood brain barrier
  • the leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis.
  • tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes.
  • tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes.
  • the initial insult following myocardial ischemia to heart tissue can be further complicated by leukocyte entry to the injured tissue causing still further insult (Vedder et al. 5 ).
  • inflammatory conditions mediated by an adhesion mechanism include, by way of example, asthma 6"8 , Alzheimer's disease, atherosclerosis 9"10 , AIDS dementia 11 , diabetes 12 14 (including acute juvenile onset diabetis), inflammatory bowel disease 15 (including ulcerative colitis and Crohn's disease), multiple sclerosis 16"17 , rheumatoid arthritis 18"21 , tissue transplantation 22 , tumor metastasis 23 28 , meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
  • This invention provides compounds which bind to VLA-4.
  • Such compounds can be used, for example, to assay for the presence of VLA-4 in a sample and, in pharmaceutical compositions, to inhibit cellular adhesion mediated by VLA-4, for example, binding of VCAM-1 to VLA-4.
  • the compounds of this invention have a binding affinity to VLA-4 as expressed by an IC 50 of about 15 ⁇ M or less (as measured by Example 95 below), which compounds are defined by formula I below:
  • R 1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
  • R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 form a saturated heterocyclic group or a saturated substituted heterocyclic group with the proviso that when monosubstituted, the substituent on said saturated heterocyclic group is not carboxyl;
  • R 5 is selected from the group consisting of -(CH 2 ) n -aryl and -(CH 2 ) n -heteroaryl, where n is an integer equal to 1 to 4;
  • Q is -C(X)NR 7 - wherein R 7 is selected from the group consisting of hydrogen and alkyl, and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof, with the proviso that when R 1 is 2,4,6-trimethylphenyl, R 2 and R 3 together with the pendent nitrogen and carbon atoms form a pyrrolidinyl ring and Q is -C(O)NH-, then R 5 is not benzyl; and with the further proviso that when R 1 is /?-methylphenyl, R 2 and R 3 together with the pendent nitrogen and carbon atoms form a pyrrolidinyl ring derived from D-proline and Q is -C(O)NH-, then R 5 is not benzyl derived from D-phenylalanine.
  • the compounds of this invention can also be provided as prodrugs which convert (e.g., hydrolyze, metabolize, etc.) in vivo to a compound of formula I above.
  • the carboxylic acid of the compound of formula I is modified into a group which, in vivo, will convert to a carboxylic acid (including salts thereof).
  • prodrugs are represented by compounds of formula IA:
  • R 1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
  • R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 form a saturated heterocyclic group or a saturated substituted heterocyclic group with the proviso that when monosubstituted, the substituent on said saturated heterocyclic group is not carboxyl;
  • R 5 is selected from the group consisting of -(CH 2 ) n -aryl and
  • n is an integer equal to 1 to 4.
  • R 6 is selected from the group consisting of amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, -O-(N-succinimidyl), -NH- adamantyl, -O-cholest-5-en-3- ⁇ -yl, -NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl,
  • -NH(CH 2 ) p COOY where p is an integer of from 1 to 8 and Y is as defined above, -OCH 2 NR 9 R 10 where R 9 is selected from the group consisting of -C(O)-aryl and -C(O)-substituted aryl and R 10 is selected from the group consisting of hydrogen and -CH 2 COOR n where R 11 is alkyl, and -NHSO 2 Z where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
  • Q is -C(X)NR 7 - wherein R 7 is selected from the group consisting of hydrogen and alkyl, and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof, with the following provisos:
  • R 1 is 4-methylphenyl
  • R 2 and R 3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring
  • R 5 is benzyl and Q is -C(O)NH-
  • R 6 is not -NH(CH 2 ) 2 CO 2 Et or -(lR,2S,5R)-(-)- menthyl ester;
  • R 1 is 4-methylphenyl
  • R 2 and R 3 together with the pendent nitrogen and carbon atoms form a 3- ⁇ -phenyl-ring derived from D- proline
  • R 5 is benzyl and Q is -C(O)NH-
  • R 6 is not -OCH 2 CH 3
  • C when R 1 is l-N-methyl-3-methyl-5-chloropyrazol-4-yl, R 2 and R 3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2- yl ring, R 5 is benzyl and Q is -C(O)NH-, then R 6 is not -OCH 3 ;
  • R 1 is 4-methylphenyl
  • R 2 and R 3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring
  • R 5 is
  • D-benzyl and Q is -C(O)NH-, then R 6 is not -OCH 2 CH 3 ;
  • R 6 is not -O-benzyl.
  • R 1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl.
  • R 1 is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1- naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl, 2- (methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4- trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4-
  • Such heterocyclic rings include thiazolidinyl
  • pyrrolidinyl e.g., L-pyrrolidin-2-yl
  • substituted pyrrolidinyl such as 4- hydroxypyrrolidinyl (e.g. , 4- ⁇ -(or ⁇ -)hydroxy-L-pyrrolidin-2-yl), 4-fluoropyrrolidinyl (e.g.
  • 4- -(or ⁇ -)fluoro-L-pyrrolidin-2-yl 3- phenylpyrrolidinyl (e.g., 3- ⁇ -(or ⁇ -)phenyl-L-pyrrolidin-2-yl), 3- thiophenylpyrrolidinyl (e.g., 3- ⁇ -(or ⁇ -)thiophenyl-L-pyrrolidin-2-yl), 4- aminopyrrolidinyl (e.g., 4- ⁇ -(or ⁇ -)amino-L-pyrrolidin-2-yl), 3- methoxypyrrolidinyl (e.g., 3- ⁇ -(or ⁇ -)methoxy-L-pyrrolidin-2-yl), 4,4- dimethylpyrrolidin-2-yl, substituted piperizinyl such as 4-N-Cbz-piperizin-2- yl, substituted thiazolidinyl such as 5,5-dimethylthiazolindin-4-yl,
  • such rings do not include those where R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 form a azetidine ring.
  • Q is preferably -C(O)NH- or -C(S)NH-.
  • R 5 is preferably selected from all possible isomers arising by substitution of the following groups: benzyl, phenethyl, -CH 2 -(3-indolyl), -CH 2 -(l-naphthyl), -CH 2 -(2-naphthyl), -CH 2 -(2-thienyl), -CH 2 -(3-pyridyl), -CH 2 -(5-imidazolyl), -CH 2 -3-(l,2,4-triazolyl), -CH 2 -(2-thiazolyl) and the like.
  • R 6 is preferably 2,4-dioxo- tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-p ⁇ opoxy , n-butoxy, t-butoxy, cyclopentoxy, ne ⁇ -pentoxy, 2- ⁇ - so-propyl-4- ⁇ - methylcyclohexoxy, 2- ⁇ -isopropyl-4- ⁇ -methylcyclohexoxy, -NH 2 , benzyloxy, -NHCH 2 COOH, -NHCH 2 CH 2 COOH, -NH-adamantyl, -NHCH 2 CH 2 COOCH 2 CH 3 , -NHSO 2 -/?-CH 3 - ⁇ , -NHOR 8 where R 8 is hydrogen, methyl, ts ⁇ -propyl or benzyl, O-(N-succinimidyl), -O-cholest-5-en-3- ⁇ -yl,
  • ester compounds recited above wherein one ester is replaced with another ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert- butyl ester.
  • This invention also provides methods for binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound of formula I or IA above under conditions wherein said compound binds to VLA-4.
  • Certain of the compounds of formula I and IA above are also useful in reducing VLA-4 mediated inflammation in vivo.
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of formula I or I A above, with the exception that R 3 and R 5 are derived from L-amino acids or other similarly configured starting materials. Alternatively, racemic mixtures can be used.
  • the pharmaceutical compositions may be used to treat VLA-4 mediated disease conditions.
  • disease conditions include, by way of example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetis), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
  • this invention also provides methods for the treatment of an inflammatory disease in a patient mediated by VLA-4 which methods comprise administering to the patient the pharmaceutical compositions described above.
  • Preferred compounds of formula I and IA above include those set forth in Table I below:
  • this invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA- 4.
  • VLA- 4 leukocyte adhesion mediated by VLA- 4.
  • alkyl refers to alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.
  • Substituted alkyl refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxy lalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxy 1-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxy lheteroaryl
  • Alkoxy refers to the group “alkyl-O-" which includes, by way of example, methoxy, ethoxy, n-propoxy, /s ⁇ -propoxy, n-butoxy, tert-butoxy, sec-butoxy, rz-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Substituted alkoxy refers to the group “substituted alkyl-O-” .
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substimted alkyl- C(O)-, alkenyl-C(O)-, substimted alkenyl-C(O)-, alkynyl-C(O)-, substimted alkynyl-C(O)- cycloalkyl-C(O)-, substimted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substimted heteroaryl-C(O), heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substimted alkenyl, alkynyl, and
  • Acylamino refers to the group -C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic, and where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic, and where each R is independently selected from the group consisting of hydrogen, alkyl,
  • R is joined to form, together with the nitrogen atom, a heterocyclic or substimted heterocyclic ring, wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic are as defined herein.
  • Thiocarbonylamino refers to the group -C(S)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substituted alkynyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic, and where each R is joined to form, together with the nitrogen atom, a heterocyclic or substimted heterocyclic ring, wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted
  • Acyloxy refers to the groups alkyl-C(0)O-, substituted alkyl-C(O)O-, alkenyl-C(O)O-, substimted alkenyl-C(O)O-, alkynyl-C(O)O-, substimted alkynyl-C(O)O-, aryl-C(O)O-, substimted aryl-C(O)O-, cycloalkyl-C(O)O-, substimted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substimted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substimted heterocyclic-C(O)O-, wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, sub
  • Alkenyl refers to an alkenyl group preferably having from 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms, and having at least
  • Substimted alkenyl refers to alkenyl groups having from 1 to 5 substiments selected from the group consisting of alkoxy, substimted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substimted aryl, aryloxy, substimted aryloxy, aryloxy aryl, substimted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxy lalkyl, carboxy 1-substituted alkyl, carboxyl- cycloalkyl, carboxy 1-substituted cycloalkyl, carboxylaryl, carboxyl- substituted aryl, carboxy lheteroaryl, carboxyl-substi
  • R is hydrogen or alkyl, mono- and di- alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-substimted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-heterocyclic amino, mono- and
  • Alkynyl refers to an alkynyl group preferably having from 2 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms, and having at least 1, and preferably from 1-2, sites of alkynyl unsaturation.
  • Substimted alkynyl refers to alkynyl groups having from 1 to 5 substiments selected from the group consisting of alkoxy, substimted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substimted aryl, aryloxy, substimted aryloxy, aryloxyaryl, substimted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxy 1-substituted alkyl, carboxyl- cycloalkyl, carboxy 1-substituted cycloalkyl, carboxy laryl, carboxyl- substituted aryl, carboxy lheteroaryl, carboxyl-sub
  • NH refers to compounds having 1 to 3 alkyl groups (e.g., alkylHNC-).
  • Thioamidino refers to the group RSC-, where R is hydrogen or
  • aminoacyl refers to the groups -NRC(O)alkyl, -NRC(O)substituted alkyl, -NRC(O)cycloalkyl, -NRC(O)substituted cycloalkyl, -NRC(O)alkenyl, -NRC(O)substituted alkenyl, -NRC(O)alkynyl,
  • R is hydrogen or alkyl, and wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic are as defined herein.
  • Aminocarbonyloxy refers to the groups -NRC(O)O-alkyl
  • Oxycarbonylamino refers to the groups -OC(O)NH 2 , -OC(O)NRR, -OC(O)NR-alkyl, -OC(O)NR-substituted alkyl, -OC(O)NR-alkenyl, -OC(O)NR-substituted alkenyl, -OC(O)NR-alkynyl, -OC(O)NR-substituted alkynyl, -OC(O)NR-cycloalkyl, -OC(O)NR-substituted cycloalkyl, -OC(O)NR-aryl, -OC(O)NR-substimted aryl, -OC(O)NR-heteroaryl, -OC(O)NR-substituted heteroaryl,- OC(O)NR-heterocyclic, and -OC(O)NR-substimted heterocyclic where R is hydrogen, alkyl
  • Oxythiocarbonylamino refers to the groups -OC(S)NH 2 , -OC(S)NRR, -OC(S)NR-alkyl, -OC(S)NR-substituted alkyl, -OC(S)NR- alkenyl, -OC(S)NR-substituted alkenyl, -OC(S)NR-alkynyl, -OC(S)NR- substimted alkynyl, -OC(S)NR-cycloalkyl, -OC(S)NR-substituted cycloalkyl, -OC(S)NR-aryl, -OC(S)NR-substimted aryl, -OC(S)NR-heteroaryl, - OC(S)NR-substimted heteroaryl, -OC(S)NR-heterocyclic, and -OC(S)NR-substituted heterocyclic where R is hydrogen
  • Aminocarbonylamino refers to the groups -NRC(O)NRR, -NRC(O)NR-alkyl, -NRC(O)NR-substituted alkyl, -NRC(O)NR-alkenyl, -NRC(O)NR-substituted alkenyl, -NRC(O)NR-alkynyl, -NRC(O)NR- substimted alkynyl, -NRC(O)NR-aryl, -NRC(O)NR-substituted aryl,
  • each R is independently hydrogen or alkyl, or where each R is joined to form, together with the nitrogen atom, a heterocyclic or substimted heterocyclic ring, as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, and wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, subs
  • Aminothiocarbonylamino refers to the groups -NRC(S)NRR, -NRC(S)NR-alkyl, -NRC(S)NR-substituted alkyl, -NRC(S)NR-alkenyl, -NRC(S)NR-substimted alkenyl, -NRC(S)NR-alkynyl, -NRC(S)NR- substimted alkynyl, -NRC(S)NR-aryl, -NRC(S)NR-substituted aryl, -NRC(S)NR-cycloalkyl, -NRC(S)NR-substimted cycloalkyl, -NRC(S)NR- heteroaryl, -NRC(S)NR-substimted heteroaryl, -NRC(S)NR-heterocyclic, and -NRC(S)NR-substituted heterocyclic where each R
  • Aryl or “Ar” refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)- one-7yl, and the like).
  • Preferred aryls include phenyl and naphthyl.
  • Substimted aryl refers to aryl groups which are substimted with from 1 to 3 substiments selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substimted alkyl, alkoxy, substimted alkoxy, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substimted aryl, aryloxy, substimted aryloxy, cycloalkoxy, substimted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alky
  • thioheteroaryl substimted thioheteroaryl, thiocycloalkyl, substituted thiocycloalkyl, thioheterocyclic, substimted thioheterocyclic, cycloalkyl, substituted cycloalkyl, guanidino, guanidinosulfone, halo, nitro, heteroaryl, substituted heteroaryl, heterocyclic, substimted heterocyclic, oxycarbonylamino, oxythiocarbonylamino, -S(O) 2 -alkyl, -S(O) 2 -substituted alkyl, -S(O) 2 -cycloalkyl, -S(O) 2 -substituted cycloalkyl, -S(O) 2 -alkenyl, -S(O) 2 -substimted alkenyl, -S(O) 2 -aryl,
  • R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di- substituted arylamino, mono- and di-heteroarylamino, mono- and di- substituted heteroarylamino, mono- and di-heterocyclic amino, unsymmetric di-substituted amines having
  • Substimted aryloxy refers to substituted aryl-O- groups.
  • Aryloxyaryl refers to the gioup -aryl-O-aryl.
  • “Substimted aryloxyaryl” refers to aryloxyaryl groups substimted with from 1 to 3 substiments on either or both aryl rings selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substimted alkyl, alkoxy, substimted alkoxy, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substimted aryl, aryloxy, substimted aryloxy, cycloalkoxy, substimted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylal
  • R is hydrogen or alkyl, mono- and di- alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substimted arylamino, mono- and di-heteroarylamino, mono- and di-substimted heteroarylamino, mono- and di-heterocyclic amino, mono- and di
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Excluded from this definition are multi-ring alkyl groups such as adamantanyl, etc.
  • Cycloalkenyl refers to cyclic alkenyl groups of from 3 to 8 carbon atoms having single or multiple unsaturation but which are not aromatic.
  • Cycloalkoxy refers to -O-cycloalkyl groups.
  • Substimted cycloalkoxy refers to -O-substituted cycloalkyl groups.
  • each R is independently hydrogen and alkyl, as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like, and wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substimted heterocyclic are as defined herein.
  • Halo or halogen refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo.
  • Heteroaryl refers to an aromatic carbocyclic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
  • Preferred heteroaryls include pyridyl, pyrrolyl, indolyl and furyl.
  • Substituted heteroaryl refers to heteroaryl groups which are substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substimted alkoxy, alkenyl, substimted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidmo, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substimted aryl, aryloxy, substimted aryloxy, cycloalkoxy, substimted cycloalkoxy, heteroaryloxy, substimted heteroaryloxy, heterocyclyloxy, substimted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substimted alkyl
  • Heteroaryloxy refers to the group -O-heteroaryl and "substimted heteroaryloxy” refers to the group -O-substituted heteroaryl.
  • Heterocycle or “heterocyclic” refers to a saturated or unsaturated group having a single ring or multiple condensed rings having from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more the rings can be aryl or heteroaryl.
  • “Saturated heterocyclic” refers to heterocycles of single or multiple condensed rings lacking unsaturation in any ring (e.g., carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).
  • Unsaturated heterocyclic refers to non-aromatic heterocycles of single or multiple condensed rings having unsaturation in any ring (e.g., carbon to carbon unsaturation, carbon to nitrogen unsaturation, nitrogen to nitrogen unsaturation, and the like).
  • heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7- tetra
  • “Saturated substimted heterocyclic” refers to substimted heterocycles of single or multiple condensed rings lacking unsamration in any ring (e.g., carbon to carbon unsamration, carbon to nitrogen unsamration, nitrogen to nitrogen unsamration, and the like).
  • Unsaturated substimted heterocyclic refers to non-aromatic substituted heterocycles of single or multiple condensed rings having unsamration in any ring (e.g., carbon to carbon unsamration, carbon to nitrogen unsamration, nitrogen to nitrogen unsamration, and the like).
  • Heterocyclyloxy refers to the group -O-heterocyclic and “substimted heterocyclyloxy” refers to the group -O-substimted heterocyclic.
  • Thiol refers to the group -SH.
  • Thioalkyl refers to the groups -S-alkyl
  • Substimted thioalkyl refers to the group -S-substimted alkyl.
  • Thiocycloalkyl refers to the groups -S-cycloalkyl.
  • Substimted thiocycloalkyl refers to the group -S-substimted cycloalkyl.
  • Thioaryl refers to the group -S-aryl and "substimted thioaryl” refers to the group -S-substimted aryl.
  • Thioheteroaryl refers to the group -S-heteroaryl and "substimted thioheteroaryl” refers to the group -S-substimted heteroaryl.
  • Thioheterocyclic refers to the group -S-heterocyclic and "substimted thioheterocyclic” refers to the group -S-substimted heterocyclic.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound of formula I or I A, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound of formula I or I A contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
  • the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. In a preferred method of synthesis, the compounds of formulas I and IA, wherein Q is -C(O)NR 7 -, are prepared by first coupling an amino acid of formula II:
  • R 2 and R 3 are as defined in formulas I and IA, and R 4 is hydrogen, with a sulfonyl chloride of formula III:
  • R 1 is as defined in formulas I and I A, to provide an N-sulfonyl amino acid of formula IV:
  • R -R are as defined above.
  • This reaction is typically conducted by reacting the amino acid of formula II with at least one equivalent, preferably about 1.1 to about 2 equivalents, of sulfonyl chloride III in an inert diluent such as dichloromethane and the like. Generally, the reaction is conducted at a temperamre ranging from about -70 °C to about 40 °C for about 1 to about 24 hours. Preferably, this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like.
  • reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like, as the base.
  • aqueous alkali such as sodium hydroxide and the like
  • the resulting N-sulfonyl amino acid IV is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration and the like.
  • amino acids of formula II employed in the above reaction are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures.
  • suitable amino acids for use in this reaction include, but are not limited to, L-proline, tr ⁇ ns-4-hydroxyl-L-proline , c/s-4-hydroxy 1-L-proline , tr ⁇ /w-3-phenyl-L- proline, s-3-phenyl-L-proline, L-(2-methyl)proline, L-pipecolinic acid, L- indoline-2-carboxylic acid, L-l ,2,3 ,4-tetrahydroisoquinoline-3-carboxylic acid, L-thiazolidine-4-carboxylic acid, L-(5,5-dimethyl)thiazolidine-4- carboxylic acid, L-thiamorpholine-3-carboxylic acid, glycine, 2-tert- butylglycine, D,L-phenylglycine, L-alanine,
  • the corresponding carboxylic acid esters of the amino acids of formula II can be employed in the above reaction with the sulfonyl chloride III.
  • the sulfonyl chlorides of formula III employed in the above reaction are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. Such compounds are typically prepared from the corresponding sulfonic acid, i.e. , from compounds of the formula R ⁇ SOsH where R 1 is as defined above, using phosphorous trichloride and phosphorous pentachloride.
  • This reaction is generally conducted by contacting the sulfonic acid with about 2 to 5 molar equivalents of phosphorous trichloride and phosphorous pentachloride, either neat or in an inert solvent, such as dichloromethane, at a temperamre in the range of about 0°C to about 80 °C for about 1 to about 48 hours to afford the sulfonyl chloride.
  • the sulfonyl chlorides of formula III can be prepared from the corresponding thiol compound, i.e., from compounds of the formula R ⁇ SH where R 1 is as defined above, by treating the thiol with chlorine (Cl 2 ) and water under conventional reaction conditions.
  • sulfonyl chlorides suitable for use in this invention include, but are not limited to, methanesulfonyl chloride, 2-propanesulfonyl chloride, 1-butanesulfonyl chloride, benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, -toluenesulfonyl chloride, -toluenesulfonyl chloride, 4-acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride,
  • 4-rert-butylbenzenesulfonyl chloride 4-bromobenzenesulfonyl chloride, 2-carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride, 3,4-dichlorobenzenesulfonyl chloride, 3,5-dichlorobenzenesulfonyl chloride, 3,4-dimethoxybenzenesulfonyl chloride, 3,5- ditrifluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-methoxybenzenesulfony 1 chloride , 2-methoxycarbony Ibenzenesulf onyl chloride, 4-methylamidobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4-thioamidobenzenesulfonyl chloride, 4- tr ifluoromethy
  • a sulfonyl fluoride, sulfonyl bromide or sulfonic acid anhydride may be used in place of the sulfonyl chloride in the above reaction to form the N-sulfonyl amino acids of formula IV.
  • R 5 -R 7 are as in formulas I and IA.
  • This coupling reaction is typically conducted using well-known coupling reagents such as carbodiimides, BOP reagent (benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphonate) and the like.
  • Suitable carbodiimides include, by way of example, dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC) and the like.
  • polymer supported forms of carbodiimide coupling reagents may also be used including, for example, those described in Tetrahedron Letters, 34(48), 7685 (1993). Additionally, well-known coupling promoters, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like, may be used to facilitate the coupling reaction.
  • This coupling reaction is typically conducted by contacting the N-sulfonylamino acid IV with about 1 to about 2 equivalents of the coupling reagent and at least one equivalent, preferably about 1 to about 1.2 equivalents, of amino acid derivative VI in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N- dimethylformamide and the like.
  • an inert diluent such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N- dimethylformamide and the like.
  • this reaction is conducted at a temperamre ranging from about 0°C to about 37°C for about 12 to about 24 hours.
  • the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.
  • the N-sulfonyl amino acid IV can be converted into an acid halide and the acid halide coupled with amino acid derivative VI to provide compounds of formula I.
  • the acid halide of VI can be prepared by contacting VI with an inorganic acid halide, such as thionyl chloride, phosphorous trichloride, phosphorous tribromide or phosphorous pentachloride, or, preferably, with oxalyl chloride under conventional conditions.
  • this reaction is conducted using about 1 to 5 molar equivalents of the inorganic acid halide or oxalyl chloride, either neat or in an inert solvent, such as dichloromethane or carbon tetrachloride, at temperamre in the range of about 0°C to about 80 °C for about 1 to about 48 hours.
  • a catalyst such as N,N-dimethylformamide, may also be used in this reaction.
  • the acid halide of N-sulfonyl amino acid IV is then contacted with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of amino acid derivative VI in an inert diluent, such as dichloromethane, at a temperamre ranging from about -70 °C to about 40 °C for about 1 to about 24 hours.
  • this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction.
  • Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like.
  • reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like.
  • aqueous alkali such as sodium hydroxide and the like.
  • the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.
  • the compounds of formula I can be prepared by first forming a diamino acid derivative of formula VII:
  • the diamino acid derivatives of formula VII can be readily prepared by coupling an amino acid of formula II with an amino acid derivative of formula VI using conventional amino acid coupling techniques and reagents, such as carbodiimides, BOP reagent and the like, as described above. Diamino acid VII can then be sulfonated using a sulfonyl chloride of formula III and using the synthetic procedures described above to provide a compound of formula I.
  • the amino acid derivatives of formula VI employed in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. For example, amino acid derivatives of formula VI can be prepared by C- alkylating commercially available diethyl 2-acetamidomalonate (Aldrich,
  • amino acid derivatives of formula VI suitable for use in the above reactions include, but are not limited to, L-tryptophan methyl ester, L-phenylalanine methyl ester, L-phenylalanine isopropyl ester, L- phenylalanine benzyl ester, L-phenylalaninamide, N-methyl-L-phenylalanine benzyl ester, D,L-homophenylalanine methyl ester, ⁇ -(l-naphthyl)-L-alanine methyl ester, ⁇ -(2-naphthyl)-L-alanine methyl ester, ⁇ -(2-thienyl)-L-alanine methyl ester, ⁇ -(2-pyridyl)-L-alanine methyl ester, ⁇ -(3-pyridyl)-L-alanine methyl ester, ⁇ -(4-pyridyl)-L-alanine methyl
  • the compounds of formula I are typically prepared as an ester, i.e. , where R 6 is an alkoxy or substimted alkoxy group and the like.
  • the ester group can be hydrolysed using conventional conditions and reagents to provide the corresponding carboxylic acid.
  • this reaction is conducted by treating the ester with at least one equivalent of an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, in an inert diluent, such as methanol or mixtures of methanol and water, at a temperamre ranging from about 0°C to about 24 °C for about 1 to about 12 hours.
  • benzyl esters may be removed by hydrogenolysis using a palladium catalyst, such as palladium on carbon.
  • the resulting carboxylic acids may be coupled, if desired, to amines such as ⁇ -alanine ethyl ester, hydroxyamines such as hydroxylamine and N- hydroxysuccinimide, alkoxyamines and substimted alkoxyamines such as O- methylhydroxylamine and O-benzylhydroxylamine, and the like, using conventional coupling reagents and conditions as described above.
  • a nitro group present on a substituent of a compound of formula I or an intermediate thereof may be readily reduced by hydrogenation in the presence of a palladium catalyst, such as palladium on carbon, to provide the corresponding amino group.
  • a palladium catalyst such as palladium on carbon
  • This reaction is typically conducted at a temperamre of from about 20 °C to about 50 °C for about 6 to about 24 hours in an inert diluent, such as methanol.
  • Compounds having a nitro group on the R 5 substituent can be prepared, for example, by using a 4- nitrophenylalanine derivative and the like in the above-described coupling reactions.
  • a pyridyl group can be hydrogenated in the presence of a platinum catalyst, such as platinum oxide, in an acidic diluent to provide the corresponding piperidinyl analogue.
  • a platinum catalyst such as platinum oxide
  • this reaction is conducted by treating the pyridine compound with hydrogen at a pressure ranging from about 20 psi to about 60 psi, preferably about 40 psi, in the presence of the catalyst at a temperamre of about 20 °C to about 50 °C for about 2 to about 24 hours in an acidic diluent, such as a mixture of methanol and aqueous hydrochloric acid.
  • a compound of formula I, or an intermediate thereof, having a substituent containing a primary or secondary amino group, such as where R 1 is a 4-aminophenyl group can be readily N-acylated using conventional acylating reagents and conditions to provide the corresponding amide.
  • This acylation reaction is typically conducted by treating the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of a carboxylic acid in the presence of a coupling reagent such as a carbodiimide, BOP reagent (benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphonate) and the like, in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N-dimethylformamide and the like, at a temperamre ranging from about 0°C to about 37 °C for about 4 to about 24 hours.
  • a promoter such as N-hydroxysuccinimide,
  • carboxylic acids suitable for use in this reaction include, but are not limited to, N-tert-butyloxycarbonylglycine, N-tert- butyloxycarbonyl-L-pheny lalanine , N-tert-butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid, N-tert-butyloxycarbonylisonipecotic acid, N- methylisonipecotic acid, N-tert-butyloxycarbonylnipecotic acid, N-tert- butyloxycarbonyl-L-tetrahydroisoquinoline-3-carboxylic acid, N-(toluene-4- sulfonyl)-L-proline and the like.
  • a compound of formula I or an intermediate thereof containing a primary or secondary amino group can be N-acylated using an acyl halide or a carboxylic acid anhydride to form the corresponding amide.
  • This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the acyl halide or carboxylic acid anhydride in an inert diluent, such as dichloromethane, at a temperamre ranging from about -70 °C to about 40 °C for about 1 to about 24 hours.
  • an acylation catalyst such as 4- (NN-dimethylamino)pyridine may be used to promote the acylation reaction.
  • the acylation reaction is preferably conducted in the presence of a suitable base to scavenge the acid generated during the reaction.
  • suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like.
  • the reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like.
  • acyl halides and carboxylic acid anhydrides suitable for use in this reaction include, but are not limited to, 2-methylpropionyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2-bromobenzoyl chloride, 2-methylbenzoyl chloride,
  • 2-trifluoromethylbenzoyl chloride isonicotinoyl chloride, nicotinoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride and the like.
  • Carbamyl chlorides such as N,N-dimethylcarbamyl chloride, N,N- diethylcarbamyl chloride and the like, can also be used in this reaction to provide ureas.
  • dicarbonates such as di-tert-butyl dicarbonate, may be employed to provide carbamates.
  • a compound of formula I or an intermediate thereof containing a primary or secondary amino group may be N-sulfonated to form a sulfonamide using a sulfonyl halide or a sulfonic acid anhydride.
  • Sulfonyl halides and sulfonic acid anhydrides suitable for use in this reaction include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chloride, -toluenesulfonyl chloride, trifluoromethanesulfonic anhydride and the like.
  • sulfamoyl chlorides such as dimethylsulfamoyl chloride, can be used to provide sulfamides (e.g., > N-SO 2 -N ⁇ ).
  • a primary and secondary amino group present on a substituent of a compound of formula I, or an intermediate thereof can be reacted with an isocyanate or a thioisocyanate to give a urea or thiourea, respectively.
  • This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the isocyanate or thioisocyanate in an inert diluent, such as toluene and the like, at a temperamre ranging from about 24 °C to about 37 °C for about 12 to about 24 hours.
  • isocyanates and thioisocyanates used in this reaction are commercially available or can be prepared from commercially available compounds using well-known synthetic procedures.
  • isocyanates and thioisocyanates are readily prepared by reacting the appropriate amine with phosgene or thiophosgene.
  • isocyanates and thioisocyanates suitable for use in this reaction include, but are not limited to, ethyl isocyanate, «-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, methyl thioisocyanate, ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3-phenylpropyl thioisocyanate, 3-(N,N-diethylamino)propyl thioisocyanate, phenyl thioisocyanate, benzyl thioisocyanate, 3-pyridyl thioisocyanate, fluorescein isothiocyanate (isomer I), and the like.
  • a compound of formula I or an intermediate thereof contains a primary or secondary amino group
  • the amino group can be reductively alkylated using aldehydes or ketones to form a secondary or tertiary amino group.
  • This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of an aldehyde or ketone and at least one equivalent based on the amino compound of a metal hydride reducing agent, such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixtures thereof and the like, at a temperamre ranging from about 0°C to about 50 °C for about 1 to about 72 hours.
  • Aldehydes and ketones suitable for use in this reaction include, by way of example, benzaldehyde, 4- chlorobenzaldehyde, valeraldehyde and the like.
  • hydroxyl group when a compound of formula I, or an intermediate thereof, has a substituent containing a hydroxyl group, the hydroxyl group can be further modified or derivatized either before or after the above coupling reactions to provide, by way of example, ethers, carbamates and the like.
  • a compound of formula I or an intermediate thereof having a substituent containing a hydroxyl group can be readily O-alkylated to form ethers.
  • This O-alkylation reaction is typically conducted by contacting the hydroxy compound with a suitable alkali or alkaline earth metal base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the like, to form the alkali or alkaline earth metal salt of the hydroxyl group.
  • This salt is generally not isolated, but is reacted in situ with at least one equivalent of an alkyl or substimted alkyl halide or sulfonate, such as an alkyl chloride, bromide, iodide, mesylate or tosylate, to afford the ether.
  • an alkyl or substimted alkyl halide or sulfonate such as an alkyl chloride, bromide, iodide, mesylate or tosylate
  • this reaction is conducted at a temperamre ranging from about 60 °C to about 150°C for about 24 to about 72 hours.
  • a catalytic amount of sodium or potassium iodide is added to the reaction mixture when an alkyl chloride or bromide is employed in the reaction.
  • alkyl or substimted alkyl halides and sulfonates suitable for use in this reaction include, but are not limited to, tert-butyl bromoacetate, N-tert-butyl chloroacetamide, 1-bromoethylbenzene, ethyl ⁇ -bromophenylacetate, 2-(N-ethyl-N-phenylamino)ethyl chloride, 2-(N,N- ethylamino)ethyl chloride, 2-(N,N-diisopropylamino)ethyl chloride, 2-(N,N- dibenzylamino)ethyl chloride, 3-(N, ⁇ -ethylamino)propyl chloride, 3-(N- benzyl-N-methylamino)propyl chloride, N-(2-chloroethyl)morpholine, 2-(hexamethy leneimino)ethyl
  • a hydroxyl group present on a substituent of a compound of formula I, or an intermediate thereof can be O-alkylated using the Mitsunobu reaction.
  • an alcohol such as 3-(N,N- dimethylamino)-l-propanol and the like
  • triphenylphosphine is reacted with about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate in an inert diluent, such as tetrahydrofuran, at a temperamre ranging from about -10 °C to about 5°C for about 0.25 to about 1 hour.
  • a hydroxy compound such as
  • N-tert-butyltyrosine methyl ester is then added and the reaction mixture is stirred at a temperamre of about 0°C to about 30 °C for about 2 to about 48 hours to provide the O-alkylated product.
  • a compound of formula I, or an intermediate thereof, containing an aryl hydroxy group can be reacted with an aryl iodide to provide a diary 1 ether.
  • this reaction is conducted by forming the alkali metal salt of the hydroxyl group using a suitable base, such as sodium hydride, in an inert diluent, such as xylenes, at a temperamre of about -25 °C to about 10°C.
  • the salt is then treated with about 1.1 to about 1.5 equivalents of cuprous bromide dimethyl sulfide complex at a temperamre ranging from about 10°C to about 30°C for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5 equivalents of an aryl iodide, such as sodium 2-iodobenzoate and the like.
  • the reaction is then heated to a temperamre from about 70 °C to about 150°C for about 2 to about 24 hours to provide the diary 1 ether.
  • a hydroxy-containing compound can also be readily derivatized to form a carbamate.
  • a hydroxy compound of formula I, or an intermediate thereof is contacted with about 1.0 to about 1.2 equivalents of 4-nitrophenyl chloroformate in an inert diluent, such as dichloromethane, at a temperamre ranging from about -25 °C to about 0°C for about 0.5 to about 2.0 hours.
  • an inert diluent such as dichloromethane
  • a trialkylamine such as triethylamine
  • a primary or secondary amine Treatment of the resulting carbonate with an excess, preferably about 2 to about 5 equivalents, of a trialkylamine, such as triethylamine, for about 0.5 to 2 hours, followed by about 1.0 to about 1.5 equivalents of a primary or secondary amine, provides the carbamate.
  • amines suitable for using in this reaction include, but are not limited to, piperazine, 1- methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine, pyrrolidine, piperidine and the like.
  • a hydroxy-containing compound is contacted with about 1.0 to about 1.5 equivalents of a carbamyl chloride in an inert diluent, such as dichloromethane, at a temperamre ranging from about 25 °C to about 70 °C for about 2 to about 72 hours.
  • this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction.
  • suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmorpholine and the like.
  • At least one equivalent (based on the hydroxy compound) of 4- (N,N-dimethylamino)pyridine is preferably added to the reaction mixmre to facilitate the reaction.
  • carbamyl chlorides suitable for use in this reaction include, by way of example, dimethylcarbamyl chloride, diethylcarbamyl chloride and the like.
  • hydroxyl groups can be readily converted into a leaving group and displaced to form, for example, amines, sulfides and fluorides.
  • derivatives of 4- hydroxy-L-proline can be converted into the corresponding 4-amino, 4-thio or 4-fluoro-L-proline derivatives via nucleophilic displacement of the derivatized hydroxyl group.
  • the stereochemistry at the carbon atom attached to the derivatized hydroxyl group is typically inverted.
  • These reactions are typically conducted by first converting the hydroxyl group into a leaving group, such as a tosylate, by treatment of the hydroxy compound with at least one equivalent of a sulfonyl halide, such as p-toluenesulfonyl chloride and the like, in pyridine. This reaction is generally conducted at a temperamre of from about 0°C to about 70 °C for about 1 to about 48 hours.
  • the resulting tosylate can then be readily displaced with sodium azide, for example, by contacting the tosylate with at least one equivalent of sodium azide in an inert diluent, such as a mixmre of N,N-dimethylformamide and water, at a temperamre ranging from about 0°C to about 37 °C for about 1 to about 12 hours to provide the corresponding azido compound.
  • the azido group can then be reduced by, for example, hydrogenation using a palladium on carbon catalyst to provide the amino (- ⁇ H 2 ) compound.
  • a tosylate group can be readily displaced by a thiol to form a sulfide.
  • This reaction is typically conducted by contacting the tosylate with at least one equivalent of a thiol, such as thiophenol, in the presence of a suitable base, such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in an inert diluent, such as N,N-dimethylformamide, at a temperamre of from about
  • a thiol such as thiophenol
  • a suitable base such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • an inert diluent such as N,N-dimethylformamide
  • a compound of formula ⁇ , or an intermediate thereof, having a substituent containing an iodoaryl group for example, when R 1 is a 4-iodophenyl group, can be readily converted either before or after the above coupling reactions into a biaryl compound.
  • this reaction is conducted by treating the iodoaryl compound with about 1.1 to about 2 equivalents of an arylzinc iodide, such as 2-(methoxycarbonyl)phenylzinc iodide, in the presence of a palladium catalyst, such as palladium tetra(triphenylphosphine), in an inert diluent, such as tetrahydrofuran, at a temperamre ranging from about 24 °C to about 30 °C until the reaction is complete.
  • a palladium catalyst such as palladium tetra(triphenylphosphine
  • an inert diluent such as tetrahydrofuran
  • the compounds of formula I, or intermediates thereof may contain substituents having one or more sulfur atoms.
  • sulfur atoms will be present, for example, when the amino acid of formula II employed in the above reactions is derived from L-thiazolidine-4-carboxylic acid, L-(5,5-dimethyl)thiazolidine-4-carboxylic acid, L-thiamorpholine-3- carboxylic acid and the like.
  • sulfur atoms can be oxidized either before or after the above coupling reactions to provide a sulfoxide or sulfone compound using conventional reagents and reaction conditions.
  • Suitable reagents for oxidizing a sulfide compound to a sulfoxide include, by way of example, hydrogen peroxide, 3 -chloroperoxy benzoic acid (MCPBA), sodium periodate and the like.
  • MCPBA 3 -chloroperoxy benzoic acid
  • the oxidation reaction is typically conducted by contacting the sulfide compound with about 0.95 to about 1.1 equivalents of the oxidizing reagent in an inert diluent, such as dichloromethane, at a temperamre ranging from about -50°C to about 75 °C for about 1 to about 24 hours.
  • the resulting sulfoxide can then be further oxidized to the corresponding sulfone by contacting the sulfoxide with at least one additional equivalent of an oxidizing reagent, such as hydrogen peroxide, MCPBA, potassium permanganate and the like.
  • an oxidizing reagent such as hydrogen peroxide, MCPBA, potassium permanganate and the like.
  • the sulfone can be prepared directly by contacting the sulfide with at least two equivalents, and preferably an excess, of the oxidizing reagent.
  • Such reactions are described further in March, "Advanced Organic Chemistry", 4th Ed., pp. 1201-1202, Wiley Publisher (1992).
  • the compounds of formula I, where Q is -C(S)NR 7 - can be prepared by using an amino thionoacid derivative in place of amino acid II in the above described synthetic procedures.
  • amino thionoacid derivatives can be prepared by the procedures described in Shalaky, et al., J. Org. Chem., 61:9045-9048 (1996) and Brain, et al., J. Org. Chem., 62:3808- 3809 (1997) and references cited therein.
  • the compounds of formula I and IA are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • compositions which contain, as the active ingredient, one or more of the compounds of formula I or IA above associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy- benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound acmally administered will be determined by a physician in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixmre of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixmre of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixmres of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored with syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixmres thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine.
  • Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulatior in an appropriate manner.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • Quantity Ingredient (mg/capsule)
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a dry powder inhaler formulation is prepared containing the following components:
  • the active mixmre is mixed with the lactose and the mixmre is added to a dry powder inhaling appliance.
  • Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows:
  • Capsules each containing 40 mg of medicament, are made as follows:
  • Quantity Ingredient (mg/capsule)
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient, are made as follows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the samrated fatty acid glycerides previously melted using the minimum heat necessary.
  • the mixmre is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
  • the medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560 mg quantities.
  • composition Example 9 An intravenous formulation may be prepared as follows:
  • a topical formulation may be prepared as follows:
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixmre is then cooled until solid.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the compounds of this invention can be employed to bind VLA-4 (c l integrin) in biological samples and, accordingly, have utility in, for example, assaying such samples for VLA-4.
  • the compounds can be bound to a solid support and the VLA-4 sample added thereto.
  • the amount of VLA-4 in the sample can be determined by conventional methods such as use of a sandwich ELISA assay.
  • labeled VLA-4 can be used in a competitive assay to measure for the presence of VLA-4 in the sample.
  • Other suitable assays are well known in the art.
  • certain of the compounds of this invention inhibit, in vivo, adhesion of leukocytes to endothelial cells mediated by VLA-4 and, accordingly, can be used in the treatment of diseases mediated by VLA-4.
  • diseases include inflammatory diseases in mammalian patients such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
  • the biological activity of the compounds identified above may be assayed in a variety of systems.
  • a compound can be immobilized on a solid surface and adhesion of cells expressing VLA-4 can be measured. Using such formats, large numbers of compounds can be screened.
  • Cells suitable for this assay include any leukocytes known to express VLA-4 such as T cells, B cells, monocytes, eosinophils, and basophils.
  • a number of leukocyte cell lines can also be used, examples include Jurkat and U937.
  • test compounds can also be tested for the ability to competitively inhibit binding between VLA-4 and VCAM-1, or between VLA-4 and a labeled compound known to bind VLA-4 such as a compound of this invention or antibodies to VLA-4.
  • the VCAM-1 can be immobilized on a solid surface.
  • VCAM-1 may also be expressed as a recombinant fusion protein having an Ig tail (e.g., IgG) so that binding to VLA-4 may be detected in an immunoassay.
  • VCAM-1 expressing cells such as activated endothelial cells or VCAM-1 transfected fibroblasts, can be used.
  • the assays described in International Patent Application Publication No. WO 91/05038 are particularly preferred. This application is incorporated herein by reference in its entirety.
  • the labelling systems can be in a variety of forms.
  • the label may be coupled directly or indirectly to the desired component of the assay according to methods well known in the art.
  • a wide variety of labels may be used.
  • the component may be labelled by any one of several methods. The most common method of detection is the use of autoradiography with 3 H, 125 1, 35 S, 14 C, or 32 P labelled compounds or the like.
  • Non-radioactive labels include ligands which bind to labelled antibodies, fluorophores, chemiluminescent agents, enzymes and antibodies which can serve as specific binding pair members for a labelled ligand.
  • the choice of label depends on sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation.
  • EAE experimental autoimmune encephalomyelitis
  • Compounds having the desired biological activity may be modified as necessary to provide desired properties such as improved pharmacological properties (e.g., in vivo stability, bio-availability), or the ability to be detected in diagnostic applications.
  • desired properties such as improved pharmacological properties (e.g., in vivo stability, bio-availability), or the ability to be detected in diagnostic applications.
  • inclusion of one or more D-amino acids in the sulfonamides of this invention typically increases in vivo stability. Stability can be assayed in a variety of ways such as by measuring the half-life of the proteins during incubation with peptidases or human plasma or serum. A number of such protein stability assays have been described (see, e.g. , Verhoef, et al., Eur. J. Drug Metab. Pharmacokinet. , 1990, 15 ⁇ 2): 83-93).
  • the compounds of the subject invention may be modified in a variety of ways for a variety of end purposes while still retaining biological activity.
  • various reactive sites may be introduced at the terminus for linking to particles, solid substrates, macromolecules, or the like.
  • Labeled compounds can be used in a variety of in vivo or in vitro applications.
  • a wide variety of labels may be employed, such as radionuclides (e.g., gamma-emitting radioisotopes such as technetium-99 or indium-Ill), fluorescers (e.g., fluorescein), enzymes, enzyme substrates, enzyme cof actors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like.
  • radionuclides e.g., gamma-emitting radioisotopes such as technetium-99 or indium-Ill
  • fluorescers e.g., fluorescein
  • enzymes enzyme substrates
  • enzyme cof actors enzyme inhibitors
  • chemiluminescent compounds chemiluminescent compounds
  • bioluminescent compounds bioluminescent compounds
  • In vitro uses include diagnostic applications such as monitoring inflammatory responses by detecting the presence of leukocytes expressing VLA-4.
  • the compounds of this invention can also be used for isolating or labeling such cells.
  • the compounds of the invention can be used to assay for potential inhibitors of VLA-4/VCAM-1 interactions.
  • radioisotopes are typically used in accordance with well known techniques.
  • the radioisotopes may be bound to the peptide either directly or indirectly using intermediate functional groups.
  • chelating agents such as diethylenetriaminepentacetic acid (DTP A) and ethylenediaminetetraacetic acid (EDTA) and similar molecules have been used to bind proteins to metallic ion radioisotopes.
  • the complexes can also be labeled with a paramagnetic isotope for purposes of in vivo diagnosis, as in magnetic resonance imaging (MRI) or electron spin resonance (ESR), both of which are well known.
  • MRI magnetic resonance imaging
  • ESR electron spin resonance
  • any conventional method for visualizing diagnostic imaging can be used.
  • gamma- and positron-emitting radioisotopes are used for camera imaging and paramagnetic isotopes are used for MRI.
  • the compounds can be used to monitor the course of amelioration of an inflammatory response in an individual. By measuring the increase or decrease in lymphocytes expressing VLA-4, it is possible to determine whether a particular therapeutic regimen aimed at ameliorating the disease is effective.
  • compositions of the present invention can be used to block or inhibit cellular adhesion associated with a number of diseases and disorders.
  • a number of inflammatory disorders are associated with integrins or leukocytes.
  • Treatable disorders include, e.g., transplantation rejection (e.g., allograft rejection), Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), retinitis, cancer metastases, rheumatoid arthritis, acute leukocyte-mediated lung injury (e.g. , adult respiratory distress syndrome), asthma, nephritis, and acute and chronic inflammation, including atopic dermatitis, psoriasis, myocardial ischemia, and inflammatory bowel disease
  • the pharmaceutical compositions are used to treat inflammatory brain disorders, such as multiple sclerosis (MS), viral meningitis and encephalitis.
  • Inflammatory bowel disease is a collective term for two similar diseases referred to as Crohn's disease and ulcerative colitis.
  • Crohn's disease is an idiopathic, chronic ulceroconstrictive inflammatory disease characterized by sharply delimited and typically transmural involvement of all layers of the bowel wall by a granulomatous inflammatory reaction. Any segment of the gastrointestinal tract, from the mouth to the anus, may be involved, although the disease most commonly affects the terminal ileum and/or colon.
  • Ulcerative colitis is an inflammatory response limited largely to the colonic mucosa and submucosa. Lymphocytes and macrophages are numerous in lesions of inflammatory bowel disease and may contribute to inflammatory injury.
  • Asthma is a disease characterized by increased responsiveness of the tracheobronchial tree to various stimuli potentiating paroxysmal constriction of the bronchial airways.
  • the stimuli cause release of various mediators of inflammation from IgE-coated mast cells, including histamine, eosinophilic and neutrophilic chemotactic factors, leukotrines, prostaglandin and platelet activating factor. Release of these factors recruits basophils, eosinophils and neutrophils, which cause inflammatory injury.
  • Atherosclerosis is a disease of arteries (e.g., coronary, carotid, aorta and iliac).
  • the basic lesion, the atheroma consists of a raised focal plaque within the intima, having a core of lipid and a covering fibrous cap.
  • Atheromas compromise arterial blood flow and weaken affected arteries.
  • Myocardial and cerebral infarcts are a major consequence of this disease. Macrophages and leukocytes are recruited to atheromas and contribute to inflammatory injury.
  • Rheumatoid arthritis is a chronic, relapsing inflammatory disease that primarily causes impairment and destruction of joints. Rheumatoid arthritis usually first affects the small joints of the hands and feet but then may involve the wrists, elbows, ankles and knees. The arthritis results from interaction of synovial cells with leukocytes that infiltrate from the circulation into the synovial lining of the joints. See e.g., Paul, Immunology, 3d ed., Raven Press (1993).
  • Another indication for the compounds of this invention is in treatment of organ or graft rejection mediated by VLA-4.
  • organs such as skin, kidney, liver, heart, lung, pancreas and bone marrow.
  • the principal outstanding problem is the lack of satisfactory agents for inducing immunotolerance in the recipient to the transplanted allograft or organ.
  • the host immune system is likely to mount an immune response to foreign antigens in the transplant (host-versus-graft disease) leading to destruction of the transplanted tissue.
  • CD8 + cells, CD4 cells and monocytes are all involved in the rejection of transplant tissues.
  • Compounds of this invention which bind to alpha-4 integrin are useful, inter alia, to block alloantigen-induced immune responses in the donee, thereby preventing such cells from participating in the destruction of the transplanted tissue or organ. See, e.g., Paul et al., Transplant International 9: 420-425 (1996); Georczynski et al., Immunology 87: 573-580 (1996); Georcyznski et al., Transplant. Immunol. 3: 55-61 (1995); Yang et al., Transplantation 60: 71-76 (1996); Anderson et al., APMIS 102: 23-27 (1994).
  • GVHD graft versus host disease
  • the disease presents an especially severe problem when immune tissue is being transplanted, such as in bone marrow transplantation; but less severe GVHD has also been reported in other cases as well, including heart and liver transplants.
  • the therapeutic agents of the present invention are used, ter alia, to block activation of the donor T-cells, thereby interfering with their ability to lyse target cells in the host.
  • a further use of the compounds of this invention is inhibiting tumor metastasis.
  • Several tumor cells have been reported to express VLA-4 and compounds which bind VLA-4 block adhesion of such cells to endothelial cells. Steinback et al., Urol. Res. 23: 175-83 (1995); Orosz et al., Int. J. Cancer £0: 867-71 (1995); Freedman et al. , Leuk. Lymphoma H: 47-52 * ⁇ (1994); Okahara et al., Cancer Res. 54: 3233-6 (1994).
  • a further use of the compounds of this invention is in treating multiple sclerosis.
  • Multiple sclerosis is a progressive neurological autoimmune disease that affects an estimated 250,000 to 350,000 people in the United States. Multiple sclerosis is thought to be the result of a specific autoimmune reaction in which certain leukocytes attack and initiate the destruction of myelin, the insulating sheath covering nerve fibers.
  • murine monoclonal antibodies directed against VLA-4 have been shown to block the adhesion of leukocytes to the endothelium, and thus prevent inflammation of the central nervous system and subsequent paralysis in the animals 16 .
  • compositions of the invention are suitable for use in a variety of drug delivery systems. Suitable formulations for use in the present invention are found in Remington 's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).
  • the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds.
  • a variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al. , U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028, each of which is incorporated herein by reference.
  • compositions are administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.
  • An amount adequate to accomplish this is defined as a "therapeutically effective dose.” Amounts effective for this use will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the inflammation, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention will vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the dose will typically be in the range of about 20 ⁇ g to about 500 ⁇ g per kilogram body weight, preferably about 100 ⁇ g to about 300 ⁇ g per kilogram body weight.
  • Suitable dosage ranges for intranasal administration are generally about 0.1 pg to 1 mg per kilogram body weight.
  • Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the following synthetic and biological examples are offered to illustrate this invention and are not to be construed in any way as limiting the scope of this invention. Unless otherwise stated, all temperatures are in degrees Celsius.
  • NaHCO 3 sodium bicarbonate
  • TsCl tosyl chloride
  • TsOH tosylate ""
  • ⁇ L microliter
  • N-Tosylation of the appropriate amino acid was conducted via the method of Cupps, Boutin and Rapoport, J. Org. Chem. , 1985, 5>0: 3972.
  • Amino acid methyl esters were prepared using the method of Brenner and Huber, Helv. Chim. Acta, 1953, 36: 1109.
  • the desired dipeptide ester was prepared by the reaction of a suitable ⁇ - protected amino acid (1 equivalent) with the appropriate amino acid ester or amino acid ester hydrochloride (1 equivalent), benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate [BOP] (2.0 equivalent), triethylamine (1.1 equivalent), and DMF.
  • BOP benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate
  • BOP triethylamine
  • the tert-butyl ester was dissolved in CH 2 C1 2 and treated with TFA. The reaction was complete in 1-3 hr, at which time the reaction mixmre was concentrated and the residue dissolved in H 2 O and lyophilized to yield the desired acid.
  • the aqueous phase was made acidic with 0.2 N HCl and the product was extracted with EtOAc.
  • the combined organic phase was washed with brine (1 x 5 mL), dried (MgSO 4 or Na 2 SO 4 ), filtered and concentrated to yield the acid as approximately a 1:1 mixmre of diastereomers.
  • Boc-L-Pro-OH and L-Phe-OBn • Hcl were treated with BOP and ⁇ MM in DMF to give, after aqueous workup and flash chromatography, Boc-L- Pro-L-Phe-OBn. This product was then treated with TFA and anisole, and the mixture was evaporated. The residue was dissolved in Et 2 O and washed with samrated aqueuos ⁇ aHCO 3 and samrated aqueous NaCl. The Et 2 O layer was dried over anhydrous MgSO 4 , filtered, and the solvent evaporated to give L-Pro-L-Phe-OBn.
  • N-Methyl-L-Phe-OH was treated with benzyl alcohol and 4-methylphenylsulfonic acid to give N-Methyl-L-Phe-OBnTsOH.
  • D-Pro-OH was treated with TsCl and ⁇ aOH in H 2 O to give, after acidification, extraction, drying over anhydrous MgSO 4 , and evaporation, N- (Toluene-4-sulfonyl)-D-Pro-OH.
  • This product was treated with H-Phe- "° ⁇ OBn • Hcl, BOP, and NMM in DMF to give, after aqueous workup and flash chromatography, N-(toluene-4-sulfonyl)-D-Pro-Phe-OBn.
  • This product was treated with 10% Pd on C in THF, and the mixmre was shaken under 50 psi H 2 . The mixmre was filtered through celite and evaporated to give the title compound as a clear oil.
  • N-(toluene-4-sulfonyl)-L-proline 250 mg, 0.92 mmol was dissolved in DMF (20 mL) with D,L-homophenylalanine methyl ester (166 mg, 1.1 eq), Et 3 ⁇ (2.1 eq, 283 ⁇ L), and BOP (1.1 eq, 410 mg).
  • the dipeptide was isolated in 73% yield (300 mg, 0.67 mmol) as an oil.
  • the ester (300 mg, 0.67 mmol) was then hydrolyzed in a 1:1 MeOH:H 2 O (5 mL) solution with NaOH (1.1 eq, 28 mg).
  • the acid was isolated as a foam in 60% yield (175 mg, 0.40 mmol).
  • N-(Toluene-4-sulfonyl)-L-(5,5-dimethyl)-thiazolidine-4-carboxylic acid was prepared from L-(5,5-dimethyl)-thiazolidine-4-carboxylic acid using the procedure described in Method 1.
  • Example 18 The product of Example 18 (56) (1.8 mmoles) was mixed with dioxane (25 mL) and IN ⁇ aOH (1.8 mmoles) and the reaction was stirred at room temperamre for 16 hours. IN HCl (1.8 mmoles) was added and the water and dioxane were removed under reduced pressure. The product was extracted with 0.2 ⁇ ⁇ aOH (50 mL) and EtOAc (2 x 50 mL) and the recovered organic layer was dried over MgSO 4 , filtered, and concentrated to yield a colorless oil.
  • N-(Toluene-4-sulfonyI)-L-thiaprolyl-L-phenylalanine N-(Toluene-4-sulfonyl)-L-thiazolidine-4-carboxylic acid was prepared from L-thiazolidine-4-carboxylic acid using the procedure described in Method 1.
  • Proline methyl ester hydrochloride (2.68 g, 16.2 mmol) was dissolved in pyridine (20 mL) and 3,5-dichlorophenylsulfonyl chloride (3.57 g, 14.6 mmol) was added to the mixmre and stirred for 19 hr. Water (5 mL) was added and the mixmre was stirred for 45 minutes before diluting with water (200 mL).
  • N-(Toluene-4-sulfonyl)-tr ⁇ w-3-phenylproline (prepared via the method of Chung et al., J. Org. Chem. , 55: 270-275 (1990)) was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 and purified by silica gel flash chromatography (93/7 CH 2 Cl 2 /MeOH) to give the ethyl ester of the title compound as a white solid.
  • the acid was prepared via hydrolysis of the ethyl ester using ⁇ aOH in ethanol.
  • NMR data was as follows:
  • Example 21 The title compound was prepared as in Example 21 (59) except that 3,4- dimethoxyphenylsulfonyl chloride was used in place of the 3,5- dichlorophenylsulfonyl chloride. ⁇ MR analysis indicated that epimerization had occurred to give a ca. 65:35 mixmre of diastereomers. ⁇ MR data was as follows:
  • N-Acetyl-cw-3-phenylproline ethyl ester (614mg, 2.35 mmol) (prepared via the method of Chung, et al., J. Org. Chem. ⁇ 5: 270-275 (1990)) was dissolved in HO Ac (4 mL) and 6 ⁇ HCl (12 mL) and heated at reflux for 18 hr. The mixmre was cooled to room temperamre and the volatiles were evaporated in vacuo to give a white solid. The solid was dissolved in IN NaOH (15 mL) and dioxane was added (10 mL), followed by 4-toluene- sulfonyl chloride (458 mg, 2.40 mmol).
  • N-(Toluene-4-sulfonyl)- ⁇ ' s-3-phenylproline was coupled to phenylalanine ethyl ester using the procedure described in Method 3.
  • the title compound was prepared via hydrolysis of the ethyl ester using ⁇ aOH in ethanol.
  • ⁇ MR data was as follows:
  • N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-tryptophan methyl ester hydrochloride using the procedure described in Method 3.
  • the title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/ water.
  • ⁇ MR data was as follows:
  • N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to ⁇ -(l- naphthyl)alanine methyl ester hydrochloride using the procedure described in Method 3.
  • the title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water.
  • N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to ⁇ -(2-naphthyl)- L-alanine methyl ester hydrochloride using the procedure described in
  • N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L- ⁇ -(3- pyridyl)alanine methyl ester dihydrochloride using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)prolyl-L- ⁇ -(3-pyridyl)alanine.
  • the title compound was prepared via hydrolysis of the methyl ester using 0.5 ⁇ aqueous ⁇ aOH in THF/water.
  • N-(Toluene-4-sulfonyl)-L-( s-4-phenylthio)prolyl-L-phenylalanine 7r ⁇ /2,s'-4-hydroxy-L-proline was treated with EtOH and HCl gas, and the mixmre was evaporated to give tra/z. ⁇ -4-hydroxy-L-proline ethyl ester hydrochloride.
  • This product was treated with TsCl in pyridine, to give after aqueous workup N-(toluene-4-sulfonyl)-tra «5 , -4-(O-(toluene-4-sulfonyl))-L- proline ethyl ester.
  • This product was treated with PhSH and DBU in DMF to give after aqueous workup and flash chromatography on silica gel, N-
  • N-(Toluene-4-sulfonyl)prolyl-L-(N-benzyl)histidine (237 mg, 0.464 mmol) was dissolved in MeOH (20 mL) and 10% Pd/C (50 mg) was added. The mixmre was hydrogenated at 50 psi H 2 for 36 hr. The mixture was filtered to remove the catalyst and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC (90: 10: 1 CH 2 Cl 2 /MeOH/ ⁇ H 4 OH) to give N-(toluene-4-sulfonyl)-L-prolyl-L-histidine methyl ester (155 mg, 79%).
  • This product was treated with BoCjO and Et 3 ⁇ in t-BuOH and H 2 O to give, after evaporation, acidification, extraction, drying with MgSO 4 , filtration, and evaporation, N-(toluene-4-sulfonyl)-ris-4-(t-butoxycarbonylamino)-L-proline.
  • This product was treated with HClPhe-O-t-Bu, BOP, and ⁇ MM in DMF to give, after aqueous workup and flash chromatography, N-(toluene-4- sulfonyl)-ris-4-(t-butoxycarbonylamino)-Pro-Phe-O-t-Bu.
  • This product was treated with TFA to give after evaporation the trifluoroacetate salt of the title compound as a clear oil.
  • N-(Toluene-4-sulfonyl)-L-proline was coupled to L-phenylalanine benzyl ester toluenesulfonic acid salt using the procedure described in Method 3 to give the title compound as an oil.
  • N-(Toluene-4-sulfonyl)-L-prolyl-L-phenylalanine was coupled to O-methylhydroxylamine hydrochloride using the mixed anhydride procedure
  • N-(Toluene-4-sulfonyl)-L-proline was reacted with L-phenylalanine amide using the procedure described in Method 12 to yield N-(toluene-4- sulfonyl)-L-prolyl-L-phenylalanine amide.
  • ⁇ aH 50% mineral oil - prewashed with THF
  • N-(toluene-4- sulfonyl)-L-prolyl-L-phenylalanine amide was stirred at 0°C for 45 minutes.
  • N-(Toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-benzyloxyamide (see Example 43 (159)) was dissolved in MeOH (10 mL) and 5% Pd/BaSO 4 (52 mg) was added. The mixmre was hydrogenated at 50 psi H > for 9 h. The mixmre was filtered through a pad of diatomaceous earth and evaporated in vacuo to give a residue which was purified by silica gel chromatography (92:8 CH 2 Cl 2 /MeOH) to give the title compound as an oil.
  • N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to phenylalanine isopropyl ester trifluoroacetate using the procedure described in Method 3 to give the title compound as an oil.
  • 3,5-Dichlorophenyl-sulfonyl-L-proline was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 to give the ethyl ester of the title compound (348 mg, 45%).
  • the title compound was prepared via hydrolysis of the ethyl ester using

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Abstract

L'invention concerne des composés se liant à VLA-4. Certains de ces composés inhibent également une adhésion de leucocytes et, notamment, une adhésion de leucocytes inhibée par VLA-4. Ces composés s'utilisent dans le traitement d'affections inflammatoires chez un patient mammalien, par exemple un humain, l'affection consistant par exemple en asthme, maladie d'Alzheimer, athérosclérose, syndrome démentiel du SIDA, diabète, affection intestinale inflammatoire, polyarthrite rhumatoïde, transplantation de tissus, métastase tumorale et ischémie myocardique. Les composés peuvent également être administrés pour le traitement d'affections cérébrales inflammatoires telles que la sclérose en plaques.
PCT/US1998/015327 1997-07-31 1998-07-31 Composes de benzyle inhibant une adhesion de leucocytes regulee par vla-4 WO1999006436A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
BR9811573-1A BR9811573A (pt) 1997-07-31 1998-07-31 Compostos de benzila que inibem a adesão de leucócitos mediada por vla-4
KR1020007000993A KR20010022413A (ko) 1997-07-31 1998-07-31 Ｖｌａ-4에 의해 매개되는 백혈구 부착을 억제하는 벤질화합물
JP2000505191A JP2001512138A (ja) 1997-07-31 1998-07-31 Ｖｌａ−４が介在する白血球付着を阻害するベンジル化合物
IL13363598A IL133635A0 (en) 1997-07-31 1998-07-31 Benzyl compounds which inhibit leukocyte adhesion mediated by vla-4
AU85851/98A AU8585198A (en) 1997-07-31 1998-07-31 Benzyl compounds which inhibit leukocyte adhesion mediated by vla-4
HU0002680A HUP0002680A3 (en) 1997-07-31 1998-07-31 Benzyl compounds which inhibit leukocyte adhesion mediated by vla-4
CA002291473A CA2291473A1 (fr) 1997-07-31 1998-07-31 Composes de benzyle inhibant une adhesion de leucocytes regulee par vla-4
EP98937054A EP1001975A1 (fr) 1997-07-31 1998-07-31 Composes de benzyle inhibant une adhesion de leucocytes regulee par vla-4
NO20000414A NO20000414L (no) 1997-07-31 2000-01-27 Benzylforbindelser som inhiberer leukocytt adhesjon mediert av VLA-4

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US08/903,585 1997-07-31

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US6596752B1 (en) 1997-06-23 2003-07-22 Tanabe Seiyaku Co., Ltd. Inhibitors of α4β1 mediated cell adhesion
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US7229970B2 (en) 1997-07-31 2007-06-12 Elan Pharmaceuticals, Inc. Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4
US6583139B1 (en) 1997-07-31 2003-06-24 Eugene D. Thorsett Compounds which inhibit leukocyte adhesion mediated by VLA-4
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US6525026B2 (en) 1997-07-31 2003-02-25 Elan Pharmaceuticals, Inc. Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4
US7288526B2 (en) 1997-07-31 2007-10-30 Elan Pharmaceuticals, Inc. Dipeptide and related compounds which inhibit leukocyte adhesion mediated by VLA-4
US6900179B2 (en) 1997-07-31 2005-05-31 Eugene D. Thorsett Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4
US7030114B1 (en) 1997-07-31 2006-04-18 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6939855B2 (en) 1997-07-31 2005-09-06 Elan Pharmaceuticals, Inc. Anti-inflammatory compositions and method
US6586602B2 (en) 1997-07-31 2003-07-01 Eugene D. Thorsett Benzyl compounds which inhibit leukocyte adhesion mediated by VLA-4
US6492421B1 (en) 1997-07-31 2002-12-10 Athena Neurosciences, Inc. Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4
US6559127B1 (en) 1997-07-31 2003-05-06 Athena Neurosciences, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US7320960B2 (en) 1997-07-31 2008-01-22 Elan Pharmaceuticals, Inc. Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4
WO1999035163A1 (fr) * 1998-01-08 1999-07-15 Celltech Therapeutics Limited Derives de phenylalanine
US6855843B2 (en) 1998-01-20 2005-02-15 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US6521666B1 (en) 1998-01-20 2003-02-18 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US6329372B1 (en) 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
US6555562B1 (en) 1998-02-26 2003-04-29 Celltech R&D Limited Phenylalanine derivatives
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
WO1999048879A1 (fr) * 1998-03-24 1999-09-30 Celltech Therapeutics Limited Derives de thiocarboxamide et leur utilisation comme inhibiteurs d'integrines alpha 4
US6362204B1 (en) 1998-05-22 2002-03-26 Celltech Therapeutics, Ltd Phenylalanine derivatives
WO1999061465A1 (fr) * 1998-05-22 1999-12-02 Celltech Therapeutics Limited Derives phenilalanine comportant une activite antagoniste du vla-4
US6110945A (en) * 1998-06-03 2000-08-29 Celltech Therapeutics Limited Aromatic amine derivatives
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US6685617B1 (en) 1998-06-23 2004-02-03 Pharmacia & Upjohn Company Inhibitors of α4β1 mediated cell adhesion
US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
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US6348463B1 (en) 1998-09-28 2002-02-19 Celltech Therapeutics Limited Phenylalanine derivatives
US6274577B1 (en) 1998-09-30 2001-08-14 Celltech Therapeutics Limited Benzodiazepines
US6319922B1 (en) 1998-11-23 2001-11-20 Celltech Therapeutics Limited Propanoic acid derivatives
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
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CA2291473A1 (fr) 1999-02-11
HUP0002680A3 (en) 2001-12-28
NO20000414D0 (no) 2000-01-27
AU8585198A (en) 1999-02-22
JP2001512138A (ja) 2001-08-21
NO20000414L (no) 2000-03-28
EP1001975A1 (fr) 2000-05-24
IL133635A0 (en) 2001-04-30
PL338510A1 (en) 2000-11-06
CN1265675A (zh) 2000-09-06
BR9811573A (pt) 2000-09-19
KR20010022413A (ko) 2001-03-15
HUP0002680A2 (hu) 2001-07-30

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