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WO1999006431A1 - Composes de type phenylalanine substituee inhibant une adhesion de leucocytes regulee par vla-4 - Google Patents

Composes de type phenylalanine substituee inhibant une adhesion de leucocytes regulee par vla-4 Download PDF

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Publication number
WO1999006431A1
WO1999006431A1 PCT/US1998/015313 US9815313W WO9906431A1 WO 1999006431 A1 WO1999006431 A1 WO 1999006431A1 US 9815313 W US9815313 W US 9815313W WO 9906431 A1 WO9906431 A1 WO 9906431A1
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Prior art keywords
substituted
alkyl
heterocyclic
sulfonyl
toluene
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PCT/US1998/015313
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English (en)
Inventor
Eugene D. Thorsett
Christopher M. Semko
Dimitrios Sarantakis
Michael A. Pleiss
Louis John Lombardo
Anthony Kreft
Andrei W. Konradi
Francine S. Grant
Darren B. Dressen
Michael S. Dappen
Reinhardt Bernhard Baudy
Susan Ashwell
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Elan Pharmaceuticals, Inc.
American Home Products Corporation
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Application filed by Elan Pharmaceuticals, Inc., American Home Products Corporation filed Critical Elan Pharmaceuticals, Inc.
Priority to NZ502582A priority Critical patent/NZ502582A/en
Priority to CA002290747A priority patent/CA2290747A1/fr
Priority to KR1020007000991A priority patent/KR20010022411A/ko
Priority to AU86611/98A priority patent/AU756696B2/en
Priority to BR9812114-6A priority patent/BR9812114A/pt
Priority to HU0004259A priority patent/HUP0004259A3/hu
Priority to IL13364098A priority patent/IL133640A0/xx
Priority to JP2000505186A priority patent/JP2001512134A/ja
Priority to EP98937990A priority patent/EP1001972A1/fr
Publication of WO1999006431A1 publication Critical patent/WO1999006431A1/fr
Priority to NO20000450A priority patent/NO20000450L/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
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    • C07K—PEPTIDES
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    • C07K5/06—Dipeptides
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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    • C07—ORGANIC CHEMISTRY
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • 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
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    • A61K38/00—Medicinal preparations containing peptides

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 ⁇ 1 chain.
  • VLA-4 for example, binds to fibronectin.
  • VLA-4 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 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.
  • an adhesion mechanism mediated by an adhesion mechanism include, by way of example, asthma 6"8 ,
  • Alzheimer's disease atherosclerosis 9"10 , AIDS dementia", 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 136 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 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and where R 1 and R 2 together with the nitrogen atom bound to R 2 and the SO 2 group bound to R 1 form a heterocyclic or a substituted heterocyclic group;
  • R 3 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and, when R 2 does not form a heterocyclic group with R 1 , R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 can form a heterocyclic or a substituted heterocyclic group;
  • R 5 is - (CH 2 ) X - Ar-R 5 where R 5 is selected from the group consisting
  • substituted alkylcarbonylamino with the proviso that at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic,
  • each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic with the proviso that at least one of R' is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and with the further proviso that when R' is substituted alkyl at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino,
  • 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, mono- and di-substituted heterocyclic
  • each R" is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when each R" is substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substit
  • substituted alkenyl or substituted alkynyl with the proviso that at least one of the substituents on the substituted alkenyl/alkynyl moiety is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when substituted with substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro
  • substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on the substituted aryloxy/heteroaryloxy is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1 ,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
  • (k) -NR-SO 2 -substituted alkyl where R is hydrogen, alkyl or aryl, with the proviso that at least one substituent on the alkyl moiety of the substituted alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2- dioxymethylene, 1 ,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
  • each R'" is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic with the proviso that when one R'" is unsaturated heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1 ,2-dioxymethylene, 1 ,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyl
  • R' is alkyl, substituted alkyl (other than unsaturated heterocyclyl substituted- alkyl), cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl and heterocyclic and substituted heterocyclic;
  • R 8 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 12 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
  • R 9 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and each R 9 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic:
  • R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and, R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
  • Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 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
  • 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, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
  • R 2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and R 1 and R 2 together with the nitrogen atom bound to R 2 and the SO 2 group bound to R 1 can form a heterocyclic or a substituted heterocyclic group;
  • R 3 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and, when R 2 does not form a heterocyclic group with R 1 , R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 can form a heterocyclic or a substituted heterocyclic group;
  • R 5 is - (CH 2 ) X -Ar-R 5 where R 5 is selected from the group consisting (a) substituted alkylcarbonylamino with the proviso that at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carb
  • each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic with the proviso that at least one of R' is substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic and substituted heterocyclic and with the further proviso that when R' is substituted alkyl at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, amino
  • each R" is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when each R" is substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxylalkyl, carboxyl-substit
  • substituted alkenyl or substituted alkynyl with the proviso that at least one of the substituents on the substituted alkenyl/alkynyl moiety is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic with the proviso that when substituted with substituted alkyl then at least one of the substituents on the substituted alkyl moiety is selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkenyl, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbo ⁇ yloxy, aryloxy, substituted aryloxy, cyano
  • 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, mono- and di-substituted heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and substituted alkyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkyl/sub
  • substituted aryloxy and substituted heteroaryloxy with the proviso that at least one substituent on the substituted aryloxy/heteroaryloxy is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
  • (k) -NR-SO 2 -substituted alkyl where R is hydrogen, alkyl or aryl, with the proviso that at least one substituent on the alkyl moiety of the substituted alkylsulfonylamino is other than halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2- dioxymethylene, 1 ,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
  • each R'" is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic with the proviso that when one R'" is unsaturated heterocyclylalkyl, aryl, heteroaryl or aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1 ,2-dioxymethylene, 1 ,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyl
  • R 8 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, and R 12 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
  • R 9 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and each R 9 is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic:
  • R' is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and, R 9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; (t) -aminocarbonyl-(N-formylheterocycyl); and (u) -alkyl-C(O)NH-heterocyclyl and -alkyl-C(O)NH-substituted heterocyclyl, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4;
  • R 6 is selected from the group consisting of 2,4-dioxo-tetrahydrofuran- 3-yl (3,4-enol), 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 ?
  • 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 ⁇ 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 proviso that when R 1 is -CH 3 - ⁇ -, R 6 is methoxy, Q is -C(O)NH-, and R 2 and R 3 are joined to form a pyrrolidinyl group, then R 5 is not/?-[-OCH 2 CH 2 N(C 2 H 5 ) 2 ]-benzyl-, ⁇ -[-OCH 2 CH 2 N(isopropyl) 2 ]-benzyl-, ?-[-OCH 2 CH 2 - 1 -pyrrolidinyl)-benzyl-, p-[-OCH 2 CH 2 - 1 -(4-pyrimidinyl)piper- azinyl]-benzyl-, ?-[-OCH 2 CH 2 -N-mo holin
  • 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, ⁇ -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- (CH 3 C(O)NH-)phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl,
  • R 2 is hydrogen, methyl, phenyl, benzyl, -(CH 2 ) 2 -2-thienyl, and -(CH 2 ) 2 - ⁇ .
  • R 1 and R 2 together with the nitrogen atom bound to R 2 and the SO 2 group bound to R 1 are joined to form a heterocyclic group or substituted heterocyclic group.
  • Preferred heterocyclic and substituted heterocyclic groups include those having from 5 to 7 ring atoms having 2 to 3 heteroatoms in the ring selected from nitrogen, oxygen and sulfur which ring is optionally fused to another ring such as a phenyl or cyclohexyl ring to provide for a fused ring heterocycle of from 10 to 14 ring atoms having 2 to 4 heteroatoms in the ring selected from nitrogen, oxygen and sulfur.
  • Specifically preferred R'/R 2 joined groups include, by way of example, benzisothiazolonyl (saccharin-2-yl).
  • Such heterocyclic rings include azetidinyl (e.g., L-azetidinyl), thiazolidinyl (e.g., L-thiazolidinyl), piperidinyl (e.g., L-piperidinyl), piperizinyl (e.g., L-piperizinyl), dihydroindolyl (e.g., L-2,3-dihydroindol-2-yl), tetrahydroquinolinyl (e.g., L-l,2,3,4-tetrahydroquinolin-2-yl), thiomorpholinyl (e.g., L-thiomorpholin-3- yl), pyrrolidinyl (e.g., L-pyrrolidinyl), substituted pyrrolidinyl such as 4- hydroxypyrrolidinyl (e.g., 4- ⁇ -(or ⁇ -)hydroxy-L-pyrrolidinyl), 4-
  • R 3 includes all of the isomers arising by substitution with methyl, phenyl, benzyl, diphenylmethyl, -CH 2 CH 2 -COOH, -CH 2 -COOH, 2-amidoethyl, wo-butyl, t- butyl, -CH 2 O-benzyl and hydroxymethyl.
  • R 3 and R 2 together with the nitrogen atom bound to R 2 can form a heterocyclic group or substituted heterocyclic group.
  • Q is preferably -C(O)NH- or -C(S)NH-.
  • R 5 is preferably selected from all possible isomers arising by substitution with the following groups:
  • R 6 is preferably 2,4-dioxo- tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, zs ⁇ -propoxy, «-butoxy, t-butoxy, cyclopentoxy, neo-pe oxy, 2- ⁇ - «o-propyl-4- ⁇ -methylcyclohexoxy, 2- ⁇ -isopropyl-4- ⁇ -methylcyclohexoxy, - ⁇ H 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, zso-propyl or benzyl, O-(N- succinimidyl), -O-cholest-5-en-3- ⁇ -yl, -OCH
  • z is 1 or 2 and W is selected from the group consisting of pyrid-3-yl, N-methylpyridyl, and N-methyl- l,4-dihydro-pyrid-3- yl, -NR"C(O)-R' where R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or -CH 2 C(O)OCH 2 CH 3 .
  • ester compounds recited above wherein one ester is replaced with another ester selected from the group consisting of methyl ester, ethyl ester, «-propyl ester, isopropyl ester, «-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.
  • 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 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, alkylamidino, thioamidino, alkylthioamidinio, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl
  • Alkoxy refers to the group “alkyl-O-" which includes, by way of example, methoxy, ethoxy, H-propoxy, ⁇ o-propoxy, «-butoxy, tert-butoxy, sec-butoxy, n-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)-, substituted alkyl- C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)- cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O), heterocyclic-C(O)-, and substituted heterocyclic-C(O)- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, substitute
  • Acylamino refers to the group -C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted 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, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl- C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substituted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl- C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substituted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl
  • Alkenyl refers to alkenyl group preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1 -2 sites of alkenyl unsaturation.
  • Substituted alkenyl refers to alkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl- substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carb
  • Alkynyl refers to 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.
  • Substituted alkynyl refers to alkynyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl- substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl
  • 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, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl
  • NH refers to compounds having 1 to 3 alkyl groups (e.g., alkylHNC-).
  • 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, -NRC(O)substituted alkynyl, -NRC(O)aryl, -NRC(O)substituted aryl, -NRC(O)heteroaryl, -NRC(O)substituted heteroaryl, -NRC(O)heterocyclic, and -NRC(O)substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted
  • Aminocarbonyloxy refers to the groups -NRC(O)O-alkyl, -NRC(O)O-substituted alkyl, -NRC(O)O-alkenyl, -NRC(O)O-substituted alkenyl, -NRC(O)O-alkynyl, -NRC(O)O-substituted alkynyl, -NRC(O)O- cycloalkyl, -NRC(O)O-substituted cycloalkyl, -NRC(O)O-aryl, -NRC(O)O- substituted aryl, -NRC(O)O-heteroaryl, -NRC(O)O-substituted heteroaryl, -NRC(O)O-heterocyclic, and -NRC(O)O-substituted heterocyclic where R is hydrogen or alkyl and wherein alky
  • 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-substituted aryl, -OC(O)NR-heteroaryl,
  • R is hydrogen, alkyl or where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • 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- substituted alkynyl, -OC(S)NR-cycloalkyl, -OC(S)NR-substituted cycloalkyl, -OC(S)NR-aryl, -OC(S)NR-substituted aryl, -OC(S)NR-heteroaryl, -OC(S)NR-substituted heteroaryl, -OC(S)NR-heterocyclic, and -OC(S)NR-substituted heterocyclic where R is hydrogen,
  • R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • 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- substituted alkynyl, -NRC(O)NR-aryl, -NRC(O)NR-substituted aryl,
  • each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted 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, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined
  • amino thiocarbonylamino refers to the groups -NRC(S)NRR,
  • 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.
  • Substituted aryl refers to aryl 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, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl
  • Aryloxy refers to the group aryl-O- which includes, by way of example, phenoxy, naphthoxy, and the like.
  • Substituted aryloxy refers to substituted aryl-O- groups.
  • Aryloxyaryl refers to the group -aryl-O-aryl.
  • Substituted aryloxyaryl refers to aryloxyaryl groups substituted with from 1 to 3 substituents on either or both aryl rings selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl,
  • 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.
  • 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, mono- and di-substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic and substituted alkynyl groups having amino groups blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or alkynyl
  • Cycloalkoxy refers to -O-cycloalkyl groups.
  • Substituted 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, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero
  • 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, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycl
  • 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, mono- and di- substituted heterocyclic amino, unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl
  • Heterocycle or “heterocyclic” refers to a saturated or unsaturated group having a single ring or multiple condensed rings, 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, azetidine, 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,
  • “Saturated substituted heterocyclic” refers to substituted 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 substituted heterocyclic refers to non-aromatic substituted 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).
  • Heterocyclyloxy refers to the group -O-heterocyclic and "substituted heterocyclyloxy” refers to the group -O-substituted heterocyclic.
  • Substituted alkylcarbonylamino refers to the group -NHC(O)- substituted alkyl.
  • Thiol refers to the group -SH.
  • Thioalkyl refers to the group -S-alkyl.
  • Substituted thioalkyl refers to the group -S-substituted alkyl.
  • Thiocycloalkyl refers to the groups -S-cycloalkyl.
  • Substituted thiocycloalkyl refers to the group -S-substituted cycloalkyl.
  • Thioaryl refers to the group -S-aryl and "substituted thioaryl” refers t the group -S-substituted aryl.
  • Thioheteroaryl refers to the group -S-heteroaryl and "substituted thioheteroaryl” refers to the group -S-substituted heteroaryl.
  • Thioheterocyclic refers to the group -S-heterocyclic and "substituted ' thioheterocyclic” refers to the group -S-substituted heterocyclic.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound of Formula I 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 molecule 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. Additionally, as will be apparent to those skilled in the art, conventional 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.
  • the compounds of formula I and IA wherein Q is -C(O)NR 7 - are prepared by first coupling an amino acid of formula II:
  • R 2 , R 3 and R 4 are as defined above, with a sulfonyl chloride of formula III: R -SO 2 -Cl III
  • R' is as defined above, to provide an N-sulfonyl amino acid of formula IV:
  • R -R are as defined above.
  • This reaction is typically conducted by contacting 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 temperature 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 triethylamme, diisopropylethylamine,
  • N-methylmorpholine and the like 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, trc7 «5'-4-hydroxyl-L-proline, cz ' -4-hydroxyl-L-proline, tra «s-3-phenyl-L- proline, c/s-3-phenyl-L-proline, L-(2-methyl)proline, L-pipecolinic acid, L- azetidine-2-carboxylic acid, L-indolin ⁇ -2-carboxylic acid, L- 1,2,3, 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
  • 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'-SO 3 H 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 temperature 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, p- toluenesulfonyl chloride, -toluenesulfonyl chloride, 4- acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride, 4- tert-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 2- carboxybenzenesulfonyl chloride, 4-cyanobenzenesulfonyl chloride, 3,4- dichlorobenzenesulfonyl chloride
  • 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.
  • the intermediate N-sulfonyl amino acids of formula IV can also be prepared by reacting a sulfonamide of formula V:
  • This reaction is typically conducted by contacting the sulfonamide V with at least one equivalent, preferably 1.1 to 2 equivalents, of the carboxylic acid derivative in the presence of a suitable base, such as triethylamine, in an inert diluent, such as DMF, at a temperature ranging from about 24 °C to about 37 °C for about 0.5 to about 4 hours.
  • a suitable base such as triethylamine
  • an inert diluent such as DMF
  • R 5 -R 7 are as defined above.
  • 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).
  • 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. Generally, this reaction is conducted at a temperature ranging from about 0°C to about 37°C for about 12 to about 24 hours. Upon completion of the reaction, the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.
  • an inert diluent such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N- dimethylformamide 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 temperature 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 temperature 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:
  • 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.
  • 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.
  • amino acid derivatives of formula VI can be prepared by C-alkylating commercially available diethyl 2-acetamidomalonate (Aldrich, Milwaukee, Wisconsin, USA) with an alkyl or substituted alkyl halide. This reaction is typically conducted by treating the diethyl 2-acetamidomalonate with at least one equivalent of sodium ethoxide and at least one equivalent of an alkyl or substituted alkyl halide in refluxing ethanol for about 6 to about 12 hours.
  • the resulting C-alkylated malonate is then deacetylated, hydrolyzed and decarboxylated by heating in aqueous hydrochloric acid at reflux for about 6 to about 12 hours to provide the amino acid, typically as the hydrochloride salt.
  • amino acid derivatives of formula VI suitable for use in the above reactions include, but are not limited to, L-4-nitrophenylalanine methyl ester, L-tyrosine methyl ester, D,L-homo-4-nitrophenylalanine methyl ester, L-(O-benzyl)tyrosine methyl ester, L-3,5-diiodotyrosine methyl ester, L- 3-iodotyrosine methyl ester and the like. If desired, of course, other esters or amides of the above-described compounds may also be employed.
  • the compounds of formula I are typically prepared as an ester, i.e., where R 6 is an alkoxy or substituted 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 temperature ranging 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 substituted 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 temperature 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 temperature 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.
  • R 5 substituent of a compound of formula I or an intermediate thereof contains a primary or secondary amino group
  • such amino groups can be further derivatized either before or after the above coupling reactions to provide, by way of example, amides, sulfonamides, ureas, thioureas, carbamates, secondary or tertiary amines and the like.
  • Compounds having a primary amino group on the R 5 substituent may be prepared, for example, by reduction of the corresponding nitro compound as described above.
  • such compounds can be prepared by using an amino acid derivative of formula VI derived from lysine, 4-aminophenylalanine and the like in the above-described coupling reactions.
  • a compound of formula I or an intermediate thereof having a substituent containing a primary or secondary amino group such as where R 5 is a (4-aminophenyl)methyl group
  • R 5 is a (4-aminophenyl)methyl group
  • 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 temperature ranging from about 0°C to about 37°C for about 4 to about 24 hours.
  • a coupling reagent such as a carbodiimide, BOP reagent (benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphonate) and the like
  • a promoter such as N-hydroxysuccinimide, 1 -hydroxybenzotriazole and the like, is used to facilitate the acylation reaction.
  • carboxylic acids suitable for use in this reaction include, but are not limited to, N-tert-butyloxycarbonylglycine, N-tert-butyloxycarbonyl-L- phenylalanine, 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 temperature ranging from about of about -70 °C to about 40°C for about 1 to about 24 hours.
  • an acylation catalyst such as 4-
  • (NpN-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-trifluoro-methylbenzoyl 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., > ⁇ -SO 2 - ⁇ ).
  • 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 temperature ranging from about 24 °C to about 37 °C for about 12 to about 24 hours.
  • the 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, fiuorescein isothiocyanate (isomer I)
  • 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 temperature 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.
  • 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.
  • Compounds having a hydroxyl group on the R 5 substituent can be prepared using an amino acid derivative of formula VI derived from tyrosine and the like in the above-described reactions.
  • 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 substituted alkyl halide or sulfonate, such as an alkyl chloride, bromide, iodide, mesylate or tosylate, to afford the ether.
  • an alkyl or substituted alkyl halide or sulfonate such as an alkyl chloride, bromide, iodide, mesylate or tosylate
  • this reaction is conducted at a temperature 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 substituted alkyl halides and sulfonates suitable for use in this reaction include, but are not limited to, tert-butyl bromoacetate,
  • a hydroxyl group present on a substituent of a compound of formula I or an intermediate thereof can be O-alkylating using the Mitsunobu reaction.
  • an alcohol such as 3-(N,N- dimethylamino)-l-propanol and the like, 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 temperature ranging from about -10°C to about 5°C for about 0.25 to about 1 hour.
  • an inert diluent such as tetrahydrofuran
  • a compound of formula I or an intermediate thereof containing a aryl hydroxy group can be reacted with an aryl iodide to provide a diaryl 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 temperature 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 temperature 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 about 70°C to about 150°C for about 2 to about 24 hours to provide the diaryl 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 temperature ranging from about -25 °C to about 0°C for about 0.5 to about 2.0 hours.
  • an inert diluent such as dichloromethane
  • amines suitable for using in this reaction include, but are not limited to, piperazine, 1- methylpiperazine, 1-acetylpiperazine, morpholine, thiomo ⁇ holine, 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 temperature 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-methylmo ⁇ holine and the like.
  • At least one equivalent (based on the hydroxy compound) of 4-(N,N-dimethylamino)pyridine is preferably added to the reaction mixture 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 temperature of from about 0°C to about 70°C for about 1 to about 48 hours.
  • a leaving group such as a tosylate
  • a sulfonyl halide such as p- toluenesulfonyl chloride and the like
  • 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 mixture of N,N- dimethylformamide and water, at a temperature ranging from about 0°C to about 37 °C for about 1 to about 12 hours to provide the corresponding azido compound.
  • an inert diluent such as a mixture of N,N- dimethylformamide and water
  • 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 temperature of from about 0°C to about 37°C for about 1 to about 12 hours to provide the sulfide.
  • 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
  • a compound of formula I or an intermediate thereof having a substituent containing an iodoaryl group for example, when R 5 is a (4-iodophenyl)methyl 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 temperature ranging from about 24°C to about 30°C until reaction completion.
  • 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-thiamo ⁇ holine-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-chloroperoxybenzoic acid (MCPBA), sodium periodate and the like.
  • MCPBA 3-chloroperoxybenzoic 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 temperature 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
  • the compounds of formula I having an R 2 substituent other an hydrogen can be prepared using an N-substituted amino acid of formula II, such as sarcosine, N-methyl-L-phenylalanine and the like, in the above-described coupling reactions.
  • N-substituted amino acid of formula II such as sarcosine, N-methyl-L-phenylalanine and the like
  • such compounds can be prepared by N-alkylation of a sulfonamide of formula I or IV (where R 2 is hydrogen) using conventional synthetic procedures.
  • this N- alkylation reaction is conducted by contacting the sulfonamide with at least one equivalent, preferably 1.1 to 2 equivalents, of an alkyl or substituted alkyl halide in the presence of a suitable base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the like, at a temperature ranging from about 25 °C to about 70°C for about 2 to about 48 hours
  • a suitable base such as potassium carbonate
  • an inert diluent such as acetone, 2-butanone and the like
  • the sulfonarmdes of formula I or IV wherein R 2 is hydrogen and R 1 is a 2-alkoxycarbonylaryl group can be intramolecularly cychzed to form l ,2-benz ⁇ soth ⁇ azol-3-one de ⁇ vatives or analogues thereof
  • This reaction is typically conducted by treating a sulfonamide, such as N-(2- methoxycarbonylphenylsulfonyl)glyc ⁇ ne-L-phenylalamne benzyl ester, with about 1 0 to 1 5 equivalents of a suitable base, such as an alkali metal hydnde, in a inert diluent, such as tetrahydrofuran, at a temperature ranging from about 0°C to about 30°C for about 2 to about 48 hours to afford the cychzed 1,2- benz ⁇ soth ⁇ azol-3-one de ⁇ vative
  • the compounds of formula I where Q is -C(S) ⁇ R 7 - are can prepared by using an amino thionoacid de ⁇ vative in place of amino acid II in the above descnbed synthetic procedures
  • amino thionoacid de ⁇ vatives can be prepared by the procedures descnbed 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 vanety 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 comp ⁇ se at least one active compound
  • compositions which contain, as the active ingredient, one or more of the compounds of formula I and 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, polyvinylpynolidone, 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.
  • 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.
  • the 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 desir° ⁇ 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 actually 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 mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture 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 separated by 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 mixtures 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 inco ⁇ orated for administration orally or by injection include aqueous solutions suitably flavored 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 mixtures 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 masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • Quantity Ingredient (mg/tablet)
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • Fo ⁇ nulation Example 3 A dry powder inhaler formulation is prepared containing the following components:
  • the active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinyl-pyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50° to 60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • Quantity Ingredient (mg/capsule)
  • the active ingredient, cellulose, starch, an magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
  • Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
  • the medicament, sucrose and xanthan gum are blended, passed through a
  • 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: Ingredient Quantity
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are inco ⁇ orated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixture 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.
  • the construction and use of 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 inco ⁇ orated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent 5,01 1,472 which is herein inco ⁇ orated by reference.
  • 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 ( ⁇ 4 ⁇ , 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 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, l4 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.,
  • 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- 111), fluorescers (e.g., fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like.
  • radionuclides e.g., gamma-emitting radioisotopes such as technetium-99 or indium- 111
  • fluorescers e.g., fluorescein
  • enzymes enzyme substrates
  • enzyme cofactors 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.
  • DTP A diethylenetriaminepentacetic acid
  • EDTA ethylenediaminetetraacetic acid
  • the complexes can also be labeled with a paramagnetic isotope for pu ⁇ oses of in vivo diagnosis, as in magnetic resonance imaging (MRI) or electron spin resonance (ESR), both of which were 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.
  • the pharmaceutical 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 (including Crohn's disease and ulcerative colitis).
  • 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 sha ⁇ ly 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).
  • GVHD graft versus host disease
  • 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 60, 867-71 (1995); Freedman et al., Leuk. Lymphoma 13, 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 inco ⁇ orated 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 "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
  • 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.
  • BOP benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate
  • EDC l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • FmocONSu N-(9-fluorenylmefhoxycarbonyl)- succinimide grams — I l l —
  • TsOH tosylate ⁇ L microliter In the examples below, all temperatures are in degrees Celcius (unless otherwise indicated). The following Methods were used to prepare the compounds set forth below as indicated.
  • N-Tosylation of the appropriate amino acid was conducted via the method of Cupps, Boutin and Rapoport J. Org. Chem. 1985, 50, 3972.
  • 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
  • reaction solution was transfened to a 250 mL separatory funnel with methylene chloride (100 mL) and extracted with IN HCl (50 mL x 3), brine (50 mL), and water (100 mL). The organic phase was dried (MgSO4) and the solvent concentrated to yield the desired product.
  • N-(Toluene-4-sulfonyl)-L-prolyl-L-4-aminophenylalanine methyl ester (2.00 g, 4.67 mmol) was dissolved 50 mL of dry DMF, with Boc-glycine (1.1 eq, 0.9 g), Et 3 ⁇ (2.2 eq, 1.43 mL), and BOP reagent (1.1 eq, 2.27g). The reaction mixture was sti ⁇ ed at room temperature for 12 hours. EtOAc (100 mL) was added. The organic layer was washed with NaHCO 3 saturated (50 mL), 10%) citric acid (20 mL), and brine (5x 50 mL). The organic layer was dried over MgSO 4 .
  • Example 1 (2) The product from Example 1 (2) (1.33 g, 2.26 mmol) was taken up in dry dichloromethane (20 mL) with trifluoroacetic acid (1.00 mL) and the reaction mixture was stined at room temperature for 12 hours. The solvents were removed under reduced pressure. The crude material was left on a vacuum pump overnight, then dissolved in methanol and cooled to 0°C. Ethyl ether was added and the product was collected, as a trifluoroacetate salt, in 50% yield (660 mg, 1.09 mmol).
  • N-(toluene-4-sulfonyl)-L-prolyl-L-4-aminophenylalanine methyl ester (455 mg, 1 mmol) was dissolved in DMF (10 mL) with Et 3 ⁇ (1.1 eq, 153 ⁇ L) and succinic anhydride (1.1 eq, 1 10 mg). The desired monoester was isolated in 53%) yield (288 mg, 0.52 mmol) as a foam. The monoester (80 mg, 0.15 mmol) was then hydrolyzed in MeOH: H 2 O 1 : 1 (5 mL) with NaOH (2.2 eq, 15 mg) for 4 hours at room temperature. EtOAc was added as well as water.
  • the aqueous layer was collected and acidified with IN HCl to pH 2.5, and reextracted with EtOAc.
  • the organic layer was dried over MgSO 4 . Upon filtration and evaporation of the solvents under reduced pressure, the diacid was isolated as a foam.
  • N- (toluene-4-sulfonyl)-L-prolyl-L-4-aminophenylalanine methyl ester (0.15 g, 0.337 mmol) was taken into 5 mL of DMF, with Et 3 ⁇ (2.0 eq, 95 ⁇ L), Boc-L- alanine (1.1 eq, 70 mg), and BOP (1.1 eq, 163 mg).
  • the desired methyl ester was isolated as an oil in 49% yield (102 mg, 0.16 mmol).
  • the ester was then hydrolyzed with NaOH (1.1 eq, 8 mg) in a 1 : 1 MeOH:H 2 O solution (4 mL).
  • the monoacid was isolated as an amo ⁇ hous solid in quantitative yields.
  • NMR data was as follows:
  • the monoacid was isolated as a film in quantitative yields.
  • N- (toluene-4-sulfonyl)-L-prolyl-L-4-aminophenylalanine methyl ester (0.15 g, 0.337 mmol) was taken into 5 mL of DMF, with Et 3 ⁇ (2.0 eq, 95 ⁇ L), Boc-L- phenylalanine (1.1 eq, 99 mg), and BOP (1.1 eq, 163 mg).
  • the desired methyl ester was isolated as an oil in 16% yield (37 mg, 0.05 mmol).
  • the ester was then hydrolyzed with NaOH (1.1 eq, 3 mg) in a 1 : 1 MeOH:H 2 O solution (2 mL).
  • Example 2 The product of Example 2 (7) was treated with NaHCO 3 and fluorescein isothiocyanate (isomer I - obtained from Aldrich Chemical Company) in EtOH and H2O. Acidification of the mixture and isolation of the resulting precipitate gave the title compound as an amo ⁇ hous orange solid. Mass Spectroscopy: (+FAB, 3-nitrobenzyl alcohol) 878 (MH+).
  • N-(Toluene-4-sulfonyl)-L-prolyl-L-(4-nitro)phenylalanine methyl ester (2.00 g, 4.48 mmol) was dissolved in MeOH (10 mL) with a catalytic amount of 10% Pd on C. The hydrogenation reaction was run at room temperature for
  • N-(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester (1.32 g, 2.95 mmol) was dissolved in dry DMF (50 mL) at room temperature. To this was added K 2 CO 3 (1.1 eq, 440 mg) and ethyl ⁇ -bromophenylacetate (1.1 eq, 750 mg). The reaction was stined for 12 hours at room temperature. Ethyl acetate (100 mL) was added, and the organic layer washed several times with brine. The organic layer was dried over MgSO 4 .
  • Example 13 (178) The product of Example 13 (178) was treated with NaOH in dioxane and water, to give after acidification, extraction, drying with MgSO 4 , filtration and evaporation the title compound as a clear oil.
  • Example 3 the product from Example 15 (172) (32 mg, 0.051 mmol) was hydrolyzed in MeOH:H 2 O 1:1 (1 mL), with NaOH (1.1 eq, 3 mg). The title material was isolated in quantitative materials, as a foam.
  • N-(Toluene-4-sulfonyl)-L-prolyl-L-p-amino-phenylalanine methyl ester (316 mg, 0.7 mmol) was dissolved in a KOAc-HOAc solution in dry methanol (10 mL) [pH 6.5], with NaCNBH, (10.0 eq, 446 mg), and carbobenzyloxy- glycinal (1.1 eq). The reaction mixture was stined at room temperature overnight , and the solvents were evaporated under reduced pressure. EtOAc was added and the organic layer washed with brine, dried over MgSO 4 .
  • N-(Toluene-4-sulfonyl)-L-prolyl-L-(4-amino)phenylalanine methyl ester was reacted with trifluoromethane sulfonyl anhydride in pyridine to produce the conesponding trifluoromethane sulfonamide.
  • This compound was alkylated on the nitrogen of the trifluoromethane sulfonamide group under
  • the methyl ester was prepared by reductive amination of N-(toluene-4- sulfonyl)-L-prolyl-L-4-aminobenzyl-L-phenylalanine with 4-NJV- dimethylaminobenzaldehyde (acetic acid, sodium triacetoxyborohydride, methylene chloride), sti ⁇ ed at room temperature overnight.
  • the crude product was purified by flash chromatography to afford the methyl ester which was hydrolyzed in the manner of Method 6 to provide the title compound.
  • Triphenylphosphine (24.4 g, 92.9 mmol) and 3-dimethylamino-l- propanol (8.72 g, 84.5 mmol) were dissolved in THF (200 mL) and cooled in an ice bath.
  • Diethyl azodicarboxylate (16.2 g, 14.6 mL, 92.9 mmol) was added dropwise via syringe over 5 minutes and stined an additional 10 minutes before addition of N-Boc-tyrosine methyl ester (24.95 g, 94.5 mmol) as a solution in 100 mL THF via cannula. The mixture was stined for 30 minutes at 0°C and 19 hr at room temperature.
  • N-Boc-L-4-(3-N,N-dimethylaminopropyloxy)phenylalanine methyl ester (26.5 g, 69.5 mmol) was dissolved in MeOH (300 mL) and saturated with HCl gas. The mixture was stined for 3 hr before removing the volatiles in vacuo to give L-4-(3-N,N-dimethylaminopropyloxy)phenylalanine methyl ester dihydrochloride (23.6 g, 90%).
  • N-(Toluene-4-sulfonyl)-L-proline hydrate was coupled to L-4-(3-N,N- dimethylaminopropyloxy)-phenylalanine methyl ester dihydrochloride using the procedure described in Method 13 to give N-(toluene-4-sulfonyl)-L-prolyl- L-4-(3-N,N-dimethylaminopropyloxy)phenylalanine methyl ester (16.3g, 89%).
  • the title compound was prepared via hydrolysis of the methyl ester using 0.5 ⁇ ⁇ aOH in THF/water (14.71 g, 99%).
  • ⁇ MR data was as follows:
  • N-Methyl-N-(toluene-p-sulfonyl)-L-serine (655 mg, 2.4 mmol) was taken up in DMF (100 mL) with L-4-(3-dimethylamino-propyloxy)phenylalanine methyl ester hydrochloride salt [see Example 18 (138) for preparation] (1.0 g,
  • Triphenylphosphine (1.1 eq) and 3-dimethylamino-l -propanol (1 eq) were dissolved in THF and cooled in an ice bath.
  • Diethyl azodicarboxylate (1 eq) was added dropwise via syringe over 5 min and sti ⁇ ed an additional 10 min before addition of N-Boc-tyrosine methyl ester (1.02 eq) as a solution in 100 mL THF via cannula.
  • the mixture was stined for 30 min at 0 °C and 19 hr at room temperature.
  • N-Boc-L-4-(3-dimethylaminopropyloxy)phenylalanine methyl ester (26.5 g, 69.5 mmol) was dissolved in MeOH (300 mL) and saturated with HCl gas. The mixture was stined for 3 hr before removing the volatiles in vacuo to give L-4-(3-dimethylaminopropyloxy)phenylalanine methyl ester dihydrochloride
  • N-(Toluene-4-sulfonyl)-L-(5,5-dimethyl)-thiaproline was coupled to L-4-(3-dimethylaminopropyloxy)-phenylalanine methyl ester dihydrochloride using the procedure described in Method 13 to give N-(toluene-4-sulfonyl)-L-
  • the methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with 2-(N-ethyl,N-phenyl)aminoefhyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide.
  • the title compound was prepared using the procedure described in Method 7.
  • the methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with 2-diisopropylaminoethyl chloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide.
  • ⁇ MR data was as follows:
  • the methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with 2-diethylaminoethyl chloride hydrochloride in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide.
  • ⁇ MR data was as follows:
  • the title compound was prepared using Method 15 and was isolated as a white, hygroscopic solid, mp - >200°C.
  • the N-methylpyrazole sulfonyl chloride was prepared by adding N- methylpyrazole to chilled (0°C) chlorosulfonic acid. The reaction mixture was allowed to warm to room temperature and the heated to 100°C overnight under a stream of ⁇ 2 . The reaction mixture was then cooled to room temperature and chilled to 0°C. To this solution was added thionyl chloride (2.5 eq.) and the reaction was stined at room temperature for 30 min, then warmed to 70 °C for two hours. The reaction was cooled to room temperature and then chilled in an ice bath. Water and ice were slowly added to the reaction mixture to precipitate a white solid which was collected by filtration.
  • the sulfonyl chloride was prepared from the thiol as taught by Roblin and
  • the sulfonyl chloride was prepared from the thiol as taught by Roblin and Clapp, JACS, 72, 4890, 1950.
  • L-Thiamo ⁇ holine-5-carboxylic acid was prepared by the method of Larsson and Carlson ⁇ Ada Chemica Scan. 1994, 4S, 517-525). N-(Toluene-4- sulfonyl)-L-thiamo ⁇ holine-5-carboxylic acid using the procedure described in Method 1. The title compound was prepared following the procedure outlined for the preparation of Example 20 (284). NMR data was as follows:
  • N-(Toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester (2.14 g, 5.16 mmol) was added to a suspension of sodium hydride (60%> in oil, 1.1 eq, 228 mg) in xylenes (50 mL) at 0°C.
  • the reaction mixture was stined for 5 minutes and cuprous bromide°dimethyl sulfide complex (1.4 eq, 1.48 g) was added.
  • the reaction mixture was stined at 23 °C for 0.5 hours.
  • 2-Iodo sodium benzoate (1.5 eq, 8.06 mmol) was added and the reaction mixture was refluxed for 12 hours.
  • the methyl ester was prepared by Mitsunobu reaction of N-(toluene-4- sulfonyl)-L-prolyl-L-tyrosine methyl ester following the procedure described for the preparation of Example 20 (284).
  • ⁇ MR data was as follows:
  • the methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with l-(2-chloropropyl)piperidine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide.
  • ⁇ MR data was as follows:
  • the methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)-
  • the methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)- L-prolyl-L-tyrosine methyl ester with l-(3-chlorophenyl)-4-(3-chloro- propyl)piperazine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide.
  • ⁇ MR data was as follows:
  • NB contains traces Tos-Pro-Phe (NMR)
  • IR (KBr, cm 1 ): 3400, 2950, 2850, 1610, 1510, 1425, 1340, 1245, 1150, 1125,825,800,675,575,525.

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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 régulée 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/US1998/015313 1997-07-31 1998-07-30 Composes de type phenylalanine substituee inhibant une adhesion de leucocytes regulee par vla-4 WO1999006431A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
NZ502582A NZ502582A (en) 1997-07-31 1998-07-30 Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4
CA002290747A CA2290747A1 (fr) 1997-07-31 1998-07-30 Composes de type phenylalanine substituee inhibant une adhesion de leucocytes regulee par vla-4
KR1020007000991A KR20010022411A (ko) 1997-07-31 1998-07-30 Ｖｌａ-4에 의해 매개되는 백혈구 부착을 억제하는 치환된페닐알라닌계의 화합물
AU86611/98A AU756696B2 (en) 1997-07-31 1998-07-30 Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4
BR9812114-6A BR9812114A (pt) 1997-07-31 1998-07-30 Compostos do tipo fenilalanina substituìda que inibem a adesão de leucócito mediada por vla-4
HU0004259A HUP0004259A3 (en) 1997-07-31 1998-07-30 Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by vla-4, pharmaceutical compositions comprising thereof
IL13364098A IL133640A0 (en) 1997-07-31 1998-07-30 Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by vla-4
JP2000505186A JP2001512134A (ja) 1997-07-31 1998-07-30 Ｖｌａ−４仲介性白血球付着を阻害する置換フェニルアラニン型化合物
EP98937990A EP1001972A1 (fr) 1997-07-31 1998-07-30 Composes de type phenylalanine substituee inhibant une adhesion de leucocytes regulee par vla-4
NO20000450A NO20000450L (no) 1997-07-31 2000-01-28 Substituerte fenylalaninforbindelser som inhiberer leukocytt- adhesjon mediert av VLA-4

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US92039497A 1997-07-31 1997-07-31
US08/920,394 1997-07-31

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Cited By (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999035163A1 (fr) * 1998-01-08 1999-07-15 Celltech Therapeutics Limited Derives de phenylalanine
WO1999061465A1 (fr) * 1998-05-22 1999-12-02 Celltech Therapeutics Limited Derives phenilalanine comportant une activite antagoniste du vla-4
WO2000009103A2 (fr) * 1998-08-14 2000-02-24 Gpi Nil Holdings, Inc. Sulfonamides a liaison n d'acides carboxyliques n-heterocycliques ou isosteres, destines a des troubles de la vision et de la memoire
WO2000009104A2 (fr) * 1998-08-14 2000-02-24 Gpi Nhl Holdings, Inc. Sulfonamides a petite molecule, destines a des troubles de la vision et de la memoire
US6093696A (en) * 1997-05-30 2000-07-25 Celltech Therapeutics, Limited Tyrosine derivatives
WO2000043415A1 (fr) * 1999-01-25 2000-07-27 Elan Pharmaceuticals, Inc. Composes inhibant l'adhesion des leucocytaire provoquee par vla-4
US6110945A (en) * 1998-06-03 2000-08-29 Celltech Therapeutics Limited Aromatic amine derivatives
US6274577B1 (en) 1998-09-30 2001-08-14 Celltech Therapeutics Limited Benzodiazepines
US6291511B1 (en) 1997-05-29 2001-09-18 Merck & Co., Inc. Biarylalkanoic acids as cell adhesion inhibitors
US6319922B1 (en) 1998-11-23 2001-11-20 Celltech Therapeutics Limited Propanoic acid derivatives
US6329372B1 (en) 1998-01-27 2001-12-11 Celltech Therapeutics Limited Phenylalanine derivatives
US6348463B1 (en) 1998-09-28 2002-02-19 Celltech Therapeutics Limited Phenylalanine derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6436904B1 (en) 1999-01-25 2002-08-20 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
US6469025B1 (en) 2000-08-02 2002-10-22 Celltech R&D Ltd. 3-substituted isoquinolin-1-yl derivatives
US6479492B1 (en) 1999-01-22 2002-11-12 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6482849B1 (en) 1997-06-23 2002-11-19 Tanabe Seiyaku Co., Ltd. Inhibitors of α4β1 mediated cell adhesion
WO2002102765A2 (fr) * 2001-06-05 2002-12-27 Forschungszentrum Jülich GmbH Derives de tyrosine proteges, leur procede de production et leur utilisation pour produire de l'o-(2-[18f]-fluorethyl)-l-tyrosine
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
US6521666B1 (en) 1998-01-20 2003-02-18 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
JP2003506491A (ja) * 1999-08-13 2003-02-18 バイオジェン インコーポレイテッド 細胞接着インヒビター
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6555562B1 (en) 1998-02-26 2003-04-29 Celltech R&D Limited Phenylalanine derivatives
US6607735B2 (en) 2000-12-21 2003-08-19 Johnson & Johnson Consumer Companies, Inc. Method for reducing the appearance of dark circles under the eyes
US6610700B2 (en) 2000-04-17 2003-08-26 Celltech R & D Limited Enamine derivatives
US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6685617B1 (en) 1998-06-23 2004-02-03 Pharmacia & Upjohn Company Inhibitors of α4β1 mediated cell adhesion
EP1389200A1 (fr) * 2001-03-20 2004-02-18 Merck & Co., Inc. Derives de n-arylsulfonyl-proline substitues utilises comme inhibiteurs puissants de l'adhesion cellulaire
US6740654B2 (en) 2000-07-07 2004-05-25 Celltech R & D Limited Squaric acid derivatives
US6903075B1 (en) 1997-05-29 2005-06-07 Merck & Co., Inc. Heterocyclic amide compounds as cell adhesion inhibitors
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
WO2004066931A3 (fr) * 2003-01-24 2005-12-15 Elan Pharm Inc Composition et methode destinees a traiter les maladies de demyelinisation et la paralysie par administration d'agents de remyelinisation
US7008949B2 (en) 2002-05-24 2006-03-07 Elan Pharmaceuticals, Inc. Heterocyclic compounds which inhibit leukocyte adhesion mediated by α4 integrins
EP1635822A2 (fr) * 2003-06-25 2006-03-22 Elan Pharmaceuticals, Inc. Methodes et compositions de traitement de polyarthrite rhumatoide
US7026501B2 (en) 2000-08-31 2006-04-11 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US7026328B2 (en) 2002-05-24 2006-04-11 Elan Pharmaceuticals, Inc. Heterocyclic compounds which inhibit leukocyte adhesion mediated by α4 integrins
US7153963B2 (en) 2000-08-18 2006-12-26 Ajinomoto Co., Inc. Phenylalanine derivatives
US7345049B2 (en) 2003-12-22 2008-03-18 Ajinomoto Co., Inc. Phenylalanine derivatives
US7396526B1 (en) 1998-11-12 2008-07-08 Johnson & Johnson Consumer Companies, Inc. Skin care composition
US7452912B2 (en) 1999-01-22 2008-11-18 Elan Pharmaceuticals, Inc. Fused ring heteroaryl and heterocyclic compounds which inhibit leukocyte adhesion mediated by VLA-4
US7476758B2 (en) 2002-02-28 2009-01-13 Mitsubishi Tanbe Pharma Corporation Process for preparing a phenylalanine derivative and intermediates thereof
US7579466B2 (en) 2006-02-27 2009-08-25 Elan Pharmaceuticals, Inc. Pyrimidinyl sulfonamide compounds which inhibit leukocyte adhesion mediated by VLA-4
WO2009126920A2 (fr) 2008-04-11 2009-10-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de sérum humain, et ses conjugués
EP2510941A2 (fr) 2007-02-20 2012-10-17 Merrimack Pharmaceuticals, Inc. Procédés de traitement de la sclérose en plaques par administration d'une alpha-foetoprotéine combinée à un antagoniste de l'intégrine
WO2015136468A1 (fr) 2014-03-13 2015-09-17 Prothena Biosciences Limited Polythérapie pour la sclérose en plaques
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

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CN119606958A (zh) * 2025-02-14 2025-03-14 江苏长泰药业股份有限公司 一种含有丙酮酸盐的组合物及其制备方法和应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2357334A1 (de) * 1972-11-24 1974-06-06 Hoffmann La Roche Peptide
DE2655636A1 (de) * 1975-12-09 1977-06-23 Mitsubishi Chem Ind N hoch 2 -arylsulfonyl-l-argininamide
WO1992016549A1 (fr) * 1991-03-18 1992-10-01 Pentapharm Ag Derives de phenylalanine substitues en position para
WO1995015973A1 (fr) * 1993-12-06 1995-06-15 Cytel Corporation Peptidomimetiques cs-1, compositions et procedes pour les utiliser
WO1996022966A1 (fr) * 1995-01-23 1996-08-01 Biogen, Inc. Inhibiteurs de l'adherence cellulaire

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2357334A1 (de) * 1972-11-24 1974-06-06 Hoffmann La Roche Peptide
DE2655636A1 (de) * 1975-12-09 1977-06-23 Mitsubishi Chem Ind N hoch 2 -arylsulfonyl-l-argininamide
WO1992016549A1 (fr) * 1991-03-18 1992-10-01 Pentapharm Ag Derives de phenylalanine substitues en position para
WO1995015973A1 (fr) * 1993-12-06 1995-06-15 Cytel Corporation Peptidomimetiques cs-1, compositions et procedes pour les utiliser
WO1996022966A1 (fr) * 1995-01-23 1996-08-01 Biogen, Inc. Inhibiteurs de l'adherence cellulaire

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6291511B1 (en) 1997-05-29 2001-09-18 Merck & Co., Inc. Biarylalkanoic acids as cell adhesion inhibitors
US6903075B1 (en) 1997-05-29 2005-06-07 Merck & Co., Inc. Heterocyclic amide compounds as cell adhesion inhibitors
US6093696A (en) * 1997-05-30 2000-07-25 Celltech Therapeutics, Limited Tyrosine derivatives
US6596752B1 (en) 1997-06-23 2003-07-22 Tanabe Seiyaku Co., Ltd. Inhibitors of α4β1 mediated cell adhesion
US6482849B1 (en) 1997-06-23 2002-11-19 Tanabe Seiyaku Co., Ltd. Inhibitors of α4β1 mediated cell adhesion
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
WO1999061465A1 (fr) * 1998-05-22 1999-12-02 Celltech Therapeutics Limited Derives phenilalanine comportant une activite antagoniste du vla-4
US6362204B1 (en) 1998-05-22 2002-03-26 Celltech Therapeutics, Ltd Phenylalanine derivatives
US6369229B1 (en) 1998-06-03 2002-04-09 Celltech Therapeutics, Limited Pyridylalanine derivatives
US6110945A (en) * 1998-06-03 2000-08-29 Celltech Therapeutics Limited Aromatic amine derivatives
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
WO2000009104A2 (fr) * 1998-08-14 2000-02-24 Gpi Nhl Holdings, Inc. Sulfonamides a petite molecule, destines a des troubles de la vision et de la memoire
WO2000009103A2 (fr) * 1998-08-14 2000-02-24 Gpi Nil Holdings, Inc. Sulfonamides a liaison n d'acides carboxyliques n-heterocycliques ou isosteres, destines a des troubles de la vision et de la memoire
WO2000009103A3 (fr) * 1998-08-14 2000-11-16 Guilford Pharm Inc Sulfonamides a liaison n d'acides carboxyliques n-heterocycliques ou isosteres, destines a des troubles de la vision et de la memoire
WO2000009104A3 (fr) * 1998-08-14 2000-12-07 Guilford Pharm Inc Sulfonamides a petite molecule, destines a des troubles de la vision et de la memoire
US6348463B1 (en) 1998-09-28 2002-02-19 Celltech Therapeutics Limited Phenylalanine derivatives
US6677339B2 (en) 1998-09-28 2004-01-13 Celltech R & D Limited Phenylalanine derivatives
US6274577B1 (en) 1998-09-30 2001-08-14 Celltech Therapeutics Limited Benzodiazepines
US7396526B1 (en) 1998-11-12 2008-07-08 Johnson & Johnson Consumer Companies, Inc. Skin care composition
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
US6903088B2 (en) 1999-01-22 2005-06-07 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6492372B1 (en) 1999-01-22 2002-12-10 Elan Pharmaceuticals, Inc. Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4
US6911439B2 (en) 1999-01-22 2005-06-28 Elan Pharmaceuticals, Inc. Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4
US7378529B2 (en) 1999-01-22 2008-05-27 Wyeth Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4
US7049306B2 (en) 1999-01-22 2006-05-23 Elan Pharmaceuticals, Inc. Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4.
US7538215B2 (en) 1999-01-22 2009-05-26 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US7452912B2 (en) 1999-01-22 2008-11-18 Elan Pharmaceuticals, Inc. Fused ring heteroaryl and heterocyclic compounds which inhibit leukocyte adhesion mediated by VLA-4
US6479492B1 (en) 1999-01-22 2002-11-12 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US7005433B2 (en) 1999-01-22 2006-02-28 Elan Pharmaceuticals, Inc. Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4
US6949570B2 (en) 1999-01-25 2005-09-27 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
WO2000043415A1 (fr) * 1999-01-25 2000-07-27 Elan Pharmaceuticals, Inc. Composes inhibant l'adhesion des leucocytaire provoquee par vla-4
US6436904B1 (en) 1999-01-25 2002-08-20 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
JP2003506491A (ja) * 1999-08-13 2003-02-18 バイオジェン インコーポレイテッド 細胞接着インヒビター
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6668527B2 (en) 1999-12-28 2003-12-30 Pfizer Inc. Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6903128B2 (en) 1999-12-28 2005-06-07 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6610700B2 (en) 2000-04-17 2003-08-26 Celltech R & D Limited Enamine derivatives
US6780874B2 (en) 2000-04-17 2004-08-24 Celltech R & D Limited Enamine derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6740654B2 (en) 2000-07-07 2004-05-25 Celltech R & D Limited Squaric acid derivatives
US6469025B1 (en) 2000-08-02 2002-10-22 Celltech R&D Ltd. 3-substituted isoquinolin-1-yl derivatives
US7872125B2 (en) 2000-08-18 2011-01-18 Ajinomoto Co., Inc. Phenylalanine derivatives
US8222405B2 (en) 2000-08-18 2012-07-17 Ajinomoto Co., Inc. Phenylalanine derivatives
US8426588B2 (en) 2000-08-18 2013-04-23 Ajinomoto Co, Inc. Phenylalanine derivatives
US7153963B2 (en) 2000-08-18 2006-12-26 Ajinomoto Co., Inc. Phenylalanine derivatives
US7671090B2 (en) 2000-08-31 2010-03-02 Mitsubishi Tanabe Pharma Corporation Inhibitors of α4 mediated cell adhesion
US7872151B2 (en) 2000-08-31 2011-01-18 Mitsubishi Tanabe Pharma Corporation Inhibitors of α4 mediated cell adhesion
US8501809B2 (en) 2000-08-31 2013-08-06 Mitsubishi Tanabe Pharma Corporation Inhibitors of α4 mediated cell adhesion
US7026501B2 (en) 2000-08-31 2006-04-11 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US7456217B2 (en) 2000-08-31 2008-11-25 Mitsubishi Tanabe Pharma Corporation Inhibitors of alpha4 mediated cell adhesion
US6607735B2 (en) 2000-12-21 2003-08-19 Johnson & Johnson Consumer Companies, Inc. Method for reducing the appearance of dark circles under the eyes
EP1389200A1 (fr) * 2001-03-20 2004-02-18 Merck & Co., Inc. Derives de n-arylsulfonyl-proline substitues utilises comme inhibiteurs puissants de l'adhesion cellulaire
EP1389200A4 (fr) * 2001-03-20 2007-03-28 Merck & Co Inc Derives de n-arylsulfonyl-proline substitues utilises comme inhibiteurs puissants de l'adhesion cellulaire
WO2002102765A3 (fr) * 2001-06-05 2003-10-30 Forschungszentrum Juelich Gmbh Derives de tyrosine proteges, leur procede de production et leur utilisation pour produire de l'o-(2-[18f]-fluorethyl)-l-tyrosine
WO2002102765A2 (fr) * 2001-06-05 2002-12-27 Forschungszentrum Jülich GmbH Derives de tyrosine proteges, leur procede de production et leur utilisation pour produire de l'o-(2-[18f]-fluorethyl)-l-tyrosine
US7476758B2 (en) 2002-02-28 2009-01-13 Mitsubishi Tanbe Pharma Corporation Process for preparing a phenylalanine derivative and intermediates thereof
US7008949B2 (en) 2002-05-24 2006-03-07 Elan Pharmaceuticals, Inc. Heterocyclic compounds which inhibit leukocyte adhesion mediated by α4 integrins
US7335663B2 (en) 2002-05-24 2008-02-26 Elan Pharmaceuticals, Inc. Heteroaryl compounds which inhibit leukocyte adhesion mediated by α4 integrins
US7026328B2 (en) 2002-05-24 2006-04-11 Elan Pharmaceuticals, Inc. Heterocyclic compounds which inhibit leukocyte adhesion mediated by α4 integrins
US7135477B2 (en) 2002-05-24 2006-11-14 Elan Pharmaceuticals, Inc. Heterocyclic compounds which inhibit leukocyte adhesion mediated by α4 integrins
AU2004207536B2 (en) * 2003-01-24 2010-05-20 Elan Pharmaceuticals Inc. Composition for and treatment of demyelinating diseases and paralysis by administration of remyelinating agents
WO2004066931A3 (fr) * 2003-01-24 2005-12-15 Elan Pharm Inc Composition et methode destinees a traiter les maladies de demyelinisation et la paralysie par administration d'agents de remyelinisation
US7576101B2 (en) 2003-01-24 2009-08-18 Elan Pharmaceuticals, Inc. Composition for and treatment of demyelinating diseases and paralysis by administration of remyelinating agents
EP1635822A2 (fr) * 2003-06-25 2006-03-22 Elan Pharmaceuticals, Inc. Methodes et compositions de traitement de polyarthrite rhumatoide
EP1635822A4 (fr) * 2003-06-25 2009-06-24 Elan Pharm Inc Methodes et compositions de traitement de polyarthrite rhumatoide
US7345049B2 (en) 2003-12-22 2008-03-18 Ajinomoto Co., Inc. Phenylalanine derivatives
US8309561B2 (en) 2003-12-22 2012-11-13 Ajinomoto Co., Inc. Phenylalanine derivatives
US7579466B2 (en) 2006-02-27 2009-08-25 Elan Pharmaceuticals, Inc. Pyrimidinyl sulfonamide compounds which inhibit leukocyte adhesion mediated by VLA-4
EP2510941A2 (fr) 2007-02-20 2012-10-17 Merrimack Pharmaceuticals, Inc. Procédés de traitement de la sclérose en plaques par administration d'une alpha-foetoprotéine combinée à un antagoniste de l'intégrine
WO2009126920A2 (fr) 2008-04-11 2009-10-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de sérum humain, et ses conjugués
EP2860260A1 (fr) 2008-04-11 2015-04-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de sérum humain et de leurs conjugués
WO2015136468A1 (fr) 2014-03-13 2015-09-17 Prothena Biosciences Limited Polythérapie pour la sclérose en plaques
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US12053462B2 (en) 2018-10-30 2024-08-06 Gilead Sciences, Inc. Quinoline derivatives
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

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TW534910B (en) 2003-06-01
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EP1001972A1 (fr) 2000-05-24
IL133640A0 (en) 2001-04-30
CN1265668A (zh) 2000-09-06
AU756696B2 (en) 2003-01-23
PL338423A1 (en) 2000-11-06
NO20000450D0 (no) 2000-01-28
ZA986827B (en) 2000-05-02
AR013384A1 (es) 2000-12-27
CA2290747A1 (fr) 1999-02-11
BR9812114A (pt) 2000-07-18
JP2001512134A (ja) 2001-08-21
NZ502582A (en) 2002-07-26
AU8661198A (en) 1999-02-22
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