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WO1999006433A1 - Composes inhibant l'adhesion leucocytaire induite par vla-4 - Google Patents

Composes inhibant l'adhesion leucocytaire induite par vla-4 Download PDF

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WO1999006433A1
WO1999006433A1 PCT/US1998/015952 US9815952W WO9906433A1 WO 1999006433 A1 WO1999006433 A1 WO 1999006433A1 US 9815952 W US9815952 W US 9815952W WO 9906433 A1 WO9906433 A1 WO 9906433A1
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Prior art keywords
substituted
alkyl
heterocyclic
aryl
heteroaryl
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PCT/US1998/015952
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English (en)
Inventor
Michael S. Dappen
Darren B. Dressen
Francine S. Grant
Michael A. Pleiss
Cynthia Y. Robinson
Dimitrios Sarantakis
Eugene D. Thorsett
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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 IL13364198A priority Critical patent/IL133641A0/xx
Priority to KR1020007001005A priority patent/KR20010022423A/ko
Priority to HU0004529A priority patent/HUP0004529A3/hu
Priority to AU86786/98A priority patent/AU8678698A/en
Priority to CA002290746A priority patent/CA2290746A1/fr
Priority to JP2000505188A priority patent/JP2001512136A/ja
Priority to BR9811569-3A priority patent/BR9811569A/pt
Priority to EP98938207A priority patent/EP1001973A1/fr
Publication of WO1999006433A1 publication Critical patent/WO1999006433A1/fr
Priority to NO20000451A priority patent/NO20000451L/no

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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 ⁇ 1 integrin and CD49d/CD29), first identified by Hemler and Takada 1 is a member of the ⁇ l integrin family of cell surface receptors, each of which comprises two subunits, an ⁇ chain and a ⁇ chain.
  • VLA-4 contains an ⁇ 4 chain and a ⁇ l chain.
  • VLA-4 for example, binds to fibronectin.
  • VLA-4 also binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed on cytokine-activated human umbilical vein endothelial cells in culture. Distinct epitopes of VLA-4 are responsible for the fibronectin and VCAM-1 binding activities and each activity has been shown to be inhibited independently. 2
  • Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a number of inflammatory responses.
  • activated vascular endothelial cells express molecules that are adhesive for leukocytes.
  • the mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release chemical mediators to combat infection.
  • adhesion receptors of the immune system see, for example, Springer 3 and Osborn 4 .
  • Inflammatory brain disorders such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of central nervous system disorders in which the endothelium leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue.
  • EAE experimental autoimmune encephalomyelitis
  • MS multiple sclerosis
  • M multiple sclerosis
  • meningitis are examples of central nervous system disorders in which the endothelium leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue.
  • BBB blood brain barrier
  • the leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis.
  • tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes.
  • tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes.
  • the initial insult following myocardial ischemia to heart tissue can be further complicated by leukocyte entry to the injured tissue causing still further insult (Vedder et al. 5 ).
  • inflammatory conditions mediated by an adhesion mechanism include, by way of example, asthma 6"8 , Alzheimer's disease, atherosclerosis 9"10 , AIDS dementia 11 , diabetes 12"14 (including acute juvenile onset diabetis), inflammatory bowel disease 15 (including ulcerative colitis and Crohn's disease), multiple sclerosis 16"17 , rheumatoid arthritis 18"21 , tissue transplantation 22 , tumor metastasis 23"28 , meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
  • This invention provides compounds which bind to VLA-4. Such compounds can be used, for example, to assay for the presence of VLA-4 in a sample and, in pharmaceutical compositions, to inhibit cellular adhesion mediated by VLA-4, for example, binding of VCAM-1 to VLA-4.
  • the compounds of this invention have a binding affinity to VLA-4 as expressed by an I Q of about 15 ⁇ M or less (as measured using the procesure shown in Example 46 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, and substituted heteroaryl, and R 1 and R 2 together with the nitrogen atom bound to R 2 and the S0 2 group bound to R 1 can form a heterocyclic or a substituted heterocyclic group;
  • R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 2 and R 3 together with the nitrogen atom bound to R 2 and the carbon atom bound to R 3 can form an unsaturated heterocyclic group or a unsaturated substituted heterocyclic group;
  • 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;
  • R 5 is -CH 2 X where X is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxy 1-substituted alkyl, carboxy 1-cycloalkyl, carboxyl-substituted cycloalkyl, carboxy laryl, carboxyl-substituted aryl, carboxy lheteroaryl, carboxyl- substituted heteroaryl, carboxy lheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, with the further provisos that:
  • R 5 is not -(CH 2 ) X -Ar-R 5' where R 5' is -0-Z-NR 8 R 8' or -O-Z-R 12 wherein R 8 and R 8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic, and R 8 and R 8 can be joined to form a heterocycle or a substituted heterocycle, R 12 is selected from the group consisting of heterocycles and substituted heterocycles, and Z is selected from the group consisting of -C(O)- and -SQ-, Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4;
  • R 5 is not -(CH 2 ) X -Ar-R 5' where R 5' is -NR 12 C(Z')NR 8 R 8 or -NR 12 C(Z)R 13 wherein Z' is selected from the group consisting of oxygen, sulfur and NR 12 , R 12 is selected from the group consisting of hydrogen, alkyl and aryl, R 8 and R 8 are independently selected from the group consisting of hydrogen, alkyl, substituted a ⁇ kyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl provided that when Z' is oxygen, at least one of R 8 and R 8 is sustituted alkyl, cycloalkyl, substituted cycloalkyl, saturated heterocyclic other than morpholino and thiomorpholino, or substituted heterocyclic or R 8 and R 8 can be joined to form a saturated heterocycle other than morpholino
  • Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, x is an integer of from 1 to 4;
  • R 5 is not -ALK-X' where ALK is an alkyl group of from 1 to 10 carbon atoms attached via a methylene group (-CH 2 -) to the carbon atom to which it is attached;
  • X' is selected from the group consisting of substituted alkylcarbonylamino, substituted alkenylcarbonylamino, substituted alkynylcarbonylamino, heterocyclylcarbonylamino, substituted heterocyclylcarbonylamino, acyl, acyloxy, aminocarbonyloxy, acylamino, oxycarbonylamino, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxy carbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryloxy carbonyl, substituted heteroaryloxy carbonyl, substituted heterocyclyloxycarbonyl, cycloalkyl
  • 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 or 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, ammothiocarbonylamin
  • 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, carboxy lalkyl, carboxyl-substit
  • substituted alkoxy with the proviso that the substitution on the alkyl moiety of said substituted alkoxy does not include alkoxy-NR"R", unsaturated heterocyclyl, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxy ethylene, 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 heterocyclic, aryl, heteroaryl or aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxy ethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, al
  • R 18 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 22 is alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic;
  • R 19 wherein 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 each R 19 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) -NR'C(0)OR 19 wherein 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 19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloal
  • R 5 is not -(CH 2 ) X -Ar-R 5" where R 5" is 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,
  • R 1 and R 2 are joined together with the S0 2 and nitrogen atom to which they are attached respectively to form a benzoisothiazolone heterocyclic ring, R 3 is hydrogen, and Q is -C(0)NH-, then R 5 is not benzyl; and
  • 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 in the compound of formula I is modified into a group which, in vivo, will convert to the 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 S0 2 group bound to R 1 can form a heterocyclic or a substituted heterocyclic group
  • R 3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroary
  • R 9 is selected from the group consisting of -C(0)-aryl and -C(0)-substituted aryl and R 10 is selected from the group consisting of hydrogen and -CH 2 COOR ⁇ where R 11 is alkyl, and - NHS0 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;
  • R 5 is -CH 2 X where X is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxy lalkyl, carboxyl-substituted alkyl, carboxy 1-cycloalky 1, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxy Iheteroaryl, carboxyl- substituted heteroaryl, carboxy Iheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substituted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic with the further provisos that:
  • R 5 is not -(CH 2 ).-Ar-R 5 where R 5' is selected from the group consisting of -0-Z-NR 8 R 8' and -O-Z-R 12 wherein R 8 and R 8' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, and where R 8 and R 8' are joined to form a heterocycle or a substituted heterocycle, R 12 is selected from the group consisting of heterocycle and substituted heterocycle, and Z is selected from the group consisting of -C(O)- and -S0 2 -,
  • Ar is aryl, heteroaryl, substituted aryl or substituted heteroaryl, x is an integer of from 1 to 4;
  • R 5 is not -(CH 2 ) X -Ar-R 5' where R 5' is selected from the group consisting of -NR 1 C(Z')NR 8 R 8' and -NR 12 C(Z')R 13 wherein Z' is selected from the group consisting of oxygen, sulfur and NR 12 , R 12 is selected from the group consisting of hydrogen, alkyl and aryl, R 8 and R 8' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl provided that when Z' is oxygen, at least one of R 8 and R 8' is sustituted alkyl, cycloalkyl, substituted cycloalkyl, saturated heterocycl
  • Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl, x is an integer of from 1 to 4;
  • R 5 is not -ALK-X' where ALK is an alkyl group of from 1 to 10 carbon atoms attached via a methylene group (-CH 2 -) to the carbon atom to which it is attached;
  • X' is selected from the group consisting of substituted alkylcarbonylamino, substituted alkenylcarbonylamino, substituted alkynylcarbonylamino, heterocyclylcarbonylamino, substituted heterocyclylcarbonylamino, acyl, acyloxy, aminocarbonyloxy, acylamino, oxycarbonylamino, alkoxycarbonyl, substituted alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryloxy carbonyl, substituted heteroaryloxy carbonyl, substituted heteroaryloxycarbonyl, substituted heterocyclyloxy carbonyl, cycloal
  • R 5 is not -(CH 2 ) X -Ar-R 5" where R 5 is a substituent selected from the group consisting of:
  • 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, ammothiocarbonylamino, aminocarbonyloxy, aryloxy, substituted aryloxy, cyano, nitro, halogen, hydroxyl, carboxyl, carboxy lalkyl, carboxyl-substituted alkyl, carboxyl- cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxy Ihetero
  • 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 or 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, aminocarbonyloxy, aryloxy, substitute
  • 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-dioxy ethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylcarbonyloxy, acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N,N-dialkylurea;
  • substituted alkoxy with the proviso that the substitution on the alkyl moiety of said substituted alkoxy does not include alkoxy-NR"R", unsaturated heterocyclic, alkyloxy, aryloxy, heteroaryloxy, aryl, heteroaryl and aryl/heteroaryl substituted with halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxy ethylene, 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 heterocyclic, 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, alkylcarbonyloxy, acyl, alkyl
  • 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 each R 19 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 19 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
  • R 5 is not -(CH 2 ) X -Ar-R 5" where R 5" is 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, aminothi
  • R 1 is ⁇ -carboxymethylphenyl
  • R 2 is hydrogen
  • R 3 is hydrogen or methyl
  • R 5 is benzyl and Q is -C(0)NH-, then R 6 is not -O-benzyl
  • R 1 and R 2 are joined to form a benzoisothiazolone heterocyclic ring, R 3 is hydrogen or methyl, R 5 is benzyl and Q is -C(0)NH-, then R 6 is not -O-benzyl;
  • R 1 is /?-methylphenyl
  • R 2 is hydrogen
  • R 5 is benzyl or /j-hydroxybenzyl
  • R 3 is -(CH 2 ) s C(0)0-t-butyl where s is 1 or 2
  • Q is -C(0)NH-, then R 6 is not -O-t-butyl;
  • R 1 is /?-methylphenyl
  • R 2 is methyl
  • R 5 is benzyl
  • R 3 is -CH( ⁇ ) 2
  • Q is -C(0)NH-
  • R 6 is not -O-benzyl
  • R 1 is /?-methylphenyl
  • R 2 is methyl
  • R 3 is methyl or t-butyl
  • R 5 is p- hydroxybenzyl
  • Q is -C(0)NH-
  • R 6 is not -O-t-butyl.
  • R 1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl.
  • R 1 is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4- chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6- trimethylphenyl, 2-(methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4- trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4-(CH 3 C(0)NH- )phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di- (trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1- N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl,
  • 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 S0 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 the group consisting of 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 the group consisting of nitrogen, oxygen and sulfur.
  • Specifically preferred RVR 2 joined groups include, by way of example, benzisothiazolonyl (saccharin-2-yl).
  • 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, /.r ⁇ -butyl, t-butyl, -CH 2 0-benzyl and hydroxymethyl.
  • Q is preferably -C(0)NH- or -C(S)NH-.
  • R 5 is preferably selected from the group consisting of all possible isomers arising by substitution with the following groups: benzyl, (N-benzylimidazol-4- yl)methyl, (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl, 4-[2- (pyridin-2-yl)ethynyl]benzyl, 4-[2-(3-hydroxyphenyl)ethynyl]benzyl, 4-iodobenzyl, 4- cyanobenzyl, 4-(2-bromobenzamido)benzyl, 4-(pyridin-4-yl-C(0)NH-)benzyl, and 4- hydroxybenzyl.
  • R 6 is preferably 2,4-dioxo-tetrahydrofuran-3-yl
  • ester compounds recited above wherein one ester is replaced with another ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl ester.
  • This invention also provides methods for binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound of formula I or I A above under conditions wherein said compound binds to VLA-4. Certain of the compounds of formula I and IA above are also useful in reducing VLA-4 mediated inflammation in vivo.
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of formula I or IA above with the exception that F? 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, memngitis, 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.
  • this invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4.
  • VLA-4 leukocyte adhesion mediated by VLA-4.
  • alkyl refers to alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.
  • Substituted alkyl refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, ammothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxylaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxy lalkyl, carboxyl-substituted alkyl, carboxy 1-cycloalky 1, carboxyl-substituted cycloalkyl, carboxy laryl, carboxyl-substituted aryl, carboxylheteroaryl
  • Alkoxy refers to the group “alky 1-0- " which includes, by way of example, methoxy, ethoxy, n-propoxy, z ' s ⁇ -propoxy, n-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(0)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.
  • alkenyl-C(0)0- substituted alkenyl-C(0)0-, alkynyl-C(0)0-, substituted alkynyl-C(0)0-, aryl-C(0)0-, substituted aryl-C(0)0-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(0)0-, heteroaryl-C(0)0-, substituted heteroaryl-C(0)0-, heterocyclic-C(0)0-, and substituted heterocyclic-C(0)0-
  • 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.
  • 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, ammothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxy lalkyl, carboxyl-substituted alkyl, carboxy 1-cycloalky 1, carboxyl-substituted cycloalkyl, carboxy laryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroary
  • 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, ammothiocarbonylamino, aminocarbonyloxy, aryl, substituted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxy lalkyl, carboxyl-substituted alkyl, carboxy 1-cycloalky 1, carboxyl-substituted cycloalkyl, carboxy laryl, carboxyl-substituted aryl, carboxylheteroaryl, carboxyl-substituted
  • -NRS(0) 2 -substituted heterocyclic -NRS(0) 2 -NR-alkyl, -NRS(0) 2 -NR- substituted alkyl, -NRS(0) 2 -NR-aryl, -NRS(0) 2 -NR-substituted aryl, -NRS(0) 2 -NR-heteroaryl, -NRS(0) 2 -NR-substituted heteroaryl, -NRS(0) 2 - NR-heterocyclic, -NRS(0) 2 -NR-substituted heterocyclic, mono- and di- alkylamino, mono- and di-(substituted alkyl)amino, mono- and di- arylamino, mono- and di-(substituted aryl)amino, mono- and di- heteroarylamino, mono- and di-(substituted heteroaryl)amino, mono- and di-heterocyclic amino, mono- and
  • jAminoacyl refers to the groups -NRC(0)alkyl
  • R is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted
  • Aminocarbonyloxy refers to the groups -NRC(0)0-alkyl, -NRC(0)0-substituted alkyl, -NRC(0)0-alkenyl, -NRC(0)0-substituted alkenyl, -NRC(0)0-alkynyl, -NRC(0)0-substituted alkynyl, -NRC(0)0- cycloalkyl, -NRC(0)0-substituted cycloalkyl, -NRC(0)0-aryl, -NRC(0)0- substituted aryl, -NRC(0)0-heteroaryl, -NRC(0)0-substituted heteroaryl,
  • R is hydrogen or alkyl 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.
  • Oxycarbonylamino refers to the groups -OC(0)NH 2 , -OC(0)NRR, -OC(0)NR-alkyl, -OC(0)NR-substituted alkyl, -OC(0)NR- alkenyl, -OC(0)NR-substituted alkenyl, -OC(0)NR-alkynyl, -OC(0)NR- substituted alkynyl, -OC(0)NR-cycloalkyl, -OC(0)NR-substituted cycloalkyl, -OC(0)NR-aryl, -OC(0)NR-substituted aryl, -OC(0)NR- heteroaryl, -OC(0)NR-substituted heteroaryl,- OC(0)NR-heterocyclic, and -OC(0)NR-substituted heterocyclic where 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 alky
  • 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
  • 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.
  • Aminocarbonylamino refers to the groups -NRC(0)NRR, -NRC(0)NR-alkyl, -NRC(0)NR-substituted alkyl, -NRC(0)NR-alkenyl, -NRC(0)NR-substituted alkenyl, -NRC(0)NR-alkynyl,
  • 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 herein.
  • conventional blocking groups such as Boc, Cbz, formyl, and the like
  • “Ammothiocarbonylamino” refers to the groups -NRC(S)NRR, -NRC(S)NR-alkyl, -NRC(S)NR-substituted alkyl, -NRC(S)NR-alkenyl, -NRC(S)NR-substituted alkenyl, -NRC(S)NR-alkynyl, -NRC(S)NR- substituted alkynyl, -NRC(S)NR-aryl, -NRC(S)NR-substituted aryl, -NRC(S)NR-cycloalkyl, -NRC(S)NR-substituted cycloalkyl, -NRC(S)NR- heteroaryl, and -NRC(S)NR-substituted heteroaryl, -NRC(S)NR- heterocyclic, and -NRC(S)NR-substituted heteroaryl,
  • 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, carboxy lalkyl, carboxyl-substituted alkyl, carboxy 1-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, ammothiocarbonylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxy lalkyl, 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.
  • 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, ary
  • each R is independently hydrogen and alkyl 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.
  • 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 the group consisting of 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, carboxy lalkyl, carboxyl-substituted alkyl, carboxyl-cycl
  • Heteroaryloxy refers to the group -O-heteroaryl and "substituted heteroaryloxy” refers to the group -O-substituted heteroaryl.
  • Heterocycle or “heterocyclic” refers to a saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from the group consisting of 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
  • “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.
  • Thiol refers to the group -SH.
  • Thioalkyl refers to the groups -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 to 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 or IA which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
  • the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • R -R 3 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 triethylamine, diisopropylethylamine, N-methylmorpholine and the like.
  • reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like, as the base.
  • aqueous alkali such as sodium hydroxide and the like
  • the resulting N-sulfonyl amino acid IV is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.
  • amino acids of formula II employed in the above reaction are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures.
  • suitable amino acids for use in this reaction include, but are not limited to, glycine, 2-tert-butylglycine, D,L-phenylglycine, L-alanine, ⁇ -methylalanine, N- methyl-L-phenylalanine, L-diphenylalanine, sarcosine, D,L- phenylsarcosine, L-aspartic acid ⁇ -tert-butyl ester, L-glutamic acid ⁇ -tert- butyl ester, L-(0-be ⁇ zyl)serine, 1-aminocyclopropanecarboxylic acid, 1- aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid
  • 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 1 -S0 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 (Cy 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, benzenesulf onyl 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 chlor
  • a sulfonyl fluoride, sulfonyl bromide or sulfonic acid anhydride may be used in place of the sulfonyl chloride in the above reaction to form the N-sulfonyl amino acids of formula IV.
  • R ⁇ SO.- ⁇ H-R 2 V wherein R 1 and R 2 are as defined above, with a carboxylic acid derivative of the formula L(R 3 )CHCOOR where L is a leaving group, such as chloro, bromo, iodo, mesylate, tosylate and the like, R 3 is as defined above and R is hydrogen or an alkyl group.
  • L is a leaving group, such as chloro, bromo, iodo, mesylate, tosylate and the like
  • R 3 is as defined above and R is hydrogen or an alkyl group.
  • 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-hy droxy succinimide, 1-hy droxy benzotriazole 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- dimethy If ormamide and the like.
  • an inert diluent such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N- dimethy If ormamide and the like.
  • this reaction is conducted at a temperature ranging from about 0°C to about, 37 °C for about 12 to about 24 hours.
  • the compound of formula I is recovered by conventional methods including neutralization, extraction, precipitation, chromatography, filtration, and the like.
  • the N-sulfonyl amino acid IV can be converted into an acid halide and the acid halide coupled with amino acid derivative VI to provide compounds of formula I.
  • the acid halide of VI can be prepared by contacting VI with an inorganic acid halide, such as thionyl chloride, phosphorous trichloride, phosphorous tribromide or phosphorous pentachloride, or preferably, with oxalyl chloride under conventional conditions.
  • this reaction is conducted using about 1 to 5 molar equivalents of the inorganic acid halide or oxalyl chloride, either neat or in an inert solvent, such as dichloromethane or carbon tetrachloride, at 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-dimethy If ormamide, 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:
  • 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,
  • amino acid derivatives of formula VI suitable for use in the above reactions include, but are not limited to, L-alanine methyl ester, L-isoleucine methyl ester, L-leucine methyl ester, L-valine methyl ester, ⁇ -tert-butyl-L-aspartic acid methyl ester, L-asparagine tert-butyl ester, e-Boc-L-lysine methyl ester, e-Cbz-L-lysine methyl ester, y-tert- butyl-L-glutamic acid methyl ester, L-glutamine tert-butyl ester, L-(N- methyl)histidine methyl ester, L-(N-benzyl)histidine methyl ester, L- methionine methyl ester, L-(O-benzyl)serine methyl ester, L-tryptophan methyl ester, L-phenylalanine methyl ester
  • 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-hy droxy succinimide, 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-hy droxy succinimide, 1-hydroxy- benzotriazole 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-buty loxycarbonylglycine, N-tert- buty loxy carbonyl-L-pheny lalanine , N-tert-buty loxycarbonyl-L-aspartic acid benzyl ester, benzoic acid, N-tert-buty loxy carbonylisonipecotic acid, N- methylisonipecotic acid, N-tert-buty loxycarbonylnipecotic 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-(N,N-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, diisopropylethylamme, 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., > N-S0 2 -N ⁇ ) .
  • a primary and secondary amino group present on a substituent of a compound of formula I or an intermediate thereof can be reacted with an isocyanate or a thioisocyanate to give a urea or thiourea, respectively.
  • This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the isocyanate or thioisocyanate in an inert diluent, such as toluene and the like, at a 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, n-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, methyl thioisocyanate, ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3- phenylpropyl thioisocyanate, 3-(N,N-diethylamino)propyl thioisocyanate, phenyl thioisocyanate, benzyl thioisocyanate, 3-pyridyl thioisocyanate, fluorescein isothiocyanate (isomer I
  • 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, N-tert-butyl chloroacetamide, 1-bromoethylbenzene, ethyl ⁇ - bromophenylacetate, 2-(N-ethyl-N-phenylamino)ethyl chloride, 2-(N,N- ethylamino)ethyl chloride, 2-(N,N-diisopropylamino)ethyl chloride, 2-(N,N- dibenzylamino)ethyl chloride, 3-(N,N-ethylamino)propyl chloride, 3-(N- benzyl-N-methylamino)propyl chloride, N-(2-chloroethyl)mo holine, 2-
  • 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
  • triphenylphosphine is reacted with about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate in an inert diluent, such as tetrahydrofuran, at a temperature ranging from about -10°C to about 5°C for about 0.25 to about 1 hour.
  • a hydroxy compound such as N-tert-buty Ityrosine methyl ester
  • 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
  • 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.
  • Treatment of the resulting carbonate with an excess, preferably about 2 to about 5 equivalents, of a trialkylamine, such as triethylamine, for about 0.5 to 2 hours, followed by about 1.0 to about 1.5 equivalents of a primary or secondary amine provides the carbamate.
  • amines suitable for using in this reaction include, but are not limited to, piperazine, 1-methylpiperazine, 1-acetylpiperazine, morpholine, thiomorpholine, pyrrolidine, piperidine and the like.
  • a hydroxy-containing compound is contacted with about 1.0 to about 1.5 equivalents of a carbamyl chloride in an inert diluent, such as dichloromethane, at a 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-methylmorpholine and the like.
  • At least one equivalent (based on the hydroxy compound) of 4-(N,N-dimethylamino)pyridine is preferably added to the reaction 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- hy droxy -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 / oluenesulfonyl 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.
  • 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-dimethy If ormamide 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-dimethy If ormamide and water
  • the azido group can then be reduced by, for example, hydrogenation using a palladium on carbon catalyst to provide the amino (-NH 2 ) compound.
  • a tosylate group can be readily displaced by a thiol to form a sulfide.
  • This reaction is typically conducted by contacting the tosylate with at least one equivalent of a thiol, such as thiophenol, in the presence of a suitable base, such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in an inert diluent, such as N,N-dimethylformamide, at a 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? 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-
  • the compounds of formula I or I A 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.
  • 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 Chemistry", 4th Ed., pp. 1201-1202, Wiley Publisher, 1992.
  • 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-pheny lalanine and the like, in the above-described coupling reactions.
  • N-substituted amino acid of formula II such as sarcosine, N-methyl-L-pheny lalanine 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 sulfonamides of formula I or IV wherein R 2 is hydrogen and R 1 is a 2-alkoxycarbonylaryl group can be intramolecularly cyclized to form 1 ,2-benzisothiazol-3-one derivatives or analogues thereof.
  • This reaction is typically conducted by treating a sulfonamide, such as N- (2-methoxycarbonylphenylsulfonyl)glycine-L-phenylalanine benzyl ester, with about 1.0 to 1.5 equivalents of a suitable base, such as an alkali metal hydride, 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 cyclized 1 ,2-benzisothiazol-3-one derivative.
  • a sulfonamide such as N- (2-methoxycarbonylphenylsulfonyl)glycine-L-phenylalanine benzyl ester
  • a suitable base such as an alkali metal hydride
  • a inert diluent such as tetrahydrofuran
  • the compounds of formula I where Q is -C(S) ⁇ R 7 - are can prepared by using an amino thionoacid derivative in place of amino acid II in the above described synthetic procedures.
  • amino thionoacid derivatives can be prepared by the procedures described in Shalaky, et al., J. Org. Chem., 61:9045-9048 (1996) and Brain, et al., J. Org. Chem.,
  • the compounds of formula I and IA are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • compositions which contain, as the active ingredient, one or more of the compounds of formula
  • 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.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi- solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhy droxy - benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound 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 an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and 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 incorporated 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.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • Stearic acid 5.0 The components are blended and compressed to form tablets, each weighing 240 mg.
  • Formulation 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.
  • Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows:
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone 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.
  • Capsules each containing 40 mg of medicament are made as follows:
  • 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.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the 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.
  • the medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560 mg quantities.
  • An intravenous formulation may be prepared as follows:
  • a topical formulation may be prepared as follows:
  • 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 incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Direct techniques can be used when it is desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. 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 5,011,472 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 ⁇ ! 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 binding assay to measure for the presence of VLA-4 in the sample.
  • Other suitable assays are well known in the art.
  • certain of the compounds of this invention inhibit, in vivo, adhesion of leukocytes to endothelial cells mediated by VLA-4 and, accordingly, can be used in the treatment of diseases mediated by VLA-4.
  • diseases include inflammatory diseases in mammalian patients such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
  • the biological activity of the compounds identified above may be assayed in a variety of systems.
  • a compound can be immobilized on a solid surface and adhesion of cells expressing VLA-4 can be measured. Using such formats, large numbers of compounds can be screened.
  • Cells suitable for this assay include any leukocytes known to express VLA-4 such as T cells, B cells, monocytes, eosinophils, and basophils.
  • a number of leukocyte cell lines can also be used, examples include Jurkat and U937.
  • test compounds can also be tested for the ability to competitively inhibit binding between VLA-4 and VCAM-1, or between VLA-4 and a labeled compound known to bind VLA-4 such as a compound of this invention or antibodies to VLA-4.
  • the VCAM-1 can be immobilized on a solid surface.
  • VCAM-1 may also be expressed as a recombinant fusion protein having an Ig tail (e.g., IgG) so that binding to VLA-4 may be detected in an immunoassay.
  • VCAM-1 expressing cells such as activated endothelial cells or VCAM-1 transfected fibroblasts can be used.
  • the assays described in International Patent Application Publication No. WO 91/05038 are particularly preferred. This application is inco ⁇ orated herein by reference in its entirety.
  • the labelling systems can be in a variety of forms.
  • the label may be coupled directly or indirectly to the desired component of the assay according to methods well known in the art.
  • a wide variety of labels may be used.
  • the component may be labelled by any one of several methods. The most common method of detection is the use of autoradiography with 3 H, 1 5 1, 35 S, 14 C, or 32 P labelled compounds and the like.
  • Non-radioactive labels include ligands which bind to labelled antibodies, fluorophores, chemiluminescent agents, enzymes and antibodies which can serve as specific binding pair members for a labelled ligand.
  • the choice of label depends on sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation.
  • EAE experimental autoimmune encephalomyelitis
  • Compounds having the desired biological activity may be modified as necessary to provide desired properties such as improved pharmacological properties (e.g., in vivo stability, bio-availability), or the ability to be detected in diagnostic applications.
  • desired properties such as improved pharmacological properties (e.g., in vivo stability, bio-availability), or the ability to be detected in diagnostic applications.
  • inclusion of one or more D-amino acids in the sulfonamides of this invention typically increases in vivo stability. Stability can be assayed in a variety of ways such as by measuring the half-life of the proteins during incubation with peptidases or human plasma or serum. A number of such protein stability assays have been described (see, e.g., Verhoef et al., Eur. J. Drug Metab. Pharmacokinet., 1990, 15i2):83-93).
  • the compounds of the subject invention may be modified in a variety of ways for a variety of end pu ⁇ oses while still retaining biological activity.
  • various reactive sites may be introduced at the terminus for linking to particles, solid substrates, macromolecules, and the like.
  • Labeled compounds can be used in a variety of in vivo or in vitro applications.
  • a wide variety of labels may be employed, such as radionuclides (e.g., gamma-emitting radioisotopes such as technetium-99 or indium-Ill), fluorescers (e.g., fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like.
  • radionuclides e.g., gamma-emitting radioisotopes such as technetium-99 or indium-Ill
  • fluorescers e.g., fluorescein
  • enzymes enzyme substrates
  • enzyme 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.
  • 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 are well known.
  • MRI magnetic resonance imaging
  • ESR electron spin resonance
  • any conventional method for visualizing diagnostic images 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).
  • CD8 + cells, CD4 cells and monocytes are all involved in the rejection of transplant tissues.
  • Compounds of this invention which bind to alpha-4 integrin are useful, inter alia, to block alloantigen-induced immune responses in the donee thereby preventing such cells from participating in the destruction of the transplanted tissue or organ. See, e.g., Paul et al., Transplant International 9, 420-425 (1996); Georczynski et al., Immunology 87, 573-580 (1996); Georcyznski et al., Transplant. Immunol. 3, 55-61 (1995); Yang et al. , Transplantation 60, 71-76 (1995); Anderson et al. , APMIS 102, 23-27 (1994).
  • GVHD graft versus host disease
  • Schlegel et al. J. Immunol. 155, 3856-3865 (1995).
  • GVHD is a potentially fatal disease that occurs when immunologically competent cells are transferred to an allogenetic recipient. In this situation, the donor's immunocompetent cells may attack tissues in the recipient. Tissues of the skin, gut epithelia and liver are frequent targets and may be destroyed during the course of GVHD.
  • the disease presents an especially severe problem when immune tissue is being transplanted, such as in bone marrow transplantation; but less severe GVHD has also been reported in other cases as well, including heart and liver transplants.
  • the therapeutic agents of the present invention are used, ter alia, to block activation of the donor T-cells thereby interfering with their ability to lyse target cells in the host.
  • a further use of the compounds of this invention is inhibiting tumor metastasis.
  • Several tumor cells have been reported to express VLA-4 and compounds which bind VLA-4 block adhesion of such cells to endothelial cells. Steinback et al., Urol. Res. 23, 175-83 (1995); Orosz et al., Int. J. Cancer 60, 867-71 (1995); Freedman et al., Leuk. Lymphoma 13, 47-52
  • 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
  • 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.
  • the amount administered to the patient will vary depending upon what is being administered, the pu ⁇ ose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like.
  • 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
  • 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.
  • EDC l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • NMM N-methylmo ⁇ holine
  • Method 9 Reductive Amination Procedure Reductive amination of Tos-Pro-p-NH 2 -Phe with the appropriate aldehyde was conducted using acetic acid, sodium triacetoxyborohydride, methylene chloride and the combined mixture was stirred at room temperature overnight. The crude product was purified by flash chromatography. Method 10 BOC Removal Procedure Anhydrous hydrochloride (HCl) gas was bubbled through a methanolic solution of the appropriate Boc-amino acid ester at 0°C for 15 minutes and the reaction mixture was stirred for three hours. The solution was concentrated to a syrup and dissolved in Et 2 0 and reconcentrated. This procedure was repeated and the resulting solid was placed under high vacuum overnight.
  • HCl anhydrous hydrochloride
  • N-methylmo ⁇ holine (1.1-2.2 equivalents) and 1-hydroxybenzotriazole (2 equivalents) were mixed, placed in an ice bath and l-(3- dimethylaminopropyl)-3-ethyl carbodiimide (1.1 equivalents) added.
  • the reaction was allowed to rise to room temperature and stirred overnight.
  • the reaction mixture was poured into H 2 0 and the organic phase was washed with sat. NaHC0 3 , brine, dried (MgS0 4 or Na 2 S0 4 ), filtered and concentrated.
  • the crude product was purified by column chromatography.
  • N-(Toluene-4-sulfonyl)-2S-indoline-2-carboxylic acid (331.2 mg, 1.04 mmol) was dissolved in dry DMF (5 mL) with 4-methyl mo ⁇ holine (3.5 eq, 400 ⁇ L), BOP (1.1 eq, 506 mg), and phenylalanine benzyl ester (1.0 eq, 444 mg).
  • the dipeptide was isolated as an oil.
  • the benzyl ester was dissolved in EtOH:H 2 0 (1:1) [2.5 mL] containing a catalytic amount of
  • the mixture was diluted with CH 2 C1 2 (40 mL) and washed with IN HCl (2 x 10 mL), IM ⁇ aHCQ, (15 mL), brine (10 mL), dried (MgS0 4 ), filtered and evaporated in vacuo.
  • the residue was purified by silica gel flash chromatography (3:2 Hexane/EtOAc) to give the dipeptide benzyl ester (0.51g, 50%).
  • the - benzyl ester was dissolved in THF (20 mL) and 10% Pd/C (60 mg) was added.
  • the mixture was hydrogenated at 15 psi H 2 for 1.5 hr.
  • Example 21 The product from Example 21 (180) (0.62 mmoles) was added to ethanol (40 mL) and 5% Pd-C (10%) and shaken under 35 psi hydrogen for
  • N-(Toluene-4-sulfonyl)phenylglycine was prepared from phenylglycine using the procedure described in Method 1.
  • N-Methyl-L-pheny lalanine 500 mg, 2.79 mmol was dissolved in IN ⁇ aOH (6 mL). Dioxane (9 mL)) was added, followed by -toluenesulfonyl chloride (532 mg, 2.79 mmol) and the mixture was vigorously stirred for 1 hr. The volatiles were removed in vacuo and the residue was dissolved in water (30 mL) and washed with Et 2 0 (2 x 30 mL) before making acidic with IN HCl.
  • N-(Toluene-4-sulfonyl)-N-methylphenylalanine was coupled to L- phenylalanine ethyl ester using the procedure described in Method 3 (400 mg, 62%).
  • the title compound was prepared via hydrolysis of the ethyl ester using ⁇ aOH in ethanol. Proton and carbon ⁇ MR analyis indicated a mixture of diastereomers.
  • N-(Toluene-4-sulfonyl)-L- diphenylalanyl-L-phenylalanine was coupled to L-phenylalanine benzyl ester using the procedure described in Method 3.
  • the Boc group was removed by treatment with TFA and anisole, and the mixture was evaporated.
  • the residue was dissolved in Et 2 0 and washed with sat. NaHC0 3 and sat. NaCl.
  • the Et 2 0 layers were dried with MgS0 4 , filtered, and evaporated to give the deprotected dipeptide.
  • the resulting ester of the title compound was tosylated using the procedure described in Method 1.
  • N-(Toluene-4-sulfonyl)sarcosine was coupled to 3-(3-pyridyl)alanine methyl ester dihydrochloride using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl- ⁇ -(3-pyridyl)alanine (166 mg, 17%).
  • the title compound was prepared via hydrolysis of the methyl ester using
  • N-(Toluene-4-sulfonyl)sarcosine was coupled to L- ⁇ -(2-pyridyl)alanine methyl ester dihydrochloride using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl- ⁇ -(2-pyridyl)alanine methyl ester.
  • the title compound was prepared via hydrolysis of the methyl ester using IN aqueous ⁇ aOH in dioxane/ water.
  • N-(Toluene-4-sulfonyl)phenylsarcosine was prepared from phenylsarcosine using the procedure described in Method 1.
  • N-(Toluene-4-sulfonyl)sarcosine was coupled to N-methyl-L- phenylalanine methyl ester using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl-N-methylphenylalanine methyl ester.
  • the title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water. Proton and carbon NMR analysis indicated a mixture of amide bond rotomers in about a 65:35 ratio.
  • N-(toluene-4-sulfonyl)-(2S-l,2,3,4-tetrahydroquinolin-3-carbonyl) (1 eq) was dissolved in DMF, with Et 3 ⁇ (2.0 eq), BOP (1.1 eq), and L-phenylalanine benzyl ester HCl salt (1.1 eq).
  • the benzyl ester was isolated as an oil.
  • Example 18 (173) The procedure used for the preparation of Example 18 (173) was utilized. The title compound was isolated as an oil.
  • N-(Toluene-4-sulfonyl)phenylglycine was prepared from phenylglycine using the procedure described in Method 1.
  • N-(toluene-4-sulfonyl)-N-methyl-L-(O-benzyl)serine (754 mg, 2.07 mmol) was dissolved in 30 mL of dry DMF with phenylalanine ethyl ester hydrochloride salt (1.1 eq, 525 mg), Et 3 ⁇ (2.2 eq, 636 mL) and BOP reagent (1.1 eq, 1.00 g). The reaction mixture was stirred at room temperature for 12 hours. EtOAc was added. The organic layer was washed with NaHC0 3 saturated, 10% citric acid, and brine. The organic layer was dried over MgS0 4 .
  • Example 23 (191) (664 mg, 1.23 mmol) was dissolved in MeOH (10 mL) with a catalytic amount of Pearlman's catalyst. The hydrogenation reaction was run for 2 hours at 5 psi. The solution was filtered over celite. Upon evaporation of the solvent under reduced pressure, an oil was isolated as the title compound in quantitative yields. NMR data was as follows:
  • Boc-L-diphenylalanine was coupled to L-phenylalanine benzyl ester using the procedure described in Method 3.
  • the Boc group was removed using the procedure described in Example 11 (86).
  • NMR data was as follows:
  • N-(Toluene-4-sulfonyl)phenylglycine was esterified with thionyl chloride in methanol to give N-(toluene-4-sulfonyl)phenylglycine methyl ester. This was then taken up in dry acetone (50 mL) with iodomethane
  • N-(Toluene-4-sulfonyl)sarcosine methyl ester was prepared from sarcosine methyl ester using the procedure described in Method 1.
  • the title compound was prepared by coupling in DMF ⁇ -(toluene-4- sulfonyl)sarcosine with (N-benzyl)histidine methyl ester in the presence of BOP and ⁇ MM, to give after aqueous workup and flash chromatography, the title compound.
  • N-Methyl-N-(toluene-4-sulfonyl)-L-serine (420 mg, 1.53 mmol) was dissolved in dry DMF (20 mL) at ice bath temperature.
  • L-(N- benzyl)histidine methyl ester hydrochloride salt (1.1 eq, 500 mg) was added as well as Et 3 ⁇ (2.2 eq, 471 mL), with HOBT (1.1 eq, 229 mg).
  • N-(Toluene-4-sulfonyl)-2-thienylethylamine was prepared using the procedure described in Method 1. This compound was reacted with t-butyl bromoacetate yielding N-(toluene-4-sulfonyl)-N-(2-thienylethyl)glycine t- butyl ester (following the method of Zuckermann, Kerr, Kent, and Moos J. Am. Chem. Soc. 1992, 114, 10646-10647). The ester was hydrolyzed using the procedure described in Method 17. The title compound was prepared following the procedure described in Method 13. NMR data was as follows:
  • N-(Toluene-4-sulfonyl)sarcosine was coupled to 4-cyanophenylalanine methyl ester hydrochloride (prepared via the method of Wagner, Voight, and Vieweg Pharmazie 1984, 39, 226-230) to give N-(toluene-4- sulfonyl)sarcosyl-D,L-4-cyanophenylalanine methyl ester.
  • the compond was prepared via hydrolysis of the methyl ester using 0.5 ⁇ ⁇ aOH in THF/water. NMR data was as follows:
  • N-(Toluene-4-sulfonyl)-L-tert-butylglycine was prepared from L-tert- butylglycine using the procedure described in Method 1.
  • the title compound was prepared by coupling in DMF ⁇ -(toluene-4-sulfonyl)-L ⁇ tert-butylglycine with an L-phenylalanine ester in the presence of BOP and NMM. Conventional deesterification provided the title compound.
  • NMR data was as follows:
  • An in vitro assay was used to assess binding of candidate compounds to 4 ⁇ ! integrin.
  • Compounds which bind in this assay can be used to assess VCAM-1 levels in biological samples by conventional assays (e.g., competitive binding assays). This assay is sensitive to I o values as low as about InM.
  • ⁇ ⁇ j integrin The activity of ⁇ ⁇ j integrin was measured by the interaction of soluble VCAM-1 with Jurkat cells (e.g., American Type Culture Collection Nos. TIB 152, TIB 153, and CRL 8163), a human T-cell line which expresses high levels of ⁇ 4 ⁇ t integrin. VCAM-1 interacts with the cell surface in an ⁇ 4 ⁇ ⁇ integrin-dependent fashion (Yednock, et al. J. Biol. Chem., 1995,
  • VCAM-1 fusion protein containing the seven extracellular domains of VCAM-1 on the N- terminus and the human IgG ! heavy chain constant region on the C- terminus.
  • the VCAM-1 fusion protein was made and purified by the manner described by Yednock, supra.
  • Jurkat cells were grown in RPMI 1640 supplemented with 10% fetal bovine serum, penicillin, streptomycin and glutamine as described by
  • each of the compounds in Examples 1-45 has an IC 50 of 15 ⁇ M or less.
  • EAE Experimental Autoimmune Encephalomyelitis
  • Log-growth Jurkat cells are washed and resuspended in normal animal plasma containing 20 ⁇ g/ml of the 15/7 antibody (described in the above example).
  • the Jurkat cells are diluted two-fold into either normal plasma samples containing known candidate compound amounts in various concentrations ranging from 66 ⁇ M to 0.01 ⁇ M, using a standard 12 point serial dilution for a standard curve, or into plasma samples obtained from the peripheral blood of candidate compound-treated animals.
  • PBS phosphate-buffered saline
  • the cells are then exposed to phycoerythrin-conjugated goat F(ab') 2 anti-mouse IgG Fc (Immunotech, Westbrook, ME), which has been adsorbed for any non-specific cross-reactivity by co-incubation with 5 % serum from the animal species being studied, at 1:200 and incubated in the dark at 4°C for 30 minutes.
  • phycoerythrin-conjugated goat F(ab') 2 anti-mouse IgG Fc immunotech, Westbrook, ME
  • This assay may also be used to determine the plasma levels needed to saturate the binding sites of other integrins, such as the ⁇ integrin, which is the integrin most closely related ⁇ 4 ⁇ (Palmer et al, 1993, J. Cell Bio., 123: 1289).
  • Such binding is predictive of in vivo utility for inflammatory conditions mediated by Og ⁇ j integrin, including by way of example, airway hyper-responsiveness and occlusion that occurs with chronic asthma, smooth muscle cell proliferation in atherosclerosis, vascular occlusion following angioplasty, fibrosis and glomerular scarring as a result of renal disease, aortic stenosis, hypertrophy of synovial membranes in rheumatoid arthritis, and inflammation and scarring that occur with the progression of ulcerative colitis and Crohn's disease.
  • the above-described assay may be performed with a human colon carcinoma cell line, SW 480 (ATTC #CCL228) transfected with cDNA encoding ⁇ 9 integrin (Yokosaki et al., 1994, J. Biol. Chem., 269:26691), in place of the Jurkat cells, to measure the binding of the integrin.
  • SW 480 cells which express other and subunits may be used.
  • another aspect of this invention is directed to a method for treating a disease in a mammalian patient, which disease is mediated by ⁇ 9 ⁇ 1? and which method comprises administering to said patient a therapeutically effective amount of a compound of this invention.
  • a compound of this invention are preferably administered in a pharmaceutical composition described herein above. Effective daily dosing will depend upon the age, weight, condition of the patient which factors can be readily ascertained by the attending clinician. However, in a preferred embodiment, the compounds are admimstered from about 20 to 500 ⁇ g/kg per day. Using a conventional oral formulation, compounds of this invention would be active in this model.
  • EAE Experimental Autoimmune (or Allergic) Encephalomyelitis
  • Brains and spinal cords of adult Hartley guinea pigs are homogenized in an equal volume of phosphate-buffered saline.
  • An equal volume of Freund's complete adjuvant (100 mg mycobacterium tuberculosis plus 10 ml Freund's incomplete adjuvant) is added to the homogenate.
  • the mixture is emulsified by circulating it repeatedly through a 20 ml syringe with a peristaltic pump for about 20 minutes.
  • Antibody GG5/3 against 4 ⁇ j integrin (Keszthelyi et al., Neurology, 1996, 47:1053-1059), which delays the onset of symptoms, is used as a positive control and is injected subcutaneously at 3 mg/kg on Day 8 and 11.
  • Body weight and motor impairment are measured daily. Motor impairment is rated with the following clinical score:
  • a candidate compound is considered active if it delays the onset of symptoms, e.g., produces clinical scores no greater than 2 or slows body weight loss as compared to the control.
  • Inflammatory conditions mediated by 4 ⁇ i integrin include, for example, airway hyper-responsiveness and occlusion that occurs with chronic asthma.
  • the following describes an asthma model which can be used to study the in vivo effects of the compounds of this invention for use in treating asthma.
  • compounds of this invention are formulated into an aerosol and admimstered to sheep which are hypersensitive to Ascaris suum antigen.
  • AHR airway hyper-responsiveness
  • Allergic sheep which are shown to develop both early and late bronchial responses to inhaled Ascaris suum antigen are used to study the airway effects of the candidate compounds. Following topical anesthesia of the nasal passages with 2% lidocaine, a balloon catheter is advanced through one nostril into the lower esophagus. The animals are then intubated with a cuffed endotracheal tube through the other nostril with a flexible fiberoptic bronchoscope as a guide.
  • Pleural pressure is estimated according to Abraham (1994). Aerosols (see formulation below) are generated using a disposable medical nebulizer that provides an aerosol with a mass median aerodynamic diameter of 3.2 ⁇ m as determined with an Andersen cascade impactor.
  • the nebulizer is connected to a dosimeter system consisting of a solenoid valve and a source of compressed air (20 psi).
  • the output of the nebulizer is directed into a plastic T-piece, one end of which is connected to the inspiratory port of a piston respirator.
  • the solenoid valve is activated for 1 second at the beginning of the inspiratory cycle of the respirator. Aerosols are delivered at V ⁇ of 500 ml and a rate of 20 breaths/minute. A 0.5 % sodium bicarbonate solution only is used as a control.
  • Bronchial biopsies can be taken prior to and following the initiation of treatment and 24 hours after antigen challenge. Bronchial biopsies can be preformed according to Abraham (1994).
  • a solution of the candidate compound in 0.5% sodium bicarbonate/saline (w/v) at a concentration of 30.0 mg/mL is prepared using the following procedure:

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Abstract

L'invention concerne des composés liant VLA-4. Certains de ces composés inhibent également l'adhésion leucocytaire, en particulier l'adhésion leucocytaire à médiation par VLA-4. De tels composés sont utiles pour le traitement de maladies inflammatoires telles que l'asthme, la maladie d'Alzheimer, l'athérosclérose, la démence liée au sida, le diabète, les affections intestinales inflammatoires, la polyarthrite rhumatoïde, les greffes tissulaires, les métastases tumorales et l'ischémie du myocarde chez les mammifères, notamment chez l'homme. Ces composés peuvent également être administrés dans le traitement de maladies cérébrales inflammatoires telles que la sclérose en plaques.
PCT/US1998/015952 1997-07-31 1998-07-31 Composes inhibant l'adhesion leucocytaire induite par vla-4 WO1999006433A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
IL13364198A IL133641A0 (en) 1997-07-31 1998-07-31 Compounds which inhibit leukocyte adhesion mediated by vla-4
KR1020007001005A KR20010022423A (ko) 1997-07-31 1998-07-31 Ｖｌａ-4에 의해 매개되는 백혈구 부착을 억제하는 화합물
HU0004529A HUP0004529A3 (en) 1997-07-31 1998-07-31 Sulfonilated dipeptide-compounds which inhibit leukocyte adhesion mediated by vla-4, pharmaceutical compositions comprising thereof and their use
AU86786/98A AU8678698A (en) 1997-07-31 1998-07-31 Compounds which inhibit leukocyte adhesion mediated by vla-4
CA002290746A CA2290746A1 (fr) 1997-07-31 1998-07-31 Composes inhibant l'adhesion leucocytaire induite par vla-4
JP2000505188A JP2001512136A (ja) 1997-07-31 1998-07-31 Ｖｌａ−４により仲介される白血球接着を抑制する化合物
BR9811569-3A BR9811569A (pt) 1997-07-31 1998-07-31 Compostos que inibem a adesão de leucócito mediada por vla-4
EP98938207A EP1001973A1 (fr) 1997-07-31 1998-07-31 Composes inhibant l'adhesion leucocytaire induite par vla-4
NO20000451A NO20000451L (no) 1997-07-31 2000-01-28 Forbindelser som inhiberer leukocyttadhesjon mediert av VLA-4

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US90441697A 1997-07-31 1997-07-31
US08/904,416 1997-07-31

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EP0998282A1 (fr) * 1997-05-29 2000-05-10 Merck & Co., Inc. (a New Jersey corp.) Sulfamides utilises en tant qu'inhibiteurs de l'adherence cellulaire
US6093696A (en) * 1997-05-30 2000-07-25 Celltech Therapeutics, Limited Tyrosine derivatives
US6110945A (en) * 1998-06-03 2000-08-29 Celltech Therapeutics Limited Aromatic amine derivatives
US6221888B1 (en) 1997-05-29 2001-04-24 Merck & Co., Inc. Sulfonamides as cell adhesion inhibitors
US6274577B1 (en) 1998-09-30 2001-08-14 Celltech Therapeutics Limited Benzodiazepines
US6319922B1 (en) 1998-11-23 2001-11-20 Celltech Therapeutics Limited Propanoic acid derivatives
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
US6362204B1 (en) 1998-05-22 2002-03-26 Celltech Therapeutics, Ltd Phenylalanine derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
WO2002002556A3 (fr) * 2000-06-30 2002-07-18 Ortho Mcneil Pharm Inc Derives d'acides amines bicycliques pontes aza utilises comme antagonistes de l'integrine alpha-4
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
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
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
WO2003024933A1 (fr) * 2001-09-12 2003-03-27 Kaken Pharmaceutical Co., Ltd. Derive d'acide 2-phenyle-3-heteroarylpropionique ou son sel et medicaments le contenant
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
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
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
US7008949B2 (en) 2002-05-24 2006-03-07 Elan Pharmaceuticals, Inc. Heterocyclic compounds which inhibit leukocyte adhesion mediated by α4 integrins
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
US7034043B2 (en) 1999-08-13 2006-04-25 Biogen Idec Ma Inc. Cell adhesion inhibitors
US7196112B2 (en) 2004-07-16 2007-03-27 Biogen Idec Ma Inc. Cell adhesion inhibitors
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
US8557983B2 (en) 2008-12-04 2013-10-15 Abbvie Inc. Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
US8952157B2 (en) 2008-12-04 2015-02-10 Abbvie Inc. Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
US9045420B2 (en) 2008-12-05 2015-06-02 Abbvie Inc. Bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases
US9072748B2 (en) 2008-12-05 2015-07-07 Abbvie Inc. BCL-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases

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US6903075B1 (en) 1997-05-29 2005-06-07 Merck & Co., Inc. Heterocyclic amide compounds as cell adhesion inhibitors
EP0998282A1 (fr) * 1997-05-29 2000-05-10 Merck & Co., Inc. (a New Jersey corp.) Sulfamides utilises en tant qu'inhibiteurs de l'adherence cellulaire
EP0998282A4 (fr) * 1997-05-29 2000-08-30 Merck & Co Inc Sulfamides utilises en tant qu'inhibiteurs de l'adherence cellulaire
US6221888B1 (en) 1997-05-29 2001-04-24 Merck & Co., Inc. Sulfonamides 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
US6521666B1 (en) 1998-01-20 2003-02-18 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US6855843B2 (en) 1998-01-20 2005-02-15 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
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
US6677339B2 (en) 1998-09-28 2004-01-13 Celltech R & D Limited Phenylalanine derivatives
US6348463B1 (en) 1998-09-28 2002-02-19 Celltech Therapeutics Limited Phenylalanine derivatives
US6274577B1 (en) 1998-09-30 2001-08-14 Celltech Therapeutics Limited Benzodiazepines
US6319922B1 (en) 1998-11-23 2001-11-20 Celltech Therapeutics Limited Propanoic acid derivatives
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
US6479492B1 (en) 1999-01-22 2002-11-12 Elan Pharmaceuticals, Inc. 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
US6911439B2 (en) 1999-01-22 2005-06-28 Elan Pharmaceuticals, Inc. Heteroaryl, heterocyclic and aryl 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
US7378529B2 (en) 1999-01-22 2008-05-27 Wyeth Heteroaryl, heterocyclic and aryl compounds which inhibit leukocyte adhesion mediated by VLA-4
US6903088B2 (en) 1999-01-22 2005-06-07 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
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
US7034043B2 (en) 1999-08-13 2006-04-25 Biogen Idec Ma Inc. Cell adhesion inhibitors
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
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
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
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
US6780874B2 (en) 2000-04-17 2004-08-24 Celltech R & D Limited Enamine derivatives
US6610700B2 (en) 2000-04-17 2003-08-26 Celltech R & D Limited Enamine derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6960597B2 (en) 2000-06-30 2005-11-01 Orth-Mcneil Pharmaceutical, Inc. Aza-bridged-bicyclic amino acid derivatives as α4 integrin antagonists
WO2002002556A3 (fr) * 2000-06-30 2002-07-18 Ortho Mcneil Pharm Inc Derives d'acides amines bicycliques pontes aza utilises comme antagonistes de l'integrine alpha-4
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
US8501809B2 (en) 2000-08-31 2013-08-06 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
US7671090B2 (en) 2000-08-31 2010-03-02 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
WO2003024933A1 (fr) * 2001-09-12 2003-03-27 Kaken Pharmaceutical Co., Ltd. Derive d'acide 2-phenyle-3-heteroarylpropionique ou son sel et medicaments le contenant
US7361679B2 (en) 2001-09-12 2008-04-22 Kaken Pharmaceutical Co., Ltd. 2-phenyl-3-heteroarylpropionic acid derivative or salt thereof and medicine containing the same
US7476758B2 (en) 2002-02-28 2009-01-13 Mitsubishi Tanbe Pharma Corporation Process for preparing a phenylalanine derivative and intermediates thereof
US7135477B2 (en) 2002-05-24 2006-11-14 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
US7008949B2 (en) 2002-05-24 2006-03-07 Elan Pharmaceuticals, Inc. Heterocyclic compounds which inhibit leukocyte adhesion mediated by α4 integrins
US7196112B2 (en) 2004-07-16 2007-03-27 Biogen Idec Ma Inc. Cell adhesion inhibitors
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
US8952157B2 (en) 2008-12-04 2015-02-10 Abbvie Inc. Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
US8557983B2 (en) 2008-12-04 2013-10-15 Abbvie Inc. Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
US9029404B2 (en) 2008-12-04 2015-05-12 Abbvie Inc. Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
US9303025B2 (en) 2008-12-04 2016-04-05 Abbvie Inc. Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
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US9073855B2 (en) 2008-12-05 2015-07-07 Abbvie Inc. BCL-2 selective apoptosis-inducing agents for the treatment of cancer and immune diseases
US9072748B2 (en) 2008-12-05 2015-07-07 Abbvie Inc. BCL-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases
US9125913B2 (en) 2008-12-05 2015-09-08 Abbvie Inc. Bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases
US9315488B2 (en) 2008-12-05 2016-04-19 Abbvie Inc. Bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases

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JP2001512136A (ja) 2001-08-21
KR20010022423A (ko) 2001-03-15
EP1001973A1 (fr) 2000-05-24
CA2290746A1 (fr) 1999-02-11
NO20000451L (no) 2000-03-23
AU8678698A (en) 1999-02-22
PL338506A1 (en) 2000-11-06
HUP0004529A3 (en) 2001-05-28
CN1265669A (zh) 2000-09-06
BR9811569A (pt) 2000-09-19
HUP0004529A2 (hu) 2001-04-28
IL133641A0 (en) 2001-04-30
NO20000451D0 (no) 2000-01-28

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