WO2000043369A1 - Composes inhibant l'adhesion aux leucocytes a mediation assuree par vla-4 - Google Patents

Composes inhibant l'adhesion aux leucocytes a mediation assuree par vla-4 Download PDF

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Publication number
WO2000043369A1
WO2000043369A1 PCT/US2000/001540 US0001540W WO0043369A1 WO 2000043369 A1 WO2000043369 A1 WO 2000043369A1 US 0001540 W US0001540 W US 0001540W WO 0043369 A1 WO0043369 A1 WO 0043369A1
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Prior art keywords
substimted
alkyl
aryl
heteroaryl
group
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PCT/US2000/001540
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English (en)
Inventor
Andrei W. Konradi
Michael A. Pleiss
Eugene D. Thorsett
Susan Ashwell
Dimitrios Sarantakis
Gregory S. Welmaker
Anthony Kreft
Christopher Semko
Robert Warren Sullivan
Christopher Joseph Soares
Kiev Sui Ly
Christine M. Tarby
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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 EP00904487A priority Critical patent/EP1144384B1/fr
Priority to CA002359113A priority patent/CA2359113A1/fr
Priority to AU26239/00A priority patent/AU2623900A/en
Priority to DE60036918T priority patent/DE60036918D1/de
Priority to JP2000594785A priority patent/JP2002535314A/ja
Publication of WO2000043369A1 publication Critical patent/WO2000043369A1/fr
Priority to HK02106386.7A priority patent/HK1045157A1/zh

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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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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 ⁇ , integrin and CD49d/CD29), first identified by Hemler and Takada 1 is a member of the ⁇ 1 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. There are at least nine ⁇ l integrins, all sharing the same ⁇ l chain and each having a distinct ⁇ chain. These nine receptors all bind a different complement of the various cell matrix molecules, such as fibronectin, laminin, and collagen. 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.
  • Large numbers of leukocytes migrate across the blood brain barrier (BBB) in subjects with these inflammatory diseases.
  • 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 diabetes), 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, for treating diseases mediated by VLA-4, 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 0 of about 15 ⁇ M or less (as measured using the procedures described in Example A below).
  • this invention is directed to a method for treating a disease mediated by VLA-4 in a patient, which method comprises administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula la and/or lb:
  • Q is selected from the group consisting of -O-, -S-, -S(O)-, -8(0) ⁇ , and -NR 4 -;
  • R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R 4 and R 1 or R 4 and R 2 , together with the atoms to which they are bound, are joined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group;
  • W is selected from the group consisting of nitrogen and carbon
  • W is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(O) 2 ;
  • X is selected from the group consisting of hydroxyl, alkoxy, substituted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substituted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy and -NR"R" where each R" is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof; provided that:
  • the compound of formula la or lb has a binding affinity to VLA-4 as expressed by an IC 50 of about 15 ⁇ M or less;
  • R 3 is -(CH 2 ) X -Ar-R 9 , where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl; R 9 is selected from the group consisting acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino, and oxysulfonyl; x is an integer from 0 to 4; and R 3' is hydrogen.
  • R 3 is a group of the formula:
  • R 9 is as defined herein.
  • R° is in the para position of the phenyl ring and x is an integer from 1 to 4, more preferably x is 1.
  • R 9 is selected from -O-Z-NR u R u' and -O-Z-R 12 wherein
  • R 11 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, and where R 11 and R 11 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 -SO 2 -, Z is preferably -C(O)-.
  • R 9 is -OC(O)NR 11 R 11' , wherein R 11 and R 11' are as defined herein, more preferably preferably R 9 is -OC(O)N(CH 3 ) 2 .
  • Q is preferably -NR 4 - wherein R 4 is as defined above, more preferably R 4 is hydrogen or alkyl, even more preferably R 4 is hydrogen.
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form a substituted or unsubstituted monocyclic heteroaryl or heterocyclic group wherein the heteroaryl group has 1 to 4 heteroatoms selected from the group consisting of N, O, or S and the heterocyclic group contains 1 to 3 heteroatoms selected from the group consisting of N, O, or S(O)n wherein n is 0 to 2.
  • the above method employs a compound of formula Ila, lib, or lie:
  • ring A is selected from the group consisting of pyrrole, pyrazole, imidazole, pyrimidine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, and thiophene wherein each of said pyrrole, pyrazole, imidazole, and thiophene ring is substituted with 1 to 3 substituent(s), and each of said pyrimidine, 1,2,3-triazole, 1,2,4-triazole, and tetrazole ring is substituted with 1 to 2 substituent(s), independently selected from the group consisting of alkyl, alkoxy, halogen, nitro, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyle, substitued heterocycle, and - SO 2 R a (wherein R a is alkyl, aryl, or substituted aryl); ring B forms a l-oxo-l,2,2,4
  • R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
  • R 6 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 -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; or optionally, one of, R 4 and ring B, R 4 and R 5 , R 4 and R 6 , or R 5 and
  • R 6 together with the atoms to which they are bound, can be joined to form a heterocyclic or substituted heterocyclic ring;
  • R 3 , R 3 , Q and X are as defined herein; and enantiomers, diastereomers, pharmaceutically acceptable salts thereof.
  • an even more preferred group of compounds is represented by formula Ila', lib', or lie':
  • R 4 is hydrogen or alkyl; preferably hydrogen or methyl; more preferably hydrogen;
  • R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
  • R° 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 -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl; R 7 is selected from the group consisting of hydrogen, halogen, hydroxy, substituted amino, heterocycle, and substituted heterocyle; R 8 is selected from the group consisting of substituted amino, heterocycle, and substituted heterocycle; b is 1 or 2; and A, B, R 3 , R 5
  • A is 3-nitrothiophen-2-yl, l-phenyltetrazol-5-yl, l,5-dimethyl-4- nitropyazol-3-yl, l-ethylpyrazol-5-yl, 4-phenylsulfonylthiophen-3-yl, 1,4- diphenylpyrazol-5-yl, l-phenylimidazol-2-yl, or 5-benzoylmethylsulfinyl-4- (3-trifluoromethylphenyl)-l,2,4-triazol-3-yl;
  • R 7 is selected from the group consisting of hydrogen, hydroxy, chloro, and -NR 30 R 31 wherein R 30 is hydrogen, alkyl, substituted alkyl, or alkenyl; and R 31 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, or -SO 2 R 32 (wherein R 32
  • R 8 is - ⁇ R 33 R 34 wherein R 33 is hydrogen, alkyl, substituted alkyl, or aryl; and R 34 is alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle substituted heterocycle, or - SO 2 R 35 (wherein R 35 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle); or R 33 and
  • R 34 together with the nitrogen atom to which they are attached form a heterocycle or substituted heterocycle; preferably R 8 is N-(5-methylisoxazol- 3-yl)amino, N-(2-(l-methylpyrrolidin-2-yl)ethylamino, N-methyl-N-(2- pyridin-2-ylethyl)amino, N, ⁇ -bis-(2-methoxyethyl)amino, N-methyl-N-(2- pyridin-2-ylethyl)amino, N-methyl-N-(2-phenylethyl)amino, N-methyl-N-(2-phenylethyl)amino, N-methyl-N-(2-
  • R 39 is selected from the group consisting of hydrogen and alkyl; preferably hydrogen, methyl, or hexyl;
  • R 40 is selected from the group consisting of alkyl and substituted alkyl; or R 39 and R 40 together with the nitrogen atom to which they are attached form a heterocyclic or substituted heterocyclic ring; preferably methyl, hexyl, or 2-(3-methylphenylureido)ethyl; and
  • R 9 selected from the group consisting of -O-Z- ⁇ R ⁇ R ⁇ and -O-Z-R 12 wherein Z is -C(O)- or -SO 2 -;
  • R 11 and R 11 ' are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic and where R 11 and R 11' are joined together to form a heterocyclic or substituted heterocyclic ring; and
  • R 12 is selected from the group consisting of heterocycle and substituted heterocycle; preferably R 9 is
  • R 5 and R 6 are as defined above; enantiomers, diastereomers, and pharmaceutically acceptable salts thereof. Within above more preferred groups, particularly preferred compounds are those selected from compounds of formulae lib" or lie".
  • this invention is directed to a method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula IVa and/or IVb:
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula IVb, R 1 and R 2 , together with the carbon atom and W' to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen,
  • R 13 is selected from the group consisting of hydrogen, C 0 alkyl, Cy, and Cy-C,. 10 alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from R a ; and Cy is optionally substituted with one to four substituents independently selected from R b ;
  • R 14 is selected from the group consisting of hydrogen, C 0 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, Cy, Cy-C 0 alkyl, Cy-C 2 . 10 alkenyl and Cy-C 2 .
  • alkynyl wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents selected from phenyl and R x , and Cy is optionally substituted with one to four substituents independently selected from R y ; or R 13 , R 14 and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteratoms selected from N, O and S; R 15 is selected from the group consisting of C 0 alkyl, C 2 . 10 alkenyl,
  • R a is selected from the group consisting of Cy and a group selected from R ⁇ wherein Cy is optionally substituted with one to four substituents independently selected from R c;
  • R b is selected from the group consisting of R ⁇ C 0 alkyl, C 2 . 10 alkenyl, C 2 . 10 alkynyl, aryl C,. 10 alkyl, heteroaryl C ⁇ . 10 alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R c ;
  • R c is selected from the group consisting of halogen, NO ⁇ , C(O)OR f , C M alkyl, C M alkoxy, aryl, aryl C,_ 4 alkyl, aryloxy, heteroaryl, NR f R g , R f C(O)R g , NR f C(O)NR f R g , and CN;
  • R d and R e are independently selected from hydrogen, ., 0 alkyl, C 2 . 10 alkenyl, C 2 ., 0 alkynyl, Cy and Cy C,. 10 alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R c ; or R d and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; R f and R s are independently selected from hydrogen, Q., 0 alkyl, Cy and Cy-C,., 0 alkyl wherein Cy is optionally substituted with Q., 0 alkyl; or R f and R g together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R h is selected from the group consisting of hydrogen,
  • alkyl, and -SO 2 R' wherein alkyl, alkenyl, and alkynl are optionally substituted with one to four substitutents independently selected from R a ; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R b ;
  • R' is selected from the group consisting of C 0 alkyl, C 2 ., 0 alkenyl, C 2 _, 0 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R c ; R* is selected from the group consisting of -OR , -NO 2 , halogen,
  • W is selected from the group consisting of carbon and nitrogen
  • W' is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O) 2 ;
  • X' is selected from the group consisting of -C(O)OR d , -P(O)(OR d )(OR e ), -P(O)(R d )(OR e ), -S(O) m OR d , -C(O)NR d R ⁇ and -5- tetrazolyl; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; provided that:
  • the compound of formula IVa or IVb has a binding affinity to VLA-4 as expressed by an IC 50 of about 15 ⁇ M or less; and (ii) in formula IVa and IVb, R 1 and R 2 , together with the carbon atom and W to which they are bound respectively, do not form a substituted or unsubstituted pyridazine ring.
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form a substituted or unsubstituted monocyclic heteroaryl or heterocyclic ring wherein the heteroaryl ring contains 1 to 4 heteroatoms selected from N, O or S and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O, or S(O)n wherein n is 0 to 2, preferably R 1 and R 2 , together with the carbon atom and W to which they are bound respectively, are joined to form substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, pyridine, pyrimidine, 1,3,5-triazine, 1- oxo-l,2,5-thiadiazole or l,l-dioxo-l,2,5-thiadiazole ring; more
  • X' is -C(O)OR d .
  • the above method employs a compound of formula Va, Vb, or Vc:
  • ring A is selected from the group consisting of pyrrole, pyrazole, imidazole, pyrimidine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, and thiophene wherein each of said pyrrole, pyrazole, imidazole, and thiophene ring is substituted with 1 to 3 substituent(s), and each of said pyrimidine, 1,2,3-triazole, 1,2,4-triazole, and tetrazole ring is substituted with 1 to 2 substituent(s), independently selected from the group consisting of alkyl, alkoxy, halogen, nitro, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyle, substitued heterocycle, and - SO 2 R 5 (wherein R 5 is alkyl, aryl, or substituted aryl);
  • R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
  • R 6 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 -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R 7 is selected from the group consisting of hydrogen, halogen, hydroxy, substituted amino, heterocycle, and substituted heterocyle; R 8 is selected from the group consisting of substituted amino, heterocycle, and substituted heterocycle; b is 1 or 2; and R 13 , R 14 , R 15
  • this invention is directed to a method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula Via and/or VIb:
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula VIb, R 1 and R 2 , together with the carbon atom and W' to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen
  • each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substituted heterocyclic;
  • R 23 is selected from the group consisting of hydrogen, Q. 10 alkyl optionally substituted with one to four substituents independently selected from R a' and Cy optionally substituted with one to four substituents independently selected from R b ;
  • R 24 is selected from the group consisting of Ar 1 -Ar 2 -C 1 ., 0 alkyl, Ar 1 -Ar 2 -C 2- ⁇ o alkenyl, A ⁇ -A ⁇ - . K , alkynyl, wherein Ar 1 and Ar 2 are independently aryl or heteroaryl each of which is optionally substituted with one to four substituents independently selected from R b' ; alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from R a ;
  • R 25 is selected from the group consisting of hydrogen, C,., 0 alkyl, C 2 ., 0 alkenyl, C 2 . 10 alkynyl, aryl, aryl Q_ ⁇ 0 alkyl, heteroaryl, and heteroaryl C,. ⁇ o alkyl, wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from R a , and aryl and heteroaryl are optionally substimted with one to four substituents independently selected from R b ;
  • R a is selected from the group consisting of Cy, -OR d , -NO 2 , halogen -S(O) m R d , -SR d , -S(O) 2 OR d , -S(O) m NR d R e , -NR d R e , -O(CR' R g ) n NR d R e , -C(O)R d , -CO 2 R d , -CO 2 (CR' R g ) n CONR d R e , -OC(O)R d , -CN, -C(O)NR d R e , -NR d C(O)R e , -OC(O)NR d R e , -NR d C(O)OR e , -NR d C(O)NR d R e , -CR d (N-OR e ),
  • R b is selected from the group consisting of R a , C,., 0 alkyl, C 2 10 alkenyl, C 2 . 10 alkynyl, aryl Q., 0 alkyl, heteroaryl C,. 10 alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substituted with a group independently selected from R c ;
  • R c' is selected from the group consisting of halogen, amino, carboxy, C M alkyl, C,. 4 alkoxy, aryl, aryl Q. 4 .alkyl, hydroxy, CF , and aryloxy;
  • R d and R e are independently selected from hydrogen, Q. 10 alkyl, C 2 . ,o alkenyl, C 2 ., 0 alkynyl, Cy and Cy Q_, 0 alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R c ; or R d' and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • R f and R g' are independently selected from hydrogen, C 0 alkyl, Cy and Cy-C,. 10 alkyl; or R r and R g' together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R h' is selected from the group consisting of hydrogen, Q., 0 alkyl, C 2 ., 0 alkenyl, C 2 .
  • alkynyl 10 alkynyl, cyano, aryl, aryl C,., 0 alkyl, heteroaryl, heteroaryl C,., 0 alkyl, or -SO 2 ; wherein alkyl, alkenyl, and alkynyl are optionally substimted with one to four substitutents independently selected from R a ; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R b ;
  • R' is selected from the group consisting of Q., 0 alkyl, C 2 ., 0 alkenyl, C 2 ., 0 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substimted with one to four substituents independently selected from R ;
  • Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl
  • X is selected from the group consisting of -C(O)OR d , -P(O)(OR d' )(OR e ), -P(O)(R d' )(OR e ), -S(O) m OR d , -C(O)NR d' R ⁇ and -5- tetrazolyl; m is an integer from 1 to 2; n is an integer from 1 to 10; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; provided that:
  • the compound of formula Via or VIb has a binding affinity to VLA-4 as expressed by an IC 50 of about 15 ⁇ M or less;
  • X" is -C(O)OR d' .
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form a substituted or unsubstituted monocyclic heteroaryl or heterocyclic group wherein the heteroaryl aryl group has 1 to 4 heteroatoms selected from the group consisting of N, O, or S and the heterocyclic group contains 1 to 3 heteroatoms selected from the group consisting of N, O, or S(O)n wherein n is 0 to 2.
  • R 24 is and R 25 is hydrogen.
  • the above method employs a compound of formula Vila, Vllb, or VIIc:
  • ring A is selected from the group consisting of pyrrole, pyrazole, imidazole, pyrimidine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, and thiophene wherein each of said pyrrole, pyrazole, imidazole, and thiophene ring is substituted with 1 to 3 substituent(s), and each of said pyrimidine,
  • 1,2,3-triazole, 1,2,4-triazole, and tetrazole ring is substituted with 1 to 2 substituent(s), independently selected from the group consisting of alkyl, alkoxy, halogen, nitro, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyle, substitued heterocycle, and - SO 2 R a (wherein R a is alkyl, aryl, or substituted aryl);
  • R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, and substimted heteroaryl; R 7 is selected from the group consisting of hydrogen, halogen, hydroxy, substituted amino, heterocycle, and substimted heterocyle;
  • R 8 is selected from the group consisting of substimted amino, heterocycle, and substimted heterocycle; b is 1 or 2; and
  • R 23 , R 24 , R 25 , and X' are as defined above.
  • the compounds and pharmaceutical compositions of this invention are useful for treating VLA-4 mediated disease conditions.
  • disease conditions include, by way of example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and
  • disease conditions include, but are not limited to, inflammatory conditions such as erythema nodosum, allergic conjunctivitis, optic neuritis, uveitis, allergic rhinitis, Ankylosing spondylitis, psoriatic arthritis, vasculitis, Reiter's syndrome, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis, dermatomyositis, Wegner's granulomatosis, aortitis, sarcoidosis, lymphocytopenia, temporal arteritis, pericarditis, myocarditis, congestive heart failure, polyarteritis nodosa, hypersensitivity syndromes, allergy, hypereosinophilic syndromes, Churg- Strauss syndrome, chronic obstructive pulmonary disease, hypersensitivity pneumonitis, chronic active hepatitis, interstitial cystitis, autoimmune endocrine failure, primary biliary
  • the disease mediated by VLA-4 is an inflammatory disease.
  • the present invention is also directed to novel compounds useful for treating a disease mediated by VLA-4. Accordingly, in one of its composition aspects, this invention is directed to a compound of formula la and lb:
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula lb, R 1 and R 2 , together with the carbon atom and W' to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen
  • R 3 is -(CH 2 ).-Ar-R 9 , where Ar is aryl, substimted aryl, heteroaryl and substimted heteroaryl; R 9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonyl- amino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl, x is an integer from 0 to 4; R 3 is selected from the group consisting of hydrogen, isopropyl, -
  • Z is hydrogen, hydroxy, acylamino, alkyl, alkoxy, aryloxy, aryl, arloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl- substituted aryl, carboxylheteroaryl, carboxyl-substituted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substituted alkyl, substimted alkoxy, substituted aryl, substituted aryloxy, substituted aryloxyaryl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, or substimted heterocyclic;
  • Q is selected from the group consisting of -O-, -S-, -S(O)-, -S(O) 2 , and -NR 4 -;
  • R 4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substimted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic or, optionally, R 4 and R 1 or R 4 and R 2 , together with the atoms to which they are bound, are joined to form a heteroaryl, a substituted heteroaryl, a heterocyclic or a substituted heterocyclic group;
  • W is selected from the group consisting of nitrogen and carbon; and W' is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(O) 2 ;
  • X is selected from the group consisting of hydroxyl, alkoxy, substimted alkoxy, alkenoxy, substituted alkenoxy, cycloalkoxy, substimted cycloalkoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substimted heterocyclyloxy and -NR"R" where each R" is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic; and enantiomers, diasteromers and pharmaceutically acceptable salts thereof; provided that:
  • the compound of formula la or lb has a binding affinity to VLA-4 as expressed by an IC 50 of about 15 ⁇ M or less;
  • R 3 is a group of the formula:
  • R 9 and x are as defined herein.
  • R 9 is in the para position of the phenyl ring; and x is an integer from 1 to 4, more preferably x is 1.
  • R 9 is selected from the group consisting of -O-Z-NR"R ⁇ and -O-Z-R 12 wherein R 11 and R" are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substimted heterocyclic, and where R 11 and R 11 are joined to form a heterocycle or a substimted 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 -SO 2 -, preferably Z is -C(O)-. More preferably, R 9 is -OC(O)NR u R ⁇ , wherein R 11 and R 11' are as defined herein, even more preferably R° is -OC(O)N(CH 3 ) 2 .
  • Q is -NR 4 - wherein R 4 is hydrogen or alkyl, preferably hydrogen.
  • this invention is directed to compounds of formula Ila, lib, or lie:
  • ring A is a substituted or unsubstituted monocyclic heteroaryl ring containing 1 to 4 heteroatoms selected from the group consisting of N, O, or
  • ring A is selected from the group consisting of pyrrole, pyrazole, imidazole, pyrimidine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, and thiophene wherein each of said pyrrole, pyrazole, imidazole, and thiophene ring is substimted with 1 to 3 substituent(s), and each of said pyrimidine, 1,2,3-triazole, 1,2,4-triazole, and tetrazole ring is substituted with 1 to 2 substituent(s), independently selected from the group consisting of alkyl, alkoxy, halogen, nitro, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyle, substitued heterocycle, and - SO 2 R 5 (wherein R 5 is alkyl, aryl, or substituted aryl); ring B forms a l-oxo-l,
  • R 3 is -(CH 2 ) X -Ar-R 9 , where Ar is aryl, substituted aryl, heteroaryl and substituted heteroaryl;
  • R 9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, ammothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl; x is an integer from 0 to 4;
  • R 3' is selected from the group consisting of hydrogen, isopropyl, - CH 2 Z wherein Z is hydrogen, hydroxy, acylamino, alkyl, alkoxy, aryloxy, aryl, arloxyaryl, carboxyl, carboxylalkyl, carboxyl-substimted alkyl, carboxyl-cycloalkyl, carboxyl-substimted cycloalkyl, carboxylaryl, carboxyl- substimted aryl, carboxylheteroaryl, carboxyl-substimted heteroaryl, carboxylheterocyclic, carboxyl-substituted heterocyclic, cycloalkyl, substimted alkyl, substimted alkoxy, substimted aryl, substituted aryloxy, substimted aryloxyaryl, substimted cycloalkyl, heteroaryl, substimted heteroaryl, heterocyclic, or substituted heterocyclic; R
  • R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substimted aryl, heteroaryl, substituted heteroaryl; or optionally, one of, R 4 and ring B, R 4 and R 5 , R 4 and R 6 , or R 5 and R 6 , together with the atoms to which they are bound, can be joined to form a heterocyclic or substimted heterocyclic ring; and
  • R 4 is hydrogen or alkyl
  • R 5 is selected from the group consisting of alkyl, substimted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substimted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substimted aryl, heteroaryl, substituted heteroaryl;
  • R 7 is selected from the group consisting of hydrogen, halogen, hydroxy, substimted amino, heterocycle, and substituted heterocyle;
  • R 8 is selected from the group consisting of substimted amino, heterocycle, and substimted heterocycle; b is 1 or 2; and
  • A, B, R 3 , and X are as defined above.
  • A is 3-nitrothiophen-2-yl, 1 -pheny ltetrazol-5-yl, l,5-dimethyl-4- nitropyazol-3-yl, l-ethylpyrazol-5-yl, 4-phenylsulfonylthiophen-3-yl, 1,4- diphenylpyrazol-5-yl, l-phenylimidazol-2-yl, or 5-benzoylmethylsulfinyl-4- (3-trifluoromethylphenyl)-l,2,4-triazol-3-yl;
  • R 7 is selected from the group consisting of hydrogen, hydroxy, chloro, and -NR 30 R 31 wherein R 30 is hydrogen, alkyl, substituted alkyl, or alkenyl; and R 31 is alkyl, substimted alkyl, aryl, substituted aryl, heteroaryl, substimted heteroaryl, cycloalkyl, or -SO 2 R 32 (wherein R 32 is aryl or substituted aryl); or R 30 and R 31 together with the nitrogen atom to which they are attached form a heterocycle or substituted heterocycle; preferably R 7 is hydrogen, hydroxy, chloro, N-(2-methylpropyl)amino, N- (phenyl)amino, N-(benzyl)amino, N-(2-(4-methylphenyl)ethyl)amino, N-(2-(4-methoxy- phenyl)ethyl)amino, N-(l -pheny lethy l)amin
  • R 8 is - ⁇ R 33 R 34 wherein R 33 is hydrogen, alkyl, substituted alkyl, or aryl; and R 34 is alkyl, cycloalkyl, substimted alkyl, aryl, substimted aryl, heteroaryl, substituted heteroaryl, heterocycle substituted heterocycle, or - SO 2 R 35 (wherein R 35 is substimted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substimted heterocycle); or R 33 and
  • R 34 together with the nitrogen atom to which they are attached form a heterocycle or substimted heterocycle; preferably R 8 is N-(5-methylisoxazol- 3-yl)amino, N-(2-(l-methylpyrrolidin-2-yl)ethylamino, N-methyl-N-(2- pyridin-2 -y lethy l)amino, N, ⁇ -bis-(2-methoxyethyl)amino, N-methy l-N-(2- pyridin-2-ylethyl)amino, N-methy l-N-(2-phenylethyl)amino, N-methyl-N-(2-
  • R 39 is selected from the group consisting of hydrogen and alkyl
  • R 40 is selected from the group consisting of alkyl and substimted alkyl; or R 39 and R 40 together with the nitrogen atom to which they are attached form a heterocyclic or substimted heterocyclic ring;
  • R 9 selected from the group consisting of -O-Z- ⁇ R ⁇ R" and -O-Z-R 12 wherein Z is -C(O)- or -SO 2 -;
  • R" and R" are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substituted heterocyclic and where R 11 and R" are joined together to form a heterocyclic or substituted heterocyclic ring;
  • R 12 is selected from the group consisting of heterocycle and substimted heterocycle; preferably R 9 is -OCON(CH 3 ) 2 and is located at the 4-position of the phenyl, and
  • R 5 and R 6 are as defined above; enantiomers, diastereomers, pharmaceutically acceptable salts thereof.
  • this invention is directed to a compound of formula IVa:
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form a monocyclic heteroaryl ring having 1 to 4 heteroatoms in the ring selected from the group nitrogen or sulfur; or a monocyclic heterocyclic ring having 1 to 3 hetereoatoms in the ring selected from the group consisting of nitrogen, oxygen, or S(O)n
  • n is o to 2
  • said heteroaryl or heterocyclic ring is optionally substituted, on any ring atom capable of substimtion, with 1-3 substiments selected from the group consisting of alkyl, substituted alkyl, alkoxy, substimted alkoxy, acyl, acylamino, thiocarbony lamino, acyloxy, amino, substituted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbony lamino, aminothiocarbony lamino, aminocarbonyloxy, aryl, substimted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, substituted aryloxyaryl, substituted aryloxyaryl, cyano, halogen, hydroxyl, nitro, oxo, carboxyl, cycloalkyl, substituted cycloalkyl, guanidino, guani
  • R 13 is selected from the group consisting of hydrogen, Q., 0 alkyl, Cy, and Cy-C,., 0 alkyl, wherein alkyl is optionally substituted with one to four substituents independently selected from R a ; and Cy is optionally substimted with one to four substiments independently selected from R b ; R 14 is selected from the group consisting of hydrogen, Q., 0 alkyl, C 2 .
  • R 15 is selected from the group consisting of Q_, 0 alkyl, C 2 ., 0 alkenyl, C 2 ., 0 alkynyl, aryl, aryl-C,_, 0 alkyl, heteroaryl, heteroaryl-C 0 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substimted with one to four substituents selected from R ⁇ and aryl and heteroaryl are optionally substimted with one to four substituents independently selected from R y ; or R 14 , R 15 and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S;
  • R a is selected from the group consisting of Cy and a group selected from R ⁇ wherein Cy is optionally substituted with one to four substituents independently selected from R c:
  • R b is selected from the group consisting of R a , C,. 10 alkyl, C 2 ., 0 alkenyl, C 2 ., 0 alkynyl, aryl C,. 10 alkyl, heteroaryl C,. 10 alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R c ;
  • R c is selected from the group consisting of halogen, NO,, C(O)OR f , C M alkyl, C,_ 4 alkoxy, aryl, aryl C,_ 4 alkyl, aryloxy, heteroaryl, NR f R g , R f C(O)R g , NR f C(O)NR f R g , and CN;
  • R d and R e are independently selected from hydrogen, Q., 0 alkyl, C 2 . 10 alkenyl, C 2 ., 0 alkynyl, Cy and Cy C,., 0 alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substimted with one to four substituents independently selected from R c ; or R d and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • R f and R g are independently selected from hydrogen, C,., 0 alkyl, Cy and Cy-C,., 0 alkyl wherein Cy is optionally substituted with C M0 alkyl; or R f and R g together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • R h is selected from the group consisting of hydrogen, Q., 0 alkyl, C 2 ., 0 alkenyl, C 2-10 alkynyl, cyano, aryl, aryl Q., 0 alkyl, heteroaryl, heteroaryl Q_ , 0 alkyl, and -SO 2 R'; wherein alkyl, alkenyl, and alkynl are optionally substimted with one to four substitutents independently selected from R a ; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R b ;
  • R' is selected from the group consisting of Q_, 0 alkyl, C 2 ., 0 alkenyl, C 2 ., 0 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R c ;
  • R x is selected from the group consisting of -OR d , -NO 2 , halogen, -S(O) m R d , -SR d , -S(O) 2 OR d , -S(O) m NR d R e , -NR d R e , -O(CR f R g ) n NR d R e , -C(O)R d , -CO 2 R d , -CO 2 (CR f R g ) n CONR d R e , -OC(O)R d , -CN, -C(O)NR d R e ,
  • R y is selected from the group consisting of R , C 1-10 alkyl, C 2 ., 0 alkenyl, C 2 . 10 alkynyl, aryl C,., 0 alkyl, heteroaryl C,., 0 alkyl, cycloalkyl, heterocyclyl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substimted with one to four substitutents independently selected from R"; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10;
  • W is selected from the group consisting of carbon and nitrogen;
  • W' is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O) 2 ;
  • X' is selected from the group consisting of -C(O)OR d , -P(O)(OR d )(OR e ), -P(O)(R )(OR e ), -S(O) m OR d , -C(O)NR d R ⁇ and -5- tetrazolyl; and enatiomers, diastereomers and pharmaceutically acceptable salts thereof; provided that:
  • the compound of formula Va has a binding affinity to VLA-4 as expressed by an IC 50 of about 15 ⁇ M or less; and (ii) when R 1 and R 2 , together with the carbon atom and W to which they are bound respectively, are joined to form a 2-arylpyrimidin-4-yl group and R 14 is hydrogen, then R 15 is not alkyl of from 1 to 6 carbon atoms optionally substituted with hydroxyl; and (iii) when R 1 and R 2 , together with the carbon atom and W to which they are attached respectively, are joined to form a 5-arylpyrazin-2-yl group and R 14 is hydrogen, then R 15 is not 4-hydroxybenzyl.
  • R 1 and R 2 together with the carbon atom and W to which they are attached respectively, are joined to form substituted or unsubstituted pyrrole, pyrazole, imidazole, pyrimidine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, pyrimidine, 1,2,3- triazole, 1,2,4-triazole, tetrazole rings, l-oxo-l,2,5-thiadiazole, 1,1-dioxo- 1,2,5-thiadiazole, pyridine or 1,3,5-triazine ring and X is -C(O)OR d .
  • this invention is directed to compounds of formula Va, Vb, or Vc:
  • ring A is selected from the group consisting of pyrrole, pyrazole, imidazole, pyrimidine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, and thiophene wherein each of said pyrrole, pyrazole, imidazole, and thiophene ring is substimted with 1 to 3 substituent(s), and each of said pyrimidine,
  • 1,2,3-triazole, 1,2,4-triazole, and tetrazole ring is substimted with 1 to 2 substituent(s), independently selected from the group consisting of alkyl, alkoxy, halogen, nitro, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyle, substimed heterocycle, and - SO 2 R a (wherein R a is alkyl, aryl, or substituted aryl);
  • R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substimted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substitute
  • R 7 is selected from the group consisting of hydrogen, halogen, hydroxy, substituted amino, heterocycle, and substituted heterocyle;
  • R 8 is selected from the group consisting of substituted amino, heterocycle, and substituted heterocycle;
  • b is 1 or 2;
  • R 13 , R 14 , R 15 , and X' are as defined above.
  • this invention is directed to a compound of formula Via and VIb:
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula VIb, R 1 and R 2 , together with the carbon atom and W' to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen
  • each R' is independently selected from the group consisting of alkyl, substituted alkyl, aryl, substimted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic;
  • R 23 is selected from the group consisting of hydrogen, Q. 10 alkyl optionally substimted with one to four substiments independently selected from R a and Cy optionally substituted with one to four substiments independently selected from R b ;
  • R 24 is selected from the group consisting of A ⁇ -Ar ⁇ ⁇ o alkyl, alkenyl, Ar'-Ar 2 -C 2 0 alkynyl, wherein Ar 1 and Ar 2 are independently aryl or heteroaryl each of which is optionally substimted with one to four substiments independently selected from R b' ; alkyl, alkenyl and alkynyl are optionally substimted with one to four substituents independently selected from R a' ;
  • R 25 is selected from the group consisting of hydrogen, Q_ 10 alkyl, C 2 .,o alkenyl, C 2 ., 0 alkynyl, aryl, aryl C,., 0 alkyl, heteroaryl, and heteroaryl
  • R a' is selected from the group consisting of Cy, -OR 1' , -NO 2 , halogen
  • R b' is selected from the group consisting of R a' , C 1-10 alkyl, C 2 . 10 alkenyl, C 2-I0 alkynyl, aryl C ⁇ . 10 alkyl, heteroaryl C 1-10 alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substimted with a group independently selected from R c ;
  • R c' is selected from the group consisting of halogen, amino, carboxy, C alkyl, C M alkoxy, aryl, aryl Q. 4 alkyl, hydroxy, CF 3 , and aryloxy;
  • R d' and R e are independently selected from hydrogen, Q. 10 alkyl, C 2- 10 alkenyl, C 2 . 10 alkynyl, Cy and Cy Q. 10 alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substimted with one to four substiments independently selected from R c ; or R and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • R f and R g are independently selected from hydrogen, Q. 10 alkyl, Cy and Cy-C,. 10 alkyl; or R r and R g together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • R h' is selected from the group consisting of hydrogen, C 0 alkyl, uo alkenyl, C 2-10 alkynyl, cyano, aryl, aryl Q., 0 alkyl, heteroaryl, heteroaryl C,.
  • alkyl, or -SO 2 R wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substitutents independently selected from R a ; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R b ; is selected from the group consisting of Q., 0 alkyl, C 2-10 alkenyl, C 2 _ 10 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R ; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • X is selected from the group consisting of -C(O)OR d' , -P(O)(OR d' )(OR e ), -P(O)(R d' )(OR e ), -S(O) m OR d' , -C(O)NR d' R ⁇ and -5- tetrazolyl; m is an integer from 1 to 2; n is an integer from 1 to 10; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; provided that:
  • the compound of formula Via or VIb has a binding affinity to VLA-4 as expressed by an IC 50 of about 15 ⁇ M or less;
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form a substimted or unsubstituted monocyclic heteroaryl or heterocyclic ring wherein the heteroaryl ring contains 1 to 4 heteroatoms selected from N, O or S and the heterocyclic ring contains 1 to 3 heteroatoms selected from N, O, or S(O)n wherein n is 0 to 2, preferably R 1 and R 2 , together with the carbon atom and
  • W to which they are bound respectively, are joined to form substituted or unsubstituted pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene, pyridine, pyrimidine, 1,3,5-triazine, l-oxo-1,2,5- thiadiazole or l,l-dioxo-l,2,5-thiadiazole ring; more preferably, substituted 1,3,5-triazine, or l,l-dioxo-l,2,5-thiadiazole ring.
  • X" is -C(O)OR d' .
  • R 24 is preferably -CH 2 -Ar 2 -Ar' and R 25 is preferably hydrogen.
  • this invention is directed to compounds of formula Vila, Vllb, or VIIc:
  • ring A is selected from the group consisting of pyrrole, pyrazole, imidazole, pyrimidine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, and thiophene wherein each of said pyrrole, pyrazole, imidazole, and thiophene ring is substituted with 1 to 3 substituent(s), and the pyrimidine, 1,2,3- triazole, 1,2,4-triazole, and tetrazole rings are substituted with 1 to 2 substituent(s), independently selected from the group consisting of alkyl, alkoxy, halogen, nitro, amino, substituted amino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyle, substitued heterocycle, and - SO 2 R a (wherein R a is alkyl, aryl, or substituted aryl);
  • R 5 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substimted alkenyl, aryl, substimted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R 7 is selected from the group consisting of hydrogen, halogen, hydroxy, substituted amino, heterocycle, and substituted heterocyle; R 8 is selected from the group consisting of substituted amino, heterocycle, and substimted heterocycle; b is 1 ro 2; and R 23 ,
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compounds defined above.
  • X when X is other than -OH or pharmaceutical salts thereof, X is a substituent which will convert (e.g., hydrolyze, metabolize, etc.) in vivo to a compound where X is -OH or a salt thereof.
  • suitable X groups are any art recognized pharmaceutically acceptable groups which will hydrolyze or otherwise convert in vivo to a hydroxyl group or a salt thereof including, by way of example, esters (X is alkoxy, substimted alkoxy, cycloalkoxy, substituted cycloalkoxy, alkenoxy, substituted alkenoxy, cycloalkenoxy, substituted cycloalkenoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, heterocyclooxy, substituted heterocyclooxy, and the like).
  • R 1 and R 2 are preferably joined to form a substituted 1,3,5-triazine group.
  • R 3 and R 15 in the above compounds are preferably selected from all possible isomers arising by substitution with the following groups:
  • R 3' is preferably hydrogen.
  • R 4 is preferably hydrogen and X is preferably hydroxyl or alkoxy.
  • preferred R 13 , R 14 and R 15 groups correspond to the R 3 , R 4 and R 5 groups, respectively, disclosed in International Patent Application Publication No. WO 98/53814 which application is inco ⁇ orated herein by reference in its entirety.
  • R 23 , R 24 and R 25 groups correspond to the R 5 , R 6 and R 7 groups, respectively, found in International Patent Application Publication No. WO 98/53817 which application is inco ⁇ orated herein by reference in its entirety.
  • R 24 is -CH 2 -Ar 2 -Ar' and R 25 is hydrogen.
  • 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- VII above under conditions wherein said compound binds to VLA-4.
  • Certain of the compounds of formula I- VII 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- VII above.
  • R 3 and R 3 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 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.
  • disease conditions include, but are not limited to, inflammatory conditions such as erythema nodosum, allergic conjunctivitis, optic neuritis, uveitis, allergic rhinitis, Ankylosing spondylitis, psoriatic arthritis, vasculitis, Reiter's syndrome, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis, dermatomyositis, Wegner's granulomatosis, aortitis, sarcoidosis, lymphocytopenia, temporal arteritis, pericarditis, myocarditis, congestive heart failure, polyarteritis nodosa, hypersensitivity syndromes, allergy, hypereosinophilic syndromes, Churg- Strauss syndrome, chronic obstructive pulmonary disease, hypersensitivity pneumonitis, chronic active hepatitis, interstitial cystitis, autoimmune endocrine failure, primary biliary
  • 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 a compound which inhibit leukocyte adhesion and, in particular, 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.
  • Substimted alkyl refers to an alkyl group, preferably of from 1 to
  • Alkoxy refers to the group “alkyl-O-" which includes, by way of example, methoxy, ethoxy, rc-propoxy, is o-p ⁇ oipoxy , rc-butoxy, tert-butoxy, .yec-butoxy, rt-pentoxy, w-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Substimted alkoxy refers to the group “substimted alkyl-O-”.
  • Alkenoxy refers to the group “alkenyl-O-”.
  • Substituted alkenoxy refers to the group “substimted alkenyl-O-”.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-
  • Acylamino refers to the group -C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substituted alkenyl, alkynyl, substimted alkynyl, aryl, substituted aryl, cycloalkyl, substimted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substimted 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, substimted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Thiocarbony lamino 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, substimted heteroaryl, heterocyclic, substituted heterocyclic and where each R is joined to form, together with the nitrogen atom a heterocyclic or substituted heterocyclic ring wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl- C(O)O-, alkenyl-C(O)O-, substituted alkenyl-C(O)O-, alkynyl-C(O)O-, substimted alkynyl-C(O)O-, aryl-C(O)O-, substituted aryl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substimted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substituted heterocyclic-C(O)O- wherein alkyl, substimted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl
  • Alkenyl refers to alkenyl group preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation.
  • Substituted alkenyl refers to alkenyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, thiocarbony lamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbony lamino, aminothio- carbony lamino, aminocarbony loxy, aryl, substimted aryl, aryloxy, substituted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl- cycloalkyl, carboxyl-substituted cycloalkyl, carboxylaryl, carboxyl- substituted aryl, carboxylheteroaryl, carboxyl-substimted hetero
  • Substituted alkynyl refers to alkynyl groups having from 1 to 5 substituents selected from the group consisting of alkoxy, substimted alkoxy, acyl, acylamino, thiocarbony lamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbony lamino, ammothiocarbonylamino, aminocarbonyloxy, aryl, substimted aryl, aryloxy, substimted aryloxy, aryloxyaryl, substituted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substimted alkyl, carboxyl- cycloalkyl, carboxyl-substimted cycloalkyl, carboxylaryl, carboxyl- substimted aryl, carboxylheteroaryl, carboxyl
  • Amino refers to the group -NH 2 .
  • Substituted amino refers to the group -NRR, where each R group is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO 2 -alkyl, -SO 2 -substimted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 - cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, -SO 2 -substituted heteroaryl, -SO 2 -he
  • Aminoacyl refers to the groups -NRC(O)alkyl, -NRC(O)substimted alkyl, -NRC(O)cycloalkyl, -NRC(O)substituted cycloalkyl, -NRC(O)alkenyl, -NRC(O)substituted alkenyl, -NRC(O)alkynyl,
  • R is hydrogen or alkyl and wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substimted heterocyclic are as defined herein.
  • aminosulfonyl refers to the groups -NRSO 2 alkyl, -NRSO 2 substimted alkyl, -NRSO 2 cycloalkyl, -NRSO 2 substituted cycloalkyl,
  • R is hydrogen or alkyl and wherein alkyl, substimted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substimted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aminocarbony loxy refers to the groups -NRC(O)O-alkyl, -NRC(O)O-substituted alkyl, -NRC(O)O-alkenyl, -NRC(O)O-substituted alkenyl, -NRC(O)O-alkynyl, -NRC(O)O-substituted alkynyl, -NRC(O)O- cycloalkyl, -NRC(O)O-substituted cycloalkyl, -NRC(O)O-aryl, -NRC(O)O- substituted aryl, -NRC(O)O-heteroaryl, -NRC(O)O-substituted heteroaryl, -NRC(O)O-heterocyclic, and -NRC(O)O-substituted heterocyclic where R is hydrogen or alkyl and wherein
  • Aminosulfonyloxy refers to the groups -NRSO 2 O-alkyl, -NRSO 2 O-substituted alkyl, -NRSO 2 O-alkenyl, -NRSO 2 O-substituted alkenyl, -NRSO 2 O-alkynyl, -NRSO 2 O-substituted alkynyl, -NRSO 2 O- cycloalkyl, -NRSO 2 O-substituted cycloalkyl, -NRSO 2 O-aryl, -NRSO 2 O- substimted aryl, -NRSO 2 O-heteroaryl, -NRSO 2 O-substimted heteroaryl,
  • R is hydrogen or alkyl and wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Oxycarbony lamino refers to the groups -OC(O)NH 2 , -OC(O)NRR, -OC(O)NR-alkyl, -OC(O)NR-substituted alkyl, -OC(O)NR-alkenyl, -OC(O)NR-substituted alkenyl, -OC(O)NR-alkynyl, -OC(O)NR-substituted alkynyl, -OC(O)NR-cycloalkyl, -OC(O)NR-substituted cycloalkyl, -OC(O)NR-aryl, -OC(O)NR-substituted aryl, -OC(O)NR-heteroaryl, -OC(O)NR-substituted heteroaryl,- OC(O)NR-heterocyclic, and -OC(O)NR-substituted heterocyclic where R is hydrogen
  • Oxysulfonylamino refers to the groups -OSO 2 NH 2 , -OSO 2 NRR,
  • -OSO 2 NR-alkyl -OSO 2 NR-substituted alkyl, -OSO 2 NR-alkenyl, -OSO 2 NR-substituted alkenyl, -OSO 2 NR-alkynyl, -OSO 2 NR-substituted alkynyl, -OSO 2 NR-cycloalkyl, -OSO 2 NR-substituted cycloalkyl, -OSO 2 NR-aryl, -OSO 2 NR-substimted aryl, -OSO 2 NR-heteroaryl, -OSO 2 NR-substituted heteroaryl, -OSO 2 NR-heterocyclic, and
  • -OSO 2 NR-substituted heterocyclic where R is hydrogen, alkyl or where each R is joined to form, together with the nitrogen atom a heterocyclic or substimted heterocyclic ring and wherein alkyl, substituted alkyl, alkenyl, substimted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Oxysulfonyl refers to the groups alkyl-SO 2 O-, substimted alkyl- SO 2 O-, alkenyl-SO 2 O-, substituted alkenyl-SO 2 O-, alkynyl-SO 2 O-, substimted alkynyl-SO 2 O-, aryl-SO 2 O-, substituted aryl-SO 2 O-, cycloalkyl-
  • 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.
  • Oxythiocarbony lamino 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-substimted heteroaryl, -OC(S)NR-heterocyclic, and -OC(S)NR-substituted heterocyclic where R is hydrogen, alkyl
  • Aminocarbonylamino refers to the groups -NRC(O)NRR, -NRC(O)NR-alkyl, -NRC(O)NR-substituted alkyl, -NRC(O)NR-alkenyl, -NRC(O)NR-substituted alkenyl, -NRC(O)NR-alkynyl, -NRC(O)NR-substituted alkynyl, -NRC(O)NR-aryl, -NRC(O)NR-substituted aryl, -NRC(O)NR-cycloalkyl, -NRC(O)NR-substituted cycloalkyl, -NRC(O)NR-substituted cycloalkyl,
  • each R is independently hydrogen, alkyl or where each R is joined to form together with the nitrogen atom a heterocyclic or substituted heterocyclic ring as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substituted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
  • Aminothiocarbony lamino 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 where each R
  • Aminosulfonylamino refers to the groups -NRSO 2 NRR, -NRSO 2 NR-alkyl, -NRSO 2 NR-substituted alkyl, -NRSO 2 NR-alkenyl, -NRSO 2 NR-substituted alkenyl, -NRSO 2 NR-alkynyl, -NRSO 2 NR-substituted alkynyl, -NRSO 2 NR-aryl, -NRSO 2 NR-substituted aryl, -NRSO 2 NR-cycloalkyl, -NRSO 2 NR-substituted cycloalkyl, -NRSO 2 NR-heteroaryl, and -NRSO 2 NR-substituted heteroaryl, -NRSO 2 NR-heterocyclic, and -NRSO 2 NR-substituted heterocyclic, where each R is independently hydrogen, alkyl,
  • 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, thiocarbony lamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substimted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbony loxy, aminocarbony lamino, aminothiocarbony lamino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substimted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalky
  • 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, substimted alkenyl, alkynyl, substituted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbony loxy, aminocarbony lamino, aminothio- carbony lamino, aryl, substimted aryl, aryloxy, substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substit
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Excluded from this definition are multi-ring alkyl groups such as adamantanyl, etc.
  • Cycloalkenyl refers to cyclic alkenyl groups of from 3 to 8 carbon atoms having single or multiple unsaturation but which are not aromatic.
  • R is hydrogen or alkyl, mono- and di-alky lamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di- substimted arylamino, mono- and di-heteroary lamino, mono- and di- substimted heteroary lamino, mono- and di-heterocyclic amino, mono- and di-substituted heterocyclic amino, unsymmetric di-
  • Cycloalkoxy refers to -O-cycloalkyl groups.
  • Substimted cycloalkoxy refers to -O-substituted cycloalkyl groups.
  • Cycloalkenoxy refers to -O-cycloalkenyl groups.
  • Substituted cycloalkenoxy refers to -O-substituted cycloalkenyl groups.
  • each R is independently hydrogen and alkyl as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substimted aryl, heteroaryl,
  • 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 oxygen, nitrogen and sulfur within the ring or oxides thereof.
  • 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.
  • Substimted heteroaryl refers to heteroaryl groups which are substimted with from 1 to 3 substiments selected from the group consisting of hydroxy, acyl, acylamino, thiocarbony lamino, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbony loxy, aminocarbony lamino, aminothiocarbony lamino, aryl, substimted aryl, aryloxy, substimted aryloxy, cycloalkoxy, substimted cycloalkoxy, heteroaryloxy, substimted heteroaryloxy, heterocyclyloxy, substimted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substituted
  • Heteroaryloxy refers to the group -O-heteroaryl and “substimted heteroaryloxy” refers to the group -O-substituted heteroaryl.
  • Heterocycle or “heterocyclic” refers to a saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more of the rings can be aryl or heteroaryl.
  • heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,
  • 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.
  • Substimted thiocycloalkyl refers to the group -S-substituted cycloalkyl.
  • Thioaryl refers to the group -S-aryl and "substimted thioaryl” refers to the group -S-substituted aryl.
  • Thioheteroaryl refers to the group -S-heteroaryl and "substimted thioheteroaryl” refers to the group -S-substituted heteroaryl.
  • Thioheterocyclic refers to the group -S-heterocyclic and "substimted thioheterocyclic” refers to the group -S-substituted heterocyclic.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • 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
  • the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the compounds of this invention are prepared by coupling an amino acid derivative of the formula:
  • R 3 and R 3' are as defined herein and Y is an alkyl group such as methyl, ethyl and the like, with a suitably fiinctionalized aryl, heteroaryl, cycloalkyl or cycloalkenyl intermediate.
  • such coupling reactions may be performed by displacing a leaving group, such as chloro, bromo, iodo, tosyl and the like, from the aryl, heteroaryl, cycloalkyl or cycloalkenyl intermediate with the amino group of the amino acid derivative; or by reductive alkylation of the amino group of amino acid derivative with a carbonyl-mnctionalized intermediate.
  • a leaving group such as chloro, bromo, iodo, tosyl and the like
  • a compound of formula lib where B is a triazine ring carrying a chloro, hydrogen, or substituted amino group at the 4- position and substituted amino group at the 6-position can prepared as shown in Scheme 1 above.
  • R 3 is as defined in the Summary of the Invention and X is alkoxy such as methoxy, ethoxy, or tert-butyoxy and the like, in the presence of a trialkylamine, such as diisopropylethylamine (DIEA), provides a compound of formula 3.
  • DIEA diisopropylethylamine
  • This reaction is typically conducted in an inert solvent such as tetrahydrofuran, at a temperature ranging from about 0°C to about ambient temperature for about 5 min. to about 6 hours, preferably 2 hours.
  • a compound of formula lib can be converted to other compounds of formula lib by methods well known in the art. For example, as shown in method (a), reaction of a compound of formula lib with an amine of formula NR 33 R 34 (wherein R 33 and R 34 are as defined above) provides a compound of formula II' wherein the triazine ring is substituted with a substimted amino group at the 4 and the 6-positions. As shown in method (b), a compound of formula lib with a chloro group in the triazine ring can hydrogenated to provide a corresponding de-chlorinated compound of formula lib".
  • compounds of formulae lib, lib', and lib" where X is alkoxy can be converted to a corresponding compound of formula lib' " where X is hydroxy under acidic hydrolysis reaction condition.
  • Suitable acids are hydrochloric acid, trifluoroacetic acid, and the like.
  • Other heteroaryls may also be employed in the above described reactions including, but not limited to, 2-chloro-4-methyl-3-nitropyridine, 2- chloro-3-nitropyridine (Aldrich Chemical Co.); 4-chloro-3-nitropyridine (J. Med. Chem. 1989, 32, 2474-2485); 4-chloro-5-nitroimidazole (J. Chem. Soc. 1930, 268); and the like, to provide compounds of this invention.
  • amino acid derivatives 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 can be prepared by C-alkylating commercially available diethyl
  • 2-acetamidomalonate (Aldrich, Milwaukee, Wisconsin, USA) with an alkyl or substimted alkyl halide.
  • This reaction is typically conducted by treating the diethyl 2-acetamidomalonate with at least one equivalent of sodium ethoxide and at least one equivalent of an alkyl or substimted alkyl halide in refluxing ethanol for about 6 to about 12 hours.
  • the resulting C-alkylated malonate is then deacetylated, hydrolyzed and decarboxylated by heating in aqueous hydrochloric acid at reflux for about 6 to about 12 hours to provide the amino acid, typically as the hydrochloride salt.
  • amino acid derivatives 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- aspaitic acid methyl ester, L-asparagine tert-butyl ester, e-Boc-L-lysine methyl ester, e-Cbz-L-lysine methyl ester, ⁇ -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-(0- benzyOserine methyl ester, L-tryptophan methyl ester, L-phenylalanine methyl ester, L-phenyl
  • ⁇ -hydroxy and ⁇ -thio carboxylic acids may also be employed in the above-described reactions.
  • Such compounds are well- known in the art and are either commercially available or may be prepared from commercially available starting materials using conventional reagents and reaction conditions.
  • R 3 , Q and X are as defined herein;
  • A' is cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heterocyclic and substituted heterocyclic; and
  • L 1 is a leaving group, such as chloro, bromo, iodo, sulfonate ester and the like.
  • this reaction is conducted by combining approximately stoichiometric equivalents of 7 and 8 in a suitable inert diluent such as water, dimethy lsulfoxide (DMSO) and the like, with an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. to scavenge the acid generated by the reaction.
  • a suitable inert diluent such as water, dimethy lsulfoxide (DMSO) and the like
  • a suitable base such as sodium bicarbonate, sodium hydroxide, etc.
  • compounds of this invention in which Q is NR 4 can be prepared by reductive amination of a suitable 2- oxocarboxylic acid ester, 10, such as a pyruvate ester, as shown in Scheme
  • A', R 3 and X are as defined herein.
  • this reaction is conducted by combining equamolar amounts of 10 and 11 in an inert diluent such as methanol, ethanol and the like under conditions which provide for imine formation (not shown).
  • the imine formed is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H 2 /palladium on carbon and the like to form the product 12.
  • the reducing agent is H 2 /palladium on carbon which is inco ⁇ orated into the initial reaction medium thereby permitting imine reduction in situ in a one pot procedure to provide 12.
  • the reaction is preferably conducted at from about 20°C to about 80°C at a pressure of from 1 to 10 atmospheres until reaction completion which typically occurs within 1 to about 24 hours.
  • reaction completion the product 12 is recovered by conventional methods including chromatography, filtration and the like.
  • A" is aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R 3 and X (preferably alkoxy) are as defined herein.
  • this reaction is conducted using rhodium acetate dimer, Rh ⁇ OAc) ⁇ in an inert diluent such as toluene at a temperamre ranging from about 25 °C to about 80 °C for about 1 to 12 hours to afford 15.
  • Rh ⁇ OAc rhodium acetate dimer
  • A" is aryl, substituted aryl, heteroaryl and substituted heteroaryl
  • X 3 is halogen, such as chloro, bromo or iodo (preferably iodo)
  • R 3 and X preferably alkoxy
  • this reaction is conducted using copper iodide (Cul) and potassium carbonate in an inert diluent such as N,N-dimethyl acetamide (DMA) at a temperamre ranging from about 60 °C to about 120°C for about 12 to 36 hours to afford 15.
  • DMA N,N-dimethyl acetamide
  • the compounds of this invention are typically prepared as an ester, i.e., where X 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.
  • an alkali metal hydroxide such as lithium, sodium or potassium hydroxide
  • an inert diluent such as methanol or mixtures of methanol and water
  • benzyl esters may be removed by hydrogenolysis using a palladium catalyst, such as palladium on carbon, and tert-butyl esters can be removed using formic acid to afford the corresponding carboxy
  • a nitro group present on a substituent of a compound of formula I- VII 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 3 and/or R 3' substituent can be prepared, for example, by using a 4- nitropheny lalanine 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 3 and/or R 3' substituent of a compound of formula I- VII 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 3 and/or R 3 substiment may be prepared, for example, by reduction of the corresponding nitro compound as described above.
  • a compound of formula I- VII or an intermediate thereof having a substiment containing a primary or secondary amino group, such as where R 3 is a (4-aminophenyl)methyl group can be readily N-acylated using conventional acylating reagents and conditions to provide the corresponding amide.
  • This acylation reaction is typically conducted by treating the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of a carboxylic acid in the presence of a coupling reagent such as a carbodiimide, BOP reagent
  • a promoter such as benzotriazol- 1 -y loxy-tris(dimethylamino)phosphonium hexafluorophosphonate) and the like, in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N- dimethylformamide and the like, at a temperamre ranging from about 0°C to about 37°C for about 4 to about 24 hours.
  • a promoter such as
  • N-hydroxysuccinimide, 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- butyloxycarbonylglycine, N-tert-butyloxycarbonyl-L-phenylalanine, N-tert- butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid, N-tert- butyloxycarbonylisonipecotic acid, N-methylisonipecotic acid, N-tert- butyloxycarbonylnipecotic acid, N-tert-butyloxycarbonyl-L- tetrahydroisoquinoline-3-carboxylic acid, N-(toluene-4-sulfonyl)-L-proline and the like.
  • a compound of formula I- VII or an intermediate thereof containing a primary or secondary amino group can be N-acylated using an acyl halide or a carboxylic acid anhydride to form the corresponding amide.
  • This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the acyl halide or carboxylic acid anhydride in an inert diluent, such as dichloromethane, at a temperamre ranging from about -70°C to about 40 °C for about 1 to about 24 hours.
  • an acylation catalyst such as 4-(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, diisopropy lethy lamine, N-methylmo ⁇ holine 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- VII 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, chloromethane- sulfonyl chloride, / toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like.
  • sulfamoyl chlorides such as dimethy lsulfamoyl chloride, can be used to provide sulfamides (e.g., > N- SO 2 -N ⁇ ).
  • a primary and secondary amino group present on a substiment of a compound of formula I- VII or an intermediate thereof can be reacted with an isocyanate or a thioisocyanate to give a urea or thiourea, respectively.
  • This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the isocyanate or thioisocyanate in an inert diluent, such as toluene and the like, at a temperamre ranging from about 24°C to about 37°C for about 12 to about 24 hours.
  • isocyanates and thioisocyanates used in this reaction are commercially available or can be prepared from commercially available compounds using well-known synthetic procedures.
  • isocyanates and thioisocyanates are readily prepared by reacting the appropriate amine with phosgene or thiophosgene.
  • isocyanates and thioisocyanates suitable for use in this reaction include, but are not limited to, ethyl isocyanate, rt-propyl isocyanate, 4-cyanophenyl isocyanate, 3 -methoxy phenyl isocyanate, 2-phenylethyl isocyanate, methyl thioisocyanate, ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3- phenylpropyl thioisocyanate, 3-(N,N-diethylamino)propyl thioisocyanate, phenyl thioisocyanate, benzyl thioisocyanate, 3-pyridyl thioisocyanate, fluorescein isothiocyanate (isomer I) and the like.
  • a compound of formula I- VII or an intermediate thereof contains a primary or secondary amino group
  • the amino group can be reductively alkylated using aldehydes or ketones to form a secondary or tertiary amino group.
  • This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of an aldehyde or ketone and at least one equivalent based on the amino compound of a metal hydride reducing agent, such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixtures thereof and the like, at a temperamre ranging from about 0°C to about 50 °C for about 1 to about 72 hours.
  • Aldehydes and ketones suitable for use in this reaction include, by way of example, benzaldehyde, 4- chlorobenzaldehyde, valeraldehyde and the like.
  • a compound of formula I- VII or an intermediate thereof has a substiment 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? substiment can be prepared using an amino acid derivative derived from tyrosine and the like in the above-described reactions.
  • a compound of formula I- VII or an intermediate thereof having a substiment containing a hydroxyl group, such as where R 3 is a (4-hydroxyphenyl)methyl group can be readily O-alkylated to form ethers.
  • This O-alkylation reaction is typically conducted by contacting the hydroxy compound with a suitable alkali or alkaline earth metal base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the like, to form the alkali or alkaline earth metal salt of the hydroxyl group.
  • This salt is generally not isolated, but is reacted in situ with at least one equivalent of an alkyl or substimted alkyl halide or sulfonate, such as an alkyl chloride, bromide, iodide, mesylate or tosylate, to afford the ether.
  • an alkyl or substimted alkyl halide or sulfonate such as an alkyl chloride, bromide, iodide, mesylate or tosylate
  • this reaction is conducted at a temperamre ranging from about 60°C to about 150°C for about 24 to about 72 hours.
  • a catalytic amount of sodium or potassium iodide is added to the reaction mixmre when an alkyl chloride or bromide is employed in the reaction.
  • alkyl or substimted alkyl halides and sulfonates suitable for use in this reaction include, but are not limited to, tert-butyl bromoacetate, N-tert-butyl chloroacetamide, 1-bromoethylbenzene, ethyl ⁇ - bromophenylacetate, 2-(N-ethyl-N-phenylamino)ethyl chloride, 2-(N,N- ethylamino)ethyl chloride, 2-(N,N-diisopropylamino)ethyl chloride, 2-(N,N- dibenzylamino)ethyl chloride, 3-(N,N-ethylamino)propyl chloride, 3-(N- benzyl-N-methylamino)propyl chloride, N-(2-chloroethyl)mo ⁇ holine, 2-
  • a hydroxyl group present on a substiment of a compound of formula I- VII or an intermediate thereof can be O-alkylating using the Mitsunobu reaction.
  • an alcohol such as 3-(N,N- dimethy lamino)- 1 -propanol and the like, is reacted with about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate in an inert diluent, such as tetrahydrofuran, at a temperamre ranging from about -10°C to about 5°C for about 0.25 to about 1 hour.
  • a compound of formula I- VII or an intermediate thereof containing an 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 temperamre of about -25 °C to about 10°C.
  • the salt is then treated with about 1.1 to about 1.5 equivalents of cuprous bromide dimethyl sulfide complex at a temperamre ranging from about 10°C to about 30°C for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5 equivalents of an aryl iodide, such as sodium 2-iodobenzoate and the like.
  • the reaction is then heated to about 70°C to about 150°C for about 2 to about 24 hours to provide the diaryl ether.
  • a hydroxy-containing compound can also be readily derivatized to form a carbamate.
  • a hydroxy compound of formula I- VII or an intermediate thereof is contacted with about 1.0 to about 1.2 equivalents of 4-nitro ⁇ henyl chloroformate in an inert diluent, such as dichloromethane, at a temperamre ranging from about -25°C to about 0°C for about 0.5 to about 2.0 hours.
  • 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, mo ⁇ holine, thiomo ⁇ holine, pyrrolidine, piperidine and the like.
  • a hydroxy-containing compound is contacted with about 1.0 to about 1.5 equivalents of a carbamyl chloride in an inert diluent, such as dichloromethane, at a temperamre ranging from about 25 °C to about 70°C for about 2 to about 72 hours.
  • this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction.
  • suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmo ⁇ holine and the like.
  • At least one equivalent (based on the hydroxy compound) of 4-(N,N-dimethylamino)pyridine is preferably added to the reaction mixmre to facilitate the reaction.
  • carbamyl chlorides suitable for use in this reaction include, by way of example, dimethy lcarbamy 1 chloride, diethy lcarbamy 1 chloride and the like.
  • hydroxyl groups can be readily converted into a leaving group and displaced to form, for example, amines, sulfides and fluorides.
  • a chiral compound is employed in these reactions, 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 7-toluenesulfonyl chloride and the like, in pyridine. This reaction is generally conducted at a temperamre of from about 0°C to about 70 °C for about 1 to about 48 hours.
  • the resulting tosylate can then be readily displaced with sodium azide, for example, by contacting the tosylate with at least one equivalent of sodium azide in an inert diluent, such as a mixmre of N,N-dimethylformamide and water, at a temperamre ranging from about 0°C to about 37 °C for about 1 to about 12 hours to provide the corresponding azido compound.
  • the azido group can then be reduced by, for example, hydrogenation using a palladium on carbon catalyst to provide the amino (- ⁇ H 2 ) compound.
  • a tosylate group can be readily displaced by a thiol to form a sulfide.
  • This reaction is typically conducted by contacting the tosylate with at least one equivalent of a thiol, such as thiophenol, in the presence of a suitable base, such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in an inert diluent, such as N,N-dimethylformamide, at a temperamre of from about 0°C to about 37°C for about 1 to about 12 hours to provide the sulfide.
  • a thiol such as thiophenol
  • a suitable base such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • a compound of formula I- VII or an intermediate thereof having a substiment containing an iodoaryl group for example, when R 3 is a (4-iodophenyl)methyl group, can be readily converted either before or after the above coupling reactions into a biaryl compound.
  • this reaction is conducted by treating the iodoaryl compound with about 1.1 to about 2 equivalents of an arylzinc iodide, such as 2-(methoxycarbonyl)- phenylzinc iodide, in the presence of a palladium catalyst, such as palladium tetra(triphenylphosphine), in an inert diluent, such as tetrahydrofuran, at a temperamre ranging from about 24°C to about 30°C until reaction completion.
  • a palladium catalyst such as palladium tetra(triphenylphosphine
  • an inert diluent such as tetrahydrofuran
  • the compounds of formula I- VII or intermediates thereof may contain substiments having one or more sulfur atoms.
  • 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 temperamre ranging from about -50 °C to about 75 °C for about 1 to about 24 hours.
  • 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 this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • compositions which contain, as the active ingredient, one or more of the compounds of formula I- VII above associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy- benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated ih a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound acmally administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixmre of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixmre of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixmres of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be inco ⁇ orated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixmres thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • Quantity Ingredient (mg/tablet)
  • Formulation Example 3 A dry powder inhaler formulation is prepared containing the following components:
  • the active mixmre is mixed with the lactose and the mixmre is added to a dry powder inhaling appliance.
  • Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows:
  • 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.
  • 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 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:
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are inco ⁇ orated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixmre is then cooled until solid.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein inco ⁇ orated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Direct or indirect placement techniques may be used when it is desirable or necessary to introduce the pharmaceutical composition to the brain.
  • 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 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, 125 I, 35 S, 14 C, or 32 P labelled compounds or the like.
  • Non-radioactive labels include ligands which bind to labelled antibodies, fluorophores, chemiluminescent agents, enzymes and antibodies which can serve as specific binding pair members for a labelled ligand.
  • the choice of label depends on sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation.
  • EAE experimental autoimmune encephalomyelitis
  • Compounds having the desired biological activity may be modified as necessary to provide desired properties such as improved pharmacological properties (e.g., in vivo stability, bio-availability), or the ability to be detected in diagnostic applications.
  • desired properties such as improved pharmacological properties (e.g., in vivo stability, bio-availability), or the ability to be detected in diagnostic applications.
  • inclusion of one or more D-amino acids in the sulfonamides of this invention typically increases in vivo stability. Stability can be assayed in a variety of ways such as by measuring the half-life of the proteins during incubation with peptidases or human plasma or serum. A number of such protein stability assays have been described (see, e.g., Verhoef et al., Eur. J. Drug Metab. Pharmacokinet., 1990, 15_£2): 83-93).
  • the compounds of the subject invention may be modified in a variety of ways for a variety of end pu ⁇ oses while still retaining biological activity.
  • various reactive sites may be introduced at the terminus for linking to particles, solid substrates, macromolecules, or the like.
  • Labeled compounds can be used in a variety of in vivo or in vitro applications.
  • a wide variety of labels may be employed, such as radionuclides (e.g. , gamma-emitting radioisotopes such as technetium-99 or indium- 111), fluorescers (e.g., fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like.
  • radionuclides e.g. , gamma-emitting radioisotopes such as technetium-99 or indium- 111
  • fluorescers e.g., fluorescein
  • enzymes enzyme substrates
  • enzyme cofactors enzyme inhibitors
  • chemiluminescent compounds chemiluminescent compounds
  • bioluminescent compounds bioluminescent compounds
  • In vitro uses include diagnostic applications such as monitoring inflammatory responses by detecting the presence of leukocytes expressing VLA-4.
  • the compounds of this invention can also be used for isolating or labeling such cells.
  • the compounds of the invention can be used to assay for potential inhibitors of VLA-4/VCAM-1 interactions.
  • radioisotopes are typically used in accordance with well known techniques.
  • the radioisotopes may be bound to the peptide either directly or indirectly using intermediate functional groups.
  • chelating agents such as diethylenetriaminepentacetic acid (DTPA) 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 imaging can be used.
  • gamma- and positron-emitting radioisotopes are used for camera imaging and paramagnetic isotopes are used for MRI.
  • the compounds can be used to monitor the course of amelioration of an inflammatory response in an individual. By measuring the increase or decrease in lymphocytes expressing VLA-4 it is possible to determine whether a particular therapeutic regimen aimed at ameliorating the disease is effective.
  • the pharmaceutical compositions of the present invention can be used to block or inhibit cellular adhesion associated with a number of diseases and disorders.
  • a number of inflammatory disorders are associated with integrins or leukocytes.
  • Treatable disorders include, e.g., transplantation rejection (e.g., allograft rejection), Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), retinitis, cancer metastases, rheumatoid arthritis, acute leukocyte-mediated lung injury (e.g., adult respiratory distress syndrome), asthma, nephritis, and acute and chronic inflammation, including atopic dermatitis, psoriasis, myocardial ischemia, and inflammatory bowel disease (including Crohn's disease and ulcerative colitis).
  • the pharmaceutical compositions are used to treat inflammatory brain disorders, such as multiple sclerosis (MS), viral meningitis and encephalitis.
  • 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.
  • Rheumatoid arthritis is a chronic, relapsing inflammatory disease that primarily causes impairment and destruction of joints. Rheumatoid arthritis usually first affects the small joints of the hands and feet but then may involve the wrists, elbows, ankles and knees. The arthritis results from interaction of synovial cells with leukocytes that infiltrate from the circulation into the synovial lining of the joints. See e.g., Paul, Immunology (3d ed., Raven Press, 1993).
  • Another indication for the compounds of this invention is in treatment of organ or graft rejection mediated by VLA-4.
  • organs such as skin, kidney, liver, heart, lung, pancreas and bone marrow.
  • the principal outstanding problem is the lack of satisfactory agents for inducing immunotolerance in the recipient to the transplanted allograft or organ.
  • the host immune system is likely to mount an immune response to foreign antigens in the transplant (host-versus-graft disease) leading to destruction of the transplanted tissue.
  • CD8 + cells, CD4 cells and monocytes are all involved in the rejection of transplant tissues.
  • GVHD graft versus host disease
  • GVHD is a potentially fatal disease that occurs when immunologically competent cells are transferred to an allogeneic 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 (1994); Okahara et al., Cancer Res. 54, 3233-6 (1994).
  • a further use of the compounds of this invention is in treating multiple sclerosis.
  • Multiple sclerosis is a progressive neurological autoimmune disease that affects an estimated 250,000 to 350,000 people in the United States. Multiple sclerosis is thought to be the result of a specific autoimmune reaction in which certain leukocytes attack and initiate the destruction of myelin, the insulating sheath covering nerve fibers.
  • murine monoclonal antibodies directed against VLA-4 have been shown to block the adhesion of leukocytes to the endothelium, and thus prevent inflammation of the central nervous system and subsequent paralysis in the animals 16 .
  • Pharmaceutical compositions of the invention are suitable for use in a variety of drug delivery systems. Suitable formulations for use in the present invention are found in Remington 's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).
  • the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds.
  • a variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al., U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is inco ⁇ orated herein by reference.
  • compositions are administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.
  • An amount adequate to accomplish this is defined as "therapeutically effective dose.
  • Amounts effective for this use will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the inflammation, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention will vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the dose will typically be in the range of about 20 ⁇ g to about 500 ⁇ g per kilogram body weight, preferably about 100 ⁇ g to about 300 ⁇ g per kilogram body weight.
  • Suitable dosage ranges for intranasal administration are generally about 0.1 pg to 1 mg per kilogram body weight.
  • Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • Compounds of this invention are also capable of binding or antagonizing the actions of ⁇ , ⁇ 9 ⁇ t , ⁇ 4 ⁇ 7 , ⁇ d ⁇ 2 , ⁇ c ⁇ 7 integrins (although ⁇ 4 ⁇ t and ⁇ are preferred in this invention). Accordingly, compounds of this invention are also useful for preventing or reversing the symptoms, disorders or diseases induced by the binding of these integrins to their respective ligands.
  • Compounds that bind ⁇ e ⁇ 7 integrin are also useful for the treatment of systemic lupus erythematosus (see, for example, M. Pang et al., Arthritis Rheum. 1998, 41(8), 1456-1463); Crohn's disease, ulcerative colitis and infammatory bowel disease (IBD) (see, for example, D. Elewaut et al., Scand J. Gastroenterol 1998, 33(7) 743-748); Sjogren's syndrome (see, for example, U. Kroneld et al., Scand J. Gastroenterol 1998, 27(3), 215-218); and rheumatoid arthritis (see, for example, Scand J. Gastroenterol 1996,
  • Amino acid methyl esters can be prepared using the method of Brenner and Huber Helv. Chim. Acta 1953, 36, 1109.
  • the desired dipeptide ester was prepared by the reaction of a carboxylic acid (1 equivalent) with the appropriate amino acid ester or amino acid ester hydrochloride (1 equivalent), benzotriazol-l-yloxy-tris(dimethylamino)- phosphonium hexafluorophosphate [BOP] (2.0 equivalent), triethylamine (1.1 equivalent), and DMF.
  • BOP benzotriazol-l-yloxy-tris(dimethylamino)- phosphonium hexafluorophosphate
  • BOP benzotriazol-l-yloxy-tris(dimethylamino)- phosphonium hexafluorophosphate
  • BOP triethylamine
  • N-Methyl piperazine (9.35 mL, 8.45 g, 84.34 mmol, 1.0 eq) was added over three minutes with stirring and stirring was continued overnight while warming to room temperamre.
  • the reaction mixmre was diluted with 700 mL hexanes and the resulting mixmre was washed repeatedly with 10% K 2 CO 3 , until no yellow color (from 4-nitrophenol) is observed in the aqueous layer.
  • the mixmre was then washed with sat. ⁇ aCl, dried over anhydrous MgSO 4 , filtered and evaporated. The residue was dissolved in 500 mL of ethanol and evaporated to remove triethylamine.
  • the compounds of this method were purified by LC/MS using 10% to 90% acetonitrile/water gradient with 0.1 % trifluoroacetic acid (12 min. run time).

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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention se rapporte à des composés représentés par les formules (Ia ou Ib) qui se lient à l'intégrine VLA-4. Certains de ces composés inhibent l'adhésion aux leucocytes et notamment l'adhésion aux leucocytes à médiation assurée par VLA-4. Ces composés s'avèrent utiles pour le traitement chez les sujets mammaliens, par exemple chez l'homme, de maladies inflammatoires telles que l'asthme, la maladie d'Alzheimer, l'athérosclérose, le syndrome démentiel lié au SIDA, le diabète, les maladies intestinales inflammatoires, la polyarthrite rhumatoïde, les maladies liées à la transplantation des tissus, la métastase des tumeurs et l'ischémie myocardique. Ces composés peuvent également être administrés aux fins de traitement des maladies cérébrales inflammatoires telles que la sclérose en plaques.
PCT/US2000/001540 1999-01-22 2000-01-21 Composes inhibant l'adhesion aux leucocytes a mediation assuree par vla-4 WO2000043369A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP00904487A EP1144384B1 (fr) 1999-01-22 2000-01-21 Composes inhibant l'adhesion aux leucocytes a mediation assuree par vla-4
CA002359113A CA2359113A1 (fr) 1999-01-22 2000-01-21 Composes inhibant l'adhesion aux leucocytes a mediation assuree par vla-4
AU26239/00A AU2623900A (en) 1999-01-22 2000-01-21 Compounds which inhibit leukocyte adhesion mediated by vla-4
DE60036918T DE60036918D1 (de) 1999-01-22 2000-01-21 Verbindungen die die vla-4 vermittelte adhäsion von leukozyten inhibieren
JP2000594785A JP2002535314A (ja) 1999-01-22 2000-01-21 Ｖｌａ−４により媒介される白血球接着を阻害する化合物
HK02106386.7A HK1045157A1 (zh) 1999-01-22 2002-08-29 抑制vla-4介導的白細胞粘着的化合物

Applications Claiming Priority (3)

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US11692399P 1999-01-22 1999-01-22
US60/116,923 1999-01-22
US60/160,999 1999-10-21

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PCT/US2000/001686 WO2000043372A1 (fr) 1999-01-22 2000-01-21 Derives d'acyle utiles pour traiter des affections associees a vla-4

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WO2002046172A2 (fr) * 2000-12-07 2002-06-13 Cv Therapeutics, Inc. Composes d'augmentation d'abca-1
WO2002100846A1 (fr) * 2001-06-11 2002-12-19 Shire Biochem Inc. Composes et methodes de traitement ou de prevention d'infections a flavivirus
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
WO2005003103A2 (fr) * 2003-06-30 2005-01-13 Astrazeneca Ab Nouveaux heterocycles 2,4,6-trisubstitues et utilisations de ceux-ci
EP1507775A1 (fr) * 2002-05-24 2005-02-23 Elan Pharmaceuticals, Inc. Composes heterocycliques inhibiteurs de l'adhesion leucocytaire provoquee par des integrines alpha4
JP2006511476A (ja) * 2002-09-23 2006-04-06 レディ ユーエス セラピューティクス インコーポレイテッド 新規トリアジン化合物の組成物および方法
WO2008072850A1 (fr) * 2006-12-11 2008-06-19 Amorepacific Corporation Dérivés de triazine ayant une action inhibitrice contre l'acetyl-coa carboxylase
US7794700B2 (en) 2004-07-08 2010-09-14 Elan Pharmaceuticals Inc. Multimeric VLA-4 antagonists comprising polymer moieties
EP2275107A2 (fr) 2004-08-14 2011-01-19 Boehringer Ingelheim International GmbH Combinaison pour le traitment de maladies liées à la proliferation cellulaire
WO2011101369A1 (fr) 2010-02-17 2011-08-25 Boehringer Ingelheim International Gmbh Dihydroptéridinones, procédé pour la production et l'utilisation de celles-ci
US8030328B2 (en) 2005-05-20 2011-10-04 Elan Pharmaceuticals, Inc. Imidazolone phenylalanine derivatives
EP2409706A1 (fr) 2004-08-14 2012-01-25 Boehringer Ingelheim International GmbH Dihydropteridinones pour le traitement des maladies cancéreuses
US8877924B2 (en) 2009-06-09 2014-11-04 NantBio Inc. Benzyl substituted triazine derivatives and their therapeutical applications
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
CN114933532A (zh) * 2022-05-13 2022-08-23 安徽英瑞骐生物科技有限公司 一种固定床连续合成2-正丁基乙酰乙酸乙酯的方法
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CA2624524C (fr) * 2005-09-29 2014-07-08 Elan Pharmaceuticals, Inc. Composes de pyrimidinyl amide qui inhibent l'adherence leucocytaire a mediation par vla-4
DE602006019296D1 (de) * 2005-09-29 2011-02-10 Elan Pharm Inc Pyrimidinylamidverbindungen, die die durch vla-4 vermittelte leukozytenadhäsion inhibieren
MX2008010988A (es) * 2006-02-27 2008-10-20 Elan Pharm Inc Compuestos de pirimidinil sulfonamida que inhiben la adhesion de los leucocitos mediada por vla-4.

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US6903128B2 (en) 1999-12-28 2005-06-07 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6668527B2 (en) 1999-12-28 2003-12-30 Pfizer Inc. Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
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US6803370B2 (en) 2000-07-21 2004-10-12 Elan Pharmaceuticals, Inc. Alpha amino acid derivatives—inhibitors of leukocyte adhesion mediated by VLA-4
WO2002008202A3 (en) * 2000-07-21 2002-04-25 Elan Pharm Inc Alpha amino acid derivatives--inhibitors of leukocyte adhesion mediated by vla-4
WO2002036578A2 (fr) * 2000-10-31 2002-05-10 Lynn Bonham INHIBITEURS DE LPAAT-β ET UTILISATION ASSOCIEE
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WO2002046172A3 (fr) * 2000-12-07 2003-02-06 Cv Therapeutics Inc Composes d'augmentation d'abca-1
WO2002046172A2 (fr) * 2000-12-07 2002-06-13 Cv Therapeutics, Inc. Composes d'augmentation d'abca-1
WO2002100846A1 (fr) * 2001-06-11 2002-12-19 Shire Biochem Inc. Composes et methodes de traitement ou de prevention d'infections a flavivirus
US7135477B2 (en) 2002-05-24 2006-11-14 Elan Pharmaceuticals, Inc. Heterocyclic compounds which inhibit leukocyte adhesion mediated by α4 integrins
EP1507775A1 (fr) * 2002-05-24 2005-02-23 Elan Pharmaceuticals, Inc. Composes heterocycliques inhibiteurs de l'adhesion leucocytaire provoquee par des integrines alpha4
EP1507775A4 (fr) * 2002-05-24 2006-05-24 Elan Pharm Inc Composes heterocycliques inhibiteurs de l'adhesion leucocytaire provoquee par des integrines alpha4
AU2003240823B2 (en) * 2002-05-24 2008-11-06 Elan Pharmaceuticals, Inc. Heterocyclic compounds which inhibit leukocyte adhesion mediated by alpha4 integrins
AU2003240823C1 (en) * 2002-05-24 2009-05-28 Elan Pharmaceuticals, Inc. Heterocyclic compounds which inhibit leukocyte adhesion mediated by alpha4 integrins
KR100978832B1 (ko) 2002-05-24 2010-08-30 엘란 파마슈티칼스, 인크. 알파-4 인테그린에 의해 매개되는 백혈구 부착 저해헤테로시클릭 화합물
JP2006188533A (ja) * 2002-09-23 2006-07-20 Reddy Us Therapeutics Inc 新規トリアジン化合物の組成物および方法
JP2006511476A (ja) * 2002-09-23 2006-04-06 レディ ユーエス セラピューティクス インコーポレイテッド 新規トリアジン化合物の組成物および方法
WO2005003103A2 (fr) * 2003-06-30 2005-01-13 Astrazeneca Ab Nouveaux heterocycles 2,4,6-trisubstitues et utilisations de ceux-ci
WO2005003103A3 (fr) * 2003-06-30 2005-11-03 Astrazeneca Ab Nouveaux heterocycles 2,4,6-trisubstitues et utilisations de ceux-ci
US8263063B2 (en) 2004-07-08 2012-09-11 Elan Pharmaceuticals, Inc. Multimeric VLA-4 antagonists comprising polymer moieties
US7794700B2 (en) 2004-07-08 2010-09-14 Elan Pharmaceuticals Inc. Multimeric VLA-4 antagonists comprising polymer moieties
EP2409706A1 (fr) 2004-08-14 2012-01-25 Boehringer Ingelheim International GmbH Dihydropteridinones pour le traitement des maladies cancéreuses
EP3560499A1 (fr) 2004-08-14 2019-10-30 Boehringer Ingelheim International GmbH Dihydropteridinones pour le traitement des cancers
EP2275107A2 (fr) 2004-08-14 2011-01-19 Boehringer Ingelheim International GmbH Combinaison pour le traitment de maladies liées à la proliferation cellulaire
US8030328B2 (en) 2005-05-20 2011-10-04 Elan Pharmaceuticals, Inc. Imidazolone phenylalanine derivatives
WO2008072850A1 (fr) * 2006-12-11 2008-06-19 Amorepacific Corporation Dérivés de triazine ayant une action inhibitrice contre l'acetyl-coa carboxylase
US8877924B2 (en) 2009-06-09 2014-11-04 NantBio Inc. Benzyl substituted triazine derivatives and their therapeutical applications
US9409903B2 (en) 2009-06-09 2016-08-09 Nantbioscience, Inc. Benzyl substituted triazine derivatives and their therapeutical applications
WO2011101369A1 (fr) 2010-02-17 2011-08-25 Boehringer Ingelheim International Gmbh Dihydroptéridinones, procédé pour la production et l'utilisation de celles-ci
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin
CN114933532A (zh) * 2022-05-13 2022-08-23 安徽英瑞骐生物科技有限公司 一种固定床连续合成2-正丁基乙酰乙酸乙酯的方法
CN114933532B (zh) * 2022-05-13 2024-01-30 安徽英瑞骐生物科技有限公司 一种固定床连续合成2-正丁基乙酰乙酸乙酯的方法

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