| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | July 1, 2003 |
| PATENT TITLE |
Benzyl compounds which inhibit leukocyte adhesion mediated by VLA-4 |
| PATENT ABSTRACT | Disclosed are compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflammatory diseases in a mammalian patient, e.g., human, wherein the disease may be, for example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumor metastasis and myocardial ischemia. The compounds can also be administered for the treatment of inflammatory brain diseases such as multiple sclerosis |
| PATENT INVENTORS | This data is not available for free |
| PATENT FILE DATE | January 14, 2002 |
| PATENT REFERENCES CITED |
V. Simanis, et al. Int. J. Pept. Protein Res. 19(1): 67-70 (1982). D. Leibfritz, et al. Tetrahedron. 38(14): 2165-2181 (1982). A.M. El-Naggar, et al. Acta. Pharm. Jugosl. 35(1): 15-22 (1985). Chemical Abstract No. 126040, vol. 74, No. 23 (Jun. 7, 1971). Chemical Abstract No. 176262, vol. 99, No. 21 (Nov. 21, 1983). Chemical Abstract No. 210288, vol. 106, No. 25 (Jun. 22, 1987). Chemical Abstract No. 167952, vol. 108, No. 19 (May 9, 1988). Chemical Abstract No. 34164, vol. 125, No. 3 (Jul. 15, 1996). Engleman, V.W., et al. "Cell Adhesion Integrins as Pharmaceutical Targets." Ann. Reports in Med. Chem. 31: 191-200 (1996). Gamo, K., et al. "Optical resolution of racemic amine derivatives." Chem. Abs. 117: 211689 (1992). Hauptmann, J., et al., "Degredation of a Benzamidine-Tupe synthetic Inhibitor of Coagulation Enzymes in Plasma of Various Species." Thrombosis Research. 61: 279-284 (1991). Leibfritz, D., et al. "Synthese Von 2-Methylalanin-Peptiden, Di pH-Abhangigkeit Ihrer 13C-NMR-Spektren Und Eine Neue Methode Zur Auswetung Uber CS-Diagramme." Tetrahedron. 18(14): 2165-2181 (1982). (Translation Enclosed). Voight, B., et al. "Synthese con Na-(Aylsofonyl-L-prolyl)-und Na-Benzyloxycarbonyl-L-prolul)-D,L-4-amidinophenyl-alaninamiden als Thrombininhibitoren." Pharmazie. 41: 233-235 (1986). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound of formula I: ##STR19## where R.sup.1 is selected from the group consisting of alkyl, substituted alkyl, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, heteroaryl and substituted heteroaryl; R.sup.2 and R.sup.3, together with the nitrogen atom bound to R.sup.2 and the carbon atom bound to R.sup.3, form a saturated heterocyclic group or a saturated substituted heterocyclic group with the proviso that when monosubstituted, the substituent on said saturated heterocyclic group is not carboxyl; R.sup.5 is selected from the group consisting of --(CH.sub.2).sub.n -aryl and --(CH.sub.2).sub.n -heteroaryl, where n is an integer equal to 1 to 4; Q is --C(X)NR.sup.7 -- wherein R.sup.7 is selected from the group consisting of hydrogen and alkyl, and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof with the proviso that when R.sup.1 is 2,4,6-trimethylphenyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a pyrrolidinyl ring and Q is --C(O)NH--, then R.sup.5 is not benzyl. 2. A compound of formula II: ##STR20## where R.sup.1 is selected from the group consisting of alkyl, substituted alkyl, phenyl, substituted phenyl, cycloalkyl, heterocyclic, substituted heterocyclic, and heteroaryl; R.sup.2 and R.sup.3, together with the nitrogen atom bound to R.sup.2 and the carbon atom bound to R.sup.3, form a saturated heterocyclic group or a saturated substituted heterocyclic group with the proviso that when monosubstituted, the substituent on said saturated heterocyclic group is not carboxyl; R.sup.5 is selected from the group consisting of --(CH.sub.2).sub.n -aryl and --(CH.sub.2).sub.n -heteroaryl, where n is an integer equal to 1 to 4; R.sup.6 is selected from the group consisting of amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, --O-(N-succinimidyl), --NH-adamantyl, --O-cholest-5-en-3-.beta.-yl, --NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl, --NH(CH.sub.2).sub.p COOY where p is an integer of from 1 to 8 and Y is as defined above, --OCH.sub.2 NR.sup.9 R.sup.10 where R.sup.9 is selected from the group consisting of --C(O)-aryl and --C(O)-substituted aryl and R.sup.10 is selected from the group consisting of hydrogen and --CH.sub.2 COOR.sup.11 where R.sup.11 is alkyl, and --NHSO.sub.2 Z where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; Q is --C(X)NR.sup.7 -- wherein R.sup.7 is selected from the group consisting of hydrogen and alkyl, and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof, with the following provisos: A. when R.sup.1 is 4-methylphenyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring, R.sup.5 is benzyl and Q is --C(O)NH--, then R.sup.6 is not --NH(CH.sub.2).sub.2 CO.sub.2 Et or -(1R,2S,5R)-(-)-menthyl ester; B. when R.sup.1 is 4-methylphenyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a 3-.beta.-phenyl-D-pyrrolidin-2-yl ring, R.sup.5 is benzyl and Q is --C(O)NH--, then R.sup.6 is not --OCH.sub.2 CH.sub.3 ; C. when R.sup.1 is 4-methylphenyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring, R.sup.5 is D-benzyl and Q is --C(O)NH--, then R.sup.6 is not --OCH.sub.2 CH.sub.3 ; and D. when R.sup.1 is 4-methylphenyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a 5,5-dimethyl-1,1-dioxo-thiaprolyl ring, R.sup.5 is benzyl and Q is --C(O)NH--, then R.sup.6 is not --OC(CH.sub.3).sub.3. 3. The compound according to claims 1 or 2, wherein R.sup.1 is selected from the group consisting of phenyl and substituted phenyl. 4. The compound according to claims 1 or 2, wherein R.sup.1 is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl, 2-(methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl, 4-(CH.sub.3 C(O)NH--)phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di-(trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, phenethyl, 4-bromophenyl,4-amidinophenyl, 4-methylamidinophenyl, 4-[CH.sub.3 SC(.dbd.NH)]phenyl, 2-thiazolyl, 4-[H.sub.2 NC(S)]phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2-yl, and 4-(3'-dimethylamino-n-propoxy)-phenyl. 5. The compound according to claims 1 or 2, wherein R.sup.2 and R.sup.3 together with the nitrogen atom bound to the R.sup.2 substituent and the carbon bound to the R.sup.3 substituent form a heterocyclic or substituted heterocyclic group of 4 to 6 ring atoms having 1 to 2 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur, which ring is optionally substituted with 1 to 2 substituents selected from the group consisting of fluoro, methyl, hydroxy, amino, phenyl, thiophenyl and thiobenzyl, or can be fused to another saturated heterocyclic or cycloalkyl ring such as a cyclohexyl ring to provide for a fused ring heterocycle of from 10 to 14 ring atoms having 1 to 2 heteroatoms in the ring selected from the group consisting of nitrogen, oxygen and sulfur. 6. A compound according to claims 1 or 2, wherein the R.sup.2 and R.sup.3 heterocyclic ring is selected from the group consisting of azetidin-2-yl, thiazolidin-4-yl, piperidin-2-yl, piperizin-2-yl, thiomorpholin-3-yl and pyrrolidin-2-yl. 7. The compound according to claims 1 or 2, wherein the R.sup.2 and R.sup.3 substituted heterocyclic ring is selected from the group consisting of 4-hydroxypyrrolidin-2-yl, 4-fluoropyrrolidin-2-yl, 3-phenylpyrrolidin-2-yl, 3-thiophenylpyrrolidin-2-yl, 4-aminopyrrolidin-2-yl, 3-methoxypyrrolidin-2-yl, 4,4-dimethylpyrrolidin-2-yl, 4-N-Cbz-piperizin-2-yl, 5,5-dimethyl-thiazolidin-4-yl, 1,1-dioxo-thiazolidin-4-yl, L-1,1-dioxo-5,5-dimethylthiazolidin-4-yl and 1,1-dioxothiomorpholinyl. 8. The compound according to claims 1 or 2, wherein R.sup.5 is selected from the group consisting of benzyl, phenethyl, --CH.sub.2 -(3-indolyl), --CH.sub.2 -(1-naphthyl), --CH.sub.2 -(2-naphthyl), --CH.sub.2 -(2-thienyl), --CH.sub.2 -(3-pyridyl), --CH.sub.2 -(5-imidazolyl), --CH.sub.2 -3-(1,2,4-triazolyl) and --CH.sub.2 -(2-thiazolyl). 9. The compound according to claim 2, wherein R.sup.6 is selected from the group consisting of methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-.alpha.-iso-propyl-4-.beta.-methylcyclohexoxy, 2-.beta.-isopropyl-4-.beta.-methylcyclohexoxy, --NH.sub.2, benzyloxy, --NHCH.sub.2 COOH, --NHCH.sub.2 CH.sub.2 COOH, --NH-adamantyl, --NHCH.sub.2 CH.sub.2 COOCH.sub.2 CH.sub.3, --NHSO.sub.2 -p-CH.sub.3 -.phi., --NHOR.sup.8 where R.sup.8 is hydrogen, methyl, iso-propyl or benzyl, O-(N-succinimidyl), --O-cholest-5-en-3-.beta.-yl, --OCH.sub.2 --OC(O)C(CH.sub.3).sub.3, --O(CH.sub.2).sub.z NHC(O)W where z is 1 or 2 and W is selected from the group consisting of pyrid-3-yl, N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl and --NR"C(O)-R' where R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or --CH.sub.2 C(O)OCH.sub.2 CH.sub.3. 10. A method for binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound according to claim 1 or 2 under conditions wherein said compound binds to VLA-4. 11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of claims 1 or 2. 12. A method for the treatment of an inflammatory disease in a patient mediated by VLA-4 which method comprises administering to the patient the pharmaceutical composition of claim 11. 13. The method according to claim 12 wherein said inflammatory disease is selected from the group consisting of 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. |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. 2. References The following publications, patents and patent applications are cited in this application as superscript numbers: .sup.1 Hemler and Takada, European Patent Application Publication No. 330,506, published Aug. 30, 1989 .sup.2 Elices, et al., Cell, 60:577-584 (1990) .sup.3 Springer, Nature, 346:425-434 (1990) .sup.4 Osborn, Cell, 62:3-6 (1990) .sup.5 Vedder, et al., Surgery, 106:509 (1989) .sup.6 Pretolani, et al., J. Exp. Med., 180:795 (1994) .sup.7 Abraham, et al., J. Clin. Invest., 93:776 (1994) .sup.8 Mulligan, et al., J. Immunology, 150:2407 (1993) .sup.9 Cybulsky, et al., Science, 251:788 (1991) .sup.10 Li, et al., Arterioscler. Thromb., 13:197 (1993) .sup.11 Sasseville, et al., Am. J. Path., 144:27 (1994) .sup.12 Yang, et al., Proc. Nat. Acad. Science (USA), 90:10494 (1993) .sup.13 Burkly, et al., Diabetes, 43:529 (1994) .sup.14 Baron, et al., J. Clin. Invest., 93:1700 (1994) .sup.15 Hamann, et al., J. Immunology, 152:3238 (1994) .sup.16 Yednock, et al., Nature, 356:63 (1992) .sup.17 Baron, et al., J. Exp. Med., 177:57 (1993) .sup.18 van Dinther-Janssen, et al., J. Immunology, 147:4207 (1991) .sup.19 van Dinther-Janssen, et al., Annals. Rheumatic Dis., 52:672 (1993) .sup.20 Elices, et al., J. Clin. Invest., 93:405 (1994) .sup.21 Postigo, et al., J. Clin. Invest., 89:1445 (1991) .sup.22 Paul, et al., Transpl. Proceed., 25:813 (1993) .sup.23 Okarhara, et al., Can. Res., 54:3233 (1994) .sup.24 Paavonen, et al., Int. J. Can., 58:298 (1994) .sup.25 Schadendorf, et al., J. Path., 170:429 (1993) .sup.26 Bao, et al., Diff., 52:239 (1993) .sup.27 Lauri, et al., British J. Cancer, 68:862 (1993) .sup.28 Kawaguchi, et al., Japanese J. Cancer Res., 83: 1304 (1992) .sup.29 Kogan, et al., U.S. Pat. No. 5,510,332, issued Apr. 23, 1996 .sup.30 International Patent Appl. Publication No. WO 96/01644 All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. 3. State of the Art VLA-4 (also referred to as .alpha.4.beta.1 integrin and CD49d/CD29), first identified by Hemler and Takada.sup.1, is a member of the .beta.1 integrin family of cell surface receptors, each of which comprises two subunits, an .alpha. chain and a .beta. chain. VLA-4 contains an .alpha.4 chain and a .beta.1 chain. There are at least nine .beta.1 integrins, all sharing the same .beta.1 chain and each having a distinct .alpha. 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 is unique among .beta..sub.1 integrins in that it also binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed on cytokine-activated human umbilical vein endothelial cells in culture. Distinct epitopes of VLA-4 are responsible for the fibronectin and VCAM-1 binding activities, and each activity has been shown to be inhibited independently..sup.2 Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a number of inflammatory responses. At the site of an injury or other inflammatory stimulus, 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. For reviews of adhesion receptors of the immune system, see, for example, Springer.sup.3 and Osborn.sup.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. Large numbers of leukocytes migrate across the blood brain barrier (BBB) in subjects with these inflammatory diseases. The leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis. In other organ systems, tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes. For example, it has been shown that 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..sup.5). Other inflammatory conditions mediated by an adhesion mechanism include, by way of example, asthma.sup.6-8, Alzheimer's disease, atherosclerosis.sup.9-10, AIDS dementia.sup.11, diabetes.sup.12-14 (including acute juvenile onset diabetes), inflammatory bowel disease.sup.15 (including ulcerative colitis and Crohn's disease), multiple sclerosis.sup.16-17, rheumatoid arthritis.sup.18-21, tissue transplantation.sup.22, tumor metastasis.sup.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. In view of the above, assays for determining the VLA-4 level in a biological sample containing VLA-4 would be useful, for example, to diagnosis VLA-4 mediated conditions. Additionally, despite these advances in the understanding of leukocyte adhesion, the art has only recently addressed the use of inhibitors of adhesion in the treatment of inflammatory brain diseases and other inflammatory conditions.sup.29,30. The present invention addresses these and other needs. SUMMARY OF THE INVENTION This invention provides compounds which bind to VLA-4. Such compounds can be used, for example, to assay for the presence of VLA-4 in a sample and, in pharmaceutical compositions, to inhibit cellular adhesion mediated by VLA-4, for example, binding of VCAM-1 to VLA-4. The compounds of this invention have a binding affinity to VLA-4 as expressed by an IC.sub.50 of about 15 .mu.M or less (as measured by Example 95 below), which compounds are defined by formula I below: ##STR1## where R.sup.1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; R.sup.2 and R.sup.3 together with the nitrogen atom bound to R.sup.2 and the carbon atom bound to R.sup.3 form a saturated heterocyclic group or a saturated substituted heterocyclic group with the proviso that when monosubstituted, the substituent on said saturated heterocyclic group is not carboxyl; R.sup.5 is selected from the group consisting of --(CH.sub.2).sub.n -aryl and --(CH.sub.2).sub.n -heteroaryl, where n is an integer equal to 1 to 4; Q is --C(X)NR.sup.7 -- wherein R.sup.7 is selected from the group consisting of hydrogen and alkyl, and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof, with the proviso that when R.sup.1 is 2,4,6-trimethylphenyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a pyrrolidinyl ring and Q is --C(O)NH--, then R.sup.5 is not benzyl; and with the further proviso that when R.sup.1 is p-methylphenyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a pyrrolidinyl ring derived from D-proline and Q is --C(O)NH--, then R.sup.5 is not benzyl derived from D-phenylalanine. In another embodiment, the compounds of this invention can also be provided as prodrugs which convert (e.g., hydrolyze, metabolize, etc.) in vivo to a compound of formula I above. In a preferred example of such an embodiment, the carboxylic acid of the compound of formula I is modified into a group which, in vivo, will convert to a carboxylic acid (including salts thereof). In a particularly preferred embodiment, such prodrugs are represented by compounds of formula IA: ##STR2## R.sup.1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl; R.sup.2 and R.sup.3 together with the nitrogen atom bound to R.sup.2 and the carbon atom bound to R.sup.3 form a saturated heterocyclic group or a saturated substituted heterocyclic group with the proviso that when monosubstituted, the substituent on said saturated heterocyclic group is not carboxyl; R.sup.5 is selected from the group consisting of --(CH.sub.2).sub.n -aryl and --(CH.sub.2).sub.n -heteroaryl, where n is an integer equal to 1 to 4; R.sup.6 is selected from the group consisting of amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, --O-(N-succinimidyl), --NH-adamantyl, --O-cholest-5-en-3-.beta.-yl, --NHOY where Y is hydrogen, alkyl, substituted alkyl, aryl, and substituted aryl, --NH(CH.sub.2).sub.p COOY where p is an integer of from 1 to 8 and Y is as defined above, --OCH.sub.2 NR.sup.9 R.sup.10 where R.sup.9 is selected from the group consisting of --C(O)-aryl and --C(O)-substituted aryl and R.sup.10 is selected from the group consisting of hydrogen and --CH.sub.2 COOR.sup.11 where R.sup.11 is alkyl, and --NHSO.sub.2 Z where Z is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, a substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic; Q is --C(X)NR.sup.7 -- wherein R.sup.7 is selected from the group consisting of hydrogen and alkyl, and X is selected from the group consisting of oxygen and sulfur; and pharmaceutically acceptable salts thereof, with the following provisos: A. when R.sup.1 is 4-methylphenyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring, R.sup.5 is benzyl and Q is --C(O)NH--, then R.sup.6 is not --NH(CH.sub.2).sub.2 CO.sub.2 Et or -(1R,2S,5R)-(-)-menthyl ester; B. when R.sup.1 is 4-methylphenyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a 3-.beta.-phenyl-ring derived from D-proline, R.sup.5 is benzyl and Q is --C(O)NH--, then R.sup.6 is not --OCH.sub.2 CH.sub.3 ; C. when R.sup.1 is 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring, R.sup.5 is benzyl and Q is --C(O)NH--, then R.sup.6 is not --OCH.sub.3 ; D. when R.sup.1 is 4-methylphenyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring, R.sup.5 is D-benzyl and Q is --C(O)NH--, then R.sup.6 is not --OCH.sub.2 CH.sub.3 ; E. when R.sup.1 is 4-methylphenyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a 5,5-dimethyl-1,1-dioxo-thiaprolyl ring, R.sup.5 is benzyl and Q is --C(O)NH--, then R.sup.6 is not --OC(CH.sub.3).sub.3 ; and F. when R.sup.1 is 4-methylphenyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring derived from D-proline, R.sup.5 is benzyl derived from D-phenylalanine and Q is --C(O)NH--, then R.sup.6 is not --OCH.sub.3 ; G. when R.sup.1 is n-butyl, R.sup.2 and R.sup.3 together with the pendent nitrogen and carbon atoms form a pyrrolidin-2-yl ring, R.sup.5 is benzyl and Q is --C(O)NH--, then R.sup.6 is not --O-benzyl. Preferably, in the compounds of formula I and IA above, R.sup.1 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclic, substituted heterocylic, heteroaryl and substituted heteroaryl. Even more preferably R.sup.1 is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, 4-chlorophenyl, 1-naphthyl, 2-naphthyl, 4-methoxyphenyl, phenyl, 2,4,6-trimethylphenyl, 2-(methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4-dirhlorophenyl, 3,4-dimethoxyphenyl, 4-(CH.sub.3 C(O)NH-)phenyl, 4-trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di-(trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-thienyl, 1-N-methyl-3-methyl-5-chloropyrazol-4-yl, phenethyl, 1-N-methylimidazol-4-yl, 4-bromophenyl, 4-amidinophenyl, 4-methylamidinophenyl, 4-[CH.sub.3 SC(.dbd.NH)]phenyl, 5-chloro-2-thienyl, 2,5-dichloro-4-thienyl, 1-N-methyl-4-pyrazolyl, 2-thiazolyl, 5-methyl-1,3,4-thiadiazol-2-yl, 4-[H.sub.2 NC(S)]phenyl, 4-aminophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3,5-difluorophenyl, pyridin-3-yl, pyrimidin-2-yl, and 4-(3'-dimethylamino-n-propoxy)-phenyl. In one preferred embodiment, R.sup.2 and R.sup.3 together with the nitrogen atom bound to the R.sup.2 substituent and the carbon bound to the R.sup.3 substituent form a heterocyclic group or substituted heterocyclic group of 4 to 6 ring atoms having 1 to 2 heteroatoms in the ring selected from nitrogen, oxygen and sulfur, which ring is optionally substituted with 1 to 2 substituents selected from fluoro, methyl, hydroxy, amino, phenyl, thiophenyl and thiobenzyl, or can be fused to another saturated heterocyclic or cycloalkyl ring such as a cyclohexyl ring to provide for a fused ring heterocycle of from 10 to 14 ring atoms having 1 to 2 heteroatoms in the ring selected from nitrogen, oxygen and sulfur. Such heterocyclic rings include thiazolidinyl (e.g., L-thiazolidin-4-yl), piperidinyl (e.g., L-piperidin-2-yl), piperizinyl (e.g., L-piperizin-2-yl), thiomorpholinyl (e.g., L-thiomorpholin-3-yl), pyrrolidinyl (e.g., L-pyrrolidin-2-yl), substituted pyrrolidinyl such as 4-hydroxypyrrolidinyl (e.g., 4-.alpha.-(or .beta.-)hydroxy-L-pyrrolidin-2-yl), 4-fluoropyrrolidinyl (e.g., 4-.alpha.-(or .beta.-)fluoro-L-pyrrolidin-2-yl), 3-phenylpyrrolidinyl (e.g., 3-.alpha.-(or .beta.-)phenyl-L-pyrrolidin-2-yl), 3-thiophenylpyrrolidinyl (e.g., 3-.alpha.-(or .beta.-)thiophenyl-L-pyrrolidin-2-yl), 4-aminopyrrolidinyl (e.g., 4-.alpha.-(or .beta.-)amino-L-pyrrolidin-2-yl), 3-methoxypyrrolidinyl (e.g., 3-.alpha.-(or .beta.-)methoxy-L-pyrrolidin-2-yl), 4,4-dimethylpyrrolidin-2-yl, substituted piperizinyl such as 4-N-Cbz-piperizin-2-yl, substituted thiazolidinyl such as 5,5-dimethylthiazolindin-4-yl, 1,1-dioxothiazolidinyl (e.g., L-1,1-dioxo-thiazolidin-4-yl), substituted 1,1-dioxothiazolidinyl such as L-1,1-dioxo-5,5-dimethylthiazolidin-4-yl, 1,1-dioxothiomorpholinyl (e.g., L-1,1-dioxo-thiomorpholin-3-yl) and the like. Preferably, such rings do not include those where R.sup.2 and R.sup.3 together with the nitrogen atom bound to R.sup.2 and the carbon atom bound to R.sup.3 form a azetidine ring. Q is preferably --C(O)NH-- or --C(S)NH--. R.sup.5 is preferably selected from all possible isomers arising by substitution of the following groups: benzyl, phenethyl, --CH.sub.2 -(3-indolyl), --CH.sub.2 -(1-naphthyl), --CH.sub.2 -(2-naphthyl), --CH.sub.2 -(2-thienyl), --CH.sub.2 -(3-pyridyl), --CH.sub.2 -(5-imidazolyl), --CH.sub.2 -3-(1,2,4-triazolyl), --CH.sub.2 -(2-thiazolyl) and the like. In the compounds of formula IA, R.sup.6 is preferably 2,4-dioxo-tetrahydrofuran-3-yl (3,4-enol), methoxy, ethoxy, iso-propoxy, n-butoxy, t-butoxy, cyclopentoxy, neo-pentoxy, 2-.alpha.-iso-propyl-4-.beta.-methylcyclohexoxy, 2-.beta.-isopropyl-4-.beta.-methylcyclohexoxy, --NH.sub.2, benzyloxy, --NHCH.sub.2 COOH, --NHCH.sub.2 CH.sub.2 COOH, --NH-adamantyl, --NHCH.sub.2 CH.sub.2 COOCH.sub.2 CH.sub.3, --NHSO.sub.2 -p-CH.sub.3 -.phi., --NHOR.sup.8 where R.sup.8 is hydrogen, methyl, iso-propyl or benzyl, O-(N-succinimidyl), --O-cholest-5-en-3-.beta.-yl, --OCH.sub.2 --OC(O)C(CH.sub.3).sub.3, --O(CH.sub.2).sub.z NHC(O)W where z is 1 or 2 and W is selected from the group consisting of pyrid-3-yl, N-methylpyridyl, and N-methyl-1,4-dihydro-pyrid-3-yl, and --NR"C(O)--R' where R' is aryl, heteroaryl or heterocyclic and R" is hydrogen or --CH.sub.2 C(O)OCH.sub.2 CH.sub.3. Preferred compounds within the scope of formula I and IA above include by way of example: N-(methanesulfonyl)-L-prolyl-L-phenylalanine N-(a-toluenesulfonyl)-L-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-L-(N-methyl)phenylalanine N-(toluene-4-sulfonyl)-L-pipecolinyl-L-phenylalanine N-(toluene-4-sulfonyl)-D-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-(4-hydroxy)prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-D,L-homophenylalanine N-(4-chlorobenzenesulfonyl)-L-prolyl-L-phenylalanine N-(1-naphthalenesulfonyl)-L-prolyl-L-phenylalanine N-(2-naphthalenelsulfonyl)-L-prolyl-L-phenylalanine N-(4-methoxybenzenesulfonyl)-L-prolyl-L-phenylalanine N-(4-tert-butylbenzenesulfonyl)-L-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-(4-fluoro)prolyl-L-phenylalanine N-(n-butanesulfonyl)-L-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-L-phenylalanine N-(2-methoxycarbonylbenzenesulfonyl)-L-prolyl-L-phenylalanine N-(2-carboxybenzenesulfonyl)-L-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-thiaprolyl-L-phenylalanine N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-L-phenylalanine N-(4-trifluoromethoxybenzenesulfonyl)-L-prolyl-L-phenylalanine N-(3,4-dichlorobenzenesulfonyl)-L-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-D,L-(3-phenyl)prolyl-L-phenylalanine N-(3,4-dimethoxybenzenesulfonyl)-L-prolyl-L-phenylalanine N-(4-nitrobenzenesulfonyl)-L-prolyl-L-phenylalanine N-(4-acetamidobenzenesulfonyl)-L-prolyl-L-phenylalanine N-(4-cyanobenzenesulfonyl)-L-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-L-tryptophan N-(toluene-4-sulfonyl)-L-prolyl-.beta.-(1-naphthyl)-L-alanine N-(toluene-4-sulfonyl)-L-prolyl-.beta.-(2-naphthyl)-L-alanine N-(toluene-4-sulfonyl)-L-prolyl-.beta.-(2-thienyl)-L-alanine N-(isopropanesulfonyl)-L-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-.beta.-(3-pyridyl)-L-alanine N-(toluene-4-sulfonyl)-L-(4-phenylthio)prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-(4-benzylthio)-L-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-L-histidine N-(toluene-4-sulfonyl)-L-(4-amino)prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalaninamide N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-methoxyamide N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-benzyloxyamide N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)amide N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalaninyl-.beta.-alanine N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-hydroxyamide N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine isopropyl ester N-(toluene-4-sulfonyl)-L-(4-hydroxy)prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalaninyl-(N-benzoyl)glycine ethyl ester N-(toluene-4-sulfonyl)-L-(4-fluoro)prolyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-L-thiaprolyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-L-(5,5-dimethyl)thiaprolyl-L-phenylalanine ethyl ester N-(2-methoxycarbonylbenzenesulfonyl)-L-prolyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-L-(3-phenyl)prolyl-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-(4-methoxy)prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine (1S,2R,5S)-(+)-menthyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine N-hydroxysuccinimide ester N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine 2-(nicotinamido)ethyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine 2-(1-methylpyridinium-3-amido)ethyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine cholesteryl ester N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine 2-(1-methyl-1,4-dihydropyridinyl-3-amido)ethyl ester N-(thiophene-2-sulfonyl)-L-prolyl-L-phenylalanine methyl ester N-(thiophene-2-sulfonyl)-L-prolyl-L-phenylalanine N-(5-chloro-1,3-dimethylpyrazole-4-sulfonyl)-L-prolyl-L-phenylalanine N-(2-phenylethanesulfonyl)-L-prolyl-L-phenylalanine N-(1-methylimidazole-4-sulfonyl)-L-prolyl-L-phenylalanine methyl ester N-(1-methylimidazole-4-sulfonyl)-L-prolyl-L-phenylalanine N-(4-amidinobenzenesulfonyl)-L-prolyl-L-phenylalanine methyl ester N-(4-amidinobenzenesulfonyl)-L-prolyl-L-phenylalanine N-(4-thiomethoxyimidatylbenzene-4-sulfonyl)-L-prolyl-L-phenylalanine methyl ester N-[4-(N-methylthioamido)benzenesulfonyl]-L-prolyl-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-prolyl-D,L-.beta.-(1,2,4-triazol-3-yl)alanine N-(toluene-4-sulfonyl)-L-prolyl-D,L-.beta.-(thiazol-2-yl)alanine N-[4-(3-dimethylaminopropyloxy)benzenesulfonyl]-L-prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-pyrrolidin-2-yl-thiocarbonyl-L-phenylalanine N-(4-thiocarbamoylbenzenesulfonyl)-L-(5,5-dimethyl)thiaprolyl-L-phenylalani ne benzyl ester N-(4-cyanobenzenesulfonyl)-L-(5,5-dimethyl)thiaprolyl-L-phenylalanine benzyl ester N-(toluene-4-sulfonyl)-L-prolyl-D-phenylalanine N-(toluene-4-sulfonyl)-L-(thiamorpholin-3-carbonyl)-L-phenylalanine N-(toluene-4-sulfonyl)-[(1,1-dioxo)thiamorpholin-3-carbonyl]-L-phenylalanin e N-(toluene-4-sulfonyl)-L-(3,3-dimethyl)prolyl-L-phenylalanine N-(toluene-4-sulfonyl)-L-(5,5-dimethyl-1,1-dioxo)thiaprolyl-L-phenylalanine N-(toluene-4-sulfonyl)-[(1,1-dioxo)thiamorpholin-3-carbonyl]-L-phenylalanin e ethyl ester N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine tert-butyl ester N-(toluene-4-sulfonyl)-L-pyrrolidin-2-yl-thiocarbonyl-L-phenylalanine methyl ester N-(benzenesulfonyl)-L-prolyl-L-phenylalanine methyl ester N-(toluene-4-sulfonyl)-L-(5-oxo)prolyl-L-phenylalanine ethyl ester N-(toluene-4-sulfonyl)-L-(5-oxo)prolyl-L-phenylalanine and pharmaceutically acceptable salts thereof, as well as any of the ester compounds recited above wherein one ester is replaced with another ester selected from the group consisting of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester and tert-butyl ester. This invention also provides methods for binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound of formula I or IA above under conditions wherein said compound binds to VLA-4. Certain of the compounds of formula I and IA above are also useful in reducing VLA-4 mediated inflammation in vivo. This invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of one or more of the compounds of formula I or IA above, with the exception that R.sup.3 and R.sup.5 are derived from L-amino acids or other similarly configured starting materials. Alternatively, racemic mixtures can be used. The pharmaceutical compositions may be used to treat VLA-4 mediated disease conditions. Such 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. Accordingly, this invention also provides methods for the treatment of an inflammatory disease in a patient mediated by VLA-4 which methods comprise administering to the patient the pharmaceutical compositions described above. Preferred compounds of formula I and IA above include those set forth in Table I below |
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