NON-PEPTIDYL INHIBITORS OF VLA-4 DEPENDENT CELL BINDING USEFUL IN TREATING INFLAMMATORY, AUTOIMMUNE, AND RESPIRATORY DISEASES

• Main Authors: DUPLANTIER, ALLEN, JACOB, MILICI, ANTHONY, JOHN, CHUPAK, LOUIS, STANLEY, LAU, WAN, FANG
• Format: Patent
• Language: English; Russian
• Published: 24.06.2004
• Edition: 7
• Subjects: ACYCLIC OR CARBOCYCLIC COMPOUNDS; CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

1. A compound of Formula (1.0.0): and pharmaceutically acceptable salts and other prodrug derivatives thereof, wherein A is (C1-C6)alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl as defined below, wherein said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl are optionally substituted with 0 to 3 R ; or A is a member selected from the group consisting of divalent radicals: A -NHC(=O)NH-A -, -A -NHC(=O)O-A -, A -OC(=O)NH-A -, A -NHSO2NH-A -, A -NHC(=O)-A -, A -C(=O)NH-A -, A -NHSO2-A -, A -SO2NH-A -, A -(CH2)rO-A -, A -O(CH2)r-A - and A -(CH2)r-A -, where A and A is each independently selected from the group consisting of hydrogen, aryl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, cycloalkyl, heteroaryl and heterocyclyl as defined herein; where said aryl, alkyl, heteroalkyl, heteroaryl or heterocyclil group is substituted with 0 to 3 R ; B is a member independently selected from the group consisting of the following formula: -where the symbol "*" indicates the point of attachment of the moiety "CR2R3" in the formula (1.0.0); and the symbol "->" indicates the point of attachment of the moiety "E" in the formula (1.0.0); and where the moiety (1.0.0) can be optionally substituted with R ; E is -CR R -; X is -O-; Y is -C(=O)- or -S(=O)2-; k is an integer independently selected from 0, 1 and 2; m is an integer independently selected from 0, 1 and 2; n is an integer independently selected from 1 and 2; p is 1; r is an integer independently selected from 1,0 and 2; R is hydrogen or (C1-C4)alkyl; R and R are both hydrogen, or R taken together with R and hydrogen and nitrogen atoms, to which they are attached, they form a pyrrolidinyl group substituted with 0 to 3 R ; R and R are independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, CF3, aryl, cycloalkyl, heteroalkyl or heterocyclyl; R is (C1-C6)alkyl, (CH2)kOR , (CH2)kNR C(=O)R , (CH2)kNR C(=O)OR , (CH2)kNR SO2R , (CH2)kNR R , F, CF3, OCF3, aryl substituted with 0 to 3 R , heterocyclyl substituted with 0 to 3 R , cycloalkyl substituted with 0 to 3 R ; or R together with R can form cycloalkyl or heterocyclic ring; or R together with R can form cycloalkyl or heterocyclic ring; R is hydrogen, F, CN, (C1-C6)alkyl or (C1-C6)alkoxy; R9 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6) cycloalkoxy, cyano, (CH2)kOH, C(=O)R , (CH2)kC(O)NR R , (CH2)kNR R , (CH2)kNR SO2R , CF3, OCF3, SO2NR R , (CH2)mC(=O)OR , and in the case when R is attached to saturated hydrogen atom, R can be =O or =S, and in the case when R is attached to sulfur atom, R can be =O; R and R are independently hydrogen, (C1-C6)alkyl, hydroxy, cyano, (C1-C6)alkoxy, NR C(=O)R , NR SO2R , NR R , CF3, F, aryl, heterocyclyl, heteroaryl, cycloalkyl, cycloalkoxy, or R together with R can form cycloalkyl or heterocyclyl ring; R is independently selected from the group including halogen, CF3, (C1-C6)alkyl, aryl, heteroaryl, heterocyclyl, hydroxy, cyano, (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C3-C6)cycloalkoxy, (C2-C6)alkynyl, (C2-C6)alkenyl, -NR R , -C(=O)NR R , SO2R , C(=O)R , NR SO2R , NR C(=O)R , C(=O)NR SO2R , NR C(=O)OR and SO2NR R ; wherein said alkyl group represents straight or branched alkyl radical comprising 1 to 6 hydrogen atoms; said alkenyl group represents straight or branched alkyl radical comprising 2 to 6 hydrogen atoms and one binary bond; said alkynyl group represents straight or branched alkyl radical comprising 2 to 6 hydrogen atoms and one triple bond; said cycloalkyl group represents cyclic alkyl radical comprising 3 to 6 hydrogen atoms; said aryl group represents phenyl group; said heteroaryl group represents 5-10-membered aromatic group comprising 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur; said heterocyclic group represents cycloalkyl group, mentioned above and comprising 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur. 2. A compound according to Claim 1, wherein when A is heteroaryl it is a member selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyranyl, parathiazinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and pyrazolo[1,5-c]triazinyl. 3. A compound according to Claim, 2 wherein A is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, benzo[b]furanyl, benzimidazolyl, or quinolinyl. 4. A compound according to Claim, 3 wherein A is pyridyl. 5. A compound according to Claim 1, wherein when A is heterocyclyl it is a member selected from the group consisting of oxiranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, benzodioxolane, and 1,3-benzodioxol-5-yl. 6. A compound according to Claim 5, wherein A is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. 7. A compound according to Claim 1, wherein A is a radical selected from the group comprising: A -NHC(=O)NH-A -, -A -NHC(=O)O-A -, A -OC(=O)NH-A -, A -NHSO2NH-A -, A -NHC(=O)-A -, A -C(=O)NH-A -, A -NHSO2-A -, A -SO2NH-A -, A -(CH2)rO-A -, A -O(CH2)r-A - and A -(CH2)r-A -, where A and A is each independently selected from the group consisting of hydrogen, aryl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, cycloalkyl, heteroaryl and heterocyclyl, where said aryl, alkyl, cycloalkyl, heteroaryl or heterocyclyl group is substituted with 0 to 3 R . 8. A compound according to Claim 7, wherein A and A each independently are both aryl or heteroaryl. 9. A compound according to Claim 8, wherein said aryl is phenyl and said heteroaryl is pyridyl, each of which is independently substituted by 0 or 1 substituent R which is a member selected from the group consisting of F, Cl, F3C-, methyl, methoxy, hydroxyl, iso-propyl, cyclopropyloxy, and cyclopentyl. 10. A compound according to Claim 9, wherein n is the integer 1 resulting in a methylene bridge. 11. A compound according to Claim 10, wherein said component A and said methylene bridge attached thereto comprise a member selected from the group consisting of: 4-hydroxyphenyl-; 3-methoxy-4-(N'-phenylurea)-phenylmethyl-; 4-(N'-phenylurea)-phenylmethyl-; 4-(N'-(2-methylphenyl)urea)-phenylmethyl-; 4-(N'-(2-methoxyphenyl)urea)-phenylmethyl-; 3-methoxy-4-(N'-(2-methylphenyl)urea)-phenylmethyl-; 4-(N'-(2-pyridyl)urea)-phenylmethyl-; 6-methoxy-5-(N'(2-methylphenyl)urea-2-pyridylmethyl-; 4-(N'-(3-methyl-2-pyridyl)urea)-phenylmethyl-; 3-methoxy-4-(N'-(3-methyl-2-pyridyl)urea-phenylmethyl-; 3-methoxy-4-(N'-(2-pyridylurea)-phenylmethyl-; 4-(N'-(2-pyridyl)urea)-phenylmethyl-; 4-(N'-(2-fluorophenyl)urea)-phenylmethyl-; 4-(N'-(2-chlorophenyl)urea)-phenylmethyl-; 4-(N'-(2-chlorophenyl)urea)-3-methoxyphenylmethyl-; 4-(N'-(4-iso-propylphenyl)urea)-phenylmethyl-; 6-methoxy-5-(N'-(o-tolyl)urea-2-pyridylmethyl-; 4-(N'-(3-cyclopropyloxy-2-pyridyl)urea)-phenylmethyl-; and 4-(N'-(o-tolyl)urea)-pyrid-5-ylmethyl-. 12. A compound according to Claim 1, wherein Y is -C(=O)-. 13. A compound according to Claim 1, wherein R , R and R are hydrogen atoms. 14. A compound according to Claim 1, wherein R and R are hydrogen atoms and R is isobutyl. 15. A compound according to Claim 1, wherein R together with R form pirrolidinyl and R is hydrogen. 16. A compound according to Claim 1, wherein p equals 1; m equals 0 or 1; and E is -CR CR -. 17. A compound according to Claim 1, wherein p equals 1; m equals 0; R is -H and R is -H. 18. A compound according to Claim 1, wherein said compound is: 2-allyloxycarbonylamino-3-{3-[1-(3,5-dichlorobenzolsulfonyl)pyrrolidine-2-yl]isoxazole-5-yl}propionic acid, 2-allyloxycarbonylamino-3-[3-(1-{[4-2,6-dichlorobenzoilamino)phenyl]acetyl}pyrrolidine-2-yl]isoxazole-5-yl]propionic acid, 2-allyloxycarbonylamino-3-[3-(1-{[4-3-o-tolylureido)-phenyl]-acetyl}-pyrrolidine-2-yl]isoxazole-5-yl]propionic acid, 3-(3-{1-[(4-acetylaminophenyl)acetyl]pyrrolidine-2-yl-isoxazol-5-yl}-allyloxycarbonylaminopropionic acid, 2-tert-butoxycarbonylamino-3-[3-(1-{[4-(3-o-tolylureido)phenyl]acetyl}-pyrrolidine-2-yl]isoxazole-5-yl]propionic acid, 2-acetylamino-4-(3-{1-[2-(4-benzyloxyphenyl)acetylamino]-3-methylbutyl}isoxazole-5-yl)propionic acid, 2-allyloxycarbonylamino-3-[3-(1-benzoylpyrrolidine-2-yl)isoxazole-5-yl]propionic acid, 2-allyloxycarbonylamino-3-{3-[1-(biphenyl-4-carbonyl)pyrrolidine-2-yl]isoxazole-5-yl]propionic acid, 2-acetylamino-3-(3-{3-methyl-1-[2-(4-naphthalene-2-ylphenyl)acetylamino}butyl}-isoxazole-5-yl)propionic acid, 2,2-dimethyl-3-[3-(3-methyl-1-{2-[4-(3-o-tolylureido)phenyl]acetylamino}butyl)-isoxazole-5-yl]propionic acid, 3-[3-(3-methyl-1-{2-[4-(3-o-tolylureido)phenyl]acetylamino-butyl)-isoxazole-5-yl]-2-phenylpropionic acid, 2-acetylamino-3-[3-(1-{[4-(3-o-tolylureido)phenyl]acetyl}pyrrolidine-2-yl) isoxazole-5-yl]propionic acid, 2-(2,6-dichluorobenxoylamino)-3-{3-(1-{{4-(3-o-tolylureido) phenyl] acetyl} pyrrolidine-2-yl) isoxazole-5-yl]propionic acid, 2-allyloxycarbnylamino-3-{3-[1-(toluene-4-sulfonyl) pyrrolidine-2-yl) isoxazole-5-yl}propionic acid, 2-allyloxycarbnylamino-3-[3-(1-{[4-(2,6-dimethoxybenzoylamino)phenyl]acetyl} pyrrolidine-2-yl) isoxazole-5-yl]propionic acid, 2-allyloxycarbnylamino-3-{3-(1-(3,4-dimethoxybenzolsulfonyl) pyrrolidine-2-yl] isoxazole-5-yl}propionic acid, 2-allyloxy Описаны непептидные соединения, характеризующиеся тем, что указанные соединения представляют собой ингибиторы VLA-4, применяемые при лечении воспалительных, аутоиммунных и респираторных заболеваний, а также тем, что указанные соединения включают соединение формулы (1.0.0) и его фармацевтически приемлемые соли и другие пролек