Roussel Uclaf

Hoechst Aktiengesellschaft

Roussel-ulcaf

Elizabeth A Kuo

Wilfred R Tully

Robert R Bartlett

Rudolf Schleyerbach

David P Kay

Robert Westwood

Charles J Hedgecock

Dankwart C Fenske

Philip T Hambleton

Edward James Little

Wilfried Schwab

Stuart D Jones

Matharu S Singh

Richard Alexander Williamson

N-Phenyl-2-cyano-3-hydroxycrotonamide derivatives and their use as pharmaceuticals having an immunomodulatory property. The use of N-phenyl-2-cyano-3-hydroxycrotonamide derivatives of the formula I ##STR1## in which R.sup.1 is a hydrogen atom or (C.sub.1 -C.sub.4)-alkyl, R.sup.2 is CN, CX.sub.3, WCX.sub.3, W(CH.sub.2).sub.n CX.sub.3, NO.sub.2, (CH.sub.2).sub.n CX.sub.3, or halogen, in which X is halogen, W is an oxygen or sulfur atom and n is an integer from 1 to 3, R.sup.3 is (C.sub.1 -C.sub.4)-alkyl, (C.sub.3 -C.sub.6)-cycloalkyl, CN or --CO--R.sup.4, in which R.sup.4 is (C.sub.1 -C.sub.4)-alkyl or (C.sub.3 -C.sub.6)-cycloalkyl, and/or their physiologically tolerable salts, for the treatment of rheumatic diseases, autoimmune diseases, and of rejection reactions of the organ recipient to the transplanted organ, is described.

Medicinal use of n-phenyl-2-cyano-3-hydroxycrotonamide derivatives

The use of N-phenyl-2-cyano-3-hydroxycrotonamide derivatives of the formula I ##STR1## in which R.sup.1 is a hydrogen atom or (C.sub.1 -C.sub.4)-alkyl, R.sup.2 is CN, CX.sub.3, WCX.sub.3, W(CH.sub.2).sub.n CX.sub.3, NO.sub.2, (CH.sub.2).sub.n CX.sub.3, or halogen, in which X is halogen, W is an oxygen or sulfur atom and n is an integer from 1 to 3, R.sup.3 is (C.sub.1 -C.sub.4)-alkyl, (C.sub.3 -C.sub.6)-cycloalkyl, CN or --CO--R.sup.4, in which R.sup.4 is (C.sub.1 -C.sub.4)-alkyl or (C.sub.3 -C.sub.6)-cycloalkyl, and/or their physiologically tolerable salts, for the treatment of rheumatic diseases, auto-immune diseases, and of rejection reactions of the organ recipient to the transplanted organ, is described.

N-Phenyl-2-cyano-3-hydroxycrotonamide derivatives

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 is cyclopropyl or --CH.sub.2 --CH.dbd.CH.sub.2, R.sub.2 is --S(O).sub.n --(CF.sub.2).sub.x --CF.sub.3, n is 1 or 2, x is 0 or 1, R.sub.3 is hydrogen or alkyl of 1 to 3 carbon atoms, m is 0 or 1 and its non-toxic, pharmaceutically acceptable addition salts with a base having anti-inflammatory activity.

2-cyano-3-hydroxy-propenamides

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms; R.sub.2 is cycloalkyl of 3 to 6 carbon atoms; R.sub.4 is selected from the group consisting of halogen, nitrile, nitro, --SCH.sub.3, -alkylcarbonyl of 1 to 6 carbon atoms, cycloalkylcarbonyl of 3 to 6 carbon atoms, --CX.sub.3, 'WCX.sub.3, --(CH.sub.2).sub.n CX.sub.3, --(CX.sub.2).sub.n CX.sub.3, --W(CX.sub.2).sub.n CX.sub.3 and a --W(CH.sub.2).sub.n CX.sub.3, in which X is halogen, W is oxygen or sulfur, and n is 1, 2 or 3; and R.sub.5 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms and cycloalkyl of 3 to 6 carbon atoms; with the proviso that if R.sub.5 is hydrogen, R.sub.4 is not --SCH.sub.3 or --CF.sub.3 and their non-toxic pharmaceutically acceptable salts having anti-prolifera-tive, anti-inflammatory and anti-tumor activity.

Isoxazoles

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms; R.sub.2 is cycloalkyl of 3 to 6 carbon atoms; R.sub.4 is selected from the group consisting of halogen, nitrile, nitro, --SCH.sub.3, -alkylcarbonyl of 1 to 6 carbon atoms, cycloalkylcarbonyl of 3 to 6 carbon atoms, --CX.sub.3, --WCX.sub.3, --(CH.sub.2).sub.n CX.sub.3, --(CX.sub.2).sub.n CX.sub.3, --W(CX.sub.2).sub.n CX.sub.3 and a --W(CH.sub.2).sub.n CX.sub.3, in which X is halogen, W is oxygen or sulfur, and n is 1, 2 or 3; and R.sub.5 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms and cycloalkyl of 3 to 6 carbon atoms; with the proviso that if R.sub.5 is hydrogen, R.sub.4 is not --SCH.sub.3 or --CF.sub.3 and their non-toxic pharmaceutically acceptable salts having anti-prolifera-tive, anti-inflammatory and anti-tumor activity.

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms and alkenyl and alkynyl of 2 to 6 carbon atoms, R.sub.2 is hydrogen or alkyl of 1 to 3 carbon atoms, Y is selected from the group consisting of ##STR2## Z.sub.1 and Z.sub.2 are individually selected from the group consisting of hydrogen, halogen, --NO.sub.2, --CN and alkyl of 1 to 3 carbon atoms, R.sub.3 is hydrogen or alkyl of 1 to 3 carbon atoms, m is an integer from 0 to 6, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are individually selected from the group consisting of hydrogen, halogen, --CN, --NO.sub.2, alkyl, alkylthio and alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, --COR.sub.10, --(CH.sub.2).sub.n --CX.sub.3, --O--(CH.sub.2).sub.n CX.sub.3 and --S--(CH.sub.2).sub.n --CX.sub.3, R.sub.10 is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and cycloalkyl of 3 to 6 carbon atoms, n is an integer from 0 to 3, X is halogen or R.sub.6 and R.sub.7 together form --O--CH.sub.2 --O-- and their non-toxic, pharmaceutically acceptable salts with a base having anti-inflammatory and immunomodulatory activity.

N-phenyl-2-cyano-3-hydroxy-propenamides

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms, W is selected from the group consisting of --O--, --S--, --SO-- and --SO.sub.2 --, Z and Y are --CH-- or one is --CH-- and the other is --N--, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are individually selected from the group consisting of hydrogen, halogen, methoxy, methylthio, alkyl of 1 to 4 carbon atoms, --WCF.sub.3, --CF.sub.3, --NO.sub.2, --CN--, --W--(CH.sub.2).sub.n --CF.sub.3, --W--(CF.sub.2).sub.n --CF.sub.3, --(CF.sub.2).sub.n --CF.sub.3 and --(CH.sub.2).sub.n --CX.sub.3, n is an integer from 1 to 3, X is a halogen or R.sub.3 and R.sub.4 together are --O--(CH.sub.2)--O-- and R.sub.2, R.sub.5 and R.sub.6 are as defined above, R.sub.7 and R.sub.8 are individually hydrogen or alkyl of 1 to 6 carbon atoms, R.sub.9 is cycloalkyl of 3 to 6 carbon atoms and their non-toxic, pharmaceutically acceptable salts with bases.

3-cycloalkyl-prop-2-enamides

A compound selected from the group consisting of all tautomeric forms of a cycloalkyl-propanamide of the formula ##STR1## wherein R.sub.1 is cycloalkyl of 3 to 6 carbon atoms, R.sub.2 is hydrogen or alkyl of 1 to 3 carbon atoms, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are individually selected from the group consisting of hydrogen, halogen, --NO.sub.2, azido, --CN, alkyl, alkoxy and alkylthio of 1 to 6 carbon atoms, --(CH.sub.2).sub.m --CF.sub.3, --O--(CH.sub.2).sub.m --CF.sub.3, --S--(CH.sub.2).sub.m --CF.sub.3, m is an integer from 0 to 3, --CF.sub.2 --Hal, --OCF.sub.2 --Hal, ##STR2## n is an integer from 1 to 3, Hal, Hal.sub.1, and Hal.sub.2 and Hal.sub.3 are individually halogen, and --COR', R' is --OH or alkyl or alkoxy of 1 to 3 carbon atoms or R.sub.4 and R.sub.5 together are --O--CH.sub.2 --O-- and their non-toxic, pharmaceutically acceptable basic salts having anti-inflammatory activity.

3-cycloalkyl-propanamides

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms, R.sub.2 is alkyl of 1 to 3 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, R.sub.3 is --COOR.sub.6, R.sub.6 is hydrogen or alkyl of 1 to 3 carbon atoms, R.sub.4 is selected from the group consisting of halogen, --CN, --NO.sub.2, --SCH.sub.3, alkylcarbonyl of 1 to 6 alkyl carbon atoms, --CX.sub.3, --WCX.sub.3, --(CH.sub.2).sub.n --CX.sub.3, --(CX.sub.2).sub.n --CX.sub.3, --W--(CX.sub.2).sub.n --CX.sub.3, and --W--(CH.sub.2).sub.n --CX.sub.3, X is halogen, W is --O-- or --S--, n is 1, 2 or 3, R.sub.5 is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms and cycloalkyl of 3 to 6 carbon atoms and their salts with non-toxic pharmaceutically acceptable bases with the proviso that if R.sub.2 is alkyl of 1 to 3 carbon atoms, R.sub.1 is hydrogen and R.sub.4 is selected from the group consisting of halogen, --CX.sub.3, --(CH.sub.2).sub.n --CX.sub.3, --(CX.sub.2).sub.n --CX.sub.3, --OCX.sub.3, --O--(CX.sub.2).sub.n --CX.sub.3, and --O--(CH.sub.2).sub.n --CX.sub.3, X is halogen and n is 1, 2 or 3, R.sub.5 cannot be hydrogen having anti-inflammatory activity and their preparation and intermediates.

Phenyl carboxamide isoxazoles

A compound selected from the group consisting of a compound of the formula ##STR1## wherein A, B and E are individually selected from the group consisting of .dbd.CH-- and .dbd.N-- with at least one being .dbd.N--, R is selected from the group consisting of cycloalkyl of 3 to 6 carbon atoms, and alkenyl and alkynyl of 2 to 6 carbon atoms, R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms, R.sub.2 and R.sub.3 together are --O--CH.sub.2 --O-- or are individually selected from the group consisting of hydrogen, halogen, --NO.sub.2, --CN, alkyl, alkylthio and alkoxy of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, --COR.sub.4, --(CH.sub.2).sub.m --CX.sub.3, --O--(CH.sub.2).sub.m --CX.sub.3, --S--(CH.sub.2).sub.m --CX.sub.3, --O--(CX.sub.2).sub.m --CX.sub.3 and --S--(CX.sub.2).sub.m --CX.sub.3, R.sub.4 is hydrogen or alkyl or cycloalkyl of up to 6 carbon atoms, X is halogen and m is 0, 1, 2 or 3 and their addition salts with a non-toxic, pharmaceutically acceptable base having anti-flammatory and immulodulatory activity and their preparation.

2-cyano-3-hydroxy-(n-pyridyl)-propenamide compounds

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 is hydrogen or alkyl of 1 to 3 carbon atoms, W is selected from the group consisting of --O--, --S--, --SO-- and --SO.sub.2 --, Z and Y are --CH-- or one is --CH-- and the other is --N--, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are individually selected from the group consisting of hydrogen, halogen, methoxy, methylthio, alkyl of 1 to 4 carbon atoms, --WCF.sub.3, --CF.sub.3, --NO.sub.2, --CN--, --W--(CH.sub.2).sub.n --CF.sub.3, --W--(CF.sub.2).sub.n --CF.sub.3, --(CF.sub.2).sub.n --CF.sub.3 and --(CH.sub.2).sub.n --CX.sub.3, is an integer from 1 to 3, X is a halogen or R.sub.3 and R.sub.4 together are --O--(CH.sub.2)--O-- and R.sub.2, R.sub.5 and R.sub.6 are as defined above, R.sub.7 and R.sub.8 are individually hydrogen or alkyl of 1 to 6 carbon atoms, R.sub.9 is cycloalkyl of 3 to 6 carbon atoms and their non-toxic, pharmaceutically acceptable salts with bases.

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R.sub.1 is selected from the group consisting of ##STR2## R.sub.13, R.sub.14 and R.sub.15 are individually selected from the group consisting of hydrogen, halogen and alkyl of 1 to 3 carbon atoms, n is an integer from 1 to 3, R.sub.2 is hydrogen or alkyl of 1 to 3 carbon atoms, R.sub.3, R.sub.4 R.sub.5, R.sub.6 and R.sub.7 are individually selected from the group consisting of hydrogen, halogen, --NO.sub.2, --CN, alkyl, alkylthio and alkoxy of 1 to 6 carbon atoms, alkylcarbonyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, ##STR3## m is 0, 1, 2 or 3, n is 1, 2 or 3; Hal, Hal.sub.1, Hal.sub.2 and Hal.sub.3 are individually halogen and ##STR4## R.sub.8, R.sub.9, R.sub.10, R.sub.11 and R.sub.12 are individually any of the groups defined above for R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 or R.sub.4 and R.sub.5 together form --O--CH.sub.2 --O-- and their non-toxic, pharmaceutically acceptable base addition salts having anti-inflammatory activity.

2-cyano-3-hydroxy-enamides

A compound selected from the group consisting of all tautomeric forms of a cycloalky-propanamide of the formula ##STR1## wherein R.sub.1 is cycloalkyl of 3 to 6 carbon atoms, R.sub.2 is hydrogen or alkyl of 1 to 3 carbon atoms, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are individually selected from the group consisting of hydrogen, halogen, --NO.sub.2, azido, --CN, alkyl, alkoxy and alkylthio of 1 to 6 carbon atoms, --(CH.sub.2).sub.m --CF.sub.3, --O--(CH.sub.2).sub.m --CF.sub.3, --S--(CH.sub.2).sub.m --CF.sub.3, m is an integer from 0 to 3, --CF.sub.2 --Hal, --OCF.sub.2 --Hal, ##STR2## n is an integer from 1 to 3, Hal, Hal.sub.1, Hal.sub.2 and Hal.sub.3 are individually halogen, and --COR', R' is --OH or alkyl or alkoxy of 1 to 3 carbon atoms or R.sub.4 and R.sub.5 together are --O--CH.sub.2 --O-- and their non-toxic, pharmaceutically acceptable basic salts having anti-inflammatory activity.

A compound selected from the group consisting of a compound of the formula ##STR1## and its non-toxic, pharmaceutically acceptable acid addition salts having anti-inflammatory activity and their preparation.

Imidazolo [1,2-a]pyrimidines and medical use thereof

A compound selected from the group consisting of a compound of the formula ##STR1## wherein the R.sub.1 s are the same and are alkyl of 1 to 3 carbon atoms or together are alkylene of 2 to 5 carbon atoms, X, Y and W are individually --O-- or --S--, R.sub.2 is hydrogen or alkyl of 1 to 3 carbon atoms, R.sub.3 is selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms and phenyl optionally substituted with at least one member of the group consisting of halogen, alkyl and alkoxy of 1 to 3 carbon atoms and --CF.sub.3, R.sub.4 and R.sub.5 are individually selected from the group consisting of hydrogen, halogen, --OH, alkyl and alkoxy of 1 to 3 carbon atoms and --CF.sub.3 with the proviso that when R.sub.1 and R.sub.2 are alkyl, X and Y are the same and their non-toxic, pharmaceutically acceptable acid addition salts having benzodiazepine inverse agonist properties.

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Swindon, United Kingdom

Elizabeth A Kuo