Styryl pyrazoles, isoxazoles and analogs thereof having activity as 5-lipoxy-genase inhibitors and pharmaceutical compositions containing them

Claim 2

A compound of the formula (I) and pharmaceutically acceptable salts thereof; wherein (1) is a single or double bond; (2) R, R 1 , and R 2 may be the same or different and are selected from the group consisting of hydrogen, lower alkyl, hydroxy, OR 3 wherein R 3 is lower alkyl, C(O)OR 4 wherein R 4 is hydrogen or lower alkyl, OC(O)R 3 wherein R 3 is independently as defined above, C(O)R 3 wherein R 3 is independently as defined above, NR 6 R 7 , wherein R 6 and R 7 may be the same or different and are hydrogen or lower alkyl, NHC(O)R 3 wherein R 3 is independently as defined above, NHCHO, NHSO 2 R 3 wherein R 3 is independently as defined above, NHCONHR 4 wherein R 4 is as defined above, hydroxymethyl, halogen, trifluoromethyl, SR 4 wherein R 4 is independently as defined above, or nitro; (3) Q is (CH 2 ) n wherein n is an integer of zero to four, CH=CH or wherein R 4 is independently as defined above; (4) X and Y are (i) N, (ii) NR 5 wherein R 5 is hydrogen, lower alkyl, wherein R and R may be the same or different and are hydrogen or lower alkyl, C(O)R 4 wherein R 4 is independently as defined above, cycloalkyl of from three to twenty carbons having of from three to eight ring carbons, aryl, or aralkyl, (iii) 0, (iv) S; with the proviso that X and Y cannot both be N, NR s , 0 or S at once and with the proviso that one of X and Y cannot be 0 at the same time the other of X and Y is S or NR 5 and that one of X and Y cannot be S at the same time the other of X and Y is NR 5 ; (5) Z is H, lower alkyl, aryl, aralkyl, OC(O)R 3 wherein R 3 is independently as defined above, C(O)OR 4 wherein R 4 is independently as defined above, C(O)R 3 wherein R 3 is independently as defined above, CH-(R )C0 2 Ri wherein R and R are independently as defined above, halogen, trifluoromethyl, wherein R, R 1 and R 2 are independently as defined above, heteroaryl, or heteroaralkyl; with the overall proviso that when one of R, R 1 , and R 2 is 2-hydroxy, X is O, Y is N and Q is CH=CH, then Z cannot be H or alkyl, and also with the overall proviso that when R, R 1 , and R 2 are hydroxy or lower alkyl, Y and X are N or NH, n is zero then Z cannot be furyl or phenyl unsubstituted or substituted with halogen, trifluoromethyl, alkyl, alkoxy or NO 2 .

Claim 3

A compound of Claim 1 wherein Q is (CH 2 ) n wherein n is zero or two, CH=CH, or wherein R 4 is as defined above, and wherein X and Y are N and NR 5 with R 5 as defined above, NR 5 and N, 0 and N or N and 0, S and N or N and S.

Claim 4

3-[β-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-methylpyrazole or 3-[β-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-5-methylpyrazole

Claim 5

3-[β-(4'-hydroxy-3'-methoxyphenyl)ethenyl]-5-methylpyrazole or 3-[β-(4'-acetoxy-3'-methoxyphenyl)ethenyl]-5-methylpyrazole

Claim 6

5-[β-(4'-hydroxy-3',-5'-bis(1,1-dimethylethyl)phenyl)ethenyl]-3-methylisoxazole or 5-[β-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-methylisoxazole.

Claim 7

5-[β-(4'-hydroxy-3',-5'-bis(1,1-dimethylethyl)phenyl)ethenyl]-3-methylisoxazole or 5-[β-(4'-hydroxy-3',5'-dimethoxyphenyl)ethenyl]-3-methylisoxazole.

Claim 8

3-[β-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl)phenyl)ethenyl)]-5-methypyrazole.

Claim 9

3-[β-(4'-hydroxy-3',5'-bis(1,1-dimethylethyl)phenyl)ethenyl)]-5-methypyrazole.

Claim 10

A pharmaceutical composition for use as inhibitors of 5-lipoxygenase or cyclooxygenase comprising a 5-lipoxygenase or cyclooxygenase inhibiting amount of a compound of formula (I) according to claim 1.

Claim 11

A sunscreen composition for use as a sunscreen comprising an ultraviolet absorbing amount of a compound of Claim 1 not including the overall provisos and a suitable carrier therefor.

Claim 12

A pharmaceutical composition as claimed in Claim 1 additionally comprising an effective amount of a second active ingredient that is a non-steoridal anti-inflammatory drug; a peripheral analgesic agent; a cyclooxygenase inhibitor; a leukotriene antagonist; an antihistaminic agent; a prostaglandin antagonist or a thromboxane antagonist.

Claim 13

A method of use of a compound of general formula I according to claim 1 alone or in combination with other pharmaceutically active compounds for the manufacture of pharmaceutical compositions for treating inflammation, arthritis, ulcers, allergies, asthma, psoriasis and cardiovascular conditions in mammals suffering therefrom or for the manufacture of compositions for protection from ultraviolet light.

Claim 14

A process for the preparation of a compound of formula I of Claim 1 which comprises (1) reacting a compound of the formula wherein R, R 1 , and R 2 are as defined above; and a compound of the formula wherein and Z is as defined above, Y and X are 0 and N, N and 0, S and N or N and S, and Ph is phenyl, in the presence of a suitable base; to obtain the compound of formula I wherein Z is as defined above, Y and X are O and N, N and 0, S and N, N and S, and R, R 1 , and R 2 are as defined above; (2) treating a compound of the formula wherein R, R 1 , R 2 , and Z are as defined above and Q is HC=CH or (CH 2 ) n ; with hydrazine, and optionally hydrogenating the bond when it is a double bond; to obtain a compound of formula I wherein X and Y are N and NH, and R, R 1 , R 2 , and Z are as defined above; (3) (step a) treating a compound of the formula wherein R, R 1 , and R 2 are as defined above; with a compound of the formula wherein Li is lithium, W is H or CO 2 R 4 wherein R 4 is as defined above and Z is as defined above; and then (step b) treating the product of the step a with hydrochloric acid in methanol; to obtain a product of formula I wherein X and Y are 0 and N and Q is and R, R 1 , R 2 , and Z are as defined above; and, alternatively, further treating the compound obtained in step b with Mo(CO) 6 and then hydrazine to obtain the compound of the formula I wherein X and Y are N and NH and R, R 1 , R 2 , or Z are as defined above; (4) treating a compound of the formula wherein R, R 1 , and R 2 are as defined above, with N-chlorosuccinimide and base followed by treating with a compound of the formula to obtain the compound of formula I wherein X is N and Y is O, Q is HC CH and R, R 1 , R 2 , and Z are as defined above. (5)a) treating a compound of the formula I of Claim 1 wherein one of X and Y is oxygen and the other is nitrogen with acetonitrile in the presence of molybdenum hexacarbonyl; and then b) treating with hydrazine to obtain a compound of the formula I of Claim 1 wherein X and Y are nitrogen (6)a) contacting a compound of the formula wherein R, R 1 , and R 2 are as defined above and a compound of the formula wherein Z and R 4 are as defined above, and one of X and Y is NH and other is N, or one of X and Y is 0 and the other is N, and then in situ either b) dehydrating and decarboxylating the product of step (a) wherein R 4 is hydrogen to obtain a compound of the formula wherein one of X and Y is NH and the other is N or one of X and Y is 0 and the other is N, and R, R 1 , R 2 and Z are as defined above; or c) dehydrating the product of step (a) (in situ) wherein R 4 is alkyl to obtain the compound of formula wherein one of X and Y is NH and the other is N, or one of X and Y is 0 and the other is N, and R, R 1 , R 2 and R 4 are as defined above.