Pyrimidine derivatives, preparation thereof and use thereof

Claim 2

A compound of the formula : wherein Z is a group selected from in which R 1 and R 2 are each hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino and R 5 is lower alkyl, R 3 is hydrogen, aryl optionally substituted with lower alkyl, lower alkoxy and/or halogen, or pyridyl optionally substituted with lower alkyl, R 4 is hydrogen, lower alkyl or phenyl optionally substituted with lower alkoxy, and Y is =O, = S or = N - R 6 , in which R 6 is lower alkyl; cyclo(lower)alkyl; ar(lower)alkyl optionally substituted with lower alkoxy; N-containing unsaturated heterocyclic group optionally substituted with lower alkyl; or aryl optionally substituted with hydroxy, lower alkyl, halogen or lower alkoxy, in which lower alkoxy substituent may be substituted with epoxy, hydroxy, amino and/or lower alkylamino, provided that Y is = N - R 6 when R 3 and R 4 are each hydrogen, and Y is = S or = N - R 6 when R1 and R 2 are each hydrogen or lower alkyl and R 3 is phenyl, and pharmaceutically acceptable salts thereof.

Claim 3

A compound of claim 1, wherein Z is a group of the formula: in which R 1 and R 2 are each as defined above.

Claim 4

A compound of claim 2, wherein Y is = N - R 6 , in which R 6 is as defined above.

Claim 5

A compound of claim 3, wherein R 1 and R 2 are each hydrogen or lower alkyl, R 3 is aryl optionally substituted with lower alkyl, lower alkoxy and/or halogen, R 4 is hydrogen, and R 6 is pyridyl or aryl optionally substituted with hydroxy, lower alkyl, halogen and/or lower alkoxy.

Claim 6

A compound of claim 4, wherein R 3 is phenyl substituted with lower alkoxy.

Claim 7

A compound of claim 5, wherein R 6 is phenyl substituted with lower alkyl, lower alkoxy and/or hydroxy.

Claim 8

A compound of claim 6, wherein R 3 is 3,4-dimethoxypheny .

Claim 9

8 . A compound of claim 7, wherein R 6 is 2,4,6-trimethoxyphenyl.

Claim 10

9 . A compound of claim 7, wherein R 6 is 2,4,6-trimethylphenyl.

Claim 11

A compound of claim 9, which is 3,4-dihydro-6-(3,4-dimethoxyphenyl)-l,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone.

Claim 12

ll. A compound of claim 9, which is 3,4-dihydro-6-(3,4-dimethoxyphenyl)-l-ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)-2(lH)-pyrimidinone.

Claim 13

A compound of claim 9, which is 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2(lH)-pyrimidinone.

Claim 14

A compound of claim 8, which is 3,4-dihydro-6-(3,4-dimethoxyphenyl)-l,3-dimethyl-4-(2,4,6-trimethoxyphenylimino)-2(lH)-pyrimidinone.

Claim 15

A compound of claim 2, wherein Y is = S .

Claim 16

A compound of claim 14, wherein R 1 and R 2 are each hydrogen or lower alkyl, R 3 is aryl optionally substituted with lower alkyl, lower alkoxy and/or halogen, and R 4 is hydrogen.

Claim 17

A compound of claim 2, wherein Y is =0.

Claim 18

A compound of claim 16, wherein R 1 and R 2 are each hydrogen or lower alkyl, R 3 is aryl substituted with lower alkyl, lower alkoxy and/or halogen, and R 4 is hydrogen.

Claim 19

A compound of claim 1, wherein Z is a group of the formula: in which R and R 5 are each as defined above.

Claim 20

A compound of claim 18, wherein R 1 is hydrogen or lower alkyl, R 3 is aryl optionally substituted with lower alkyl, lower alkoxy and/or halogen, R 4 is hydrogen, and Y is = 0 or =N-R 6 , in which R 6 is as defined above.

Claim 21

A compound of claim 19, which is 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-ethoxy-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine.

Claim 22

A compound of claim 1, wherein Z is a group of the formula: in which R 2 and R 5 are each as defined above.

Claim 23

A process for preparing a compound of the formula: wherein Z is a group selected from in which R 1 and R 2 are each hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino and R 5 is lower alkyl, R 3 is hydrogen, aryl optionally substituted with lower alkyl, lower alkoxy and/or halogen, or pyridyl optionally substituted with lower alkyl, R 4 is.hydrogen, lower alkyl or phenyl optionally substituted with lower alkoxy, and Y is =0, = S or = N - R 6 , in which R 6 is lower alkyl; cyclo(lower)alkyl; ar(lower)alkyl optionally substituted with lower alkoxy; N-containing unsaturated heterocyclic group optionally substituted with lower alkyl; or aryl optionally substituted with hydroxy, lower alkyl, halogen and/or lower alkoxy, in which lower alkoxy substituent may be substituted with epoxy, hydroxy, amino and/or lower alkylamino, provided that Y is = N - R 6 when R 3 and R 4 are each hydrogen, and Y is = S or =N-R 6 when R1 and R 2 are each hydrogen or lower alkyl and R 3 is phenyl, and pharmaceutically acceptable salts thereof, which comprises a) reacting a compound of the formula: or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, R 1 , R 2 , R 3 and R 4 are each as defined above; or b) reacting a compound of the formula: or its salt with a compound of the formula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, one of and is hydrogen and another is hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino, one of and is alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino and another is hydrogen, alkenyl, ar(lower)-alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino, R 7 is alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino, Y is = O or =N - R 6 , in which R 6 is as defined above, and R 3 and R 4 are each as defined above; or c) alkylating a compound of the formula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, Z a is a group of the formula: in which R 1 , R 2 and R 5 are each as defined above, and , , R 3 , R 4 and Y a are each as defined above; or d) aminating a compound of the formula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, one of and is lower alkyl which is substituted with epoxy and another is hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino, one of and is lower alkyl which is substituted with hydroxy and amino or lower alkylamino and another is hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with hydroxy, amino and/or lower alkylamino, and R 3 and R 4 are each as defined above; or e) reacting a compound of the formula: or its salt with phosphorus pentasulfide to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, R 3 , R 4 and Z are each as defined above; or f) reacting a compound of the formula: or its reactive derivative at the thioxo group or a salt thereof with a compound of the formula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, R 3 , R 4 , R 6 and Z are each as defined above; or g) reacting a compound of the formula: or its salt with a compound of theiformula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, R 8 is lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino, X is a leaving group, and R 3 , R 4 and Z are each as defined above; or h) aminating a compound of the formula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, is lower alkyl substituted with epoxy, is lower alkyl substituted with hydroxy and amino or lower alkylamino, and R 3 , and Z are each as defined above.

Claim 24

A process for preparing a compound of the formula: wherein Z is a group selected from in which R 1 and R 2 are each hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino and R 5 is lower alkyl, R 3 is hydrogen, aryl optionally substituted with lower alkyl, lower alkoxy and/or halogen, or pyridyl optionally substituted with lower alkyl, R 4 is.hydrogen, lower alkyl or phenyl optionally substituted with lower alkoxy, and Y is =0, = S or = N - R 6 , in which R 6 is lower alkyl; cyclo(lower)alkyl; ar(lower)alkyl optionally substituted with lower alkoxy; N-containing unsaturated heterocyclic group optionally substituted with lower alkyl; or aryl optionally substituted with hydroxy, lower alkyl, halogen and/or lower alkoxy, in which lower alkoxy substituent may be substituted with epoxy, hydroxy, amino and/or lower alkylamino, provided that Y is = N - R 6 when R 3 and R 4 are each hydrogen, and Y is = S or =N-R 6 when R1 and R 2 are each hydrogen or lower alkyl and R 3 is phenyl, and pharmaceutically acceptable salts thereof, which comprises a) reacting a compound of the formula: or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, R 1 , R 2 , R 3 and R 4 are each as defined above; or b) reacting a compound of the formula: or its salt with a compound of the formula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, one of and is hydrogen and another is hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino, one of and is alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino and another is hydrogen, alkenyl, ar(lower)-alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino, R 7 is alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino, Y is = O or =N - R 6 , in which R 6 is as defined above, and R 3 and R 4 are each as defined above; or c) alkylating a compound of the formula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, Z a is a group of the formula: in which R 1 , R 2 and R 5 are each as defined above, and , , R 3 , R 4 and Y a are each as defined above; or d) aminating a compound of the formula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, one of and is lower alkyl which is substituted with epoxy and another is hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino, one of and is lower alkyl which is substituted with hydroxy and amino or lower alkylamino and another is hydrogen, alkenyl, ar(lower)alkyl or lower alkyl optionally substituted with hydroxy, amino and/or lower alkylamino, and R 3 and R 4 are each as defined above; or e) reacting a compound of the formula: or its salt with phosphorus pentasulfide to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, R 3 , R 4 and Z are each as defined above; or f) reacting a compound of the formula: or its reactive derivative at the thioxo group or a salt thereof with a compound of the formula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, R 3 , R 4 , R 6 and Z are each as defined above; or g) reacting a compound of the formula: or its salt with a compound of theiformula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, R 8 is lower alkyl optionally substituted with epoxy, hydroxy, amino and/or lower alkylamino, X is a leaving group, and R 3 , R 4 and Z are each as defined above; or h) aminating a compound of the formula: or its salt to provide a compound of the formula: or its pharmaceutically acceptable salt, in the above formulas, is lower alkyl substituted with epoxy, is lower alkyl substituted with hydroxy and amino or lower alkylamino, and R 3 , and Z are each as defined above.

Claim 25

A pharmceutical composition comprising a compound of claim 1 as an effective ingredient, in association with a pharmaceutically acceptable, substantially nontoxic carrier or excipient.