Thiazole derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same

Claim 2

A compound of the formula : wherein R 1 is lower alkyl, carboxy, a derivative of carboxy, hydroxymethyl, halomethyl, lower alkylthiomethyl, hydroxyiminomethyl or alkenyl which may be substituted with lower alkoxycarbonyl, pyridyl or cyano, R 2 is hydrogen, hydroxy, lower alkyl, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino optionally substituted with dimethylaminomethylene, or ar(lower)alkylamino optionally substituted with lower alkoxy, R 3 is lower alkyl, halo(lower)alkyl or N-containing unsaturated heterocyclic group which may be substituted with halogen, lower alkyl, lower alkoxy, carboxy, a derivative of carboxy, hydroxy, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino, N-oxide-or ar(lower)alkylamino optionally substituted with lower alkoxy, Q is -CO-, and n is an integer of 0 or 1, provided that when both of R 1 and R 3 are lower alkyl then n is an integer of 1 and R 2 is lower alkyl, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino optionally substituted with dimethylaminomethylene, or ar(lower)alkylamino optionally substituted with lower alkoxy, and when R 1 is lower alkyl and R 3 is halo(lower)alkyl then n is an integer of 1, and pharmaceutically acceptable salts thereof.

Claim 3

A compound of claim 1, wherein R is lower alkyl, carboxy, a derivative of carboxy, hydroxymethyl, halomethyl, lower alkylthiomethyl, hydroxyiminomethyl or alkenyl which may be substituted with lower alkoxycarbonyl, pyridyl or cyano, R 2 is hydrogen, hydroxy, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino optionally substituted with dimethylaminomethylene, or ar(lower)alkylamino optionally substituted with lower alkoxy, and R 3 is lower alkyl, halo(lower)alkyl or N-containing unsaturated heterocyclic group which may be substituted with halogen, lower alkyl, lower alkoxy, amino, lower alkylamino, guanidino or N-oxide.

Claim 4

A compound of claim 2, wherein R 1 is lower alkyl, a derivative of carboxy or alkenyl which may be substituted with lower alkoxycarbonyl, pyridyl or cyano, R 2 is hydroxy, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, N-(lower)alkyl-N-acylamino, guanidino optionally substituted dimethylaminomethylene,or ar(lower)alkylamino optionally substituted with lower alkoxy, and R 3 is N-containing unsaturated heterocyclic group which may be substituted with halogen, lower alkyl, lower alkoxy, amino, lower alkylamino or guanidino.

Claim 5

A compound of claim 3, wherein R 1 is lower alkyl or an esterified carboxy, R 2 is amino, lower alkylamino or guanidino optionally substituted with dimethylaminomethylene, and R 3 is pyridyl, thiazolyl or imidazo[1,2-a]pyridyl, in which these groups may be substituted with halogen, lower alkyl, amino, lower alkylamino or guanidino.

Claim 6

A compound of claim 4, wherein R 1 is lower alkyl and n is an integer of 0.

Claim 7

A compound of claim 5, wherein R 2 is guanidino optionally substituted with dimethylaminomethylene.

Claim 8

A compound of claim 6, wherein R3is pyridyl.

Claim 9

A compound of claim 7, which is 2-guanidino-4-methyl-5-(4-pyridyl)thiazole.

Claim 10

A compound of claim 7, which is 2-guanidino-4-methyl-5-(3-pyridyl)thiazole.

Claim 11

A compound of claim 5, wherein R2is amino.

Claim 12

A compound of claim 10, wherein R 3 is pyridyl.

Claim 13

A compound of claim 11, which is 2-amino-4-propyl-5-(4-pyridyl)thiazole.

Claim 14

A compound of claim 11, which is 2-amino-3-methyl-5-(4-pyridyl)thiazole.

Claim 15

A compound of claim 5, wherein R 2 is lower alkylamino.

Claim 16

A compound of claim 14, wherein R 3 is imidazo[1,2-a]pyridyl or thiazolyl optionally substituted with guanidino.

Claim 17

A compound of claim 15, which is 2-(2-methylamino-4-methylthiazol-5-yl)imidazo-[l,2-a]pyridine.

Claim 18

A compound of claim 15, which is 2-methylamino-4-methyl-5-(2-guanidinothiazol-4-yl)thiazole.

Claim 19

A process for preparing a compound of the formula: wherein R 1 is lower alkyl, carboxy, a derivative of carboxy, hydroxymethyl, halomethyl, lower alkylthiomethyl, hydroxyiminomethyl or alkenyl which may be substituted with lower alkoxycarbonyl, pyridyl or cyano, R 2 is hydrogen, hydroxy, lower alkyl, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino optionally substituted with dimethylaminomethylene, or ar(lower)alkylamino optionally substituted with lower alkoxy, R 3 is lower alkyl, halo(lower)alkyl or N-containing unsaturated heterocyclic group which may be substituted with halogen, lower alkyl, carboxy, a derivative of carboxy, lower alkoxy, hydroxy, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino, N-oxide or ar(lower)alkylamino optionally substituted .with lower alkoxy, Q is -CO-, and n is an integer of 0 or 1, provided that when both of R 1 and R 3 are lower alkyl then n is an integer of 1 and R 2 is lower alkyl, acylamino, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, N-(lower)alkyl-N-acylamino, guanidino optionally substituted with dimethylaminomethylene, or ar(lower)-alkylamino optionally substituted with lower alkoxy, and when R 1 is lower alkyl and R 3 is halo(lower)alkyl then n is an integer of 1, and pharmaceutically acceptable salts thereof, which comprises a) reacting a compound of the formula : wherein R 3 , Q and n are each as defined above, is lower alkyl or a derivative of carboxy, and X is halogen, or its salt with a compound of the formula : wherein is hydrogen, lower alkyl, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino or ar(lower)-alkylamino optionally substituted with lower alkoxy, or its salt to provide a compound of the formula: wherein , , R 3 , Q and n are each as defined above, or its pharmaceutically acceptable salt, or b) reacting a compound of the formula : wherein , R 3 , X, Q and n are each as defined above, or its salt with a compound of the formula : wherein R 4 is a protective group of hydroxy, or its salt to provide a compound of the formula: wherein R1, R 3 , Q and n are each as defined above, or its pharmaceutically acceptable salt, or c) reducing a compound of the formula: wherein , R 2 , Q and n are each as defined above, and is N-containing unsaturated heterocyclic N-oxide group which may be substituted with halogen, lower alkyl, lower alkoxy, carboxy, a derivative of carboxy, hydroxy, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino or ar(lower)-alkylamino optionally substituted with lower alkoxy, or its salt to provide a compound of the formula: wherein , R 2 , Q and n are each as defined above, and is N-containing unsaturated heterocyclic group which may be substituted with halogen, lower alkyl, lower alkoxy, carboxy, a derivative of carboxy, hydroxy, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino or ar(lower)-alkylamino optionally substituted with lower alkoxy, or its pharmaceutically acceptable salt, or d) halogenating a compound of the formula: wherein and R 2 are each as defined above, and R 5 is hydrogen or lower alkyl, or its salt to provide a compound of the formula: wherein , R 2 , R 5 and X are each as defined above, or its pharmaceutically acceptable salt, or e) reacting a compound of the formula: wherein , R 2 , R 5 and X are each as defined above, or its salt with a compound of the formula: wherein Z is taken together with the adjacent C=N group to form an unsaturated heterocyclic ring which may contain additional N and/or S atom(s), and R 6 is hydrogen, amino, lower alkyl or halogen, or its salt to provide a compound of the formula: wherein , R 2 , R 5 , R 6 and Z are each as defined above, or its pharmaceutically acceptable salt, or f) halogenating a compound of the formula: wherein , R 2 , R 6 and Z are each as defined above, or its salt to provide a compound of the formula: wherein , R 2 , R 6 , Z and X are each as defined above, or its pharmaceutically acceptable salt, or g) halogenating a compound of the formula: wherein is as defined above, and then reacting a reaction product with a compound of the formula: wherein and R 4 are each as defined above, or a salt thereof to provide a compound of the formula: wherein and R 2 are each as defined above, or its pharmaceutically acceptable salt, or h) reacting a compound of the formula: wherein , R 2 , R 5 and X are each as defined above, or its salt with a compound of the formula: wherein and R 4 are each as defined above, or a salt thereof to provide a compound of the formula: wherein , R 2 and R 5 are each as defined above, or its pharmaceutically acceptable salt, or i) hydrolyzing a compound of the formula: wherein R 2 , R 3 , Q and n are each as defined above, and is a protected carboxy, or its salt to provide a compound of the formula: wherein R 2 , R 3 , Q and n are each as defined above, or its pharmaceutically acceptable salt, or j) amidating a compound of the formula: wherein R 2 , R 3 , Q and n are each as defined above, or its reactive derivative at the carboxy group or a salt thereof to provide a compound of the formula: wherein R 2 , R 3 , Q and n are each as defined above, and R 1 is substituted or unsubstituted c carbamoyl, or its pharmaceutically acceptable salt, or k) dehydrating a compound of the formula: wherein R 2 , R 3 , Q and n are each as defined above, or its salt to provide a compound of the formula: wherein R 2 , R 3 , Q and n are each as defined above, or its pharmaceutically acceptable salt, or ℓ) reducing a compound of the formula: wherein R 2 and R 3 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof to provide a compound of the formula: wherein R 2 and R 3 are each as defined above, or its pharmaceutically acceptable salt, or m) reducing a compound of the formula: wherein R 2 and R 3 are each as defined above, or its salt to provide a compound of the formula: wherein R 2 and R 3 are each as defined above, or its pharmaceutically acceptable salt, or n) reacting a compound of the formula: wherein R 2 and R 3 are each as defined above, or its salt with a compound of the formula: wherein R 7 is hydrogen or lower alkyl, and R 8 is hydrogen, lower alkyl, lower alkoxycarbonyl, pyridyl or cyano, to provide a compound of the formula: wherein R 2 , R 3 , R 7 and R 8 are each as defined above, or its pharmaceutically acceptable salt, or o) reacting a compound of the formula: wherein R 2 and R 3 are each as defined above, or its salt with hydroxylamine or its salt to provide a compound of the formula: wherein R 2 and R 3 are each as defined above, or its pharmaceutically acceptable salt, or p) halogenating a compound of the formula: wherein R 2 and R 3 are each as defined above, or its salt to provide a compound of the formula: wherein R 2 , R 3 and X are each as defined above, or its pharmaceutically acceptable salt, or q) reacting a compound of the formula: wherein R 2 , R 3 and X are each as defined above, or its salt with a compound of the formula: wherein R 9 is lower alkyl, or its salt to provide a compound of the formula: wherein R 2 , R 3 and R 9 are each as defined above, or its pharmaceutically acceptable salt, or r) reacting a compound of the formula: wherein R 1 and R 2 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula: wherein and are each hydrogen or lower alkoxy, or its reactive derivative at the amino group or a salt thereof to provide a compound of the formula: wherein R 1 , R 2 , and are each as defined above, or its salt, and then cyclodehydrating said compound to provide a compound of the formula: wherein R 1 , R 2 , and are each as defined above, or its pharmaceutically acceptable salt, or s) acylating a compound of the formula: wherein R 1 , R 3 , Q and n are each as defined above, and R 11 is hydrogen or lower alkyl, or its reactive derivative at the amino group or a salt thereof to provide a compound of the formula: wherein R l , R3, Q and n are each as defined above, and is acylamino or N-(lower)alkyl-N-acylamino, or its pharmaceutically acceptable salt, or t) deacylating a compound of the formula: wherein R 1 , R 2 b , R 3 , Q and n are each as defined above, or its salt to provide a compound of the formula: wherein R 1 , R 3 , R 11 , Q and n are each as defined above, or its pharmaceutically acceptable salt, or u) deaminating a compound of the formula: wherein R 1 , R 3 , Q and n are each as defined above, or its salt to provide a compound of the formula: wherein R 1 , R 3 , Q and n are each as defined above, or its pharmaceutically acceptable salt.

Claim 20

A process for preparing a compound of the formula: wherein R 1 is lower alkyl, carboxy, a derivative of carboxy, hydroxymethyl, halomethyl, lower alkylthiomethyl, hydroxyiminomethyl or alkenyl which may be substituted with lower alkoxycarbonyl, pyridyl or cyano, R 2 is hydrogen, hydroxy, lower alkyl, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino optionally substituted with dimethylaminomethylene, or ar(lower)alkylamino optionally substituted with lower alkoxy, R 3 is lower alkyl, halo(lower)alkyl or N-containing unsaturated heterocyclic group which may be substituted with halogen, lower alkyl, carboxy, a derivative of carboxy, lower alkoxy, hydroxy, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino, N-oxide or ar(lower)alkylamino optionally substituted .with lower alkoxy, Q is -CO-, and n is an integer of 0 or 1, provided that when both of R 1 and R 3 are lower alkyl then n is an integer of 1 and R 2 is lower alkyl, acylamino, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, N-(lower)alkyl-N-acylamino, guanidino optionally substituted with dimethylaminomethylene, or ar(lower)-alkylamino optionally substituted with lower alkoxy, and when R 1 is lower alkyl and R 3 is halo(lower)alkyl then n is an integer of 1, and pharmaceutically acceptable salts thereof, which comprises a) reacting a compound of the formula : wherein R 3 , Q and n are each as defined above, is lower alkyl or a derivative of carboxy, and X is halogen, or its salt with a compound of the formula : wherein is hydrogen, lower alkyl, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino or ar(lower)-alkylamino optionally substituted with lower alkoxy, or its salt to provide a compound of the formula: wherein , , R 3 , Q and n are each as defined above, or its pharmaceutically acceptable salt, or b) reacting a compound of the formula : wherein , R 3 , X, Q and n are each as defined above, or its salt with a compound of the formula : wherein R 4 is a protective group of hydroxy, or its salt to provide a compound of the formula: wherein R1, R 3 , Q and n are each as defined above, or its pharmaceutically acceptable salt, or c) reducing a compound of the formula: wherein , R 2 , Q and n are each as defined above, and is N-containing unsaturated heterocyclic N-oxide group which may be substituted with halogen, lower alkyl, lower alkoxy, carboxy, a derivative of carboxy, hydroxy, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino or ar(lower)-alkylamino optionally substituted with lower alkoxy, or its salt to provide a compound of the formula: wherein , R 2 , Q and n are each as defined above, and is N-containing unsaturated heterocyclic group which may be substituted with halogen, lower alkyl, lower alkoxy, carboxy, a derivative of carboxy, hydroxy, pyridyl, amino, lower alkylamino, pyridylamino, arylamino, acylamino, N-(lower)alkyl-N-acylamino, guanidino or ar(lower)-alkylamino optionally substituted with lower alkoxy, or its pharmaceutically acceptable salt, or d) halogenating a compound of the formula: wherein and R 2 are each as defined above, and R 5 is hydrogen or lower alkyl, or its salt to provide a compound of the formula: wherein , R 2 , R 5 and X are each as defined above, or its pharmaceutically acceptable salt, or e) reacting a compound of the formula: wherein , R 2 , R 5 and X are each as defined above, or its salt with a compound of the formula: wherein Z is taken together with the adjacent C=N group to form an unsaturated heterocyclic ring which may contain additional N and/or S atom(s), and R 6 is hydrogen, amino, lower alkyl or halogen, or its salt to provide a compound of the formula: wherein , R 2 , R 5 , R 6 and Z are each as defined above, or its pharmaceutically acceptable salt, or f) halogenating a compound of the formula: wherein , R 2 , R 6 and Z are each as defined above, or its salt to provide a compound of the formula: wherein , R 2 , R 6 , Z and X are each as defined above, or its pharmaceutically acceptable salt, or g) halogenating a compound of the formula: wherein is as defined above, and then reacting a reaction product with a compound of the formula: wherein and R 4 are each as defined above, or a salt thereof to provide a compound of the formula: wherein and R 2 are each as defined above, or its pharmaceutically acceptable salt, or h) reacting a compound of the formula: wherein , R 2 , R 5 and X are each as defined above, or its salt with a compound of the formula: wherein and R 4 are each as defined above, or a salt thereof to provide a compound of the formula: wherein , R 2 and R 5 are each as defined above, or its pharmaceutically acceptable salt, or i) hydrolyzing a compound of the formula: wherein R 2 , R 3 , Q and n are each as defined above, and is a protected carboxy, or its salt to provide a compound of the formula: wherein R 2 , R 3 , Q and n are each as defined above, or its pharmaceutically acceptable salt, or j) amidating a compound of the formula: wherein R 2 , R 3 , Q and n are each as defined above, or its reactive derivative at the carboxy group or a salt thereof to provide a compound of the formula: wherein R 2 , R 3 , Q and n are each as defined above, and R 1 is substituted or unsubstituted c carbamoyl, or its pharmaceutically acceptable salt, or k) dehydrating a compound of the formula: wherein R 2 , R 3 , Q and n are each as defined above, or its salt to provide a compound of the formula: wherein R 2 , R 3 , Q and n are each as defined above, or its pharmaceutically acceptable salt, or ℓ) reducing a compound of the formula: wherein R 2 and R 3 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof to provide a compound of the formula: wherein R 2 and R 3 are each as defined above, or its pharmaceutically acceptable salt, or m) reducing a compound of the formula: wherein R 2 and R 3 are each as defined above, or its salt to provide a compound of the formula: wherein R 2 and R 3 are each as defined above, or its pharmaceutically acceptable salt, or n) reacting a compound of the formula: wherein R 2 and R 3 are each as defined above, or its salt with a compound of the formula: wherein R 7 is hydrogen or lower alkyl, and R 8 is hydrogen, lower alkyl, lower alkoxycarbonyl, pyridyl or cyano, to provide a compound of the formula: wherein R 2 , R 3 , R 7 and R 8 are each as defined above, or its pharmaceutically acceptable salt, or o) reacting a compound of the formula: wherein R 2 and R 3 are each as defined above, or its salt with hydroxylamine or its salt to provide a compound of the formula: wherein R 2 and R 3 are each as defined above, or its pharmaceutically acceptable salt, or p) halogenating a compound of the formula: wherein R 2 and R 3 are each as defined above, or its salt to provide a compound of the formula: wherein R 2 , R 3 and X are each as defined above, or its pharmaceutically acceptable salt, or q) reacting a compound of the formula: wherein R 2 , R 3 and X are each as defined above, or its salt with a compound of the formula: wherein R 9 is lower alkyl, or its salt to provide a compound of the formula: wherein R 2 , R 3 and R 9 are each as defined above, or its pharmaceutically acceptable salt, or r) reacting a compound of the formula: wherein R 1 and R 2 are each as defined above, or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula: wherein and are each hydrogen or lower alkoxy, or its reactive derivative at the amino group or a salt thereof to provide a compound of the formula: wherein R 1 , R 2 , and are each as defined above, or its salt, and then cyclodehydrating said compound to provide a compound of the formula: wherein R 1 , R 2 , and are each as defined above, or its pharmaceutically acceptable salt, or s) acylating a compound of the formula: wherein R 1 , R 3 , Q and n are each as defined above, and R 11 is hydrogen or lower alkyl, or its reactive derivative at the amino group or a salt thereof to provide a compound of the formula: wherein R l , R3, Q and n are each as defined above, and is acylamino or N-(lower)alkyl-N-acylamino, or its pharmaceutically acceptable salt, or t) deacylating a compound of the formula: wherein R 1 , R 2 b , R 3 , Q and n are each as defined above, or its salt to provide a compound of the formula: wherein R 1 , R 3 , R 11 , Q and n are each as defined above, or its pharmaceutically acceptable salt, or u) deaminating a compound of the formula: wherein R 1 , R 3 , Q and n are each as defined above, or its salt to provide a compound of the formula: wherein R 1 , R 3 , Q and n are each as defined above, or its pharmaceutically acceptable salt.

Claim 21

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