Substituted thiazole derivatives bearing 3-pyridyl groups, process for preparing the same and use thereof
View Patent ↗The present invention provides a pharmaceutical composition having a steroid C 17,20 -lyase inhibitory activity, which is useful as a prophylactic or therapeutic agent of prostatism, tumor such as breast cancer and the like, more particularly, a steroid C 17,20 -lyase inhibitor containing a compound represented by the formula: wherein A 1 is an aromatic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, one of A 2 and A 3 is a hydrogen atom, a halogen atom, a C 1-4 aliphatic hydrocarbon group optionally having substituents or an optionally esterified carboxyl group, the other of A 2 and A 3 is an aromatic hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, and at least one of A 1 , A 2 and A 3 is a 3-pyridyl group optionally having substituents, or a salt thereof or a prodrug thereof.
1. A compound represented by the formula:
wherein
n is an integer of 1 to 5,
R 1c is a carbamoyl group optionally having substituents selected from the group consisting of a C 1-6 alkyl and a C 6-14 aryl, or an alkylsulfonyl group optionally having halogen atom as a substituent, or two R 1c substituting adjacent carbon atoms are bonded to designate a C 1-2 alkylenedioxy group, and when n is not less than 2, R 1c in the number of n are the same or different,
m is an integer of 1 to 5,
R 2 is 1) a hydrogen atom, 2) a C 1-4 aliphatic hydrocarbon group optionally having substitutents selected from the group consisting of halogen atom, a hydroxy and carboxy, 3) a carboxyl group optionally esterified by C 1-6 alkyl group, 4) a carbamoyl group optionally having substitutents selected from a C 1-6 alkyl and a C 6-14 aryl, 5) an amino group optionally having substitutents selected from the group consisting of a C 1-6 alkyl, a C 6-14 aryl, a formyl, a C 1-6 alkyl-carbonyl, a C 1-4 aryl-carbonyl, a C 1-6 alkoxy-carbonyl, a C 1-6 alkylsulfonyl and a C 6-14 arylsulfonyl, 6) an unsubstituted C 1-6 alkylthio, optionally halogenated C 1-6 alkylthio or a C 7-16 aralkylthio, or 7) an optionally halogenated C 1-6 alkoxy group or a C 1-6 alkoxy-carbonyl-C 1-6 alkoxy group, or two R 2 substituting adjacent carbon atoms may be bonded to form 8) a saturated or unsaturated divalent C 3-5 carbon chain, and when m is not less than 2, R 2 in the number of m may be the same or different, and
R 3 is 1) a hydrogen atom, 2) a halogen atom, 3) a C 1-4 aliphatic hydrocarbon group optionally having sub stituents selected from the group consisting of halogen atom, a hydroxy and carboxy or 4) a carboxyl group optionally esterified by C 1-6 alkyl group,
or a salt thereof.
2. The compound of claim 1 , wherein R 1c is 1) a carbamoyl group optionally having C 1-4 alkyl or C 7-9 aralkyl as a substituent or 2) a C 1-4 alkylsulfonyl group, or two R 1b substituting adjacent carbon atoms are bonded to designate a C 1-2 alkylenedioxy group, R 2 is 1) a hydrogen atom, 2) a C 1-4 alkyl optionally having halogen or hydroxy as a substituent, 3) a carboxyl group, 4) a C 1-4 alkoxycarbonyl group, 5) a carbamoyl group optionally having C 1-4 alkyl or C 7-9 aralkyl as a substituent, 6) an amino group optionally having C 1-4 alkyl, carbamoyl-C 1-4 alkyl or C 7-10 aralkyl as a substituent, 7) a C 1-4 alkylthio group or 8) a C 1-4 alkoxy group, or two R 2 substituting adjacent carbon atoms are bonded to form 9) a butadienylene group, and R 3 is 1) a hydrogen atom, 2) a halogen atom, 3) a C 1-4 alkyl group, 4) a carboxyl group or 5) a C 1-4 alkoxycarbonyl group.
3. A compound represented by the formula:
wherein
n is an integer of 1 to 5,
m is an integer of 1 to 5,
R 1c is a carbamoyl group, a methylcarbamoyl group, or a dimethylcarbamoyl group,
R 2 is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group, and
R 3 is a hydrogen atom, a chlorine atom, a methyl group or an isopropyl group,
or a salt thereof.
4. A compound represented by the formula:
wherein
n is an integer of 1 to 5,
R 1c is a carbamoyl group optionally having substituents selected from the group consisting of a C 1-6 alkyl and a C 6-14 aryl, or an alkylsulfonyl group optionally having a halogen atom as a substituent, or two R 1c substituting adjacent carbon atoms are bonded to designate a C 1-2 alkylenedioxy group, and when n is not less than 2, R 1c in the number of n are the same or different,
R 2a and R 2b are the same or different and each is 1) a hydrogen atom, 2) a C 1-4 aliphatic hydrocarbon group optionally having substituents selected from the group consisting of halogen atom, a hydroxy and carboxy, 3) a carboxyl group optionally esterified by C 1-6 alkyl group, 4) a carbamoyl group optionally having substituents selected from the group consisting a C 1-6 alkyl and a C 6-14 aryl, 5) an amino group optionally having substituents selected from the group consisting of a C 1-6 alkyl, a C 6-14 aryl, a formyl, a C 1-6 alkyl-carbonyl, a C 6-14 aryl-carbonyl, a C 1-6 alkoxy-carbonyl, a C 1-6 alkylsulfonyl and a C 6-14 arylsulfonyl, 6) an unsubstituted C 1-6 alkylthio, optionally halogenated C 1-6 alkylthio or a C 7-16 aralkylthio or 7) an optionally halogenated C 1-6 alkoxy group or a C 1-6 alkoxy-carbonyl-C 1-6 alkoxy group, or R 2a and R 2b may be bonded to form 8) a saturated or unsaturated divalent C 3-5 carbon chain, and
R 3 is 1) a hydrogen atom, 2) a halogen atom, 3) a C 1-4 aliphatic hydrocarbon group optionally having substituents selected from the group consisting of halogen atom, a hydroxy and carboxy or 4) a carboxyl group optionally esterified by C 1-6 alkyl group,
or a salt thereof.
5. The compound of claim 4 , wherein R 1c is 1) a carbamoyl group optionally having C 1-4 alkyl or C 7-9 aralkyl as a substituent or 2) a C 1-4 alkylsulfonyl group, or two R 1b substituting adjacent carbon atoms are bonded to designate a C 1-2 alkylenedioxy group, R 2a and R 2b are the same or different and each is 1) a hydrogen atom, 2) a C 1-4 alkyl optionally having halogen or hydroxy as a substituent, 3) a carboxyl group or C 1-4 alkoxycarbonyl group, 4) a carbamoyl group optionally having C 1-4 alkyl or C 7-9 aralkyl as a substituent, 5) an amino group optionally having C 1-4 alkyl, carbamoyl-C 1-4 alkyl or C 7-10 aralkyl as a substituent, 6) a C 1-4 alkylthio group or 7) a C 1-4 alkoxy group, or R 2a and R 2b are bonded to form a butadienylene group, and R 3 is 1) a hydrogen atom, 2) a halogen atom, 3) a C 1-4 alkyl group, 4) a carboxyl group or 5) a C 1-4 alkoxycarbonyl group.
6. A compound represented by the formula:
wherein
n is an integer of 1 to 5, R 1c is a carbamoyl group, a methylcarbamoyl group, or a dimethylcarbamoyl group, R 2a is a methyl group, an ethyl group or an isopropyl group, R 2b is a hydrogen atom, and R 3 is a hydrogen atom, a chlorine atom, a methyl group or an isopropyl group,
or a salt thereof.
7. A compound represented by the formula:
wherein
n is an integer of 1 to 5,
R 1b is 1) a sulfamoyl group optionally having a C 1-6 alkyl or a C 7-15 aralkyl as a substituent, 2) a carbamoyl group optionally having substituents selected from the group consisting of a C 1-6 alkyl and a C 6-14 aryl, 3) an alkyl group optionally having a halogen atom or a hydroxy as a substituent, 4) a carboxyl group optionally esterified by C 1-6 alkyl group, 5) a halogen atom, 6) an ammo group optionally having substituents selected from the group consisting of a C 1-6 alkyl, a C 6-14 aryl, a formyl, a C 1-6 alkyl-carbonyl, a C 6-14 aryl-carbonyl, a C 1-6 alkoxy-carbonyl, a C 1-6 alkylsulfonyl and a C 6-14 arylsulfonyl, 7) a nitro group, 8) an unsubstituted hydroxy, optionally halogenated C 1-8 alkoxy, a C 1-6 alkoxy-carbonyl-C 1-6 alkoxy, a C 6-14 aryloxy, a C 7-16 aralkyloxy, a C 1-6 alkyl-carbonyloxy, a C 6-14 aryl-carbonyloxy, a C 1-6 alkoxy-carbonyloxy, a mono-C 1-6 alkyl-carbamoyloxy, a di-C 1-6 alkyl-carbamoyloxy, or a C 6-14 aryl-carbamoyloxy, or 9) an alkylsulfonyl group optionally having halogen atom as a substituent, or two R 1b substituting adjacent carbon atoms are bonded to designate a C 1-2 alkylenedioxy group, and when n is not less than 2, R 1b in the number of n may be the same or different, and
R 3 is 1) a hydrogen atom, 2) a halogen atom, 3) a C 1-4 aliphatic hydrocarbon group optionally having substituents selected from the group consisting of halogen atom, a hydroxy and carboxy or 4) a carboxyl group optionally esterified by C 1-6 alkyl group,
or a salt thereof.
8. The compound of claim 7 , wherein R 1b is 1) a sulfamoyl group optionally having C 1-4 alkyl or C 7-9 aralkyl as a substituent, 2) a carbamoyl group optionally having C 1-4 alkyl or C 7-9 aralkyl as a substituent, 3) a C 1-4 alkyl group optionally having halogen as a substituent, 4) a carboxyl group, 5) a C 1-4 alkoxycarbonyl group, 6) a halogen atom, 7) an amino group optionally having C 1-6 alkanoyl, C 1-4 alkyl or C 1-4 alkylsulfonyl as a substituent, 8) a nitro group, 9) a hydroxy group optionally having C 1-4 alkyl or C 1-6 alkanoyl as a substituent or 10) a C 1-4 alkylsulfonyl group, or two R 1b substituting adjacent carbon atoms are bonded to designate a C 1-2 alkylenedioxy group, and R 3 is 1) a hydrogen atom, 2) a halogen atom, 3) a C 1-4 alkyl group, 4) a carboxyl group or 5) a C 1-4 alkoxycarbonyl group.
9. The compound of claim 7 , wherein R 1b is a sulfamoyl group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, a methyl group, a chlorine atom, a fluorine atom, an acetylamino group, a formylamino group or nitro group, and R 3 is a hydrogen atom, a chlorine atom, a methyl group or an isopropyl group.
10. A compound represented by the formula:
wherein
m is an integer of 1 to 5,
R 2 is 1) a hydrogen atom, 2) a C 1-4 aliphatic hydrocarbon group optionally having substituents selected from the group consisting of halogen atom, a hydroxy and carboxy, 3) a carboxyl group optionally esterified by C 1-6 alkyl group, 4) a carbamoyl group optionally having substituents selected from the group consisting of a C 1-6 alkyl and a C 6-14 aryl, 5) an amino group optionally having substituents selected from the group consisting of a C 1-6 alkyl, a C 6-14 aryl, a formyl, a C 1-6 alkyl-carbonyl, a C 6-14 aryl-carbonyl, a C 1-6 alkoxy-carbonyl, a C 1-6 alkylsulfonyl, and a C 6-14 arylsulfonyl, 6) an unsubstituted C 1-6 alkylthio, optionally halogenated C 1-6 alkylthio or a C 7-16 aralkylthio, or 7) an optionally halogenated C 1-6 alkoxy group or a C 1-6 alkoxy-carbonyl-C 1-6 alkoxy group, or two R 2 substituting adjacent carbon atoms are bonded to form 8) a saturated or unsaturated divalent C 3-5 carbon chain, and when m is not less than 2, R 2 in the number of m may be the same or different, and
R 3 is 1) a hydrogen atom, 2) a halogen atom, 3) a C 1-4 aliphatic hydrocarbon group optionally having substituents selected from the group consisting of halogen atom, a hydroxy and carboxy or 4) a carboxyl group optionally esterified by C 1-6 alkyl group,
or a salt thereof.
11. A compound represented by the formula:
wherein
m is an integer of 1 to 5,
R 2 is 1) a hydrogen atom, 2) a C 1-4 alkyl optionally having halogen or hydroxy as a substituent, 3) a carboxyl group, 4) a C 1-4 alkoxycarbonyl group, 5) a carbamoyl group optionally having C 1-4 alkyl or C 7-9 aralkyl as a substituent, 6) an amino group optionally having C 1-4 alkyl, carbamoyl-C 1-4 alkyl or C 7-10 aralkyl as a substituent, 7) a C 1-4 alkylthio group or 8) a C 1-4 alkoxy group, or two adjacent R 2 are bonded to form 9) a butadienylene group, and
R 3 is 1) a hydrogen atom, 2) a halogen atom, 3) a C 1-4 alkyl group, 4) a carboxyl group or 5) a C 1-4 alkoxycarbonyl group,
or a salt thereof.
12. A compound represented by the formula:
wherein
m is an integer of 1 to 5,
R 2 is a hydrogen atom, a methyl group or an ethyl group and
R 3 is a hydrogen atom or a methyl group,
or a salt thereof.
13. A compound represented by the formula:
wherein
p is 0 or an integer of 1 to 5,
R a and R b
are the same or different and each is a hydrogen atom or a C 1-6 lower alkyl group,
R 1d is 1) a hydrogen atom, 2) a C 1-4 aliphatic hydrocarbon group optionally having substituents selected from the group consisting of halogen atom, a hydroxy and carboxy, 3) a sulfamoyl group optionally having substituents selected from the group consisting of a C 1-6 alkyl and a C 7-15 aralkyl, 4) a carbamoyl group optionally having substituents selected from the group consisting of a C 1-6 alkyl and a C 6-14 aryl, 5) a carboxyl group optionally esterified by C 1-6 alkyl group, 6) a halogen atom, 7) an amino group optionally having substituents selected from the group consisting of a C 1-6 alkyl, a C 6-14 aryl, a formyl, a C 1-6 alkyl-carbonyl, a C 6-14 aryl-carbonyl, a C 1-6 alkoxy-carbonyl, a C 1-6 alkylsulfonyl and a C 6-14 arylsulfonyl, 8) an unsubstituted hydroxyl, optionally halogenated C 1-8 atkoxy, a C 1-6 alkoxy-carbonyl-C 1-6 alkoxy, a C 6-14 aryloxy, a C 7-16 aralkyloxy, a C 1-6 alkyl-carbonyloxy, a C 6-14 aryl-carbonyloxy, a C 1-6 alkoxy-carbonyloxy, a mono-C 1-6 alkyl-carbamoyloxy, a di-C 1-6 alkyl-carbamoyloxy and a C 6-14 aryl-carbamoyloxy, 9) an unsubstituted C 1-6 alkylthio, optionally halogenated C 1-6 alkylthio or a C 7-16 aralkylthio, 10) a nitro group, 11) an alkylsulfonyl group optionally having halogen atom as a substituent, or 12) two R 1d substituting adjacent carbon atoms maybe bonded to form 12a) a C 1-2 alkylenedioxy group or 12b) a saturated or unsaturated divalent C 3-5 carbon chain, and when p is not less than 2, R 1d in the number of p may be the same or different, and
R 3 is 1) a hydrogen atom, 2) a halogen atom, 3) a C 1-4 aliphatic hydrocarbon group optionally having substituents selected from the group consisting of halogen atom, a hydroxy and carboxy or 4) a carboxyl group optionally esterified by C 1-6 alkyl group,
or a salt thereof.
14. A compound represented by the formula:
wherein
p is 0 or an integer of 1 to 5, R a and R b are the same or different and each is a hydrogen atom or a methyl group, R 1d is a hydrogen atom, a methyl group, a chlorine atom or a fluorine atom, and
R 3 is a hydrogen atom, a chlorine atom, a methyl group or an isopropyl group,
or a salt thereof.
15. 3-[2-(4-fluorophenyl)-1,3-thiazol-4-yl]-4-methylpyridine, 4-[4-(4-methyl-pyridin-3-yl)-1,3-thiazol-2-yl]benzenesulfonamide or a salt thereof.
16. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition which comprises a compound of claim 4 and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition which comprises a compound of claim 7 and a pharmaceutically acceptable carrier.
19. A pharmaceutical composition which comprises a compound of claim 10 and a pharmaceutically acceptable carrier.
20. A pharmaceutical composition which comprises a compound of claim 13 and a pharmaceutically acceptable carrier.
21. A pharmaceutical composition which comprises a compound of claim 15 and a pharmaceutically acceptable carrier.