Imidazole derivatives, production method thereof and use thereof
View Patent ↗The present invention provides a compound having a steroid C 17,20 -lyase-inhibitory activity and useful for the therapy and prophylaxis of tumor such as prostatism, breast cancer and the like, and a method for efficiently separating an optically active compound of this compound from a mixture of optical isomers thereof, a compound of the formula: wherein each symbol is as defined in the specification, a salt thereof or a prodrug thereof, and a method for obtaining an optically active compound by optically resolving a mixture of optical isomers by the use of a resolving agent such as tartranilic acid and the like.
1. A compound of the formula:
wherein
n is 1 and
Ar is a group of the formula:
wherein m1 is an integer of 1 to 4,
m2 is an integer of 0 to 3,
R 1 and R 2 are the same or different and each is independently a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, an acyl group, a halogen atom or an optionally substituted hydrocarbon group,
a group of the formula:
wherein m3 is an integer of 1 to 5,
m4 is an integer of 0 to 4,
R 3 and R 4 are the same or different and each is independently a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, an acyl group, a halogen atom or an optionally substituted hydrocarbon group, or
a group of the formula:
wherein m5 is an integer of 1 to 4 and
R 5 is hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, an acyl group, a halogen atom or an optionally substituted hydrocarbon group,
or a salt thereof
or a prodrug thereof.
2. The compound of claim 1 , wherein Ar is a group of the formula:
wherein R 6 and R 7 are the same or different and each is independently a hydrogen atom or a lower alkyl group, or a group of the formula:
wherein m4 is an integer of 0 to 4, R 3 and R 4 are the same or different and each is independently a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, an acyl group, a halogen atom or an optionally substituted hydrocarbon group.
3. The compound of claim 1 , wherein Ar is a group of the formula:
wherein R 6 and R 7 are the same or different and each is independently a hydrogen atom or lower alkyl group.
4. The compound of claim 1 , wherein the compound of the formula (I) is selected from the group consisting of the following compounds:
(±)-7-(5-methoxybenzo[b]thiophen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol,
(±)-7-(5-fluorobenzo[b]thiophen-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol,
(±)-7-(4′-fluoro[1,1′-biphenyl]-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol,
(±)-7-(4′-fluoro[1,1′-biphenyl]-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol,
(±)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide,
(±)-N-ethyl-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-2-naphthamide,
(±)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-isopropyl-2-naphthamide, and
(±)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1 ,2-c]imidazol-7-yl)-2-naphthamide.
5. The compound of claim 1 , which is an enantiomer wherein the steric configuration is an S configuration.
6. The compound of claim 1 , which is an enantiomer wherein the steric configuration is an R configuration.
7. The compound of claim 1 , wherein the compound of the formula (I) is selected from the group consisting of the following compounds:
(±)-7-(4′-fluoro[1,1′-biphenyl]-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol,
(±)-7-(4′-fluoro[1,1 ′-biphenyl]-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol,
(±)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide, and
(±)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-2-naphthamide.
8. The compound of claim 1 , wherein the compound of the formula (I) is selected from the group consisting of the following compounds:
(+)-7-(4′-fluoro[1,1′-biphenyl]-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol,
(−)-7-(4′-fluoro[1,1′-biphenyl]-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol,
(+)-7-(4′-fluoro[1,1′-biphenyl]-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol,
(−)-7-(4′-fluoro[1,1′-biphenyl]-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-ol,
(+)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide,
(−)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide,
(+)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-2-naphthamide, and
(−)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-2-naphthamide.
9. A pharmaceutical composition containing the compound of claim 1 or a prodrug thereof and a pharmaceutically acceptable carrier, excipient or diluent.
10. A diastereomeric salt of a compound of the formula (I-1)
wherein n is 1,
m1 is an integer of 1 to 4,
m2 is an integer of 0 to 3,
R 1 and R 2 are the same or different and each is independently a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, an acyl group, a halogen atom or an optionally substituted hydrocarbon group, and
* shows the position of an asymmetric carbon,
and a compound of the formula (IV)
wherein each R 9 is the same or different and is a hydrogen atom, C 1-3 alkyl group, C 1-3 alkoxy group, a hydroxyl group, a nitro group, or a halogen atom,
m6 is an integer of 0 to 3, and
* shows the position of an asymmetric carbon.
11. A diastereomeric salt of a compound of the formula (I-2)
wherein n is 1,
R 6 and R 7 are the same or different and each is independently a hydrogen atom or a lower alkyl group and
* shows the position of an asymmetric carbon
and a compound of the formula (IV)
wherein each R 9 is the same or different and is a hydrogen atom, C 1-3 alkyl group, C 1-3 alkoxy group, a hydroxyl group, a nitro group, or a halogen atom,
m6 is an integer of 0 to 3, and
* shows the position of an asymmetric carbon.
12. A diastereomeric salt of 6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide and an optically active tartranilic acid.
13. A salt of (+)-6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]unidazol-7 -yl)-N-methyl-2-naphthamide and (2S,3 S)-(−)-tartranilic acid.
14. A pharmaceutical composition containing, as an active ingredient, an optically active compound of the compound of the formula (I-1)
wherein n is 1,
m1 is an integer of 1 to 4,
m2 is an integer of 0 to 3,
R 1 and R 2 are the same or different and each is independently a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted amino group, an acyl group, a halogen atom or an optionally substituted hydrocarbon group, and
* shows the position of an asymmetric carbon
and a pharmaceutically acceptable carrier, excipient or diluent.
15. A pharmaceutical composition containing the compound or a prodrug thereof of claim 2 and a pharmaceutically acceptable carrier, excipient or diluent.
16. A pharmaceutical composition containing the compound or a prodrug thereof of claim 3 and a pharmaceutically acceptable carrier, excipient or diluent.
17. A pharmaceutical composition containing the compound or a prodrug thereof of claim 4 and a pharmaceutically acceptable carrier, excipient or diluent.
18. A pharmaceutical composition containing the compound or a prodrug thereof of claim 5 and a pharmaceutically acceptable carrier, excipient or diluent.
19. A pharmaceutical composition containing the compound or a prodrug thereof of claim 6 and a pharmaceutically acceptable carrier, excipient or diluent.
20. A pharmaceutical composition containing the compound or a prodrug thereof of claim 7 and a pharmaceutically acceptable carrier, excipient or diluent.
21. A pharmaceutical composition containing the compound or a prodrug thereof of claim 8 and a pharmaceutically acceptable carrier, excipient or diluent.