Amine derivative
The present invention provide a compound of the formula: wherein X and X′ are the same or different and each represents a hydrogen atom, etc.; R 1 and R 2 are the same or different and each represents a hydrogen atom, etc.; R 3 represents a hydrocarbon group optionally having substituents, etc.; R 4 represents a hydrogen atom, etc.; Y and Ya are the same or different and each represents a bond or a spacer having a main chain of 1 to 8 atoms; Z and Za are the same or different and each represents a hydrogen atom, etc.; or a salt thereof or a prodrug thereof, having a somatostatin receptor binding inhibitory activity and is useful for preventing and/or treating diseases associated with somatostatin.
1 . A compound of the formula:
X and X′ are the same or different and each represents a hydrogen atom, a halogen atom or an amino optionally having substituents;
R 1 and R 2 are the same or different and each represents a hydrogen atom or a C 1-6 alkyl optionally having substituents, or R 1 and R 2 form, together with the adjacent nitrogen atom, a nitrogen containing heterocyclic ring optionally having substituents;
R 3 represents a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents;
R 4 represents a hydrogen atom, a hydrocarbon group optionally having substituents or a heterocyclic group optionally having substituents, or
R 3 and R 4 may form, together with the adjacent carbon atom, a ring optionally having substituents;
Y and Ya are the same or different and each represents a bond or a spacer having a main chain of 1 to 8 atoms; and
Z and Za are the same or different and each represents a hydrogen atom, a halogen atom or a cyclic group optionally having substituents; or a salt thereof or a prodrug thereof.
2 . The compound according to claim 1 , wherein X is a halogen atom and X′ is a hydrogen atom.
3 . The compound according to claim 1 , wherein R 1 and R 2 are the same or different and each is a C 1-6 alkyl.
4 . The compound according to claim 1 , wherein R 3 is a C 1-6 alkyl.
5 . The compound according to claim 1 , wherein R 4 is a hydrogen atom.
6 . The compound according to claim 1 , wherein the spacers having a main chain of 1 to 8 atoms represented by Y and Ya are a divalent group comprising 1 to 5 groups selected from —O—, —S—, —CO—, —SO—, —SO 2 —, —NR 5 — (R 5 is a hydrogen atom, a C 1-6 alkyl optionally having substituents, a C 1-6 alkyl-carbonyl optionally having substituents or a C 1-6 alkylsulfonyl optionally having substituents) and a divalent C 1-6 non-cyclic hydrocarbon group optionally having substituents.
7 . The compound according to claim 1 , wherein Y is —CO—.
8 . The compound according to claim 1 , wherein Y is —CH 2 —.
9 . The compound according to claim 1 , wherein Z is a cyclic group optionally having substituents.
10 . The compound according to claim 9 , wherein the cyclic group optionally having substituents is a 4- to 10-membered monocyclic non-aromatic heterocyclic group, which may have 1 to 3 substituents selected from an oxo, an optionally halogenated C 1-6 alkyl, a C 6-14 aryloxy optionally having substituents, a C 7-19 aralkyl optionally having substituents, a carbamoyl, an optionally halogenated C 1-6 alkyl-carbonyl, an optionally halogenated C 1-6 alkylsulfonyl, a C 6-14 aryl-carbonyl optionally having substituents, a C 6-14 aryl-sulfonyl optionally having substituents, a C 7-19 aralkyloxy-carbonyl optionally having substituents, a heterocyclic carbonyl optionally having substituents, a C 6-14 aryl optionally having substituent an aromatic heterocyclic group optionally having substituents, a 5- to 7-membered non-aromatic heterocyclic group optionally having substituents and a C 7-19 aralkyloxy optionally having substituents.
11 . The compound according to claim 1 , wherein Ya is a bond and Za is a hydrogen atom.
12 . The compound according to claim 1 , which is
N-[(1R,2S)-1-[((3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydro-1(2H)-quinolinyl)carbonyl]-2-(1H-indol-3-yl)propyl]-1-[(1-methyl-1H-indol-2-yl)carbonyl]-4-piperidinecarboxamide,
N-[(1R,2S)-1-[((3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydro-1(2H)-quinolinyl)carbonyl]-2-(1H-indol-3-yl)propyl]-4-phenoxy-1-piperidinecarboxamide,
(−)-N-[1-[((3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydro-1(2H)-quinolinyl)carbonyl]-2-(1H-indol-3-yl)propyl]-4-(4-hydrophenoxy)-1-piperidinecarboxamide,
N-[(1R,2S)-1-[[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydro-1(2H)-quinolinyl]carbonyl]-2-(1H-indol-3-yl)propyl]-4-(4-fluorophenoxy)-1-piperidinecarboxamide,
4-benzoyl-N-[(1R,2S)-1-[[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydro-1(2H)-quinolinyl]carbonyl]-2-(1H-indol-3-yl)propyl]-1-piperazinecarboxamide, or a salt thereof.
13 . A pharmaceutical composition comprising the compound according to claim 1 , a salt thereof or a prodrug thereof.
14 . The composition according to claim 13 , which is a somatostatin receptor binding inhibitor.
15 . The composition according to claim 14 , which is a somatostatin subtype 2 receptor binding inhibitor.
16 . The composition according to claim 13 , which is a somatostatin receptor agonist.
17 . The composition according to claim 16 , which is a somatostatin subtype 2 receptor agonist.
18 . The composition according to claim 13 , which is an agent for preventing or treating diabetes or diabetic complications.
19 . Use of the compound according to claim 1 , a salt thereof or a prodrug thereof for manufacturing a somatostatin receptor binding inhibitor.
20 . A method for inhibiting binding of a somatostatin receptor in a mammal, which comprises administering an effective amount of the compound according to claim 1 , a salt thereof or a prodrug thereof to the mammal.
21 . Use of the compound according to claim 1 , a salt thereof or a prodrug thereof for manufacturing an agent for preventing or treating diabetes or diabetic complications.
22 . A method for preventing or treating diabetes or diabetic complications in a mammal, which comprises administering an effective amount of the compound according to claim 1 , a salt thereof or a prodrug thereof to the mammal.