Compound having agonistic activity on somatostatin receptor, and use thereof for medical purposes

Patent metadata

Field	Value
Publication number	US-10214540-B2
Application number	US-201815906875-A
Country	US
Kind code	B2
Filing date	Feb 27, 2018
Priority date	Jul 3, 2012
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

Provision of orally-available and low-toxic somatostatin receptor subtype 2 agonist. Since the compound represented by the general formula (I):

wherein all symbols represent the same meanings as those described in the description, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is non-peptidic low-molecular compound which has strong somatostatin receptor subtype 2 agonist activity, the compound is orally-available. Additionally, since the compound is low-toxic, the compound is useful for the prevention and/or treatment of the somatostatin related diseases such as acromegaly or gastrointestinal obstruction.

First claim

What is claimed is:

1. A compound of the following formula (I):

wherein
R 1 is (1) halogen, (2) hydroxyl, (3) C1-4 alkyl which may be substituted with substituents selected from the group consisting of (a) —OR 7 and (b) halogen, (4) C1-4 alkoxy, or (5) C3-8 cycloalkyl;
p is an integer of 0 to 3;
when p is 2 or more, each R 1 may be same or different;
R 2 is (1) halogen, (2) oxo, (3) —OR 3 , (4) —COR 4 , (5) —COOR 5 , (6) —SO 2 R 6 , (7) C1-4 alkyl which may be substituted with substituents selected from the group consisting of (a) —OR 7 , (b) —COR 8 , (c) —COOR 9 , (d) —SO 2 R 10 , (e) halogen, and (f) cyano, (8) C3-6 monocyclic carbon ring which may be substituted with substituents selected from the group consisting of (a) C1-4 alkyl, (b) phenyl, and (c) hydroxymethyl, (9) 5 to 6 membered monocyclic hetero ring which may be substituted with substituents selected from the group consisting of (a) C1-4 alkyl, (b) phenyl, and (c) hydroxymethyl, (10) —NR 76 R 77 , (11) —CONR 78 R 79 , (12) —NR 80 COR 81 or (13) cyano;
R 3 and R 7 are independently (1) hydrogen, (2) C1-4 alkyl, (3) C1-4 haloalkyl, or (4) —COR 4 ;
R 4 and R 8 are independently C1-4 alkyl or amino;
R 5 , R 6 , R 9 and R 10 are independently hydrogen or C1-4 alkyl;
R 76 to R 81 are independently hydrogen or C1-4 alkyl;
q is an integer of 0 to 3;
when q is 2 or more, more than one R 2 may be same or different;
Ring A is benzene, benzimidazole, indazole, indole, imidazole, triazole, pyrazole, pyridine, pyrimidine, thiophene, oxazole, thiazole, or oxadiazole;
Ring G is benzene;
Y in Ring B is N or CH;
L is (1) bond, (2) —CR 21 ═CR 22 →, (3) —X→, (4) —X—CR 23 R 24 →, (5) —CR 25 R 26 —X→, (6) —X—CR 27 R 28 —O→, (7) —X—O—CR 29 R 30 →, (8) —O—CR 31 R 32 —X→, or (9) —CR 33 R 34 —O—X→, wherein the arrow is a binding position in each group;
R 21 to R 34 is independently hydrogen or C1-4 alkyl;
X is (1) —O—, (2) —C(═O)—, (3) —NR 41 —, (4) —C(═O)—NR 42 —, or (5) —NR 43 —C(═O)—;
R 41 to R 43 are independently hydrogen or C1-4 alkyl;
M is (1) bond, (2) —O—(C1-3 alkylene)-, or (3) —(C1-3 alkylene)-O—;
Z is pyrrolidine, piperidine, or octahydropyridooxazine, which each may be substituted with the substituents selected from the group consisting of (a) halogen, (b) —NR 53 R 54 , (c) —OR 55 , (d) C1-4 alkyl which may be substituted with —NR 56 R 57 and/or —OR 58 , and (e) oxo, with the proviso that Z is not piperidine, when M is bond and Y in Ring B is N;
R 53 to R 58 are independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 acyl, —C(═O)—O—(C1-4 alkyl), —C(═O)—OCH 2 R 68 , oxetanyl, or oxolanyl; and
R 68 is (1) C5-6 monocyclic carbon ring which may be substituted with the substituents selected from the group consisting of (a) C1-4 alkyl and (b) oxo, or (2) 5 to 6 membered monocyclic hetero ring which may be substituted with the substituents selected from the group consisting of (a) C1-4 alkyl and (b) oxo,
a salt thereof, an N-oxide thereof, or a solvate thereof,
with the proviso that the following compounds are excluded:
1,3-diphenyl-2-(1-pyrrolidinyl)benzene, 1,3-diphenyl-2-(1-piperidinyl)benzene, N-[2-(2,6-diphenylphenoxy)ethyl]piperidine, N-[2-(2,6-diphenylphenoxy)ethyl]-N-methylpiperidinium tetrafluoroborate, and N-[3-(2,6-diphenylphenoxy)propyl]-N-methylpiperidinium tetrafluoroborate.

2. The compound according to claim 1 , wherein M-Z is the following Formula (MZ1):

wherein
(B) is a binding position to Ring B;
R Z1-1 is hydrogen or a substituent selected from the group consisting of (a) halogen, (b) —NR 53 R 54 , (c) —OR 55 , (d) C1-4 alkyl which may be substituted with —NR 56 R 57 and/or —OR 58 ;
E 1 is methylene;
m1 is an integer of 0 to 3;
n1 is an integer of 0 or 1;
m1+n1 is an integer of 0 to 3;
R Z1-2 and R Z1-3 represent independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 acyl, —C(═O)—O—(C1-4 alkyl), oxolanyl, or oxetanyl; and
the other symbols represent the same meanings as those described in claim 1 .

3. A compound of the following formula (I-2);

wherein
Y 1 is N or CH;
L 2 is bond;
R Z1-1 is hydrogen or a substituent selected from the group consisting of (a) halogen, (b) —NR 53 R 54 , (c) —OR 55 , (d) C1-4 alkyl which may be substituted with —NR 56 R 57 and/or —OR 58 ;
E 1 is methylene;
m1 is an integer of 0 to 3;
m1+n1 is an integer of 1 to 3;
R Z1-2 and R Z1-3 represent independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 acyl, —C(═O)—O—(C1-4 alkyl), oxolanyl, or oxetanyl; and
the other symbols represent the same meanings as those described in claim 1 ,
a salt thereof, an N-oxide thereof, or a solvate thereof.

4. A compound of the following formula (I-3)

wherein
L 3 is vinylene (—CH═CH—);
Y 1 is N or CH;
R Z1-1 is hydrogen or a substituent selected from the group consisting of (a) halogen, (b) —NR 53 R 54 , (c) —OR 55 , (d) C1-4 alkyl which may be substituted with —NR 56 R 57 and/or —OR 58 ;
E 1 is methylene;
m1 is an integer of 0 to 3;
m1+n1 is an integer of 1 to 3;
R Z1-2 and R Z1-3 represent independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 acyl, —C(═O)—O—(C1-4 alkyl), oxolanyl, or oxetanyl; and
the other symbols represent the same meanings as those described in claim 1 ,
a salt thereof, an N-oxide thereof, or a solvate thereof.

5. A compound of the following formula (I-1)

wherein
L 1 is —C(═O)—NH— or —NH—C(═O)—;
Y 1 is N or CH;
R Z1-2 is hydrogen or a substituent selected from the group consisting of (a) halogen, (b) —NR 53 R 54 , (c) —OR 55 , (d) C1-4 alkyl which may be substituted with —NR 56 R 57 and/or —OR 58 ;
E 1 is methylene;
m1 is an integer of 0 to 3;
m1+n1 is an integer of 1 to 3;
R Z1-2 and R Z1-3 represent independently hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 acyl, —C(═O)—O—(C1-4 alkyl), oxolanyl, or oxetanyl; and
the other symbols represent the same meanings as those described in claim 1 ,
a salt thereof, an N-oxide thereof, or a solvate thereof.

6. The compound according to claim 1 , wherein the compound is (1) 5-[(E)-2-{5-(3-fluoro-5-methylphenyl)-4-[rac-(4aR,8aR)-octahydro-6H-pyrido[3,4-b][1,4]oxazin-6-yl]-3-pyridinyl}vinyl]nicotinonitrile or (2) rac-(4aR,8aR)-6-[3-(6-chloro-1H-benzimidazol-2-yl)-5-(3-fluoro-5-methylphenyl)-4-pyridinyl]octahydro-1H-pyrido[3,4-b][1,4]oxazine.

7. A pharmaceutical composition which comprises the compound of the formula (I) according to claim 1 , a salt thereof, an N-oxide thereof, a solvate thereof, and a pharmaceutically acceptable excipients.

8. A medicine comprising the compound according to claim 1 , a salt thereof, an N-oxide thereof, or a solvate thereof and at least one drug selected from the group consisting of pegvisomant, bromocriptine, and cabergoline.

9. A medicine comprising the compound according to claim 1 , a salt thereof, an N-oxide thereof, or a solvate thereof and at least

Assignees

• Ono Pharmaceutical Co

Inventors

• Ishida Akiharu
• Matsushita Takeshi
• Sekiguchi Tetsuya
• Komagata Tatsuya
• Nishio Takuya

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P5/06

  of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title