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

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 one drug selected from the group consisting of prochlorperazine, levomepromazine, risperidone, metoclopramide, domperidone, diphenhydramine, chlorpheniramine, dimenhydrinate, promethazine, diprophylline, famotidine, cimetidine, scopolamine, tropisetron, granisetron, ondansetron, azasetron, ramosetron, indisetron, palonosetron, cisapride, mosapride, dexamethasone, betamethasone, prednisolone, aprepitant, olanzapine, quetiapine, perospirone, methylnaltrexone and morphine.

10. A method for treating a somatostatin related disease, comprising administering to a mammal in need thereof an effective amount of the compound of formula (I) according to claim 1 , a salt thereof, an N-oxide thereof, or a solvate thereof,

wherein the somatostatin related disease is a digestive symptom which is caused by a gastrointestinal obstruction in an advanced or recurrence cancer patient, or acromegaly.

11. The method according to claim 10 , wherein the gastrointestinal obstruction in the advanced or recurrent cancer patient is a gastrointestinal obstruction in the advanced or recurrence cancer patient who is under palliative treatment.