RU2000129161A

RU2000129161A - DERIVATIVE 1 - [(1-SUBSTITUTED-4-PIPERIDINYL) METHYL] -4-PIPERIDINE, METHOD FOR ITS PRODUCTION, PHARMACEUTICAL COMPOSITION CONTAINING THE INDICATED COMPOUND, AND THE INTERMEDIATE PRODUCT

Info

Publication number: RU2000129161A
Application number: RU2000129161/04A
Authority: RU
Inventors: Сиро КАТО; Есихито ТОЕТОМИ; Хиротака ТАТЕИСИ; Хироси ХАРАДА; Наоюки ЕСИДА; Кацуо МОРИКАГЕ; Юкико МОРИКАГЕ
Original assignee: Дайниппон Фармасьютикал Ко., Лтд.
Priority date: 1998-04-28
Filing date: 1999-04-19
Publication date: 2003-01-27

Claims

1. The compound of formula (I)

where Ar represents a group of the following formula (Ar-1) or (Ar-2):

in which R ¹ represents a halogen atom, R ² represents a hydrogen atom or a lower alkyl group, R ³ represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group,
R ⁴ represents a hydrogen atom or a lower alkyl group, and R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a lower alkyl group and n has the value 1, 2 or 3,
A represents a group of the following formula (A-1), (A-2) or (A-3):
-ZN (Q ¹ ) (Q ² ) (A-1)
in which Z represents —CO—, —CS— or —SO ₂ -,
Q ¹ and Q ² are the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenyl lower alkyl group or Q ¹ and Q ² can combine together with a nitrogen atom with which they are linked to form a pyrrolidine ring, a piperidine ring, a hexahydroazepine ring, a morpholine ring, a thiomorpholine ring, or a piperazine ring, optionally containing lower alkyl or benzyl th substituent on the other nitrogen atom;
-CO-R ⁷ (A-2)
in which R ⁷ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl group substituted with a hydroxy, lower alkoxy or lower alkoxycarbonyl group, or a substituted or unsubstituted phenyl group;
- (CH ₂ ) _p -CH (R ⁸ ) -COR ⁹ (A-3)
in which p is 0, 1, 2, 3, 4 or 5, R ⁸ represents a hydrogen atom or a lower alkyl group, and R ⁹ represents a lower alkyl group or a lower alkoxy group, or a pharmaceutically acceptable acid addition salt thereof.

2. The compound according to claim 1, where in the formula (Ar-1) R ² and R ³ both represent hydrogen atoms and R ⁴ represents a methyl group, an ethyl group, a propyl group or an isopropyl group, or in the formula (Ar-2 ), R ² and R ³ are both hydrogen atoms, R ⁵ and R ⁶ are both hydrogen atoms or one of them is a methyl group and the other is a hydrogen atom, and n is 1 or a pharmaceutically acceptable acid addition salt thereof .

3. The compound according to claim 1, which is a compound of formula (II)

where R ¹ represents a halogen atom, R ⁴¹ represents a methyl group, an ethyl group, a propyl group or an isopropyl group, A ¹ represents a group of the following formula (A ¹ -1), (A ¹ -2) or (A ¹ -3 ):
-ZN (Q ¹¹ ) (Q ²¹ ) (A ¹ -1)
in which Z represents —CO—, —CS— or —SO ₂ -, Q ¹¹ and Q ²¹ are the same or different and each represents a methyl group, an ethyl group, a propyl group, an isopropyl group, or Q ¹¹ represents a hydrogen atom, and Q ²¹ represents a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a substituted or unsubstituted phenyl group (these substituents may be a halogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group, or Q ¹¹ and Q ²¹ can combine with a nitrogen atom, with which they are associated with the formation of a pyrrolidine ring or morpholine ring;
-CO-R ⁷¹ (A ¹ -2)
wherein R ⁷¹ represents a hydrogen atom, a methyl, ethyl group, a propyl group, a methoxy group, an ethoxy group, a C ₁ -C ₄ alkyl group, a substituted methoxy, ethoxy, methoxycarbonyl or ethoxycarbonyl group, or a substituted or unsubstituted phenyl group (these substituents can be from 1 to 3 groups selected from halogen atoms, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group and an amino group);
- (CH ₂ ) _{p '} -CH (R ⁸¹ ) -COR ⁹¹ (A ¹ -3)
in which p 'is 0, 1 or 2, R ⁸¹ represents a hydrogen atom, a methyl group or an ethyl group, R ⁹¹ represents a methyl group, an ethyl group, a methoxy group or an ethoxy group, or a pharmaceutically acceptable acid addition salt thereof.

4. The compound according to claim 1, which is a compound of the formula (I-1 ¹ )

where R ¹ represents a halogen atom, and A ¹ represents a group of the following formula (A ¹ -1), (A ¹ -2) or (A ¹ -3):
-ZN (Q ¹¹ ) (Q ²¹ ) (A ¹ -1)
in which Z represents —CO—, —CS— or —SO ₂ -, Q ¹¹ and Q ²¹ are the same or different and each represents a methyl group, an ethyl group, a propyl group, an isopropyl group, or Q ¹¹ represents a hydrogen atom, and Q ²¹ represents a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a substituted or unsubstituted phenyl group (these substituents may be a halogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ alkoxy group), or Q ¹¹ and Q ²¹ can be combined with a nitrogen atom, with with which they are linked to form a pyrrolidine ring or morpholine ring;
-CO-R ⁷¹ (A ¹ -2)
in which R ⁷¹ represents a hydrogen atom, methyl, ethyl group, propyl group, methoxy group, ethoxy group, C ₁ -C ₄ alkyl group, substituted methoxy, ethoxy, methoxycarbonyl or ethoxycarbonyl group, or substituted or unsubstituted phenyl group (these substituents can be from 1 to 3 groups selected from a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkoxy group and an amino group;
- (CH ₂ ) _{p '} -CH (R ⁸¹ ) -COR ⁹¹ (A ¹ -3)
in which p 'is 0, 1 or 2, R ⁸¹ represents a hydrogen atom, a methyl group, or an ethyl group, R ⁹¹ represents a methyl group, an ethyl group, a methoxy group, or an ethoxy group,
or a pharmaceutically acceptable acid addition salt thereof.

5. The compound according to claim 3, which is a compound of formula (I-2)

where R ¹¹ represents a chlorine atom or a bromine atom, R ⁴¹ represents a methyl group, an ethyl group, a propyl group, or an isopropyl group, R ⁸² represents a hydrogen atom, a methyl group or an ethyl group, R ⁹² represents a methyl group, an ethyl group or ethoxy group, and p "has the value 0, 1 or 2,
or a pharmaceutically acceptable acid addition salt thereof.

6. The compound according to claim 4, which is a compound of formula (I-3)

where R ¹¹ represents a chlorine atom or a bromine atom, Z ² represents —CO— or —CS—, Q ¹² represents a hydrogen atom, a methyl group, or an ethyl group, Q ²² represents a methyl group, an ethyl group, or a phenyl group , or Q ¹² and Q ²² may combine with the nitrogen atom to which they are attached to form a pyrrolidine ring,
or a pharmaceutically acceptable acid addition salt thereof.

7. The compound according to claim 3, which is a compound of formula (I-4):

where R ¹¹ represents a chlorine atom or a bromine atom, R ⁴² represents a methyl group, an ethyl group, or an isopropyl group, Z ² represents —CO— or —CS—, Q ^{12 ′} represents a hydrogen atom, a methyl group, or ethyl a group, Q ^{22 ′} represents a methyl group, an ethyl group, or a phenyl group, or Q ^{12 ′} and Q ^{22 ′} can combine together with the nitrogen atom to which they are attached to form a pyrrolidine ring, or a pharmaceutically acceptable acid addition salt thereof .

8. The compound according to claim 1 or 6, which is selected from the following substances:
4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide;
4-amino-5-chloro-N- [1- (1-diethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide;
4-amino-5-chloro-N- [1- (1-dimethylthiocarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide;
4-amino-5-chloro-N- [1- [1- (1-pyrrolidinecarbonyl) -4-piperidinylmethyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide; and
4-amino-5-chloro-N- [1- (1-phenylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2,3-dihydrobenzo [b] furan-7-carboxamide,
or a pharmaceutically acceptable acid addition salt thereof.

9. The compound according to claim 1, which is selected from the following substances:
4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxybenzamide;
4-amino-5-chloro-N- [1- (1- (N-ethyl-N-methylcarbamoyl) -4-piperidinylmethyl] -4-piperidinyl] -2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N- [1- [1- (N-methyl-N-phenylcarbamoyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide;
4-amino-5-chloro-N- [1- (1-dimethylthiocarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxybenzamide;
4-amino-5-chloro-2-methoxy-N- [1- [1- (1-pyrrolidinecarbonyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide;
4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-ethoxybenzamide;
4-amino-5-bromo-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-methoxybenzamide;
4-amino-5-chlorop-N- [1- (1-diethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-ethoxybenzamide;
4-amino-5-chloro-N- [1- (1-dimethylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] -2-isopropoxybenzamide;
4-amino-5-bromo-2-methoxy-N- [1- [1- (1-pyrrolidinecarbonyl) -4-piperidinylmethyl] -4-piperidinyl] benzamide;
4-amino-5-chloro-2-methoxy-N- [1- (1-phenylcarbamoyl-4-piperidinylmethyl) -4-piperidinyl] benzamide, and
4-amino-5-chloro-2-methoxy-N- [1- [1- (2-butanon-3-yl) -4-piperidinylmethyl] -4-piperidinyl] benzamide,
or a pharmaceutically acceptable acid addition salt thereof.

10. The compound according to any one of paragraphs. 1-9, for the treatment of patients suffering from diseases caused by a lack of stimulation of serotonin receptors 4.

11. The compound according to any one of paragraphs. 1-9 for the treatment of patients suffering from disorders of gastrointestinal motility or gastrointestinal dysfunction.

12. A pharmaceutical composition comprising, as an active ingredient, a compound as defined in any one of claims. 1-9, or a pharmaceutically acceptable acid addition salt thereof.

13. The method of obtaining the compounds of formula (I):

where Ar represents a group of the following formula (Ar-1) or (Ar-2):

in which R ¹ represents a halogen atom, R ² represents a hydrogen atom or a lower alkyl group, R ³ represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group,
R ⁴ represents a hydrogen atom or a lower alkyl group, R ⁵ and R ⁶ are the same or different and each of them is a hydrogen atom or a lower alkyl group, and n has the value 1, 2 or 3,
A represents a group of the following formula (A-1), (A-2) or (A-3):
-ZN (Q ¹ ) (Q ² ) (A-1)
in which Z represents —CO—, —CS— or —SO ₂ , Q ¹ and Q ² are the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenyl-lower alkyl group, or Q ¹ and Q ² may combine together with the nitrogen atom to which they are attached to form a pyrrolidine ring, a piperidine ring, geksagidroazepinovogo ring, morpholine ring, thiomorpholine ring, or a piperazine ring, neobyazate having no lower alkyl or benzyl substituent on the other nitrogen atom;
-CO-R ⁷ (A-2)
in which R ⁷ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl group substituted with a hydroxy, lower alkoxy or lower alkoxycarbonyl group, or a substituted or unsubstituted phenyl group;
- (CH ₂ ) p-CH (R ⁸ ) -COR ⁹ (A-3)
in which p has the value 0, 1, 2, 3, 4 or 5, R ⁸ represents a hydrogen atom or a lower alkyl group, and R ⁹ represents a lower alkyl group or a lower alkoxy group,
or a pharmaceutically acceptable acid addition salt thereof,
which includes the following steps (a), (b), (c), (d), (e), or (f):
(a) when the compound (I) is a compound of the formula (I), wherein A is a group of the formula (A-1),
the interaction of the compounds of formula (II):

where Ar has the meaning defined above, with the compound of formula (III):
XZN (Q ¹ ) (Q ² ) (III)
where X represents a halogen atom, and Z, Q ¹ and Q ² are as defined above;
(b) when compound (I) is a compound of formula (I), wherein A is a group of formula (A-1), Q ¹ is a hydrogen atom, and Z is —CO— or —CS—,
the interaction of the compounds of formula (II):

where Ar has the meaning defined above, with a compound of formula (IVa) or (IVb):
O = C = NQ ²³ (IVa)
S = O = NQ ²³ (IVb),
where Q ²³ represents the same substituents as defined above for Q ² , or a trimethylsilyl group;
(c) when compound (I) is a compound of formula (I), wherein A is a group of formula (A-1) and Z is —CO—,
the interaction of the compounds of formula (V):

where L ⁴ represents a leaving group, and Ar has the meaning defined above, with the compound of formula (VI):
HN (Q ¹ ) (Q ² )
where Q ¹ and Q ² are as defined above;
(d) the interaction of the compounds of formula (VII):
Ar-COOH,
where Ar has the meanings defined above, or its reactive derivative, with a compound of formula (VIII):

where A has the meanings defined above;
(e) when the compound (I) is a compound of the formula (I), wherein A is a group of the formula (A-2),
the interaction of the compounds of formula (II):

where Ar has the meanings defined above, with the compound of formula (A-2 '):
HO-CO-R ⁷²
where R ⁷² has the same meanings as R ⁷ or its reactive derivative, provided that when (1) R ⁷² represents a lower alkyl group substituted by a hydroxy group, the reactive derivative of the compound (A-2 ') should not be used, and when (2) R ⁷² represents a lower alkoxy group, then the acid chloride of compound (A-2 ′) is used; or
(f) when compound (I) is a compound of formula (I), where A is a group of formula (A-3), the interaction of the compounds of formula (II):

where Ar has the meanings defined above, with the compound of the formula (A-3 ') or (A-3 "):
M- (CH ₂ ) p-CH (R ⁸ ) -COR ⁹ (A-3 ')
O = CH- (CH ₂ ) p'-CH (R ⁸ ) -COR ⁹ (A-3 ")
where M represents a reactive residue of the alcohol portion of the ester, p 'is 1, 2, 3 or 4, and R ⁸ , R ⁹ and p are as defined above,
and, if necessary, with subsequent conversion of the product to its pharmaceutically acceptable acid addition salt.

14. An agonist of serotonin receptor 4, containing as an active ingredient a compound as defined in any one of claims. 1-9, or a pharmaceutically acceptable acid addition salt thereof.

15. A method of treating diseases caused by a lack of stimulation of serotonin receptors 4 in patients, comprising administering an effective amount of a compound as defined in any one of claims. 1-9, or a pharmaceutically acceptable acid addition salt thereof, to a patient suffering from said diseases.

16. The method according to p. 15 for the treatment of disorders of gastrointestinal motility or gastrointestinal dysfunction.

17. A gastrointestinal prokinetic agent containing, as an active ingredient, a compound as defined in any one of claims. 1-9, or a pharmaceutically acceptable acid addition salt thereof.

18. The compound of formula (II-2):

where R 'represents a halogen atom, R ² represents a hydrogen atom or a lower alkyl group, R ³ represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group, R ³ and R ⁶ are the same or different and each represents a hydrogen atom or a lower alkyl group, and n is 1, 2 or 3, or an acid addition salt thereof.

19. The compound of formula (VIII):

where A represents a group of the following formula (A-1), (A-2) or (A-3):
-ZN (Q ¹ ) (Q ² ) (A-1)
in which Z represents —CO—, —CS— or —SO ₂ -, Q ¹ and Q ² are the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted phenyl group, or substituted or an unsubstituted phenyl lower alkyl group, or Q ¹ and Q ² can combine together with the nitrogen atom to which they are attached to form a pyrrolidine ring, piperidine ring, hexahydroazepine ring, morpholine ring, thiomorpholine ring, or piperazine ring, optional flaxly containing a lower alkyl or benzyl substituent on another nitrogen atom;
-CO-R ⁷ (A-2)
in which R ⁷ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkyl group substituted with a hydroxy, lower alkoxy or lower alkoxycarbonyl group, or a substituted or unsubstituted phenyl group;
(CH ₂ ) p-CH (R ⁸ ) -COR ⁹ (A-3)
in which p is 0, 1, 2, 3, 4, or 5, R ⁸ represents a hydrogen atom or lower alkyl group, and R ⁴ represents a lower alkyl group or lower alkoxy group, or a pharmaceutically acceptable acid addition salt thereof.