RU2003107572A

RU2003107572A - N-Methyl-D-Aspartate Receptor Ligand Drugs (NMDA)

Info

Publication number: RU2003107572A
Application number: RU2003107572/04A
Authority: RU
Inventors: Александер АЛАНЕН; Бернд БЮТТЕЛЛЬМАНН; Хольгер ФИШЕР; Мари-Поль ЭТС-НЕДАР; Йёрг ХУВИЛЕР; Георг Йэшке; Эмманюэль Пинар; Рене Виле
Original assignee: Ф.Хоффманн-Ля Рош Аг
Priority date: 2000-08-21
Filing date: 2001-08-20
Publication date: 2004-08-10

Claims

1. Compounds of the general formula

where R means

(a) —C (O) (CH ₂ ) _n C (O) OH,

b)

where R ¹ means —N (R ² ) (R ³ ) (and R ² / R ³ each means independently hydrogen or lower alkyl or a cyclic tertiary amine optionally substituted with lower alkyl),

(c) -P (O) (OH) ₂ or

(d) means —C (O) (CH ₂ ) _n NHC (O) (CH ₂ ) _n N (R ² ) (R ³ ); and

n = 1, 2, 3 or 4,

and their pharmaceutically acceptable acid addition salts.

2. The compound of formula I according to claim 1, where R is —C (O) (CH ₂ ) _n C (O) OH, and n = 2.

3. The compound according to claim 2, which means mono {(3S, 4S) -4- [2- (4-benzyl-3-hydroxypiperidin-1-yl) ethanesulfonyl] phenyl} succinic acid ester.

4. The compound of formula I according to claim 1, where R means

R ¹ is morpholinyl, 4-methylpiperazinyl or —N (R ² ) (R ³ ), and R ² / R ³ each is independently hydrogen or lower alkyl.

5. The compound according to claim 4, which means (3S, 4S) -4- [2- (4-benzyl-3-hydroxypiperidin-1-yl) ethanesulfonyl] phenyl ester of 4-morpholin-4-ylmethylbenzoic acid,

(3S, 4S) -4- [2- (4-benzyl-3-hydroxypiperidin-1-yl) ethanesulfonyl] 4- (4-methylpiperazin-1-ylmethyl) benzoic acid phenyl ester,

(3S, 4S) -4- [2- (4-benzyl-3-hydroxypiperidin-1-yl) ethanesulfonyl] 3- (4-methylpiperazin-1-ylmethyl) benzoic acid phenyl ester,

(3S, 4S) -4- [2- (4-benzyl-3-hydroxypiperidin-1-yl) ethanesulfonyl] 3-morpholin-4-ylmethylbenzoic acid phenyl ester,

(3S, 4S) -4- [2- (4-benzyl-3-hydroxypiperidin-1-yl) ethanesulfonyl] 4-aminomethylbenzoic acid phenyl ester,

(3S, 4S) -4- [2- (4-benzyl-3-hydroxypiperidin-1-yl) ethanesulfonyl] 3-methylaminomethylbenzoic acid phenyl ester or

(3S, 4S) -4- [2- (4-benzyl-3-hydroxypiperidin-1-yl) ethanesulfonyl] phenyl ester of 4-methylaminomethylbenzoic acid.

6. The compound of formula I according to claim 1, where R is —P (O) (OH) ₂ .

7. The compound according to claim 6, which means mono [(3S, 4S) -4- [2- (4-betyl-3-hydroxypiperidin-1-yl) ethanesulfonyl] phenyl) phosphoric acid ester.

8. The compound of formula I according to claim 1, where R is —C (O) (CH ₂ ) ₂ NHC (O) (CH ₂ ) ₂ NH ₂ .

9. The compound of claim 8, which means (3S, 4S) -4- [2- (4-benzyl-3-hydroxypiperidin-1-yl) ethanesulfonyl] phenyl ether 3- (3-aminopropionyl-amino) propionic acid.

10. A medicament containing one or more compounds of formula I, according to any one of claims 1 to 9, and pharmaceutically acceptable excipients.

11. The drug of claim 10 for the treatment of diseases associated with NMDA receptor subtype blockers.

12. The method of obtaining the compounds of formula I, as described in claim 1, which includes

(a) the interaction of the compounds of formula

from

with the formation of the compounds of formula

where m = 1-3;

n = 2-4, or

(b) reacting a compound of formula II with (BnO) ₂ P (H) O / CCl ₄ / BMAP / Hunig base and hydrogenating the resulting compound to a compound of formula

(c) reacting a compound of formula II with a compound of formula

with cleavage of the Boc group and the formation of a compound of the formula

(d) reacting a compound of formula II with a compound of formula

with the removal of the Boc group under the action of TFA (trifluoroacetic acid) to form a compound of the formula

(d) the interaction of the compounds of formula

with morpholine or 4-methylpiperazine to form a compound of the formula

or

and optionally converting the resulting compound into a pharmaceutically acceptable acid addition salt.

13. The compound of formula I according to any one of claims 1 to 9, whenever it is obtained in such a manner as claimed in claim 12, or in any equivalent way.

14. The use of the compounds of formula I according to any one of claims 1 to 9 for the treatment of diseases.

15. The use of the compounds of formula I according to any one of claims 1 to 9 for the manufacture of medicaments containing one or more compounds of the formula I for the treatment of diseases associated with selective NMDA receptor subtype blockers.

16. The use of the compounds of formula I according to any one of claims 1 to 9 as a prodrug of the parent compound of the formula