Derivatives of 4-aminopiperidine and their use as a medicament
View Patent ↗A subject of the present application is new derivatives of 4-aminopiperidines of formula in which R 1 , R 2 and R 3 represent various radical, and their preparation processes by synthetic methods in parallel in liquid and solid phase. These products having a good affinity with certain sub-types of somatostatin receptors, they are particularly useful for treating the pathological states or diseases in which one (or more) somatostatin receptors are involved.
1. A compound of the formula
in racemic, enantiomeric form or all combinations of these forms wherein R 1 is —(CH 2 ) m -Z 12 wherein
Z 12 is aryl optionally substituted by at least one member independently selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl and alkoxy,
R 2 is —C(Y)NHX 1 ,
Y is oxygen or sulfur;
X 1 is —(CH 2 ) p -Z 22 wherein
Z 22 is aryl optionally substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF 3 , OCF 3 , nitro, cyano, azido, piperidinosulfonyl, —C(O)—O-alkyl, —C(O)-alkyl, and phenyl,
R 3 is alkyl,
m is 1;
p is 0;
and their non-toxic pharmaceutically acceptable acid addition salts.
2. A compound of claim 1 wherein R 1 is —(CH 2 ) m -Z 12 wherein
Z 12 is selected from the group consisting of naphthyl, bis-phenyl, substituted by oxy or phenyl, optionally substituted by at least one member selected from the group consisting of bromo, fluoro, chloro, alkyl, alkoxy, CF 3 and OCF 3 .
3. A compound of claim 1 wherein R 2 is —C(Y)NHX 1 ,
X 1 is —(CH 2 ) p -Z 22 ,
Z 22 is selected from the group consisting of bis-phenyl, or phenyl and naphthyl, all optionally substituted by at least one member selected from the group consisting of fluoro, chloro, bromo, iodo, alkyl, alkoxy, alkylthio, CF 3 , OCF 3 , nitro, cyano, azido, piperidinosulfonyl, —C(O)—O-alkyl, —C(O)-alkyl and phenyl.
4. A compound of claim 1 wherein R 3 is methyl.
5. A process for the preparation, in liquid phase, of a compound of claim 1 comprising reducing amination of a N-substituted piperidone of the formula
wherein R is methyl or Boc, in the presence of an amine of the formula R 1 NH 2 wherein R 1 has the meaning of claim 1 to obtain the compound of the formula
and reacting the latter with a compound of the formula X 1 NC(Y) wherein X 1 and Y have the meaning of claim 1 to obtain a compound of the formula
which compound is a compound of formula I wherein R 3 is Me.
6. The process, in solid phase, for a compound of claim 1 comprising reducing amination of a ketonic resin of the formula
in the presence of an amine of the formula R 1 NH 2 wherein R 1 has the meaning of claim 1 to obtain the compound of the formula
reacting the latter with a compound of the formula X 1 NC(O) wherein X 1 has the meaning of claim 1 to obtain a compound of the formula
reacting the latter with a compound of the formula R 3 X wherein R 3 is as defined in claim 1 and X is Br or I, followed by cleavage of the resin to obtain the corresponding compound of formula I.
7. A pharmaceutical composition containing, as active ingredient, a compound of claim 1 , in combination with a pharmaceutically acceptable support.
8. A composition for treating acromegalia, hypophyseal adenomas and endocrine gastroenteropancreatic tumors comprising an effective amount of a compound of claim 1 and a pharmaceutical carrier.
9. A method of treating acromegalia, hypophyseal adenomas and endocrine gastroenteropancreatic tumors in warm-blooded animals comprising administering to warm-blooded animals in need thereof an effective amount of a compound of claim 1 .