US 2005/0090533 A1 · Dual NK1/NK3 receptor antagonists

Abstract

The present invention provides a method for the treatment of schizophrenia which comprises administering a compound of formula wherein the substituents are as described herein or a pharmaceutically active acid-addition salt thereof. In particular, the invention provides methods for treating both positive and negative symptoms of schizophrenia through dual inhibition of NK1 and NK3 receptors. The invention also provides novel compounds with formula I and methods for preparing compounds of the invention.

A method of treating schizophrenia comprising administering to an individual an effective amount of a compound of formula I

wherein
R1 is aryl, unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, —(CH2)dOH, —C(O)H, CF3, CN, S-alkyl,
—S(O)b-alkyl, —C(O)NR′R″, —NR′R″, —NR′C(O)-alkyl, and —NR′S(O)2-alkyl, or
is heteroaryl, selected from the group consisting of pyridin-2-or 3-yl, imidazolyl and oxazolyl, each of which is unsubstituted or substituted by alkyl, halogen or alkoxy;
R2 and R3 are each independently hydrogen, halogen, alkyl, alkoxy, OCHF2, OCH2F, OCF3 or CF3;
R4 and R5 are each independently
hydrogen,
—(CR′R″)l—(CR′R″)l—(CR′R″)a—OH or —(CR′R″)l—(CR′R″)l—(CR′R″)a-alkyl, wherein R′ and R″ on each carbon atom may be the same or different from each other,
—Cb-alkyl,
—C(O)H,
—(CH2)dcycloalkyl, unsubstituted or substituted by hydroxy,
—(CH2)cNR′R″,
—(CH2)cNR′C(O)-alkyl,
—(CH2)cNR′S(O)2-alkyl,
—(CH2)dS(O)-alkyl,
—(CH2)dS-alkyl,
—(CH2)dS(O)2-alkyl, or
—(CH2)dS(O)2—NR′R″;
R′ is hydrogen, alkyl, —(CH2)oOH, —C(O)H, —C(O)-alkyl, —C(O)-cycloalkyl, —S(O)2-alkyl, —S(O)2-halogen-alkyl, —S(O)-alkyl, —S-alkyl or —S(O)2—N-di-alkyl,
R″ is hydrogen or alkyl;
or
R4 and R5 form together with the N-atom to which they are attached a ring
with —(CH2)e-, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF3, —(CR′R″)dOH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH2)e, or
by —(CH2)dNR′—C(O)-alkyl, —(CH2)d—C(O)-alkyl, —(CH2)d—C(O)-cycloalkyl, —(CH2)dOC(O)NR′R″, —(CH2)d—S(O)2-alkyl, —(CH2)d—S(O)-alkyl, —(CH2)d—S-alkyl, —(CH2)d—S(O)2—NR′R″, —(CH2)d-pyrrolidinyl, or —C(O)NR′R″, or with
—(CH2)c—NR′—(CH2)2—, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF3, —(CR′R″)dOH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH2)e, or
by —(CH2)dNR′—C(O)-alkyl, —(CH2)d—C(O)-alkyl, —(CH2)d—C(O)-cycloalkyl, —(CH2)dOC(O)NR′R″, —(CH2)d—S(O)2-alkyl, —(CH2)d—S(O)-alkyl, —(CH2)d—S-alkyl, —(CH2)d—S(O)2—NR′R″, —(CH2)d-pyrrolidinyl or —C(O)NR′R″, or with
—(CH2)c—O—(CH2)2—, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF3, —(CR′R″)dOH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH2)e, or
by —(CH2)dNR′—C(O)-alkyl, —(CH2)d—C(O)-alkyl, —(CH2)d—C(O)-cycloalkyl, —(CH2)dOC(O)NR′R″, —(CH2)d—S(O)2-alkyl, —(CH2)d—S(O)-alkyl, —(CH2)d—S-alkyl, —(CH2)d—S(O)2—NR′R″, —(CH2)d-pyrrolidinyl or —C(O)NR′R″, or with
—(CH2)c—S(O)f—(CH2)c—, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF3, —(CR′R″)dOH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH2)e, or
by —(CH2)dNR′—C(O)-alkyl, —(CH2)d—C(O)-alkyl, —(CH2)d—C(O)-cycloalkyl, —(CH2)dOC(O)NR′R″, —(CH2)d—S(O)2-alkyl, —(CH2)d—S(O)-alkyl, —(CH2)d—S-alkyl, —(CH2)d—S(O)2—NR′R″, —(CH2)d-pyrrolidinyl or —C(O)NR′R″, or with
—CH2CH═CH—CH2—, which is unsubstituted or substituted
by one or more substituents selected from the group consisting of alkyl, halogen, CF3, —(CR′R″)dOH, ═O, —CHO, and —NR′R″, wherein R′ and R″ are as described above or may form together with the N-atom to which they are attached a ring with —(CH2)e, or
by —(CH2)dNR′—C(O)-alkyl, —(CH2)d—C(O)-alkyl, —(CH2)d—C(O)-cycloalkyl, —(CH2)dOC(O)NR′R″, —(CH2)d—S(O)2-alkyl, —(CH2)d—S(O)-alkyl, —(CH2)d—S-alkyl, —(CH2)d—S(O)2—NR′R″, —(CH2)d-pyrrolidinyl or —C(O)NR′R″;
or with
—(CH2)2—S(O)2N(CH3)—CH2, or with
—S(O)—O—(CH2)2,3—;
or —NR4R5 is
a is 0 or 1;
b is 1 or 2;
c is 1, 2, or 3;
d is 0, 1, 2, or 3;
e is 3, 4, or 5;
and
f is 0, 1, or 2;
or a pharmaceutically active acid-addition salt thereof.

46 more elements

Dual NK1/NK3 receptor antagonists

Life of this patent

Dual NK1/NK3 receptor antagonists

Life of this patent

Abstract

Claims37