Benzamide derivatives as modulators of the follicle stimulating hormone

Patent metadata

Field	Value
Publication number	US-9409897-B2
Application number	US-201314364193-A
Country	US
Kind code	B2
Filing date	Jan 9, 2013
Priority date	Jan 10, 2012
Publication date	Aug 9, 2016
Grant date	Aug 9, 2016

Abstract

Novel benzamide derivatives of formula (I)

wherein W 1 , W 2 , R 1 to R 10 and X have the meaning according to the claims, are positive allosteric modulators of the FSH receptor, and can be employed, inter alia, for the treatment of fertility disorders.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
W 1 , W 2 each denote independently from one another N or CH,
with the proviso that at least one of W 1 or W 2 denotes N;

R 1 denotes —(CY 2 ) n -E-Het 3 , —(CY 2 ) n -Cyc-Het 3 , —(CY 2 ) n -Het 1 , —(CY 2 ) n —CONH-Het 1 , —(CY 2 ) n —NHCO-Het 1 , —(CY 2 ) n —Ar, —(CY 2 ) n -Cyc, —(CY 2 ) n —CONH-Cyc, —(CY 2 ) n —NHCO-Cyc, A, —(CYR 8 ) n —OY, —(CY 2 ) n —COOY, —(CY 2 ) n —SO 2 Y, —(CYR 8 ) n —CONY 2 , —(CYR 8 ) n —NY 2 , —(CYR 8 ) n —NYCOY, —(CY 2 ) n —NYCOOY, —(CY 2 ) n —NYCONY 2 or —(CY 2 ) n —NHCO—CH═CH 2 ; or
R 1 , R 2 together denote —(CY 2 ) p —NH—(CY 2 ) p —, —(CY 2 ) p —NHCO—(CY 2 ) p —, —(CY 2 ) p —CONH—(CY 2 ) p —, —(CY 2 ) p —N(COA)-(CY 2 ) p —, —(CY 2 ) p —N(COOA)-(CY 2 ) p —,

R 3 denotes —(CY 2 ) n -Het 1 , —(CY 2 ) n -Het 3 , —(CY 2 ) n —Ar, H, A or —(CY 2 ) n -Cyc;
R 4 , R 9 each denote independently from one another Y;
R 5 denotes E-Ar, H, A, COOY, SO 2 Y, Het 1 or Het 3 ;
R 2 , R 6 , R 7 each denote independently from one another H; or
R 6 , R 7 together denote —(CY 2 ) p —;
R 8 denotes Y or Ar;
R 10 denotes Hal, Y, OY, —O(CY 2 ) n —OY, NY 2 , Cyc, COOY, CONH 2 , NHCOY or CN;
with the proviso that both R 9 and R 10 are not H; or

R 2 , R 10 together denote —(CY 2 ) p — or —(CY) 2 —;
X denotes O, CO, —COO— or SO 2 ;
each E denote independently from one another —(CY 2 ) m —, O, CO, —COO— or SO 2 ;
each Y is independently H or A;
each A is independently unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms can be replaced independently from one another by Hal and/or ═O;
each Cyc is independently cycloalkyl having 3-7 C atoms,
in which 1-4 H atoms can be replaced independently from one another by Hal, OH or COOY;

each Ar is independently an unsaturated or aromatic mono- or bicyclic carbocycle having 3-10 C atoms,
which can be substituted by at least one substituent selected from the group of A, Hal, OY, COOY, CONH 2 , NHCOY, —(CY 2 ) n —NY 2 , NO 2 , SO 2 Y, CN and Het 2 , or which can be fused to Cyc;

each Het 1 is independently an unsaturated or aromatic mono- or bicyclic heterocycle having 1-10 C atoms and 1-4 N, O and/or S atoms,
which can be substituted by at least one substituent selected from the group of Hal, A, Cyc, OY, COOY, CONH 2 , NHCOY, NY 2 , SO 2 Y, SO 2 NY 2 , NHSO 2 Y, CN and Ar;

each Het 2 is independently an unsaturated monocyclic 5-membered heterocycle having
1-3 C atoms and 2-4 N and/or S atoms,
which can be substituted by A;

each Het 3 is independently a saturated mono- or bicyclic heterocycle having 3-7 C atoms and 1-4 N, O and/or S atoms,
which can be substituted by at least one substituent selected from the group of ═O, A, Hal, —(CY 2 ) n -Cyc, —(CY 2 ) n —OY, COY, COOY, CONY 2 , NHCOY, NY 2 , CN, SO 2 Y and —(CY 2 ) n —Ar;

each Hal is independently F, Cl, Br or I;
m, n denote independently from one another 0, 1, 2, 3, 4, 5 or 6; and
p denotes 1, 2 or 3;
and/or physiologically acceptable salts thereof.

2. The compound according to claim 1 , wherein
W 1 , W 2 each denote N;
R 6 , R 7 together denote —(CY 2 ) p —; and
p denotes 2.

3. The compound according to claim 1 , wherein
X denotes CO.

4. The compound according to claim 1 , wherein
R 9 denotes H; and
R 10 denotes Hal, A, OY, —O(CY 2 ) n —OY, NY 2 or Cyc.

5. The compound according to claim 1 , of sub-formula (I-B)

wherein
R 1 denotes Het 3 , Het 1 , Ar or Cyc;
R 2 denotes H;
R 5 denotes Ar or Het 1 ;
R 10 denotes Hal, Y, OY, —O(CY 2 ) n —OY, NY 2 or Cyc;
with the proviso that both R 9 , and R 10 are not H; or

R 2 , R 10 together denote —(CY 2 ) 2 — or —(CY) 2 —;
Y denotes H or A;
A denotes unbranched or branched alkyl having 1-6 C atoms, in which 1-4 H atoms can be replaced independently from one another by Hal and/or ═O;
Cyc denotes cycloalkyl having 3-6 C atoms, in which 1-3 H atoms can be replaced independently from one another by OH or COOY;
Ar denotes an aromatic monocyclic carbocycle having 6-8 C atoms, which can be mono- or disubstituted by at least one substituent selected from the group of A, Hal, OA, CONH 2 , —(CY 2 ) n —NY 2 , NO 2 and CN;
Het 1 denotes an unsaturated or aromatic monocyclic heterocycle having 1-6 C atoms and 1-4 N, O and/or S atoms, which can be mono- or disubstituted by at least one substituent selected from the group of Hal, A, Cyc, OA, CONH 2 , NHCOA, NHA, SO 2 NH 2 and CN, or an aromatic bicyclic heterocycle having 6-9 C atoms and 1-3 N and/or S atoms, which can be monosubstituted by A;
Het 3 denotes a saturated monocyclic heterocycle having 3-6 C atoms and 1-3 N, O and/or S atoms, which can be mono- or disubstituted by at least one substituent selected from the group of ═O, A, Cyc, OY, COA, COOA, CONHA and SO 2 A;
Hal denotes F, Cl, Br or I; and
n denotes 0, 1, 2 or 3;
and/or physiologically acceptable salts thereof.

6. The compound according to claim 1 , of sub-formula (I-C)

wherein
R 1 denotes Het 3 or Cyc;
R 2 denotes H;
R 10 denotes Hal, A, OA, —O(CY 2 ) n -OA, NA 2 or Cyc; or
R 2 , R 10 together denote —(CH 2 ) 2 — or —(CH) 2 —;
Y denotes H or A;
A denotes unbranched or branched alkyl having 1-6 C atoms, in which 1-4 H atoms can be replaced independently from one another by Hal;
Cyc denotes cycloalkyl having 3-6 C atoms, in which 1-3 H atoms can be replaced independently from one another by OH or COOH;
Ar denotes an aromatic monocyclic carbocycle having 6-8 C atoms, which can be mono- or disubstituted by A or Hal;
Het 1 denotes an unsaturated or aromatic monocyclic heterocycle having 1-6 C atoms and 1-3 N, O and/or S atoms, which can be mono- or disubstituted by at least one substituent selected from the group of Cyc, A or Hal;
Het 3 denotes a saturated monocyclic heterocycle having 3-6 C atoms and 1-3 N, O and/or S atoms, which can be mono- or disubstituted by at least one substituent selected from the group of ═O, A or Hal;
Hal denotes F, CI or Br; and
n denotes 0, 1, 2 or 3;
and/or physiologically acceptable salts thereof.

7. The compound according to claim 1 , selected from the group of:

and/or physiologically acceptable salts thereof.

8. A process for manufacturing a compound of formula (I) comprising the steps of:
(a) reacting a compound of formula (II)

 wherein W 1 , W 2 , R 1 , R 2 and R 4 to R 10 are as defined in claim 1 ,
with a compound of formula (III)

Assignees

• Merck Patent Gmbh

Inventors

• Yu Henry
• Richardson Thomas E
• Bharathi Pandi
• Heasley Brian H
• Jenks Matthew G
• Foglesong Robert J

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P15/08

  for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis · CPC title

• C07D413/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61B17/435

  for embryo {or ova} transplantation · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title