Dihydropyrazoles

Patent metadata

Field	Value
Publication number	US-9775830-B2
Application number	US-201615342550-A
Country	US
Kind code	B2
Filing date	Nov 3, 2016
Priority date	Jul 1, 2011
Publication date	Oct 3, 2017
Grant date	Oct 3, 2017

Abstract

Novel dihydropyrazole derivatives of formula (I)

wherein L, R, R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 , X 3 , X 4 , Y, m and n 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 method of treating fertility disorders, wherein an effective amount of at least one compound of formula I, or a physiologically acceptable salt thereof, is administered to a mammal in need of such treatment:

wherein
R, L each independently denote Ar 1 or Het 1 ;
R 1 denotes Hal, A, —(CY 2 ) p —OY, —(CY 2 ) p —NY 2 , COOY, CONY 2 , NHCOY, CN, SO 2 Y, -E-(CY 2 ) p —Ar 2 , -E-(CY 2 ) p -Het 1 or -E-(CY 2 ) p -Het 3 ;
R 2 denotes Hal, A, —(CY 2 ) p —OY, —(CY 2 ) p —NY 2 , COY, COOY, CONY 2 , —CONY—Cyc, —O-Cyc, NO 2 , CN, SY, SOY, SO 2 Y, SO 2 NY 2 , NHSO 2 Y, alkenyl or -E-(CY 2 ) p —Ar 2 ;
R 3 , R 4 , R 5 , R 6 denote independently from one another H, A or Ar 2 ;
R 7 denotes Y, OY or NY 2 ;
X 1 , X 2 , X 3 , X 4 denote independently from one another a single bond,
E denotes —C≡C—, SO 2 , —SO 2 —NY—, O, NY or a single bond;
Y denotes H or A;
A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms can be replaced by Hal;
Cyc denotes cycloalkyl having 3-7 C atoms,
in which 1-4 H atoms can be replaced independently from one another by Hal or A;

Ar 1 denotes a saturated, 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 R 1 , R 2 and —C≡C—C(A) 2 OH, and/or which can be fused to Cyc, Het 1 or Het 3 ;

Ar 2 denotes an aromatic, mono- or bicyclic carbocycle having 6-10 C atoms, which can be substituted by at least one substituent selected from the group of Hal, A and —(CY 2 ) p —OY;
Het 1 denotes an unsaturated or aromatic mono- or bicyclic heterocycle having 3-8 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, —(CY 2 ) p —OY, —(CY 2 ) p —NY 2 , —(CY 2 ) p —Ar 2 , —CO—Ar 2 , SO 2 —Ar 2 , —(CY 2 ) p -Het 2 , Het 3 and CN;

Het 2 denotes an aromatic monocyclic heterocycle having 5-7 C atoms and 1-3 N atoms,
which can be substituted by at least one substituent selected from the group of Hal, A and —(CY 2 ) p —OY;

Het 3 denotes a saturated monocyclic 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 Hal, A, —(CY 2 ) p —OY, —(CY 2 ) p —NY 2 , COOY, COY, —CONY 2 , ═O and CN;

Hal denotes F, Cl, Br or I;
m is 0;
n is 0; and
p is 0, 1, 2, 3 or 4;

or
wherein
R, L each independently denote Ar 1 or Het 1 ;
R 1 denotes Hal, A, —(CY 2 ) p —OY, —(CY 2 ) p —NY 2 , COOY, CONY 2 , NHCOY, CN, SO 2 Y, -E-(CY 2 ) p —Ar 2 , -E-(CY 2 ) p -Het 1 or -E-(CY 2 ) p -Het 3 ;
R 2 denotes Hal, A, —(CY 2 ) p —OY, —(CY 2 ) p —NY 2 , COY, COOY, CONY 2 , —CONY—Cyc, —O-Cyc, NO 2 , CN, SY, SOY, SO 2 Y, SO 2 NY 2 , NHSO 2 Y, alkenyl or -E-(CY 2 ) p —Ar 2 ;
R 3 , R 4 , R 5 , R 6 denote independently from one another H, A or Ar 2 ;
R 7 denotes Y, OY or NY 2 ;
X 1 denotes a single bond;
X 2 denotes O or a single bond;
X 3 denotes O, NY or a single bond;
X 4 denotes a single bond;
with the proviso that m denotes 0 if X 1 and X 2 denote a single bond;

E denotes —C≡C—, SO 2 , —SO 2 —NY—, O, NY or a single bond;
Y denotes H or A;
A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms can be replaced by Hal;
Cyc denotes cycloalkyl having 3-7 C atoms,
in which 1-4 H atoms can be replaced independently from one another by Hal or A;

Ar 1 denotes a saturated, 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 R 1 , R 2 and —C≡C—C(A) 2 OH, and/or which can be fused to Cyc, Het 1 or Het 3 ;

Ar 2 denotes an aromatic, mono- or bicyclic carbocycle having 6-10 C atoms, which can be substituted by at least one substituent selected from the group of Hal, A and —(CY 2 ) p —OY;
Het 1 denotes an unsaturated or aromatic mono- or bicyclic heterocycle having 3-8 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, —(CY 2 ) p —OY, —(CY 2 ) p —NY 2 , —(CY 2 ) p —Ar 2 , —CO—Ar 2 , SO 2 —Ar 2 , —(CY 2 ) p -Het 2 , Het 3 and CN;

Het 2 denotes an aromatic monocyclic heterocycle having 5-7 C atoms and 1-3 N atoms,
which can be substituted by at least one substituent selected from the group of Hal, A and —(CY 2 ) p —OY;

Het 3 denotes a saturated monocyclic 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 Hal, A, —(CY 2 ) p —OY, —(CY 2 ) p —NY 2 , COOY, COY, —CONY 2 , ═O and CN;

Hal denotes F, Cl, Br or I; and
m is 0 or 1;
n is 0 or 1;
p is 0, 1, 2, 3 or 4

wherein at least one of m or n is not 0.

2. The method of claim 1 , wherein the compound is selected from:

or a physiologically acceptable salt thereof.

3. A method for in-vitro fertilization comprising the steps of:
(a) treating a mammal according to the method of claim 1 ,
(b) collecting ova from said mammal,
(c) fertilizing said ova, and
(d) implanting said fertilized ova into a host mammal.

4. The method of claim 3 , wherein the compound is selected from:

or a physiologically acceptable salt thereof.

Assignees

• Merck Patent Gmbh

Inventors

• Yu Henry
• Richardson Thomas E
• Foglesong Robert James
• Deselm Lizbeth Celeste
• Goutopoulos Andreas

Classifications

• A61P43/00

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

• A61P5/06

  of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH · CPC title

• A61P15/08

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

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K9/0014

  Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00) · CPC title