Dihydropyrazoles

Patent metadata

Field	Value
Publication number	US-9517227-B2
Application number	US-201414300945-A
Country	US
Kind code	B2
Filing date	Jun 10, 2014
Priority date	Jul 1, 2011
Publication date	Dec 13, 2016
Grant date	Dec 13, 2016

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 compound of formula (I)

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;
and/or a physiologically acceptable salt thereof.

2. The compound according to claim 1 , wherein
R, L denote Ar 1 .

3. The compound according to claim 1 , wherein
X 2 is O,
X 1 is a single bond, and
X 3 and X 4 denote a single bond.

4. The compound according to claim 1 , wherein
Ar 1 denotes an aromatic, monocyclic carbocycle having 5-8 C atoms, which is mono-, di- or trisubstituted by at least one substituent selected from the group of R 1 and R 2 .

5. The compound according to claim 1 , wherein
Het 1 denotes an unsaturated or aromatic monocyclic heterocycle having 3-6 C atoms and 1-3 N, O and/or S atoms, which is substituted by at least one substituent selected from the group of Hal, A and OA.

6. The compound according to claim 1 , wherein
X 3 is O or NY,
X 4 is a single bond, and
X 1 and X 2 denote a single bond.

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

and/or a physiologically acceptable salt thereof.

8. A pharmaceutical composition comprising at least one compound according to claim 1 and/or a physiologically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8 , comprising pharmaceutically tolerable adjuvants for oral administration.

10. The pharmaceutical composition according to claim 8 , comprising at least a second active pharmaceutical ingredient.

11. A method for modulating an FSH receptor comprising the steps of:
(a) providing (i) a system expressing said FSH receptor and (ii) at least one compound of formula (I)

wherein
R, L denote independently from one another Ar 1 , Het 1 , A or OY;
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 O, NY or 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, n, p denote independently from one another 0, 1, 2, 3 or 4;
and/or a physiologically acceptable salt thereof, and
(b) contacting said system expressing said FSH receptor with said compound of formula (I) under conditions such that said FSH receptor is modulated.

12. The method according to claim 11 , wherein an effective amount of at least one compound and/or a physiologically acceptable salt thereof is administered to a mammal in need of treating fertility disorders.

13. Process for manufacturing a compound of formula (I) comprising the steps of:
(a) reacting a compound of formula (II)

wherein
L, R 3

Assignees

• Merck Patent Gmbh

Inventors

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

Classifications

• A61P5/06

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

• 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

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/415 Primary

  1,2-Diazoles · CPC title