Use of chymase inhibitors for the treatment of endometriosis, post operative fibrosis and diseases which are characterized by fibrosis formation

Patent metadata

Field	Value
Publication number	US-11266646-B2
Application number	US-201716471928-A
Country	US
Kind code	B2
Filing date	Dec 13, 2017
Priority date	Dec 20, 2016
Publication date	Mar 8, 2022
Grant date	Mar 8, 2022

Abstract

The present application relates to the use of bicyclic-substituted uracil derivatives, alone or in combinations with other active ingredients for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of inflammatory and fibrotic disorders, for the treatment of endometriosis, of endometriosis-associated fibrosis, of adenomyosis and of pain associated with an endometriosis disorder and also of postoperative peritoneal fibrosis and adhesion formation.

First claim

The invention claimed is:

1. A method for the treatment and/or prophylaxis of endometriosis, endometriosis-associated fibrosis, adenomyosis, and pain associated with an endometriosis disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I)

in which
R 1 is hydrogen or (C 1 -C 4 )-alkyl,
R 2 is a group of the formula

 where
* is the point of attachment to the uracil nitrogen atom,
A is —CH 2 —, —CH 2 —CH 2 —, —O—CH 2 -## or oxygen,
in which
## is the point of attachment to the phenyl ring,

m is a number 0, 1 or 2,
R 4 is halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, difluoromethoxy, trifluoromethoxy or (C 1 -C 4 )-alkoxy,
R 5A is hydrogen or deuterium,
R 5B is hydrogen, deuterium or (C 1 -C 4 )-alkyl,
R 6 is hydrogen or fluorine,
R 7 is hydrogen or fluorine,
R 8 is halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl or nitro,
R 9 is hydrogen, halogen, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkyl, nitro or (C 1 -C 4 )-alkylthio,

R 3 is a group of the formula

where
# is the point of attachment to the uracil nitrogen atom,
the ring Q is 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
in which 5- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl may be substituted by 1 to 4 substituents independently selected from the group of halogen, difluoromethyl, trifluoromethyl, trideuteromethyl, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, oxo, hydroxyl, (C 1 -C 4 )-alkylcarbonyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl and (C 1 -C 4 )-alkyl sulfonyl,
in which (C 1 -C 6 )-alkyl and (C 3 -C 7 )-cycloalkyl may in turn be substituted by 1 to 3 substituents independently selected from the group of halogen, cyano, trifluoromethyl, (C 3 -C 7 )-cycloalkyl, hydroxyl, (C 1 -C 4 )-alkoxy and 4- to 7-membered heterocyclyl,
 and
in which two (C 1 -C 6 )-alkyl radicals bonded to a carbon atom of 5- to 7-membered heterocyclyl and 5- or 6-membered heteroaryl, together with the carbon atom to which they are bonded, may form a 3- to 6-membered carbocycle,

R 24 is halogen, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy,
n is a number 0, 1, 2 or 3,

or a salt, solvate or solvate of a salt thereof.

2. The method according to claim 1 , in which
R 1 is hydrogen, methyl or ethyl,
R 2 is a group of the formula

where
* is the point of attachment to the uracil nitrogen atom,
A is CH 2 —, —CH 2 —CH 2 —, —O—CH 2 -## or oxygen,
in which
## is the point of attachment to the phenyl ring,

R 4A is hydrogen, fluorine, chlorine, trifluoromethyl or methyl,
R 4B is hydrogen, fluorine, chlorine, trifluoromethyl or methyl,
with the proviso that at least one of the R 4A and R 4B radicals is not hydrogen,
R 5A is hydrogen,
R 5B is hydrogen,
R 6 is hydrogen,
R 7 is hydrogen,
R 8 is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,
R 9 is fluorine, chlorine, difluoromethyl, trifluoromethyl or methyl,

R 3 is a group of the formula

 where
# is the point of attachment to the uracil nitrogen atom,
E 1 is CR 11 or N,
in which
R 11 is hydrogen, (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl or aminocarbonyl,

E 2 is CR 12 or N,
in which
R 12 is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl,

E 3 is NR 14 or S,
in which
R 14 is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl,

G 1 is C═O or SO 2 ,
G 2 is CR 16A R 16B , NR 17 , O or S,
in which
R 16A is hydrogen, fluorine, (C 1 -C 4 )-alkyl or hydroxy,
R 16B is hydrogen, fluorine, chlorine, (C 1 -C 4 )-alkyl or trifluoromethyl,
or
R 16A and R 16B together with the carbon atom to which they are bonded form a 3- to 6-membered carbocycle,
R 17 is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 1 -C 4 )-alkoxycarbonyl,
in which (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents independently selected from the group of fluorine, trifluoromethyl, cyano, (C 3 -C 7 )-cycloalkyl, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl,

G 3 is CR 18A R 18B , NR 19 , O or S,
in which
R 18A is hydrogen, fluorine, (C 1 -C 4 )-alkyl or hydroxy,
R 18B is hydrogen, fluorine, chlorine, (C 1 -C 4 )-alkyl or trifluoromethyl,
or
R 18A and R 18B together with the carbon atom to which they are bonded form a 3- to 6-membered carbocycle,
R 19 is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 1 -C 4 )-alkoxycarbonyl,
in which (C 1 -C 6 )-alkyl may be substituted by 1 to 3 substituents independently selected from the group of fluorine, trifluoromethyl, cyano, (C 3 -C 7 )-cycloalkyl, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl,

G 4 is CH 2 , C═O or SO 2 ,
K 1 is CH 2 or O,
K 2 is CH 2 or O,
with the proviso that only one of the K 1 and K 2 groups is O,
D 1 , D 2 , D 3 and D 4 are each independently CR 23 or N,
in which
R 23 is hydrogen, halogen, (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl,

with the proviso that not more than 2 of the D 1 , D 2 , D 3 and D 4 groups are N,
R 24 is fluorine or methyl,
n is a number 0 or 1,
R 10 is (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl,
in which (C 1 -C 4 )-alkyl may be substituted by 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl,

R 3 is hydrogen, (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl,
R 15 is hydrogen, (C 1 -C 6 )-alkyl or (C 3 -C 7 )-cycloalkyl,
in which (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl,

R 20 is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 1 -C 4 )-alkylcarbonyl, in which (C 1 -C 6 )-alkyl may be substituted by 1 or 2 substituents independently selected from the group of fluorine, trifluoromethyl, cyclopropyl, cyclobutyl, hydroxyl, methoxy, ethoxy, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl,
R 21 is hydrogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl or (C 1 -C 4 )-alkylsulfonyl,
R 22A is hydrogen or C 1 -C 4 -alkyl,
R 22B is hydrogen or C 1 -C 4 -alkyl,
or
R 22A and R 22B together with the carbon atom to which they are bonded form a carbonyl group.

3. The method according to claim 1 , in which
R 1 is hydrogen,
R 2 is a group of the formula

where
* is the point of attachment to the uracil nitrogen atom,
A is —CH 2 —,
R 4A is chlorine or trifluoromethyl,
R 4B is hydrogen,

R 3 is a group of the formula

Assignees

• Bayer Pharma AG

Inventors

• Peters Michaele
• Koch Markus
• Zollner Thomas

Classifications

• A61P41/00

  Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution · CPC title

• A61P15/02

  for disorders of the vagina · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61P5/30

  Oestrogens · CPC title

• A61K31/536

  ortho- or peri-condensed with carbocyclic ring systems · CPC title