US 9,186,381 B2Granted

Medicament for liver regeneration and for treatment of liver failure

AssigneesHelmholtz-Zentrum fuer Infektionsforschung GmbH, Medizinische Hochschule Hannover

InventorsLars Zender, Torsten Wuestefeld

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Abstract

The present invention relates to the use of a compound which inhibits the activity of MKK4 as a medicament for the treatment of a patient suffering from an impaired liver function, to the use of a compound as a medicament for the treatment of liver failure, including acute/fulminant or chronic liver failure and/or for increasing the regeneration of liver tissue in a patient.

Claims3

Dependent claims

A method of treating liver failure in a subject in need thereof, comprising administering to the subject an effective amount of a compound, wherein the compound is an inhibitor of the activity of MKK4, wherein MKK4 is encoded by mRNA with SEQ ID NO:

1204, and wherein the compound is selected from the group consisting of:
Compound
Structural formula
SYN22174524 5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-7- oxo-N-phenyl- 1H-pyrazolo- [1,5-a]- pyrimidine-3- carboxamide
SYN22174787;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-3-(4- fluorophenyl)- 1H-pyrazolo- [1,5-a]- pyrimidin- 7-one
SYN22175977;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-3-(4- methylphenyl)- 1H-pyrazolo- [1,5-a]- pyrimidin- 7-one
SYN22176267;
3-(4-chloro- phenyl)-5- [2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-2- (methoxy- methyl)- 1H-pyrazolo- [1,5-a]- pyrimidin- 7-one
SYN22176367;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-2- (methoxy- methyl)-3- (4-methyl- phenyl)-1H- pyrazolo- [1,5-a]- pyrimidin- 7-one
SYN22176842;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-2- (3-methoxy- phenyl)-3- methyl- pyrazolo- [5,1-b]- pyrimidin-7-ol
SYN22136990;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-2- (2-methoxy- phenyl)-3- methyl- pyrazolo- [5,1-b]- pyrimidin-7-ol
SYN22177890;
3-(4-chloro- phenyl)-5-[2- (3,5-dimethyl- 1H-pyrazol-4- yl)ethyl]-2- methyl-1H- pyrazolo- [1,5-a]- pyrimidin- 7-one
IUPAC Name;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl)-7- oxo-N- phenyl-1H- pyrazolo- [1,5-a]- pyrimidin-3- carboxamide
IUPAC Name;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl)-3- (4-methyl- phenyl)-1H- pyrazolo- [1,5-a]- pyrimidin- 7-one
IUPAC Name;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl)-2- (methoxy- methyl)-3- phenyl-1H- pyrazolo- [1,5-a]- pyrimidin- 7-one
IUPAC Name;
3-(4-chloro- phenyl)-5- [2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl)-2- (methoxy- methyl)-1H- pyrazolo- [1,5-a]- pyrimidin- 7-one
IUPAC Name;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-2- (methoxy- methyl)- 3-(4-methyl- phenyl)-1H- pyrazolo- [1,5-a]- pyrimidin- 7-one
2-(3,4- dimethoxy- phenyl)-5- [2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]- pyrazolo- [5,1-b]- pyrimidin- 7-ol
5-[2-(3,5- dimethyl- 1H-pyrazol- 4-yl)ethyl]- 2-(3-methoxy- phenyl)-3- methyl- pyrazolo- [5,1-b]- pyrimidin- 7-ol
5-[2-(3,5- dimethyl- 1H-pyrazol- 4-yl)ethyl]- 2-(2-methoxy- phenyl)-3- methyl- pyrazolo- [5,1-b]- pyrimidin- 7-ol
5-[2-(3,5- dimethyl- 1H-pyrazol- 4-yl)ethyl]- 3-methyl- 2-(2-thionyl)- pyrazolo- [5,1-b]- pyrimidin- 7-ol
IUPAC Name;
5-[2-(3,5- dimethyl- 1H-pyrazol- 4-yl)ethyl]- 2-methyl- 3-phenyl- 1H-pyrazolo- [1,5-a]- pyrimidin- 7-one
5-[2-(3,5- dimethyl- 1H-pyrazol- 4-yl)ethyl]- 2-(4-fluoro- phenyl)- pyrazolo- [5,1-b]- pyrimidin- 7-one
and
IUPAC Name;
3-(4-chloro- phenyl)- 5-[2-(3,5- dimethyl- 1H-pyrazol- 4-yl)ethyl]- 1H-pyrazolo- [1,5-a]- pyrimidin- 7-one

35 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/009,738Filed 10 Apr 2012 · us provisional application
Priority: EP 111615887 Apr 2011
Published: US 2014/0141510 A122 May 2014
Granted: 17 Nov 2015
Term ends: Not estimatedThe source records don’t support an estimate.

Classification49 codes

A61K 35/407
Digestive system: liver; Hepatocytes
A61K 31/00
Medicinal preparations containing organic active ingredients
A61K 31/352
Having six-membered rings with one oxygen as the only ring hetero atom: condensed with carbocyclic rings, e.g. methantheline
A61K 31/353
Condensed with carbocyclic rings, e.g. methantheline: 3,4-Dihydrobenzopyrans, e.g. chroman, catechin

Family

Application61/473,015Us provisional application · filed 7 Apr 2011
US 2014/0141510 A1Pre-grant publication · published 22 May 2014
US 9,186,381 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

1204, and wherein the compound is selected from the group consisting of:
Compound
Structural formula
SYN22174524 5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-7- oxo-N-phenyl- 1H-pyrazolo- [1,5-a]- pyrimidine-3- carboxamide
SYN22174787;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-3-(4- fluorophenyl)- 1H-pyrazolo- [1,5-a]- pyrimidin- 7-one
SYN22175977;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-3-(4- methylphenyl)- 1H-pyrazolo- [1,5-a]- pyrimidin- 7-one
SYN22176267;
3-(4-chloro- phenyl)-5- [2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-2- (methoxy- methyl)- 1H-pyrazolo- [1,5-a]- pyrimidin- 7-one
SYN22176367;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-2- (methoxy- methyl)-3- (4-methyl- phenyl)-1H- pyrazolo- [1,5-a]- pyrimidin- 7-one
SYN22176842;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-2- (3-methoxy- phenyl)-3- methyl- pyrazolo- [5,1-b]- pyrimidin-7-ol
SYN22136990;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-2- (2-methoxy- phenyl)-3- methyl- pyrazolo- [5,1-b]- pyrimidin-7-ol
SYN22177890;
3-(4-chloro- phenyl)-5-[2- (3,5-dimethyl- 1H-pyrazol-4- yl)ethyl]-2- methyl-1H- pyrazolo- [1,5-a]- pyrimidin- 7-one
IUPAC Name;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl)-7- oxo-N- phenyl-1H- pyrazolo- [1,5-a]- pyrimidin-3- carboxamide
IUPAC Name;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl)-3- (4-methyl- phenyl)-1H- pyrazolo- [1,5-a]- pyrimidin- 7-one
IUPAC Name;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl)-2- (methoxy- methyl)-3- phenyl-1H- pyrazolo- [1,5-a]- pyrimidin- 7-one
IUPAC Name;
3-(4-chloro- phenyl)-5- [2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl)-2- (methoxy- methyl)-1H- pyrazolo- [1,5-a]- pyrimidin- 7-one
IUPAC Name;
5-[2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]-2- (methoxy- methyl)- 3-(4-methyl- phenyl)-1H- pyrazolo- [1,5-a]- pyrimidin- 7-one
2-(3,4- dimethoxy- phenyl)-5- [2-(3,5- dimethyl-1H- pyrazol-4- yl)ethyl]- pyrazolo- [5,1-b]- pyrimidin- 7-ol
5-[2-(3,5- dimethyl- 1H-pyrazol- 4-yl)ethyl]- 2-(3-methoxy- phenyl)-3- methyl- pyrazolo- [5,1-b]- pyrimidin- 7-ol
5-[2-(3,5- dimethyl- 1H-pyrazol- 4-yl)ethyl]- 2-(2-methoxy- phenyl)-3- methyl- pyrazolo- [5,1-b]- pyrimidin- 7-ol
5-[2-(3,5- dimethyl- 1H-pyrazol- 4-yl)ethyl]- 3-methyl- 2-(2-thionyl)- pyrazolo- [5,1-b]- pyrimidin- 7-ol
IUPAC Name;
5-[2-(3,5- dimethyl- 1H-pyrazol- 4-yl)ethyl]- 2-methyl- 3-phenyl- 1H-pyrazolo- [1,5-a]- pyrimidin- 7-one
5-[2-(3,5- dimethyl- 1H-pyrazol- 4-yl)ethyl]- 2-(4-fluoro- phenyl)- pyrazolo- [5,1-b]- pyrimidin- 7-one
and
IUPAC Name;
3-(4-chloro- phenyl)- 5-[2-(3,5- dimethyl- 1H-pyrazol- 4-yl)ethyl]- 1H-pyrazolo- [1,5-a]- pyrimidin- 7-one

35 more elements

Facts

Application

14/009,738Filed 10 Apr 2012 · us provisional application

Priority

EP 111615887 Apr 2011

Published

US 2014/0141510 A122 May 2014

Granted

17 Nov 2015

Term ends

Not estimatedThe source records don’t support an estimate.

Classification49 codes

A61K 35/407
Digestive system: liver; Hepatocytes
A61K 31/00
Medicinal preparations containing organic active ingredients
A61K 31/352
Having six-membered rings with one oxygen as the only ring hetero atom: condensed with carbocyclic rings, e.g. methantheline
A61K 31/353
Condensed with carbocyclic rings, e.g. methantheline: 3,4-Dihydrobenzopyrans, e.g. chroman, catechin