Substituted 6-fluoro-1H-pyrazolo[4,3-b]pyridines and use thereof

Patent metadata

Field	Value
Publication number	US-9309239-B2
Application number	US-201113882118-A
Country	US
Kind code	B2
Filing date	Nov 3, 2011
Priority date	Nov 4, 2010
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

The present application relates to novel substituted 6-fluoro-1H-pyrazolo[4,3-b]pyridines, to processes for preparation thereof, to the use thereof, alone or in combinations, for treatment and/or prophylaxis of diseases and to the use thereof for preparing Medicaments for the treatment and/or prophylaxis of diseases, especially for treatment and/or prophylaxis of cardiovascular disorders.

First claim

The invention claimed is:

1. A compound of formula (I)

in which
R 1 represents hydrogen or (C 1 -C 4 )-alkyl,
where (C 1 -C 4 )-alkyl may be substituted by one or two substituents independently of one another selected from the group consisting of fluorine and trifluoromethyl,

R 2 represents (C 1 -C 4 )-alkyl, (C 3 -C 7 )-cycloalkyl or a 4- to 7-membered heterocycle,
where (C 1 -C 4 )-alkyl may be substituted by one or two substituents independently selected from the group consisting of fluorine, trifluoromethyl and (C 3 -C 7 )-cycloalkyl,

R 3 is (C 1 -C 6 )-alkyl or benzyl,
where (C 1 -C 6 )-alkyl is substituted by one trifluoromethyl substituent,
where (C 1 -C 6 )-alkyl may be substituted by 1 to 3 fluorine substituents, and
where benzyl is substituted by 1 to 3 fluorine substituents,

or a salt thereof.

2. A compound of formula (I)

in which
R 1 represents hydrogen, methyl or ethyl,
where methyl may be substituted by a trifluoromethyl substituent,

R 2 represents methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl or oxetanyl,
where methyl and ethyl may be substituted by one or two substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl and cyclopropyl,

R 3 represents 3,3,3-trifluoroprop-1-yl, 3,3,4,4,4-pentafluorobut-1-yl or benzyl,
where benzyl is substituted by 1 or 2 fluorine substituents,

or a salt thereof.

3. The compound of claim 1 in which
R 1 represents hydrogen, methyl, ethyl or 2,2,2-trifluoroethyl,
R 2 represents methyl, ethyl or cyclopropylmethyl,
R 3 represents 2-fluorobenzyl,
or a salt thereof.

4. A pharmaceutical composition, comprising the compound of claim 1 , and an inert, non-toxic, pharmaceutically acceptable excipient.

5. The pharmaceutical composition of claim 4 , further comprising an active compound selected from the group consisting of an organic nitrate, an NO donor, a cGMP-PDE inhibitor, an antithrombotic agent, a hypotensive agent and a lipid metabolism modifier.

6. A method of treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and arteriosclerosis comprising administering to a human or animal in need thereof an effective amount of at least one compound of claim 1 .

7. A method of treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemias, vascular disorders, renal insufficiency, thromboembolic disorders, fibrotic disorders and arteriosclerosis comprising administering to a human or animal in need thereof an effective amount of a pharmaceutical composition of claim 4 .

8. A process for preparing a compound of formula (I) as defined in claim 1 comprising
[A] reacting a compound of formula (II)

in which R 3 has the meaning given in claim 1
in an inert solvent in the presence of a suitable base with a compound of formula (III)

to give a compound of formula (IV)

in which R 3 has the meaning given in claim 1
reducing the compound of fornnula (V) in an inert solvent with a reducing agent to give a compound of formula (V)

in which R 3 has the meaning given in claim 1
reacting the compound of formula (V) in the presence of a suitable base in the presence or absence of a solvent with a compound of formula (VI)

in which R 2 has the meaning given in claim 1
to give a compound of formula (I-A)

in which R 2 and R 3 are each as defined in claim 1 ,

or
[B] converting the compound of formula (II) in an inert solvent under acidic conditions with aminoacetonitrile into a compound of formula (VII)

in which R 3 has the meaning given in claim 1
reacting the compound of formula (VII) in an inert solvent in the presence of a suitable base with the compound of formula (VIII)

to give a compound of formula (IX)

in which R 3 has the meaning given in claim 1
and reducing the compound of formula (IX) in an inert solvent in the presence of a suitable reducing agent to give the compound of formula (V), and
reacting the resulting compound of formula (V) is according to process [A] to give the compound of formula (I-A),

or
[C] reacting a compound of formula (I-A) in an inert solvent with a compound of formula (X)
R 1 —X 1   (X)

in which R 1 is as defined in claim 1 and
X 1 is a suitable leaving group,
to give a compound of formula (I-B)

in which R 1 , R 2 and R 3 are each as defined in claim 1 ,
and optionally converting the resulting compound of formula (I-A) or (I-B) with a (i) solvent and/or (ii) acid or base into a salt thereof.

Assignees

• Follmann Markus
• Stasch Johannes-Peter
• Redlich Gorden
• Ackerstaff Jens
• Griebenow Nils
• Knorr Andreas
• Wunder Frank
• Li Volkhart Min-Jian
• Mittendorf Joachim
• Schlemmer Karl-Heinz
• Jautelat Rolf
• Bayer Ip Gmbh

Inventors

• Follmann Markus
• Stasch Johannes-Peter
• Redlich Gorden
• Ackerstaff Jens
• Griebenow Nils
• Knorr Andreas
• Wunder Frank
• Li Volkhart Min-Jian
• Mittendorf Joachim
• Schlemmer Karl-Heinz
• Jautelat Rolf

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/12

  Antihypertensives · CPC title