US 8,299,096 B2Granted

Method for treating pulmonary diseases using rho kinase inhibitor compounds

AssigneeInspire Pharmaceuticals, Inc.

InventorsTomas Navratil, Ward M. Peterson, John W. Lampe, Emilee H. Fulcher, Scott D. Sorensen

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Abstract

This invention is directed to methods of preventing or treating diseases or conditions of the lungs associated with excessive cell proliferation, remodeling, inflammation, vasoconstriction, bronchoconstriction, airway hyperreactivity and edema. Particularly, this invention is directed to methods of treating pulmonary diseases such as asthma; chronic obstructive pulmonary disease; respiratory tract illness caused by respiratory syncytial virus; pulmonary arterial hypertension; acute respiratory distress syndrome and ventilator induced lung injury; cystic fibrosis; bronchiectasis; alpha-1-antitrypsin deficiency; rhinitis; rhinosinusitis; primary ciliary dyskinesia; pneumonia; bronchiolitis caused by agents other than respiratory syncytial virus; and interstitial lung disease including lymphangioleiomyomatosis; idiopathic pulmonary fibrosis; obliterative bronchiolitis or bronchiolitis obliterans organizing pneumonia due to lung transplantation or HSCT; nonspecific interstitial pneumonia; cryptogenic organizing pneumonia; acute interstitial pneumonia; respiratory bronchiolitis-associated interstitial lung disease; or pulmonary sarcoidosis. The method comprises administering to a subject an effective amount of a rho kinase inhibitor compound to treat the disease.

Claims17

Dependent claims

A method of treating a pulmonary disease selected from the group consisting of asthma;

chronic obstructive pulmonary disease;
respiratory tract illness caused by respiratory syncytial virus;
pulmonary arterial hypertension;
acute respiratory distress syndrome and ventilator induced lung injury;
cystic fibrosis;
bronchiectasis;
alpha-1-antitrypsin deficiency;
rhinitis;
rhinosinusitis;
primary ciliary dyskinesia;
pneumonia;
bronchiolitis caused by agents other than respiratory syncytial virus;
and interstitial lung disease;
the method comprises the steps of first identifying a subject suffering from the pulmonary disease, then administering to the subject an effective amount of a compound of Formula II to treat said disease;
wherein:
Q is (CR4R5)n3;
n1 is 1, or 2;
n2 is 1;
n3 is 1, 2, or 3;
R2 is R2-1, optionally substituted:
Ar is a monocyclic or bicyclic aryl or heteroaryl ring;
X is from 1 to 3 substituents on Ar, and each is independently selected from the group consisting of OR8, NR8R9, SR8, SOR8, SO2R8, SO2NR8R9, NR8SO2R9, CONR8R9, NR8C(═O)R9, NR8C(═O)OR9, OC(═O)NR8R9, and NR8C(═O)NR9R10,
R3-R5 are independently H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylalkynyl, optionally substituted;
R8-R10 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, or heterocycle;
optionally substituted by one or more halogen or heteroatom-containing substituents selected from the group consisting of OR11, NR11R12, NO2, SR11, SOR11, SO2R11, SO2NR11R12, NR11SO2R12, OCF3, CONR11R12, NR11C(═O)R12, NR11C(═O)OR12, OC(═O)NR11R12, and NR11C(═O)NR12R13;
R11-R13 are independently H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, (heterocycle)alkyl, (heterocycle)alkenyl, (heterocycle)alkynyl, or heterocycle;
with the first proviso that if X is acyclic and is connected to Ar by a carbon atom, then X contains at least one nitrogen or sulfur atom, and
with the second proviso that if X is acyclic and is connected to Ar by an oxygen or nitrogen atom, then X contains at least one additional oxygen, nitrogen or sulfur atom.

25 more elements

A method of treating a pulmonary disease selected from the group consisting of asthma;

chronic obstructive pulmonary disease;
respiratory tract illness caused by respiratory syncytial virus;
pulmonary arterial hypertension;
acute respiratory distress syndrome and ventilator induced lung injury;
cystic fibrosis;
bronchiectasis;
alpha-1-antitrypsin deficiency;
rhinitis;
rhinosinusitis;
primary ciliary dyskinesia;
pneumonia;
bronchiolitis caused by agents other than respiratory syncytial virus;
and interstitial lung disease;
the method comprises the steps of first identifying a subject suffering from the pulmonary disease, then administering to the subject an effective amount of a compound, wherein said compound is Compound 1.074, which is (R)—N-(1-(4-(methylthio)benzyl)piperidin-3-yl)-1H-indazol-5-amine;
Compound 1.075, which is (S)—N-(1-(4-(methylthio)benzyl)piperidin-3-yl)-1H-indazol-5-amine;
Compound 1.091, which is (S)—N-(3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)phenyl)methanesulfonamide;
Compound 1.093, which is (R)—N-(3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)phenyl)methanesulfonamide;
Compound 1.123, which is (R)—N-(3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)phenyl)ethanesulfonamide;
Compound 1.124, which is (S)—N-(3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)phenyl)ethanesulfonamide;
Compound 1.126, which is (R)-2-(3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)phenoxy)-N-(pyridin-3-yl)acetamide;
Compound 1.152, which is (S)-2-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenoxy)ethanol;
Compound 1.157, which is (S)—N-(1-(3-(methylsulfonylmethyl)benzyl)piperidin-3-yl)-1H-indazol-5-amine;
Compound 1.158, which is (S)—N-(1-(3-(methylthio)benzyl)piperidin-3-yl)-1H-indazol-5-amine;
Compound 1.161, which is (R)-2-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenoxy)ethanol;
Compound 1.195, which is (S)-2-(3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)phenoxy)acetamide;
Compound 1.200, which is (S)-ethyl 2-(3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)phenoxy)acetate;
Compound 1.212, which is (R)—N-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-chlorophenyl)methanesulfonamide;
Compound 1.213, which is (S)—N-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-chlorophenyl)methanesulfonamide;
Compound 1.215, which is (S)-3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)benzenesulfonamide;
Compound 1.219, which is (S)-3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)benzamide;
Compound 1.233, which is (S)—N-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenyl)methanesulfonamide;
Compound 1.236, which is (S)—N-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenyl)butane-1-sulfonamide;
Compound 1.237, which is (S)—N-(2-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-5-methylphenyl)-N′,N′ dimethylaminosulfamide;
Compound 1.238, which is (S)—N-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenyl)propane-1-sulfonamide;
Compound 1.239, which is (S)—N-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenyl)-4-methylbenzenesulfonamide;
Compound 1.249, which is (R)-3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)benzenesulfonamide;
Compound 1.253, which is (S)—N-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenyl)ethanesulfonamide;
Compound 1.258, which is (R)—N-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenyl)methanesulfonamide;
Compound 1.259, which is (R)—N-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenyl)ethanesulfonamide;
Compound 1.260, which is (R)—N-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenyl)-4-methylbenzenesulfonamide;
Compound 1.261, which is (S)—N-(3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)phenyl)-N′,N′ dimethylaminosulfamide;
Compound 1.262, which is (R)—N-(2-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-5-methylphenyl)-′N,N′ dimethylaminosulfamide;
Compound 1.270, which is (S)—N-(3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)phenyl)piperidine-1-sulfonamide;
Compound 1.275, which is (S)—N-(3-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenyl)-N′,N′ dimethylaminosulfamide;
and Compound 1.281, which is (R)-2-(5-((3-(1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenyl1H-indazol-5-ylamino)piperidin-1-yl)methyl)-2-methylphenoxy)acetamide.

42 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/492,494Filed 26 Jun 2009 · us provisional application
Priority: 26 Jun 2008
Published: US 2009/0325958 A131 Dec 2009
Granted: 30 Oct 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

A61K 31/4545
Containing further heterocyclic ring systems: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
A61K 31/4025
Having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil: not condensed and…
A61K 31/416
1,2-Diazoles: condensed with carbocyclic ring systems, e.g. indazole
A61K 31/437
Ortho- or peri-condensed with heterocyclic ring systems: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring…

Family

Application61/076,055Us provisional application · filed 26 Jun 2008
Application61/169,239Us provisional application · filed 14 Apr 2009
Application61/169,639Us provisional application · filed 15 Apr 2009
Application61/169,635Us provisional application · filed 15 Apr 2009
US 2009/0325958 A1Pre-grant publication · published 31 Dec 2009
US 8,299,096 B2This patent

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