4-amino-imidazoquinoline compounds

Patent metadata

Field	Value
Publication number	US-9447097-B2
Application number	US-201615093481-A
Country	US
Kind code	B2
Filing date	Apr 7, 2016
Priority date	Apr 22, 2014
Publication date	Sep 20, 2016
Grant date	Sep 20, 2016

Abstract

This invention relates to novel 4-amino-imidazoquinoline compounds of the formula

wherein R 1 to R 4 are as defined in the description and in the claims, as well as pharmaceutically acceptable salts thereof. These compounds are TLR agonists and may therefore be useful as medicaments for the treatment of diseases such as cancer or infectious diseases.

First claim

What is claimed is:

1. A method of treating cancer, an autoimmune disease or infectious disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I

wherein
R 1 is C 1-7 -alkyl or C 1-7 -alkoxy-C 1-7 -alkyl;
R 2 is selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxy-C 1-7 -alkyl, alkoxy-C 1-7 -alkyl, carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 2-7 -alkenyl, aminocarbonyl-C 1-7 -alkyl, aminocarbonyl-C 2-7 -alkenyl, C 1-7 -alkylamino-carbonyl-C 1-7 -alkyl, C 1-7 -alkylamino-carbonyl-C 2-7 -alkenyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl-C 2-7 -alkenyl, C 1-7 -alkyl-sulfonyl-C 1-7 -alkyl, sulfamoyl-C 1-7 -alkyl, C 1-7 -alkyl-sulfamoyl-C 1-7 -alkyl,
phenyl, said phenyl being unsubstituted or substituted with one, two or three groups selected from the group consisting of C 1-7 -alkyl, C 1-7 -cycloalkyl, halogen, halogen-C 1-7 -alkyl, halogen-C 1-7 -alkoxy, hydroxy, hydroxy-C 1-7 -alkyl, C 1-7 -alkoxy, cyano, carboxyl, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkylsulfonyl, hydroxy-C 1-7 -alkylsulfonyl, C 1-7 -alkoxy-C 1-7 -alkylsulfonyl, carboxyl-C 1-7 -alkylsulfonyl, C 1-7 -alkoxy-carbonyl-C 1-7 -alkylsulfonyl, amino, C 1-7 -alkylamino, di-C 1-7 -alkylamino and nitro, and
phenoxy, said phenoxy group being unsubstituted or substituted with one, two or three groups selected from the group consisting of C 1-7 -alkyl, C 1-7 -cycloalkyl, halogen, halogen-C 1-7 -alkyl, halogen-C 1-7 -alkoxy, hydroxy, hydroxy-C 1-7 -alkyl, C 1-7 -alkoxy, cyano, carboxyl, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkyl-sulfonyl, hydroxy-C 1-7 -alkylsulfonyl, C 1-7 -alkoxy-C 1-7 -alkylsulfonyl, carboxyl-C 1,7 -alkylsulfonyl, C 1-7 -alkoxy-carbonyl-C 1-7 -alkylsulfonyl, amino, C 1-7 -alkylamino, di-C 1-7 -alkylamino and nitro;

R 3 is hydrogen or halogen;
R 4 is selected from the group consisting of
—O—(CH 2 ) m -NHR 5 , and
—O—(CO)—(CH 2 ) n -NHR 6 ,
wherein
m is selected from 1, 2 or 3,
n is selected from 1 or 2,
R 5 is selected from the group consisting of hydrogen, hydroxy-C 1-7 -alkyl, amino-C 1-7 -alkyl, C 1-7 -alkylcarbonyl, phenylcarbonyl, heteroarylcarbonyl, carboxyl, carboxyl-C 1-7 -alkyl and C 1-7 - alkoxycarbonyl-amino-C 1-7 -alkyl-carbonyl, and
R 6 is selected from the group consisting of hydrogen, hydroxy-C 1-7 -alkyl, amino-C 1-7 -alkyl, C 1-7 -alkylcarbonyl, phenylcarbonyl, heteroarylcarbonyl, carboxyl, carboxyl-C 1-7 -alkyl and C 1-7 - alkoxycarbonyl-amino-C 1-7 -alkyl-carbonyl,

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein the compound of formula I is selected from the group consisting of
1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine,
1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl 2-aminoacetate,
N-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethyl)nicotinamide,
N-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethyl)acetamide,
3-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylamino)propan-1-ol,
tert-butyl 6-(2-(1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylamino)-6-oxohexylcarbamate,
ethyl (E)-3-[4-amino-1-[2-(2-aminoethoxy)-2-methylpropyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate,
ethyl 3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate,
ethyl 3-(4-amino-1-(2-(2-aminoacetoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate,
1-(2-(2-aminoethoxy)-2-methylpropyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine, and
1-(2-(2-aminoethoxy)-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine, or a pharmaceutically acceptable salt thereof.

3. The method of claim 1 wherein the compound of formula I is 1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine, or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 wherein the compound of formula I is 1-(4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl 2-aminoacetate,
or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 wherein the compound of formula I is ethyl 3-(4-amino-1-(2-(2-aminoethoxy)-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-7-yl)propanoate, or a pharmaceutically acceptable salt thereof.

6. The method of any one of claims 1 to 5 wherein the cancer is bladder cancer, head and neck cancer, prostate cancer, colorectal cancer, kidney cancer, breast cancer, lung cancer, ovarian cancer, cervical cancer, pancreatic cancer, bowel cancer, colon cancer, stomach cancer, thyroid cancer, melanoma, brain cancer, leukemia, and Hodgkin's or non-Hodgkin's lymphoma.

7. The method of any one of claims 1 to 5 wherein the autoimmune diseases is rheumatoid arthritis, Sjogren's syndrome, scleroderma, SLE, lupus nephritis, polymyositis/dermatomyositis, cryoglobulinemia, anti-phospholipid antibody syndrome, psoriatic arthritis, inflammatory bowel diseases, ulcerative colitis, Crohn's disease, autoimmune gastritis, pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, celiac disease, ANCA-negative vasculitis, ANCA-associated vasculitis, Churg-Strauss vasculitis, Wegener's granulomatosis, microscopic polyangiitis, multiple sclerosis, opsoclonus myoclonus syndrome, myasthenia gravis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, glomerulonephritis, Goodpasture's syndrome, Berger's disease, psoriasis, urticaria, hives, pemphigus vulgaris, bullous pemphigoid, and cutaneous lupus erythematosus, thrombocytopenic purpura, thrombotic thrombocytopenic purpura, post-transfusion purpura, autoimmune hemolytic anemia, atherosclerosis, uveitis, Behcet's disease, Raynaud's syndrome, insulin-dependent diabetes mellitus (IDDM), Addison's disease, Graves' disease, thyroiditis, food allergies, drug allergies, insect allergies, mastocytosis, eczema, or asthma.

8. The method any one of claims 1 to 5 wherein the infectious disease is human papilloma virus, genital warts, common warts, plantar warts, herpes simplex virus, molluscum contagiosum, hepatitis B virus (HBV), hepatitis C virus (HCV), Dengue virus, variola virus, human immunodeficiency virus (HIV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, enterovirus, adenovirus, coronavirus, influenza, mumps or parainfluenza.

9. The method of any one of claims 1 to 5 wherein the infectious disease is a bacterial, fungal or parasitic disease selected from mycobacterium tuberculosis, mycobacterium avium, mycobacterium leprae , chlamydia, candidiasis, aspergillosis, cryptococcal meningitis, Pneumocystis carnii, pneumonia, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection or leishmaniasis.

10. A process for the manufacture of a compound of formula I,

wherein
R 1 is C 1-7 -alkyl or C 1-7 -alkoxy-C 1-7 -alkyl;
R 2 is selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxy-C 1-7 -alkyl, alkoxy-C 1-7 -alkyl, carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 2-7 -alkenyl, aminocarbonyl-C 1-7 -alkyl, aminocarbonyl-C 2-7 -alkenyl, C 1-7 -alkylamino-carbonyl-C 1-7 -alkyl, C 1-7 -alkylamino-carbonyl-C 2-7 -alkenyl, C 1-7 -alkoxycarbonyl-C

Assignees

• Hoffmann La Roche

Inventors

• Hoves Sabine
• Kuhn Bernd
• Ricklin Fabienne
• Roever Stephan

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title