IP Library › Granted Patent US 12,201,633
Granted Patent B2
US 12,201,633 · App. 17/844,772 · Granted Jan 21, 2025

Compounds and methods for treatment of visceral pain

Inventors: Cheryl Geraldine Lassen (Zurich, CH); Marcelo Fabian Piccirillo (Cary, NC)
Assignee: Arena Pharmaceuticals, Inc.
A61K31/497A61P29/00
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Quick Facts
Patent No.
US 12,201,633
App. No.
17/844,772
Granted
Jan 21, 2025
Kind
B2
Abstract

The present invention relates to certain compounds of Formula Ia and pharmaceutical compositions thereof and their use in methods for the alleviation and/or treatment of visceral pain, for example abdominal pain; pelvic pain; male pelvic pain; pain from an internal organ; bladder pain; painful bladder syndrome; post-surgical abdominal pain (e.g., GI resection, hysterectomy, oophorectomy, C-section, and the like); or pain arising from or related to: pancreatitis (e.g., chronic pancreatitis), prostatitis (e.g., chronic prostatitis), inflammatory bowel disease (e.g., Crohn's disease), endometriosis, interstitial cystitis, prostatitis (e.g., chronic prostatitis), epididymitis (e.g., chronic epididymitis), or post-surgical abdominal lesions. In some embodiments, the visceral pain is consequent to inflammatory bowel disease, for example Crohn's disease.

Claims (125)

1. A method for treating or alleviating visceral pain selected from the group consisting of pelvic pain, painful bladder syndrome, or pain associated with: pancreatitis, chronic pancreatitis, endometriosis, interstitial cystitis, interstitial cystitis induced by chemotherapy, ulcerative interstitial cystitis, nonulcerative interstitial cystitis, autoimmune interstitial cystitis, prostatitis, chronic prostatitis, or post-surgical abdominal lesion in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts and N-oxides thereof:

wherein:

R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from: H and C 1 -C 6 alkyl;

X is NR 7 and Y is CC(O)N(R 8 )R 9 ; or

X is CC(O)N(R 8 )R 9 and Y is NR 7 ;

R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:

R 10 is selected from: C 1 -C 6 alkylene, heteroarylene, and heterocyclylene; or R 10 is absent;

R 11 is selected from: —C(O)NH— and C 1 -C 6 alkylene; or R 11 is absent;

R 12 is C 1 -C 6 alkylene; or R 12 is absent; and

R 13 is selected from: C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl, aryl, and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, amino, C 3 -C 7 cycloalkyl, cyano, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkyl, halogen, and hydroxyl;

R 8 is —R 14 —R 15 —R 16 —R 17 ; wherein:

R 14 is selected from: C 1 -C 6 alkylene, C 3 -C 7 cycloalkenylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said C 1 -C 6 alkylene and heterocyclylene are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, carboxy, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl and aryl are optionally substituted with one substituent selected from: C 1 -C 6 alkoxy, aryl, halogen, heteroaryl, and hydroxyl; or R 14 is absent;

R 15 is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with C 1 -C 6 alkyl; or R 15 is absent;

R 16 is C 1 -C 6 alkylene; or R 16 is absent; and

R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, amino, aryl, arylamino, aryloxy, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylamino, heteroaryl, heterobicyclyl, heterocyclyl, and ureyl are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, amino, aryl, carboxy, cyano, C 3 -C 7 cycloalkyl, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and

R 9 is selected from H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or

R 8 and R 9 together with the nitrogen atom to which they are both bonded form a group selected from: heterocyclyl and heterobicyclyl, each optionally substituted with one or more substituents selected from: Carbo-C 1 -C 6 -alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, carbo-C 1 -C 6 -alkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl; wherein said aryl, C 1 -C 6 alkyl, and heteroaryl are optionally substituted with one substituent selected from: C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, halogen, and hydroxyl.

2. The method according to claim 1 , wherein the compound of Formula Ia is selected from compounds of Formula Ic and pharmaceutically acceptable salts, and N-oxides thereof:

wherein:

R 1 and R 6 are each independently selected from: H, and C 1 -C 6 alkyl;

X is NR 7 and Y is CC(O)N(R 8 )R 9 ; or

X is CC(O)N(R 8 )R 9 and Y is NR 7 ;

R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:

R 10 is selected from: C 1 -C 6 alkylene, heteroarylene, and heterocyclylene; or R 10 is absent;

R 11 is selected from: —C(O)NH— and C 1 -C 6 alkylene; or R 11 is absent;

R 12 is C 1 -C 6 alkylene; or R 12 is absent; and

R 13 is selected from: C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl, aryl, and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, amino, C 3 -C 7 cycloalkyl, cyano, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkyl, halogen, and hydroxyl;

R 8 is —R 14 —R 15 —R 16 —R 17 ; wherein:

R 14 is selected from: C 1 -C 6 alkylene, C 3 -C 7 cycloalkenylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said C 1 -C 6 alkylene and heterocyclylene are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, carboxy, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl and aryl are optionally substituted with one substituent selected from: C 1 -C 6 alkoxy, aryl, halogen, heteroaryl, and hydroxyl; or R 14 is absent;

R 15 is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with C 1 -C 6 alkyl; or R 15 is absent;

R 16 is C 1 -C 6 alkylene; or R 16 is absent; and

R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, amino, aryl, arylamino, aryloxy, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylamino, heteroaryl, heterobicyclyl, heterocyclyl, and ureyl are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, amino, aryl, carboxy, cyano, C 3 -C 7 cycloalkyl, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and

R 9 is selected from H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or

R 8 and R 9 together with the nitrogen atom to which they are both bonded form a group selected from: heterocyclyl and heterobicyclyl, each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, carbo-C 1 -C 6 -alkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl; wherein said aryl, C 1 -C 6 alkyl, and heteroaryl are optionally substituted with one substituent selected from: C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, halogen, and hydroxyl.

3. The method according to claim 1 , wherein the compound of Formula Ia is selected from compounds of Formula Ie and pharmaceutically acceptable salts, and N-oxides thereof:

wherein:

R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:

R 10 is selected from: 1,1-dimethylethylene, 1,1-dimethylmethylene, ethylene, methylene, 1,4-piperidinylene, 2,5-pyrazinylene, and 2,4-pyridinylene; or R 10 is absent;

R 11 is selected from: —C(O)NH— and methylene; or R 11 is absent;

R 12 is methylene; or R 12 is absent; and

R 13 is selected from: C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl, aryl, and heteroaryl are each optionally substituted with one or two substituents selected from: fluoro, bromo, chloro, methoxy, cyano, methyl, tert-butyl, isopropyl, hydroxyl, ethyl, heptafluoropropyl, cyclobutyl, trifluoromethyl, cyclopropyl, dimethylamino, methoxy, ethoxy, methylamino, propyl, amino, and methanesulfonyl;

R 8 is —R 14 —R 15 —R 16 —R 17 ; wherein:

R 14 is selected from: C 1 -C 6 alkylene, C 3 -C 7 cycloalkenylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said C 1 -C 6 alkylene and heterocyclylene are each optionally substituted with one or more substituents selected from: methyl, tert-butyl, ethyl, tetrahydro-2H-pyranyl, isopropyl, benzyl, pyridinyl, hydroxymethyl, 4-fluoro-phenyl, tert-butoxycarbonyl, carboxy, methoxymethyl, hydroxyethyl, tetrahydro-furanyl, 3H-imidazolylmethyl, hydroxyl, pyrrolidinyl, and cyclopropyl; or R 14 is absent;

R 15 is selected from: —C(O)NH—, —C(O)—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with methyl; or R 15 is absent;

R 16 is selected from: ethylene and methylene; or R 16 is absent; and

R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, aryl, arylamino, aryloxy, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylamino, heteroaryl, heterobicyclyl, heterocyclyl, and ureyl are each optionally substituted with one or more substituents selected from: amino, 1-tert-butoxycarbonylamino, methyl, 1-tert-butoxycarbonyl, ethyl, hydroxyl, isopropyl, tert-butyl, fluoro, chloro, methoxy, methanesulfonyl, carboxy, trifluoromethoxy, difluoromethoxy, dimethylamino, methoxycarbonyl, ethoxycarbonyl, carboxy, carboxamide, trifluoromethyl, diethylamino, cyano, tert-butylamino, cyclopropyl, cyclobutyl, phenyl, bromo, and 1-methyl-pyrrolidinyl; and

R 9 is selected from H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or

R 8 and R 9 together with the nitrogen atom to which they are both bonded form a group selected from: heterocyclyl and heterobicyclyl, each optionally substituted with one or more substituents selected from: carbo-C 1 -C 6 -alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, carbo-C 1 -C 6 -alkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl; wherein said aryl, C 1 -C 6 alkyl, and heteroaryl are optionally substituted with one substituent selected from: C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, halogen, and hydroxyl.

4. The method of claim 1 , wherein the compound of Formula Ia is selected from the following compounds and pharmaceutically acceptable salts, and N-oxides thereof:

(1aR,5aR)-2-(5-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

(1aR,5aR)-2-(2,4-Dichloro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-hydroxymethyl-cyclopropyl)-amide;

(1aR,5aR)-2-(5-Cyano-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

(1aR,5aR)-2-(5-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

1-(2,4-Difluoro-phenyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

(1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid tert-butylamide;

(1aR,5aR)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (cyano-dimethyl-methyl)-amide;

(1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;

(1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide;

Phosphoric acid mono-(2-{[(1aR,5aR)-2-(4-cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-2-methyl-propyl) ester;

(1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid [2,2-dimethyl-1-((S)-methylcarbamoyl)-propyl]-amide;

Phosphoric acid mono-{(S)-3,3-dimethyl-2-[((1aR,5aR)-2-pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl)-amino]-butyl} ester;

(1aR,5aR)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-2-hydroxy-1-tetrahydro-pyran-4-yl-ethyl)-amide;

(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2-methyl-propyl)-amide;

(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;

(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-hydroxymethyl-cyclobutyl)-amide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-pyridin-2-yl-cyclobutyl)-amide;

Phosphoric acid mono-((S)-3,3-dimethyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl) ester;

(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide;

(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-methylcarbamoyl-phenyl-methyl)-amide;

(S)-3,3-Dimethyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyric acid methyl ester;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-trifluoromethyl-cyclobutyl)-amide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((R)-2,2-dimethyl-1-pyridin-2-yl-propyl)-amide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-2,2-dimethyl-1-pyridin-2-yl-propyl)-amide;

(1aR,5aR)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide;

(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-methyl-cyclobutyl)-amide;

(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((R)-1,2-dimethyl-propyl)-amide;

(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid [(S)-2-hydroxy-1-(tetrahydro-pyran-4-yl)-ethyl]-amide;

(1aR,5aR)-Pentanedioic acid mono-((S)-3-methyl-2-{[(1aR,5aR)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl) ester;

(1aS,5aS)—(S)-2-Amino-3-methyl-butyric acid (S)-3,3-dimethyl-2-{[2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-butyl ester;

(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-fluoro-1-fluoromethyl-1-hydroxymethyl-ethyl)-amide;

(1aS,5aS)-2-(4-Cyano-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-3,3,3-trifluoro-1-hydroxymethyl-propyl)-amide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2-methyl-propyl)-amide;

(1aS,5aS)-2-(4-Chloro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-fluoro-1,1-dimethyl-ethyl)-amide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid N′-tert-butyl-hydrazide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-fluoro-1,1-dimethyl-ethyl)-amide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((R)-1,2-dimethyl-propyl)-amide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-2-hydroxy-1-phenyl-ethyl)-amide;

(1aR,5aR)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-fluoromethyl-2,2-dimethyl-propyl)-amide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((1S,2S)-2-hydroxy-indan-1-yl)-amide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((1S,2R)-2-hydroxy-indan-1-yl)-amide;

(1aS,5aS)-2-(4-Oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-fluoromethyl-cyclobutyl)-amide;

(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-trifluoromethyl-cyclobutyl)-amide;

(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2,2,2-trifluoro-1,1-dimethyl-ethyl)-amide;

(1aS,5aS)-2-Pyrazin-2-yl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1-trifluoromethyl-cyclopropyl)-amide; and

(1aR,5aR)-2-(4-Fluoro-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide.

5. The method of claim 1 , wherein the compound of Formula Ia is (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (Compound A), having the structure:

or a pharmaceutically acceptable salt or crystal form thereof.

6. The method according to claim 5 , wherein the patient is administered a dose from 10 mg to 500 mg of Compound A.

7. The method according to claim 5 , wherein the patient is administered a dose from 10 mg to 400 mg of Compound A.

8. The method according to claim 5 , wherein the patient is administered a dose of 25 mg, 50 mg, or 100 mg of Compound A.

9. The method according to claim 6 , wherein the dose is administered once, twice, or three times per day.

10. The method according to claim 5 , wherein Compound A is administered in a pharmaceutical composition comprising Compound A and a pharmaceutically acceptable carrier.

11. A method for activating a CB 2 receptor in a patient experiencing visceral pain selected from the group consisting of pelvic pain, painful bladder syndrome, or pain associated with: pancreatitis, chronic pancreatitis, endometriosis, interstitial cystitis, interstitial cystitis induced by chemotherapy, ulcerative interstitial cystitis, nonulcerative interstitial cystitis, autoimmune interstitial cystitis, prostatitis, chronic prostatitis, or post-surgical abdominal lesion, comprising administering to the patient a therapeutically effective amount of a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts and N-oxides thereof:

wherein:

R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are each independently selected from: H and C 1 -C 6 alkyl;

X is NR 7 and Y is CC(O)N(R 8 )R 9 ; or

X is CC(O)N(R 8 )R 9 and Y is NR 7 ;

R 7 is —R 10 —R 11 —R 12 —R 13 ; wherein:

R 10 is selected from: C 1 -C 6 alkylene, heteroarylene, and heterocyclylene; or R 10 is absent;

R 11 is selected from: —C(O)NH— and C 1 -C 6 alkylene; or R 11 is absent;

R 12 is C 1 -C 6 alkylene; or R 12 is absent; and

R 13 is selected from: C 1 -C 6 alkyl, aryl, C 3 -C 7 cycloalkyl, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl, aryl, and heteroaryl are each optionally substituted with one or two substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, amino, C 3 -C 7 cycloalkyl, cyano, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkyl, halogen, and hydroxyl;

R 8 is —R 14 —R 15 —R 16 —R 17 ; wherein:

R 14 is selected from: C 1 -C 6 alkylene, C 3 -C 7 cycloalkenylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said C 1 -C 6 alkylene and heterocyclylene are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, carboxy, heteroaryl, heterocyclyl, and hydroxyl; wherein said C 1 -C 6 alkyl and aryl are optionally substituted with one substituent selected from: C 1 -C 6 alkoxy, aryl, halogen, heteroaryl, and hydroxyl; or R 14 is absent;

R 15 is selected from: —C(O)NH—, —C(O)—, —C(O)O—, C 1 -C 6 alkylene, C 3 -C 7 cycloalkylene, heteroarylene, and heterocyclylene; wherein said heterocyclylene is optionally substituted with C 1 -C 6 alkyl; or R 15 is absent;

R 16 is C 1 -C 6 alkylene; or R 16 is absent; and

R 17 is selected from: H, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylcarboxamide, C 2 -C 6 alkynyl, ureyl, amino, aryl, arylamino, arylcarbonyl, aryloxy, carbo-C 1 -C 6 -alkoxy, carboxamide, carboxy, cyano, C 3 -C 7 cycloalkyl, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkylamino, C 2 -C 8 dialkylamino, C 2 -C 8 dialkylsulfonamide, C 1 -C 6 haloalkyl, heteroaryl, heteroaryloxy, heterobicyclyl, heterocyclyl, hydroxyl, and phosphonooxy; wherein said C 1 -C 6 alkylamino, amino, aryl, arylamino, aryloxy, C 5 -C 11 bicycloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylamino, heteroaryl, heterobicyclyl, heterocyclyl, and ureyl are each optionally substituted with one or more substituents selected from: C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, amino, aryl, carboxy, cyano, C 3 -C 7 cycloalkyl, C 2 -C 8 dialkylamino, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl; and

R 9 is selected from H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl; or

R 8 and R 9 together with the nitrogen atom to which they are both bonded form a group selected from: heterocyclyl and heterobicyclyl, each optionally substituted with one or more substituents selected from: Carbo-C 1 -C 6 -alkoxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, aryl, carbo-C 1 -C 6 -alkoxy, C 1 -C 6 haloalkyl, halogen, heteroaryl, heteroaryloxy, heterocyclyl, and hydroxyl; wherein said aryl, C 1 -C 6 alkyl, and heteroaryl are optionally substituted with one substituent selected from: C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, halogen, and hydroxyl.

12. The method according to claim 1 , wherein the patient has a visual analogue scale pain score of ≥40 mm.

13. The method according to claim 11 , wherein the compound of Formula Ia is (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide (Compound A), having the structure:

or a pharmaceutically acceptable salt or crystal form thereof.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 27, 2022
From: LASSEN, CHERYL GERALDINE; PICCIRILLO, MARCELO FABIAN
To: ARENA PHARMACEUTICALS, INC.
Reel/Frame 060321/0110 →
Continuity (3)
Continuation 16611174
Provisional Application 62503280 · May 8, 2017
Related Publication 20230033510A1 · Feb 2, 2023
References Cited (232)
US 5605906A · Lau · 1997 [cited by applicant]
US 5971080A · Kikuchi et al. · 1999 [cited by applicant]
US 5977108A · Kikuchi et al. · 1999 [cited by applicant]
US 6329402B1 · Kikuchi et al. · 2001 [cited by applicant]
US 6541474B2 · Kikuchi et al. · 2003 [cited by applicant]
US 6630463B2 · Kikuchi et al. · 2003 [cited by applicant]
US 6884808B2 · Kikuchi et al. · 2005 [cited by applicant]
US 7741350B1 · Luo · 2010 [cited by applicant]
US 8778950B2 · Jones · 2014 [cited by applicant]
US 9458136B2 · Blackburn · 2016 [cited by applicant]
US 9492447B2 · Thatte · 2016 [cited by applicant]
US 9597340B2 · Thatte · 2017 [cited by applicant]
US 9867822B2 · Thatte · 2018 [cited by applicant]
US 9944606B2 · Jones et al. · 2018 [cited by applicant]
US 10183930B2 · Blackburn · 2019 [cited by applicant]
US 10632134B2 · Thatte · 2020 [cited by examiner]
US 10981895B2 · Blackburn · 2021 [cited by examiner]
US 11214548B2 · Jones · 2022 [cited by examiner]
US 11560369B2 · Blackburn · 2023 [cited by examiner]
US 11771695B2 · Thatte · 2023 [cited by examiner]
US 20030079746A1 · Hickle · 2003 [cited by applicant]
US 20050020544A1 · Garzon et al. · 2005 [cited by applicant]
US 20060205955A1 · Boatman et al. · 2006 [cited by applicant]
US 20070041994A1 · Kerr et al. · 2007 [cited by applicant]
US 20070191362A1 · Liotta et al. · 2007 [cited by applicant]
US 20080051386A1 · Lohray et al. · 2008 [cited by applicant]
US 20080064740A1 · Bolli et al. · 2008 [cited by applicant]
US 20080139635A1 · Martin · 2008 [cited by applicant]
US 20100160288A1 · Astles et al. · 2010 [cited by applicant]
US 20120088751A1 · Lazzari et al. · 2012 [cited by applicant]
US 20120142748A1 · Muthuppalaniappan et al. · 2012 [cited by applicant]
US 20130165412A1 · Jones et al. · 2013 [cited by applicant]
US 20140135345A1 · Blackburn et al. · 2014 [cited by applicant]
US 20140206649A1 · Thatte et al. · 2014 [cited by applicant]
US 20150126477A1 · Thatte et al. · 2015 [cited by applicant]
US 20170304327A1 · Thatte et al. · 2017 [cited by applicant]
US 20180252736A1 · Unett et al. · 2018 [cited by applicant]
US 20180280386A1 · Thatte et al. · 2018 [cited by applicant]
US 20180354907A1 · Jones et al. · 2018 [cited by applicant]
US 20190160058A1 · Shanahan · 2019 [cited by applicant]
US 20190308952A1 · Blackburn et al. · 2019 [cited by applicant]
US 20200078358A1 · Lassen · 2020 [cited by applicant]
US 20200289458A1 · Wong · 2020 [cited by examiner]
US 20210060040A1 · Thatte · 2021 [cited by examiner]
US 20220306586A1 · Jones · 2022 [cited by examiner]
DE 102004054666 · 2006 [cited by applicant]
EP 0838453 · 2005 [cited by applicant]
EP 1177187 · 2007 [cited by applicant]
FR 2875230 · 2006 [cited by applicant]
WO WO9702244 · 1997 [cited by applicant]
WO WO0064888 · 2000 [cited by applicant]
WO WO2004060882 · 2004 [cited by applicant]
WO WO2005123677 · 2005 [cited by applicant]
WO WO2006025069 · 2006 [cited by applicant]
WO WO2006030124 · 2006 [cited by applicant]
WO WO2006069242 · 2006 [cited by applicant]
WO WO2006129178 · 2006 [cited by applicant]
WO WO2008003665 · 2008 [cited by applicant]
WO WO2008039645 · 2008 [cited by applicant]
WO WO2008048914 · 2008 [cited by applicant]
WO WO2008053341 · 2008 [cited by applicant]
WO WO2008063781 · 2008 [cited by applicant]
WO WO2008064054 · 2008 [cited by applicant]
WO WO2008079316 · 2008 [cited by applicant]
WO WO2008085302 · 2008 [cited by applicant]
WO WO2008109007 · 2008 [cited by applicant]
WO WO2008119694 · 2008 [cited by applicant]
WO WO2008157500 · 2008 [cited by applicant]
WO WO2008157751 · 2008 [cited by applicant]
WO WO2009009550 · 2009 [cited by applicant]
WO WO2009015169 · 2009 [cited by applicant]
WO WO2009025785 · 2009 [cited by applicant]
WO WO2010088050 · 2010 [cited by applicant]
WO WO2011025541 · 2011 [cited by applicant]
WO WO2012116276 · 2012 [cited by applicant]
WO WO2012116277 · 2012 [cited by applicant]
WO WO2012116278 · 2012 [cited by applicant]
WO WO2012116279 · 2012 [cited by applicant]
WO WO2016085941 · 2016 [cited by applicant]
WO WO2017039643 · 2017 [cited by applicant]
WO WO2017180528 · 2017 [cited by applicant]
WO WO2018208847A1 · 2018 [cited by examiner]
WO WO2022187208A2 · 2022 [cited by examiner]
WO WO2023059610A1 · 2023 [cited by examiner]
Farrell; Front Pharmacol. 2014, 5, 27. https://doi.org/10.3389%2Ffphar.2014.00027 (Year: 2014). [cited by examiner]
Han; ACS Med. Chem. Lett. 2017, 8, 12, 1309-1313. https://doi.org/10.1021/acsmedchemlett.7b00396 (Year: 2017). [cited by examiner]
Plan; Clin Pharmacol Ther 2012, 91, 820-828. https://doi.org/10.1038/clpt.2011.301 (Year: 2012). [cited by examiner]
“GW pharmaceuticals announces positive preliminary results in a phase III clinical trial with Sativex in 177 patients with severe cancer pain,” GW Pharmaceuticals Press Release, Jan. 5, 2019 and Jun. 19, 2007, 5 pages. [cited by applicant]
“PI3K / Akt Cell Signaling,” (2010) www.cellsignal.com. [cited by applicant]
“Sativex, a canabis-based medicine, significantly reduces central neuropathis pain in people with multiple sclerosis,” GW Pharmaceuticals Press Release, Sep. 27, 2005, 2 pages. [cited by applicant]
“The Facts About Inflammatory Bowel Diseases. New York,” NY: Crohn's and Colitis Foundation of America, 2014, 24 pages. Downloaded Apr. 19, 2021 from https://www.crohnscolitisfoundation.org/sites/default/files/2019-02/U… [cited by applicant]
Agarwal et al., “Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors”, Nat. Neurosci., 2007, 10(7):870-879. [cited by applicant]
Ahmed et al., “Therapeutic Use of Cannabis in Inflammatory Bowel Disease,” Gastroenterology and Hepatology, Nov. 2016, 12(11):668-679. [cited by applicant]
Akhmetshina et al., “The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis,” Arthritis Rheum, 2009, 60:1129-1136. [cited by applicant]
Alexander et al., “Cannabinoids in the treatment of cancer,” Cancer Letters, 2009, 285: 6-12. [cited by applicant]
Anand et al., “Cannabinoid Receptor CB2 localisation And Agonist-Mediated Inhibition Of Capsaicin Responses In Human Sensory Neurons” Pain, 2008, 138(3):667-680. [cited by applicant]
Ashton et al., “The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration”, Curr. Neuropharmacol., 2007, 5(2):73-80. [cited by applicant]
Atwood et al., “Functional Selectivity in CB2 Cannabinoid Receptor Signaling and Regulation: Implications for the Therapeutic Potential of CB2 Ligands,” Molecular Pharmacology, 2012, 81(2): 250-263. [cited by applicant]
Baldassarre et al., “The endocannabinoid system in advanced liver cirrhosis: pathophysiological implication and future perspectives,” Liver International, 2012, 33(9):1298-1308. [cited by applicant]
Barutta et al., “Protective Role of Cannabinoid Receptor in Type 2 in a Mouse Model of Diabetic Nephropathy,” Diabetes, 2011, 60:2386-2396. [cited by applicant]
Belvisi et al., “Inhibitory Activity Of The Novel CB2 Receptor Agonist, GW833972A, On Guinea-Pig And Human Sensory Nerve Function In The Airways” British Journal of Pharmacology, 2008 1-11. [cited by applicant]
Berge et al., “Pharmaceutical salts”, J. of Pharm. Sci., 1977, 66:1-19. [cited by applicant]
Bingham et al., “Species-specific In Vitro Pharmacological Effects Of The Cannabinoid Receptor 2 (CB2) Selective Ligand AM1241 And Its Resolved Enantiomers” British Journal of Pharmacology, 2007, 151:1061-1070. [cited by applicant]
Boatman et al., “Potent tricyclic pyrazole tetrazole agonists of the nicotinic acid receptor (GPR109a),” Bioorganic & Medicinal Chemistry Letters, 2010, 20: 2797-2800. [cited by applicant]
Bouaboula et al., “Signaling Pathway Associated With Stimulation Of CB2 Peripheral Cannabinoid Receptor” Eur. J. Biochem., 1996, 237:704-711. [cited by applicant]
Caffarel et al., “Cannabinoids Reduce ErbB2-Driven Breast Cancer Progression Through Akt Inhibition” Molecular Cancer, 2010, 9:196 and Supplement. [cited by applicant]
Calignano et al., “Bidirectional control of airway responsiveness by endogenous cannabinoids”, Nature, 2000, 408:96-101. [cited by applicant]
Calignano et al., “Control of pain initiation by endogenous cannabinoids,” Nature, 1998, 394:277-281. [cited by applicant]
Carracedo et al., “Cannabinoids Induce Apoptosis of Pancreatic Tumor Cells via Endoplasmic Reticulum Stress-Related Genes” Cancer Res, 2006, 66:6748-6755. [cited by applicant]
Casanova et al., “Inhibition Of Skin Tumor Growth And Angiogenesis In Vivo By Activation Of Cannabinoid Receptors” J. Clin. Invest., 2003, 111:43-50. [cited by applicant]
Chaplan et al., “Quantitative assessment of tactile allodynia in the tat pay”, J. Neuroscience Methods, 1994, 531(1):1022-1027. [cited by applicant]
Cheng et al., “Discovery and Optimization of a Novel Series of N-Arylamide Oxadiazoles as Potent, Highly Selective and Orally Bioavailable Cannabinoid Receptor 2 (CB2) Agonists” J. Med. Chem., 2008, 51:5019-5034. [cited by applicant]
Collier et al., “Radiosynthesis and in-vivi evaluation of the psuedopeptie δ-opioid antagonist [125I]-1TIPP(Ψ)”, J. Labelled Compd. Radiopharm., 1999, 42:S264-S266. [cited by applicant]
Compton et al., “Aminoalkylindole Analogs: Cannabimimetic Activity of a Class of Compounds Structurally Distinct from A9-Tetrahydrocannabinols” JPET, 1992, 263:1118-1126. [cited by applicant]
Dhopeshwarkar “cb2 cannabinoid receptors as a therapeutic target-what does the future hold?” Mol. Phar., 2014, 86: 430-437. [cited by applicant]
Di Marzo et al., “Plant, Synthetic, And Endogenous Cannabinoids In Medicine” Annu. Rev. Med., 2006, 57:553-74. [cited by applicant]
Di Mauro et al., “Structural Modifications Of N-arylamide Oxadiazoles: Identification Of N-Arylpiperidine Oxadiazoles As Potent And Selective Agonists Of CB2” Bioorganic & Medicinal Chemistry Letters, 2008, 18:4267-4274. [cited by applicant]
Diaz et al., “Design and Synthesis of a Novel Series of N-Alkyl Isatin Acylhydrazone Derivatives that Act as Selective Cannabinoid Receptor 2 Agonists for the Treatment of Neuropathic Pain” J. Med. Chem., 2008, 51 :4932… [cited by applicant]
Dorwald, “Side Reactions in Organic Synthesis: A Guide to Successful Synthesis Design,” Weinhelm: Wiley-VCH Verlag GmbH & Co. KGaA, 2005, Preface. [cited by applicant]
Dubois et al., “Quantitative validation of voxel-wise statistical analyses of autoradiographic rat brain vols. application to unilateral visual stimulation,” J. Cereb. Blood Flow Metab., 2007, 27:1387-96. [cited by applicant]
Dvorak et al., “Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin”, Inflamm. Res., 2003, 52:238-245. [cited by applicant]
El Bakali et al., “Conformational Restriction Leading to a Selective CB2 Cannabinoid Receptor Agonist Orally Active Against Colitis,” ACS Med. Chem. Lett. Feb. 2015, 6(2):198-2030. [cited by applicant]
Ermann et al., “Arylsulfonamide CB2 receptor agonists: SAR and Optimization of CB2 selectivity” Bioorganic & Medicinal Chemistry Letters, 2008, 18:1725-1729. [cited by applicant]
Furuse et al., “Reduction of bone cancer pain by activation of spinal cannabinoid receptor 1 and its expression in the superficial dorsal horn of the spinal cord in a murine model of bone cancer pain,” Anesthesiology, 2… [cited by applicant]
Gabriel et al., “High throughput screening technologies for direct cyclic AMP measurement,” ASSAY and Drug Development Technologies, 2003, 1:291-303. [cited by applicant]
Galiegue et al., “Expression Of Central And Peripheral Cannabinoid Receptors In Human Immune Tissues And Leukocyte Subpopulations” Eur. J. Biochem., 1995, 232:54-61. [cited by applicant]
Gennaro et al., Remington, “The Science and Practice of Pharmacy” 20th Edition, 2000, Lippincott Williams & Wilkins. [cited by applicant]
Giblin et al., “Discovery of 2-[(2,4-Dichlorophenyl)amino]-N-[(tetrahydro-2H-pyran-4-yl)methyl]-4-(trifluoromethyl)-5-pyrimidinecarboxamide, a Selective CB2 Receptor Agonist for the Treatment of Inflammatory Pain” J. Me… [cited by applicant]
Goncalves et al., “A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner”, Mal. Cell Neurosci., 2008, 38(4):526-36. [cited by applicant]
Goodman et al., “CB2 selective Sulfamoyl Benzamides: Optimization Of The Amide Functionality” Bioorganic & Medicinal Chemistry Letters, 2009, 19:309-313. [cited by applicant]
Graham et al., “Cannabinoid Receptors: A Brief History And What's Hot” Frontiers in Bioscience, 2009, 14:944-957. [cited by applicant]
Gratzke et al., “Effects of cannabinor, a novel selective cannabinoid 2 receptor agonist, on bladder function in normal rats,” Eur. Urol., 2010, 57:1093-1100, figure 2a-b. [cited by applicant]
Guillory, “Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids,” in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Britain, 1999, 95:202-209. [cited by applicant]
Guillot et al., “Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver,” J Hepatology, 2014, 59(1):296-306. [cited by applicant]
Guindon et al., “Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain,” Br. J. Pharmacol., 2008, 153:319-334. [cited by applicant]
Han et al., “Therapeutic utility of cannabinoid receptor type 2 (CB2) selective agonists,” Journal of Medicinal Chmeistry, 2013, 56(21):8224-8256. [cited by applicant]
Hanus et al., (1999) “HU-308: A Specific Agonist For CB2, A Peripheral Cannabinoid Receptor” PNAS, 1999, 96:14228-14233. [cited by applicant]
Hasenoehrl et al., “Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go?,”Expert Review of Gastroenterology and Hepatology, Apr. 2017, 11(4)329-337. [cited by applicant]
Hollinshead et al., “Selective Cannabinoid Receptor Type 2 (CB2) Agonists: Optimization of a Series of Purines Leading to the Identification of a Clinical Candidate for the Treatment of Osteoarthritic Pain,” J. Med. Che… [cited by applicant]
Hosohata et al., “AM630 Antagonism Of Cannabinoid-Stimulated [″˜S]GTP yS Binding In The Mouse Brain” European Journal of Pharmacology, 1997, 321: R1-R3. [cited by applicant]
Hu et al., “Depression-like behaviour in rats with mononeuropathy is reduced by the CB2-selective agonist GW405833”, Pain, 2009, 143:206-212. [cited by applicant]
Ibn-e-Sina, Abu Ali; A1 Qaanoon fil Tibb, 1987, p. 327. w/ English translation. [cited by applicant]
Ibrahim et al., “Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS,” Proc. Natl. Acad. Sci., 2003, 100(18):10529-10533. [cited by applicant]
Ibrahim et al., “CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids”, PNAS, 2005, 102(8):3093-8. [cited by applicant]
Ibrahim et al., “Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS”, Proc. Natl. Aca. Sci., 2003, 100(18):10529-10533. [cited by applicant]
International Preliminary Report on Patentability in International Appln. No. PCT/US2018/031688, dated Nov. 12, 2019, 7 pages. [cited by applicant]
International Search Report and Written Opinion in International Appln. No. PCT/US2018/031688, dated Aug. 2, 2018, 10 pages. [cited by applicant]
Iwata et al., “Identification of a highly potent and selective CB2 agonist, RQ-00202730, for the treatment of irritable bowel syndrome,” Bioorganic & Medicinal Chemistry Letters, 2015, 25(2):236-240. [cited by applicant]
Izzo et al., “Cannabinoids in intestinal inflammation and cancer,” Pharmacological Research, 2009, 60(2):117-125. [cited by applicant]
Johnson et al., Neuroscience poster: A novel selective cB2 agonist, LY28283620 is efficacious in chronic pain models, 2012. [cited by applicant]
Jordan, “Tamoxifen: a most unlikely pioneering medicine,” Nature Reviews: Drug Discovery, 2003, 2:205-213. [cited by applicant]
Julien et al., “Antifibrogenic role of the cannabinoid receptor CB2 in the liver,” Gastroenterology, 2005, 128:742-755. [cited by applicant]
Kalbhen et al., “Chemical model of osteoarthritis—a pharmacological evaluation,” J Rheumatol, 1987, 14:130-1. [cited by applicant]
Karsak et al., “Attenuation of allergic contact dermatitis through the endocannabinoid system”, Science, 2007, 316(5830):1494-1497. [cited by applicant]
Khan, Mohammad Naimul Ghani; Khazaain al Advia, 1911, Pa 887. w/ English translation. [cited by applicant]
Khan, Mohammad Najmul Ghani; Khazaain al Advia, 1911, Pa 886. w/ English translation. [cited by applicant]
Khan, Mohammad Najmul Ghani; Khazaain al Advia, 1911, Pa 889. w/ English translation. [cited by applicant]
Kikuchi et al., “Pharmacological Evaluation of a Novel Cannabinoid 2 (CB2) Ligand, PF-03550096, In Vitro and In Vivo by Using a Rat Model of Visceral Hypersensitivity,” J. Pharmacol. Sci., 2008, 106:219-224. [cited by applicant]
Kozela et al., “Cannabinoids decrease the th 17 inflammatory autoimmune phenotype,” J Neuroimmune Pharmacology, 2013, 8(5):1265-76. [cited by applicant]
Le Bas et al., “Radioiodinated Analogs of EP 00652218 for the Exploration of the Tachykinin NK1 Receptor by Spect”, J. Labelled Compd. Radiopharm., 2001, S280-S282. [cited by applicant]
Lotersztajn et al., “CB2 receptors as new therapeutic targets for liver diseases,” Br J Pharmacol, 2008, 153:286-289. [cited by applicant]
Lozano-Ondoua et al., “A Cannabinoid 2 Receptor Agonist Attenuates Bone Cancer-Induced Pain And Bone Loss” Life Sciences, 2010, 86:646-653. [cited by applicant]
Iwata et al., “Identification of a highly potent and selective CB2 agonist, RQ-00202730, for the treatment of irritable bowel syndrome,” Bioorg. Med. Chem. Lett., Jan. 2015, 25:236-240. [cited by applicant]
Majoosi, Ali Ibn-e-Abbass, Kaamil-al-Sena'ah, 2005, p. 303. w/ English translation. [cited by applicant]
Malan et al., “CB2 cannabinoid receptor-mediated peripheral antinociception”, Pain, 2001, 93:239-245. [cited by applicant]
Mallat et al., “Cannabinoid signaling and liver therapeutics,” J Hepatology, 2013, 59(4):891-896. [cited by applicant]
Manzanares et al., “Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes,” Current Neuropharmacology, 2006, 4:239-57. [cited by applicant]
Maresz et al., “Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells”, Nat. Med., 2007, 13(4):492-497. [cited by applicant]
Markt et al., “Discovery of Novel CB2 Receptor Ligands by a Pharmacophore-Based Virtual Screening Workflow” J. Med. Chem., 2009, 52:369-378. [cited by applicant]
Marx et al., “Discovery Of a-Amidosulfones As Potent And Selective Agonists Of CB2: Synthesis, SAR, And Pharmacokinetic Properties” Bioorganic & Medicinal Chemistry Letters, 2009, 19:31-35. [cited by applicant]
Matsuda et al., “Molecular cloning of a human cannabinoid receptor which is also expressed in testis”, Nature, 1990, 346:561-564. [cited by applicant]
Matsuda et al., “Structure of a cannabinoid receptor and functional expression of the cloned cDNA,” Nature, 1990, 346:561-564. [cited by applicant]
Mbvundula et al., “Arthritis and cannabinoids: HU-210 and Win-55,212-2 prevent IL-1 α-induced matrix degradation in bovine articular chondrocytes in-vitro”, J. Pharm. And Pharmacol., 2006, 58:351-358. [cited by applicant]
McKallip et al., “Targeting CB2 Cannabinoid Receptors As A Novel Therapy To Treat Malignant Lymphoblastic Disease” Blood, 2002, 100:627-634. [cited by applicant]
Mendez-Sanchez et al., “Endocannabinoid receptor CB2 in nonalcoholic fatty liver disease,” Liver International, 2007, 7(2):215-219. [cited by applicant]
Merriam et al., “Cannabinoid receptor 2 is increased in acutely and chronically inflamed bladder of rats”, Neurosci Lett., 2008, 445(1):130-134. [cited by applicant]
Michalski et al., “Cannabinoids In Pancreatic Cancer: Correlation With Survival And Pain” Int J Cancer., 2008, 122:742-750. [cited by applicant]
Mitchell et al., “Pyridine-3-carboxamides As Novel CB2 Agonists For Analgesia” Bioorganic & Medicinal Chemistry Letters, 2009, 19:259-263. [cited by applicant]
Morita et al., “Antitussive effect of WIN 55212-2, a cannabinoid receptor agonist”, Eur. J. Pharmacol., 2003, 474:269-272. [cited by applicant]
Munoz-Lugue et al., “Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats,” J Pharmacol Exp Ther., 2008, 324:475-483. [cited by applicant]
Munro et al., “Molecular characterization of a peripheral receptor for cannabinoids”, Nature, 1993, 365:61-65. [cited by applicant]
Naguib et al., “MDA7: A Novel Selective Agonist For CB2 Receptors That Prevents Allodynia In Rat Neuropathic Pain Models” British Journal of Pharmacology, 2008, 1-13. [cited by applicant]
Narayanan et al., “GRC 10622 : A Novel Orally Active CB2 Receptor Agonist With Potential Anti-Hyperalgesic Effects”, poster submitted at Society for Neuroscience—Oct. 14-18, 2006, Atlanta, GA, USA. [cited by applicant]
Ni et al., “Win 55212-2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial interactions in an experimental autoimmune encephalomyelitis model”, Mult. Sclerosis, 2004, 10(2):158-64. [cited by applicant]
Nunez et al., “Cannabinoid CB2 Receptors Are Expressed by Perivascular Microglial Cells in the Human Brain: An Immunohistochemical Study” Synapse, 2004, 53:208-213. [cited by applicant]
Ofek et al., “Peripheral cannabinoid receptor, CB2, regulates bone mass”, PNAS, 2006, 103(3):696-701. [cited by applicant]
Ohta et al., “I mine Derivatives As New Potent And Selective CB2 Cannabinoid Receptor Agonists With An Analgesic Action” Bioorganic & Medicinal Chemistry, 2008, 16:1111-1124. [cited by applicant]
Ohta et al., “N-Alkylidenearylcarboxamides As New Potent And Selective CB2 Cannabinoid Receptor Agonists With Good Oral Bioavailability” Bioorganic & Medicinal Chemistry Letters, 2007, 17:6299-6304. [cited by applicant]
Olea-Herrero et al., “Inhibition of human tumour prostate PC-3 cell growth by cannabinoids R(+)-Methanandamide and JWH-015: Involvement of CB2,” British Journal of Cancer, 2009, 101:940-950. [cited by applicant]
Omura et al., “The SAR Studies of Novel CB2 Selective Agonists, Benzimidazolone Derivatives” Bioorganic & Medicinal Chemistry Letters, 2008, 18(11):3310-3314. [cited by applicant]
Pacher et al., “The endocannabinoid system as an emerging target of pharmacotherapy”, Pharmacol Rev., 2006, 58(3):389-462. [cited by applicant]
Page et al., “New 1,2,3,4-Tetrahydropyrrolo[3,4-b]indole Derivatives As Selective CB2 Receptor Agonists” Bioorganic & Medicinal Chemistry Letters, 2007, 17:6183-6187. [cited by applicant]
Page et al., “Novel Benzimidazole Derivatives As Selective CB2 Agonists” Bioorganic & Medicinal Chemistry Letters, 2008, 18:3695-3700. [cited by applicant]
Palazuelos et al., “The CB(2) cannabinoid receptor controls myeloid progenitor trafficking: involvement in the pathogenesis of an animal model of multiple sclerosis”, Biol. Chem., 2008, 283(19):13320-9. [cited by applicant]
Parfieniuk et al., “Role of cannabinoids in chronic liver diseases,” World J Gastroenterol., 2008, 28; 14(40):6109-14. [cited by applicant]
Pasquini et al., “Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 2. Synthesis and Structure#Activity Relationship of Potent and Selective Cannabinoid- 2 Receptor Agonists Endowed with Analgesic Activity in V… [cited by applicant]
Patel et al., “Inhibition of guinea-pig and human sensory nerve activity and the cough reflex in guinea-pigs by cannabinoid (CB2) receptor activation”, British J. Pharma., 2003, 140:261-8. [cited by applicant]
Petrov et al., “Mastering tricyclic ring systems for desirable functional cannabinoid activity,” Eur. J. Med. Chem., Nov. 2013, 69: 881-907. [cited by applicant]
Pisanti et al., “Use Of Cannabinoid Receptor Agonists In Cancer Therapy As Palliative And Curative Agents” Best Practice & Research Clinical Endocrinology & Metabolism, 2009, 23:117-131. [cited by applicant]
Preet et al., “Cannabinoid Receptors, CB1 and CB2, as Novel Targets for Inhibition of Non- Small Cell Lung Cancer Growth and Metastasis” Published Online First on Nov. 19, 2010 as 10.1158/1940-6207.CAPR-10-0181. [cited by applicant]
Pryce et al., “Cannabinoids inhibit neurodegeneration in models of multiple sclerosis”, Brian, 2003, 126:2191-2202. [cited by applicant]
Richardson et al., “Antihyperalgesic effects of spinal cannabinoids,” Eur. J. Pharmacol., 1997, 345:145-153. [cited by applicant]
Rinaldi-Carmona et al., “SR 144528, the First Potent and Selective Antagonist of the CB2 Cannabinoid Receptor” JPET, 1998, 284:644-650. [cited by applicant]
Rukwied et al., “Cannabinoid agonists attenuate capsaicin-induced responses in human skin,” Pain, 2003, 102:283-288. [cited by applicant]
Sanchez et al., “Inhibition of Glioma Growth in Vivo by Selective Activation of the CB2 Cannabinoid Receptor” Cancer Research, 2001, 61:5784-5789. [cited by applicant]
Servettaz et al., “Targeting the cannabinoid pathway limits the development of fibrosis and autoimmunity in a mouse model of systemic sclerosis,” Am J Pathol, 2010, 177:187-19. [cited by applicant]
Sharma et al., “Cell Line-Based Platforms To Evaluate The Therapeutic Efficacy Of Candidate Anticancer Agents” Nature Reviews I Cancer, 2010, 10:241-253. [cited by applicant]
Shi et al., “Cannabinoid 2 Receptor Induction By IL-12 And Its Potential As A Therapeutic Target For The Treatment Of Anaplastic Thyroid Carcinoma” Cancer Gene Therapy, 2008, 15:101-107. [cited by applicant]
Slipetz et al., “Activation of the Human Peripheral Cannabinoid Recepto Results in Inhibition of Adenylyl Cyclase” Molecular Pharmacology, 1995, 48:352-361. [cited by applicant]
Stahly, “Diversity in Single- and Multiple-Component Crystals. The Search for and Prevalence of Polymorphs and Cocrystals”, Crystal Growth & Design, 2007, 7(6):1007-1026. [cited by applicant]
Stansfield et al., “Development Of Carboxylic Acid Replacements In Indole-N-acetamide Inhibitors Of Hepatitis C Virus NS5B Polymerase” Bioorganic & Medicinal Chemistry Letters, 2007, 17:5143-5149. [cited by applicant]
Steffans et al., “Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice”, Nature, 2005, 434:782-786. [cited by applicant]
T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems vol. 14 of the A.C.S. Symposium Series; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon P… [cited by applicant]
Tambaro et al., “Evaluation of selective cannabinoid CB(1) and CB(2) receptor agonists in a mouse model of lipopolysaccharide-induced interstitial cystitis”, Eur J Pharmacol, 2014, 15(729):67-74. [cited by applicant]
Trebicka et al., “Role of cannabinoid receptors in alcoholic hepatic injury: steatosis and fibrogenesis are increased in CB2 receptor-deficient mice and decreased in CB1 receptor,” Liver Int, 2011, 31:860-870. [cited by applicant]
Valenzano et al., “Pharmacological And Pharmacokinetic Characterization Of The Cannabinoid Receptor 2 Agonist, GW405833, Utilizing Rodent Models Of Acute And Chronic Pain, Anxiety, Ataxia And Catalepsy” Neuropharmacolog… [cited by applicant]
Van Sickle et al., “Identification and Functional Characterization of Brainstem Cannabinoid CB2 Receptors” Science, 2005, 310:329. [cited by applicant]
Verbist et al., “5-Sulfonyl-benzimidazoles As Selective CB2 Agonists” Bioorganic & Medicinal Chemistry Letters, 2008, 18:2574-2579. [cited by applicant]
Vincenzi et al., “Antinociceptive effects of the selective CB2 agonist MT178 in inflammatory and chronic rodent pain models,” PAIN, Jun. 2013, 154(6):864-873. [cited by applicant]
Walker and Huang, “Cannabinoid analgesia,” Pharmacol. Ther., 2002, 95:127-135. [cited by applicant]
Wei et al., “Presence and regulation of cannabinoid receprots in human retinal pigment epithelial cells,” Mol. Vis., 2009, 15:1243-51. [cited by applicant]
Whiteside et al., “The Role of the Cannabinoid CB2 Receptor in Pain Transmission and Therapeutic Potential of Small Molecule CB2 Receptor Agonists” Current Medicinal Chemistry, 2007, 14:917-936. [cited by applicant]
Widmer et al., “High concentrations of cannabinoids activate apoptosis in human U373MG glioma cells”, Neurosci. Res., 2008, 86(14):3212-20. [cited by applicant]
Worm et al., “Sulfamoyl Benzamides As Novel CB2 Cannabinoid Receptor Ligands” Bioorganic & Medicinal Chemistry Letters, 2008, 18:2830-2835. [cited by applicant]
Wotherspoon et al., “Peripheral Nerve Injury Induces Cannabinoid Receptor 2 Protein Expression In Rat Sensory Neurons” Neuroscience, 2005, 135:235--245. [cited by applicant]
Wright et al., “Cannabinoid CB 2 receptors in the gastrointestinal tract: A regulatory system in states of inflammation,” British Journal of Pharmacology, Feb. 2008, 153:263-270. [cited by applicant]
Yan et al., “Cell-based high-throughput screening assay system for monitoring G protein-coupled receptor activation using beta-galactosidase enzyme complementation technology”, J. Biomol. Scree, 2002, 7:451-459. [cited by applicant]
Yao et al., “Characterization of a Cannabinoid CB2 Receptor Selective Agonist, A-836339, in In Vitro Pharmacological assays and In Vivo Pain Models” JPET, 2008, 328(1):141-151. [cited by applicant]
Yao et al., “In Vitro And In Vivo Characterization Of A-796260: A Selective Cannabinoid CB2 Receptor Agonist Exhibiting Analgesic Activity In Rodent Pain Models” British Journal of Pharmacology, 2008, 153:390-401. [cited by applicant]
Zhang et al., “Cannabinoid CB(2) receptor activation decreases cerebral infarction in a mouse focal ischemia/reperfusion model”, J. Cereb. Blood Flow Metab., 2007, 27:1387-96. [cited by applicant]
Zhu et al., “Synthesis and mode of action of (125)I- and (3)H-labeled thieno[2,3-c]pyridine antagonists of cell adhesion molecule expression”, J. Org. Che., 2002, 67:943-948. [cited by applicant]
Zindell et al., “Morpholine Containing CB2 Selective Agonists” Bioorganic & Medicinal Chemistry Letters, 2009, 19:1604-1609. [cited by applicant]