IP Library Patent Application 15024766
Patent Application
App. No. 15/024,766

NOVEL FUNCTIONALIZED 5-(PHENOXYMETHYL)-1,3-DIOXANE ANALOGS EXHIBITING CYTOCHROME P450 INHIBITION AND THEIR METHOD OF USE

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Patent No.
US None
App. No.
15/024,766
Abstract

Pharmaceutical compositions described in this document comprise 5-(phenoxymethyl)-1,3-dioxane analogs having a disease-modifying action in the treatment of diseases associated with the production of cortisol that include metabolic syndrome, obesity, headache, depression, hypertension, diabetes mellitus, Cushing's Syndrome, pseudo-Cushing syndrome, cognitive impairment, dementia, heart failure, renal failure, psoriasis, glaucoma, cardiovascular disease, cancer, stroke, incidentalomas, or any diseases involving the overproduction of cortisol.

Claims (59)

1 - 34 . (canceled)

35 . A compound comprising formula (I):

or a hydrate, solvate, enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug or complex thereof, wherein

Q is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl,

R 1a , R 1b , R 1c , R 1d , and R 1e are each independently selected from the group consisting of hydrogen, halogen, OH, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 1-6 haloalkyl, C 1-6 , optionally substituted alkoxy, —NR 4a R 4b , —NR 5 COR 6 , —CO 2 R 6 , —CO 2 NR 4a R 4b , —NHSO 2 R 7 , —SH, —SR 7 , SO 2 R 7 and —SO 2 NHR 6 ;

R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2g are each independently selected from the group consisting of hydrogen, halogen, OH, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 1-6 haloalkyl, C 1-6 optionally substituted alkoxy, —NR 4a R 4b , —NR 5 COR 6 , —CO 2 R 6 , —CO 2 NR 4a R 4b , —NHSO 2 R 7 , —SH, —SR 7 , SO 2 R 7 and —SO 2 NHR 6 ;

R 3 is selected from a group consisting of —SO 2 R 8 , —C(O)NR 9 R 10 , —C(O)OR 7 ,

R 4a and R 4b are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, and optionally substituted C 3-7 cycloalkyl;

R 5 is selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, and optionally substituted C 3-7 cycloalkyl;

R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, and optionally substituted C 3-7 cycloalkyl;

R 7 is selected from the group consisting of optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, and optionally substituted C 3-7 cycloalkyl;

R 8 is selected from the group consisting of optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 1-6 haloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C3-7 heterocyclyl;

R 9 is selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 1-6 haloalkyl,

R 10 is selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, and optionally substituted C 1-6 branched alkyl; and

R 11a and R 11b are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, optionally substituted aryl, optionally substituted benzyl, —CH 2 OR 6 , and CH 2 heteroaryl.

36 . The compound of claim 35 , wherein the compound is selected from the group consisting of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (Xa), and any hydrate, solvate, enantiomer, disastereomer, pharmaceutically acceptable salt, prodrug, or complex thereof.

37 . The compound of claim 35 , wherein the compound is selected from the group consisting of:

1-(4-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)piperazin-1-yl)ethanone;

1-(4-(4-((((2r,5r)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)piperazin-1-yl)ethanone;

1-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)piperazine:

3-((4-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)piperazin-1-yl)sulfonyl)benzonitrile;

1-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)-4-((3-chloropropyl)sulfonyl)piperazine;

1-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)-4-(cyclopropylsulfonyl)piperazine;

1-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)-4-(isopropylsulfonyl)piperazine;

1-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)-4-(ethylsulfonyl)piperazine;

1-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)-4-((1H-imidazol-4-yl)sulfonyl)piperazine;

1-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)-4-((3-(trifluoromethoxy)phenyl)sulfonyl)piperazine;

1-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)-4-(pyridin-3-ylsulfonyl)piperazine;

1-(4-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2-chlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)piperazin-1-yl)ethanone;

1-(4-(4-((((2r,5r)-2-((1H-imidazol-1-yl)methyl)-2-(2-chlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)piperazin-1-yl)ethanone;

4-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2,4-dichlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)pyridine;

4-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2-chlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)morpholine;

4-(4-((((2r,5r)-2-((1H-imidazol-1-yl)methyl)-2-(2-chlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)morpholine;

1-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2-chlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)-4-(methylsulfonyl)piperazine;

1-(4-((((2r,5r)-2-((1H-imidazol-1-yl)methyl)-2-(2-chlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)-4-(methylsulfonyl)piperazine;

2-methoxyethyl 4-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2-chlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)piperazine-1-carboxylate;

2-methoxyethyl 4-(4-((((2r,5r)-2-((1H-imidazol-1-yl)methyl)-2-(2-chlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)piperazine-1-carboxylate;

ethyl 2-(4-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2-chlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)piperazine-1-carboxamido)acetate;

ethyl 2-(4-(4-((((2r,5r)-2-((1H-imidazol-1-yl)methyl)-2-(2-chlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)piperazine-1-carboxamido)acetate;

4-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2-chlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)-N,N-dimethylpiperazine-1-carboxamide;

4-(4-((((2s,5s)-2-((1H-imidazol-1-yl)methyl)-2-(2-chlorophenyl)-1,3-dioxan-5-yl)oxy)methyl)phenyl)pyridine;

and a pharmaceutically acceptable salt form thereof.

38 . The compound of claim 35 included in an effective amount in a composition.

39 . The compound of claim 38 wherein the composition comprises at least one excipient.

40 . A compound selected from the group consisting of formula (X), formula (Xa) and any hydrate, solvate, enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug or complex thereof, wherein

R 1a , R 1b , R 1c , R 1d , and R 1e are each independently selected from the group consisting of hydrogen, halogen, OH, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 1-6 haloalkyl, C 1-6 , optionally substituted alkoxy, —NR 4a R 4b , —NR 5 COR 6 , —CO 2 R 6 , —CO 2 NR 4a R 4b , —NHSO 2 R 7 , —SH, —SR 7 , SO 2 R 7 and —SO 2 NHR 6 ;

R 2a , R 2b , R 2c , R 2d , R 2e , R 2f and R 2g are each independently selected from the group consisting of hydrogen, halogen, OH, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 1-6 haloalkyl, C 1-6 optionally substituted alkoxy, —NR 4a R 4b , —NR 5 COR 6 , —CO 2 R 6 , —CO 2 NR 4a R 4b , —NHSO 2 R 7 , —SH, —SR 7 , SO 2 R 7 and —SO 2 NHR 6 ;

R 4a and R 4b are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, and optionally substituted C 3-7 cycloalkyl;

R 5 is selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, and optionally substituted C 3-7 cycloalkyl;

R 6 is selected from the group consisting of hydrogen, optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, and optionally substituted C 3-7 cycloalkyl; and

R 7 is selected from the group consisting of optionally substituted C 1-6 linear alkyl, optionally substituted C 1-6 branched alkyl, and optionally substituted C 3-7 cycloalkyl.

41 . The compound of claim 40 included in an effective amount in a composition.

42 . The compound of claim 41 wherein the composition comprises at least one excipient.

43 . A method of treating a disease associated with overproduction of cortisol, said method comprising administering to a subject having the disease an effective amount of a pharmaceutical composition comprising a compound of claim 35 .

44 . The method of claim 43 , wherein the disease associated with overproduction of cortisol is metabolic syndrome, obesity, headache, depression, hypertension, diabetes mellitus, Cushing's Syndrome, pseudo-Cushing syndrome, cognitive impairment, dementia, heart failure, renal failure, psoriasis, glaucoma, cardiovascular disease, stroke or incidentalomas.

45 . The method of claim 43 , wherein the disease is also associated with excess Cyp17 activity.

46 . The method of claim 43 , wherein the disease is also associated with excess Cyp21 activity.

47 . The method of claim 43 , wherein the disease is also associated with excess Cyp11B1 activity.

48 . The method of claim 43 , wherein the pharmaceutical composition comprises at least one excipient.

Assignments (3)
RELEASE OF SECURITY INTEREST Recorded Jul 14, 2017
From: OXFORD FINANCE LLC, IN ITS CAPACITY AS COLLATERAL AGENT AND AS LENDER
To: CORTENDO AB (PUBL)
Reel/Frame 043012/0062 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 28, 2017
From: BLASS, BENJAMIN ERIC; ABOU-GHARBIA, MAGID A.; CHILDERS, WAYNE E.; IYER, PRAVIN; BORUWA, JOSHODEEP; BOBBALA, RAMREDDY; NIMMAREDDY, RAJASHEKAR REDDY
To: CORTENDO AB (PUBL)
Reel/Frame 042837/0712 →
SECURITY INTEREST Recorded Dec 29, 2016
From: CORTENDO AB (PUBL)
To: OXFORD FINANCE LLC, AS COLLATERAL AGENT AND LENDER
Reel/Frame 040807/0199 →