IP Library › Granted Patent US 10,207,993
Granted Patent B2
US 10,207,993 · App. 15/674,033 · Granted Feb 19, 2019

Compounds as anti-tubercular agents

Inventors: Sundeep Dugar (Haryana, IN); Dinesh Mahajan (Haryana, IN); Santosh Kumar Rai (Haryana, IN); Kanury Rao (Haryana, IN); Varshneya Singh (Haryana, IN)
Assignees: SPHAERA PHARMA PVT. LTD.; DRUG DISCOVERY RESEARCH CENTRE
C07D211/42A61K31/445A61K45/06C07C59/64C07D205/04C07D207/09C07D207/12C07D211/46C07D211/56C07D211/58C07D213/75C07D265/30C07D453/04
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Quick Facts
Patent No.
US 10,207,993
App. No.
15/674,033
Granted
Feb 19, 2019
Kind
B2
Abstract

The present invention relates to novel compounds of formula (1): The present invention also discloses compounds of formula (1) along with other pharmaceutical acceptable excipients and use of the compounds as anti-tubercular agents.

Claims (143)

1. A method for treatment of an infection caused by resistant or non-resistant Mycobacterium tuberculosis , comprising administering to a subject in need thereof a compound of structural Formula (1), including its salts, hydrates or stereoisomers:

wherein

X is O, NH or N(alkyl);

R 1 and R 2 are independently hydrogen, but with the proviso that R 1 and R 2 are not both hydrogen, deuterium, hydroxyl, C 1-10 straight chain or branched chain alkyl, 3-7 membered cycloalkyl, C 1-6 alkoxy, aryl, amino, NH(alkyl), N(alkyl) 2 ,OCOR 5 , heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N and S; or R 1 and R 2 may combined to form an aryl or a heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of O, N and S; R 3 is a non-aromatic heterocyclic ring or fused heterocyclic ring selected from:

X may in conjunction with R 3 form a 5-7 membered heterocyclic ring comprising 1-3 heteroatoms selected from group consisting of N, O and S, wherein the heterocyclic ring be further substituted with one or more lower alkyl groups, halogens, amino, NH(alkyl), N(alkyl) 2 , NH-aralkyl;

R 4 is a hydrogen, lower straight chain or branched alkyl, halogen, deuterium, C 1-6 alkoxy, amino, NH(alkyl), N(alkyl) 2 , —COOR 8 , or CONR 8 R 9 ;

R 5 is hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, NH(alkyl), or N(alkyl) 2 ;

R 6 and R 7 are independently selected from the group consisting of hydrogen, C 1-10 alkyl, —COR 8 , —CH 2 OCOR 8 , —CH 2 OCONHR 8 R 9 , —COOR 8 , —CONR 8 R 9 , —SO 2 R 8 , aryl, and aralkyl;

R 8 and R 9 are independently selected from the group consisting of hydrogen, and C 1-6 straight chain or branched chain alkyl; and

n is 1, 2, or 3.

2. The method of claim 1 , wherein the infection is drug-sensitive, mono-drug resistance, multi drug-resistant (MDR), extensively drug-resistant (XDR) or totally drug resistant (TDR) tuberculosis caused by a strain of Mycobacterium tuberculosis.

3. The method of claim 1 , wherein in the compound of structural Formula (1):

X is NH;

R 1 and R 2 are independently selected from hydrogen, hydroxyl, C 1-10 alkyl,C 1-6 alkox;

R 3 is selected from substituted aromatic or non-aromatic heterocyclic ring or fused heterocyclic ring selected from:

R 4 is selected from hydrogen, deuterium, halogen, C 1-6 straight chain or branched chain alkyl,

C 1-6 alkoxy, amino, NH(alkyl), N(alkyl) 2 ;

R 6 and R 7 are independently selected from hydrogen, C 1-10 alkyl, —COR 8 , —CH 2 OCOR 8 , —CH 2 OCONHR 8 R 9 , —COOR 8 , —CONR 8 R 9 , —SO 2 R 8 , phenyl, benzyl;

R 8 and R 9 are independently selected from hydrogen or C 1-6 straight chain or branched chain alkyl; and

n is 1,2 or 3.

4. The method of claim 1 , wherein the compound of Formula (1), including its salts, hydrates and stereoisomers thereof wherein said compound is selected from the group consisting of:

i. 1-Methylpiperidin-3-yl-2-hydroxy-2,2-diphenylacetate;

ii. 3-(2-Hydroxy-2,2-diphenylacetoxy)-1-(((isopropylcarbamoyl)oxy)methyl)-1-methylpiperidin-1-ium;

iii. Piperidin-3-yl 2-hydroxy-2,2-diphenylacetate;

iv. 1-Benzylpiperidin-3-yl 2-hydroxy-2,2-diphenylacetate;

v. 1-(Methylsulfonyl)piperidin-3-yl 2-hydroxy-2,2-diphenylacetate;

vi. 1-(Dimethylcarbamoyl) piperidin-3-yl 2-hydroxy-2,2-diphenylacetate;

vii. 1-Benzylpiperidin-4-yl 2-hydroxy-2,2-diphenylacetate;

viii. 3-(2-Hydroxy-2,2-diphenylacetoxy)-1-methylquinuclidin-1-ium;

ix. 1-Benzylpyrrolidin-3-yl 2-hydroxy-2,2-diphenylacetate;

x. 1-Ethylpiperidin-3-yl 2-hydroxy-2,2-diphenylacetate;

xi. 1-(Isopropylcarbamoyl) piperidin-3-yl 2-hydroxy-2,2-diphenylacetate;

xii. 1-Propylpiperidin-3-yl 2-hydroxy-2,2-diphenylacetate;

xiii. 1-Methylpiperidin-4-yl 2-hydroxy-2,2-diphenylacetate;

xiv. 1-Benzylazetidin-3-yl 2-hydroxy-2,2-diphenylacetate;

xv. 1-Acetylpiperidin-3-yl 2-hydroxy-2,2-diphenylacetate;

xvi. 2-Hydroxy-2,2-diphenyl-N-(piperidin-3-yl)acetamide;

xvii. N-(1-Benzylpiperidin-4-yl)-2-hydroxy-2,2-diphenylacetamide;

xviii. 1-Methylpyrrolidin-3-yl 2-hydroxy-2,2-diphenylacetate;

xix. Quinuclidin-3-yl 2-hydroxy-2,2-diphenylacetate;

xx. 2-Hydroxy-N-(1-methylpiperidin-3-yl)-2,2-diphenylacetamide;

xxi. N-(1-Benzylpiperidin-4-yl)-2-hydroxy-2,2-diphenylacetamide;

xxii. N-(1-Benzylazetidin-3-yl)-2-hydroxy-2,2-diphenylacetamide;

xxiii. Azetidin-3-yl 2-hydroxy-2,2-diphenylacetate;

xiv. (S)-1-Benzylpiperidin-3-yl 2-hydroxy-2,2-diphenylacetate;

xv. (R)-1-Benzylpiperidin-3-yl 2-hydroxy-2,2-diphenylacetate;

xvi. (S)-1-Methylpiperidin-3-yl 2-hydroxy-2,2-diphenylacetate;

xvii. (R)-1-Methylpiperidin-3-yl 2-hydroxy-2,2-diphenylacetate;

xviii. (R)-N-(1-Benzylpiperidin-3-yl)-2-hydroxy-2,2-diphenylacetamide;

xxix. (R)-N-(1-Benzylpiperidin-3-yl)-2-hydroxy-2,2-diphenylacetamide;

xxx. 2-Hydroxy-2,2-diphenyl-N-(piperidin-4-yl)acetamide;

xxxi. (S)-2-Hydroxy-N-(1-methylpiperidin-3-yl)-2,2-diphenylacetamide;

xxxii. (R)-2-Hydroxy-N-(1-methylpiperidin-3-yl)-2,2-diphenylacetamide;

xxxiii. 1-Benzylazetidin-3-yl 2-hydroxy-2-phenylpropanoate;

xxxiv. (R)-N-(1-Benzylpiperidin-3-yl)-2,2-diphenylacetamide;

xxxv. N-((S)-1-Benzylpiperidin-3-yl)-2-hydroxy-2-phenylacetamide;

xxxvi. N-((R)-1-Benzylpiperidin-3-yl)-2-hydroxy-2-phenylpropanamide;

xxxvii. (R)-(R)-1-Methylpiperidin-3-yl 2-hydroxy-2-phenylacetate;

xxxviii. (R)-(S)-1-Methylpiperidin-3-yl 2-hydroxy-2-phenylacetate;

xxxix. (S)-(R)-1-Methylpiperidin-3-yl 2-hydroxy-2-phenylacetate;

xl. (S)-(S)-1-Methylpiperidin-3-yl 2-hydroxy-2-phenylacetate;

xli. (R)-1-Methylpiperidin-4-yl 2-hydroxy-2-phenylacetate;

xlii. (S)-2-Hydroxy-N-(1-methylpiperidin-4-yl)-2-phenylacetamide;

xliii. (R)-2-Hydroxy-N-(1-methylpiperidin-4-yl)-2-phenylacetamide;

xliv. (R)-2-Hydroxy-N-((R)-1-methylpiperidin-3-yl)-2-phenylacetamide;

xlv. (R)-2-Hydroxy-N-((S)-1-methylpiperidin-3-yl)-2-phenylacetamide;

xlvi. (S)-2-Hydroxy-2-phenyl-N-(pyridin-3-yl)acetamide;

xlvii. (S)-1-Methylpiperidin-4-yl 2-hydroxy-2-phenylacetate;

xlviii. (S)-1-Benzylazetidin- 3-yl 2-hydroxy-2-phenylacetate;

xlix. (S)-(R)-Quinuclidin-3-yl 2-hydroxy-2-phenylacetate;

l. (S)-(S)-Quinuclidin-3-yl 2-hydroxy-2-phenylacetate;

li. (R)-N-(1-B enzylpiperidin-4-yl)-2-hydroxy-2-phenylacetamide;

lii. (S)-N-(1-B enzylpiperidin-4-yl)-2-hydroxy-2-phenylacetamide;

liii. (R)-3-((R)-2-Hydroxy-2-phenylacetoxy)-1,1-dimethylpiperidin-1-ium;

liv. (S)-3-((R)-2-Hydroxy-2-phenylacetoxy)-1,1-dimethylpiperidin-1-ium;

lv. (R)-2-Hydroxy-2-phenyl-N-(pyridin-3-yl)acetamide;

lvi. (R)-(S)-1-Methylpiperidin-3-yl 2-acetoxy-2-phenylacetate;

lvii. (R)-(R)-1-Methylpyrrolidin-3-yl 2-hydroxy-2-phenylacetate;

lviii. (R)-(S)-1-Methylpyrrolidin-3-yl 2-hydroxy-2-phenylacetate;

lix. (S)-(R)-1-Methylpiperidin-3-yl 2-methoxy-2-phenylacetate;

lx. (R)-2-Hydroxy-2-phenyl-N-(piperidin-4-yl)acetamide;

lxi. (R)-Piperidin-4-yl 2-hydroxy-2-phenylacetate;

lxii. (R)-3-(2-Hydroxy-2,2-diphenylacetoxy)-1,1-dimethylpiperidin-1-ium;

lxiii. (R)-3-(2-Hydroxy-2,2-diphenylacetoxy)-1,1-dimethylpiperidin-1-ium;

lxiv. (R)-3-((R)-2-Hydroxy-2-phenylacetoxy)-1,1-dimethylpiperidin-1-ium;

lxv. (R)-3-((R)-2-Hydroxy-2-phenylacetoxy)-1,1-dimethylpiperidin-1-ium;

lxvi. (S)-(R)-1-Methylpiperidin-3-yl 2-methoxy-2-phenylacetate;

lxvii. (S)-(S)-1-Methylpiperidin-3-yl 2-methoxy-2-phenylacetate;

lxviii. (S)-2-Hydroxy-N-((R)-1-methylpiperidin-3-yl)-2-phenylacetamide;

lxix. (S)-2-Hydroxy-N-((S)-1-methylpiperidin-3-yl)-2-phenylacetamide;

lxx. 3-(2,2-Diphenylacetamido)-1,1-dimethylpiperidin-1-ium;

lxxi. (2S)-1-Benzyl-2-((2,2-diphenylacetamido)methyl)-1-methylpyrrolidin-1-ium;

lxxii. 3-(2-Hydroxy-2,2-diphenylacetamido)-1,1-dimethylpiperidin-1-ium;

lxxiii. (R)-2-Methoxy-1-((S)-3-methylmorpholino)-2-phenylethanone;

lxxiv. (1S,3R)-1-Benzyl- 3-(2,2-diphenylacetamido)- 1-methylpiperidin-1-ium;

lxxv. (1S,3R)-1-Benzyl-3-(2,2-diphenylacetamido)-1-methylpiperidin-1-ium;

lxxvi. (1R,3R)-1-Benzyl-3-(2,2-diphenylacetamido)-1-methylpiperidin-1-ium;

lxxvii. 1-(3 - (Benzylamino)piperidin-l-yl)-2,2-diphenylethanone;

lxxviii. N-((1 -Benzylpyrrolidin-2-yl)methyl)-2,2-diphenylacetamide;

lxxix. 1-Benzyl-2-((2,2-diphenylacetamido)methyl)-1-methylpyrrolidin-1-ium;

lxxx. (R)-2-Methoxy-2-phenyl-N-(piperidin-4-yl)acetamide;

lxxxi. 2-Hydroxy-2-phenyl-N-(piperidin-4-yl)acetamide;

lxxxii. (S)-2-Hydroxy-2-phenyl-N-(piperidin-4-yl)acetamide;

lxxxiii. (S)-2-Methoxy-2-phenyl-N-(piperidin-4-yl)acetamide;

lxxxiv. 2-Hydroxy-2-phenyl-N-(piperidin-4-yl)propanamide;

lxxxv. 2-(3-Bromo-2,6-difluorophenyl)-2-hydroxy-N-(piperidin-4-yl)acetamide;

lxxxvi. (R)-2-Methoxy-N-methyl-2-phenyl-N-(piperidin-4-yl)acetamide;

lxxxvii. (R)-N-(1-Benzylpiperidin-4- yl)-2-methoxy-N-methyl-2-phenylacetamide;

lxxxviii. (S)-1-Benzylpiperidin-4- yl 2-methoxy-2-phenylacetate; and

lxxxix. (R)-Ethyl 4-(2-methoxy-2-phenylacetamido)piperidine-1-carboxylate.

5. The method of claim 1 , wherein the compound having Formula (1), including its salts, hydrates and stereoisomers thereof is selected from the group consisting of:

i. (R)-2-Methoxy-2-phenyl-N-(piperidin-4-yl)acetamide;

ii. 2-Hydroxy-2-phenyl-N-(piperidin-4-yl)acetamide;

iii. (S)-2-Hydroxy-2-phenyl-N-(piperidin-4-yl)acetamide;

iv. (S)-2-Methoxy-2-phenyl-N-(piperidin-4-yl)acetamide;

v. 2-Hydroxy-2-phenyl-N-(piperidin-4-yl)propanamide;

vi. 2-(3-Bromo-2,6-difluorophenyl)-2-hydroxy-N-(piperidin-4-yl)acetamide;

vii. (R)-2-Hydroxy-2-phenyl-N-(piperidin-4-yl)acetamide; and

viii. (R)-3-(2-Hydroxy-2,2-diphenylacetoxy)-1,1-dimethylpiperidin-1-ium.

6. A method for treatment of an infection caused by resistant or non-resistant Mycobacterium tuberculosis , comprising inhibiting GPR109A in the Mycobacterium tuberculosis by a compound of structural Formula (1), including its salts, hydrates or stereoisomers:

wherein

X is O, NH or N(alkyl);

R 1 and R 2 are independently hydrogen, but with the proviso that R 1 and R 2 are not both hydrogen, deuterium, hydroxyl, C 1-10 straight chain or branched chain alkyl, 3-7 membered cycloalkyl, C 1-6 alkoxy, aryl, amino, NH(alkyl), N(alkyl) 2 ,OCOR 5 , heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N and S; or R 1 and R 2 may combined to form an aryl or a heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of O, N and S;

R 3 is a non-aromatic heterocyclic ring or fused heterocyclic ring selected from:

X may in conjunction with R 3 form a 5-7 membered heterocyclic ring comprising 1-3 heteroatoms selected from group consisting of N, O and S, wherein the heterocyclic ring be further substituted with one or more lower alkyl groups, halogens, amino, NH(alkyl), N(alkyl) 2 , NH-aralkyl;

R 4 is a hydrogen, lower straight chain or branched alkyl, halogen, deuterium, C 1-6 alkoxy, amino, NH(alkyl), N(alkyl) 2 , —COOR 8 , or CONR 8 R 9 ;

R 5 is hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, NH(alkyl), or N(alkyl) 2 ;

R 6 and R 7 are independently selected from the group consisting of hydrogen, C 1-10 alkyl, —COR 8 , —CH 2 OCOR 8 , —CH 2 OCONHR 8 R 9 , —COOR 8 , —CONR 8 R 9 , —SO 2 R 8 , aryl, and aralkyl;

R 8 and R 9 are independently selected from the group consisting of hydrogen, and C 1-6 straight chain or branched chain alkyl; and

n is 1, 2, or 3.

7. The method of claim 6 , wherein the infection is drug-sensitive, mono-drug resistance, multi drug-resistant (MDR), extensively drug-resistant (XDR) or totally drug resistant (TDR) tuberculosis caused by a strain of Mycobacterium tuberculosis.

8. A method for treatment of resistant or non-resistant tuberculosis infection in a subject in need thereof, comprising inhibiting GPR109A in the subject by a compound of structural Formula (1), including its salts, hydrates or stereoisomers:

wherein

X is O, NH or N(alkyl);

R 1 and R 2 are independently hydrogen, but with the proviso that R 1 and R 2 are not both hydrogen, deuterium, hydroxyl, C 1-10 straight chain or branched chain alkyl, 3-7 membered cycloalkyl, C 1-6 alkoxy, aryl, amino, NH(alkyl), N(alkyl) 2 ,OCOR 5 , heteroaryl containing 1-3 heteroatoms selected from the group consisting of O, N and S; or R 1 and R 2 may combined to form an aryl or a heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of O, N and S;

R 3 is a non-aromatic heterocyclic ring or fused heterocyclic ring selected from:

X may in conjunction with R 3 form a 5-7 membered heterocyclic ring comprising 1-3 heteroatoms selected from group consisting of N, O and S, wherein the heterocyclic ring be further substituted with one or more lower alkyl groups, halogens, amino, NH(alkyl), N(alkyl) 2 , NH-aralkyl;

R 4 is a hydrogen, lower straight chain or branched alkyl, halogen, deuterium, C 1-6 alkoxy, amino, NH(alkyl), N(alkyl) 2 , —COOR 8 , or CONR 8 R 9 ;

R 5 is hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, NH(alkyl), or N(alkyl) 2 ;

R 6 and R 7 are independently selected from the group consisting of hydrogen, C 1-10 alkyl, —COR 8 , —CH 2 OCOR 8 , —CH 2 OCONHR 8 R 9 , —COOR 8 , —CONR 8 R 9 , —SO 2 R 8 , aryl, and aralkyl;

R 8 and R 9 are independently selected from the group consisting of hydrogen, and C 1-6 straight chain or branched chain alkyl; and

n is 1, 2, or 3.

9. The method of claim 8 , wherein the infection is drug-sensitive, mono-drug resistance, multi drug-resistant (MDR), extensively drug-resistant (XDR) or totally drug resistant (TDR) tuberculosis caused by a strain of Mycobacterium tuberculosis.

Assignments (2)
CHANGE OF NAME Recorded Oct 29, 2020
From: DRUG DISCOVERY RESEARCH CENTRE
To: TRANSLATIONAL HEALTH SCIENCE AND TECHNOLOGY INSTITUTE
Reel/Frame 054939/0368 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 16, 2017
From: DUGAR, SUNDEEP; MAHAJAN, DINESH; RAI, SANTOSH KUMAR; RAO, KANURY; SINGH, VARSHNEYA
To: SPHAERA PHARMA PVT. LTD.; DRUG DISCOVERY RESEARCH CENTRE
Reel/Frame 044477/0351 →
Priority Claims (1)
IN 1431/DEL/2014 · May 30, 2014 · national
Continuity (2)
Division 15313986
Related Publication 20170334851A1 · Nov 23, 2017