US 8,912,176 B2Granted

Azetidines as histamine H3 receptor antagonists

AssigneeEvotec AG

InventorsAdam James Davenport, David James Hallett, Christopher Charles Stimson

Life of this patent

Estimating the term…

Abstract

The invention relates to compounds of formula (I), wherein R, R1, m, n and X1 to X3 have the meaning as cited in the description and the claims. Said compounds are useful as Histamine H3 receptor antagonists. The invention also relates to pharmaceutical compositions, the preparation of such compounds as well as the production and use as medicament.

Claims14

Dependent claims

A compound of formula (I)

or a pharmaceutically acceptable salt, wherein
R1 is C1-5 alkyl;
C2-5 alkenyl;
C2-5 alkynyl;
or T0, wherein C1-5 alkyl;
C2-5 alkenyl;
C2-5 alkynyl are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen;
OH;
OCH3;
OCH2F;
OCHF2;
OCF3;
CN;
and T0;
T0 is C3-5 cycloalkyl;
or 4 to 5 membered saturated heterocyclyl, wherein T0 is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen;
C1-5 alkyl;
C2-5 alkenyl;
C2-5 alkynyl;
OH;
O—C1-5 alkyl;
O—C2-5 alkenyl;
O—C2-5 alkynyl;
and CN, wherein C1-5 alkyl;
C2-5 alkenyl;
C2-5 alkynyl;
O—C1-5 alkyl;
O—C2-5 alkenyl;
and O—C2-5 alkynyl are optionally substituted with one or more halogen, which are the same or different;
n is 2;
X1 is N;
X2 is O;
S;
N—CN;
N—OH;
or N—OC1-4 alkyl;
X3 is (CH2)n1X4(CH2)n2R2;
R is F;
m is 0, 1, 2, 3, or 4;
n1;
n2 are independently selected from the group consisting of 0;
1;
and 2;
X4 is C(O);
C(O)O;
OC(O);
O;
C(O)N(R1a);
N(R1a)C(O);
S(O)2N(R1a);
N(R1a)S(O)2;
S(O)N(R1a);
N(R1a)S(O);
S(O)2;
S(O);
N(R1a)S(O)2N(R1b);
S;
N(R1a);
N(R1a)C(O)N(R1b);
N(R1a)C(O)O;
or OC(O)N(R1a);
R1a, R1b are independently selected from the group consisting of H;
C1-4 alkyl;
C2-4 alkenyl;
and C2-4 alkynyl, wherein C1-4 alkyl;
C2-4 alkenyl;
and C2-4 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R2 is H;
T;
or C1-6 alkyl;
C2-6 alkenyl;
or C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more R3, which are the same or different;
R3 is halogen;
CN;
C(O)R4;
C(O)OR4;
OR4;
C(O)N(R4R4a);
S(O)2N(R4R4a);
S(O)N(R4R4a);
S(O)2R4;
S(O)R4;
N(R4)S(O)2N(R4aR4b);
SR4;
N(R4R4a);
NO2;
OC(O)R4;
N(R4)C(O)R4a;
N(R4)SO2R4a;
N(R4)S(O)R4a;
N(R4)C(O)N(R4aR4b);
N(R4)C(O)OR4a;
OC(O)N(R4R4a);
or T;
R4, R4a, R4b are independently selected from the group consisting of H;
T;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more R5, which are the same or different;
R5 is halogen;
CN;
C(O)R6;
C(O)OR6;
OR6;
C(O)N(R6R6a);
S(O)2N(R6R6a);
S(O)N(R6R6a);
S(O)2R6;
S(O)R6;
N(R6)S(O)2N(R6aR6b);
SR6;
N(R6R6a);
NO2;
OC(O)R6;
N(R6)C(O)R6a;
N(R6)SO2R6a;
N(R6)S(O)R6a;
N(R6)C(O)N(R6aR6b);
N(R6)C(O)OR6a;
OC(O)N(R6R6a);
or T;
R6, R6a, R6b independently selected from the group consisting of H;
T;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T is phenyl;
naphthyl;
azulenyl;
indenyl;
indanyl;
C3-7 cycloalkyl;
3 to 7 membered heterocyclyl;
or 7 to 11 membered heterobicyclyl, wherein T is optionally substituted with one or more R7, which are the same or different;
R7 is halogen;
CN;
C(O)OR8;
OR8;
C(O)R8;
C(O)N(R8R8a);
S(O)2N(R8R8a);
S(O)N(R8R8a);
S(O)2R8;
S(O)R8;
N(R8)S(O)2N(R8aR8b);
SR8;
N(R8R8a);
NO2;
OC(O)R8;
N(R8)C(O)R8a;
N(R8)S(O)2R8a;
N(R8)S(O)R8a;
N(R8)C(O)OR8a;
N(R8)C(O)N(R8aR8b);
OC(O)N(R8R8a);
oxo (═O), where the ring is at least partially saturated;
T1;
C1-6 alkyl;
C2-6 alkenyl;
or C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more R9, which are the same or different;
R8, R8a, R8b are independently selected from the group consisting of H;
T1;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more R10, which are the same or different;
R9, R10 are independently selected from the group consisting of halogen;
CN;
C(O)R11;
C(O)OR11;
OR11;
C(O)N(R11R11a);
S(O)2N(R11R11a);
S(O)N(R11R11a);
S(O)2R11;
S(O)R11;
N(R11)S(O)2N(R11aR11b);
SR11;
N(R11R11a);
NO2;
OC(O)R11;
N(R11)C(O)R11a;
N(R11)SO2R11a;
N(R11)S(O)R11a;
N(R11)C(O)N(R11aR11b);
N(R11)C(O)OR11a;
OC(O)N(R11R11a);
and T1;
R11, R11a;
R11b are independently selected from the group consisting of H;
T1;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T1 is phenyl;
C3-7 cycloalkyl;
or 3 to 7 membered heterocyclyl, wherein T1 is optionally substituted with one or more R12, which are the same or different;
R12 is halogen;
CN;
C(O)OR13;
OR13;
C(O)R13;
C(O)N(R13R13a);
S(O)2N(R13R13a);
S(O)N(R13R13a);
S(O)2R13;
S(O)R13;
N(R13)S(O)2N(R13aR13b);
SR13;
N(R13R13a);
NO2;
OC(O)R13;
N(R13)C(O)R13a;
N(R13)S(O)2R13a;
N(R13)S(O)R13a;
N(R13)C(O)OR13a;
N(R13)C(O)N(R13aR13b);
OC(O)N(R13R13a);
oxo (═O), where the ring is at least partially saturated;
C1-6 alkyl;
C2-6 alkenyl;
or C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R13, R13a, R13b are independently selected from the group consisting of H;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different.

238 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/147,337Filed 29 Jan 2010 · us provisional application
Priority: EP 091518662 Feb 2009
Published: US 2012/0040952 A116 Feb 2012
Granted: 16 Dec 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification30 codes

C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents

Family

Application61/151,395Us provisional application · filed 10 Feb 2009
US 2012/0040952 A1Pre-grant publication · published 16 Feb 2012
US 8,912,176 B2This patent

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

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Abstract

A compound of formula (I)

or a pharmaceutically acceptable salt, wherein
R1 is C1-5 alkyl;
C2-5 alkenyl;
C2-5 alkynyl;
or T0, wherein C1-5 alkyl;
C2-5 alkenyl;
C2-5 alkynyl are optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen;
OH;
OCH3;
OCH2F;
OCHF2;
OCF3;
CN;
and T0;
T0 is C3-5 cycloalkyl;
or 4 to 5 membered saturated heterocyclyl, wherein T0 is optionally substituted with one or more substituents, which are the same or different and selected from the group consisting of halogen;
C1-5 alkyl;
C2-5 alkenyl;
C2-5 alkynyl;
OH;
O—C1-5 alkyl;
O—C2-5 alkenyl;
O—C2-5 alkynyl;
and CN, wherein C1-5 alkyl;
C2-5 alkenyl;
C2-5 alkynyl;
O—C1-5 alkyl;
O—C2-5 alkenyl;
and O—C2-5 alkynyl are optionally substituted with one or more halogen, which are the same or different;
n is 2;
X1 is N;
X2 is O;
S;
N—CN;
N—OH;
or N—OC1-4 alkyl;
X3 is (CH2)n1X4(CH2)n2R2;
R is F;
m is 0, 1, 2, 3, or 4;
n1;
n2 are independently selected from the group consisting of 0;
1;
and 2;
X4 is C(O);
C(O)O;
OC(O);
O;
C(O)N(R1a);
N(R1a)C(O);
S(O)2N(R1a);
N(R1a)S(O)2;
S(O)N(R1a);
N(R1a)S(O);
S(O)2;
S(O);
N(R1a)S(O)2N(R1b);
S;
N(R1a);
N(R1a)C(O)N(R1b);
N(R1a)C(O)O;
or OC(O)N(R1a);
R1a, R1b are independently selected from the group consisting of H;
C1-4 alkyl;
C2-4 alkenyl;
and C2-4 alkynyl, wherein C1-4 alkyl;
C2-4 alkenyl;
and C2-4 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R2 is H;
T;
or C1-6 alkyl;
C2-6 alkenyl;
or C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more R3, which are the same or different;
R3 is halogen;
CN;
C(O)R4;
C(O)OR4;
OR4;
C(O)N(R4R4a);
S(O)2N(R4R4a);
S(O)N(R4R4a);
S(O)2R4;
S(O)R4;
N(R4)S(O)2N(R4aR4b);
SR4;
N(R4R4a);
NO2;
OC(O)R4;
N(R4)C(O)R4a;
N(R4)SO2R4a;
N(R4)S(O)R4a;
N(R4)C(O)N(R4aR4b);
N(R4)C(O)OR4a;
OC(O)N(R4R4a);
or T;
R4, R4a, R4b are independently selected from the group consisting of H;
T;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more R5, which are the same or different;
R5 is halogen;
CN;
C(O)R6;
C(O)OR6;
OR6;
C(O)N(R6R6a);
S(O)2N(R6R6a);
S(O)N(R6R6a);
S(O)2R6;
S(O)R6;
N(R6)S(O)2N(R6aR6b);
SR6;
N(R6R6a);
NO2;
OC(O)R6;
N(R6)C(O)R6a;
N(R6)SO2R6a;
N(R6)S(O)R6a;
N(R6)C(O)N(R6aR6b);
N(R6)C(O)OR6a;
OC(O)N(R6R6a);
or T;
R6, R6a, R6b independently selected from the group consisting of H;
T;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T is phenyl;
naphthyl;
azulenyl;
indenyl;
indanyl;
C3-7 cycloalkyl;
3 to 7 membered heterocyclyl;
or 7 to 11 membered heterobicyclyl, wherein T is optionally substituted with one or more R7, which are the same or different;
R7 is halogen;
CN;
C(O)OR8;
OR8;
C(O)R8;
C(O)N(R8R8a);
S(O)2N(R8R8a);
S(O)N(R8R8a);
S(O)2R8;
S(O)R8;
N(R8)S(O)2N(R8aR8b);
SR8;
N(R8R8a);
NO2;
OC(O)R8;
N(R8)C(O)R8a;
N(R8)S(O)2R8a;
N(R8)S(O)R8a;
N(R8)C(O)OR8a;
N(R8)C(O)N(R8aR8b);
OC(O)N(R8R8a);
oxo (═O), where the ring is at least partially saturated;
T1;
C1-6 alkyl;
C2-6 alkenyl;
or C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more R9, which are the same or different;
R8, R8a, R8b are independently selected from the group consisting of H;
T1;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more R10, which are the same or different;
R9, R10 are independently selected from the group consisting of halogen;
CN;
C(O)R11;
C(O)OR11;
OR11;
C(O)N(R11R11a);
S(O)2N(R11R11a);
S(O)N(R11R11a);
S(O)2R11;
S(O)R11;
N(R11)S(O)2N(R11aR11b);
SR11;
N(R11R11a);
NO2;
OC(O)R11;
N(R11)C(O)R11a;
N(R11)SO2R11a;
N(R11)S(O)R11a;
N(R11)C(O)N(R11aR11b);
N(R11)C(O)OR11a;
OC(O)N(R11R11a);
and T1;
R11, R11a;
R11b are independently selected from the group consisting of H;
T1;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T1 is phenyl;
C3-7 cycloalkyl;
or 3 to 7 membered heterocyclyl, wherein T1 is optionally substituted with one or more R12, which are the same or different;
R12 is halogen;
CN;
C(O)OR13;
OR13;
C(O)R13;
C(O)N(R13R13a);
S(O)2N(R13R13a);
S(O)N(R13R13a);
S(O)2R13;
S(O)R13;
N(R13)S(O)2N(R13aR13b);
SR13;
N(R13R13a);
NO2;
OC(O)R13;
N(R13)C(O)R13a;
N(R13)S(O)2R13a;
N(R13)S(O)R13a;
N(R13)C(O)OR13a;
N(R13)C(O)N(R13aR13b);
OC(O)N(R13R13a);
oxo (═O), where the ring is at least partially saturated;
C1-6 alkyl;
C2-6 alkenyl;
or C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R13, R13a, R13b are independently selected from the group consisting of H;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different.

238 more elements

Facts

Application

13/147,337Filed 29 Jan 2010 · us provisional application

Priority

EP 091518662 Feb 2009

Published

US 2012/0040952 A116 Feb 2012

Granted

16 Dec 2014

Term ends

Not estimatedThe source records don’t support an estimate.

Classification30 codes

C07D 403/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents