US2010029608A1PendingUtilityA1
Histamine H3 Receptor Agents, Preparation and Therapeutic Uses
Est. expiryAug 23, 2024(expired)· nominal 20-yr term from priority
Inventors:Don Richard FinleyTerry Patrick FinnPhilip Arthur HipskindWilliam J. HornbackCynthia Darshini JesudasonTakako Takakuwa
A61P 43/00C07D 417/14C07D 405/10C07D 417/10C07D 409/14C07D 207/327C07D 413/14A61P 25/00C07D 401/14C07D 403/10A61P 3/04C07D 409/10
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Claims
Abstract
The present invention provides a novel compound of Formula (I) or a pharmaceutically acceptable salt thereof, having histamine-113 receptor antagonist or inverse agonist activity, as well as methods for preparing such compounds. In another, embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula (I) as well as methods of using them to treat obesity, cognitive deficiencies, narcolepsy, and other histamine H3 receptor-related diseases.
Claims
exact text as granted — not AI-modified1 - 15 . (canceled)
16 . A method for treatment of a nervous system disorder which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula I
or a pharmaceutically acceptable salt thereof wherein:
X independently represents carbon (substituted with hydrogen or the optional substituents indicated herein), or nitrogen:
R1 is independently —HET (optionally substituted on carbon independently, one to three times with R2, and optionally once substituted on nitrogen with R3), or -Benzofused heterocycle (optionally substituted on carbon, independently, one to three times with R2, and optionally once substituted on nitrogen with R3);
R2 is independently at each occurrence
—H, -halogen, —(C 1 -C 7 ) alkyl (optionally substituted with one to three halogens), —CN, —C(O)R7, —C(O)OR7, —C(O)(C 3 -C 5 )cycloalkyl (optionally substituted with one to three halogens), —C(O)NR7R8, —OR7, —NO 2 , —NR7R8, —NR9SO 2 R7, —NR9C(O)R7, —NR9CO 2 R7, —NR9C(O)NR7R8, —SR7, —SO 2 R7, —SO 2 NR7R8, —S(O)R7, -phenyl-R9, —C(H)═NO—R7, -pyridinyl, —HET-R9, or —(C 1 -C 7 )alkyl-NHC(O)R7 (provided that not more than one occurrence of R2 is —HET-R9 or -phenyl-R9);
R3 is independently at each occurrence
—H, —(C 1 -C 7 ) alkyl (optionally substituted with one to three halogens), —SO 2 R7, —C(O)R7, —C(O)NR7R8, or —C(O)OR7:
R4 and R5 are independently
—H, —OH, -halogen, —(C 1 -C 3 )alkyl (optionally substituted with one to three halogens), or —OR9, provided that when X is nitrogen, then R4 and R5 are not attached to X;
R6 is independently
—H, -halogen, —(C 1 -C 3 ) alkyl (optionally substituted with one to three halogens), —NH 2 , —NR7R8, —OH, or —OR7;
R7 and R8 are independently
—H, -phenyl, —(C 1 -C 7 ) alkyl (optionally substituted with one to three halogens); or R7 and R8 combine with the atom to which they are attached to form a 4 to 7 membered ring;
R9 is
—H, -halogen, —(C 1 -C 3 ) alkyl (optionally substituted with one to three halogens), or —OR7.
17 . The method of claim 16 wherein the compound of formula I is selected from the group consisting of formula X1 to X43, X45 to X57:
Number
Structure
X1
X2
X3
X4
X5
X6
X7
X8
X9
X10
X11
X12
X13
X14
X15
X16
X17
X18
X19
X20
X21
X22
X23
X24
X25
X26
X27
X28
X29
X30
X31
X32
X33
X34
X35
X36
X37
X38
X39
X40
X41
X42
X43
X45
X46
X47
X48
X49
X50
X51
X52
X53
X54
X55
X56
X57
or a pharmaceutically acceptable salt thereof.
18 . (canceled)
19 . The method of claim 16 wherein the compound of formula I is selected from the group consisting of:
5-[4-(2(S)-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-thiophene-2-carbonitrile; 5-{4-[2-(2(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-phenyl}-thiophene-2-carbonitrile: 5-[4-(2(S)-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-thiophene-2-carboxylic acid amide; (2(S)-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(4-thiophen-2-yl-phenyl)-methanone; 5-[4-(2(S)-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-thiophene-2-carboxylic acid dimethylamide: 2-Methyl-1-{5-[4-(2(S)-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-thiophen-2-yl}-propan-1-one: 5-[4-(2(S)-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-thiophene-2-sulfonic acid amide; [4-(5-Oxazol-5-yl-thiophen-2-yl)-phenyl]-(2(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; [4-(5-Methylsulfanyl-thiophen-2-yl)-phenyl]-(2(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone: [4-(5-Methanesulfonyl-thiophen-2-yl)-phenyl]-(2(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; {4-[5-(Pyrrolidine-1-carbonyl)-thiophen-2-yl]-phenyl}-(2(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; 3-[4-(2(S)-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-thiophene-2-carbonitrile: [4-(5-Methanesulfonyl-thiophen-2-yl)-phenyl]-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone: [4-(5-Ethanesulfonyl-thiophen-2-yl)-phenyl]-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone: 5-[3-Fluoro-4-(2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-thiophene-2-carbonitrile; 5-{3-Fluoro-4-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-phenyl}-thiophene-2-carbonitrile; 4-{4-[2-(S)-(2-(R)-Methyl-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-phenyl}-thiophene-2-carboxylic acid amide; [4-(5-Bromo-thiophen-2-yl)-phenyl]-(2(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (2(S)-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(6-thiophen-2-yl-pyridin-3-yl)-methanone: (2(S)-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(6-thiophen-3-yl-pyridin-3-yl)-methanone; 4-{4-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-phenyl}-thiophene-2-carbonitrile; (2-(S)-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(4-thiazol-4-yl-phenyl)-methanone: (2-(S)-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(4-thiazol-2-yl-phenyl)-methanone: [4-(2-Methanesulfonyl-thiazol-4-yl)-phenyl]-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone; [4-(5-Phenyl-thiophen-2-yl)-phenyl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (4-Benzofuran-2-yl-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; [4-(4-Methyl-thiophen-2-yl)-phenyl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone: 1-{5-[4-((S)-2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-thiophen-2-yl}-ethanone; 4-Benzo[b]thiophen-2-yl-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; ((S)-2-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(4-thiophen-3 -yl-phenyl)-methanone: (2-Fluoro-4-thiophen-2-yl-phenyl)-((S)-2-pyrrolidin- 1 -ylmethyl-pyrrolidin-1-yl)-methanone; [4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (S)-2-[4-(2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-isoindole-1,3-dione; (S)-[4-(4-Pyridin-4-yl-pyrazol-1-yl)-phenyl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (S)-{4-[4-(4-Chloro-phenyl)-pyrazol-1-yl]-phenyl}-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (S)-(4-Benzothiazol-2-yl-phenyl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; (S)-[4-(6-Methoxy-benzo[b]thiophen-2-yl)-phenyl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone: (S)-(2-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-(4-[1,2,3]thiadiazol-4-yl-phenyl)-methanone; [4-(4-Pyridin-3-yl-thiazol-2-yl)-phenyl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; N-(1-Methyl-1-{2-[4-(2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-thiazol-4-yl}-ethyl)-acetamide: {4-[4-(3-Ethoxy-phenyl)-thiazol-2-yl]-phenyl}-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone; N-(1-Methyl-1-{2-[4-(2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-thiazol-4-yl}-ethyl)-benzamide; [4-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone: [4-(5-Chloro-1H-benzoimidazol-2-yl)-phenyl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone: [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-{4-[5-(pyrrolidine-1-carbonyl)-thiophen-2-yl]-phenyl}-methanone; {4-[5-(Azetidine-1-carbonyl)-thiophen-2-yl]-phenyl}-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone; [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-{4-[5-(piperidine-1-carbonyl)-thiophen-2-yl]-phenyl}-methanone: [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-{4-[5-(pyrrolidine-1-carbonyl)-thiazol-2-yl]-phenyl}-methanone; {2-Fluoro-4-[5-(pyrrolidine-1-carbonyl)-thiophen-2-yl]-phenyl}-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone; [2-Fluoro-4-(5-methanesulfonyl-thiophen-2-yl)-phenyl]-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone: [4-(5-Ethanesulfonyl-thiophen-2-yl)-2-fluoro-phenyl]-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone, 5-{4-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-phenyl}-thiophene-3-carbonitrile: [4-(1-Methyl-1H-imidazol-2-yl)-phenyl]-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone: {2-Fluoro-4-[5-(pyrrolidine-1-carbonyl)-thiazol-2-yl]-phenyl}-[2-(S)-(2-(R)-methyl pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-methanone, 5-{4-[2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidine-1-carbonyl]-phenyl}-thiophene-2-carbaldehyde O-methyl-oxime; 5-Methyl-1-[4-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-1H-pyrazole-4-carboxylic acid ethyl ester L-tartrate: and {5-Methyl-1-[4-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl]-1H-pyrazol-4-yl}-pyrrolidin-1-yl-methanone: or a pharmaceutically acceptable salt thereof.
20 . (canceled)
21 . (canceled)
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