U.S. patent application number 14/627333 was filed with the patent office on 2016-02-18 for phenylcyclopropylamine derivatives and their medical use.
The applicant listed for this patent is ORYZON GENOMICS S.A.. Invention is credited to Julio CASTRO-PALOMINO LARIA, Nathalie GUIBOURT, Alberto ORTEGA MUNOZ.
Application Number | 20160045456 14/627333 |
Document ID | / |
Family ID | 41258723 |
Filed Date | 2016-02-18 |
United States Patent
Application |
20160045456 |
Kind Code |
A1 |
GUIBOURT; Nathalie ; et
al. |
February 18, 2016 |
PHENYLCYCLOPROPYLAMINE DERIVATIVES AND THEIR MEDICAL USE
Abstract
The present invention relates to phenylcyclopropylamine
derivatives. In particular, pharmaceutical compositions comprising
phenylcyclopropylamine derivatives are provided. The compounds of
this invention can, inter alia, be used for the treatment and the
prevention of cancer as well as neurodegenerative diseases or
disorders.
Inventors: |
GUIBOURT; Nathalie;
(Barcelona, ES) ; ORTEGA MUNOZ; Alberto;
(Barcelona, ES) ; CASTRO-PALOMINO LARIA; Julio;
(Barcelona, ES) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ORYZON GENOMICS S.A. |
Cornella de Llobreegat |
|
ES |
|
|
Family ID: |
41258723 |
Appl. No.: |
14/627333 |
Filed: |
February 20, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13138143 |
Sep 12, 2011 |
8993808 |
|
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PCT/EP2010/050697 |
Jan 21, 2010 |
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14627333 |
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Current U.S.
Class: |
514/311 ; 435/25;
514/351; 514/352; 514/357; 514/364; 514/365; 514/415; 514/438;
514/450; 514/452; 514/456; 514/466; 514/469; 514/524; 514/643;
514/647 |
Current CPC
Class: |
A61K 31/14 20130101;
A61P 35/00 20180101; A61K 31/47 20130101; G01N 2500/04 20130101;
A61K 31/4245 20130101; C07C 211/40 20130101; C07C 2601/02 20170501;
A61K 31/357 20130101; C07D 333/20 20130101; A61K 31/137 20130101;
C12Q 1/26 20130101; A61K 31/343 20130101; C07C 255/58 20130101;
A61K 31/381 20130101; C07D 213/61 20130101; A61K 31/4402 20130101;
C07D 333/28 20130101; A61K 31/44 20130101; A61K 31/353 20130101;
G01N 2500/20 20130101; C07D 213/38 20130101; A61K 31/4406 20130101;
A61K 31/4409 20130101; A61K 31/4045 20130101; A61K 31/277 20130101;
C07D 277/28 20130101; C07C 217/74 20130101; A61K 31/36 20130101;
A61K 31/426 20130101; C07C 217/58 20130101 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61K 31/277 20060101 A61K031/277; A61K 31/4402
20060101 A61K031/4402; A61K 31/4406 20060101 A61K031/4406; A61K
31/4409 20060101 A61K031/4409; A61K 31/426 20060101 A61K031/426;
A61K 31/381 20060101 A61K031/381; A61K 31/47 20060101 A61K031/47;
A61K 31/44 20060101 A61K031/44; A61K 31/4045 20060101 A61K031/4045;
A61K 31/343 20060101 A61K031/343; A61K 31/36 20060101 A61K031/36;
A61K 31/357 20060101 A61K031/357; A61K 31/353 20060101 A61K031/353;
A61K 31/4245 20060101 A61K031/4245; C12Q 1/26 20060101 C12Q001/26;
A61K 31/14 20060101 A61K031/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 21, 2009 |
EP |
09000790.7 |
Claims
1-31. (canceled)
32. A method for treating or preventing a cancer comprising the
administration to a subject in need of such treatment or prevention
a therapeutically effective amount of a compound of formula I
##STR00099## wherein: each of R1-R5 is independently chosen from
--H, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
-L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy,
alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is a -L-heterocyclyl
wherein the ring or ring system of said -L-heterocyclyl has from
0-3 substituents and wherein said 0-3 substituents are chosen from
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; or R8 is
-L-aryl wherein the ring or ring system of said -L-aryl has from
1-3 substituents and wherein said 1-3 substituents are chosen from
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and each n is independently
chosen from 0, 1, 2, and 3; or a pharmaceutically thereof.
33. The method of claim 32 wherein said cancer is chosen from
breast cancer, lung cancer, prostate cancer, testicular cancer,
brain cancer, colorectal cancer, blood cancer, and skin cancer.
34. The method of claim 32 wherein said subject is a human.
35. A method of identifying LSD1 selective and LSD1/MAO-B dual
inhibitors comprising determining the ability of a test compound to
inhibit LSD1, MAO-A, and MAO-B wherein a LSD1 selective inhibitor
is identified when the test compound inhibits LSD1 to a greater
extent than MAO-A and MAO-B and wherein a LSD1/MAO-B dual inhibitor
is identified when the test compound inhibits LSD1 and MAO-B to a
greater extent than it inhibits MAO-A wherein said test compound is
a compound of Formula I: ##STR00100## wherein: each of R1-R5 is
independently chosen from --H, halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; R6 is
chosen from --H and alkyl; R7 is chosen from --H, alkyl, and
cycloalkyl; R8 is a -L-heterocyclyl wherein the ring or ring system
of said -L-heterocyclyl has from 0-3 substituents and wherein said
0-3 substituents are chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, 0-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; or R8 is
-L-aryl wherein the ring or ring system of said -L-aryl has from
1-3 substituents and wherein said 1-3 substituents are chosen from
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n, and each n is independently
chosen from 0, 1, 2, and 3; or a compound of Formula I where the
phenyl ring attached to the cyclopropylamine moiety is replaced by
an optionally substituted heteroaryl group and the other variables
R6-R8 are as defined above.
36. The method of claim 32, wherein R6 and R7 are --H.
37. The method of claim 32, wherein L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and each n is independently
chosen from 0, 1, 2, and 3.
38. The method of claim 32, wherein L is --CH.sub.2-- or a covalent
bond.
39. The method of claim 32, wherein L is a covalent bond.
40. The method of claim 32, wherein: R8 is a -L-heterocyclyl
wherein the ring or ring system of said -L-heterocyclyl has from
0-3 substituents and wherein said 0-3 substituents are chosen from
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amino; or R8 is
-L-aryl, wherein said aryl is phenyl or naphtyl, wherein the ring
or ring system of said -L-aryl has from 1-3 substituents and
wherein said 1-3 substituents are chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.
41. The method of claim 32, wherein R8 is a -L-heterocyclyl wherein
the ring or ring system of said -L-heterocyclyl has from 0-3
substituents and wherein said 0-3 substituents are chosen from
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; or R8 is
-L-phenyl, wherein the phenyl ring of said -L-phenyl has from 1-3
substituents and wherein said 1-3 substituents are chosen from
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.
42. The method of claim 32, wherein R8 is a -L-heterocyclyl wherein
the ring or ring system of said -L-heterocyclyl has from 0-3
substituents and wherein said 0-3 substituents are chosen from
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanate, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.
43. The method of claim 32, wherein R8 is -L-phenyl, wherein the
phenyl ring of said -L-phenyl has from 1-3 substituents and wherein
said 1-3 substituents are chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.
44. The method of claim 32, wherein the substituents on the
cyclopropyl ring have the trans configuration.
45. The method of claim 32, wherein the compound is chosen from:
(trans)-N-(4-fluorobenzyl)-2-phenylcyclopropanamine;
(trans)-N-(4-fluorobenzyl)-2-phenylcyclopropanaminium;
4-(((trans)-2-phenylcyclopropylamino)methyl)benzonitrile;
(trans)-N-(4-cyanobenzyl)-2-phenylcyclopropanaminium;
(trans)-2-phenyl-N-(4-(trifluoromethyl)benzyl)cyclopropanamine;
(trans)-2-phenyl-N-(4-(trifluoromethyl)benzyl)cyclopropanaminium;
(trans)-2-phenyl-N-(pyridin-2-ylmethyl)cyclopropanamine;
(trans)-2-phenyl-N-(pyridin-3-ylmethyl)cyclopropanamine;
(trans)-2-phenyl-N-(pyridin-4-ylmethyl)cyclopropanamine;
(trans)-N-((6-methylpyridin-2-yl)methyl)-2-phenylcyclopropanamine;
(trans)-2-phenyl-N-(thiazol-2-ylmethyl)cyclopropanamine;
(trans)-2-phenyl-N-(thiophen-2-ylethyl)cyclopropanamine;
(trans)-N-((3-bromothiophen-2-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-((4-bromothiophen-2-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-(3,4-dichlorobenzyl)-2-phenylcyclopropanamine;
(trans)-N-(3-fluorobenzyl)-2-phenylcyclopropanaminium;
(trans)-N-(2-fluorobenzyl)-2-phenylcyclopropanamine;
(trans)-2-phenyl-N-(quinolin-4-ylmethyl)cyclopropanamine;
(trans)-N-(3-methoxybenzyl)-2-phenylcyclopropanamine;
(trans)-2-phenyl-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)cyclopropanam-
ine;
(trans)-N-((6-chloropyridin-3-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-((4-methylpyridin-2-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-((6-methoxypyridin-2-yl)methyl)-2-phenylcyclopropanamine;
2-(((trans)-2-phenylcyclopropylamino)methyl)pyridin-3-ol;
(trans)-N-((6-bromopyridin-2-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-(4-(benzyloxy)benzyl)-2-phenylcyclopropanamine;
(trans)-2-phenyl-N-(quinolin-2-ylmethyl)cyclopropanamine;
(trans)-2-phenyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropanam-
ine,
(trans)-N-((3-fluoropyridin-2-ylmethyl)-2-phenylcyclopropanamine;
(trans)-2-phenyl-N-(quinolin-3-ylmethyl)cyclopropanamine;
(trans)-N-((6-methoxypyridin-3-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-((5-methoxypyridin-3-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-((2-methoxypyridin-3-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-((3H-indol-3-ylmethyl)-2-phenylcyclopropanamine;
3-(((trans)-2-phenylcyclopropylamino)methyl)benzonitrile;
(trans)-N-(2-methoxybenzyl)-2-phenylcyclopropanamine;
3-(((trans)-2-phenylcyclopropylamino)methyl)pyridin-2-amine;
(trans)-N-((2-chloropyridin-3-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-(3,4-dimethoxybenzyl)-2-phenylcyclopropanamine;
(trans)-N-((2,3-dihydrobenzafuren-5-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-phenylcyclopropanamine;
(trans)-N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-phenylcycloprop-
anamine;
(trans)-N-(2,6-difluoro-4-methoxybenzyl)-2-phenylcyclopropanamine-
; (trans)-2-phenyl-N-(4-(trifluoromethoxy)benzyl)cyclopropanamine;
(trans)-N-(5-fluoro-2-methoxybenzyl)-2-phenylcyclopropanamine;
(trans)-N-(2-fluoro-4-methoxybenzyl)-2-phenylcyclopropanamine;
(trans)-N-((4-methoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-(2-fluoro-6-methoxybenzyl)-2-phenylcyclopropanamine;
(trans)-N-((2-methoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-((4,7-dimethoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine-
; (trans)-N-(4-methoxy-3-methylbenzyl)-2-phenylcyclopropanamine;
(trans)-N-(3-chloro-4-methoxybenzyl)-2-phenylcyclopropanamine;
(trans)-N-(3-fluoro-4-methoxybenzyl)-2-phenylcyclopropanamine;
(trans)-N-(4-methoxy-2-methylbenzyl)-2-phenylcyclopropanamine;
(trans)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)methyl)-2-phenylcyc-
lopropanamine,
(trans)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-phenylcyc-
lopropanamine;
(trans)-N-((2,2-dimethylchroman-6-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-(4-methoxy-2,3-dimethylbenzyl)-2-phenylcyclopropanamine;
(trans)-N-(4-methoxy-2,5-dimethylbenzyl)-2-phenylcyclopropanamine;
(trans)-N-(2-fluoro-4,5-dimethoxybenzyl)-2-phenylcyclopropanamine;
(trans)-N-(3-chloro-4,5-dimethoxybenzyl)-2-phenylcyclopropanamine;
(trans)-N-(2-chloro-3,4-dimethoxybenzyl)-2-phenylcyclopropanamine;
(trans)-N-(2,4-dimethoxy-6-methylbenzyl)-2-phenylcyclopropanamine;
(trans)-N-(2,5-dimethoxybenzyl)-2-phenylcyclopropanamine;
(trans)-N-(2,3-dimethoxybenzyl)-2-phenylcyclopropanamine;
(trans)-N-(2-chloro-3-methoxybenzyl)-2-phenylcyclopropanamine;
(trans)-N-((1H-indol-5-yl)methyl)-2-phenylcyclopropanamine;
(trans)-N-(1-(4-methoxyphenyl)ethyl)62-phenylcyclopropanamine;
(trans)-N-(1-(3,4-dimethoxyphenyl)ethyl)-2-phenylcyclopropanamine;
(trans)-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-phenylcyclopro-
panamine;
(trans)-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)-2-phenylcyclopropa-
namine;
(trans)-N-(1-(3,4-dimethoxyphenyl)propan-2-yl)-2-phenylcyclopropan-
amine;
(trans)-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2-phenylcycloprop-
anamine; and pharmaceutically acceptable salts of any thereof.
Description
[0001] The present invention relates to phenylcyclopropylamine
derivatives. In particular, pharmaceutical compositions comprising
phenylcyclopropylamine derivatives are provided. The compounds of
this invention can, inter alia, be used for the treatment and the
prevention of cancer as well as neurodegenerative diseases or
disorders.
[0002] Cancer is prevalent: there were about 3.2 million cancer
cases diagnosed (53% men, 47% women) and 1.7 million deaths from
cancer (56% men, 44% women) in Europe (Ferlay et al. (2007) Ann.
Oncol. 18(3):581-92). In the United States, the probability of
developing invasive cancer is 38% for females and 46% for males
that live to be 70 years older and older. In the US about 1.4
million new cases of cancer are expected for 2006. Although the
five year survival rate for cancer is now 65%, up from about 50% in
the mid-nineteen seventies, cancer is deadly. It is estimated that
565,000 people in the United States will die from cancer in 2006
(American Cancer Society, Surveillance Research, 2006). Despite
tremendous advances in cancer treatment and diagnosis, cancer
remains a major public health concern. Accordingly, there is a need
for new therapeutics with activity in cancer.
[0003] Another health crisis is facing industrialized nations. As
the population in these countries age, neurodegenerative diseases
are affecting more and more people, posing a tremendous economic
burden to national health systems. Alzheimer's disease is the
largest neurodegenerative disease; disease modifying drugs have
long been sought, but to-date, none have been identified. Other
neurodegenerative conditions include Parkinson's disease,
Huntington's disease, Lewy Body dementia, and which are all
characterized by disease progression which robs the patients of
their ability to perform normal daily activities, eventually
leading to death.
[0004] One similar characteristic amongst many cancers and
neurodegenerative diseases is aberrant gene expression. A number of
compounds have been shown to alter gene expression, including
histone deacetylase inhibitors which alter the histone acetylation
profile of chromatin. Histone deacetylase inhibitors have been
shown to alter gene expression. Another modification that is
involved in regulating gene expression is lysine methylation.
Methylation of histone lysines has recently been shown to be
important in regulating gene expression. A group of enzymes known
as lysine demethylases are involved in this histone modification.
One particular human histone lysine demethylase enzyme called
Lysine Specific Demethylase-1 (LSD1) was recently discovered (Shi
et al. (2004) Cell 119:941). LSD1 is also involved in regulating
the methylation of some non-histone lysines. LSD1 has a fair degree
of structural similarity, and amino acid identity/homology to
monoamine oxidases, all of which (i.e., MAO-A, MAO-B and LSD1) are
flavin dependent oxidases. Recent experiments with LSD1 have shown
that it is involved in diverse process such as carcinogenesis (Kahl
et al. (2006) Cancer Res. 66:1341-11347) and vascular inflammation
(Reddy et al. (2008) Circ. Res. 103:615). It was found that a
commercially available antidepressant, Parnate.RTM., which targets
monoamine oxidase (MAO), also inhibits LSD1 at clinically relevant
concentrations (Lee et al. (2006) Chem. Biol. 13:563-567). Lee et
al. initially reported that Parnate was a better inhibitor of LSD1
than either MAO-A and MAO-B but subsequent study by some of the
same authors found "IC.sub.50 values for 2-PCPA of 20.7.+-.2.1
.mu.M for LSD1, 2.3.+-.0.2 .mu.M for MAO A, and 0.95.+-.0.07 .mu.M
for MAO B." See Schmidt et al. (2007) Biochemistry 46(14)4408-4416.
Thus, Parnate (2-PCPA; tranylcypromine) is a better inhibitor of
MAO-A and MAO-B as compared to LSD1. Monoamine oxidase inhibitors
are useful for treating a number of conditions including depression
and neurodegenerative conditions like Parkinson's disease. Parnate
is part of a class of compounds known as phenylcyclopropylamines
which are related to another group of clinical useful MAO
inhibitors called propargylamines, exemplified by Pargyline which
also inhibits LSD1. Additionally, derivatives of Parnate also can
inhibit LSD1 (Gooden et al. (2008) Bioorg. Med. Chem. Let.
18:3047-3051). Another class of compounds was recently disclosed to
inhibit LSD1 activity: polyamines (Huang et al. (2007) PNAS
104:8023-8028). The polyamines inhibit LSD1 modestly and were shown
to cause the reexpression of genes aberrantly silenced in cancer
cells. Lee et al. ((2006) Chem. Biol. 13:563-567) reported that
tranylcypromine inhibits histone H3K4 demethylation and can
derepress Egr1 gene expression in some cancer lines. A body of
evidence is accumulating that Egr-1 is a tumor suppressor gene in
many contexts. Calogero et al ((2004) Cancer Cell International
4:1) reported that Egr-1 is downregulated in brain cancers and
exogenous expression of Egr-1 resulted in growth arrest and
eventual cell death in primary cancer cell lines. Lucerna et al.
((2006) Cancer Research 66, 6708-6713) showed that sustained
expression of Egr-1 causes antiangiogenic effects and inhibits
tumor growth in some models. Ferraro et al ((2005) J Clin Oncol.
March 20; 23(9):1921-6) reported that Egr-1 is downregulated in
lung cancer patients with a higher risk of recurrence and may be
more resistant to therapy. Scoumanne et al. ((2007) J Biol Chem.
May 25; 282(21):15471-5) observed that LSD1 is required for cell
proliferation. They found that deficiency in LSD1 leads to a
partial cell cycle arrest in G2/M and sensitizes cells to growth
suppression induced by DNA damage. Kahl et al ((2006) Cancer Res.
66(23):11341-7) found that LSD1 expression is correlated with
prostate cancer aggressiveness. Metzger et al. ((2005) Nature 15;
437(7057):436-9) reported that LSD1 modulation by siRNA and
pargyline regulates androgen receptor (AR) and may have therapeutic
potential in cancers where AR plays a role, like prostate, testis,
and brain cancers. Thus, a body of evidence has implicated LSD1 in
a number of cancers, which suggested that LSD1 is a therapeutic
target for cancer.
[0005] The phenylcyclopropylamines have been the subject of many
studies designed to elucidate an SAR for MAO inhibition. Kaiser et
al. ((1962) J. Med. Chem. 5:1243-1265) and Zirkle et al. ((1962) J.
Med. Chem. 1265-1284) have disclosed the synthesis and activity of
a number of phenylcyclopropylamine related compounds. Zirkle et al.
((1962) J. Med. Chem. 1265-1284) reported that mono- and
disubstitution of the amino group of trans-2-phenylcyclopropylamine
with methyl decreases the activity only slightly whereas
monosubstitution with larger groups like alkyl and aralkyl groups
results in considerable loss of activity in the tryptamine
potentiation assay for MAO activity. Studies have also been
conducted with phenylcyclopropylamine related compounds to
determine selectivity for MAO-A versus MAO-B since MAO-A inhibitors
can cause dangerous side-effects (see e.g., Yoshida et al. (2004)
Bioorg. Med Chem. 12(10):2645-2652; Hruschka et al. (2008) Biorg
Med Chem. (16):7148-7166; Folks et al. (1983) J. Clin.
Psychopharmacol. (3)249; and Youdim et al. (1983) Mod. Probl.
Pharmacopsychiatry (19):63). Other phenylcyclopropylamine type
compounds are disclosed in Bolesov et al ((1974) Zhurnal
Organicheskoi Khimii 10:8 1661-1669) and Russian Patent No. 230169
(19681030). Gooden et al. ((2008) Bioorg. Med. Chem. Let.
18:3047-3051) describe the synthesis of phenylcyclopropylamine
derivatives and analogs as well as their activity against MAO-A,
MAO-B, and LSD1. None of the compounds made in Gooden et al. showed
a lower Ki for LSD1 as compared to either MAO-A or MAO-B.
Additionally, most of the Gooden et al. phenylcyclopropylamine
derivatives were better inhibitors of MAO-A as compared to MAO-B.
Recently, Han et al. (Euro. J. Pharma. (2008)
doi:10.1016/j.ejphar.2008.12.025) reported that
phenylcyclopropylamine displays neuroprotective activity in PC12
cells.
[0006] Phenylcyclopropylamine derivatives are also disclosed in
U.S. Pat. No. 3,106,578, U.S. Pat. No. 6,211,244, US-A-2003/236225,
WO 03/093297, WO 2007/025144, and in Westland R D, et al. J Med
Chem. 1968. 11(4): 824-829.
[0007] In view of the lack of adequate treatments for conditions
such as cancer and neurodegeneration, there is a desperate need for
disease modifying drugs and drugs that work by inhibiting novel
targets. There is a need for the development of LSD1 selective
inhibitors particularly those which selectively inhibit LSD1 and
those which are dual inhibitors of MAO-B/LSD1.
[0008] This problem is solved by the embodiments of the present
invention as characterized herein below, in the appended examples
and the claims.
[0009] The present invention relates to phenylcyclopropylamine
derivatives. In particular, pharmaceutical compositions comprising
phenylcyclopropylamine derivatives are provided. The compounds of
this invention can, inter alia, be used for the treatment and the
prevention of diseases. The present invention provides compounds of
Formula I, pharmaceutical compositions comprising a compound of
Formula I and a pharmaceutically acceptable carrier, and their use
for treating and/or preventing diseases. One use of the compounds
of Formula I is for treating cancer. Another use for the compounds
of Formula I is to inhibit LSD1. Another use of the compounds of
Formula I is as dual inhibitors of MAO-B and LSD1. Compounds of
Formula I can have monoamine oxidase inhibition activity and
therefore can be used to treat and/or prevent disease like
depression and Parkinson's disease as well as other
neurodegenerative conditions.
[0010] In one embodiment, the invention provides a pharmaceutical
composition comprising a compound of Formula I and a
pharmaceutically acceptable carrier:
##STR00001##
wherein each of R1-R5 is independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is -L-heterocyclyl or
-L-aryl, wherein the ring or ring system of said -L-heterocyclyl or
-L-aryl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof.
[0011] In one specific aspect of the pharmaceutical compositions of
this embodiment, R8 is -L-heterocyclyl wherein said heterocyclyl
has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In a more
specific aspect, R8 is -L-heteroaryl wherein said heteroaryl has
from 0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect, R8 is heteroaryl (L is a bond) wherein said
heteroaryl has from 0-3 substituents chosen from halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. Unless otherwise specified, according
to the aspects described in this paragraph each L is independently
chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0012] In one specific aspect of the pharmaceutical compositions of
this embodiment, R8 is -L-aryl wherein said aryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In a more
specific aspect, R8 is aryl (L is a bond) wherein said aryl has
from 0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect, R8 is a phenyl group wherein said phenyl has
from 0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. Unless
otherwise specified, according to the aspects described in this
paragraph each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0013] The invention provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula I which is a selective inhibitor of LSD1. LSD1 selective
inhibitors have IC50 values for LSD1 which are at least 2-fold
lower than the IC50 value for MAO-A and/or MAO-B.
[0014] The invention also provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula I which is a dual inhibitor selective for LSD1 and MAO-B.
Dual LSD1/MAO-B selective inhibitors have IC50 values for LSD1 and
MAO-B which are at least 2-fold lower than the IC50 value for
MAO-A.
[0015] In one embodiment, the invention provides a compound of
Formula I for treating and/or preventing cancer:
##STR00002##
wherein each of R1-R5 is independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is -L-heterocyclyl or
-L-aryl, wherein the ring or ring system of said -L-heterocyclyl or
-L-aryl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof.
[0016] In one specific aspect of this embodiment, the cancer is
prostate cancer. In another specific aspect of this embodiment, the
cancer is brain cancer. In yet another specific aspect of this
embodiment, the cancer is breast cancer. In yet another specific
aspect of this embodiment, the cancer is lung cancer. In yet
another specific aspect of this embodiment, the cancer is
testicular cancer. In yet another specific aspect of this
embodiment, the cancer is colorectal cancer. In yet another
specific aspect of this embodiment, the cancer is blood cancer
(e.g., leukemia). In yet another specific aspect of this
embodiment, the cancer is skin cancer.
[0017] In one specific aspect of this embodiment the invention
provides a compound of Formula I for treating and/or preventing
cancer where R8 is -L-heterocyclyl wherein said heterocyclyl has
from 0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In a more
specific aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing cancer where
R8 is -L-heteroaryl wherein said heteroaryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing cancer where
R8 is heteroaryl (L is a bond) wherein said heteroaryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. Unless
otherwise specified, according to the aspects described in this
paragraph each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0018] In one specific aspect of this embodiment the invention
provides a compound of Formula I for treating and/or preventing
cancer where R8 is -L-aryl wherein said aryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In a more
specific aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing cancer where
R8 is aryl (L is a bond) wherein said aryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing cancer where
R8 is a phenyl group wherein said phenyl has from 0-3 substituents
chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl,
haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino,
acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl,
heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro,
sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl. N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. Unless otherwise specified, according
to the aspects described in this paragraph each L is independently
chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0019] In one embodiment, the invention provides a compound of
Formula I for treating and/or preventing a neurodegenerative
disease or disorder:
##STR00003##
wherein each of R1-R5 is independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is -L-heterocyclyl or
-L-aryl, wherein the ring or ring system of said -L-heterocyclyl or
-L-aryl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof.
[0020] In one specific aspect of this embodiment the invention
provides a compound of Formula I for treating and/or preventing a
neurodegenerative disease or disorder where R8 is -L-heterocyclyl
wherein said heterocyclyl has from 0-3 substituents chosen from
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. In a more specific aspect of this
embodiment the invention provides a compound of Formula I for
treating and/or preventing a neurodegenerative disease or disorder
where R8 is -L-heteroaryl wherein said heteroaryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing a
neurodegenerative disease or disorder where R8 is heteroaryl (L is
a bond) wherein said heteroaryl has from 0-3 substituents chosen
from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
-L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy,
alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. Unless otherwise specified, according
to the aspects described in this paragraph each L is independently
chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0021] In one specific aspect of this embodiment the invention
provides a compound of Formula I for treating and/or preventing a
neurodegenerative disease or disorder where R8 is -L-aryl wherein
said aryl has from 0-3 substituents chosen from halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. In a more specific aspect of this
embodiment the invention provides a compound of Formula I for
treating and/or preventing a neurodegenerative disease or disorder
where R8 is aryl (L is a bond) wherein said aryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing a
neurodegenerative disease or disorder where R8 is a phenyl group
wherein said phenyl has from 0-3 substituents chosen from halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. Unless otherwise specified, according
to the aspects described in this paragraph each L is independently
chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0022] In one embodiment, the invention provides a compound of
Formula I:
##STR00004##
wherein each of R1-R5 is independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is a -L-heterocyclyl or
-L-aryl, wherein the ring or ring system of said -L-heterocyclyl or
-L-aryl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof; with the provision that when R1, R2, R3,
R4, R5, R6, and R7 are all hydro and L is a bond, then R8 is not
2,4-dimethoxyphenyl, 4-nitrophenyl, phenyl, 4-bromophenyl,
4-methoxyphenyl, 4-chlorophenyl, or furan-2-yl, and also when R1,
R2, R3, R4, R5, and R7 are all hydro, L is a bond and R8 is phenyl,
then R6 is not methyl, ethyl or isopentyl.
[0023] In one aspect of this embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of Formula I as defined above.
[0024] In one specific aspect of this embodiment the invention
provides a compound of Formula I where R8 is -L-heterocyclyl
wherein said heterocyclyl has from 0-3 substituents chosen from
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. In a more specific aspect of this
embodiment the invention provides a compound of Formula I where R8
is -L-heteroaryl wherein said heteroaryl has from 0-3 substituents
chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl,
haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino,
acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl,
heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro,
sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. In an even more specific aspect of
this embodiment the invention provides a compound of Formula I
where R8 is heteroaryl (L is a bond) wherein said heteroaryl has
from 0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, hetero arylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. Unless
otherwise specified, according to the aspects described in this
paragraph each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0025] In one specific aspect of this embodiment the invention
provides a compound of Formula I where R8 is -L-aryl wherein said
aryl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In a more
specific aspect of this embodiment the invention provides a
compound of Formula I where R8 is aryl (L is a bond) wherein said
aryl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect of this embodiment the invention provides a
compound of Formula I where R8 is a phenyl group wherein said
phenyl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. According
to the aspects described in this paragraph each L is independently
chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0026] In one embodiment, the invention provides a compound of
Formula I wherein R8 is heterocyclyl having from 0-3 substituents
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heteroaryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; with the
provision that when R1, R2, R3, R4, R5, R6, and R7 are all hydro,
then R8 is not furan-2-yl.
[0027] In one embodiment, the invention provides compounds of
Formula I wherein R6 and R7 are hydro.
[0028] In one embodiment, the invention provides a compound of
Formula I wherein R1-R7 are each hydro and R8 is aryl group having
from 0-3 substituents independently chosen from halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heteroaryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; with the provision that when R1, R2,
R3, R4, R5, R6, and R7 are all hydro, then R8 is not
2,4-dimethoxyphenyl, 4-nitrophenyl, phenyl, 4-bromophenyl,
4-methoxyphenyl, or 4-chlorophenyl.
[0029] In one embodiment, the invention provides a compound of
Formula I wherein the phenyl ring attached to the cyclopropyl ring
has at least one substituent that is not hydro, i.e. at least one
of R1 to R5 is not hydro.
[0030] In one embodiment, the invention provides a method of
treating a cancer comprising administering, to a patient in need of
treatment, a therapeutically effective amount of a composition
comprising a compound of Formula I and a pharmaceutically
acceptable carrier. Accordingly, in one embodiment, the invention
provides a method for treating or preventing a cancer comprising
the administration of a therapeutically effective amount of a
compound of Formula I or a pharmaceutical composition comprising
said compound and a pharmaceutically acceptable carrier to a
subject (e.g. a human) in need of such a treatment or prevention.
In a related embodiment, the invention provides a compound of
Formula I for treating and/or preventing cancer. In another related
embodiment, the invention provides for the use of a compound of
Formula I for the manufacture of a medicament for treating and/or
preventing cancer. In a specific aspect of the embodiments of this
paragraph, the cancer is chosen from breast cancer, lung cancer,
prostate cancer, testicular cancer, brain cancer, colorectal
cancer, blood cancer (e.g., leukemia), or skin cancer. In a more
specific aspect of the embodiments of this paragraph, the cancer is
chosen from breast cancer, lung cancer, prostate cancer, testicular
cancer, or brain cancer.
[0031] In one embodiment, the invention provides a method of
inhibiting LSD1 activity comprising administering, to a patient in
need of treatment, an amount of a composition comprising a compound
of Formula I and a pharmaceutically acceptable carrier sufficient
to inhibit LSD1 activity. In a related embodiment, the invention
provides a compound of Formula I for inhibiting LSD1. In another
related embodiment, the invention provides for the use of a
compound of Formula I for the manufacture of a medicament for
inhibiting LSD1.
[0032] In one embodiment, the invention provides a method of
treating a neurodegenerative disease or disorder comprising
administering, to a patient in need of treatment, a therapeutically
effective amount of a composition comprising a compound of Formula
I and a pharmaceutically acceptable carrier. Accordingly, in one
embodiment, the invention provides a method for treating or
preventing a neurodegenerative disease comprising the
administration of a therapeutically effective amount of a compound
of Formula I or a pharmaceutical composition comprising said
compound and a pharmaceutically acceptable carrier to a subject
(e.g. a human) in need of such a treatment or prevention. In a
related embodiment, the invention provides a compound of Formula I
for treating and/or preventing a neurodegenerative disease. In
another related embodiment, the invention provides for the use of a
compound of Formula I for the manufacture of a medicament for
treating and/or preventing a neurodegenerative disease. In a
specific aspect of the embodiments of this paragraph, the
neurodegenerative disease or disorder is chosen from Alzheimer's
disease, Parkinson's disease, Huntington's disease, or Lewy Body
dementia.
[0033] In one embodiment, the invention provides a method of
inhibiting monoamine oxidase activity comprising administering, to
a patient in need of treatment, an amount of a composition
comprising a compound of Formula I and a pharmaceutically
acceptable carrier sufficient to inhibit monoamine oxidase
activity. In a related embodiment, the invention provides a
compound of Formula I for treating and/or preventing Parkinson's
disease and/or depression. In another related embodiment, the
invention provides for the use of a compound of Formula I for the
manufacture of a medicament for inhibiting monoamine oxidase. In
one specific aspect of this embodiment, the monoamine oxidase is
MAO-B.
[0034] In one embodiment, the invention provides a method for
identifying LSD1 selective inhibitors comprising determining the
ability of a test compound to inhibit LSD1 and monoamine oxidase
(MAO-A and/or MAO-B) wherein a test compound that inhibits LSD1
better than monoamine oxidase (MAO-A and/or MAO-B) is LSD1
selective. In one aspect of this embodiment, the test compound is
chosen from a phenylcyclopropylamine derivative, homolog or
analog.
[0035] In one embodiment, the invention provides a method for
identifying a dual inhibitor selective for LSD1/MAO-B as compared
to MAO-A comprising determining the ability of a test compound to
inhibit LSD1 and monoamine oxidase (MAO-A and MAO-B) wherein a test
compound that inhibits LSD1 and MAO-B better than LSD1 and
monoamine oxidase (MAO-A and/or MAO-B) is a dual LSD1/MAO-B
selective inhibitor. In one aspect of this embodiment, the test
compound is chosen from a phenylcyclopropylamine derivative,
homolog or analog.
[0036] Phenylcyclopropylamine derivatives, homologs, and analogs
can be made by methods known in the art e.g., including, but not
limited to the methods disclosed herein and in the references cited
herein.
[0037] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention pertains.
Although methods and materials similar or equivalent to those
described herein can be used in the practice or testing of the
present invention, suitable methods and materials are described
below. In case of conflict, the present specification, including
definitions, will control. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting.
[0038] Other features and advantages of the invention will be
apparent from the following detailed description, and from the
claims.
[0039] The present invention relates to compounds, the
identification of compounds and their use for treating and/or
preventing diseases. The present invention provides compounds of
Formula I, pharmaceutical compositions comprising a compound of
Formula I and a pharmaceutically acceptable carrier, and their use
for treating and/or preventing diseases. One use of the compounds
of Formula I is to treat and/or prevent cancer. Compounds of the
invention also inhibit monoamine oxidases, and can therefore be
used for treating and/or preventing a disease in which monoamine
oxidase inhibition is useful. Some compounds of Formula I can be
used as LSD1 selective inhibitors that inhibit LSD1 to a greater
extent than MAO-A and/or MAO-B. Some compounds of Formula I can be
used as dual LSD1/MAO-B selective inhibitors that inhibit LSD1 and
MAO-B to a greater extent than MAO-A. Some of the compounds of
Formula I can be used as inhibitors of MAO-A, MAO-B and LSD1. In
particular it was surprisingly found that phenylcyclopropylamine
derivatives with monosubstitution on the amine group with ring
bearing substituents yields compounds with unexpectedly potent LSD1
inhibition. For example, some of the compounds of Formula I have
IC50 values for LSD1 inhibition of less than 1 micromolar (see
Table 1) which makes them at least 20-30-fold more potent than
tranylcypromine for LSD1 inhibition. Furthermore, these types of
compounds also are potent inhibitors of the monoamine oxidases.
[0040] In one embodiment, the invention provides a pharmaceutical
composition comprising a compound of Formula I and a
pharmaceutically acceptable carrier:
##STR00005##
wherein each of R1-R5 is independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is -L-heterocyclyl or
-L-aryl, wherein the ring or ring system of said -L-heterocyclyl or
-L-aryl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof.
[0041] In one specific aspect of the pharmaceutical compositions of
this embodiment, R8 is -L-heterocyclyl wherein said heterocyclyl
has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In a more
specific aspect, R8 is -L-heteroaryl wherein said heteroaryl has
from 0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect, R8 is heteroaryl (L is a bond) wherein said
heteroaryl has from 0-3 substituents chosen from halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. Unless otherwise specified, according
to the aspects described in this paragraph each L is independently
chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0042] In one specific aspect of the pharmaceutical compositions of
this embodiment, R8 is L-aryl wherein said aryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In a more
specific aspect, R8 is aryl (L is a bond) wherein said aryl has
from 0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect, R8 is a phenyl group wherein said phenyl has
from 0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkynyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. Unless
otherwise specified, according to the aspects described in this
paragraph each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0043] In one aspect of this embodiment, the 0-3 substituents on
the ring or ring system of R8 are independently chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In a more specific aspect, the R8 ring
or ring system has 1 substituent chosen from hydroxyl, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, --N(C.sub.1-3
alkyl).sub.2, --NH(C.sub.1-3 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(C.sub.1-3 alkyl), --C(.dbd.O)N(C.sub.1-3
alkyl).sub.2, --S(.dbd.O).sub.2(C.sub.1-3alkyl),
--S(.dbd.O).sub.2NH.sub.2, --S(O).sub.2N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2NH(C.sub.1-3 alkyl), --CHF.sub.2, --OCF.sub.3,
--OCHF.sub.2--CF.sub.3, --CN, --NH.sub.2, and --NO.sub.2. In an
even more specific aspect, the R8 ring or ring system has 1
substituent chosen from halo, alkyl, alkoxy, haloalkyl, cyano, and
hydroxyl.
[0044] In one aspect of this embodiment, the ring or ring system of
R8 has 0-3 substituents. In a more specific aspect, the ring or
ring system of R8 has 1-3 substituents. In a more specific aspect,
the ring or ring system of R8 has 1 or 2 substituents. In an even
more specific aspect, the ring or ring system of R8 has 1
substituent.
[0045] In a further aspect of this embodiment, the aforementioned
substituent(s) on the ring or ring system of R8 are/is
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido, wherein
each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and further wherein each n
is independently chosen from 0, 1, 2, and 3. In a more specific
aspect of this embodiment, the aforementioned substituent(s) on the
ring or ring system of R8 are/is independently chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In an even more specific aspect, the
aforementioned substituent(s) on the ring or ring system of R8
are/is independently chosen from halo, alkyl, alkoxy, haloalkyl,
cyano, and hydroxyl.
[0046] In one aspect of this embodiment, R7 is chosen from --H and
cycloalkyl. In a more specific aspect of this embodiment, R7 is
--H.
[0047] In one aspect of this embodiment, L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is chosen from a covalent bond or --CH.sub.2--. In an
even more specific aspect, L is a covalent bond.
[0048] The invention provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula I, as defined herein above, which is a selective inhibitor
of LSD1. LSD1 selective inhibitors have IC50 values for LSD1 which
are at least 2-fold lower than the IC50 value for MAO-A and/or
MAO-B.
[0049] The invention also provides a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and a compound of
Formula I, as defined herein above, which is a dual inhibitor
selective for LSD1 and MAO-B. Dual LSD1/MAO-B selective inhibitors
have IC50 values for LSD1 and MAO-B which are at least 2-fold lower
than the IC50 value for MAO-A.
[0050] In one embodiment, the invention provides a compound of
Formula I for treating and/or preventing cancer:
##STR00006##
wherein each of R1-R5 is independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is -L-heterocyclyl or
-L-aryl, wherein the ring or ring system of said -L-heterocyclyl or
-L-aryl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof.
[0051] In one aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing cancer,
wherein the 0-3 substituents on the R8 ring or ring system are
independently chosen from hydroxyl, halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, alkyl).sub.2, --NH(C.sub.1-3
alkyl), --C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In a more specific aspect, the R8 ring
or ring system has 1 substituent chosen from hydroxyl, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, --N(C.sub.1-3
alkyl).sub.2, --NH(C.sub.1-3 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(C.sub.1-3 alkyl), --C(.dbd.O)N(C.sub.1-3
alkyl).sub.2, --S(.dbd.O).sub.2(C.sub.1-3alkyl),
--S(.dbd.O).sub.2NH.sub.2, --S(O).sub.2N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2NH(C.sub.1-3 alkyl), --CHF.sub.2, --OCF.sub.3,
--OCHF.sub.2, --CF.sub.3, --CN, --NH.sub.2, and --NO.sub.2. In an
even more specific aspect, the R8 ring or ring system has from 1
substituent chosen from halo, alkyl, alkoxy, haloalkyl, cyano, and
hydroxyl.
[0052] In one aspect of this embodiment, the ring or ring system of
R8 has 0-3 substituents. In a more specific aspect, the ring or
ring system of R8 has 1-3 substituents. In a more specific aspect,
the ring or ring system of R8 has 1 or 2 substituents. In an even
more specific aspect, the ring or ring system of R8 has 1
substituent. In a further aspect of this embodiment, the
aforementioned substituent(s) on the ring or ring system of R8
are/is independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido, wherein
each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and further wherein each n
is independently chosen from 0, 1, 2, and 3. In a more specific
aspect of this embodiment, the aforementioned substituent(s) on the
ring or ring system of R8 are/is independently chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CN, --NH.sub.2,
and --NO.sub.2. In an even more specific aspect, the aforementioned
substituent(s) on the ring or ring system of R8 are/is
independently chosen from halo, alkyl, alkoxy, haloalkyl, cyano,
and hydroxyl.
[0053] In one aspect of this embodiment, R7 is chosen from --H and
cycloalkyl. In a more specific aspect of this embodiment, R7 is
--H.
[0054] In one aspect of this embodiment, L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is chosen from a covalent bond or --CH.sub.2--. In an
even more specific aspect, L is a covalent bond.
[0055] In one specific aspect of this embodiment, the cancer is
prostate cancer. In another specific aspect of this embodiment, the
cancer is brain cancer. In yet another specific aspect of this
embodiment, the cancer is breast cancer. In yet another specific
aspect of this embodiment, the cancer is lung cancer. In yet
another specific aspect of this embodiment, the cancer is
testicular cancer. In yet another specific aspect of this
embodiment, the cancer is colorectal cancer. In yet another
specific aspect of this embodiment, the cancer is blood cancer
(e.g., leukemia). In yet another specific aspect of this
embodiment, the cancer is skin cancer.
[0056] In one specific aspect of this embodiment the invention
provides a compound of Formula I for treating and/or preventing
cancer where R8 is -L-heterocyclyl wherein said heterocyclyl has
from 0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In a more
specific aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing cancer where
R8 is -L-heteroaryl wherein said heteroaryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing cancer where
R8 is heteroaryl (L is a bond) wherein said heteroaryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. Unless
otherwise specified, according to the aspects described in this
paragraph each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0057] In one aspect of this embodiment, the invention provides a
compound of Formula I for treating and/or preventing cancer,
wherein the 0-3 substituents on the R8 ring or ring system are
independently chosen from hydroxyl, halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, alkyl).sub.2, --NH(C.sub.1-3
alkyl), --C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In a more specific aspect, the R8 ring
or ring system has 1 substituent chosen from hydroxyl, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, --N(C.sub.1-3
alkyl).sub.2, --NH(C.sub.1-3 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(C.sub.1-3 alkyl), --C(.dbd.O)N(C.sub.1-3
alkyl).sub.2, --S(.dbd.O).sub.2(C.sub.1-3alkyl),
--S(.dbd.O).sub.2NH.sub.2, --S(O).sub.2N(C.sub.1-3 alkyl).sub.2,
S(.dbd.O).sub.2NH(C.sub.1-3 alkyl), --CHF.sub.2, --OCF.sub.3,
--OCHF.sub.2, --CF.sub.3, --CN, --NH.sub.2, and --NO.sub.2. In an
even more specific aspect, the R8 ring or ring system has from 1
substituent chosen from halo, alkyl, alkoxy, haloalkyl, cyano, and
hydroxyl.
[0058] In one aspect of this embodiment, the ring or ring system of
R8 has 0-3 substituents. In a more specific aspect, the ring or
ring system of R8 has 1-3 substituents. In a more specific aspect,
the ring or ring system of R8 has 1 or 2 substituents. In an even
more specific aspect, the ring or ring system of R8 has 1
substituent.
[0059] In a further aspect of this embodiment, the aforementioned
substituent(s) on the ring or ring system of R8 are/is
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido, wherein
each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and further wherein each n
is independently chosen from 0, 1, 2, and 3. In a more specific
aspect of this embodiment, the aforementioned substituent(s) on the
ring or ring system of R8 are/is independently chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In an even more specific aspect, the
aforementioned substituent(s) on the ring or ring system of R8
are/is independently chosen from halo, alkyl, alkoxy, haloalkyl,
cyano, and hydroxyl.
[0060] In one aspect of this embodiment, R7 is chosen from --H and
cycloalkyl. In a more specific aspect of this embodiment, R7 is
--H.
[0061] In one aspect of this embodiment, L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is chosen from a covalent bond or --CH.sub.2--. In an
even more specific aspect, L is a covalent bond.
[0062] In one specific aspect of this embodiment the invention
provides a compound of Formula I for treating and/or preventing
cancer, wherein R8 is -L-aryl wherein said aryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In a more
specific aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing cancer where
R8 is aryl (L is a bond) wherein said aryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing cancer where
R8 is a phenyl group wherein said phenyl has from 0-3 substituents
chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl,
haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino,
acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl,
heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro,
sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. According to the aspects described in
this paragraph each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0063] In one specific aspect of this embodiment the invention
provides a compound of Formula I for treating and/or preventing
cancer, wherein R8 is -L-aryl wherein said aryl has from 1-3 (i.e.
1, 2 or 3) substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In a more
specific aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing cancer where
R8 is aryl (L is a bond) wherein said aryl has from 1-3 (i.e. 1, 2
or 3) substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect of this embodiment the invention provides a
compound of Formula I for treating and/or preventing cancer where
R8 is a phenyl group wherein said phenyl has from 1-3 (i.e. 1, 2 or
3) substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. According
to the aspects described in this paragraph each L is independently
chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0064] In one aspect of this embodiment, the invention provides a
compound of Formula I for treating and/or preventing cancer,
wherein the 0-3 substituents or the 1-3 substituents on the R8 ring
or ring system are independently chosen from hydroxyl, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, --N(C.sub.1-3
alkyl).sub.2, --NH(C.sub.1-3 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(C.sub.1-3 alkyl), --C(.dbd.O)N(C.sub.1-3
alkyl).sub.2, --S(.dbd.O).sub.2(C.sub.1-3alkyl),
--S(.dbd.O).sub.2NH.sub.2, --S(O).sub.2N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2NH(C.sub.1-3 alkyl), --CHF.sub.2, --OCF.sub.3,
--OCHF.sub.2, --CN, --NH.sub.2, and --NO.sub.2. In a more specific
aspect, the R8 ring or ring system has 1 substituent chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In an even more specific aspect, the R8
ring or ring system has from 1 substituent chosen from halo, alkyl,
alkoxy, haloalkyl, cyano, and hydroxyl.
[0065] In one aspect of this embodiment, the ring or ring system of
R8 has 0-3 substituents. In a more specific aspect, the ring or
ring system of R8 has 1-3 substituents. In a more specific aspect,
the ring or ring system of R8 has 1 or 2 substituents. In an even
more specific aspect, the ring or ring system of R8 has 1
substituent.
[0066] In a further aspect of this embodiment, the aforementioned
substituent(s) on the ring or ring system of R8 are/is
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido, wherein
each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and further wherein each n
is independently chosen from 0, 1, 2, and 3. In a more specific
aspect of this embodiment, the aforementioned substituent(s) on the
ring or ring system of R8 are/is independently chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In an even more specific aspect, the
aforementioned substituent(s) on the ring or ring system of R8
are/is independently chosen from halo, alkyl, alkoxy, haloalkyl,
cyano, and hydroxyl.
[0067] In one aspect of this embodiment, R7 is chosen from --H and
cycloalkyl. In a more specific aspect of this embodiment, R7 is
--H.
[0068] In one aspect of this embodiment, L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is chosen from a covalent bond or --CH.sub.2--. In an
even more specific aspect, L is a covalent bond.
[0069] In one aspect of this embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of Formula I as defined in the above
described embodiment.
[0070] In a preferred aspect of this embodiment, the invention
provides a compound of Formula I for use in treating and/or
preventing cancer:
##STR00007##
wherein: each of R1-R5 is independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is a -L-heterocyclyl
wherein the ring or ring system of said -L-heterocyclyl has from
0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; or R8 is
-L-aryl wherein the ring or ring system of said -L-aryl has from
1-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; or a pharmaceutically
acceptable salt thereof.
[0071] In another more preferred aspect, R8 is a -L-heterocyclyl
wherein the ring or ring system of said -L-heterocyclyl has from
0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.
[0072] In another more preferred aspect, R8 is -L-heterocyclyl
wherein said -L-heterocyclyl is -L-heteroaryl wherein the ring or
ring system of said -L-heteroaryl has from 0-3 substituents chosen
from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
-L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy,
alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl. N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido.
[0073] In another more preferred aspect, R8 is a -L-heterocyclyl
wherein the ring or ring system of said -L-heterocyclyl has from
0-3 substituents and further wherein said ring or ring system is
chosen from pyridyl, thiazolyl, thiophenyl, quinolinyl, indolyl,
oxadiazolyl, 2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl,
2,3-dihydrobenzo[b][1,4]dioxinyl,
3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, and chromanyl.
[0074] In another more preferred aspect, R8 is a -L-heteroaryl
wherein the ring or ring system of said -L-heteroaryl has from 0-3
substituents and further wherein said ring or ring system is chosen
from pyridyl, thiazolyl, thiophenyl, quinolinyl, indolyl, and
oxadiazolyl. In another more preferred aspect, R8 is a
-L-heteroaryl wherein the ring or ring system of said -L-heteroaryl
has from 0-3 substituents and further wherein said ring or ring
system is pyridyl.
[0075] In another more preferred aspect, R8 is -L-aryl wherein the
ring or ring system of said -L-aryl has from 1-3 (i.e. 1, 2 or 3)
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.
[0076] In another more preferred aspect, R8 is aryl (L is a bond)
wherein said aryl has from 1-3 (i.e. 1, 2 or 3) substituents chosen
from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
-L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy,
alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido.
[0077] In another more preferred aspect, L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, wherein each n is
independently chosen from 0, 1, 2, and 3. In another more preferred
aspect, L is --CH.sub.2-- or a covalent bond. In another more
preferred aspect, L is a covalent bond.
[0078] In another more preferred aspect, R6 and R7 are hydro.
[0079] In another more preferred aspect, at least one of R1 to R5
is not hydro. In another more preferred aspect, one of R1-R5 is
chosen from -L-aryl, -L-heterocyclyl, and -L-carbocyclyl.
[0080] In another more preferred aspect, the substituent or the
substituents on the R8 ring or ring system are chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl). --CN, --NH.sub.2, and --NO.sub.2. In another more preferred
aspect, the R8 ring or ring system has 1 substituent chosen from
halo, alkyl, alkoxy, haloalkyl, cyano, and hydroxyl.
[0081] In another more preferred aspect, the cancer to be treated
and/or prevented is chosen from breast cancer, lung cancer,
prostate cancer, testicular cancer, brain cancer, colorectal
cancer, blood cancer, and skin cancer.
[0082] In one embodiment, the invention provides a compound of
Formula I:
##STR00008##
wherein each of R1-R5 is independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is a -L-heterocyclyl or
-L-aryl, wherein the ring or ring system of said -L-heterocyclyl or
-L-aryl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof; with the provision that when R1, R2, R3,
R4, R5, R6, and R7 are all hydro and L is a bond, then R8 is not
2,4-dimethoxyphenyl, 4-nitrophenyl, phenyl, 4-bromophenyl,
4-methoxyphenyl, 4-chlorophenyl or furan-2-yl, and also when R1,
R2, R3, R4, R5, and R7 are all hydro, R8 is phenyl and L is a bond,
then R6 is not methyl, ethyl or isopentyl.
[0083] In one aspect of this embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of Formula I as defined in the above
described embodiment.
[0084] In one specific aspect of this embodiment the invention
provides a compound of Formula I where R8 is -L-heterocyclyl
wherein said heterocyclyl has from 0-3 substituents chosen from
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. In a more specific aspect of this
embodiment the invention provides a compound of Formula I where R8
is -L-heteroaryl wherein said heteroaryl has from 0-3 substituents
chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl,
haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino,
acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl,
heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro,
sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. In an even more specific aspect of
this embodiment the invention provides a compound of Formula I
where R8 is heteroaryl (L is a bond) wherein said heteroaryl has
from 0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. Unless
otherwise specified, according to the aspects described in this
paragraph each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0085] In one specific aspect of this embodiment the invention
provides a compound of Formula I where R8 is -L-aryl wherein said
aryl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In a more
specific aspect of this embodiment the invention provides a
compound of Formula I where R8 is aryl (L is a bond) wherein said
aryl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect of this embodiment the invention provides a
compound of Formula I where R8 is a phenyl group wherein said
phenyl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. Unless
otherwise specified, according to the aspects described in this
paragraph each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0086] In one specific aspect of this embodiment the invention
provides a compound of Formula I where R8 is -L-aryl wherein said
aryl has from 1-3 (i.e. 1, 2 or 3) substituents chosen from halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. In a more specific aspect of this
embodiment the invention provides a compound of Formula I where R8
is aryl (L is a bond) wherein said aryl has from 1-3 (i.e. 1, 2 or
3) substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. In an even
more specific aspect of this embodiment the invention provides a
compound of Formula I where R8 is a phenyl group wherein said
phenyl has from 1-3 (i.e. 1, 2 or 3) substituents chosen from halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. Unless otherwise specified, according
to the aspects described in this paragraph each L is independently
chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
definition, L is chosen from a covalent bond or --CH.sub.2--. In a
more specific definition, L is a covalent bond.
[0087] In one aspect of this embodiment, the invention provides a
compound of Formula I wherein the 0-3 substituents or the 1-3
substituents on the R8 ring or ring system are independently chosen
from hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl,
haloalkoxy, --N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In a more specific aspect, the R8 ring
or ring system has 1 substituent chosen from hydroxyl, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, --N(C.sub.1-3
alkyl).sub.2, --NH(C.sub.1-3 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(C.sub.1-3 alkyl), --C(.dbd.O)N(C.sub.1-3
alkyl).sub.2, --S(.dbd.O).sub.2(C.sub.1-3alkyl),
--S(.dbd.O).sub.2NH.sub.2, --S(O).sub.2N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2NH(C.sub.1-3 alkyl), --CHF.sub.2, --OCF.sub.3,
--OCHF.sub.2, --CF.sub.3, --CN, --NH.sub.2, and --NO.sub.2. In an
even more specific aspect, the R8 ring or ring system has from 1
substituent chosen from halo, alkyl, alkoxy, haloalkyl, cyano, and
hydroxyl.
[0088] In one aspect of this embodiment, the ring or ring system of
R8 has 0-3 substituents. In a more specific aspect, the ring or
ring system of R8 has 1-3 substituents. In a more specific aspect,
the ring or ring system of R8 has 1 or 2 substituents. In an even
more specific aspect, the ring or ring system of R8 has 1
substituent.
[0089] In a further aspect of this embodiment, the aforementioned
substituent(s) on the ring or ring system of R8 are/is
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido, wherein
each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and further wherein each n
is independently chosen from 0, 1, 2, and 3. In a more specific
aspect of this embodiment, the aforementioned substituent(s) on the
ring or ring system of R8 are/is independently chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In an even more specific aspect, the
aforementioned substituent(s) on the ring or ring system of R8
are/is independently chosen from halo, alkyl, alkoxy, haloalkyl,
cyano, and hydroxyl.
[0090] In one aspect of this embodiment, R7 is chosen from --H and
cycloalkyl. In a more specific aspect of this embodiment, R7 is
--H.
[0091] In one aspect of this embodiment, L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is chosen from a covalent bond or --CH.sub.2--. In an
even more specific aspect, L is a covalent bond.
[0092] In a preferred aspect of this embodiment, the invention
provides a compound of Formula I:
##STR00009##
wherein: each of R1-R5 is independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is a -L-heterocyclyl
wherein the ring or ring system of said -L-heterocyclyl has from
0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; or R8 is
-L-aryl wherein the ring or ring system of said -L-aryl has from
1-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and each n is independently
chosen from 0, 1, 2, and 3; or a pharmaceutically acceptable salt
thereof; with the provision that when L is a bond and R1, R2, R3,
R4, R5, R6, and R7 are all hydro, then R8 is not
2,4-dimethoxyphenyl, 4-nitrophenyl, phenyl, 4-bromophenyl,
4-methoxyphenyl, 4-chlorophenyl, or furan-2-yl, and also when R1,
R2, R3, R4, R5, and R7 are all hydro, L is a bond and R8 is phenyl,
then R6 is not methyl, ethyl, or isopentyl.
[0093] In a more preferred aspect, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, wherein each n is
independently chosen from 0, 1, 2, and 3. In another more preferred
aspect, L is CH.sub.2-- or a covalent bond. In another more
preferred aspect, L is a covalent bond.
[0094] In another more preferred aspect, R6 and R7 are each
hydro.
[0095] In another more preferred aspect, R8 is an -L-heterocycyl
wherein the ring or ring system of said -L-heterocyclyl has from
0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.
[0096] In another more preferred aspect, R8 is an -L-heterocyclyl
wherein said -L-heterocycyl is a -L-heteroaryl and wherein the ring
or ring system of said -L-heteroaryl has from 0-3 substituents
chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl,
haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino,
acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl,
heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro,
sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido.
[0097] In another more preferred aspect, R8 is a -L-heterocyclyl
wherein the ring or ring system of said -L-heterocyclyl has from
0-3 substituents and further wherein said ring or ring system is
chosen from pyridyl, thiazolyl, thiophenyl, quiolinyl, indolyl,
oxadiazolyl, 2,3-dihydrobenzofuranyl, benzo[d][1,3]dioxolyl,
2,3-dihydrobenzo[b][1,4]dioxinyl,
3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, and chromanyl.
[0098] In another more preferred aspect, R8 is a -L-heteroaryl
wherein the ring or ring system of said -L-heteroaryl has from 0-3
substituents and further wherein said ring or ring system is chosen
from pyridyl, thiazolyl, thiophenyl, quinolinyl, indolyl, and
oxadiazolyl. In another more preferred aspect, R8 is a
-L-heteroaryl wherein the ring or ring system of said -L-heteroaryl
has from 0-3 substituents and further wherein said ring or ring
system is pyridyl.
[0099] In another more preferred aspect, R8 is -L-aryl wherein the
ring or ring system of said -L-aryl has from 1-3 substituents
chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl,
haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino,
acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl,
heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro,
sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido.
[0100] In another more preferred aspect, R8 is an -L-aryl that has
3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.
[0101] In another more preferred aspect, one of R1, R2, R3, R4, and
R5 is not a hydro.
[0102] In another more preferred aspect, one of R1, R2, R3, R4, and
R5 is chosen from -L-heterocyclyl, -L-aryl, and -L-carbocyclyl.
[0103] In another more preferred aspect, the substituent or the
substituents on the R8 ring or ring system are chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CN, --NH.sub.2, and --NO.sub.2.
[0104] In another more preferred aspect, the R8 ring or ring system
has 1 substituent chosen from halo, alkyl, alkoxy, haloalkyl,
cyano, and hydroxyl.
[0105] In one embodiment, the invention provides a compound of
Formula I for treating and/or preventing cancer:
##STR00010##
wherein each of R1-R5 is independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heteroaryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy,
alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is chosen from
-L-heterocyclyl and -L-aryl wherein the ring or ring system of said
-L-heterocyclyl or -L-aryl has from 0-3 substituents independently
chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl,
haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino,
acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl,
heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro,
sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof; with the provision that when R1, R2, R3,
R4, R5, R6, and R7 are all hydro and L is a bond, then R8 is not
2,4-dimethoxyphenyl, 4-nitrophenyl, phenyl, 4-bromophenyl,
4-methoxyphenyl, 4-chlorophenyl, or furan-2-yl, and also when R1,
R2, R3, R4, R5, and R7 are all hydro, R8 is phenyl and L is a bond,
then R6 is not methyl, ethyl or isopentyl.
[0106] In one aspect of this embodiment, the invention provides a
compound of Formula I for treating and/or preventing cancer wherein
the 0-3 substituents on the R8 ring or ring system are
independently chosen from hydroxyl, halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, --N(C.sub.1-3 alkyl).sub.2,
--NH(C.sub.1-3 alkyl), --C(.dbd.)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3
alkyl), --C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In a more specific aspect, the R8 ring
or ring system has 1 substituent chosen from hydroxyl, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, alkyl).sub.2,
--NH(C.sub.1-3 alkyl), --C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3
alkyl), --C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In an even more specific aspect, the R8
ring or ring system has from 1 substituent chosen from halo, alkyl,
alkoxy, haloalkyl, cyano, and hydroxyl.
[0107] In one aspect of this embodiment, the ring or ring system of
R8 has 0-3 substituents. In a more specific aspect, the ring or
ring system of R8 has 1-3 substituents. In a more specific aspect,
the ring or ring system of R8 has 1 or 2 substituents. In an even
more specific aspect, the ring or ring system of R8 has 1
substituent.
[0108] In a further aspect of this embodiment, the aforementioned
substituent(s) on the ring or ring system of R8 are/is
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido, wherein
each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and further wherein each n
is independently chosen from 0, 1, 2, and 3. In a more specific
aspect of this embodiment, the aforementioned substituent(s) on the
ring or ring system of R8 are/is independently chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In an even more specific aspect, the
aforementioned substituent(s) on the ring or ring system of R8
are/is independently chosen from halo, alkyl, alkoxy, haloalkyl,
cyano, and hydroxyl.
[0109] In one aspect of this embodiment, R7 is chosen from --H and
cycloalkyl. In a more specific aspect of this embodiment, R7 is
--H.
[0110] In one aspect of this embodiment, L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is chosen from a covalent bond or --CH.sub.2--. In an
even more specific aspect, L is a covalent bond.
[0111] In one embodiment, the invention provides a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and a
compound of Formula I wherein
each of R1-R5 is independently chosen from --H, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is chosen from
-L-heterocyclyl and -L-aryl wherein the ring or ring system of said
-L-heterocyclyl or -L-aryl has from 0-3 substituents independently
chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl,
haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino,
acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl,
heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro,
sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof; with the provision that when R1, R2, R3,
R4, R5, R6, and R7 are all hydro and L is a bond, then R8 is not
2,4-dimethoxyphenyl, 4-nitrophenyl, phenyl, 4-bromophenyl,
4-methoxyphenyl, 4-chlorophenyl or furan-2-yl, and also when R1,
R2, R3, R4, R5, and R7 are all hydro, R8 is phenyl and L is a bond,
then R6 is not methyl, ethyl or isopentyl.
[0112] In one aspect of this embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of Formula I wherein the 0-3 substituents on
the R8 ring or ring system are independently chosen from hydroxyl,
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sup.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In a more specific aspect, the R8 ring
or ring system has 1 substituent chosen from hydroxyl, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, --N(C.sub.1-3
alkyl).sub.2, --NH(C.sub.1-3 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(C.sub.1-3 alkyl), --C(.dbd.O)N(C.sub.1-3
alkyl).sub.2, S(.dbd.O).sub.2(C.sub.1-3alkyl),
--S(.dbd.O).sub.2NH.sub.2, --S(O).sub.2N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2NH(C.sub.1-3 alkyl), --CHF.sub.2, --OCF.sub.3,
--OCHF.sub.2, --CF.sub.3, --CN, --NH.sub.2, and --NO.sub.2. In an
even more specific aspect, the R8 ring or ring system has from 1
substituent chosen from halo, alkyl, alkoxy, haloalkyl, cyano, and
hydroxyl.
[0113] In one aspect of this embodiment, the ring or ring system of
R8 has 0-3 substituents. In a more specific aspect, the ring or
ring system of R8 has 1-3 substituents. In a more specific aspect,
the ring or ring system of R8 has 1 or 2 substituents. In an even
more specific aspect, the ring or ring system of R8 has 1
substituent.
[0114] In a further aspect of this embodiment, the aforementioned
substituent(s) on the ring or ring system of R8 are/is
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido, wherein
each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and further wherein each n
is independently chosen from 0, 1, 2, and 3. In a more specific
aspect of this embodiment, the aforementioned substituent(s) on the
ring or ring system of R8 are/is independently chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In an even more specific aspect, the
aforementioned substituent(s) on the ring or ring system of R8
are/is independently chosen from halo, alkyl, alkoxy, haloalkyl,
cyano, and hydroxyl.
[0115] In one aspect of this embodiment, R7 is chosen from --H and
cycloalkyl. In a more specific aspect of this embodiment, R7 is
--H.
[0116] In one aspect of this embodiment, L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is chosen from a covalent bond or --CH.sub.2--. In an
even more specific aspect, L is a covalent bond.
[0117] In one embodiment, the invention provides a compound of
Formula I wherein each of R1-R5 is independently chosen from --H,
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido;
R6 is chosen from --H and C.sub.1-6 alkyl; R7 is chosen from --H,
alkyl, and cycloalkyl; R8 is -L-heterocyclyl or -L-aryl wherein the
ring or ring system of said -L-heterocyclyl or -L-aryl has from 0-3
substituents wherein said substituents are chosen from hydroxyl,
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3 alkyl),
--CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2; each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof; with the provision that when R1, R2, R3,
R4, R5, R6, and R7 are all hydro and L is a bond, then R8 is not
2,4-dimethoxyphenyl, 4-nitrophenyl, phenyl, 4-bromophenyl,
4-methoxyphenyl, 4-chlorophenyl or furan-2-yl, and also when R1,
R2, R3, R4, R5, and R7 are all hydro, R8 is phenyl and L is a bond,
then R6 is not methyl, ethyl or isopentyl.
[0118] In one aspect of this embodiment, R7 is chosen from --H and
cycloalkyl. In a more specific aspect of this embodiment, R7 is
--H.
[0119] In a more specific aspect of this embodiment, R6 and R7 are
each hydro. In an even more specific aspect, R1, R2, R3, R4, R5,
R6, and R7 are each hydro.
[0120] In a specific aspect of this embodiment, R8 is a heteroaryl
having from 0-3 substituents. In a specific aspect, the heteroaryl
ring is chosen from thiazolyl, pyridyl, thiophenyl, and quinolinyl.
In one specific aspect, R8 is a heteroaryl that has from 1 to 3
substituents independently chosen from hydroxyl, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, alkyl).sub.2,
--NH(C.sub.1-3 alkyl), --C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3
alkyl), --C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In a more specific aspect, R8 is a
heteroaryl that has from 1-3 substituents independently chosen from
halo, alkyl, alkoxy, haloalkyl, cyano and hydroxyl.
[0121] In one aspect of this embodiment, R8 is not an unsubstituted
furan-2-yl or phenyl group when L is a bond.
[0122] In one specific aspect of this embodiment, the invention
provides a compound of Formula I wherein R1, R2, R3, R4, R5, R6 and
R7 are each hydro and R8 is an -L-aryl group having from 0 to 3
substituents on the ring or ring system of said -L-aryl, the
substituents being independently chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido;
each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof; provided that when L is a bond, R8 is not
2,4-dimethoxyphenyl, phenyl, 4-nitrophenyl, 4-bromophenyl,
4-methoxyphenyl or 4-chlorophenyl.
[0123] In a more specific aspect, R8 is a phenyl group having from
1 to 3 substituents. In a more specific aspect, the substituents on
the R8 phenyl ring are chosen from halo, alkyl, alkoxy,
cycloalkoxy, cyano, haloalkyl and hydroxyl. In another more
specific aspect the substituents on the R8 ring are chosen from F,
--Cl, --Br, --CH.sub.3, --OH, --CF.sub.3, cyano, and
--OCH.sub.3.
[0124] Each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof;
provided that when L is a bond, R8 is not 2,4-dimethoxyphenyl,
4-nitrophenyl, 4-bromophenyl, 4-methoxyphenyl or
4-chlorophenyl.
[0125] In one aspect of this embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of Formula I as defined above.
[0126] In one embodiment, the invention provides a compound of
Formula I wherein: one of R1-R5 is chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido;
and the others of R1-R5 are independently chosen from H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is chosen from
-L-heterocyclyl and -L-aryl wherein the ring or ring system of said
-L-heterocyclyl or -L-aryl has from 0-3 substituents independently
chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl,
haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino,
acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl,
heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro,
sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof.
[0127] In one aspect of this embodiment, the ring or ring system of
R8 has 0-3 substituents. In a more specific aspect, the ring or
ring system of R8 has 1-3 substituents. In a more specific aspect,
the ring or ring system of R8 has 1 or 2 substituents. In an even
more specific aspect, the ring or ring system of R8 has 1
substituent.
[0128] In a further aspect of this embodiment, the aforementioned
substituent(s) on the ring or ring system of R8 are/is
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido, wherein
each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and further wherein each n
is independently chosen from 0, 1, 2, and 3. In a more specific
aspect of this embodiment, the aforementioned substituent(s) on the
ring or ring system of R8 are/is independently chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In an even more specific aspect, the
aforementioned substituent(s) on the ring or ring system of R8
are/is independently chosen from halo, alkyl, alkoxy, haloalkyl,
cyano, and hydroxyl.
[0129] In one aspect of this embodiment, R7 is chosen from --H and
cycloalkyl. In a more specific aspect of this embodiment, R7 is
--H.
[0130] In one aspect of this embodiment, L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is chosen from a covalent bond or --CH.sub.2--. In an
even more specific aspect, L is a covalent bond.
[0131] In one aspect of this embodiment, the invention provides a
compound of Formula I wherein one of R1-R5 is a substituent chosen
from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
-L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy,
alkylthio, cyclo alkylthio, alkynyl, amino, alkylamino, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido;
and the others of R1-R5 are each hydro; R6 and R7 are each hydro;
and R8 is chosen from aryl or heterocyclyl wherein the ring or ring
system of said aryl or heterocyclyl has from 0-3 substituents
chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl,
haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino,
acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino,
aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy,
arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl,
heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro,
sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof.
[0132] In one aspect of this embodiment, the ring or ring system of
R8 has 1-3 substituents as described and defined above. In a more
specific aspect, the ring or ring system of R8 has 1 or 2
substituents as defined above. In an even more specific aspect, the
ring or ring system of R8 has 1 substituent as defined above.
[0133] In one specific aspect of this embodiment, R8 has from 1-3
substituents independently chosen from hydroxyl, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, --N(C.sub.1-3
alkyl).sub.2, --NH(C.sub.1-3 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(C.sub.1-3 alkyl), --C(.dbd.O)N(C.sub.1-3
alkyl).sub.2, --S(.dbd.O).sub.2(C.sub.1-3 alkyl),
--S(.dbd.O).sub.2NH.sub.2, --S(O).sub.2N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2NH(C.sub.1-3 alkyl), --CHF.sub.2, --OCF.sub.3,
--OCHF.sub.2, --CF.sub.3, --CN, --NH.sub.2, and --NO.sub.2.
[0134] In one specific aspect of this embodiment, the one of R1-R5
is chosen from -L-aryl, -L-heterocyclyl, and -L-carbocyclyl. In an
even more specific aspect, the one of R1-R5 is -L-aryl. In an even
more specific aspect, the one of R1-R5 is benzyloxy.
[0135] In one specific aspect of this embodiment, the
substituent(s) on R8 are independently chosen from halo, alkyl,
alkoxy, cycloalkoxy, cyano, haloalkyl, and hydroxyl.
[0136] In one aspect of this embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of Formula I as defined above.
[0137] In one embodiment, the invention provides a compound of
Formula I wherein: each of R1-R5 is independently chosen from --H,
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido;
R6 is --H;
R7 is --H;
[0138] R8 is chosen from -L-heterocyclyl and -L-aryl, wherein the
ring or ring system of said -L-heterocyclyl or -L-aryl has from 0-3
substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof; with the provision that when R1, R2, R3,
R4, and R5 are all hydro and L is a bond, then R8 is not
2,4-dimethoxyphenyl, 4-nitrophenyl, 4-bromophenyl, 4-methoxyphenyl,
4-chlorophenyl, or furan-2-yl.
[0139] In one aspect of this embodiment, L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is chosen from a covalent bond or --CH.sub.2--. In an
even more specific aspect, L is a covalent bond.
[0140] In one aspect of this embodiment, the ring or ring system of
R8 has 0-3 substituents. In a more specific aspect, the ring or
ring system of R8 has 1-3 substituents. In a more specific aspect,
the ring or ring system of R8 has 1 or 2 substituents. In an even
more specific aspect, the ring or ring system of R8 has 1
substituent.
[0141] In a further aspect of this embodiment, the aforementioned
substituent(s) on the ring or ring system of R8 are/is
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido, wherein
each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and further wherein each n
is independently chosen from 0, 1, 2, and 3. In a more specific
aspect of this embodiment, the aforementioned substituent(s) on the
ring or ring system of R8 are/is independently chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In an even more specific aspect, the
aforementioned substituent(s) on the ring or ring system of R8
are/is independently chosen from halo, alkyl, alkoxy, haloalkyl,
cyano, and hydroxyl.
[0142] In one aspect of this embodiment, the invention provides a
compound of Formula I wherein the 0-3 substituents on the R8 ring
or ring system are independently chosen from halo, alkoxy,
cycloalkoxy, cyano, and alkyl. In a more specific aspect the R8
ring or ring system has 1 or 2 substituents independently chosen
from halo, alkoxy, cycloalkoxy, cyano, and alkyl. In an even more
specific aspect, the R8 ring or ring system has 1 substituent
independently chosen from halo, alkoxy, cyano, and alkyl.
[0143] In one aspect of this embodiment, the invention provides a
compound of Formula I wherein the 0-3 substituents on the R8 ring
or ring system are independently chosen from --Cl, --Br, --F,
cyano, and methoxy. In a more specific aspect the R8 ring or ring
system has 1 or 2 substituents independently chosen from --Cl,
--Br, --F, cyano, and methoxy. In an even more specific aspect, the
R8 ring or ring system has 1 substituent independently chosen from
--Cl, --Br, --F, cyano, and methoxy.
[0144] In one aspect of this embodiment, the invention provides a
compound of Formula I wherein R8 is chosen from phenyl, thiazolyl,
pyridyl, thiophenyl, and quinolinyl.
[0145] In one aspect of this embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of Formula I as defined above.
[0146] In one embodiment, the invention provides compounds of
Formula I wherein each of R1-R5 is independently chosen from --H,
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido;
R6 is chosen from --H and alkyl; R7 is chosen from --H, alkyl, and
cycloalkyl; R8 is chosen from -L-heterocyclyl and -L-aryl wherein
the ring or ring system of said -L-heterocyclyl or -L-aryl has from
0-3 substituents independently chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--,
--(CH.sub.2).sub.n--, --(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof; with the provision that when R1 to R7 are
all hydro and L is a bond, then R8 is not an unsubstituted phenyl
group, a 4-halophenyl group, a 4-methoxyphenyl group, a
2,4-dimethoxyphenyl group, a 4-nitrophenyl group or a furanyl
group, and also when R1 to R5 and R7 are all hydro, R8 is phenyl
and L is a bond, then R6 is not methyl, ethyl or isopentyl.
[0147] In one aspect of this embodiment, R7 is chosen from --H and
cycloalkyl. In a more specific aspect of this embodiment, R7 is
--H.
[0148] In one aspect of this embodiment, the ring or ring system of
R8 has 1-3 substituents as described and defined above. In a more
specific aspect, the ring or ring system of R8 has 1 or 2
substituents as defined above. In an even more specific aspect, the
ring or ring system of R8 has 1 substituent as defined above.
[0149] In one aspect of this embodiment, the invention provides a
compound of Formula I wherein R8 is aryl wherein the ring or ring
system of said aryl has from 0-3 substituents independently chosen
from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
-L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy,
alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido.
[0150] In one aspect of this embodiment, the invention provides a
compound of Formula I wherein R8 is heteroaryl wherein the ring or
ring system of said heteroaryl has from 0-3 substituents
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.
[0151] In one aspect of this embodiment, the invention provides a
compound of Formula I wherein R8 is heterocyclyl wherein the ring
or ring system of said heterocyclyl has from 0-3 substituents
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cyclo alkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, hetero arylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.
[0152] In one aspect of this embodiment, the invention provides a
compound of Formula I wherein R8 is chosen from phenyl, pyridinyl,
thiazolyl, and thiophenyl, wherein the ring of said group has from
0-3 substituents independently chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.
[0153] In one aspect of this embodiment, the invention provides a
compound of Formula I wherein the substituents on the R8 ring or
ring system are independently chosen from hydroxyl, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, --N(C.sub.1-3
alkyl).sub.2, --NH(C.sub.1-3 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(C.sub.1-3 alkyl), --C(.dbd.O)N(C.sub.1-3
alkyl).sub.2, --S(.dbd.O).sub.2(C.sub.1-3alkyl),
--S(.dbd.O).sub.2NH.sub.2, --S(O).sub.2N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2NH(C.sub.1-3 alkyl), CHF.sub.2, --OCF.sub.3,
--OCHF.sub.2, --CF.sub.3, --CN, --NH.sub.2, and --NO.sub.2.
[0154] In one aspect of this embodiment, the invention provides a
compound of Formula I wherein the 0-3 substituents on the R8 ring
or ring system are independently chosen from halo, alkoxy,
cycloalkoxy, cyano, and alkyl. In a more specific aspect, the R8
ring or ring system has 1 or 2 substituents independently chosen
from halo, alkoxy, cycloalkoxy, cyano, and alkyl. In an even more
specific aspect, the R8 ring or ring system has 1 substituent
chosen from halo, alkoxy, cyano, and alkyl.
[0155] In one aspect of this embodiment, the invention provides a
compound of Formula I wherein the 0-3 substituents on the R8 ring
or ring system are independently chosen from --Cl, --Br, --F,
cyano, and methoxy. In a more specific aspect the R8 ring or ring
system has 1 or 2 substituents independently chosen from --Cl,
--Br, --F, cyano, and methoxy. In an even more specific aspect, the
R8 ring or ring system has 1 substituent chosen from --Cl, --Br,
--F, cyano, and methoxy.
[0156] In one aspect of this embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of Formula I as defined above.
[0157] In one embodiment, the invention provides a compound of
Formula I wherein
R1, R2, R3, R4, and R5 are each hydro; R6 is chosen from --H and
alkyl; R7 is chosen from --H, alkyl, and cycloalkyl; R8 is chosen
from -L-heterocyclyl and -L-aryl wherein the ring or ring system of
said -L-heterocyclyl or -L-aryl has from 0-3 substituents
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof, with the provision that when R6 and R7
are both hydro and L is a bond, then R8 is not 2,4-dimethoxyphenyl,
4-nitrophenyl, phenyl, 4-bromophenyl, 4-methoxyphenyl,
4-chlorophenyl, or furan-2-yl, and also when R7 is hydro, L is a
bond and R8 is phenyl, then R6 is not methyl, ethyl or
isopentyl.
[0158] In one aspect of this embodiment, R7 is chosen from --H and
cycloalkyl. In a more specific aspect of this embodiment, R7 is
--H.
[0159] In one aspect of this embodiment, the ring or ring system of
R8 has 0-3 substituents. In a more specific aspect, the ring or
ring system of R8 has 1-3 substituents. In a more specific aspect,
the ring or ring system of R8 has 1 or 2 substituents. In an even
more specific aspect, the ring or ring system of R8 has 1
substituent.
[0160] In a further aspect of this embodiment, the aforementioned
substituent(s) on the ring or ring system of R8 are/is
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido, wherein
each L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and further wherein each n
is independently chosen from 0, 1, 2, and 3. In a more specific
aspect of this embodiment, the aforementioned substituent(s) on the
ring or ring system of R8 are/is independently chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCF.sub.3, --OCHF.sub.2, --CF.sub.3, --CN,
--NH.sub.2, and --NO.sub.2. In an even more specific aspect, the
aforementioned substituent(s) on the ring or ring system of R8
are/is independently chosen from halo, alkyl, alkoxy, haloalkyl,
cyano, and hydroxyl.
[0161] In one aspect of this embodiment, L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is independently chosen from
--(CH.sub.2).sub.n--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is chosen from a covalent bond or --CH.sub.2--. In an
even more specific aspect, L is a covalent bond.
[0162] In one aspect of this embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of Formula I as defined above.
[0163] In one embodiment, the invention provides a compound of
Formula I wherein one of R1, R2, R3, R4, and R5 is chosen from
halo, alkyl, alkoxyl, haloalkyl, haloalkoxy, cyano, amino,
alkylamino, -L-heterocyclyl, -L-aryl, and -L-carbocyclyl; and the
others of R1, R2, R3, R4, and R5 are chosen from H, halo, alkyl,
alkoxyl, haloalkyl, haloalkoxy, cyano, amino, alkylamino,
-L-heterocyclyl, -L-aryl, and -L-carbocyclyl;
R6 is chosen from --H and alkyl; R7 is chosen from --H, alkyl, and
cycloalkyl; R8 is chosen from heteroaryl and aryl, wherein the ring
or ring system of said heteroaryl or aryl has from 0-3 substituent
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heteroaryl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and where each n is
independently chosen from 0, 1, 2, and 3; and pharmaceutically
acceptable salts thereof.
[0164] In one aspect of this embodiment, R7 is chosen from --H and
cycloalkyl. In a more specific aspect of this embodiment, R7 is
--H.
[0165] In one aspect of this embodiment, the ring or ring system of
R8 has 0-3 substituents. In a more specific aspect, the ring or
ring system of R8 has 1-3 substituents. In a more specific aspect,
the ring or ring system of R8 has 1 or 2 substituents. In an even
more specific aspect, the ring or ring system of R8 has 1
substituent.
[0166] In a further aspect of this embodiment, the aforementioned
substituent(s) on the ring or ring system of R8 are/is
independently chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido, wherein
each L is independently chosen from
--(CH.sub.2)--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and further wherein each n
is independently chosen from 0, 1, 2, and 3. In a more specific
aspect of this embodiment, the aforementioned substituent(s) on the
ring or ring system of R8 are/is independently chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(O).sub.2N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2NH(C.sub.1-3
alkyl), --CHF.sub.2, --OCHF.sub.2, --CF.sub.3, --CN, --NH.sub.2,
and --NO.sub.2. In an even more specific aspect, the aforementioned
substituent(s) on the ring or ring system of R8 are/is
independently chosen from halo, alkyl, alkoxy, haloalkyl, cyano,
and hydroxyl.
[0167] In one aspect of this embodiment, L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is independently chosen from
--(CH.sub.2)--(CH.sub.2).sub.n-- and
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3. In a more specific
aspect, L is chosen from a covalent bond or --CH.sub.2--. In an
even more specific aspect, L is a covalent bond.
[0168] In one specific aspect of this embodiment, the invention
provides a compound of Formula I wherein one of R1, R2, R3, R4, and
R5 is chosen from -L-heterocyclyl, -L-aryl, and -L-carbocyclyl. In
a more specific aspect of this embodiment, one of R1, R2, R3, R4,
and R5 is chosen from -L-heterocyclyl, -L-aryl, and -L-carbocyclyl,
and the others are hydro. In an even more specific aspect L is a
covalent bond.
[0169] In one specific aspect of this embodiment, the invention
provides a compound of Formula I wherein R6 and R7 are hydro, and
one of R1, R2, R3, R4, and R5 is chosen from -L-heterocyclyl,
-L-aryl, and -L-carbocyclyl. In a more specific aspect of this
embodiment, R6 and R7 are hydro, one of R1, R2, R3, R4, and R5 is
chosen from -L-heterocyclyl, -L-aryl, and -L-carbocyclyl, and the
others of R1 to R5 are hydro. In an even more specific aspect L is
a covalent bond.
[0170] In one aspect of this embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of Formula I as defined above.
[0171] Furthermore, in one aspect of all the embodiments provided
herein, the ring or ring system of R8 has at least one substituent
chosen from the substituents described and defined in the
respective embodiments.
[0172] In one aspect of all the embodiments provided herein, the
ring or ring system of R8 has three substituents chosen from the
substituents described and defined in the respective embodiments.
For example, said three substituents may be independently chosen
from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
-L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy,
alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido.
[0173] In one aspect of all the embodiments provided herein, R8 is
aryl (such as, e.g., phenyl) or heterocyclyl (such as, e.g.,
pyridinyl, thiazolyl, or thiophenyl), wherein the ring or ring
system of said aryl has 1-3 substituents (such as, e.g., 1 or 2
substituents) and further wherein the ring or ring system of said
heterocyclyl has from 0-3 substituents (such as, e.g., 1 or 2
substituents), said substituents being independently chosen from
halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido. In a more specific aspect, said
substituents are independently chosen from hydroxyl, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, --N(C.sub.1-3
alkyl).sub.2, --NH(C.sub.1-3 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(C.sub.1-3 alkyl), --C(.dbd.O)N(C.sub.1-3
alkyl).sub.2, --S(.dbd.O).sub.2(C.sub.1-3alkyl),
--S(.dbd.O).sub.2NH.sub.2, --S(O).sub.2N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2NH(C.sub.1-3 alkyl), --CHF.sub.2, --OCF.sub.3,
--OCHF.sub.2, --CF.sub.3, --CN, --NH.sub.2, and --NO.sub.2. In an
even more specific aspect, said substituents are independently
chosen from halo, alkyl, alkoxy, cycloalkoxy, and cyano.
[0174] In one specific aspect of all the embodiments provided
herein, one of R1-R5 is chosen from -L-aryl, -L-heterocyclyl, and
-L-carbocyclyl. In a more specific aspect, one of R1-R5 is -L-aryl.
In an even more specific aspect, one of R1-R5 is benzyloxy.
[0175] In a further aspect of all the embodiments provided herein,
R3 is benzyloxy and each of R1, R2, R4 and R5 is hydro.
[0176] In one aspect of all the embodiments provided herein, a
compound wherein R1 to R7 are hydro and R8 is unsubstituted phenyl
is excluded.
[0177] In one preferred aspect of all the embodiments provided
herein, when the ring or ring system of R8 is a heterocycyl said
ring system is chosen from pyridyl, thiazolyl, thiophenyl,
quinolinyl, indolyl, oxadiazolyl, 2,3-dihydrobenzofuranyl,
benzo[d][1,3]dioxolyl, 2,3-dihydrobenzo[b][1,4]dioxinyl,
3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, and chromanyl.
[0178] In one preferred aspect of all the embodiments provided
herein, when the ring or ring system of R8 is a heteroaryl said
ring system is chosen from pyridyl, thiazolyl, thiophenyl,
quinolinyl, indolyl, and oxadiazolyl. In an even more preferred
aspect R8 is pyridyl.
[0179] In one embodiment, the invention provides a compound of
Formula I (or a pharmaceutically acceptable salt thereof), a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a compound of Formula I (or a pharmaceutically
acceptable salt thereof), and a compound of Formula I (or a
pharmaceutically acceptable salt thereof) for use in treating or
preventing cancer, wherein: R1 to R7 are hydro and R8 is phenyl
having 1, 2 or 3 substituents chosen from hydroxyl, halo, alkyl,
alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, --N(C.sub.1-3
alkyl).sub.2, --NH(C.sub.1-3 alkyl), --C(.dbd.O)NH.sub.2,
--C(.dbd.O)NH(C.sub.1-3 alkyl), --C(.dbd.O)N(C.sub.1-3
alkyl).sub.2, --S(.dbd.O).sub.2(C.sub.1-3 alkyl),
--S(.dbd.O).sub.2NH.sub.2, --S(O).sub.2N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2NH(C.sub.1-3 alkyl), --CN, --NH.sub.2, and
--NO.sub.2.
[0180] In one aspect of all the embodiments provided herein, the
compound of Formula I is chosen from: [0181]
(trans)-N-(4-fluorobenzyl)-2-phenylcyclopropanamine; [0182]
(trans)-N-(4-fluorobenzyl)-2-phenylcyclopropanaminium; [0183]
4-(((trans)-2-phenylcyclopropylamino)methyl)benzonitrile; [0184]
(trans)-N-(4-cyanobenzyl)-2-phenylcyclopropanaminium; [0185]
(trans)-2-phenyl-N-(4-(trifluoromethyl)benzyl)cyclopropanamine;
[0186]
(trans)-2-phenyl-N-(4-(trifluoromethyl)benzyl)cyclopropanaminium;
[0187] (trans)-2-phenyl-N-(pyridin-2-ylmethyl)cyclopropanamine;
[0188] (trans)-2-phenyl-N-(pyridin-3-ylmethyl)cyclopropanamine;
[0189] (trans)-2-phenyl-N-(pyridin-4-ylmethyl)cyclopropanamine;
[0190]
(trans)-N-((6-methylpyridin-2-yl)methyl)-2-phenylcyclopropanamine;
[0191] (trans)-2-phenyl-N-(thiazol-2-ylmethyl)cyclopropanamine;
[0192] (trans)-2-phenyl-N-(thiophen-2-ylmethyl)cyclopropanamine;
[0193]
(trans)-N-((3-bromothiophen-2-yl)methyl)-2-phenylcyclopropanamine;
[0194]
(trans)-N-((4-bromothiophen-2-yl)methyl)-2-phenylcyclopropanamine;
[0195] (trans)-N-(3,4-dichlorobenzyl)-2-phenylcyclopropanamine;
[0196] (trans)-N-(3-fluorobenzyl)-2-phenylcyclopropanaminium;
[0197] (trans)-N-(2-fluorobenzyl)-2-phenylcyclopropanamine; [0198]
(trans)-2-phenyl-N-(quinolin-4-ylmethyl)cyclopropanamine; [0199]
(trans)-N-(3-methoxybenzyl)-2-phenylcyclopropanamine; [0200]
(trans)-2-phenyl-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)cyclopropanam-
ine; [0201]
(trans)-N-((6-chloropyridin-3-yl)methyl)-2-phenylcyclopropanamine;
[0202]
(trans)-N-((4-methylpyridin-2-yl)methyl)-2-phenylcyclopropanamine;
[0203]
(trans)-N-((6-methoxypyridin-2-yl)methyl)-2-phenylcyclopropanamine;
[0204] 2-(((trans)-2-phenylcyclopropylamino)methyl)pyridin-3-ol;
[0205]
(trans)-N-((6-bromopyridin-2-yl)methyl)-2-phenylcyclopropanamine;
[0206]
4-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)benzonitrile;
[0207] (trans)-N-(4-(benzyloxy)benzyl)-2-phenylcyclopropanamine;
[0208] (trans)-N-benzyl-2-(4-(benzyloxy)phenyl)cyclopropanamine;
[0209]
(trans)-2-(4-(benzyloxy)phenyl)-N-(4-methoxybenzyl)cyclopropanamine;
[0210]
(trans)-2-(4-(benzyloxy)phenyl)-N-(4-fluorobenzyl)cyclopropanamine-
; and pharmaceutically acceptable salts thereof.
[0211] Accordingly, the invention provides a compound of Formula I
chosen from the above compounds, in particular for use as a
medicament and also for use in treating and/or preventing
cancer.
[0212] In one aspect of all the embodiments provided herein, the
compound of Formula I is chosen from: [0213]
(trans)-2-phenyl-N-(quinolin-2-ylmethyl)cyclopropanamine; [0214]
(trans)-2-phenyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropanam-
ine; [0215]
(trans)-N-((3-fluoropyridin-2-yl)methyl)-2-phenylcyclopropanamine;
[0216] (trans)-2-phenyl-N-(quinolin-3-ylmethyl)cyclopropanamine;
[0217]
(trans)-N-((6-methoxypyridin-3-yl)methyl)-2-phenylcyclopropanamine;
[0218]
(trans)-N-((5-methoxypyridin-3-yl)methyl)-2-phenylcyclopropanamine-
; [0219]
(trans)-N-((2-methoxypyridin-3-yl)methyl)-2-phenylcyclopropanamin-
e; [0220]
(trans)-N-((3H-indol-3-yl)methyl)-2-phenylcyclopropanamine; [0221]
3-(((trans)-2-phenylcyclopropylamino)methyl)benzonitrile; [0222]
(trans)-N-(2-methoxybenzyl)-2-phenylcyclopropanamine; [0223]
3-(((trans)-2-phenylcyclopropylamino)methyl)pyridin-2-amine [0224]
(trans)-N-((2-chloropyridin-3-yl)methyl)-2-phenylcyclopropanamine;
[0225] (trans)-N-(3,4-dimethoxybenzyl)-2-phenylcyclopropanamine;
[0226]
(trans)-N-((2,3-dihydrobenzofuran-5-yl)methyl)-2-phenylcyclopropanamine;
[0227]
(trans)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-phenylcyclopropanamin-
e; [0228]
(trans)-N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-phenyl-
cyclopropanamine; [0229]
(trans)-N-(2,6-difluoro-4-methoxybenzyl)-2-phenylcyclopropanamine;
[0230]
(trans)-2-phenyl-N-(4-(trifluoromethoxy)benzyl)cyclopropanamine;
[0231]
(trans)-N-(5-fluoro-2-methoxybenzyl)-2-phenylcyclopropanamine;
[0232]
(trans)-N-(2-fluoro-4-methoxybenzyl)-2-phenylcyclopropanamine;
[0233]
(trans)-N-((4-methoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine;
[0234]
(trans)-N-(2-fluoro-6-methoxybenzyl)-2-phenylcyclopropanamine;
[0235]
(trans)-N-((2-methoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanam-
ine; [0236]
(trans)-N-((4,7-dimethoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine-
; [0237]
(trans)-N-(4-methoxy-3-methylbenzyl)-2-phenylcyclopropanamine;
[0238]
(trans)-N-(3-chloro-4-methoxybenzyl)-2-phenylcyclopropanamine;
[0239]
(trans)-N-(3-fluoro-4-methoxybenzyl)-2-phenylcyclopropanamine;
[0240]
(trans)-N-(4-methoxy-2-methylbenzyl)-2-phenylcyclopropanamine;
[0241]
(trans)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)methyl)-2-ph-
enylcyclopropanamine; [0242]
(trans)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-phenylcyc-
lopropanamine; [0243]
(trans)-N-((2,2-dimethylchroman-6-yl)methyl)-2-phenylcyclopropanamine;
[0244]
(trans)-N-(4-methoxy-2,3-dimethylbenzyl)-2-phenylcyclopropanamine;
[0245]
(trans)-N-(4-methoxy-2,5-dimethylbenzyl)-2-phenylcyclopropanamine;
[0246]
(trans)-N-(2-fluoro-4,5-dimethoxybenzyl)-2-phenylcyclopropanamine;
[0247]
(trans)-N-(3-chloro-4,5-dimethoxybenzyl)-2-phenylcyclopropanamine;
[0248]
(trans)-N-(2-chloro-3,4-dimethoxybenzyl)-2-phenylcyclopropanamine;
[0249]
(trans)-N-(2,4-dimethoxy-6-methylbenzyl)-2-phenylcyclopropanamine;
[0250] (trans)-N-(2,5-dimethoxybenzyl)-2-phenylcyclopropanamine;
[0251] (trans)-N-(2,3-dimethoxybenzyl)-2-phenylcyclopropanamine;
[0252]
(trans)-N-(2-chloro-3-methoxybenzyl)-2-phenylcyclopropanamine;
[0253] (trans)-N-((1H-indol-5-yl)methyl)-2-phenylcyclopropanamine;
[0254]
(trans)-2-(4-(benzyloxy)phenyl)-N-(pyridin-2-ylmethyl)cyclopropanamine;
[0255]
(trans)-2-(4-(benzyloxy)phenyl)-N-(2-methoxybenzyl)cyclopropanamin-
e; [0256]
(trans)-N-(1-(4-methoxyphenyl)ethyl)-2-phenylcyclopropanamine;
[0257]
(trans)-N-(1-(3,4-dimethoxyphenyl)ethyl)-2-phenylcyclopropanamine;
[0258]
(trans)-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-phenylc-
yclopropanamine; [0259]
(trans)-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)-2-phenylcyclopropanamine;
[0260]
(trans)-N-(1-(3,4-dimethoxyphenyl)propan-2-yl)-2-phenylcyclopropan-
amine; [0261]
(trans)-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2-phenylcyclopropanamin-
e; and pharmaceutically acceptable salts thereof.
[0262] Accordingly, the invention provides a compound of Formula I
chosen from the above compounds, in particular for use as a
medicament and also for use in treating and/or preventing
cancer.
[0263] The invention provides compounds of Formula I which are
selective inhibitors of LSD1. LSD1 selective inhibitors have IC50
values for LSD1 which are at least 2-fold lower than the IC50 value
for MAO-A and/or MAO-B. In some embodiments, the LSD1 selective
inhibitors have IC50 values which are at least 5-fold lower for
LSD1 as compared to MAO-A and MAO-B. In some embodiments, the LSD1
selective inhibitors have IC50 values which are at least 10-fold
lower for LSD1 as compared to MAO-A and MAO-B.
[0264] The invention also provides compounds of Formula I which are
dual inhibitors selective for LSD1 and MAO-B. Dual LSD1/MAO-B
selective inhibitors have IC50 values for LSD1 and MAO-B which are
at least 2-fold lower than the IC50 value for MAO-A. In some
embodiments, the dual LSD1/MAO-B selective inhibitors have IC50
values which are at least 5-fold lower for LSD1 and MAO-B as
compared to MAO-A. In some embodiments, the dual LSD1/MAO-B
selective inhibitors have IC50 values which are at least 10-fold
lower for LSD1 and MAO-B as compared to MAO-A. In one aspect of
this embodiment, the LSD1/MAO-B inhibitor avoids the deleterious
side-effects associated with inhibition of MAO-A.
[0265] In one embodiment, the invention provides a method of
treating a cancer comprising administering, to a patient in need of
treatment, a therapeutically effective amount of a composition
comprising a compound of Formula I and a pharmaceutically
acceptable carrier. In a related embodiment, the invention provides
a compound of Formula I for treating and/or preventing cancer. In
another related embodiment, the invention provides for the use of a
compound of Formula I for the manufacture of a medicament for
treating and/or preventing cancer.
[0266] Previous reports of LSD1 have found that it is involved in
cell proliferation and growth. Some studies have implicated LSD1 as
a therapeutic target for cancer. Huang et al. (2007) PNAS
104:8023-8028 found that polyamines inhibitors of LSD1 modestly
cause the reexpression of genes aberrantly silenced in cancer cells
and particularly colorectal cancer (Huang et al. Clin Cancer Res.
(2009) Dec. 1; 15(23):7217-28. Epub 2009 Nov. 24. PMID: 19934284).
Scoumanne et al. ((2007) J. Biol. Chem. May 25; 282(21):15471-5)
found that deficiency in LSD1 leads to a partial cell cycle arrest
in G2/M and sensitizes cells to growth suppression induced by DNA
damage. Kahl et al. ((2006) Cancer Res. 66(23):11341-7) found that
LSD1 expression is correlated with prostate cancer aggressiveness.
Metzger et al. reported that LSD1 modulation by siRNA and pargyline
regulates androgen receptor (AR) and may have therapeutic potential
in cancers where AR plays a role, like prostate, testis, and brain
cancers. Lee et al. ((2006) Chem. Biol. 13:563-567) reported that
tranylcypromine derepresses Egr-1 gene expression in some cancer
lines. A body of evidence is accumulating that Egr-1 is a tumor
suppressor gene in many contexts (see e.g., Calogero et al. (2004)
Cancer Cell International 4:1 exogenous expression of EGR-1
resulted in growth arrest and eventual cell death in primary cancer
cell lines; Lucerna et al. (2006) Cancer Research 66, 6708-6713
show that sustained expression of Egr-1 causes antiangiogenic
effects and inhibits tumor growth in some models; Ferraro et al.
((2005) J. Clin. Oncol. March 20; 23(9):1921-6) reported that Egr-1
is downregulated in lung cancer patients with a higher risk of
recurrence and may be more resistant to therapy. Thus, increasing
Egr-1 expression via inhibition of LSD1 is a therapeutic approach
for some cancers. Recent studies have also implicated LSD1 in brain
cancer (Schulte et al. (2009) Cancer Res. March 1; 69(5):2065-71).
Other studies have implicated LSD1 in breast cancer (Lims et al.
Carcinogenesis. 2009 Dec. 30. [Epub ahead of print] PMID:
20042638).
[0267] Thus, a body of evidence has implicated LSD1 in a number of
cancers, which suggests that LSD1 is a therapeutic target for
cancer. The instant inventors have discovered a class of LSD1
inhibitors that can be used to treat diseases where LSD1 is
implicated as a therapeutic target like cancer. Accordingly, the
phenylcyclopropylamine compounds of the invention can be used to
treat and/or prevent such diseases.
[0268] As the skilled artisan readily recognizes the compounds
disclosed herein are surprisingly and significantly more potent
than tranylcypromine for LSD1 inhibition. Han et al. (Euro. J.
Pharma. (2008) doi:10.1016/j.ejphar.2008.12.025) reported that
phenylcyclopropylamine displays neuroprotective activity in PC12
cells thus the compounds of Formula I may be used as a
neuroprotectant (e.g., used to treat and/or prevent conditions
characterized by neurodegeneration). Furthermore, since the
compounds of Formula I are potent LSD1 inhibitor they can be used
to treat and/or prevent diseases where LSD1 inhibition is
desirable, e.g., cancer.
[0269] Without being bound by theory, it is believed that compounds
provided herein are particularly useful in the treatment and/or
prevention of cancer because they interfere with LSD1 activity
(i.e. inhibit LSD1 activity), wherein LSD1 activity is part of a
metabolic mechanism specifically involved in cancer as described
elsewhere herein. Potent LSD1 inhibitors to be used in the
treatment of cancer are shown in Table 1, wherein compounds with a
low IC50 value (in particular compounds having a lower IC50 value
than the prior art compound parnate) are preferred.
[0270] Furthermore, and without being bound by theory, dual
MAO-B/LSD1 inhibitors provided herein are thought of interfering
with a mechanism involved in neurodegenerative diseases.
Accordingly, compounds that potently inhibit both MAO-B and LSD1
activity are preferred in the treatment of neurodegenerative
diseases. Exemplary compounds in this context are shown in Table 1,
wherein compounds with a low IC50 value (in particular compounds
having a lower IC50 value than the prior art compound parnate) are
preferred.
[0271] Also compounds that inhibit both MAO A/B activity and LSD1
activity are envisaged herein in the treatment of diseases, in
particular neurodegenerative diseases, wherein compounds that
inhibit LSD1 activity more potently than parnate are preferred.
[0272] In one embodiment, the invention provides a method of
inhibiting LSD1 activity comprising administering, to a patient in
need of treatment, an amount of a composition comprising a compound
of Formula I and a pharmaceutically acceptable carrier sufficient
to inhibit LSD1 activity. In a related embodiment, the invention
provides a compound of Formula I for inhibiting LSD1. In another
related embodiment, the invention provides for the use of a
compound of Formula I for the manufacture of a medicament for
inhibiting LSD1.
[0273] In one embodiment, the invention provides a method of
treating a neurodegenerative disease or disorder comprising
administering, to a patient in need of treatment, a therapeutically
effective amount of a composition comprising a compound of Formula
I and a pharmaceutically acceptable carrier. In a related
embodiment, the invention provides a compound of Formula I for
treating and/or preventing a neurodegenerative disease. In another
related embodiment, the invention provides for the use of a
compound of Formula I for the manufacture of a medicament for
treating and/or preventing a neurodegenerative disease.
[0274] In one embodiment, the invention provides a method of
inhibiting monoamine oxidase activity comprising administering, to
a patient in need of treatment, an amount of a composition
comprising a compound of Formula I and a pharmaceutically
acceptable carrier sufficient to inhibit monoamine oxidase
activity. In a related embodiment, the invention provides a
compound of Formula I for treating and/or preventing Parkinson's
disease and/or depression. In another related embodiment, the
invention provides for the use of a compound of Formula I for the
manufacture of a medicament for inhibiting monoamine oxidase. In a
related embodiment, the invention provides a compound of Formula I
for treating and/or preventing neurogeneration.
[0275] In some of the embodiments related to Formula I, the
compound does not have the structure of the compounds having CAS
registration nos. 22783-31-9, 1041848-33-2, 903487-42-3,
53578-57-7, 53578-56-6, 53578-54-4, 53578-53-3, 53578-52-2,
53578-50-0, 39933-77-2, 32752-01-5, and/or 22783-27-3.
[0276] In one embodiment, the invention provides a method of
treating a disease or condition comprising administering, to a
patient in need of treatment, a therapeutically effective amount of
a composition comprising a compound of Formula I and a
pharmaceutically acceptable carrier. In one aspect of this
embodiment, the disease is cancer or a neurodegenerative
disease.
[0277] In one embodiment, the invention provides a method of
treating a cancer comprising administering, to a patient in need of
treatment, a therapeutically effective amount of a composition
comprising a compound of Formula I and a pharmaceutically
acceptable carrier. In one aspect of this embodiment, the cancer is
prostate cancer. In another specific aspect of this embodiment, the
cancer is brain cancer. In yet another specific aspect of this
embodiment, the cancer is breast cancer. In yet another specific
aspect of this embodiment, the cancer is lung cancer. In yet
another specific aspect of this embodiment, the cancer is
testicular cancer. In yet another specific aspect of this
embodiment, the cancer is colorectal cancer. In yet another
specific aspect of this embodiment, the cancer is blood cancer
(e.g., leukemia). In yet another specific aspect of this
embodiment, the cancer is skin cancer.
[0278] In one embodiment, the invention provides a method of
treating a neurodegenerative disease or disorder comprising
administering, to a patient in need of treatment, a therapeutically
effective amount of a composition comprising a compound of Formula
I and a pharmaceutically acceptable carrier.
[0279] In one embodiment, the invention provides a method for
identifying LSD1 selective inhibitors comprising determining the
ability of a test compound to inhibit LSD1 and monoamine oxidase
(MAO-A and/or MAO-B) wherein a test compound that inhibits LSD1
better than monoamine oxidase (MAO-A and/or MAO-B) is LSD1
selective. In one aspect of this embodiment, the selective
inhibitor has an IC50 value at least two-fold lower for LSD1 as
compared to MAO-A and MAO-B. In one aspect of this embodiment, the
LSD1 selective inhibitor has an 1050 value at least five-fold lower
for LSD1 as compared to MAO-A and MAO-B. In one aspect of this
embodiment, the LSD1 selective inhibitor has an IC50 value at least
ten-fold lower for LSD1 as compared to MAO-A and MAO-B. In one
aspect of this embodiment, the test compound is chosen from a
phenylcyclopropylamine derivative, homolog or analog. In one
specific aspect of this embodiment the phenylcyclopropylamine
analog has the phenyl group replaced with another ring system
(e.g., aryl, heterocyclyl and/or heteroaryl which is optionally
substituted) and the amine group is substituted with a functional
group (see e.g., examples). In another aspect, the test compound is
a phenylcyclopropylamine analog or derivative where the amine group
is substituted with a functional group. In another aspect, the test
compound is a phenylcyclopropylamine analog or derivative where the
amine group is substituted with a functional group and the phenyl
group has at least one substituent that is not a hydrogen atom. In
a related embodiment, the invention provides a method of inhibiting
LSD1 selectively as compared to MAO-B and MAO-A comprising
administering to an individual a phenylcyclopropylamine derivative,
homolog, or analog that selectively inhibits LSD1. In a related
embodiment, the invention provides a method of inhibiting LSD1
selectively as compared to MAO-B and MAO-A comprising administering
to an individual a compound of Formula I as defined in the
embodiments described in this invention, that selectively inhibits
LSD1.
[0280] In one embodiment, the invention provides a method for
identifying a dual inhibitor selective for LSD1/MAO-B as compared
to MAO-A comprising determining the ability of a test compound to
inhibit LSD1 and monoamine oxidase (MAO-A and MAO-B) wherein a test
compound that inhibits LSD1 and MAO-B better than LSD1 and
monoamine oxidase (MAO-A and/or MAO-B) is a dual LSD1/MAO-B
selective inhibitor. In one aspect of this embodiment, the dual
LSD1/MAO-B selective inhibitor has an IC50 value at-least two-fold
lower for LSD1 and MAO-B as compared to MAO-A. In one aspect of
this embodiment, the dual LSD1/MAO-B selective inhibitor has an
IC50 value at-least five-fold lower for LSD1 and MAO-B. In one
aspect of this embodiment, the dual LSD1/MAO-B selective inhibitor
has an IC50 value at-least ten-fold lower for LSD1 and MAO-B as
compared to MAO-A.
[0281] In one aspect of this embodiment, the test compound is
chosen from a phenylcyclopropylamine derivative, homolog or analog.
In one specific aspect of this embodiment the
phenylcyclopropylamine analog has the phenyl group replaced with
another ring system (e.g., aryl, heterocyclyl and/or heteroaryl
which is optionally substituted) and the amine group is substituted
with a functional group (see e.g., examples). In another aspect,
the test compound is a phenylcyclopropylamine analog or derivative
where the amine group is substituted with a functional group. In
another aspect, the test compound is a phenylcyclopropylamine
analog or derivative where the amine group is substituted with a
functional group and the phenyl group has at-least one substituent
that is not a hydrogen. In a related embodiment, the invention
provides a method of inhibiting LSD1 and MAO-B selectively as
compared to MAO-A comprising administering to an individual a
phenylcyclopropylamine derivative, homolog, or analog that
selectively inhibits LSD1 and MAO-B. In a related embodiment, the
invention provides a method of inhibiting LSD1 and MAO-B
selectively as compared to MAO-A comprising administering to an
individual a compound of Formula I as defined in the embodiments
described in this invention, and that selectively inhibits LSD1 and
MAO-B.
[0282] Phenylcyclopropylamine derivatives, homologs, and analogs
can be made by methods known in the art e.g., including, but not
limited to the methods disclosed herein and in the references cited
herein. See for example, Kaiser et al. (1962) J. Med. Chem.
5:1243-1265 and Zirkle et al. (1962) J. Med. Chem. 1265-1284
Yoshida et al. (2004) Bioorg. Med Chem. 12(10):2645-2652; Hruschka
et al. (2008) Biorg Med Chem. (16):7148-7166; and Gooden et al.
(2008) Bioorg. Med. Chem. Let. 18:3047-3051 which describe various
phenylcyclopropropylamine analogs, derivatives and homologs. The
amine groups of these compounds can be alkylated as described in
the examples to give substituted phenylcyclopropylamine derivative,
analogs, and homologs.
[0283] Thus, in a specific embodiment, the invention provides a
method of identifying LSD1 selective and LSD1/MAO-B inhibitors
comprising determining the ability of a test compound to inhibit
LSD1, MAO-A, and MAO-B wherein a LSD1 selective inhibitor is
identified when the test compound inhibits LSD1 to a greater extent
than MAO-A and MAO-B and wherein a LSD1/MAO-B dual inhibitor is
identified when the test compound inhibits LSD1 and MAO-B to a
greater extent than it inhibits MAO-A wherein said test compound is
compound of Formula I:
##STR00011##
wherein: each of R1-R5 is independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is -L-heterocyclyl or
-L-aryl, wherein the ring or ring system of said -L-heterocyclyl or
-L-aryl has from 0-3 substituents chosen from halo, alkyl, alkoxy,
cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl,
-L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio,
alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl,
arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano,
cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy,
isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3; or a compound of Formula
I where the phenyl ring attached to the cyclopropylamine moiety is
replaced by an optionally substituted heteroaryl group and the
other variables R6-R8 as defined above.
[0284] Compounds that are identified as LSD1 selective and
LSD1/MAO-B dual inhibitors can be used to prepare pharmaceutical
compositions for treating diseases according to the methods of the
invention as described herein. Preferably the diseases can be
treated by inhibiting LSD1, LSD1 and MAO-B, and/or by modulating
histone methylation levels.
[0285] In a specific aspect of this embodiment, the invention
provides a method of identifying LSD1 selective and LSD1/MAO-B dual
inhibitors comprising determining the ability of a test compound to
inhibit LSD1, MAO-A, and MAO-B wherein a LSD1 selective inhibitor
is identified when the test compound inhibits LSD1 to a greater
extent than MAO-A and MAO-B and wherein a LSD1/MAO-B dual inhibitor
is identified when the test compound inhibits LSD1 and MAO-B to a
greater extent than it inhibits MAO-A wherein said test compound is
compound of Formula I:
##STR00012##
wherein: each of R1-R5 is independently chosen from --H, halo,
alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl,
-L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio,
cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl,
arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido; R6 is chosen from --H and alkyl; R7 is
chosen from --H, alkyl, and cycloalkyl; R8 is a -L-heterocyclyl
wherein the ring or ring system of said -L-heterocyclyl has from
0-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; or R8 is
-L-aryl wherein the ring or ring system of said -L-aryl has from
1-3 substituents chosen from halo, alkyl, alkoxy, cycloalkoxy,
haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl,
acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino,
alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy,
aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl,
hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato,
isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido,
thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl,
N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; each L is
independently chosen from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, where each n is
independently chosen from 0, 1, 2, and 3; or a compound of Formula
I where the phenyl ring attached to the cyclopropylamine moiety is
replaced by an optionally substituted heteroaryl group and the
other variables R6-R8 are as defined above.
[0286] As used herein, the term "alkyl" refers to a saturated
aliphatic hydrocarbon including straight chain and/or branched
chain groups. In a more specific definition, the alkyl group is
further defined as having 1 to 20 carbon atoms (whenever it appears
herein, a numerical range such as "1 to 20" refers to each integer
in the given range; e.g., "1 to 20 carbon atoms" means that the
alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon
atoms, etc. up to and including 20 carbon atoms). In another more
specific definition, it is an alkyl having 1 to 10 carbon atoms. In
yet another more specific definition, it is an alkyl having 1 to 6
carbon atoms, and in yet another more specific definition, it is an
alkyl having 1 to 4 carbon atoms.
[0287] As used herein, the term "alkenyl" refers to an unsaturated
hydrocarbon including straight chain and/or branched chain groups,
comprising at least one carbon-to-carbon double bond. In a more
specific definition, the alkenyl group is further defined as having
2 to 20 carbon atoms. In another more specific definition, it is an
alkenyl having 2 to 10 carbon atoms. In yet another more specific
definition, it is an alkenyl having 2 to 6 carbon atoms, and in yet
another more specific definition, it is an alkenyl having 2 to 4
carbon atoms.
[0288] As used herein, the term "alkynyl" refers to an unsaturated
hydrocarbon including straight chain and/or branched chain groups,
comprising at least one carbon-to-carbon triple bond. In a more
specific definition, the alkynyl group is further defined as having
2 to 20 carbon atoms. In another more specific definition, it is an
alkynyl having 2 to 10 carbon atoms. In yet another more specific
definition, it is an alkynyl having 2 to 6 carbon atoms, and in yet
another more specific definition, it is an alkynyl having 2 to 4
carbon atoms.
[0289] As used herein, the term "halo" refers to a group chosen
from chloro, fluoro, bromo, and iodo.
[0290] As used herein, the term "hydro" refers to a hydrogen atom
(--H group) which is also denoted as --H.
[0291] As used herein, the term "hydroxyl" refers to an --OH
group.
[0292] As used herein, the term "alkoxy" refers to an --O-alkyl
group, wherein the alkyl group is as defined herein above.
[0293] As used herein, the term "cycloalkoxy" refers to an
--O-cycloalkyl group, wherein the cycloalkyl group is as defined
herein below.
[0294] As used herein, the term "aryloxy" refers to an --O-aryl
group, wherein the aryl group is as defined herein below.
[0295] As used herein, the term "heteroaryloxy" refers to an
--O-heteroaryl group, wherein the heteroaryl group is as defined
herein below.
[0296] As used herein, the term "mercapto" refers to an --SH
group.
[0297] As used herein, the term "alkylthio" refers to an --S-alkyl
group, wherein the alkyl group is as defined herein above.
[0298] As used herein, the term "cycloalkylthio" refers to an
--S-cycloalkyl group, wherein the cycloalkyl group is as defined
herein below.
[0299] As used herein, the term "arylthio" refers to an --S-aryl
group, wherein the aryl group is as defined herein below.
[0300] As used herein, the term "heteroarylthio" refers to an
--S-heteroaryl group, wherein the heteroaryl group is as defined
herein below.
[0301] As used herein, the term "carbonyl" refers to a
--C(.dbd.O)R'' group, wherein R'' is as defined herein below.
[0302] Unless specified otherwise, R'' is selected from the group
consisting of hydro, alkyl, cycloalkyl, aryl, heteroaryl (bonded
through a ring carbon atom) and heterocyclyl (bonded through a ring
carbon atom), wherein said hydro, alkyl, cycloalkyl, aryl,
heteroaryl and heterocyclyl are as defined herein.
[0303] As used herein, the term "aldehyde" group refers to a
carbonyl group as defined herein above, wherein R'' is hydro.
[0304] As used herein, the term "cycloketone" group refers to a
cycloalkyl group as defined herein below, wherein one of the carbon
atoms which form the ring has an ".dbd.O" bonded to it, i.e., one
of the ring carbon atoms of the cycloalkyl group is a --C(.dbd.O)--
group.
[0305] As used herein, the term "thiocarbonyl" refers to a
--C(.dbd.S)R'' group, wherein R'' is as defined herein above.
[0306] As used herein, the term "O-carboxy" refers to an
--OC(.dbd.O)R'' group, wherein R'' is as defined herein above.
[0307] As used herein, the term "C-carboxy" refers to a
--C(.dbd.O)OR'' group, wherein R'' is as defined herein above.
[0308] As used herein, the term "ester" refers to a C-carboxy group
as defined herein above or a molecule comprising such group,
wherein R'' is as defined herein above and R'' is not hydro.
[0309] As used herein, the term "C-carboxy salt" refers to a
--C(.dbd.O)R'' group or a molecule comprising such group, wherein
M.sup.+ is selected from the group consisting of lithium, sodium,
magnesium, calcium, potassium, barium, iron, zinc and quaternary
ammonium, and further wherein the " " in M.sup.+ does not reflect
the actual number of positive charges which depends on the
respective ion.
[0310] As used herein, the term "acetyl" refers to a
--C(.dbd.O)CH.sub.3 group.
[0311] As used herein, the term "carboxyalkyl" refers to a
--(CH.sub.2).sub.rC(.dbd.O)OR'' group, wherein r is 1 to 6 and R''
is as defined herein above.
[0312] As used herein, the term "carboxyalkyl salt" refers to a
--(CH.sub.2).sub.rC(.dbd.O)O.sup.-M.sup.+ group or a molecule
comprising such group, wherein r is 1 to 6 and M.sup.+ is selected
from the group consisting of lithium, sodium, potassium, calcium,
magnesium, barium, iron, zinc and quaternary ammonium, and further
wherein the "+" in M.sup.+ does not reflect the actual number of
positive charges which depends on the respective ion.
[0313] As used herein, the term "carboxylic acid" refers to a
C-carboxy group as defined herein above, wherein R'' is hydro.
[0314] As used herein, the term "haloalkyl" refers to an alkyl
group substituted with 1 to 6 halo groups, wherein the alkyl group
and the halo groups are as defined herein above, and further
wherein the halo groups are independently selected. In a more
specific definition, haloalkyl is a --CX.sub.3 group, wherein each
X independently is a halo group.
[0315] As used herein, the term "trihalomethanesulfonyl" refers to
an --S(.dbd.O).sub.2CX.sub.3 group, wherein each X is a halo group
as defined herein above.
[0316] As used herein, the term "cyano" refers to a --C.ident.N
group.
[0317] As used herein, the term "cyanato" refers to an --OCN
group.
[0318] As used herein, the term "isocyanato" refers to an --NCO
group.
[0319] As used herein, the term "thiocyanato" refers to an --SCN
group.
[0320] As used herein, the term "isothiocyanato" refers to an --NCS
group.
[0321] As used herein, the term "sulfinyl" refers to an
--S(.dbd.O)R'' group, wherein R'' is as defined herein above.
[0322] As used herein, the term "sulfonyl" refers to an
--S(.dbd.O).sub.2R'' group, wherein R'' is as defined herein
above.
[0323] As used herein, the term "sulfonamido" refers to an
--S(.dbd.O).sub.2NR.sub.17R.sub.18 group, wherein R.sub.17 and
R.sub.18 are as defined herein below.
[0324] Unless specified otherwise, R.sub.17 and R.sub.18 are
independently chosen from hydro, alkyl, aryl, carbocyclyl,
heterocyclyl, --(CH.sub.2)aryl, --(CH.sub.2)carbocyclyl, and
--(CH.sub.2)heterocyclyl, wherein hydro, alkyl, aryl, carbocyclyl
and heterocyclyl are as defined herein.
[0325] As used herein, the term "trihalomethanesulfonamido" refers
to an --N(R.sub.17)S(.dbd.O).sub.2CX.sub.3 group, wherein X is a
halo group as defined herein above and R.sub.17 is as defined as
herein above.
[0326] As used herein, the term "O-carbamyl" refers to an
--OC(.dbd.O)NR.sub.17R.sub.18 group, wherein R.sub.17 and R.sub.18
are as defined herein above.
[0327] As used herein, the term "N-carbamyl" refers to an
--N(R.sub.17)C(.dbd.O)OR.sub.18 group, wherein R.sub.17 and
R.sub.18 are as defined herein above.
[0328] As used herein, the term "O-thiocarbamyl" refers to an
--OC(.dbd.S)NR.sub.17R.sub.18 group, wherein R.sub.17 and R.sub.18
are as defined herein above.
[0329] As used herein, the term "N-thiocarbamyl" refers to an
--N(R.sub.17)C(.dbd.S)OR.sub.18 group, wherein R.sub.17 and
R.sub.18 are as defined herein above.
[0330] As used herein, the term "amino" refers to an --NH.sub.2
group.
[0331] As used herein, the term "alkylamino" refers to an
--NR.sub.23R.sub.24 group, wherein R.sub.23 and R.sub.24 are
independently chosen from --H, C.sub.1-8 alkyl (i.e., an alkyl
having 1 to 8 carbon atoms), and phenyl.
[0332] As used herein, the term "C-amido" refers to a
--C(.dbd.O)NR.sub.17R.sub.18 group, wherein R.sub.17 and R.sub.18
are as defined herein above.
[0333] As used herein, the term "N-amido" refers to an
--N(R.sub.17)C(.dbd.O)R.sub.18 group, wherein R.sub.17 and R.sub.18
are as defined herein above.
[0334] As used herein, the term "nitro" refers to an --NO.sub.2
group.
[0335] As used herein, the term "quaternary ammonium" refers to an
--NR.sub.20R.sub.21R.sub.22 group, wherein R.sub.20, R.sub.21, and
R.sub.22 are independently selected from the group consisting of
hydro and C.sub.1-6 alkyl.
[0336] As used herein, the term "methylenedioxy" refers to an
--OCH.sub.2O-- group, wherein the two oxygen atoms are bonded to
adjacent ring carbon atoms.
[0337] As used herein, the term "ethylenedioxy" refers to an
--OCH.sub.2CH.sub.2O-- group, wherein the two oxygen atoms are
bonded to adjacent ring carbon atoms.
[0338] As used herein, the term "carbocyclyl" refers to an
all-carbon monocyclic or fused ring (i.e., rings which share an
adjacent pair of ring carbon atoms) group, wherein one or more of
the rings does not have a completely conjugated pi-electron system.
In a more specific definition, it refers to a cycloalkyl group
having 3 to 12 carbon atoms or a cycloalkenyl group having 3 to 12
carbon atoms. In another more specific definition, it refers to a
cycloalkyl group having 3 to 6 carbon atoms or a cycloalkenyl group
having 3 to 6 carbon atoms. Examples, without limitation, of
carbocyclyl groups are cycloalkyls such as cyclopropane,
cyclobutane, cyclopentane, cyclohexane, adamantane, cycloheptane
and cycloalkenes such as cycloheptatriene, cyclopentene, and
cyclohexadiene.
[0339] As used herein, the term "cycloalkyl" refers to an
all-carbon monocyclic or fused ring (i.e., rings which share an
adjacent pair of ring carbon atoms) group, wherein said monocyclic
or fused ring group does not have a double or triple bond. In a
more specific definition, it refers to a C.sub.3-12 cycloalkyl
group, i.e., an all-carbon monocyclic or fused ring group having 3
to 12 carbon atoms, wherein said monocyclic or fused ring group
does not have a double or triple bond. In another more specific
definition, it refers to a C.sub.3-6 cycloalkyl group, i.e., an
all-carbon monocyclic or fused ring group having 3 to 6 carbon
atoms, wherein said monocyclic or fused ring group does not have a
double or triple bond. Examples, without limitation, of cycloalkyl
groups are cyclopropane, cyclobutane, cyclopentane, cyclohexane,
adamantane, and cycloheptane.
[0340] As used herein, the term "heterocyclyl" (or "heterocycle" or
"heterocyclic") refers to a saturated or partially saturated
monocyclic or fused-ring polycyclic group having 3 to 14 ring
atoms, said ring atoms comprising carbon atoms and from one to four
heteroatoms independently selected from the group consisting of O,
N, and S, wherein the nitrogen and sulfur heteroatoms can be
optionally oxidized, the nitrogen heteroatoms can be optionally
quaternized, and including any bicyclic group in which any of the
above-defined heterocyclic rings is fused to a benzene ring.
"Heterocyclyl" thus also include heteroaryl groups as defined
herein below. In a more specific definition, "heterocyclyl" refers
to a saturated or partially saturated 3-7 membered monocyclic, or
7-10 membered bicyclic ring system, which consists of carbon atoms
and from one to four heteroatoms independently selected from the
group consisting of O, N, and S, wherein the nitrogen and sulfur
heteroatoms can be optionally oxidized, the nitrogen heteroatoms
can be optionally quaternized, and including any bicyclic group in
which any of the above-defined heterocyclic rings is fused to a
benzene ring. Non-limiting examples of saturated or partially
saturated heterocyclyl groups include tetrahydrofuranyl, pyranyl,
piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl,
imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,
isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and
tetramoyl groups. Examples of "heterocycles" or "heterocyclic"
rings also include, but are not limited to, morpholino, piperidyl,
piperazinyl, pyrrolidinyl, thiomorpholino, homopiperazinyl,
imidazolyl, imidazolidinyl, pyrazolidinyl, dioxanyl and
dioxolanyl.
[0341] As used herein, the term "aryl" refers to an all-carbon
monocyclic or fused-ring polycyclic (i.e., rings which share an
adjacent pair of ring carbon atoms) aromatic group having a
completely conjugated pi-electron system. Examples, without
limitation, of aryl groups are phenyl, naphthalenyl and
anthracenyl.
[0342] As used herein, the term "heteroaryl" refers to a monocyclic
or fused-ring polycyclic group having 5 to 14 ring atoms; having 6,
10 or 14 pi electrons shared in a cyclic array; and containing
carbon atoms and 1, 2 or 3 heteroatoms independently selected from
the group consisting of O, N, and S. In a more specific definition,
it refers to a monocyclic or fused-ring polycyclic aromatic group
having 5 to 9 ring atoms and comprising 1, 2 or 3 heteroatoms
independently selected from the group consisting of O, N, and S.
Non-limiting examples of heteroaryl groups include thienyl
(thiophenyl), benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl,
furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl,
phenoxathiinyl, pyrrolyl (including, without limitation,
2H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (pyridinyl; including,
without limitation, 2-pyridyl, 3-pyridyl, and 4-pyridyl),
pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl,
indolyl (including, without limitation, 3H-indolyl), indazolyl,
purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl,
naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl,
beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,
phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,
isoxazolyl, furazanyl, phenoxazinyl,
1,4-dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin,
pyrido[1,2-a]pyrimidin-4-one, pyrazolo[1,5-a]pyrimidinyl
(including, without limitation, pyrazolo[1,5-a]pyrimidin-3-yl),
1,2-benzisoxazol-3-yl, benzimidazolyl, 2-oxindolyl and
2-oxobenzimidazolyl. When the heteroaryl group contains a nitrogen
ring atom, such nitrogen atom may optionally be in the form of an
N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl
N-oxide.
[0343] As used herein and unless specified otherwise, the term
"optional substituent" or "optionally substituted" refers to one or
more substituents covalently linked to the parent group, wherein
said substituents are independently chosen from halo, alkyl,
alkynyl, alkenyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
-L-carbocyclyl, -L-aryl, -L-heteroaryl, -L-heterocyclyl, acylamino,
acyloxy, alkylthio, cycloalkylthio, amino, alkylamino, aryl,
arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio,
heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy,
heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl,
sulfonyl, sulfonamido, thiocarbonyl, thiocyanato,
trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl,
N-thiocarbamyl, and C-amido, wherein each L is independently chosen
from --(CH.sub.2).sub.n--(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nNH(CH.sub.2).sub.n--,
--(CH.sub.2).sub.nO(CH.sub.2).sub.n--, and
--(CH.sub.2).sub.nS(CH.sub.2).sub.n--, and wherein each n is
independently chosen from 0, 1, 2, and 3. In an alternative
definition, the one or more optional substituents are chosen from
hydroxyl, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy,
--N(C.sub.1-3 alkyl).sub.2, --NH(C.sub.1-3 alkyl),
--NHC(.dbd.O)(C.sub.1-3 alkyl), --C(.dbd.O)OH,
--C(.dbd.O)O(C.sub.1-6 alkyl), --C(.dbd.O)(C.sub.1-3 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)NH(C.sub.1-3 alkyl),
--C(.dbd.O)NH(cycloalkyl), --C(.dbd.O)N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2(C.sub.1-3 alkyl), --S(.dbd.O).sub.2NH.sub.2,
--S(.dbd.O).sub.2N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2NH(C.sub.1-3 alkyl), --CHF.sub.2, --OCF.sub.3,
--OCHF.sub.2, --CF.sub.3, --CN, --NH.sub.2, --NO.sub.2, and
tetrazolyl.
[0344] As used herein, the term "arylalkyl" refers to a C.sub.1-10
alkyl group (an alkyl group having 1-10 carbon atoms), as defined
herein above, substituted by a C.sub.6-14 aryl group (an aryl group
having 6 to 14 carbon atoms), as defined herein above. Non-limiting
examples of arylalkyl groups include benzyl, phenethyl, and
naphthylmethyl.
[0345] As used herein, the term "arylalkenyl" refers to a
C.sub.2-10 alkenyl group substituted by a C.sub.6-14 aryl group (an
aryl group having 6 to 14 carbon atoms), as defined herein
above.
[0346] As used herein, the term "arylalkynyl" refers to a
C.sub.2-10 alkynyl group substituted by a C.sub.6-14 aryl group (an
aryl group having 6 to 14 carbon atoms), as defined herein
above.
[0347] As used herein, the term "arylalkoxy" refers to a C.sub.1-10
alkoxy group, as defined herein above, substituted by an aryl
group, as defined herein above. Examples of arylalkoxy groups
include benzyloxy and phenethyloxy.
[0348] As used herein, the term "aryloxy" refers to an oxygen
substituted by a C.sub.6-14 aryl group, as defined herein above.
Examples of aryloxy groups include phenoxy and 4-methylphenoxy.
[0349] As used herein, the term "arylthio" refers to an --S-aryl
group, wherein the aryl group is as defined herein above.
[0350] As used herein, the term "heteroarylthio" refers to an
--S-heteroaryl group, wherein the heteroaryl group is as defined
herein above.
[0351] As used herein, the term "haloalkoxy" refers to an alkoxy
group which is substituted with 1 to 6 halo groups, wherein the
alkoxy group and the halo groups are as defined herein above, and
further wherein the halo groups are independently selected.
[0352] As used herein, the term "haloaryl" refers to an aryl group
which is substituted with 1 to 6 halo groups, wherein the aryl
group and the halo groups are as defined herein above, and further
wherein the halo groups are independently selected.
[0353] As used herein, the term "acylamino" refers to an
--N(R.sub.17)C(.dbd.)R.sub.18 group, wherein R.sub.17 and R.sub.18
are as defined herein above.
[0354] As used herein, the term "acyloxy" refers to an
--O--C(.dbd.O)R.sub.17 group, wherein R.sub.17 is as defined herein
above.
[0355] As used herein, the term "heteroaryloxy" refers to an
--O-heteroaryl group, wherein the heteroaryl group is as defined
herein above.
[0356] As used herein, the term "heteroarylalkoxy" refers to a
C.sub.1-10 alkoxy group, as defined herein above, substituted by a
heteroaryl group, as defined herein above.
[0357] As used herein, the term "preventing an increase in a
symptom" refers to both not allowing a symptom to increase or
worsen, as well as reducing the rate of increase in the symptom.
For example, a symptom can be measured as the amount of particular
disease marker, i.e., a protein. In another example the symptom can
be cognitive decline. Preventing an increase, according to the
definition provided herein, means that the amount of symptom {e.g.,
protein or cognitive decline) does not increase or that the rate at
which it increases is reduced.
[0358] As used herein, the term "treating a disease or disorder"
refers to a slowing of or a reversal of the progress of the
disease. Treating a disease or disorder includes treating a symptom
and/or reducing the symptoms of the disease.
[0359] As used herein, the term "preventing a disease or disorder"
refers to a slowing of the disease or of the onset of the disease
or the symptoms thereof. Preventing a disease or disorder can
include stopping the onset of the disease or symptoms thereof. As
used herein, the term "unit dosage form" refers to a physically
discrete unit, such as a capsule or tablet suitable as a unitary
dosage for a human patient. Each unit contains a predetermined
quantity of a compound of Formula I, which was discovered or
believed to produce the desired pharmacokinetic profile which
yields the desired therapeutic effect. The dosage unit is composed
of a compound of Formula I in association with at least one
pharmaceutically acceptable carrier, salt, excipient, or
combination thereof.
[0360] The patient or subject, such as the subject in need of
treatment or prevention, may be e.g. a eukaryote, an animal, a
vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a
hamster, a rat, a mouse), a murine (e.g. a mouse), a canine (e.g. a
dog), a feline (e.g. a cat), an equine (e.g. a horse), a primate, a
simian (e.g. a monkey or ape), a monkey (e.g. a marmoset, a
baboon), an ape (e.g. gorilla, chimpanzee, orangutang, gibbon), or
a human. The meaning of the terms "eukaryote", "animal", "mammal",
etc. is well known in the art and can, for example, be deduced from
Wehner and Gehring (1995; Thieme Verlag). In the context of this
invention, it is particularly envisaged that animals are to be
treated which are economically, agronomically or scientifically
important. Scientifically important organisms include, but are not
limited to, mice, rats, rabbits, fruit flies like Drosophila
melagonaster and nematodes like Caenorhabditis elegans.
Non-limiting examples of agronomically important animals are sheep,
cattle and pig, while, for example, cats and dogs may be considered
as economically important animals. Preferably, the subject/patient
is a mammal; more preferably, the subject/patient is a human.
[0361] As used herein, the term "dose" or "dosage" refers the
amount of active ingredient that an individual takes or is
administered at one time. For example, a 40 mg dose of a compound
of Formula I refers to, in the case of a twice-daily dosage
regimen, a situation where the individual takes 40 mg of a compound
of Formula I twice a day, e.g., 40 mg in the morning and 40 mg in
the evening. The 40 mg of a compound of Formula I dose can be
divided into two or more dosage units, e.g., two 20 mg dosage units
of a compound of Formula I in tablet form or two 20 mg dosage units
of a compound of Formula I in capsule form.
[0362] As used herein, a "pharmaceutically acceptable prodrug" is a
compound that may be converted under physiological conditions or by
solvolysis to the specified compound or to a pharmaceutically
acceptable salt of such compound.
[0363] As used herein, a "pharmaceutically active metabolite" is
intended to mean a pharmacologically active product produced
through metabolism in the body of a specified compound or salt
thereof. Metabolites of a compound may be identified using routine
techniques known in the art and their activities determined using
tests such as those described herein.
[0364] As used herein, a "pharmaceutically acceptable salt" is
intended to mean a salt that retains the biological effectiveness
of the free acids and bases of the specified compound and that is
not biologically or otherwise undesirable. A compound for use in
the invention may possess a sufficiently acidic, a sufficiently
basic, or both functional groups, and accordingly react with any of
a number of inorganic or organic bases, and inorganic and organic
acids, to form a pharmaceutically acceptable salt. Exemplary
pharmaceutically acceptable salts include those salts prepared by
reaction of the compounds of the present invention with a mineral
or organic acid or an inorganic base, such as salts including
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,
phosphates, monohydrophosphates, dihydrophosphates, metaphosphates,
pyrophosphates, chlorides, bromides, iodides, acetates,
propionates, decanoates, caprylates, acrylates, formates,
isobutyrates, caproates, heptanoates, propiolates, oxalates,
malonates, succinates, suberates, sebacates, fumarates, maleates,
butyne-1,4 dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methylbenzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, xylenesulfonates,
phenylacetates, phenylpropionates, phenylbutyrates, citrates,
lactates, gamma-hydroxybutyrates, glycollates, tartrates,
methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, and mandelates.
[0365] As used herein, a "pharmaceutically acceptable carrier"
refers to a non-API (API refers to Active Pharmaceutical
Ingredient) substances such as disintegrators, binders, fillers,
and lubricants used in formulating pharmaceutical products. They
are generally safe for administering to humans according to
established governmental standards, including those promulgated by
the United States Food and Drug Administration and the European
Medical Agency.
[0366] As is understood by the skilled artisan, certain variables
in the list of substituents are repetitive (different name for the
same substituent), generic to other terms in the list, and/or
partially overlap in content with other terms. In the compounds of
the invention, the skilled artisan recognizes that substituents may
be attached to the remainder of the molecule via a number of
positions and the preferred positions are as illustrated in the
Examples.
[0367] Additionally, the compounds of Formula I can contain
asymmetric carbon atoms and can therefore exist in racemic and
optically active forms. Thus, optical isomers or enantiomers,
racemates, tautomers, and diastereomers are also encompassed in the
compounds of Formula I in all embodiments described herein. The
methods of the present invention include the use of all such
isomers and mixtures thereof. Methods of separation of enantiomeric
and diastereomeric mixtures are well known to one skilled in the
art. The present invention encompasses any isolated racemic or
optically active form of compounds described in Formula I, or any
mixture thereof. In one aspect, the compounds of the invention have
a trans configuration around the cyclopropyl ring as in
trans-phenylcyclopropylamine. In one aspect, the compounds of the
invention have a cis configuration around the cyclopropyl ring as
in cis-phenylcyclopropylamine.
[0368] Typically, compounds according to Formula I can be effective
at an amount of from about 0.01 .mu.g/kg to about 100 mg/kg per day
based on total body weight. The active ingredient may be
administered at once, or may be divided into a number of smaller
doses to be administered at predetermined intervals of time. The
suitable dosage unit for each administration can be, e.g., from
about 1 .mu.g to about 2000 mg, preferably from about 5 .mu.g to
about 1000 mg.
[0369] It should be understood that the dosage ranges set forth
above are exemplary only and are not intended to limit the scope of
this invention. The therapeutically effective amount for each
active compound can vary with factors including but not limited to
the activity of the compound used, stability of the active compound
in the patient's body, the severity of the conditions to be
alleviated, the total weight of the patient treated, the route of
administration, the ease of absorption, distribution, and excretion
of the active compound by the body, the age and sensitivity of the
patient to be treated, and the like, as will be apparent to a
skilled artisan. The amount of administration can be adjusted as
the various factors change over time.
[0370] For oral delivery, the active compounds can be incorporated
into a formulation that includes pharmaceutically acceptable
carriers such as binders (e.g., gelatin, cellulose, gum
tragacanth), excipients (e.g., starch, lactose), lubricants (e.g.,
magnesium stearate, silicon dioxide), disintegrating agents (e.g.,
alginate, Primogel, and corn starch), and sweetening or flavoring
agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and
peppermint). The formulation can be orally delivered in the form of
enclosed gelatin capsules or compressed tablets. Capsules and
tablets can be prepared in any conventional techniques. The
capsules and tablets can also be coated with various coatings known
in the art to modify the flavors, tastes, colors, and shapes of the
capsules and tablets. In addition, liquid carriers such as fatty
oil can also be included in capsules.
[0371] Suitable oral formulations can also be in the form of
suspension, syrup, chewing gum, wafer, elixir, and the like. If
desired, conventional agents for modifying flavors, tastes, colors,
and shapes of the special forms can also be included. In addition,
for convenient administration by enteral feeding tube in patients
unable to swallow, the active compounds can be dissolved in an
acceptable lipophilic vegetable oil vehicle such as olive oil, corn
oil and safflower oil.
[0372] The active compounds can also be administered parenterally
in the form of solution or suspension, or in lyophilized form
capable of conversion into a solution or suspension form before
use. In such formulations, diluents or pharmaceutically acceptable
carriers such as sterile water and physiological saline buffer can
be used. Other conventional solvents, pH buffers, stabilizers,
anti-bacteria agents, surfactants, and antioxidants can all be
included. For example, useful components include sodium chloride,
acetates, citrates or phosphates buffers, glycerin, dextrose, fixed
oils, methyl parabens, polyethylene glycol, propylene glycol,
sodium bisulfate, benzyl alcohol, ascorbic acid, and the like. The
parenteral formulations can be stored in any conventional
containers such as vials and ampoules.
[0373] Routes of topical administration include nasal, bucal,
mucosal, rectal, or vaginal applications. For topical
administration, the active compounds can be formulated into
lotions, creams, ointments, gels, powders, pastes, sprays,
suspensions, drops and aerosols. Thus, one or more thickening
agents, humectants, and stabilizing agents can be included in the
formulations. Examples of such agents include, but are not limited
to, polyethylene glycol, sorbitol, xanthan gum, petrolatum,
beeswax, or mineral oil, lanolin, squalene, and the like. A special
form of topical administration is delivery by a transdermal patch.
Methods for preparing transdermal patches are disclosed, e.g., in
Brown, et al. (1988) Ann. Rev. Med. 39:221-229 which is
incorporated herein by reference.
[0374] Subcutaneous implantation for sustained release of the
active compounds may also be a suitable route of administration.
This entails surgical procedures for implanting an active compound
in any suitable formulation into a subcutaneous space, e.g.,
beneath the anterior abdominal wall. See, e.g., Wilson et al.
(1984) J. Clin. Psych. 45:242-247. Hydrogels can be used as a
carrier for the sustained release of the active compounds.
Hydrogels are generally known in the art. They are typically made
by crosslinking high molecular weight biocompatible polymers into a
network, which swells in water to form a gel like material.
Preferably, hydrogels are biodegradable or biosorbable. For
purposes of this invention, hydrogels made of polyethylene glycols,
collagen, or poly(glycolic-co-L-lactic acid) may be useful. See,
e.g., Phillips et al. (1984) J. Pharmaceut. Sci., 73:
1718-1720.
[0375] The active compounds can also be conjugated, to a water
soluble non-immunogenic non-peptidic high molecular weight polymer
to form a polymer conjugate. For example, an active compound is
covalently linked to polyethylene glycol to form a conjugate.
Typically, such a conjugate exhibits improved solubility,
stability, and reduced toxicity and immunogenicity. Thus, when
administered to a patient, the active compound in the conjugate can
have a longer half-life in the body, and exhibit better efficacy.
See generally, Burnham (1994) Am. J. Hosp. Pharm. 15:210-218.
PEGylated proteins are currently being used in protein replacement
therapies and for other therapeutic uses. For example, PEGylated
interferon (PEG-INTRON A.RTM.) is clinically used for treating
Hepatitis B. PEGylated adenosine deaminase (ADAGEN.RTM.) is being
used to treat severe combined immunodeficiency disease (SCIDS).
PEGylated L-asparaginase (ONCAPSPAR.RTM.) is being used to treat
acute lymphoblastic leukemia (ALL). It is preferred that the
covalent linkage between the polymer and the active compound and/or
the polymer itself is hydrolytically degradable under physiological
conditions. Such conjugates known as "prodrugs" can readily release
the active compound inside the body. Controlled release of an
active compound can also be achieved by incorporating the active
ingredient into microcapsules, nanocapsules, or hydrogels generally
known in the art. Other pharmaceutically acceptable prodrugs of the
compounds of this invention include, but are not limited to,
esters, carbonates, thiocarbonates, N-acyl derivatives,
N-acyloxyalkyl derivatives, quaternary derivatives of tertiary
amines, N-Mannich bases, Schiff bases, aminoacid conjugates,
phosphate esters, metal salts and sulfonate esters.
[0376] Liposomes can also be used as carriers for the active
compounds of the present invention. Liposomes are micelles made of
various lipids such as cholesterol, phospholipids, fatty acids, and
derivatives thereof. Various modified lipids can also be used.
Liposomes can reduce the toxicity of the active compounds, and
increase their stability. Methods for preparing liposomal
suspensions containing active ingredients therein are generally
known in the art. See, e.g., U.S. Pat. No. 4,522,811; Prescott,
Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York,
N. Y. (1976).
[0377] The active compounds can also be administered in combination
with another active agent that synergistically treats or prevents
the same symptoms or is effective for another disease or symptom in
the patient treated so long as the other active agent does not
interfere with or adversely affect the effects of the active
compounds of this invention. Such other active agents include but
are not limited to anti-inflammation agents, antiviral agents,
antibiotics, antifungal agents, antithrombotic agents,
cardiovascular drugs, cholesterol lowering agents, anti-cancer
drugs, hypertension drugs, and the like.
[0378] Examples of antineoplastic agents that can be used in
combination with the compounds and methods of the present invention
include, in general, and as appropriate, alkylating agents,
anti-metabolites, epidophyllotoxins, antineoplastic enzymes,
topoisomerase inhibitors, procarbazines, mitoxantrones, platinum
coordination complexes, biological response modifiers and growth
inhibitors, hormonal/anti-hormonal therapeutic agents and
haematopoietic growth factors. Exemplary classes of antineoplastic
include the anthracyclines, vinca drugs, mitomycins, bleomycins,
cytotoxic nucleosides, epothilones, discodermolides, pteridines,
diynenes and podophyllotoxins. Particularly useful members of those
classes include, for example, carminomycin, daunorubicin,
aminopterin, methotrexate, methopterin, dichloromethotrexate,
mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine,
gemcitabine, cytosine arabinoside, podophyllotoxin or
podo-phyllotoxin derivatives such as etoposide, etoposide phosphate
or teniposide, melphalan, vinblastine, vincristine, leurosidine,
vindesine, leurosine, paclitaxel and the like. Other useful
antineoplastic agents include estramustine, carboplatin,
cyclophosphamide, bleomycin, gemcitibine, ifosamide, melphalan,
hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate,
dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan,
ara-C, bicalutamide, flutamide, leuprolide, pyridobenzoindole
derivatives, interferons and interleukins.
General Synthetic Route Description
[0379] The compounds of Formula (I), in which R1, R2, R3, R4, R5,
R6 and R7 represent a hydrogen atom and R8 represents an optionally
substituted aryl, heteroaryl, or heterocyclic group can be
synthesized by the general route described in the scheme
##STR00013##
[0380] Commercially available trans-Phenylcyclopropylamine
(ALDRICH) of Formula (II) is reductively alkylated using
commercially available aldehydes of Formula (III) R8CHO, in which
R8 is as defined earlier (e.g., in the markush groups described
above), to give the compounds of Formula (IV), which are a
particular case of the compounds claimed in the present
invention.
[0381] The procedures for preparing the compounds of Formula (I),
e.g., where the phenyl ring of the phenylcyclopropylamine core is
substituted (in this scheme with a benzyloxy moiety; other moieties
substituting the phenyl ring of the phenylcyclopropylamine core can
be used as is recognized by the skilled artisan) are exemplified in
Scheme 2.
##STR00014##
[0382] Cyclopropanation reaction of commercially available
nitroolefin derivatives of Formula (V) using trimethylsulfoxonium
iodide gives derivatives of Formula (VI). Reduction of the nitro
group by zinc, followed by protection, with Boc, of the resulting
amino group by tertbutyloxycarbonyl leads to the derivatives of
Formula (VII). These derivatives were alkylated using a base and an
alkylating reagent of Formula (VIII), where R8 is as defined before
and X represents a halogen atom (e.g., --Cl or --Br). Deprotection
of the Boc group using sulfuric acid affords the derivatives of
Formula (IX), which are specific examples of the compounds of
Formula (I).
[0383] Compounds of Formula (I), in which R1, R2, R3, R4, R5 and R6
represent a hydrogen atom, R7 represents alkyl or cycloalkyl and R8
represents an optionally substituted aryl, heteroaryl, or
heterocyclic group can be synthesized by the general route
described in the scheme 3.
##STR00015##
[0384] Commercially available trans-phenylcyclopropylamine
(ALDRICH) of Formula (II) is reductively alkylated using
commercially available ketones of Formula (X), in which R7 and R8
are as defined earlier, to give the compounds of Formula (XI),
which are also subjects of the present invention.
[0385] Compounds of Formula (I), where R1 to R5 may be different
than a hydrogen and R8 represents an optionally substituted
oxadiazole can be synthesized by the general route described in the
scheme 4.
##STR00016##
[0386] The trans phenylcyclopropylamino derivatives of formula
(XIV) (including trans ((1S,2R), (1R,2S)) version as well the
individual diastereoisomers corresponding to (1S,2R) and (1R,2S)
can be used) are reacted with methyl 2-bromoacetate in acetonitrile
using N,N-diisopropylethylamine as a base to give methyl
2-((trans)-2-phenylcyclopropylamino)acetate derivatives of formula
(XVI). Hydrolysis with lithium hydroxide using
tetrahydrofurane-water solution as a solvent and later reaction
with t-butyl dicarbonate in tetrahydrofurane leads to
2-(tert-butoxycarbonyl((trans)-2-phenylcyclopropyl)amino)acetic
acid derivatives of formula (XVII), which are reacted with
commercially available formamidoxime derivatives of formula (XVIII)
and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in diglyme to
obtain
tert-butyl(1,2,4-oxadiazol-5-yl)methyl((trans)-2-phenylcyclopropyl)carbam-
ate derivatives of formula (XIX). Final Boc-deprotection using HCl
2M in diethyl ether using diethyl ether as a solvent leads to the
formation of the corresponding hydrochloride salt of the
(trans)-N-((1,2,4-oxadiazol-5-yl)methyl)-2-phenylcyclopropanamine
derivatives of formula (XX), which are also subjects of the present
invention.
[0387] The compounds in the examples below can be synthesized using
these procedures described above or modifications thereof by an
ordinary artisan skilled in the art of synthetic organic
chemistry.
[0388] It is to be understood that wherever a substituent in a
structure depicted herein is not specified (e.g. is "missing" in
the structure) said substituent is a hydrogen atom.
[0389] The title Example compounds below were named using the
ChemBioDraw Ultra version 11.0.1 by CambridgeSoft program. In the
case of a conflict between a name and a drawn structure, the drawn
structure is the controlling definition.
EXAMPLES
Example 1
(trans)-N-(4-fluorobenzyl)-2-phenylcyclopropanamine
##STR00017##
[0391] A mixture of (trans)-2-phenylcyclopropanamine hydrochloride
(0.25 g, 1.50 mmol) and 4-fluorobenzaldehyde (0.18 mL, 1.65 mmol)
in CH.sub.2Cl.sub.2 (8 mL) and water (0.5 mL) was vigorously
stirred at room temperature for 10 min. Then, NaBH(OAc).sub.3 (0.41
g, 1.95 mmol) was slowly added and stirring continued for 1.5 h.
The reaction mixture was washed with an aqueous saturated solution
of NaHCO.sub.3 (10 mL), the organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and, after removal of the solvent, the
residual oil was purified by column chromatography on silica gel
(3% MeOH/CH.sub.2Cl.sub.2) affording 0.18 g of
N-(4-fluorobenzyl)-N-[(trans)-2-phenylcyclopropyl]amine [Rf=0.5 (5%
MeOH/CH.sub.2Cl.sub.2), colorless oil, 49% yield].
Example 2
(trans)-N-(4-fluorobenzyl)-2-phenylcyclopropanaminium chloride
##STR00018##
[0393] 2 M ethereal solution of HCl (0.24 mL, 0.47 mmol) was slowly
added to a solution of
N-(4-fluorobenzyl)-N-[(trans)-2-phenylcyclopropyl]amine (95 mg,
0.39 mmol) in dry Et.sub.2O (10 mL) cooled at -78.degree. C., and
allowed to reach room temperature. After 10 min the white
precipitate was allowed to settle and Et.sub.2O was decanted, the
solid was washed with Et.sub.2O (10 mL) and vacuum dried, rendering
90 mg of N-(4-fluorobenzyl)-N-[(trans)-2-phenylcyclopropyl]amine
hydrochloride (white solid, 83% yield).
[0394] .sup.1H-NMR (MeOD, 250 MHz, .delta.): 7.59-7.49 (m, 2H,
ArH); 7.34-7.05 (m, 7H, ArH); 4.38 (s, 2H, CH2); 3.02-2.93 (m, 1H,
CH); 2.52-2.40 (m, 1H, CH); 1.58-1.31 (m, 2H, CH2).
Example 3
4-(((trans)-2-phenylcyclopropylamino)methyl)benzonitrile
##STR00019##
[0396] A mixture of (trans)-2-phenylcyclopropanamine hydrochloride
(0.25 g, 1.50 mmol) and 4-cyanobenzaldehyde (0.22 g, 1.65 mmol) in
CH.sub.2Cl.sub.2 (8 mL) and water (0.5 mL) was vigorously stirred
at room temperature for 10 min. Then, NaBH(OAc).sub.3 (0.41 g, 1.95
mmol) was slowly added and stirring continued for 1.5 h. The
reaction mixture was washed with an aqueous saturated solution of
NaHCO.sub.3 (10 mL), the organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and, after removal of the solvent, the
residual oil was purified by column chromatography on silica gel
(1% MeOH/CH.sub.2Cl.sub.2) affording 0.07 g of
4-({[(trans)-2-phenylcyclopropyl]amino}methyl)benzonitrile [Rf=0.6
(5% MeOH/CH.sub.2Cl.sub.2), colorless oil, 19% yield].
Example 4
(trans)-N-(4-cyanobenzyl)-2-phenylcyclopropanaminium chloride
##STR00020##
[0398] 2 M ethereal solution of HCl (0.14 mL, 0.27 mmol) was slowly
added to a solution of
4-({[(trans)-2-phenylcyclopropyl]amino}methyl)benzonitrile (67 mg,
0.27 mmol) in dry Et.sub.2O (5 mL) cooled at -78.degree. C., and
allowed to reach room temperature. After 10 min the white
precipitate was allowed to settle and Et.sub.2O was decanted, the
solid was washed with Et.sub.2O (20 mL) and vacuum dried, rendering
65 mg of 4-({[(trans)-2-phenylcyclopropyl]amino}methyl)benzonitrile
hydrochloride (white solid, 84% yield).
[0399] .sup.1H-NMR (MeOD, 250 MHz, .delta.): 7.81 (d, J=8.5 Hz, 2H,
ArH); 7.71 (d, J=8.5 Hz, 2H, ArH); 7.35-7.19 (m, 3H, ArH);
7.14-7.07 (m, 2H, ArH); 4.49 (s, 2H, CH2); 3.06-2.98 (m, 1H, CH);
2.52-2.43 (m, 1H, CH); 1.61-1.50 (m, 1H, CH2); 1.44-1.33 (m, 1H,
CH2).
Example 5
(trans)-2-phenyl-N-(4-(trifluoromethyl)benzyl)cyclopropanamine
##STR00021##
[0401] A mixture of (trans)-2-phenylcyclopropanamine hydrochloride
(0.23 g, 1.36 mmol) and 4-(trifluoromethyl)benzaldehyde (0.20 mL,
1.49 mmol) in CH.sub.2Cl.sub.2 (8 mL) and water (0.5 mL) was
vigorously stirred at room temperature for 10 min. Then,
NaBH(OAc).sub.3 (0.37 g, 1.76 mmol) was slowly added and stirring
continued for 30 min. The reaction mixture was washed with an
aqueous saturated solution of NaHCO.sub.3 (8 mL), the organic layer
was dried over anhydrous Na.sub.2SO.sub.4, filtered and, after
removal of the solvent, the residual oil was purified by column
chromatography on silica gel (1% MeOH/CH.sub.2Cl.sub.2) affording
0.15 g of
N-[(trans)-2-phenylcyclopropyl]-N-[4-(trifluoromethyl)benzyl]amine
[Rf=0.6 (5% MeOH/CH.sub.2Cl.sub.2), colorless oil, 38% yield].
Example 6
(trans)-2-phenyl-N-(4-(trifluoromethyl)benzyl)cyclopropanaminium
chloride
##STR00022##
[0403] 2 M ethereal solution of HCl (0.28 mL, 0.57 mmol) was slowly
added to a solution of
N-[(trans)-2-phenylcyclopropyl]-N-[4-(trifluoromethyl)benzyl]amine
(150 mg, 0.51 mmol) in dry Et.sub.2O (8 mL) cooled at -78.degree.
C., and allowed to reach room temperature. After 10 min the white
precipitate was allowed to settle and Et.sub.2O was decanted, the
solid was washed with Et.sub.2O (10 mL) and vacuum dried, rendering
105 mg of
N-[(trans)-2-phenylcyclopropyl]-N-[4-(trifluoromethyl)benzyl]amine
hydrochloride (white solid, 62% yield). .sup.1H-NMR (MeOD, 250 MHz,
.delta.): 7.78-7.65 (m, 4H, ArH); 7.34-7.20 (m, 3H, ArH); 7.13-7.06
(m, 2H, ArH); 4.49 (s, 2H, CH2); 3.07-2.97 (m, 1H, CH); 2.51-2.40
(m, 1H, CH); 1.61-1.49 (m, 1H, CH2); 1.46-1.34 (m, 1H, CH2).
Example 7
(trans)-2-phenyl-N-(pyridin-2-ylmethyl)cyclopropanamine
##STR00023##
[0405] A mixture of (trans)-2-phenylcyclopropanamine hydrochloride
(0.25 g, 1.50 mmol) and pyridine-2-carbaldehyde (0.17 mL, 1.80
mmol) in CH.sub.2Cl.sub.2 (12 mL) and water (0.5 mL) was vigorously
stirred at room temperature for 10 min. Then, NaBH(OAc).sub.3 (0.48
g, 2.25 mmol) was slowly added and stirring continued for 2 h. The
reaction mixture was washed with an aqueous saturated solution of
NaHCO.sub.3 (10 mL), the organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and, after removal of the solvent, the
residual oil was purified by column chromatography on silica gel
[4% MeOH+1% NH.sub.3 (aq)/CH.sub.2Cl.sub.2] followed by preparative
layer chromatography (5% MeOH/CH.sub.2Cl.sub.2) affording 0.08 g of
N-[(trans)-2-phenylcyclopropyl]-N-(pyridin-2-ylmethyl)amine [Rf=0.3
(5% MeOH/CH.sub.2Cl.sub.2), colorless oil, 24% yield]. .sup.1H-NMR
(CDCl.sub.3, 250 MHz, .delta.): 8.60-8.54 (m, 1H, ArH); 7.62 (td,
J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 5H, ArH); 7.03-6.97 (m, 2H,
ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H, CH); 2.09 (br s, 1H,
NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m, 1H, CH2); 1.02-0.94 (m,
1H, CH2).
[0406] The following examples 8 to 25 have been synthesized using
the procedure described for examples 1-6 starting with the
corresponding aldehydes.
Example 8
(trans)-2-phenyl-N-(pyridin-3-ylmethyl)cyclopropanamine
##STR00024##
[0408] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 8.60-8.54 (m,
1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 5H,
ArH); 7.03-6.97 (in, 2H, ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H,
CH); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m, 1H,
CH2); 1.02-0.94 (m, 1H, CH2).
Example 9
(trans)-2-phenyl-N-(pyridin-4-ylmethyl)cyclopropanamine
##STR00025##
[0410] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 8.60-8.54 (m,
1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 5H,
ArH); 7.03-6.97 (m, 2H, ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H,
CH); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m, 1H,
CH2); 1.02-0.94 (m, 1H, CH2).
Example 10
(trans)-N-((6-methylpyridin-2-yl)methyl)-2-phenylcyclopropanamine
##STR00026##
[0412] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 8.60-8.54 (m,
1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 5H,
ArH); 7.03-6.97 (m, 2H, ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H,
CH); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 4H); 1.19-1.10 (m, 1H,
CH2); 1.02-0.94 (m, 1H, CH2).
Example 11
(trans)-2-phenyl-N-(thiazol-2-ylmethyl)cyclopropanamine
##STR00027##
[0414] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 7.72 (d, J=3.3
Hz, 1H, ArH); 7.28-7.09 (m, 4H, ArH); 7.04-6.96 (m, 2H, ArH); 4.24
(s, 2H, CH2); 2.54-2.46 (m, 1H, CH); 2.37 (br s, 1H, NH); 2.05-1.94
(m, 1H, CH); 1.19-1.09 (m, 1H, CH2); 1.05-0.95 (m, 1H, CH2).
Example 12
(trans)-2-phenyl-N-(thiophen-2-ylmethyl)cyclopropanamine
##STR00028##
[0416] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 7.72 (d, 2H,
ArH); 7.28-7.09 (m, 4H, ArH); 7.04-6.96 (m, 2H, ArH); 4.24 (s, 2H,
CH2); 2.54-2.46 (m, 1H, CH); 2.37 (br s, 1H, NH); 2.05-1.94 (m, 1H,
CH); 1.19-1.09 (m, 1H, CH2); 1.05-0.95 (m, 1H, CH2).
Example 13
(trans)-N-((3-bromothiophen-2-yl)methyl)-2-phenylcyclopropanamine
##STR00029##
[0418] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 7.72 (d, 1H,
ArH); 7.28-7.09 (m, 4H, ArH); 7.04-6.96 (m, 2H, ArH); 4.24 (s, 2H,
CH2); 2.54-2.46 (m, 1H, CH); 2.37 (br s, 1H, NH); 2.05-1.94 (m, 1H,
CH); 1.19-1.09 (m, 1H, CH2); 1.05-0.95 (m, 1H, CH2).
Example 14
(trans)-N-((4-bromothiophen-2-yl)methyl)-2-phenylcyclopropanamine
##STR00030##
[0420] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 7.72 (d, 1H,
ArH); 7.28-7.09 (m, 4H, ArH); 7.04-6.96 (m, 2H, ArH); 4.24 (s, 2H,
CH2); 2.54-2.46 (m, 1H, CH); 2.37 (br s, 1H, NH); 2.05-1.94 (m, 1H,
CH); 1.19-1.09 (m, 1H, CH2); 1.05-0.95 (m, 1H, CH2).
Example 15
(trans)-N-(3,4-dichlorobenzyl)-2-phenylcyclopropanamine
##STR00031##
[0422] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 8.60-8.54 (m,
1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 5H,
ArH); 7.03-6.97 (m, 2H, ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H,
CH); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m, 1H,
CH2); 1.02-0.94 (m, 1H, CH2).
Example 16
(trans)-N-(3-fluorobenzyl)-2-phenylcyclopropanaminium chloride
##STR00032##
[0424] .sup.1H-NMR (MeOD, 250 MHz, .delta.): 7.59-7.49 (m, 2H,
ArH); 7.34-7.05 (m, 7H, ArH); 4.38 (s, 2H, CH2); 3.02-2.93 (m, 1H,
CH); 2.52-2.40 (m, 1H, CH); 1.58-1.31 (m, 2H, CH2).
Example 17
(trans)-N-(2-fluorobenzyl)-2-phenylcyclopropanamine
##STR00033##
[0426] .sup.1H-NMR (MeOD, 250 MHz, .delta.): 7.59-7.49 (m, 2H,
ArH); 7.34-7.05 (m, 7H, ArH); 4.38 (s, 2H, CH2); 3.02-2.93 (m, 1H,
CH); 2.52-2.40 (m, 1H, CH); 1.58-1.31 (2H, CH2).
Example 18
(trans)-2-phenyl-N-(quinolin-4-ylmethyl)cyclopropanamine
##STR00034##
[0428] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 8.60-8.54 (m,
1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 7H,
ArH); 7.03-6.97 (m, 2H, ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H,
CH); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m, 1H,
CH2); 1.02-0.94 (m, 1H, CH2).
Example 19
(trans)-N-(3-methoxybenzyl)-2-phenylcyclopropanamine
##STR00035##
[0430] .sup.1H-NMR (MeOD, 250 MHz, .delta.): 7.56-7.42 (m, 5H,
ArH); 7.36-7.19 (m, 3H, ArH); 7.16-7.09 (m, 2H, ArH); 4.38 (s, 2H,
CH2); 3.03-2.95 (m, 1H, CH); 2.50-2.39 (m, 1H, CH); 1.55-1.33 (m,
2H, CH2).
Example 20
(trans)-2-phenyl-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)cyclopropanami-
ne
##STR00036##
[0432] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 8.60-8.54 (m,
1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, H, ArH);
7.03-6.97 (m, 2H, ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H, CH);
2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m, 1H, CH2);
1.02-0.94 (m, 1H, CH2).
Example 21
(trans)-N-((6-chloropyridin-3-yl)methyl)-2-phenylcyclopropanamine
##STR00037##
[0434] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 8.60-8.54 (m,
1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 4H,
ArH); 7.03-6.97 (m, 2H, ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H,
CH); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m, 1H,
CH2); 1.02-0.94 (m, 1H, CH2).
Example 22
(trans)-N-((4-methylpyridin-2-yl)methyl)-2-phenylcyclopropanamine
##STR00038##
[0436] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 8.60-8.54 (m,
1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 4H,
ArH); 7.03-6.97 (m, 2H, ArH); 4.01 (s, 2H, CH2); 2.44-2.37 (m, 1H,
CH); 2.29 (s, 3H, CH3); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH);
1.19-1.10 (m, 1H, CH2); 1.02-0.94 (m, 1H, CH2).
Example 23
(trans)-N-((6-methoxypyridin-2-yl)methyl)-2-phenylcyclopropanamine
##STR00039##
[0438] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 8.60-8.54 (m,
1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 4H,
ArH); 7.03-6.97 (m, 2H, ArH); 4.01 (s, 5H, CH2+CH3); 2.44-2.37 (m,
1H, CH); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m,
1H, CH2); 1.02-0.94 (m, 1H, CH2).
Example 24
2-(((trans)-2-phenylcyclopropylamino)methyl)pyridin-3-ol
##STR00040##
[0440] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 8.60-8.54 (m,
1H, ArH); 7.62 (td, J=7.8, 1.6 Hz, 1H, ArH); 7.28-7.09 (m, 3H,
ArH); 7.03-6.97 (m, 2H, ArH); 4.01 (s, 5H, CH2+CH3); 2.44-2.37 (m,
1H, CH); 2.09 (br s, 1H, NH); 2.01-1.92 (m, 1H, CH); 1.19-1.10 (m,
1H, CH2); 1.02-0.94 (m, 1H, CH2).
Example 25
(trans)-N-((6-bromopyridin-2-yl)methyl)-2-phenylcyclopropanamine
##STR00041##
[0442] .sup.1H-NMR (CDCl.sub.3, 250 MHz, .delta.): 7.60-7.00 (m,
8H, ArH); 3.90 (s, 2H, CH2); 2.44-2.37 (m, 1H, CH); 2.09 (br s, 1H,
NH); 2.01-1.92 (m, 4H); 1.19-1.10 (m, 1H, CH2); 1.02-0.94 (m, 1H,
CH2).
Example 26
4-(((trans)-2-(4-(benzyloxy)phenyl)cyclopropylamino)methyl)benzonitrile
##STR00042##
[0444] .sup.1H-NMR (MeOD, 250 MHz, .delta.): 7.88-7.22 (m, 9H,
ArH); 6.82 (m, 4H, ArH); 5.01 (s, 2H, CH2); 3.85 (s, 2H, CH2);
2.25-2.18 (m, 1H, CH); 1.90-1.81 (m, 1H, CH); 1.07-0.97 (m, 1H,
CH2); 0.95-0.85 (m, 1H, CH2).
Example 27
(trans)-N-(4-(benzyloxy)benzyl)-2-phenylcyclopropanamine
##STR00043##
[0446] .sup.1H-NMR (MeOD, 250 MHz, .delta.): 7.44-7.21 (m, 9H,
ArH); 6.94-6.81 (m, 4H, ArH); 5.01 (s, 2H, CH2); 3.82 (s, 2H, CH2);
2.25-2.18 (m, 1H, CH); 1.90-1.81 (m, 1H, CH); 1.07-0.97 (m, 1H,
CH2); 0.95-0.85 (m, 1H, CH2).
Intermediate 1:
1-(benzyloxy)-4-[(trans)-2-nitrocyclopropyl]benzene
##STR00044##
[0448] Trimethylsulfoxonium iodide (0.62 g, 2.82 mmol) was added in
portions to a solution of t-BuOK (0.32 g, 2.82 mmol) in dry DMSO (5
mL). After 10 min a solution of
1-(benzyloxy)-4-[(E)-2-nitrovinyl]benzene (0.60 g, 2.35 mmol) in
DMSO (5 mL) was transferred via canula and the mixture was stirred
at room temperature for 6 h. The reaction was poured over water (10
mL) and extracted with Et.sub.2O (3.times.10 mL); the organic
layers were washed with brine (2.times.15 mL), dried over anhydrous
Na.sub.2SO.sub.4 and filtered. After removal of the solvent, the
residual orange oil was purified by column chromatography on silica
gel (5% EtOAc/hexanes) affording 0.16 g of
1-(benzyloxy)-4-[(1R,2S)-2-nitrocyclopropyl]benzene [Rf=0.5 (20%
EtOAc/hexanes), white solid, 26% yield].
Intermediate 2: Trans-2-[4-(benzyloxy)phenyl]cyclopropanamine
##STR00045##
[0450] Zn dust (1.97 g, 30 mol) was added in small portions, over a
period of 30 min, to a vigorously stirred solution of
1-(benzyloxy)-4-[(1R,2S)-2-nitrocyclopropyl]benzene (0.81 g, 3.0
mmol) in i-PrOH (25 mL) and HCl (11 mL of aqueous solution 2.7 N,
30 mmol). After 17 h the mixture was filtered through a pad of
celite, that was washed with 10 mL of methanol. The filtrate was
concentrated and 10 mL of water were added, washing with
CH.sub.2Cl.sub.2 (3.times.15 mL). The organic layers were dried
over anhydrous Na.sub.2SO.sub.4 and filtered. After removal of the
solvent, the crude product was purified by column chromatography on
silica gel (10% MeOH/CH.sub.2Cl.sub.2) affording 0.50 g of
(trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine [Rf=0.2 (10%
MeOH/CH.sub.2Cl.sub.2), white solid, 70% yield]. .sup.1H-NMR (MeOH,
250 MHz, .delta.): 7.45-7.27 (m, 5H, ArH); 6.96 (d, J=8.5 Hz, 2H,
ArH); 6.86 (d, J=8.5 Hz, 2H, ArH); 5.03 (s, 2H, CH2); 2.41-2.34 (m,
1H, CH); 1.86-1.76 (m, 1H, CH); 0.98-0.85 (m, 2H, CH2).
Intermediate 3: Intermediate
tert-Butyl(trans)-2-[4-(benzyloxy)phenyl]cyclopropylcarbamate
##STR00046##
[0452] 200 mg of intermediate x
(trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine were dissolved in
pyridine (5 mL) and tertbutyl carbonate (200 mg) was then added.
The mixture was stirred at room temperature for 12 h, the poured
into ice-water. The desired compound was filtered and dried.
.sup.1H-NMR (MeOH, 250 MHz, .delta.): 7.45-7.27 (m, 5H, ArH); 6.96
(d, 8.5 Hz, 2H, ArH); 6.86 (d, J:=8.5 Hz, 2H, ArH); 5.03 (s, 2H,
CH2); 2.41-2.34 (m, 1H, CH); 1.86-1.76 (m, 10H, CH); 0.98-0.85 (m,
2H, CH2).
Example 28
(trans)-N-benzyl-2-(4-(benzyloxy)phenyl)cyclopropanamine
##STR00047##
[0454] NaH (17 mg, 60% in mineral oil, 0.42 mmol) was added to a
solution of
tert-Butyl(trans)-2-[4-(benzyloxy)phenyl]cyclopropylcarbamate (110
mg, 0.32 mmol) in DMF (4 mL) at 0.degree. C. After 30 minutes,
benzyl bromide (0.05 mL, 0.42 mmol) was added and the reaction was
allowed to reach r.t. and stirred for additional 16 h. The reaction
mixture was poured into H.sub.2O (15 mL) and extracted with
Et.sub.2O (3.times.5 mL); the organic layers were washed with brine
(10 mL), dried over anhydrous Na.sub.2SO.sub.4 and filtered.
[0455] After removal of the solvent, the residual yellowish oil was
solved in a mixture of 1,4-dioxane/H.sub.2SO.sub.4 (4 mL, 10:1,
v/v) and stirred for 40 min. The solution was basified by addition
of 6 mL of aqueous NaOH (10%) and extracted with Et.sub.2O
(2.times.10 mL); the organic layers were washed with brine (15 mL),
dried over anhydrous Na.sub.2SO.sub.4 and filtered. After removal
of the solvent, the crude residue was purified by column
chromatography on silica gel (10-40% EtOAc/hexanes) to afford 58 mg
of N-benzyl-N-{(trans)-2-[4-(benzyloxy)phenyl]cyclopropyl}amine
[Rf=0.2 (5% MeOH/CH.sub.2Cl.sub.2), white solid, 55% yield].
.sup.1H-NMR (MeOD, 250 MHz, .delta.): 7.44-7.21 (m, 10H, ArH);
6.94-6.81 (m, 4H, ArH); 5.01 (s, 2H, CH2); 3.82 (s, 2H, CH2);
2.25-2.18 (m, 1H, CH); 1.90-1.81 (m, 1H, CH); 1.07-0.97 (m, 1H,
CH2); 0.95-0.85 (m, 1H, CH2).
[0456] Following examples have been synthesized using the procedure
described for Example 28 and the corresponding starting
materials.
Example 29
(trans)-2-(4-(benzyloxy)phenyl)-N-(4-methoxybenzyl)cyclopropanamine
##STR00048##
[0458] .sup.1H-NMR (MeOD, 250 MHz, .delta.): 7.44-7.21 (m, 9H,
ArH); 6.94-6.81 (m, 4H, ArH); 5.01 (s, 2H, CH2); 3.65 (s, 3H,
OCH3); 3.82 (s, 2H, CH2); 2.25-2.18 (m, 1H, CH); 1.90-1.81 (m, 1H,
CH); 1.07-0.97 (m, 1H, CH2); 0.95-0.85 (m, 1H, CH2).
Example 30
(trans)-2-(4-(benzyloxy)phenyl)-N-(4-fluorobenzyl)cyclopropanamine
##STR00049##
[0460] .sup.1H-NMR (MeOD, 250 MHz, .delta.): 7.44-7.21 (m, 8H,
ArH); 6.94-6.81 (m, 4H, ArH); 5.01 (s, 2H, CH2); 3.82 (s, 2H, CH2);
2.25-2.18 (m, 1H, CH); 1.90-1.81 (m, 1H, CH); 1.07-0.97 (m, 1H,
CH2); 0.95-0.85 (m, 1H, CH2).
[0461] Following examples have been synthesized using the procedure
described for Examples 1 and 2 and the corresponding starting
materials.
Example 31
(trans)-2-phenyl-N-(quinolin-2-ylmethyl)cyclopropanamine
##STR00050##
[0463] .sup.1H-NMR (CDCl3) .delta. (ppm): 1.00 (q, 1H), 1.18 (quin,
1H), 2.00 (m, 1H), 2.49 (m, 1H), 4.22 (s, 2H), 7.02 (d, 2H), 7.16
(q, 2H), 7.23 (d, 1H), 7.40 (d, 1H), 7.53 (t, 1H), 7.69 (t, 1H),
7.80 (d, 1H), 8.09 (t, 2H). MS (M+H): 275.0
Example 32
(trans)-2-phenyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropanami-
ne
##STR00051##
[0465] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.98 (q, 1H), 1.13 (quin,
1H), 1.93 (m, 1H), 2.40 (m, 1H), 4.07 (s, 2H), 6.98 (d, 2H), 7.13
(d, 1H), 7.22 (t, 2H), 7.40 (d, 1H), 7.84 (d, 1H), 8.82 (s, 1H). MS
(M+H): 292.8
Example 33
(trans)-N-((3-fluoropyridin-2-yl)methyl)-2-phenylcyclopropanamine
##STR00052##
[0467] .sup.1H-NMR (CDCl3) .delta. (ppm): 1.01 (q, 1H), 1.18 (quin,
1H), 1.99 (m, 1H), 2.41 (m, 1H), 4.11 (s, 2H), 7.02 (d, 2H), 7.25
(m, 5H), 8.38 (s, 1H). MS (M+H): 242.8
Example 34
(trans)-2-phenyl-N-(quinolin-3-ylmethyl)cyclopropanamine
##STR00053##
[0469] .sup.1H-NMR (CDCl3) .delta. (ppm): 1.00 (q, 1H), 1.12 (quin,
1H), 1.94 (m, 1H), 2.40 (m, 1H), 4.10 (s, 2H), 6.95 (d, 2H), 7.14
(t, 1H), 7.20 (t, 2H), 7.54 (t, 1H), 7.70 (t, 1H), 7.76 (d, 1H),
8.04 (s, 1H), 8.10 (d, 1H), 8.90 (s, 1H). MS (M+H): 275.0
Example 35
(trans)-N-((6-methoxypyridin-3-yl)methyl)-2-phenylcyclopropanamine
##STR00054##
[0471] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.98 (q, 1H), 1.10 (quin,
1H), 1.94 (m, 1H), 2.36 (m, 1H), 3.82 (s, 2H), 3.92 (s, 3H), 6.70
(d, 1H), 7.00 (d, 2H), 7.14 (t, 1H), 7.24 (d, 2H), 7.54 (d, 1H),
8.08 (s, 1H). MS (M+H): 255.0
Example 36
(trans)-N-((5-methoxypyridin-3-yl)methyl)-2-phenylcyclopropanamine
##STR00055##
[0473] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.98 (q, 1H), 1.12 (quin,
1H), 1.92 (m, 1H), 2.36 (m, 1H), 3.78 (s, 2H), 3.90 (s, 3H), 6.98
(s, 2H), 7.14 (s, 2H), 7.24 (t, 2H), 8.20 (d, 2H). MS (M+H):
255.0
Example 37
(trans)-N-((2-methoxypyridin-3-yl)methyl)-2-phenylcyclopropanamine
##STR00056##
[0475] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.98 (q, 1H), 1.12 (quin,
1H), 1.92 (m, 1H), 2.32 (m, 1H), 3.84 (s, 2H), 3.94 (s, 3H), 6.82
(t, 1H), 7.00 (d, 2H), 7.14 (t, 1H), 7.24 (d, 2H), 7.48 (d, 1H),
8.08 (d, 1H). MS (M+H): 255.0
Example 38
(trans)-N-((3H-indol-3-yl)methyl)-2-phenylcyclopropanamine
##STR00057##
[0477] .sup.1H-NMR (CDCl3) .delta. (ppm): 1.00 (q, 1H), 1.20 (quin,
1H), 2.02 (m, 1H), 2.48 (m, 1H), 4.10 (s, 2H), 7.02 (d, 2H), 7.14
(m, 4H), 7.20 (t, 2H), 7.36 (d, 1H), 7.66 (d, 1H), 8.02 (s, 1H). MS
(M+H): 263.0
Example 39
3-(((trans)-2-phenylcyclopropylamino)methyl)benzonitrile
##STR00058##
[0479] .sup.1H-NMR (CDCl3) .delta. (ppm): 1.00 (q, 1H), 1.10 (quin,
1H), 1.92 (m, 1H), 2.36 (m, 1H), 3.92 (s, 2H), 6.96 (d, 2H), 7.16
(t, 1H), 7.26 (d, 2H), 7.40 (t, 1H), 7.56 (d, 2H), 7.62 (s, 1H). MS
(M+H): 249.0
Example 40
(trans)-N-(2-methoxybenzyl)-2-phenylcyclopropanamine
##STR00059##
[0481] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.96 (q, 1H), 1.12 (quin,
1H), 1.88 (m, 1H), 2.36 (m, 1H), 3.80 (s, 3H), 3.90 (s, 2H), 6.88
(q, 2H), 6.98 (d, 2H), 7.12 (d, 1H), 7.21 (q, 4H). MS (M+H):
257.1
Example 41
3-(((trans)-2-phenylcyclopropylamino)methyl)pyridin-2-amine
##STR00060##
[0483] .sup.1H-NMR (CDCl3) .delta. (ppm): 1.01 (q, 1H), 1.08 (quin,
1H), 1.98 (m, 1H), 2.34 (m, 1H), 3.86 (s, 2H), 5.44 (br, 2H), 6.56
(t, 1H), 6.92 (d, 2H), 7.14 (t, 1H), 7.24 (t, 3H), 7.98 (d, 1H). MS
(M+H): 240.0
Example 42
(trans)-N-((2-chloropyridin-3-yl)methyl)-2-phenylcyclopropanamine
##STR00061##
[0485] .sup.1H-NMR (CDCl3) .delta. (ppm): 1.01 (q, 1H), 1.16 (quin,
1H), 1.98 (m, 1H), 2.36 (m, 1H), 3.99 (s, 2H), 6.99 (d, 2H), 7.18
(m, 2H), 7.26 (d, 2H), 7.72 (q, 1H), 8.30 (d, 1H). MS (M+H):
259.0/260.9
Example 43
(trans)-N-(3,4-dimethoxybenzyl)-2-phenylcyclopropanamine
##STR00062##
[0487] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.98 (q, 1H), 1.14 (quin,
1H), 1.94 (m, 1H), 2.36 (m, 1H), 3.76 (s, 3H), 3.84 (s, 2H), 3.88
(s, 3H), 6.80 (m, 3H), 7.00 (d, 2H), 7.14 (t, 1H), 7.23 (d, 2H). MS
(M+H): 284.1
Example 44
(trans)-N-((2,3-dihydrobenzofuran-5-yl)methyl)-2-phenylcyclopropanamine
hydrochloride
##STR00063##
[0489] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.24 (q, 1H), 1.48
(quin, 1H), 2.40 (m, 1H), 2.84 (br, 1H), 3.10 (q, 2H), 4.16 (s,
2H), 4.52 (t, 2H), 6.76 (d, 1H), 7.09 (d, 2H), 7.22 (q, 2H), 7.28
(t, 2H), 7.34 (s, 1H), 9.50 (br, 2H). MS (M+H): 266.1
Example 45
(trans)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-phenylcyclopropanamine
hydrochloride
##STR00064##
[0491] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.24 (q, 1H), 1.48
(quin, 1H), 2.44 (m, 1H), 2.82 (br, 1H), 4.18 (s, 2H), 6.02 (s,
2H), 6.92 (d, 1H), 7.09 (d, 1H), 7.12 (t, 3H), 7.20 (t, 1H), 7.27
(t, 2H), 9.60 (br, 2H). MS (M+H): 268.1
Example 46
(trans)-N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-phenylcyclopropa-
namine hydrochloride
##STR00065##
[0493] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.24 (q, 1H), 1.48
(quin, 1H), 2.48 (br, 1H), 4.12 (br, 2H), 4.20 (s, 4H), 6.78 (d,
1H), 6.92 (d, 1H), 7.09 (s, 3H), 7.18 (t, 1H), 7.26 (t, 2H), 9.74
(br, 2H). MS (M+H): 283.0
Example 47
(trans)-N-(2,6-difluoro-4-methoxybenzyl)-2-phenylcyclopropanamine
##STR00066##
[0495] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.96 (q, 1H), 1.10 (quin,
1H), 1.94 (m, 1H), 2.03 (br, 1H), 2.32 (m, 1H), 3.76 (s, 3H), 3.90
(s, 2H), 6.42 (d, 2H), 7.00 (d, 2H), 7.13 (t, 1H), 7.23 (t, 2H). MS
(M+H): 290.1
Example 48
(trans)-2-phenyl-N-(4-(trifluoromethoxy)benzyl)cyclopropanamine
##STR00067##
[0497] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.98 (q, 1H), 1.11 (quin,
1H), 1.91 (m, 1H), 1.96 (br, 1H), 2.36 (m, 1H), 3.89 (d, 2H), 6.97
(d, 2H), 7.16 (d, 3H), 7.24 (t, 2H), 7.32 (d, 2H). MS (M+H):
308.1
Example 49
(trans)-N-(5-fluoro-2-methoxybenzyl)-2-phenylcyclopropanamine
##STR00068##
[0499] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.96 (q, 1H), 1.12 (quin,
1H), 1.94 (m, 1H), 2.12 (br, 1H), 2.34 (m, 1H), 3.78 (s, 3H), 3.86
(q, 2H), 6.76 (m, 1H), 6.96 (m, 4H), 7.14 (t, 1H), 7.24 (d, 2H). MS
(M+H): 272.1
Example 50
(trans)-N-(2-fluoro-4-methoxybenzyl)-2-phenylcyclopropanamine
##STR00069##
[0501] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.96 (q, 1H), 1.12 (quin,
1H), 1.88 (br, 1H), 1.94 (m, 1H), 2.36 (m, 1H), 3.78 (s, 3H), 3.88
(s, 2H), 6.76 (m, 2H), 6.99 (d, 2H), 7.14 (m, 2H), 7.24 (m, 2H). MS
(M+H): 272.1
Example 51
(trans)-N-((4-methoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine
##STR00070##
[0503] .sup.1H-NMR (CDCl3) .delta. (ppm): 1.00 (q, 1H), 1.16 (quin,
1H), 1.86 (br, 1H), 1.98 (m, 1H), 2.46 (m, 1H), 3.98 (s, 3H), 4.27
(s, 2H), 6.70 (d, 1H), 6.99 (d, 2H), 7.14 (t, 1H), 7.24 (d, 2H),
7.32 (d, 1H), 7.50 (m, 2H), 8.06 (d, 1H), 8.30 (d, 1H). MS (M+H):
304.1
Example 52
(trans)-N-(2-fluoro-6-methoxybenzyl)-2-phenylcyclopropanamine
##STR00071##
[0505] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.96 (q, 1H), 1.12 (quin,
1H), 1.92 (m, 1H), 2.10 (br, 1H), 2.30 (m, 1H), 3.72 (s, 3H), 3.96
(s, 2H), 6.66 (m, 2H), 6.99 (d, 2H), 7.14 (m, 2H), 7.22 (m, 2H). MS
(M+H): 272.1
Example 53
(trans)-N-((2-methoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine
##STR00072##
[0507] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.96 (q, 1H), 1.20 (quin,
1H), 1.92 (br, 1H), 1.96 (m, 1H), 2.40 (m, 1H), 3.84 (s, 3H), 4.38
(s, 2H), 6.98 (d, 2H), 7.12 (t, 1H), 7.24 (m, 3H), 7.32 (t, 1H),
7.40 (t, 1H), 7.80 (d, 2H), 8.02 (d, 1H). MS (M+H): 304.1
Example 54
(trans)-N4-(4,7-dimethoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine
##STR00073##
[0509] .sup.1H-NMR (CDCl3) .delta. (ppm): 1.01 (q, 1H), 1.20 (quin,
1H), 1.80 (br, 1H), 2.00 (m, 1H), 2.48 (m, 1H), 3.92 (s, 3H), 3.96
(s, 3H), 4.24 (s, 2H), 6.60 (d, 1H), 7.01 (d, 2H), 7.16 (t, 2H),
7.24 (m, 2H), 7.30 (m, 1H), 7.36 (s, 1H), 8.20 (d, 1H). MS (M+H):
334.0
Example 55
(trans)-N-(4-methoxy-3-methylbenzyl)-2-phenylcyclopropanamine
hydrochloride
##STR00074##
[0511] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.26 (q, 1H), 1.50
(quin, 1H), 2.06 (s, 3H), 2.80 (br, 1H), 3.76 (s, 3H), 4.16 (s,
2H), 6.94 (d, 1H), 7.10 (d, 2H), 7.28 (m, 5H), 9.50 (br, 2H). MS
(M+H): 268.0
Example 56
(trans)-N-(3-chloro-4-methoxybenzyl)-2-phenylcyclopropanamine
##STR00075##
[0513] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.98 (q, 1H), 1.10 (quin,
1H), 1.90 (m, 2H), 2.36 (m, 1H), 3.80 (s, 2H), 3.90 (s, 3H), 6.86
(d, 1H), 7.00 (d, 2H), 7.16 (t, 2H), 7.24 (d, 2H), 7.32 (s, 1H). MS
(M+H): 287.9
Example 57
(trans)-N-(3-fluoro-4-methoxybenzyl)-2-phenylcyclopropanamine
##STR00076##
[0515] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.96 (q, 1H), 1.10 (quin,
1H), 1.92 (m, 2H), 2.36 (m, 1H), 3.80 (s, 2H), 3.88 (s, 3H), 6.90
(t, 1H), 6.99 (d, 3H), 7.06 (d, 1H), 7.16 (d, 1H), 7.24 (d, 2H). MS
(M+H): 271.96
Example 58
(trans)-N-(4-methoxy-2-methylbenzyl)-2-phenylcyclopropanamine
##STR00077##
[0517] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.98 (q, 1H), 1.12 (quin,
1H), 1.82 (br, 1H), 1.94 (m, 1H), 2.34 (s, 3H), 2.40 (m, 1H), 3.78
(s, 3H), 3.82 (s, 2H), 6.68 (d, 1H), 6.72 (s, 1H), 7.01 (d, 2H),
7.14 (t, 2H), 7.24 (d, 2H). MS (M+H): 268.0
Example 59
(trans)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)methyl)-2-phenylcycl-
opropanamine
##STR00078##
[0519] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.98 (q, 1H), 1.14 (quin,
1H), 1.86 (br, 1H), 1.90 (m, 1H), 2.18 (m, 2H), 2.36 (m, 1H), 3.88
(s, 2H), 4.20 (s, 4H), 6.88 (m, 3H), 7.00 (d, 2H), 7.14 (t, 1H),
7.24 (d, 2H). MS (M+H): 295.9
Example 60
(trans)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-phenylcycl-
opropanamine hydrochloride
##STR00079##
[0521] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.25 (q, 1H), 1.46 (m,
1H), 2.08 (m, 2H), 2.38 (m, 1H), 2.88 (m, 1H), 4.10 (m, 4H), 4.17
(s, 2H), 6.96 (d, 1H), 7.10 (m, 3H), 7.13 (s, 1H), 7.19 (t, 1H),
7.26 (t, 2H), 9.38 (br, 2H). MS (M+H): 295.9
Example 61
(trans)-N-((2,2-dimethylchroman-6-yl)meth
yl)-2-phenylcyclopropanamine
##STR00080##
[0523] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.96 (q, 1H), 1.14 (quin,
1H), 1.32 (s, 6H), 1.78 (t, 2H), 1.94 (m, 2H), 2.38 (m, 1H), 2.70
(t, 3H), 3.78 (s, 2H), 6.72 (d, 1H), 7.00 (m, 4H), 7.14 (t, 1H),
7.24 (d, 2H). MS (M+H): 308.1
Example 62
(trans)-N-(4-methoxy-2,3-dimethylbenzyl)-2-phenylcyclopropanamine
hydrochloride
##STR00081##
[0525] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.28 (q, 1H), 1.52
(quin, 1H), 2.06 (s, 3H), 2.20 (s, 3H), 2.42 (m, 1H), 2.94 (br,
1H), 3.76 (s, 3H), 4.26 (s, 2H), 6.84 (d, 1H), 7.09 (d, 2H), 7.20
(t, 1H), 7.28 (d, 3H), 9.32 (br, 2H). MS (M+H): 282.1
Example 63
(trans)-N-(4-methoxy-2,5-dimethylbenzyl)-2-phenylcyclopropanamine
##STR00082##
[0527] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.98 (q, 1H), 1.14 (quin,
1H), 1.82 (br, 1H), 1.94 (m, 1H), 2.12 (s, 3H), 2.32 (s, 3H), 2.38
(m, 1H), 3.80 (s, 5H), 6.62 (s, 1H), 6.97 (s, 1H), 7.01 (d, 2H),
7.14 (t, 1H), 7.24 (d, 2H). MS (M+H): 282.1
Example 64
(trans)-N-(2-fluoro-4,5-dimethoxybenzyl)-2-phenylcyclopropanamine
##STR00083##
[0529] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.96 (q, 1H), 1.14 (quin,
1H), 1.92 (br, 1H), 2.00 (br, 1H), 2.34 (br, 1H), 3.68 (s, 2H),
3.84 (s, 6H), 6.60 (d, 1H), 6.70 (d, 1H), 6.99 (d, 2H), 7.14 (q,
1H), 7.24 (m, 2H). MS (M+H): 301.99
Example 65
(trans)-N-(3-chloro-4,5-dimethoxybenzyl)-2-phenylcyclopropanamine
hydrochloride
##STR00084##
[0531] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.28 (q, 1H), 1.48 (m,
1H), 2.36 (m, 1H), 2.88 (m, 1H), 3.72 (s, 6H), 4.24 (s, 2H), 7.08
(d, 2H), 7.20 (s, 2H), 7.28 (d, 3H). MS (M+H): 318.0
Example 66
(trans)-N-(2-chloro-3,4-dimethoxybenzyl)-2-phenylcyclopropanamine
##STR00085##
[0533] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.98 (q, 1H), 1.16 (quin,
1H), 2.00 (m, 1H), 2.36 (m, 1H), 3.88 (s, 6H), 3.96 (s, 2H), 6.76
(d, 1H), 7.02 (m, 3H), 7.16 (t, 1H), 7.24 (d, 2H). MS (M+H):
318.0
Example 67
(trans)-N-(2,4-dimethoxy-6-methylbenzyl)-2-phenylcyclopropanamine
hydrochloride
##STR00086##
[0535] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.28 (q, 1H), 1.48
(quin, 1H), 2.32 (s, 3H), 2.38 (m, 1H), 2.90 (m, 1H), 3.72 (s, 3H),
3.76 (s, 3H), 4.14 (s, 2H), 6.42 (s, 2H), 7.11 (d, 2H), 7.22 (t,
1H), 7.28 (t, 2H), 8.96 (br, 2H). MS (M+H): 298.0
Example 68
(trans)-N-(2,5-dimethoxybenzyl)-2-phenylcyclopropanamine
hydrochloride
##STR00087##
[0537] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.22 (q, 1H), 1.48
(quin, 1H), 2.36 (m, 1H), 2.80 (m, 1H), 3.68 (s, 6H), 4.16 (s, 2H),
6.92 (s, 2H), 7.08 (m, 3H), 7.18 (t, 1H), 7.28 (t, 2H), 9.30 (br,
2H). MS (M+H): 284.0
Example 69
(trans)-N-(2,3-dimethoxybenzyl)-2-phenylcyclopropanamine
hydrochloride
##STR00088##
[0539] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.26 (q, 1H), 1.46
(quin, 1H), 2.38 (m, 1H), 2.88 (m, 1H), 3.76 (s, 3H), 3.80 (s, 3H),
4.21 (s, 2H), 7.09 (t, 5H), 7.20 (t, 1H), 7.26 (t, 2H). MS (M+H):
284.0
Example 70
(trans)-N-(2-chloro-3-methoxybenzyl)-2-phenylcyclopropanamine
hydrochloride
##STR00089##
[0541] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.28 (q, 1H), 1.56
(quin, 1H), 2.48 (m, 1H), 2.92 (m, 1H), 3.86 (s, 3H), 4.37 (s, 2H),
7.09 (d, 2H), 7.21 (t, 2H), 7.28 (t, 3H), 7.37 (t, 1H). MS (M+H):
287.9
Example 71
(trans)-N-((1H-indol-5-yl)methyl)-2-phenylcyclopropanamine
hydrochloride
##STR00090##
[0543] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.26 (q, 1H), 1.50
(quin, 1H), 2.48 (m, 1H), 2.86 (m, 1H), 3.86 (s, 3H), 4.32 (s, 2H),
6.40 (s, 1H), 7.09 (d, 2H), 7.24 (m, 4H), 7.38 (t, 2H), 7.67 (s,
1H), 9.46 (br, 1H). MS (M+H): 287.9
[0544] Following examples have been synthesized using the procedure
described for Example 28 and the corresponding starting
materials.
Example 72
(trans)-2-(4-(benzyloxy)phenyl)-N-(pyridin-2-ylmethyl)cyclopropanamine
##STR00091##
[0546] .sup.1H-NMR (CD3OD) .delta. (ppm): 0.91 (q, 1H), 1.02 (quin,
1H), 1.84 (m, 1H), 2.22 (m, 1H), 3.96 (s, 2H), 5.02 (s, 2H), 6.87
(q, 4H), 7.38 (m, 8H), 7.78 (t, 1H), 8.49 (d, 1H). MS (M+H):
331.1
Example 73
(trans)-2-(4-(benzyloxy)phenyl)-N-(2-methoxybenzyl)cyclopropanamine
##STR00092##
[0548] .sup.1H-NMR (CD3OD) .delta. (ppm): 1.29 (q, 1H), 1.38 (quin,
1H), 2.27 (m, 1H), 2.84 (m, 1H), 3.78 (s, 3H), 4.33 (s, 2H), 5.04
(s, 2H), 6.96 (m, 6H), 7.36 (m, 7H). MS (M+H): 360.3
Example 74
(trans)-N-(1-(4-methoxyphenyl)ethyl)-2-phenylcyclopropanamine
##STR00093##
[0550] 1-(4-methoxyphenyl)ethanone (138 mg, 0.75 mmol) and
molecular sieve (3 A--previously activated by microwaves) was added
to a solution of (trans)-2-phenylcyclopropanamine hydrochloride in
2 mL of MeOH anh., HCl 2N in dioxane (2 drops) was added and the
reaction was stirred at room temperature for 3 hours. The reaction
was cooled to 0.degree. C. and NaBH.sub.3CN (99 mg, 1.5 mmol) was
added. It was stirred overnight at room temperature.
[0551] A solution of NH.sub.4Cl sat. (2 mL) was added. After
removal of the solvent the crude was dissolved in CH2Cl2 and washed
with a aqueous saturated solution of NH.sub.4Cl. It was finally
washed with brine and the extracted organic layer was dried over
MgSO4 anh. The crude was purified by chromatography using
Hexane-AcOEt (80:20 to 70:30 in 10 min) to get colourless oil, 102
mg (yield=48.1%)
[0552] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.90 (q, 1H), 0.96 (quin,
1H), 1.42 (s, 3H), 2.00 (br, 1H), 2.20 (m, 1H), 3.78 (d, 3H), 3.92
(m, 1H), 6.84 (q, 3H), 7.00 (d, 1H), 7.16 (m, 2H), 7.24 (d, 3H). MS
(M+H): 268.0
[0553] Following examples have been synthesized using the procedure
described for Example 74 and the corresponding starting
materials.
Example 75
(trans)-N-(1-(3,4-dimethoxyphenyl)ethyl)-2-phenylcyclopropanamine
##STR00094##
[0555] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.94 (m, 1H), 1.08 (br,
1H), 1.40 (s, 3H), 1.76 (br, 2H), 2.20 (m, 1H), 3.76 (s, 1H), 3.85
(t, 6H), 6.80 (m, 4H), 7.00 (d, 1H), 7.18 (m, 3H). MS (M+H):
298.0
Example 76
(trans)-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-phenylcycloprop-
anamine
##STR00095##
[0557] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.90-0.96 (m, 1H), 1.08
(br, 1H), 1.38 (d, 3H), 1.84-1.96 (br, 1H), 2.19-2.23 (m, 1H), 3.84
(m, 1H), 4.24 (s, 4H), 6.82 (m, 4H), 7.00 (d, 1H), 7.20 (m, 3H). MS
(M+H): 296.0
Example 77
(trans)-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)-2-phenylcyclopropanamine
##STR00096##
[0559] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.92 (q, 1H), 1.06 (m,
1H), 1.36 (d, 3H), 1.80-1.92 (m, 1H), 2.18 (m, 1H), 3.70 (s, 3H),
4.22-4.28 (m, 1H), 6.74 (m, 1H), 6.86 (m, 2H), 6.99 (m, 2H), 7.12
(m, 1H), 7.20 (m, 2H). MS (M+H): 286.0
Example 78
(trans)-N-(1-(3,4-dimethoxyphenyl)propan-2-yl)-2-phenylcyclopropanamine
##STR00097##
[0561] .sup.1H-NMR (CDCl3) .delta. (ppm): 0.96 (q, 1H), 1.06 (m,
1H), 1.14 (d, 3H), 1.79-1.86 (m, 1H), 2.18-2.32 (m, 1H), 2.63-2.71
(m, 2H), 3.04 (m, 1H), 3.85 (d, 6H), 6.70 (m, 2H), 6.79 (d, 1H),
7.02 (m, 2H), 7.13 (m, 1H), 7.23 (m, 2H). MS (M+H): 312.1
Example 79
(trans)-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2-phenylcyclopropanamine
hydrochloride
##STR00098##
[0562] Step 1:
[0563] N,N-Diisopropylethylamine (3 mL, 17.16 mmol) was added to a
solution of (trans)-2-phenylcyclopropanamine hydrochloride (1.5 g,
8.58 mmol) in 70 mL of CH.sub.3CN. After complete dissolution of
the amine the methyl 2-bromoacetate (930 .mu.L, 9.44 mmol) was
added and then stirred overnight at room temperature. After solvent
removal the crude was purified by flash chromatography eluting with
CH.sub.2Cl.sub.2/MeOH (99:1 to 90:10) to get methyl
2-((trans)-2-phenylcyclopropylamino)acetate as colourless oil (1.76
g, Yield=100%).
Step 2:
[0564] A solution of LiOH (432 mg, 10.30 mmol) in 17 mL of H.sub.2O
was added to the solution of methyl
2-((trans)-2-phenylcyclopropylamino)acetate (1.76 g, 8.58 mmol) in
70 mL de THF and it was stirred vigorously for 2 hours at room
temperature. Di-tert-butyl dicarbonate (2.7 g, 12 mmol) was added
and stirred for 3 hours. After solvent removal the crude was solved
in 60 mL of AcOEt and washed with 40 mL of brine. The organic layer
was dried over MgSO4 anh., filtered and the solvent was removed.
The crude was purified by flash chromatography eluting with
CH2Cl2/MeOH (98:2 to 90:10) to get
2-(tert-butoxycarbonyl((trans)-2-phenylcyclopropyl)amino)acetic
acid as colourless oil (2.08 g. Yield=83.3%).
Step 3:
[0565] EDC (107 .mu.L, 0.585 mmol) and acetoamidoxime (41 mg, 0.532
mmol) was added to a stirred solution of
2-(tert-butoxycarbonyl((trans)-2-phenylcyclopropyl)amino)acetic
acid (163 mg, 0.532 mmol) in diglyme (2 mL) under argon atmosphere.
The mixture was stirred at 50.degree. C. overnight and then at
110.degree. C. for 14 hours. After removal of solvent under vacuum,
the reaction mixture was purified by flash chromatography eluting
with hexane/MTBE (80:20 to 0:100) to afford
tert-butyl(3-methyl-1,2,4-oxadiazol-5-yl)methyl((1S,2S)-2-phenylcycloprop-
yl)carbamate as a colourless oil (35 mg. Yield=20%).
Step 4:
[0566] HCl 2N in Et.sub.2O was added to
tert-butyl(3-methyl-1,2,4-oxadiazol-5-yl)methyl((1S,2S)-2-phenylcycloprop-
yl)carbamate (35 mg, 0.106 mmol). The Et.sub.2O was decanted and
the solid was washed twice with 5 mL of Et.sub.2O. The solid was
dried by vacuum to get
(trans)-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2-phenylcyclopropan-
amine hydrochloride (14 mg. Yield 12.8%)
[0567] .sup.1H-NMR (DMSO-d6) .delta. (ppm): 1.28 (q, 1H), 1.52
(quin, 1H), 2.35 (s, 3H), 3.00 (m, 1H), 4.71 (s, 2H), 7.12 (d, 2H),
7.20 (t, 1H), 7.28 (t, 2H). MS (M+H): 229.9
Example 80
Biological Assays--LSD1
[0568] The compounds of the invention can be tested for their
ability to inhibit LSD1. The ability of the compounds of the
invention to inhibit LSD1 can be tested as follows. Human
recombinant LSD1 protein was purchased from BPS Bioscience Inc. In
order to monitor LSD1 enzymatic activity and/or its inhibition rate
by our inhibitor(s) of interest, di-methylated H3-K4 peptide
(Millipore) was chosen as a substrate. The demethylase activity was
estimated, under aerobic conditions, by measuring the release of
H.sub.2O.sub.2 produced during the catalytic process, using the
Amplex.RTM. Red peroxide/peroxidase-coupled assay kit
(Invitrogen).
[0569] Briefly, a fixed amount of LSD1 was incubated on ice for 15
minutes, in the absence and/or in the presence of various
concentrations of inhibitor (from 0 to 75 .mu.M, depending on the
inhibitor strength). Tranylcypromine (Biomol International) was
used as a control for inhibition. Within the experiment, each
concentration of inhibitor was tested in triplicate. After leaving
the enzyme interacting with the inhibitor, 12.5 .mu.M of
di-methylated H3-K4 peptide was added to each reaction and the
experiment was left for 1 hour at 37.degree. C. in the dark. The
enzymatic reactions were set up in a 50 mM sodium phosphate, pH 7.4
buffer. At the end of the incubation, Amplex.RTM. Red reagent and
horseradish peroxidase (HPR) solution were added to the reaction
according to the recommendations provided by the supplier
(Invitrogen), and left to incubate for 30 extra minutes at room
temperature in the dark. A 1 .mu.M H.sub.2O.sub.2 solution was used
as a control of the kit efficiency. The conversion of the
Amplex.RTM. Red reagent to resorufin due to the presence of
H.sub.2O.sub.2 in the assay, was monitored by fluorescence
(excitation at 540 nm, emission at 590 nm) using a microplate
reader (Infinite 200, Tecan). Arbitrary units were used to measure
level of H.sub.2O.sub.2 produced in the absence and/or in the
presence of inhibitor.
[0570] The maximum demethylase activity of LSD1 was obtained in the
absence of inhibitor and corrected for background fluorescence in
the absence of LSD1. The Ki of each inhibitor was estimated at half
of the maximum activity.
[0571] A number of the compounds of the invention were tested for
their ability to inhibit LSD1 and were found to have Ki values
lower than 100 .mu.M, including many of the compounds in examples
that were tested. Compound of examples 3 and 17, were found to have
Ki values for LSD1 of less than 10 .mu.M. Compounds of examples 1,
8, 9, 11 were found to have Ki values for LSD1 of less than 1
micromolar. Parnate (2-trans phenylcyclopropylamine) was found to
have a Ki of from about 15 to 35 micromolar depending on the enzyme
preparation.
[0572] Previous studies reported in the literature indicated that
substitutions on the amine group of phenylcyclopropylamines reduced
the ability of the compound to inhibit monoamine oxidases, which
have significant structural homology to LSD1. For example Zirkle et
al. ((1962) J. Med. Chem. 1265-1284) found that a methyl
substituent on the amine group decreased activity slightly whereas
substitution with larger alkyl groups and groups bearing ring
system like aralkyls reduced MAO activity substantially. The
inventors of the instant invention have surprisingly found that
ring bearing substitutions on the amine group of phenylcyclopropyl
amine produce potent LSD1 inhibitors.
[0573] Previous reports of LSD1 have found that it is involved in
cell proliferation and growth. Some studies have implicated LSD1 as
a therapeutic target for cancer. Huang et al. (2007) PNAS
104:8023-8028 found that polyamines inhibitors of LSD1 modestly
cause the reexpression of genes aberrantly silenced in cancer cells
and particularly colorectal cancer (Huang et al. Clin Cancer Res.
(2009) Dec. 1; 15(23):7217-28. Epub 2009 Nov. 24. PMID: 19934284).
Scoumanne et al. ((2007) J. Biol. Chem. May 25; 282(21):15471-5)
found that deficiency in LSD1 leads to a partial cell cycle arrest
in G2/M and sensitizes cells to growth suppression induced by DNA
damage. Kahl et al. ((2006) Cancer Res. 66(23):11341-7) found that
LSD1 expression is correlated with prostate cancer aggressiveness.
Metzger et al. reported that LSD1 modulation by siRNA and pargyline
regulates androgen receptor (AR) and may have therapeutic potential
in cancers where AR plays a role, like prostate, testis, and brain
cancers. Lee et al. ((2006) Chem. Biol. 13:563-567) reported that
tranylcypromine derepresses Egr-1 gene expression in some cancer
lines. A body of evidence is accumulating that Egr-1 is a tumor
suppressor gene in many contexts (see e.g., Calogero et al. (2004)
Cancer Cell International 4:1 exogenous expression of EGR-1
resulted in growth arrest and eventual cell death in primary cancer
cell lines; Lucerna et al. (2006) Cancer Research 66, 6708-6713
show that sustained expression of Egr-1 causes antiangiogenic
effects and inhibits tumor growth in some models; Ferraro et al.
((2005) J. Clin. Oncol. March 20; 23(9):1921-6) reported that Egr-1
is downregulated in lung cancer patients with a higher risk of
recurrence and may be more resistant to therapy. Thus, increasing
Egr-1 expression via inhibition of LSD1 is a therapeutic approach
for some cancers. Recent studies have also implicated LSD1 in brain
cancer (Schulte et al. (2009) Cancer Res. March 1; 69(5):2065-71).
Other studies have implicated LSD1 in breast cancer (Lims et al.
Carcinogenesis. 2009 Dec. 30. [Epub ahead of print] PMID:
20042638).
[0574] Thus, a body of evidence has implicated LSD1 in a number of
cancers, which suggests that LSD1 is a therapeutic target for
cancer. The instant inventors have discovered a class of LSD1
inhibitors that can be used to treat diseases where LSD1 is
implicated as a therapeutic target like cancer. According, the
phenylcyclopropylamine compounds of the invention can be used to
treat and/or prevent such diseases.
Example 81
Biological Assays--Monoamine Oxidase Assays
[0575] Human recombinant monoamine oxidase proteins MAO-A and MAO-B
were purchased from Sigma Aldrich. MAOs catalyze the oxidative
deamination of 1.degree., 2.degree. and 3.degree. amines. In order
to monitor MAO enzymatic activities and/or their inhibition rate by
inhibitor(s) of interest, a fluorescent-based (inhibitor)-screening
assay was set up. 3-(2-Aminophenyl)-3-oxopropamamine (kynuramine
dihydrobromide, Sigma Aldrich), a non fluorescent compound was
chosen as a substrate. Kynuramine is a non-specific substrate for
both MAOs activities. While undergoing oxidative deamination by MAO
activities, kynuramine is converted into 4-hydroxyquinoline (4-HQ),
a resulting fluorescent product.
[0576] The monoamine oxidase activity was estimated by measuring
the conversion of kynuramine into 4-hydroxyquinoline. Assays were
conducted in 96-well black plates with clear bottom (Corning) in a
final volume of 100 .mu.L. The assay buffer was 100 mM HEPES, pH
7.5. Each experiment was performed in triplicate within the same
experiment.
[0577] Briefly, a fixed amount of MAO (0.25 .mu.g for MAO-A and 0.5
.mu.g for MAO-B) was incubated on ice for 15 minutes in the
reaction buffer, in the absence and/or in the presence of various
concentrations of inhibitor (from 0 to 50 .mu.M, depending on the
inhibitor strength). Tranylcypromine (Biomol International) was
used as a control for inhibition.
[0578] After leaving the enzyme(s) interacting with the inhibitor,
60 to 90 .mu.M of kynuramine was added to each reaction for MAO-B
and MAO-A assay respectively, and the reaction was left for 1 hour
at 37.degree. C. in the dark. The oxidative deamination of the
substrate was stopped by adding 50 .mu.L (v/v) of NaOH 2N. The
conversion of kynuramine to 4-hydroxyquinoline, was monitored by
fluorescence (excitation at 320 nm, emission at 360 nm) using a
microplate reader (Infinite 200, Tecan). Arbitrary units were used
to measure levels of fluorescence produced in the absence and/or in
the presence of inhibitor.
[0579] The maximum of oxidative deamination activity was obtained
by measuring the amount of 4-hydroxyquinoline formed from
kynuramine deamination in the absence of inhibitor and corrected
for background fluorescence in the absence of MAO enzymes. The Ki
of each inhibitor was measure at Vmax/2.
[0580] Using the above described assay a number of the compounds of
the invention were tested for their ability to inhibit MAO-B and
were found to have Ki values lower than 100 .mu.M, including many
of the compounds in examples tested. Compound of examples 1, 4, 16,
11, and 17 were found to have Ki (IC50) values for MAO-B of less
than 100 .mu.M. Trans-2-phenylcyclopropylamine (tranylcypromine)
was found to have a Ki for MAO-A of about 2 micromolar and a Ki of
about 0.6 micromolar for MAO-B.
[0581] Previous reports in the literature (Zirkle et al. (1962) J.
Med. Chem. 1265-1284) indicated that substitutions on the amine
group of phenylcyclopropylamine with small alkyl groups like methyl
reduce MAO inhibitory activity slightly whereas disubstitution of
the amine with methyl or mono substitution with larger ring bearing
substituents like benzyl reduce MAO inhibitory activity
substantially. The inventors of the instant invention found that
larger ring bearing substituents on the amine group of
phenylcyclopropylamine could produce potent inhibitors of monoamine
oxidases and particularly MAO-B.
[0582] A number of the compounds of the invention were tested for
their ability to inhibit MAO-A using the above described assay and
were found to have Ki values for MAO-A higher than that for MAO-B
(i.e., inhibit MAO-B better than MAO-A) e.g., like the compounds of
Examples 11 and 13 which both a better MAO-B inhibitors than MAO-A
inhibitors which MAO-B IC50 values below 50 micromolar.
[0583] Thus, unexpectedly compounds having large ring bearing
substituents on the amine group of phenylcyclopropylamine were
found to be potent LSD1 inhibitors as well as potent MAO-B
inhibitors.
[0584] The invention therefore provides inhibitors selective for
LSD1. LSD1 selective inhibitors have IC50 values for LSD1 which are
at least 2-fold lower than the IC50 value for MAO-A and/or MAO-B.
One example of an LSD1 selective inhibitor is given in Example 2
which has an IC50 for LSD1 which is about 10-fold lower than for
MAO-A and MAO-B. Another example of an LSD1 selective inhibitor is
in Example 16 which has an IC50 for LSD1 which is more than 5-fold
lower than the IC50 for MAO-A and MAO-B. Yet another example of a
selective LSD1 inhibitor is given in Example 17 which has an IC50
which is more than 3-fold lower for LSD1 than MAO-A and MAO-B.
[0585] The invention also provides dual inhibitors selective for
LSD1 and MAO-B. Dual LSD1/MAO-B selective inhibitors have IC50
values for LSD1 and MAO-B which are at least 2-fold lower than the
IC50 value for MAO-A. One example of a dual LSD1/MAO-B selective
inhibitor is given in Example 11 which has an IC50 for LSD1 and
MAO-B which is about 2-fold lower than for MAO-A. Another example
of a dual LSD1/MAO-B inhibitor is even in Example 7 where the MAO-B
IC50 is less than half the value it is for MAO-A and the LSD1 IC50
is about 1 micromolar.
TABLE-US-00001 TABLE 1 IC50 Values (micromolar) for Selected
Examples Example Compound No. MAO-A MAO-B LSD1 2 10 10 0.8 4 1.4 7
0.33 6 3.2 1 2.8 7 31 11 1 8 13 13 0.21 9 39 17 0.7 10 29 14 0.7 11
>50 28 0.8 12 nd nd 4.5 16 18 16 2.0 17 16 10 2.3 19 3 4 0.4 20
1 2 0.28 21 3 6 0.41 22 12 8 0.5 23 1.7 2.3 0.74 24 nd nd 4.6 25
12.8 5.33 0.21 29 3 3 4.6 30 9 6 3 31 3.8 3 0.46 32 5.5 6.1 1.12 33
33.8 8 0.55 34 1.2 1.9 0.14 35 1.6 3.3 0.18 36 13 35.5 0.25 37
>>50 50 0.25 38 8.5 18.2 0.19 39 2.4 5.4 0.16 40 27.8 15.5
0.39 41 8.1 8.1 0.16 42 >>50 34.3 0.09 43 2.8 24 0.06 44 2.5
2.4 0.30 45 1.8 2.2 0.40 46 2.4 3.5 0.67 47 24 14 0.96 48 nd nd 4.5
49 37 9.6 0.30 50 7 10.4 0.36 51 24.5 >50 1.95 52 38.8
>>50 0.22 53 16.4 >50 0.06 54 18.5 >>50 0.05 55 2.8
21.6 0.45 56 1.8 9.8 0.51 57 3.4 8.6 0.51 58 10 13.8 0.08 59 26.6
9.5 0.28 60 1.7 2.5 0.30 61 7.4 1.5 0.04 62 21.3 25.3 0.07 63 8.1
23.8 0.07 64 nd nd 0.21 65 nd nd 0.147 66 >>50 7.9 0.06 67 nd
nd nd 68 nd nd nd 69 nd nd nd 70 nd nd nd 71 3 9.8 0.18 72 2.1 2.1
0.91 73 5.9 2.3 0.05 74 nd nd 26% at 2.5 microM 75 nd nd 0.21 76 16
7.4 0.005 77 nd nd nd 78 >50 >50 0.28 79 38 >50 0.014
Tranylcypromine 2 0.6 25
[0586] All results reported in Table 1 are the average of at-least
two determinations of the IC50 value and usually more, unless
otherwise noted, and signifies not determined. The IC50 LSD1 values
for the inhibitors of examples 20, 21, 23, and 25 represent only
one measurement.
[0587] As can be seen from Table 1, the compounds of Formula I can
have IC50 values for LSD1 of less than that for parnate, less than
10 micromolar, less than 1 micromolar, and less than 500 nanomolar.
Typically the IC50 values of the compounds of Formula I for LSD1
are less than 1 micromolar.
[0588] As can be seen from Table 1, the compounds of Formula I can
have IC50 values for MAO-A of less than 20 micromolar, less than 10
micromolar, and less than 5 micromolar. Typically the IC50 values
of the compounds of Formula I for MAO-A are greater than 1
micromolar.
[0589] As can be seen from Table 1, the compounds of Formula I can
have IC50 values for MAO-B of less than 20 micromolar, less than 10
micromolar, and less than 5 micromolar. Typically the IC50 values
of the compounds of Formula I for MAO-B are greater than 1
micromolar.
[0590] Most of the compounds of the Examples are selective LSD1
inhibitors in that they inhibit LSD1 to a greater extent than MAO-A
and MAO-B. Some of the compounds of the Examples inhibit both MAO-B
and LSD1 to a greater extent than MAO-A.
[0591] As the skilled artisan readily recognizes the compounds
disclosed herein are surprisingly and significantly more potent
than tranylcypromine for LSD1 inhibition. Han et al. (Euro. J.
Pharma. (2008) doi:10.1016/j.ejphar.2008.12.025) reported that
phenylcyclopropylamine displays neuroprotective activity in PC12
cells thus the compounds of Formula I may be used as a
neuroprotectant (e.g., used to treat and/or prevent conditions
characterized by neurodegeneration). Furthermore, since the
compounds of Formula I are potent LSD1 inhibitor they can be used
to treat and/or prevent diseases where LSD1 inhibition is
desirable, e.g., cancer.
[0592] All publications and patent applications mentioned in the
specification are indicative of the level of those skilled in the
art to which this invention pertains. All publications and patent
applications are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference. The mere mentioning of the publications and patent
applications does not necessarily constitute an admission that they
are prior art to the instant application.
[0593] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it will be obvious that certain changes and
modifications may be practiced within the scope of the appended
claims.
* * * * *