U.S. patent application number 12/259085 was filed with the patent office on 2009-02-26 for substituted heterocyclic compounds.
Invention is credited to Elfatih Elzein, Prabha Ibrahim, Venkata Palle, Kenneth Rehder, Jeffery Zablocki.
Application Number | 20090054457 12/259085 |
Document ID | / |
Family ID | 34710215 |
Filed Date | 2009-02-26 |
United States Patent
Application |
20090054457 |
Kind Code |
A1 |
Elzein; Elfatih ; et
al. |
February 26, 2009 |
SUBSTITUTED HETEROCYCLIC COMPOUNDS
Abstract
Disclosed are novel substituted heterocyclic derivatives having
the structure of Formula I: ##STR00001## The compounds are useful
for the treatment of various disease states, in particular
cardiovascular diseases such as atrial and ventricular arrhythmias,
intermittent claudication, Prinzmetal's (variant) angina, stable
and unstable angina, exercise induced angina, congestive heart
disease, diabetes, and myocardial infarction.
Inventors: |
Elzein; Elfatih; (Fremont,
CA) ; Ibrahim; Prabha; (Mountain View, CA) ;
Palle; Venkata; (Gurgaon, IN) ; Rehder; Kenneth;
(Durham, NC) ; Zablocki; Jeffery; (Mountain View,
CA) |
Correspondence
Address: |
Michael J. Beck;CV Theurapeutics, Inc.
3172 Porter Drive
Palo Alto
CA
94304
US
|
Family ID: |
34710215 |
Appl. No.: |
12/259085 |
Filed: |
October 27, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11845720 |
Aug 27, 2007 |
7452889 |
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12259085 |
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11452479 |
Jun 13, 2006 |
7262198 |
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11845720 |
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11015915 |
Dec 17, 2004 |
7115610 |
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11452479 |
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60531253 |
Dec 18, 2003 |
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Current U.S.
Class: |
514/254.02 ;
514/321; 544/368; 546/198 |
Current CPC
Class: |
A61P 19/00 20180101;
A61P 21/00 20180101; A61P 9/04 20180101; A61P 9/10 20180101; A61P
9/06 20180101; C07D 417/12 20130101; C07D 277/64 20130101; A61P
3/10 20180101; C07D 211/58 20130101; A61P 9/00 20180101 |
Class at
Publication: |
514/254.02 ;
544/368; 546/198; 514/321 |
International
Class: |
A61K 31/496 20060101
A61K031/496; C07D 417/02 20060101 C07D417/02; A61K 31/454 20060101
A61K031/454; A61P 3/10 20060101 A61P003/10; A61P 21/00 20060101
A61P021/00; A61P 9/00 20060101 A61P009/00 |
Claims
1. A compound of Formula I: ##STR00054## wherein: R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
hydrogen, lower alkyl, or --C(O)R, in which R is --OR.sup.111 or
--NR.sup.11R.sup.12, where R.sup.11 and R.sup.12 are independently
hydrogen or lower alkyl; or R.sup.1 and R.sup.2, R.sup.3 and
R.sup.4, R.sup.5 and R.sup.6, R.sup.7 and R.sup.8, when taken
together with the carbon to which they are attached, represent
carbonyl; or R.sup.1 and R.sup.5, or R.sup.1 and R.sup.7, or
R.sup.3 and R.sup.5, or R.sup.3 and R.sup.7, when taken together
form a bridging group --(CR.sup.13R.sup.14).sub.n--, in which n is
1, 2 or 3, and R.sup.13 and R.sup.14 are independently hydrogen or
lower alkyl; with the provisos that i. the maximum number of
carbonyl groups is 1, ii. the maximum number of
--C(O)NR.sup.11R.sup.12 groups is 1, and iii. the maximum number of
bridging groups is 1; R.sup.9 and R.sup.10 are independently
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted alkynyl, optionally substituted cycloalkyl,
optionally substituted heterocycle, optionally substituted aryl, or
optionally substituted heteroaryl; T is --O--, --S--,
--NHSO.sub.2--, --SO.sub.2NH--, or --CO--NH--; or R.sup.9 and T are
taken together are optionally substituted heterocyclyl; Q is
--N< or --NH--CH<; X is a covalent bond or an optionally
substituted alkylene of 1-6 carbon atoms; Y is optionally
substituted alkylene of 1-3 carbon atoms; and Z is a covalent bond,
--O--, --S--, or --N(R.sup.15)--, wherein R.sup.15 is hydrogen or
C.sub.1-4 alkyl.
2. The compound of claim 1, wherein R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen or
lower alkyl.
3. The compound of claim 2, wherein Y is methylene.
4. The compound of claim 3, wherein Z is --O--.
5. The compound of claim 4, wherein R.sup.10 is optionally
substituted aryl or optionally substituted heteroaryl.
6. The compound of claim 5, wherein Q is --N<.
7. The compound of claim 6, wherein X is C.sub.1-4 alkyl.
8. The compound of claim 7, wherein T is --O--.
9. The compound of claim 8, selected from the group consisting of:
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(3-phenoxypropyl)piperazinyl]p-
ropan-2-ol;
(2R)-1-{4-[2-(4-fluorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol;
(2R)-1-{4-[3-(4-fluorophenoxy)propyl]piperazinyl}-3-(2-methylbenzothiazol-
-5-yloxy)propan-2-ol;
(2R)-1-{4-[2-(4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol;
(2R)-1-{4-[2-(phenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)-
propan-2-ol;
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-phenoxybutyl)piperazinyl]pr-
opan-2-ol
(2R)-1-{4-[4-(4-chlorophenoxy)butyl]piperazinyl}-3-(2-methylbenz-
othiazol-5-yloxy)propan-2-ol;
(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-{4-[2-(2-methylphenoxy)ethyl]pipe-
razinyl}propan-2-ol;
(2R)-1-{4-[2-(4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol;
(2R)-1-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperazinyl}-3-(2-methylben-
zothiazol-5-yloxy)propan-2-ol;
(2R)-1-{4-[2-(2-methoxy-4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylben-
zothiazol-5-yloxy)propan-2-ol;
(2R)-1-{4-[2-(3-chloro-4-fluorophenoxy)ethyl]piperazinyl}-3-(2-methylbenz-
othiazol-5-yloxy)propan-2-ol;
(2R)-1-{4-[2-(4-phenylphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol;
(2R)-1-{4-[2-(2-methoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-
-5-yloxy)propan-2-ol;
(2R)-1-{4-[2-(4-trifluoromethylphenoxy)ethyl]piperazinyl}-3-(2-methylbenz-
othiazol-5-yloxy)propan-2-ol;
(2R)-1-{4-[2-(3,5-dichlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothia-
zol-5-yloxy)propan-2-ol;
(2R)-1-{4-[2-(3-chloro-4-bromophenoxy)ethyl]piperazinyl}-3-(2-methylbenzo-
thiazol-5-yloxy)propan-2-ol;
(2R)-1-{4-[2-(4-methoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-
-5-yloxy)propan-2-ol;
(2R)-1-{4-[2-(3,5-bis(trifluoromethyl)phenoxy)ethyl]piperazinyl}-3-(2-met-
hylbenzothiazol-5-yloxy)propan-2-ol;
(2R)-1-{4-[3-(4-trifluoromethylphenoxy)propyl]piperazinyl}-3-(2-methylben-
zothiazol-5-yloxy)propan-2-ol;
(2R)-1-{4-[4-(4-trifluoromethylphenoxy)butyl]piperazinyl}-3-(2-methylbenz-
othiazol-5-yloxy)propan-2-ol;
(2R)-3-[4-(4-indan-5-yloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yl-
oxy)propan-2-ol;
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-(2-5,6,7,8-tetrahydronaphth-
yloxy)butyl)piperazinyl]propan-2-ol;
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[1-methyl-5-(trifluoromethy-
l)pyrazol-3-yloxy]butyl}piperazinyl)propan-2-ol;
-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}butoxy)-2,3a,7a-trihydrobenzo[2,1-b]furan-3-one; ethyl
2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenyl]acetate; ethyl
3-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenyl]propanoate;
2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenyl]acetic acid;
(2R)-1-[4-(4-indan-2-yloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yl-
oxy)propan-2-ol;
(2R)-1-[4-(4-cyclohexyloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yl-
oxy)propan-2-ol; ethyl
2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenoxy]acetate; ethyl
2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenoxy]-2-methylpropanoate;
2-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenoxy]-2-methylpropanoic acid;
3-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenyl]propanoic acid;
(2R)-3-[4-(4-cyclopentyloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-y-
loxy)propan-2-ol;
(2R)-1-(4-{4-[4-(tert-butyl)cyclohexyloxy]butyl}piperazinyl)-3-(2-methylb-
enzothiazol-5-yloxy)propan-2-ol;
(2R)-1-[4-(4-cyclopentyloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-y-
loxy)propan-2-ol;
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-{4-[4-(1,7,7-trimethylbicyclo[2.2-
.1]hept-2-yloxy)butyl]piperazinyl}propan-2-ol;
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-(1,2,3,4-tetrahydronaphthyl-
oxy)butyl)piperazinyl]propan-2-ol;
(2R)-1-{4-[4-(1-methoxyindan-2-yloxy)butyl]piperazinyl}-3-(2-methylbenzot-
hiazol-5-yloxy)propan-2-ol;
2-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenoxy]acetic acid;
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{6-[4-(trifluoromethyl)phenoxy-
]hexyl}piperazinyl)propan-2-ol;
(2R)-1-[4-(4-(2H-3,4,5,6-tetrahydropyran-4-yloxy)butyl)piperazinyl]-3-(2--
methylbenzothiazol-5-yloxy)propan-2-ol;
(2R)-1-[4-(4-cyclobutoxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-ylox-
y)propan-2-ol; and
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[4-(trifluoromethyl)cyclohe-
xyloxy]butyl}piperazinyl)propan-2-ol.
10. The compound of claim 9, wherein T and R.sup.9 together form an
optionally substituted heterocyclyl.
11. The compound of claim 10, wherein T and R.sup.9 together form
an optionally substituted pyrrolidin-2-one.
12. The compound of claim 11, selected from the group consisting
of:
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-phenylpyrrolidin-2-one;
4-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-(4-fluorophenyl)pyrrolidin-2-one;
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one;
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one;
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-(4-methylphenyl)pyrrolidin-2-one; and
4-[(4-{(2R)-3-[2-(2-chlorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}pipe-
razinyl)methyl]-1-(4-fluorophenyl)pyrrolidin-2-one.
13. The compound of claim 10, wherein T and R.sup.9 together form
an optionally substituted azolidine-2,5-dionyl moiety.
14. The compound of claim 13, selected from the group consisting
of:
1-(3-fluorophenyl)-3-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl-
]piperazinyl}azolidine-2,5-dione;
1-[4-(tert-butyl)phenyl]-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-y-
loxy)propyl]piperazinyl}azolidine-2,5-dione;
1-benzoxazol-2-yl-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)pr-
opyl]piperazinyl}azolidine-2,5-dione;
1-(4-bromophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)pr-
opyl]piperazinyl}azolidine-2,5-dione;
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-[3-(trifluoromethyl)phenyl]azolidine-2,5-dione;
1-(4-chlorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)p-
ropyl]piperazinyl}azolidine-2,5-dione;
1-(2-chlorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)p-
ropyl]piperazinyl}azolidine-2,5-dione;
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
[4-(trifluoromethyl)phenyl]azolidine-2,5-dione;
1-(4-fluorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)p-
ropyl]piperazinyl}azolidine-2,5-dione;
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
[4-(trifluoromethoxy)phenyl]azolidine-2,5-dione;
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-(4-vinylphenyl)azolidine-2,5-dione;
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-phenylazolidine-2,5-dione;
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-phenylazolidine-2,5-dione;
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-naphthylazolidine-2,5-dione;
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-[4-(trifluoromethyl)phenyl]azolidine-2,5-dione;
1-(4-fluorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-
propyl]piperazinyl}methyl)azolidine-2,5-dione;
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-[3-(trifluoromethyl)phenyl]azolidine-2,5-dione;
1-(3-fluorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-
propyl]piperazinyl}methyl)azolidine-2,5-dione;
1-[4-(tert-butyl)phenyl]-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5--
yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione;
1-(4-chlorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-
propyl]piperazinyl}methyl)azolidine-2,5-dione;
1-[3-(tert-butyl)-4-chlorophenyl]-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzot-
hiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione;
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-naphthylazolidine-2,5-dione; and
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-(4-methylphenyl)azolidine-2,5-dione.
15. The compound of claim 10, wherein T and R.sup.9 together form
an optionally substituted benzo[c]azolidine-1,3-dione moiety.
16. The compound of claim 15, namely
2-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaziny-
l}ethyl)benzo[c]azolidine-1,3-dione.
17. The compound of claim 6, wherein T is --SO.sub.2NH--.
18. The compound of claim 17, selected from the group consisting
of:
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) (phenylsulfonyl)amine
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) [(4-methylphenyl)sulfonyl]amine;
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(4-trifluoromethyl)phenylsulfonyl]amine;
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) [4-chlorophenylsulfonyl]amine;
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) [(4-trifluoromethoxy)phenylsulfonyl]amine;
(3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
propyl) [(4-trifluoromethyl)phenylsulfonyl]amine;
(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
butyl) [(4-trifluoromethyl)phenylsulfonyl]amine;
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(3-trifluoromethyl)phenylsulfonyl]amine;
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(2,5-dimethyl)phenylsulfonyl]amine;
{[5-(dimethylamino)naphthyl]sulfonyl}(2-{4-[(2R)-2-hydroxy-3-(2-methylben-
zothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine;
[(3,4-dimethoxyphenyl)sulfonyl](2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothia-
zol-5-yloxy)propyl]piperazinyl}ethyl)amine;
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) [(3-methylphenyl)sulfonyl]amine;
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(2,3,5,6-tetramethylphenyl)sulfonyl]amine;
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(2,3,4,5,6-pentafluorophenyl)sulfonyl]amine;
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(2,4,6-trimethylphenyl)sulfonyl]amine;
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)(naphthylsulfonyl)amine;
{[4-(1,1-dimethylpropyl)phenyl]sulfonyl}(2-{4-[2-hydroxy-3-(2-methylbenzo-
thiazol-5-yloxy)propyl]piperazinyl}ethyl)amine;
[(4-ethylphenyl)sulfonyl](2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5--
yloxy)propyl]piperazinyl}ethyl)amine; and
{[4-(tert-butyl)phenyl]sulfonyl}(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothi-
azol-5-yloxy)propyl]piperazinyl}ethyl)amine.
19. The compound of claim 6, wherein T is --NHSO.sub.2--.
20. The compound of claim 19, selected from the group consisting
of:
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl]phenylamine
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][4-(trifluoromethyl)phenyl]amine;
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][4-(tertbutyl)phenyl]amine;
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][4-(methyl)phenyl]amine;
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][4-(trifluoromethoxy)phenyl]amine;
[3,5-bis(trifluoromethyl)phenyl][(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzoth-
iazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine;
(4-chlorophenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)pr-
opyl]piperazinyl}ethyl)sulfonyl]amine;
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl]naphthylamine;
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl](2,4,6-trimethylphenyl)amine;
[(3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}propyl)sulfonyl][4-(tertbutyl)phenyl]amine;
(2,5-dimethylphenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-ylox-
y)propyl]piperazinyl}ethyl)sulfonyl]amine;
(3,4-dimethoxyphenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-ylo-
xy)propyl]piperazinyl}ethyl)sulfonyl]amine;
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][3-(trifluoromethyl)phenyl]amine; and
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl](2,3,4,5,6-pentafluorophenyl)amine.
21. The compound of claim 6, wherein T is --CO--NH--.
22. The compound of claim 21 selected from the group consisting of:
(2,6-difluorophenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yl-
oxy)propyl]piperazinyl}ethyl)carboxamide;
N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaziny-
l}ethyl)benzamide;
(4-chlorophenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-
propyl]piperazinyl}ethyl)carboxamide; and
(4-trifluoromethylphenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-
-5-yloxy)propyl]piperazinyl}ethyl)carboxamide.
23. The compound of claim 5, wherein Q is --NH--CH<.
24. The compound of claim 23 selected from the group consisting of:
(3R)-1-(4-fluorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-y-
loxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one;
(3R)-1-(4-chlorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-y-
loxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one;
3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)--
1-(4-chlorophenyl)pyrrolidin-2-one;
(3R)-1-(2-fluorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-y-
loxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one;
3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)--
1-(4-fluorophenyl)pyrrolidin-2-one;
3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)--
1-(2-fluorophenyl)pyrrolidin-2-one;
3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl-
)}amino)(3R)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one;
3-({1-[3-(2-fluorophenoxy)-(2R)-2-hydroxypropyl](4-piperidyl)}amino)(3R)--
1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one;
(3R)-1-(4-chlorophenyl)-3-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)p-
ropyl]piperazinyl}pyrrolidin-2-one; and
4-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)(3R)-1-(4-fluorophenyl)pyrrolidin-2-one.
25. A method of treating a disease state chosen from diabetes,
damage to skeletal muscles resulting from trauma or shock and a
cardiovascular disease in a mammal by administration of a
therapeutically effective dose of a compound of claim 1.
26. The method of claim 25, wherein the cardiovascular disease is
atrial arrhythmia, intermittent claudication, ventricular
arrhythmia, Prinzmetal's (variant) angina, stable angina, unstable
angina, congestive heart failure, or myocardial infarction.
27. The method of claim 26, wherein the disease state is
diabetes.
28. The method of claim 26, wherein the disease state is congestive
heart failure.
29. A pharmaceutical composition comprising at least one
pharmaceutically acceptable excipient and a therapeutically
effective amount of a compound of claim 1.
Description
[0001] This application is a Continuation Application of Divisional
Application U.S. patent application Ser. No. 11/845,720, filed Aug.
27, 2007, which is a Divisional Application of U.S. patent
application Ser. No. 11/452,479, filed Jun. 13, 2006, now issued as
U.S. Pat. No. 7,262,198, which was a Divisional Application of U.S.
patent application Ser. No. 11/015,915, filed Dec. 17, 2004, now
issued as U.S. Pat. No. 7,115,610, which claimed priority to U.S.
Provisional Patent Application Ser. No. 60/531,253, filed Dec. 18,
2003, all of which are incorporated by reference herein in their
entireties.
FIELD OF THE INVENTION
[0002] The present invention relates to novel heterocyclic
compounds and to their use in the treatment of various disease
states, including cardiovascular diseases such as atrial and
ventricular arrhythmias, intermittent claudication, Prinzmetal's
(variant) angina, stable and unstable angina, exercise induced
angina, congestive heart disease, ischemia, reperfusion injury and
myocardial infarction, and diabetes and disease states related to
diabetes. The invention also relates to methods for their
preparation, and to pharmaceutical compositions containing such
compounds.
BACKGROUND OF THE INVENTION
[0003] Certain classes of piperazine compounds are known to be
useful for the treatment of cardiovascular diseases, including
arrhythmias, angina, myocardial infarction, and related diseases
such as intermittent claudication. For example, U.S. Pat. No.
4,567,264 discloses a class of substituted piperazine compounds
that includes a compound known as ranolazine,
(.+-.)--N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]--
1-piperazineacetamide, and its pharmaceutically acceptable salts,
and their use in the above disease states.
[0004] Despite the desirable properties demonstrated by ranolazine,
which is a very effective cardiac therapeutic agent, believed to
function as a fatty acid oxidation inhibitor and late sodium
channel blocker, there remains a need for compounds that have
similar therapeutic properties to ranolazine, but are more potent
and have a longer half-life.
SUMMARY OF THE INVENTION
[0005] It is an object of this invention to provide novel
substituted heterocyclic compounds that function as fatty acid
oxidation inhibitors and/or late sodium channel blockers.
Accordingly, in a first aspect, the invention relates to compounds
of Formula I:
##STR00002##
wherein: [0006] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are hydrogen, lower alkyl, or
--C(O)R, in which R is --OR.sup.11 or --NR.sup.11R.sup.12, where
R.sup.11 and R.sup.12 are hydrogen or lower alkyl; or [0007]
R.sup.1 and R.sup.2, R.sup.3 and R.sup.4, R.sup.5 and R.sup.6,
R.sup.7 and R.sup.8, when taken together with the carbon to which
they are attached, represent carbonyl; or [0008] R.sup.1 and
R.sup.5, or R.sup.1 and R.sup.7, or R.sup.3 and R.sup.5, or R.sup.3
and R.sup.7, when taken together form a bridging group
--(CR.sup.12R.sup.13).sub.n--, in which n is 1, 2 or 3, and
R.sup.12 and R.sup.13 are independently hydrogen or lower alkyl;
[0009] with the proviso that [0010] the maximum number of carbonyl
groups is 1; [0011] the maximum number of --C(O)NR.sup.11R.sup.12
groups is 1; and [0012] the maximum number of bridging groups is 1;
[0013] R.sup.9 and R.sup.10 are independently optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted alkynyl, optionally substituted cycloalkyl, optionally
substituted heterocycle, optionally substituted aryl, or optionally
substituted heteroaryl; [0014] T is --O--, --S--, --NHSO.sub.2--,
--SO.sub.2NH--, or --CO--NH--; or [0015] R.sup.9 and T when taken
together are optionally substituted heterocyclyl; [0016] Q is
--N< or --NH--CH<; [0017] X is a covalent bond or an
optionally substituted alkylene of 1-6 carbon atoms; [0018] Y is
optionally substituted alkylene of 1-3 carbon atoms; and [0019] Z
is a covalent bond, --O--, --S--, or --N(R.sup.15)-, wherein
R.sup.15 is hydrogen or C.sub.1-4 alkyl.
[0020] A second aspect of this invention relates to pharmaceutical
formulations, comprising a therapeutically effective amount of a
compound of Formula I and at least one pharmaceutically acceptable
excipient.
[0021] A third aspect of this invention relates to a method of
using the compounds of Formula I in the treatment of a disease or
condition in a mammal that is amenable to treatment by a fatty acid
oxidation inhibitor or late sodium channel blocker. Such diseases
include, but are not limited to, protection of skeletal muscles
against damage resulting from trauma, intermittent claudication,
shock, and cardiovascular diseases including atrial and ventricular
arrhythmias, Prinzmetal's (variant) angina, stable angina, exercise
induced angina, congestive heart disease, diabetes, and myocardial
infarction. The compounds of Formula I are also useful for lowering
plasma level of HbA1c, lowering glucose plasma levels, lowering
total cholesterol plasma levels, lowering triglyceride plasma
levels, raising HDL cholesterol levels, and/or delaying onset of
diabetic retinopathy. They can also be used to preserve donor
tissue and organs used in transplants.
[0022] The preferred compounds presently include: [0023]
(2,6-difluorophenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yl-
oxy)propyl]piperazinyl}ethyl)carboxamide; [0024]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) [(4-methylphenyl)sulfonyl]amine; [0025]
N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaziny-
l}ethyl)benzamide; [0026]
(4-chlorophenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-
propyl]piperazinyl}ethyl)carboxamide; [0027]
(4-trifluoromethylphenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-
-5-yloxy)propyl]piperazinyl}ethyl)carboxamide; [0028]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(3-phenoxypropyl)piperazinyl]p-
ropan-2-ol; [0029]
(2R)-1-{4-[2-(4-fluorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol; [0030]
(2R)-1-{4-[3-(4-fluorophenoxy)propyl]piperazinyl}-3-(2-methylbenzothiazol-
-5-yloxy)propan-2-ol; [0031]
(3R)-1-(4-fluorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-y-
loxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one; [0032]
(3R)-1-(4-chlorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-y-
loxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one; [0033]
3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)--
1-(4-chlorophenyl)pyrrolidin-2-one; [0034]
(3R)-1-(2-fluorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-y-
loxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one; [0035]
3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)--
1-(4-fluorophenyl)pyrrolidin-2-one; [0036]
3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)--
1-(2-fluorophenyl)pyrrolidin-2-one; [0037]
(2R)-1-{4-[2-(4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol; [0038]
(2R)-1-{4-[2-(phenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)-
propan-2-ol; [0039]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-phenoxybutyl)piperazinyl]pr-
opan-2-ol; [0040]
(2R)-1-{4-[4-(4-chlorophenoxy)butyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol; [0041]
(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-{4-[2-(2-methylphenoxy)ethyl]pipe-
razinyl}propan-2-ol; [0042]
(2R)-1-{4-[2-(4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol; [0043]
(2R)-1-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperazinyl}-3-(2-methylben-
zothiazol-5-yloxy)propan-2-ol; [0044]
(2R)-1-{4-[2-(2-methoxy-4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylben-
zothiazol-5-yloxy)propan-2-ol; [0045]
(2R)-1-{4-[2-(3-chloro-4-fluorophenoxy)ethyl]piperazinyl}-3-(2-methylbenz-
othiazol-5-yloxy)propan-2-ol; [0046]
(2R)-1-{4-[2-(4-phenylphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol; [0047]
(2R)-1-{4-[2-(2-methoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-
-5-yloxy)propan-2-ol; [0048]
(2R)-1-{4-[2-(4-trifluoromethylphenoxy)ethyl]piperazinyl}-3-(2-methylbenz-
othiazol-5-yloxy)propan-2-ol; [0049]
(2R)-1-{4-[2-(3,5-dichlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothia-
zol-5-yloxy)propan-2-ol; [0050]
(2R)-1-{4-[2-(3-chloro-4-bromophenoxy)ethyl]piperazinyl}-3-(2-methylbenzo-
thiazol-5-yloxy)propan-2-ol; [0051]
(2R)-1-{4-[2-(4-methoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-
-5-yloxy)propan-2-ol; [0052]
(2R)-1-{4-[2-(3,5-bis(trifluoromethyl)phenoxy)ethyl]piperazinyl}-3-(2-met-
hylbenzothiazol-5-yloxy)propan-2-ol; [0053]
(2R)-1-{4-[3-(4-trifluoromethylphenoxy)propyl]piperazinyl}-3-(2-methylben-
zothiazol-5-yloxy)propan-2-ol; [0054]
(2R)-1-{4-[4-(4-trifluoromethylphenoxy)butyl]piperazinyl}-3-(2-methylbenz-
othiazol-5-yloxy)propan-2-ol; [0055]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)(phenylsulfonyl)amine; [0056]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl]phenylamine; [0057]
3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl-
)}amino)(3R)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one; [0058]
3-({1-[3-(2-fluorophenoxy)-(2R)-2-hydroxypropyl](4-piperidyl)}amino)(3R)--
1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one; [0059]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(4-trifluoromethyl)phenylsulfonyl]amine; [0060]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) [4-chlorophenylsulfonyl]amine; [0061]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) [(4-trifluoromethoxy)phenylsulfonyl]amine; [0062]
(3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
propyl) [(4-trifluoromethyl)phenylsulfonyl]amine; [0063]
(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
butyl) [(4-trifluoromethyl)phenylsulfonyl]amine; [0064]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(3-trifluoromethyl)phenylsulfonyl]amine; [0065]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(2,5-dimethyl)phenylsulfonyl]amine; [0066]
{[5-(dimethylamino)naphthyl]sulfonyl}(2-{4-[(2R)-2-hydroxy-3-(2-methylben-
zothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine; [0067]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][4-(trifluoromethyl)phenyl]amine; [0068]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][4-(tertbutyl)phenyl]amine; [0069]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][4-(methyl)phenyl]amine; [0070]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][4-(trifluoromethoxy)phenyl]amine; [0071]
[3,5-bis(trifluoromethyl)phenyl][(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzoth-
iazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine; [0072]
(4-chlorophenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)pr-
opyl]piperazinyl}ethyl)sulfonyl]amine; [0073]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl]naphthylamine; [0074]
[(3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}propyl)sulfonyl][4-(tertbutyl)phenyl]amine; [0075]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl](2,4,6-trimethylphenyl)amine; [0076]
(2,5-dimethylphenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-ylox-
y)propyl]piperazinyl}ethyl)sulfonyl]amine; [0077]
[(3,4-dimethoxyphenyl)sulfonyl](2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothia-
zol-5-yloxy)propyl]piperazinyl}ethyl)amine; [0078]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) [(3-methylphenyl)sulfonyl]amine; [0079]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(2,3,5,6-tetramethylphenyl)sulfonyl]amine; [0080]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(2,3,4,5,6-pentafluorophenyl)sulfonyl]amine; [0081]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(2,4,6-trimethylphenyl)sulfonyl]amine; [0082]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)(naphthylsulfonyl)amine; [0083]
{[4-(1,1-dimethylpropyl)phenyl]sulfonyl}(2-{4-[2-hydroxy-3-(2-methylbenzo-
thiazol-5-yloxy)propyl]piperazinyl}ethyl)amine; [0084]
[(4-ethylphenyl)sulfonyl](2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5--
yloxy)propyl]piperazinyl}ethyl)amine; [0085]
{[4-(tert-butyl)phenyl]sulfonyl}(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothi-
azol-5-yloxy)propyl]piperazinyl}ethyl)amine; [0086]
(3,4-dimethoxyphenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-ylo-
xy)propyl]piperazinyl}ethyl)sulfonyl]amine; [0087]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][3-(trifluoromethyl)phenyl]amine; [0088]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl](2,3,4,5,6-pentafluorophenyl)amine; [0089]
1-(3-fluorophenyl)-3-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl-
]piperazinyl}azolidine-2,5-dione; [0090]
1-[4-(tert-butyl)phenyl]-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-y-
loxy)propyl]piperazinyl}azolidine-2,5-dione; [0091]
1-benzoxazol-2-yl-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)pr-
opyl]piperazinyl}azolidine-2,5-dione; [0092]
1-(4-bromophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)pr-
opyl]piperazinyl}azolidine-2,5-dione; [0093]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-[3-(trifluoromethyl)phenyl]azolidine-2,5-dione; [0094]
1-(4-chlorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)p-
ropyl]piperazinyl}azolidine-2,5-dione; [0095]
1-(2-chlorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)p-
ropyl]piperazinyl}azolidine-2,5-dione; [0096]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-[4-(trifluoromethyl)phenyl]azolidine-2,5-dione; [0097]
1-(4-fluorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)p-
ropyl]piperazinyl}azolidine-2,5-dione; [0098]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-[4-(trifluoromethoxy)phenyl]azolidine-2,5-dione; [0099]
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-phenylazolidine-2,5-dione; [0100]
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-naphthylazolidine-2,5-dione; [0101]
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-[4-(trifluoromethyl)phenyl]azolidine-2,5-dione; [0102]
1-(4-fluorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-
propyl]piperazinyl}methyl)azolidine-2,5-dione; [0103]
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-[3-(trifluoromethyl)phenyl]azolidine-2,5-dione; [0104]
1-(3-fluorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-
propyl]piperazinyl}methyl)azolidine-2,5-dione; [0105]
1-[4-(tert-butyl)phenyl]-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5--
yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione; [0106]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-naphthylazolidine-2,5-dione; [0107]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-(4-methylphenyl)azolidine-2,5-dione; [0108]
1-(4-chlorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-
propyl]piperazinyl}methyl)azolidine-2,5-dione; [0109]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-phenylpyrrolidin-2-one; [0110]
1-[3-(tert-butyl)-4-chlorophenyl]-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzot-
hiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione;
[0111]
(2R)-3-[4-(4-indan-5-yloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yl-
oxy)propan-2-ol; [0112]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-(2-5,6,7,8-tetrahydronaphth-
yloxy)butyl)piperazinyl]propan-2-ol; [0113]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[1-methyl-5-(trifluoromethy-
l)pyrazol-3-yloxy]butyl}piperazinyl)propan-2-ol; [0114]
6-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaziny-
l}butoxy)-2,3a,7a-trihydrobenzo[2,1-b]furan-3-one; [0115] ethyl
2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenyl]acetate; [0116] ethyl
3-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenyl]propanoate; [0117]
2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenyl]acetic acid; [0118]
(2R)-1-[4-(4-indan-2-yloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yl-
oxy)propan-2-ol; [0119]
(2R)-1-[4-(4-cyclohexyloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yl-
oxy)propan-2-ol; [0120]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one; [0121]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one; [0122]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-(4-methylphenyl)pyrrolidin-2-one; [0123]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-(4-vinylphenyl)azolidine-2,5-dione; [0124]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-phenylazolidine-2,5-dione; [0125] ethyl
2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenoxy]acetate; [0126] ethyl
2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenoxy]-2-methylpropanoate; [0127]
2-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenoxy]-2-methylpropanoic acid; [0128]
3-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenyl]propanoic acid; [0129]
(2R)-1-(4-{4-[4-(tert-butyl)cyclohexyloxy]butyl}piperazinyl)-3-(2-methylb-
enzothiazol-5-yloxy)propan-2-ol; [0130]
(2R)-1-[4-(4-cyclopentyloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-y-
loxy)propan-2-ol; [0131]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-{4-[4-(1,7,7-trimethylbicyclo[2.2-
.1]hept-2-yloxy)butyl]piperazinyl}propan-2-ol; [0132]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-(1,2,3,4-tetrahydronaphthyl-
oxy)butyl)piperazinyl]propan-2-ol; [0133]
(2R)-1-{4-[4-(1-methoxyindan-2-yloxy)butyl]piperazinyl}-3-(2-methylbenzot-
hiazol-5-yloxy)propan-2-ol; [0134]
2-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenoxy]acetic acid; [0135]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{6-[4-(trifluoromethyl)phenoxy-
]hexyl}piperazinyl)propan-2-ol; [0136]
(2R)-1-[4-(4-(2H-3,4,5,6-tetrahydropyran-4-yloxy)butyl)piperazinyl]-3-(2--
methylbenzothiazol-5-yloxy)propan-2-ol; [0137]
(2R)-1-[4-(4-cyclobutoxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-ylox-
y)propan-2-ol; [0138]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[4-(trifluoromethyl)cyclohe-
xyloxy]butyl}piperazinyl)propan-2-ol; [0139]
(3R)-1-(4-chlorophenyl)-3-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)p-
ropyl]piperazinyl}pyrrolidin-2-one; [0140]
4-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)(3R)-1-(4-fluorophenyl)pyrrolidin-2-one; and [0141]
4-[(4-{(2R)-3-[2-(2-chlorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}pipe-
razinyl)methyl]-1-(4-fluorophenyl)pyrrolidin-2-one.
DEFINITIONS AND GENERAL PARAMETERS
[0142] As used in the present specification, the following words
and phrases are generally intended to have the meanings as set
forth below, except to the extent that the context in which they
are used indicates otherwise.
[0143] The term "alkyl" refers to a monoradical branched or
unbranched saturated hydrocarbon chain having from 1 to 20 carbon
atoms. This term is exemplified by groups such as methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl,
n-decyl, tetradecyl, and the like.
[0144] The term "substituted alkyl" refers to: [0145] 1) an alkyl
group as defined above, having 1, 2, 3, 4 or 5 substituents,
preferably 1 to 3 substituents, selected from the group consisting
of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,
acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,
azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,
carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,
aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-aryl,
--SO-heteroaryl, --SO.sub.2-alkyl, SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or [0146] 2) an
alkyl group as defined above that is interrupted by 1-10 atoms
independently chosen from oxygen, sulfur and NR.sub.a--, where
R.sub.a is chosen from hydrogen, alkyl, cycloalkyl, alkenyl,
cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclyl. All
substituents may be optionally further substituted by alkyl,
alkoxy, halogen, CF.sub.3, amino, substituted amino, cyano, or
--S(O).sub.nR, in which R is alkyl, aryl, or heteroaryl and n is 0,
1 or 2; or [0147] 3) an alkyl group as defined above that has both
1, 2, 3, 4 or 5 substituents as defined above and is also
interrupted by 1-10 atoms as defined above.
[0148] The term "lower alkyl" refers to a monoradical branched or
unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6
carbon atoms. This term is exemplified by groups such as methyl,
ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl,
and the like.
[0149] The term "substituted lower alkyl" refers to lower alkyl as
defined above having 1 to 5 substituents, preferably 1, 2, or 3
substituents, as defined for substituted alkyl, or a lower alkyl
group as defined above that is interrupted by 1, 2, 3, 4, or 5
atoms as defined for substituted alkyl, or a lower alkyl group as
defined above that has both 1, 2, 3, 4 or 5 substituents as defined
above and is also interrupted by 1, 2, 3, 4, or 5 atoms as defined
above.
[0150] The term "alkylene" refers to a diradical of a branched or
unbranched saturated hydrocarbon chain, preferably having from 1 to
20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1,
2, 3, 4, 5 or 6 carbon atoms. This term is exemplified by groups
such as methylene (--CH.sub.2--), ethylene (--CH.sub.2CH.sub.2--),
the propylene isomers (e.g., --CH.sub.2CH.sub.2CH.sub.2-- and
--CH(CH.sub.3)CH.sub.2--) and the like.
[0151] The term "lower alkylene" refers to a diradical of a
branched or unbranched saturated hydrocarbon chain, preferably
having from 1, 2, 3, 4, 5, or 6 carbon atoms.
[0152] The term "substituted alkylene" refers to: [0153] (1) an
alkylene group as defined above having 1, 2, 3, 4, or 5
substituents selected from the group consisting of alkyl, alkenyl,
alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino,
acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,
halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl,
arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,
aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,
heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino,
alkoxyamino, nitro, --SO-alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, SO.sub.2-aryl and --SO.sub.2-heteroaryl. Unless
otherwise constrained by the definition, all substituents may
optionally be further substituted by 1, 2, or 3 substituents chosen
from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,
halogen, CF.sub.3, amino, substituted amino, cyano, and
--S(O).sub.nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1
or 2; or [0154] (2) an alkylene group as defined above that is
interrupted by 1-20 atoms independently chosen from oxygen, sulfur
and NR.sub.a--, where R.sub.a is chosen from hydrogen, optionally
substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and
heterocyclyl, or groups selected from carbonyl, carboxyester,
carboxyamide and sulfonyl; or [0155] (3) an alkylene group as
defined above that has both 1, 2, 3, 4 or 5 substituents as defined
above and is also interrupted by 1-20 atoms as defined above.
Examples of substituted alkylenes are chloromethylene (--CH(Cl)-),
aminoethylene (--CH(NH.sub.2)CH.sub.2--), methylaminoethylene
(--CH(NHMe)CH.sub.2--), 2-carboxypropylene
isomers(--CH.sub.2CH(CO.sub.2H)CH.sub.2--), ethoxyethyl
(--CH.sub.2CH.sub.2O--CH.sub.2CH.sub.2--), ethylmethylaminoethyl
(--CH.sub.2CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2--),1-ethoxy-2-(2-ethoxy-et-
hoxy)ethane
(--CH.sub.2CH.sub.2O--CH.sub.2CH.sub.2--OCH.sub.2CH.sub.2--OCH.sub.2CH.su-
b.2--), and the like.
[0156] The term "aralkyl" refers to an aryl group covalently linked
to an alkylene group, where aryl and alkylene are defined herein.
"Optionally substituted aralkyl" refers to an optionally
substituted aryl group covalently linked to an optionally
substituted alkylene group. Such aralkyl groups are exemplified by
benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.
[0157] The term "alkoxy" refers to the group R--O--, where R is
optionally substituted alkyl or optionally substituted cycloalkyl,
or R is a group --Y-Z, in which Y is optionally substituted
alkylene and Z is optionally substituted alkenyl, optionally
substituted alkynyl; or optionally substituted cycloalkenyl, where
alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined
herein. Preferred alkoxy groups are alkyl-O-- and include, by way
of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,
tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy,
and the like.
[0158] The term "lower alkoxy" refers to the group R--O-- in which
R is optionally substituted lower alkyl as defined above. This term
is exemplified by groups such as methoxy, ethoxy, n-propoxy,
iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, n-hexyloxy, and the
like.
[0159] The term "alkylthio" refers to the group R--S--, where R is
as defined for alkoxy.
[0160] The term "alkenyl" refers to a monoradical of a branched or
unbranched unsaturated hydrocarbon group preferably having from 2
to 20 carbon atoms, more preferably 2 to 10 carbon atoms and even
more preferably 2 to 6 carbon atoms and having 1-6, preferably 1,
double bond (vinyl). Preferred alkenyl groups include ethenyl or
vinyl (--CH.dbd.CH.sub.2), 1-propylene or allyl
(--CH.sub.2CH.dbd.CH.sub.2), isopropylene
(--C(CH.sub.3).dbd.CH.sub.2), bicyclo[2.2.1]heptene, and the like.
In the event that alkenyl is attached to nitrogen, the double bond
cannot be alpha to the nitrogen.
[0161] The term "lower alkenyl" refers to alkenyl as defined above
having from 2 to 6 carbon atoms.
[0162] The term "substituted alkenyl" refers to an alkenyl group as
defined above having 1, 2, 3, 4 or 5 substituents, and preferably
1, 2, or 3 substituents, selected from the group consisting of
alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,
acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,
azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,
carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,
aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-aryl,
--SO-heteroaryl, --SO.sub.2-alkyl, SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0163] The term "alkynyl" refers to a monoradical of an unsaturated
hydrocarbon, preferably having from 2 to 20 carbon atoms, more
preferably 2 to 10 carbon atoms and even more preferably 2 to 6
carbon atoms and having at least 1 and preferably from 1-6 sites of
acetylene (triple bond) unsaturation. Preferred alkynyl groups
include ethynyl, (--C.ident.CH), propargyl (or propynyl,
--C.ident.CCH.sub.3), and the like. In the event that alkynyl is
attached to nitrogen, the triple bond cannot be alpha to the
nitrogen.
[0164] The term "substituted alkynyl" refers to an alkynyl group as
defined above having 1, 2, 3, 4 or 5 substituents, and preferably
1, 2, or 3 substituents, selected from the group consisting of
alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,
acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,
azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,
carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,
aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-aryl,
--SO-heteroaryl, --SO.sub.2-alkyl, SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0165] The term "aminocarbonyl" refers to the group --C(O)NRR where
each R is independently hydrogen, alkyl, cycloalkyl, aryl,
heteroaryl, heterocyclyl or where both R groups are joined to form
a heterocyclic group (e.g., morpholino). Unless otherwise
constrained by the definition, all substituents may optionally be
further substituted by 1, 2, or 3 substituents chosen from alkyl,
carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,
CF.sub.3, amino, substituted amino, cyano, and --S(O).sub.nR, where
R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0166] The term "ester" or "carboxyester" refers to the group
--C(O)OR, where R is alkyl, cycloalkyl, aryl, heteroaryl, or
heterocyclyl, which may be optionally further substituted by alkyl,
alkoxy, halogen, CF.sub.3, amino, substituted amino, cyano, or
--S(O).sub.nR.sub.a, in which R.sub.a is alkyl, aryl, or heteroaryl
and n is 0, 1 or 2.
[0167] The term "acylamino" refers to the group --NRC(O)R where
each R is independently hydrogen, alkyl, aryl, heteroaryl, or
heterocyclyl. All substituents may be optionally further
substituted by alkyl, alkoxy, halogen, CF.sub.3, amino, substituted
amino, cyano, or --S(O).sub.nR, in which R is alkyl, aryl, or
heteroaryl and n is 0, 1 or 2.
[0168] The term "acyloxy" refers to the groups --O(O)C-alkyl,
--O(O)C-cycloalkyl, --O(O)C-aryl, --O(O)C-heteroaryl, and
--O(O)C-heterocyclyl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0169] The term "aryl" refers to an aromatic carbocyclic group of 6
to 20 carbon atoms having a single ring (e.g., phenyl) or multiple
rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g.,
naphthyl, fluorenyl, and anthryl). Preferred aryls include phenyl,
fluorenyl, naphthyl and the like.
[0170] Unless otherwise constrained by the definition for the aryl
substituent, such aryl groups can optionally be substituted with 1,
2, 3, 4 or 5 substituents, preferably 1, 2, or 3 substituents,
selected from the group consisting of alkyl, alkenyl, alkynyl,
alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,
aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,
keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,
heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,
heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,
heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,
--SO-alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
SO.sub.2-aryl and --SO.sub.2-heteroaryl. Unless otherwise
constrained by the definition, all substituents may optionally be
further substituted by 1, 2, or 3 substituents chosen from alkyl,
carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,
CF.sub.3, amino, substituted amino, cyano, and --S(O).sub.nR, where
R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0171] The term "aryloxy" refers to the group aryl-O-- wherein the
aryl group is as defined above, and includes optionally substituted
aryl groups as also defined above. The term "arylthio" refers to
the group R--S--, where R is as defined for aryl.
[0172] The term "amino" refers to the group --NH.sub.2.
[0173] The term "substituted amino" refers to the group --NRR where
each R is independently selected from the group consisting of
hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl
provided that both R groups are not hydrogen, or a group --Y-Z, in
which Y is optionally substituted alkylene and Z is alkenyl,
cycloalkenyl, or alkynyl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0174] The term "carboxyalkyl" refers to the groups --C(O)O-alkyl,
--C(O)O-cycloalkyl, where alkyl and cycloalkyl, are as defined
herein, and may be optionally further substituted by alkyl,
alkenyl, alkynyl, alkoxy, halogen, CF.sub.3, amino, substituted
amino, cyano, or --S(O).sub.nR, in which R is alkyl, aryl, or
heteroaryl and n is 0, 1 or 2.
[0175] The term "cycloalkyl" refers to cyclic alkyl groups of from
3 to 20 carbon atoms having a single cyclic ring or multiple
condensed rings. Such cycloalkyl groups include, by way of example,
single ring structures such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclooctyl, and the like, or multiple ring structures
such as adamantanyl, and bicyclo[2.2.1]heptane, or cyclic alkyl
groups to which is fused an aryl group, for example indan, and the
like.
[0176] The term "substituted cycloalkyl" refers to cycloalkyl
groups having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or
3 substituents, selected from the group consisting of alkyl,
alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl,
acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino,
azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy,
carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio, thiol,
alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,
aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, --SO-alkyl, --SO-aryl,
--SO-heteroaryl, --SO.sub.2-alkyl, SO.sub.2-aryl and
--SO.sub.2-heteroaryl. Unless otherwise constrained by the
definition, all substituents may optionally be further substituted
by 1, 2, or 3 substituents chosen from alkyl, carboxy,
carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF.sub.3,
amino, substituted amino, cyano, and --S(O).sub.nR, where R is
alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
[0177] The term "halogen" or "halo" refers to fluoro, bromo,
chloro, and iodo.
[0178] The term "acyl" denotes a group --C(O)R, in which R is
hydrogen, optionally substituted alkyl, optionally substituted
cycloalkyl, optionally substituted heterocyclyl, optionally
substituted aryl, and optionally substituted heteroaryl.
[0179] The term "heteroaryl" refers to an aromatic group (i.e.,
unsaturated) comprising 1 to 15 carbon atoms and 1 to 4 heteroatoms
selected from oxygen, nitrogen, and sulfur within at least one
ring.
[0180] Unless otherwise constrained by the definition for the
heteroaryl substituent, such heteroaryl groups can be optionally
substituted with 1 to 5 substituents, preferably 1, 2, or 3
substituents selected from the group consisting of alkyl, alkenyl,
alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino,
acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,
halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl (an
alkyl ester), arylthio, heteroaryl, heteroarylthio,
heterocyclylthio, thiol, alkylthio, aryl, aryloxy, aralkyl,
heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,
heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,
--SO-alkyl, --SO-aryl, --SO-heteroaryl, --SO.sub.2-alkyl,
SO.sub.2-aryl and --SO.sub.2-heteroaryl. Unless otherwise
constrained by the definition, all substituents may optionally be
further substituted by 1, 2, or 3 substituents chosen from alkyl,
carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen,
CF.sub.3, amino, substituted amino, cyano, and --S(O).sub.nR, where
R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2. Such heteroaryl
groups can have a single ring (e.g., pyridyl or furyl) or multiple
condensed rings (e.g., indolizinyl, benzothiazole, or
benzothienyl). Examples of nitrogen heterocycles and heteroaryls
include, but are not limited to, pyrrole, imidazole, pyrazole,
pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole,
indole, indazole, purine, quinolizine, isoquinoline, quinoline,
phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline,
pteridine, carbazole, carboline, phenanthridine, acridine,
phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,
phenothiazine, imidazolidine, imidazoline, and the like as well as
N-alkoxy-nitrogen containing heteroaryl compounds.
[0181] The term "heteroaryloxy" refers to the group
heteroaryl-O--.
[0182] The term "heterocyclyl" refers to a monoradical saturated
group having a single ring or multiple condensed rings, having from
1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to
4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or
oxygen within the ring.
[0183] Unless otherwise constrained by the definition for the
heterocyclic substituent, such heterocyclic groups can be
optionally substituted with 1 to 5, and preferably 1, 2, or 3
substituents, selected from the group consisting of alkyl, alkenyl,
alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino,
acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano,
halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl,
arylthio, heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,
aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,
heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino,
alkoxyamino, nitro, --SO-alkyl, --SO-aryl, --SO-heteroaryl,
--SO.sub.2-alkyl, SO.sub.2-aryl and --SO.sub.2-heteroaryl. Unless
otherwise constrained by the definition, all substituents may
optionally be further substituted by 1, 2, or 3 substituents chosen
from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,
halogen, CF.sub.3, amino, substituted amino, cyano, and
--S(O).sub.nR, where R is alkyl, aryl, or heteroaryl and n is 0, 1
or 2. Heterocyclic groups can have a single ring or multiple
condensed rings. Preferred heterocyclics include tetrahydrofuranyl,
morpholino, piperidinyl, and the like.
[0184] The term "thiol" refers to the group --SH.
[0185] The term "substituted alkylthio" refers to the group
--S-substituted alkyl.
[0186] The term "heteroarylthiol" refers to the group
--S-heteroaryl wherein the heteroaryl group is as defined above
including optionally substituted heteroaryl groups as also defined
above.
[0187] The term "sulfoxide" refers to a group --S(O)R, in which R
is alkyl, aryl, or heteroaryl. "Substituted sulfoxide" refers to a
group --S(O)R, in which R is substituted alkyl, substituted aryl,
or substituted heteroaryl, as defined herein.
[0188] The term "sulfone" refers to a group --S(O).sub.2R, in which
R is alkyl, aryl, or heteroaryl. "Substituted sulfone" refers to a
group --S(O).sub.2R, in which R is substituted alkyl, substituted
aryl, or substituted heteroaryl, as defined herein.
[0189] The term "keto" refers to a group --C(O)--. The term
"thiocarbonyl" refers to a group --C(S)--. The term "carboxy"
refers to a group --C(O)--OH.
[0190] "Optional" or "optionally" means that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances in which it does not.
[0191] The term "compound of Formula I" is intended to encompass
the compounds of the invention as disclosed, and the
pharmaceutically acceptable salts, pharmaceutically acceptable
esters, hydrates, polymorphs, and prodrugs of such compounds.
Additionally, the compounds of the invention may possess one or
more asymmetric centers, and can be produced as a racemic mixture
or as individual enantiomers or diastereoisomers. The number of
stereoisomers present in any given compound of Formula I depends
upon the number of asymmetric centers present (there are 2.sup.n
stereoisomers possible where n is the number of asymmetric
centers). The individual stereoisomers may be obtained by resolving
a racemic or non-racemic mixture of an intermediate at some
appropriate stage of the synthesis, or by resolution of the
compound of Formula I by conventional means. The individual
stereoisomers (including individual enantiomers and
diastereoisomers) as well as racemic and non-racemic mixtures of
stereoisomers are encompassed within the scope of the present
invention, all of which are intended to be depicted by the
structures of this specification unless otherwise specifically
indicated.
[0192] "Isomers" are different compounds that have the same
molecular formula.
[0193] "Stereoisomers" are isomers that differ only in the way the
atoms are arranged in space.
[0194] "Enantiomers" are a pair of stereoisomers that are
non-superimposable mirror images of each other. A 1:1 mixture of a
pair of enantiomers is a "racemic" mixture. The term "(.+-.)" is
used to designate a racemic mixture where appropriate.
[0195] "Diastereoisomers" are stereoisomers that have at least two
asymmetric atoms, but which are not mirror-images of each
other.
[0196] The absolute stereochemistry is specified according to the
Cahn-Ingold-Prelog R--S system. When the compound is a pure
enantiomer the stereochemistry at each chiral carbon may be
specified by either R or S. Resolved compounds whose absolute
configuration is unknown are designated (+) or (-) depending on the
direction (dextro- or laevorotary) that they rotate the plane of
polarized light at the wavelength of the sodium D line.
[0197] The term "compound of Formula I" is intended to encompass
the compounds of the invention as disclosed, and the
pharmaceutically acceptable salts, pharmaceutically acceptable
esters, polymorphs, and prodrugs of such compounds.
[0198] The term "therapeutically effective amount" refers to that
amount of a compound of Formula I that is sufficient to effect
treatment, as defined below, when administered to a mammal in need
of such treatment. The therapeutically effective amount will vary
depending upon the subject and disease condition being treated, the
weight and age of the subject, the severity of the disease
condition, the manner of administration and the like, which can
readily be determined by one of ordinary skill in the art.
[0199] The term "treatment" or "treating" means any treatment of a
disease in a mammal, including: [0200] (i) preventing the disease,
that is, causing the clinical symptoms of the disease not to
develop; [0201] (ii) inhibiting the disease, that is, arresting the
development of clinical symptoms; and/or [0202] (iii) relieving the
disease, that is, causing the regression of clinical symptoms.
[0203] In many cases, the compounds of this invention are capable
of forming acid and/or base salts by virtue of the presence of
amino and/or carboxyl groups or groups similar thereto.
[0204] The term "pharmaceutically acceptable salt" refers to salts
that retain the biological effectiveness and properties of the
compounds of Formula I, and which are not biologically or otherwise
undesirable. Pharmaceutically acceptable base addition salts can be
prepared from inorganic and organic bases. Salts derived from
inorganic bases, include by way of example only, sodium, potassium,
lithium, ammonium, calcium and magnesium salts. Salts derived from
organic bases include, but are not limited to, salts of primary,
secondary and tertiary amines, such as alkyl amines, dialkyl
amines, trialkyl amines, substituted alkyl amines, di(substituted
alkyl) amines, tri(substituted alkyl) amines, alkenyl amines,
dialkenyl amines, trialkenyl amines, substituted alkenyl amines,
di(substituted alkenyl) amines, tri(substituted alkenyl) amines,
cycloalkyl amines, di(cycloalkyl)amines, tri(cycloalkyl) amines,
substituted cycloalkyl amines, disubstituted cycloalkyl amine,
trisubstituted cycloalkyl amines, cycloalkenyl amines,
di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted
cycloalkenyl amines, disubstituted cycloalkenyl amine,
trisubstituted cycloalkenyl amines, aryl amines, diaryl amines,
triaryl amines, heteroaryl amines, diheteroaryl amines,
triheteroaryl amines, heterocyclic amines, diheterocyclic amines,
triheterocyclic amines, mixed di- and tri-amines where at least two
of the substituents on the amine are different and are selected
from the group consisting of alkyl, substituted alkyl, alkenyl,
substituted alkenyl, cycloalkyl, substituted cycloalkyl,
cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl,
heterocyclic, and the like. Also included are amines where the two
or three substituents, together with the amino nitrogen, form a
heterocyclic or heteroaryl group.
[0205] Specific examples of suitable amines include, by way of
example only, isopropylamine, trimethyl amine, diethyl amine,
tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine,
2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine,
caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,
glucosamine, N-alkylglucamines, theobromine, purines, piperazine,
piperidine, morpholine, N-ethylpiperidine, and the like.
[0206] Pharmaceutically acceptable acid addition salts may be
prepared from inorganic and organic acids. Salts derived from
inorganic acids include hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. Salts
derived from organic acids include acetic acid, propionic acid,
glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,
succinic acid, maleic acid, fumaric acid, tartaric acid, citric
acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid,
and the like.
[0207] As used herein, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents and the like. The use of such media and agents for
pharmaceutically active substances is well known in the art. Except
insofar as any conventional media or agent is incompatible with the
active ingredient, its use in the therapeutic compositions is
contemplated. Supplementary active ingredients can also be
incorporated into the compositions.
[0208] "Fatty acid oxidation inhibitors" refers to compounds that
suppress ATP production from the oxidation of fatty acids and
consequently stimulate ATP production from the oxidation of glucose
and lactate. In the heart, most of the ATP production is acquired
through the metabolism of fatty acids. The metabolism of glucose
and lactate provides a lesser proportion of ATP. However, the
generation of ATP from fatty acids is less efficient with respect
to oxygen consumption than the generation of ATP from the oxidation
of glucose and lactate. Thus, the use of fatty acid oxidation
inhibitors results in more energy production per molecule of oxygen
consumed, allowing the heart to be energized more efficiently.
Fatty acid oxidation inhibitors are especially useful, therefore,
for treating an ischemic environment in which oxygen levels are
reduced.
Nomenclature
[0209] The naming and numbering of the compounds of the invention
is illustrated with a representative compound of Formula I in which
where R.sup.9 is 4-chromanyl, R.sup.10 is
2-methylbenzothiazol-5-yl, T is --O--, X is --(CH.sub.2).sub.4--,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and
R.sup.8 are hydrogen, Y is methylene, and Z is oxygen;
##STR00003##
which is named:
(2R)-1-[4-(4-chroman-4-yloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5--
yloxy)propan-2-ol
Synthetic Reaction Parameters
[0210] The terms "solvent," "inert organic solvent" or "inert
solvent" refer to a solvent inert under the conditions of the
reaction being described in conjunction therewith [including, for
example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"),
dimethylformamide ("DMF"), chloroform, methylene chloride (or
dichloromethane), diethyl ether, methanol, pyridine and the like].
Unless specified to the contrary, the solvents used in the
reactions of the present invention are inert organic solvents, and
the reactions are carried out under an inert gas, preferably
nitrogen.
[0211] The term "q.s." means adding a quantity sufficient to
achieve a stated function, e.g., to bring a solution to the desired
volume (i.e., 100%).
Synthesis of the Compounds of Formula I
[0212] The compounds of the invention may be prepared using
conventional and well-known synthetic methods. Typically, the
portion of the molecule containing the central nitrogen heterocycle
is prepared first and then the desired Y-Z-R.sup.9 substituents
added. When T is O, S, or --CO--NH--, or when R.sup.9 and T form an
optionally substituted heterocyclic ring, the addition of the
X-T-R.sup.9 substituents may be accomplished using a simple
substitution reaction. Reaction Scheme I illustrates this general
synthetic pathway when Q is --N<.
##STR00004##
[0213] in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, X, Y, and Z are as
defined in the Summary of the Invention, Hal is halogen, and t-but
is tertiary butyl.
Starting Materials
[0214] The compounds of formula (1), (2), and (4) are either
commercially available or can be made by conventional methods well
known to those of ordinary skill in the art.
[0215] For example, the precursor to a compound of formula (4)
where R.sup.1 and R.sup.5 when taken together represent a bridging
methylene group, i.e.;
##STR00005##
[0216] is commercially available
[(1S,4S)-(+)-2,5-diazabicyclo[2.2.1]heptane], or can be made by a
procedure disclosed in J. Org. Chem., 1990, 55, 1684-7. Similarly,
the precursor to a compound of formula (4) where R.sup.1 and
R.sup.5 when taken together represent a bridging methylene group,
and the precursor to a compound of formula (4) where R.sup.1 and
R.sup.7 when taken together represent a bridging methylene group,
can be made by published procedures found in J. Med. Chem., 1974,
17, 481-7. The precursor to a compound of formula (4) in which
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7
are hydrogen and R.sup.8 is --C(O)NH.sub.2 is prepared from
piperazine-2-carboxamide, a commercially available compound.
Step 1--Preparation of Formula (3)
[0217] The compound of formula (3) is prepared conventionally by
reaction of a compound of formula (1), for example
5-hydroxy-2-methylbenzothiazole, with an epoxide of formula (2),
which may be racemic or chiral. In general, the two compounds are
mixed in an inert solvent, preferably a ketone, for example
acetone, and a tertiary organic base or an inorganic base,
preferably potassium carbonate, at a temperature of about reflux,
for about 8-48 hours, preferably overnight. When the reaction is
substantially complete, the product of formula (3) is isolated by
conventional means, for example by filtration, removal of the
solvent under reduced pressure, followed by chromatography of the
residue on silica gel. Alternatively, the product can be
crystallized from the filtrate after filtration.
Step 2--Preparation of Formula (5)
[0218] The compound of formula (3) is then reacted with a protected
piperazine of formula (4). In general, the two compounds are mixed
in an inert solvent, preferably a halogenated solvent, for example
methylene chloride, optionally in the presence of a catalyst, for
example ytterbium (III) trifluoromethanesulfonate. In the presence
of a catalyst the reaction is conducted at about 0-30.degree. C.,
preferably at about room temperature, for about 8-48 hours,
preferably overnight. In the absence of a catalyst, the mixture is
refluxed for a similar period of time in ethanol in the presence of
triethylamine. When the reaction is substantially complete, the
product of formula (5) is isolated by conventional means, for
example by removal of the solvent under reduced pressure, followed
by chromatography of the residue on silica gel.
Step 3--Preparation of Formula (6)
[0219] The compound of formula (5) is then deprotected by
hydrolyzing the N-Boc protected carbamate. In general, the compound
of formula (5) is dissolved in a mixture of an inert solvent,
preferably a halogenated solvent, for example methylene chloride,
and a strong acid, for example trifluoroacetic acid. The reaction
is conducted at about 0-30.degree. C., preferably at about room
temperature, for about 8-48 hours, preferably overnight. When the
reaction is substantially complete, the product of formula (6) is
isolated by conventional means, for example by adding a base to
remove excess acid, and removal of the solvent under reduced
pressure.
Step 4--Preparation of a Compound of Formula I
[0220] The compound of formula (6) is then reacted with a compound
of formula (7) (R.sup.9-T-X-Hal), for example
(4-bromobutoxy)cyclopentane. Examples of such compounds are
3(4-chlorobutoxy)benzene, 2-bromo-1-(2-methylphenoxy)ethane, or
4-bromo-1-indan-5-yloxybutane, and the like. Such compounds are
either commercially available, prepared by means well known in the
art (see, for example, see J. Med. Chem., 1996, 39, 237-243) or
prepared as shown herein. In general, the two compounds are mixed
in an inert solvent, preferably a protic solvent, for example
ethanol, in the presence of an inorganic or tertiary organic base,
preferably triethylamine. The reaction is conducted at about
30-100.degree. C., preferably at about reflux, for about 8-48
hours, preferably overnight. When the reaction is substantially
complete, the product of Formula I is isolated by conventional
means, for example by removal of the solvent under reduced
pressure, followed by chromatography.
Variations to the Synthesis of the Compounds of Formula I
Alternative Preparation of Formula (6)
[0221] A modified procedure can be used for preparing compounds of
formula (6) in which R.sup.8 is lower alkyl and R.sup.1-R.sup.7 are
hydrogen that avoids the use of a protecting group. An example
where R.sup.8 is methyl is shown in Reaction Scheme IA.
##STR00006##
[0222] The compound of formula (3) is reacted with
2-methylpiperazine. In general, the two compounds are mixed in a
protic solvent, for example ethanol. The reaction is conducted at
about 5-100.degree. C., preferably at about 80.degree. C., for
about 1-12 hours, preferably about 5 hours. When the reaction is
substantially complete, the product of formula (6) is isolated by
conventional means, for example by removal of the solvent under
reduced pressure, followed by chromatography of the residue on
silica gel.
[0223] The compound of formula (6) is then reacted with a compound
of formula (7) as described above in Reaction Scheme I, step 4, to
provide a compound of Formula I in which R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are hydrogen and R.sup.8 is
methyl.
Alternative Preparations Using a Compound of Formula (7a)
[0224] Alternatively, the R.sup.9-T-X moiety may be added to the
central ring prior to addition of the
CH.sub.2--CH(OH)--Y-Z-R.sup.10 substituent. An example where and
R.sup.1-R.sup.3 and R.sup.5-R.sup.8 are hydrogen and R.sup.4 is
methyl is shown in Reaction Scheme IB.
##STR00007##
[0225] The compound of formula (7) is reacted with
2-methylpiperazine. In general, the two compounds are mixed in an
inert solvent, preferably a protic solvent, for example ethanol, in
the presence of an inorganic or tertiary organic base, preferably
triethylamine. The reaction is conducted at about 30-100.degree.
C., preferably at about 80.degree. C., for about 2-12 hours,
preferably about 8 hours. When the reaction is substantially
complete, the product of formula (7a) is isolated by conventional
means, for example by removal of the solvent under reduced
pressure, followed by chromatography.
[0226] The compound of formula (7a) is then reacted with an epoxide
of formula (3) as described in Reaction Scheme I, step 2, to
provide a compound of Formula I in which R.sup.1, R.sup.2, R.sup.3,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen and R.sup.4 is
methyl.
[0227] The compound of formula (7a) may also be synthesized by
using a vinyl derivative of the compound of formula (7). An example
where and R.sup.1-R.sup.3 and R.sup.5-R.sup.8 are hydrogen and
R.sup.4 is methyl is shown in Reaction Scheme IC.
##STR00008##
[0228] The compound of formula (7') is reacted with
2-methylpiperazine. In general, the two compounds are mixed in an
inert solvent, preferably a protic solvent, for example acetic
acid. The reaction is conducted at about 30-100.degree. C.,
preferably at about 50.degree. C., for about 8-24 hours, preferably
about 14 hours. When the reaction is substantially complete, the
product of formula (7a) is isolated by conventional means, for
example by removal of the solvent under reduced pressure, followed
by chromatography.
[0229] Compounds of formula (7') may also be reacted with compounds
having the structure of formula (6) to provide Formula I compounds.
As described above, the two compounds will be mixed in an inert,
protic solvent, such as acetic acid and allowed to react at
30.degree.-100.degree. C. for approximately 8 to 24 hours. The
Formula I compound may then be isolated and purified using
conventional methods.
[0230] It will be appreciated that a protected version of the
central ring may also be used in the synthesis of the compound of
formula (7a). An example where and R.sup.1-R.sup.3 and
R.sup.5-R.sup.8 are hydrogen and R.sup.4 is methyl is shown in
Reaction Scheme ID.
##STR00009##
Reaction Scheme ID
[0231] The compound of formula (7) is reacted with N-Boc protected
2-methylpiperazine according to the procedure described for step 2.
The resulting protected compound, here (7a'), is then deprotected
as done in step 3 to produce the compound of formula (7a).
Alternative Preparations for Compounds wherein Q is
--NH--CH<
Methods Using a Compound of Formula (4a)
[0232] A method similar to the method depicted in Reaction Scheme I
may be employed to prepare compounds of Formula I in which Q is
--NH--CH<, starting from a compound of formula (4a):
##STR00010##
[0233] Compounds of formula (4a), which are optionally substituted
4-aminopiperidines, protected as BOC derivatives, are either
commercially available, or can be made by means well known in the
art. The compound of formula (4a) is then reacted as shown in steps
2, 3, and 4 above, to provide a compound of Formula I in which X is
--NH--CH.
Methods Using a Compound of Formula (4b)
[0234] An additional method that may be employed to prepare
compounds of Formula I in which Q is --NH--CH<, starts from a
compound of formula (4b):
##STR00011##
[0235] Compounds of formula (4b), which are optionally substituted
piperidin-4-ones, usually obtained in the form of an HCl salt, are
either commercially available, or can be made by means well known
in the art. The compound of formula (4b) is reacted with a compound
of formula (3) as shown in step 2 above to provide a compound of
formula (5b):
##STR00012##
[0236] The compound of formula (5b) is then reacted with an amine
derivative of a compound of formula (7), i.e., a compound of
formula (7b) (R.sup.9-T-X--NH.sub.2), for example
(3R)-3-amino-1-(4-chlorophenyl)pyrrolidin-2-one,
(3R)-3-amino-1-(4-fluorophenyl)pyrrolidin-2-one,
(3R)-3-amino-1-(4-methylphenyl)pyrrolidin-2-one, or
(3R)-3-amino-1-(2-chloro-4-fluoro-phenyl)pyrrolidin-2-one, and the
like. Such compounds are either commercially available, prepared by
means well known in the art (see, for example, see J. Med. Chem.,
1996, 39, 237-243) or prepared as shown herein.
[0237] In general, the two compounds are mixed in an inert solvent,
preferably a protic solvent, for example ethanol, in the presence
of an inorganic or tertiary organic base and/or other reducing
agent. One preferred combination of base/reducing agent is a
mixture of diisopropylamine and sodium triacetoxyborohydride. The
reaction is conducted at about 20-30.degree. C., preferably at room
temperature, for about 8-72 hours, preferably for at least two
days. When the reaction is substantially complete, the product of
Formula I is isolated by conventional means, for example by removal
of the solvent under reduced pressure, followed by
chromatography.
Alternative Preparations for Compounds wherein T is
--SO.sub.2--NH-- or --NH--SO.sub.2--
Methods when T is --SO.sub.2--NH--
[0238] When T is --SO.sub.2--NH-- or --NH--SO.sub.2--, the
synthesis will generally be more involved. In instances when T is
--SO.sub.2--NH--, the T moiety will be formed in place with the
innermost amino first bound to the core of the molecule and then
the sulfonyl portion added in a final step. A suitable reaction
pathway is depicted in Reaction Scheme II. It will be noted by
those of ordinary skill in the art that, in Reaction Scheme II, X
cannot be a covalent bond.
##STR00013##
Step 1--Preparation of Formula (9)
[0239] As shown in Reaction Scheme II, a haloalkylphthalimide is
reacted at approximately 80.degree. C. to approximately 100.degree.
C. with a compound of formula (6) in triethylamine for 12 to 24
hours. It should be noted that a compound of formula (6a) could
also be used. The resulting product, a compound of formula (9), may
be concentrated and purified using conventional method.
Step 2--Preparation of Formula (10)
[0240] The compound of formula (9) is placed in a polar solvent
such as methanol and reacted with hydrazine hydrate for 12 to 18
hours. Acid, such as HCl, is added to the solution and the mixture
is heated to approximately 85.degree. C. for one hour. The
application of heat and addition of acid results in the
precipitation of phthalimide residue from solution. The compound of
formula (10) is then purified from the filtrate by first raising
the pH of the filtrate to approximately 14 and then extracting the
compound with a solvent such as Et.sub.2O.
Step 3--Preparation of Formula (11), a Compound of Formula I
[0241] Once the amine compound of formula (10) has been prepared,
the R.sup.9--SO.sub.2 portion of the Formula I compound is added by
simple substitution. A halogenated sulfonyl compound, such as a
sulfonyl chloride, may be used and is typically reacted in a polar
solvent such as dimethoxyethane for 1 to 20 hours at 0.degree. C.
The resulting Formula I compound, here a compound of formula (11),
may then be purified using conventional methods.
Methods when T is --NH--SO.sub.2--
[0242] In instances when T is --NH--SO.sub.2--, a halogen-based
substitution reaction may be used to synthesize the desired
compound. The halogenated precursor may be obtained commercially or
may be conventionally synthesized. A suitable reaction pathway is
depicted in Reaction Scheme III.
##STR00014##
Step 1--Preparation of Formula (13)
[0243] As shown in Reaction Scheme III, an R.sup.9-amine precursor
(11) is reacted with a dihaloalkylsulfonyl compound of formula (12)
in triethylamine and then rinsed with acid. Conventional separation
and purification provides the resulting vinyl substituted R.sup.9
sulfonamide precursor of formula (13).
Step 2--Preparation of a Compound of Formula I
[0244] Once the vinyl substituted R.sup.9 sulfonamide precursor of
formula (13) has been prepared, it may be reacted with compound of
formula (6), or optionally (6a), to provide the desired Formula I
compound. Generally, this reaction takes place in a polar solvent
such as EtOH in the presence of diisopropylethylamine (DIEA). The
resulting Formula I compound, here a compound of formula (14), may
then be purified using conventional methods.
[0245] As before, a different procedure may be used were the
R.sup.9-T-X moiety may be added to the central ring prior to
addition of the CH.sub.2--CH(OH)--Y-Z-R.sup.10 substituent. An
example where R.sup.1-R.sup.3 and R.sup.5-R.sup.8 are hydrogen,
R.sup.4 is methyl, and X is ethylene is shown in Reaction Scheme
IIIA.
##STR00015##
[0246] The compound of formula (13) is reacted with
2-methylpiperazine. In general, the two compounds are mixed in an
inert solvent, preferably a protic solvent, for example ethanol, in
the presence of an inorganic or tertiary organic base, preferably
triethylamine. The reaction is conducted at about 30-100.degree.
C., preferably at about 80.degree. C., for about 2-12 hours,
preferably about 8 hours. When the reaction is substantially
complete, the product of formula (7b) is isolated by conventional
means, for example by removal of the solvent under reduced
pressure, followed by chromatography.
[0247] The compound of formula (7b) is then reacted with an epoxide
of formula (3) as described in Reaction Scheme I, step 2, to
provide a compound of Formula I in which R.sup.1, R.sup.2, R.sup.3,
R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are hydrogen, R.sup.4 is
methyl, and T is --NH--SO.sub.2--.
Utility, Testing and Administration
General Utility
[0248] The compounds of Formula I are effective in the treatment of
conditions known to respond to administration of fatty acid
oxidation inhibitors and/or late sodium channel blockers, including
protection of skeletal muscles against damage resulting from
trauma, intermittent claudication, shock, and cardiovascular
diseases including atrial and ventricular arrhythmias, Prinzmetal's
(variant) angina, stable angina, unstable angina, ischemia and
reperfusion injury in cardiac, kidney, liver and the brain,
exercise induced angina, congestive heart disease, and myocardial
infarction. The compounds of Formula I can also be used to preserve
donor tissue and organs used in transplants, and may be
co-administered with thrombolytics, anticoagulants, and other
agents.
Testing
[0249] Activity testing is conducted as described in those patents
and patent applications referenced above, and in the Examples
below, and by methods apparent to one skilled in the art.
Pharmaceutical Compositions
[0250] The compounds of Formula I are usually administered in the
form of pharmaceutical compositions. This invention therefore
provides pharmaceutical compositions that contain, as the active
ingredient, one or more of the compounds of Formula I, or a
pharmaceutically acceptable salt or ester thereof, and one or more
pharmaceutically acceptable excipients, carriers, including inert
solid diluents and fillers, diluents, including sterile aqueous
solution and various organic solvents, permeation enhancers,
solubilizers and adjuvants. The compounds of Formula I may be
administered alone or in combination with other therapeutic agents.
Such compositions are prepared in a manner well known in the
pharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences,
Mace Publishing Co., Philadelphia, Pa. 17.sup.th Ed. (1985) and
"Modern Pharmaceutics", Marcel Dekker, Inc. 3.sup.rd Ed. (G. S.
Banker & C. T. Rhodes, Eds.).
Administration
[0251] The compounds of Formula I may be administered in either
single or multiple doses by any of the accepted modes of
administration of agents having similar utilities, for example as
described in those patents and patent applications incorporated by
reference, including rectal, buccal, intranasal and transdermal
routes, by intra-arterial injection, intravenously,
intraperitoneally, parenterally, intramuscularly, subcutaneously,
orally, topically, as an inhalant, or via an impregnated or coated
device such as a stent, for example, or an artery-inserted
cylindrical polymer.
[0252] One mode for administration is parental, particularly by
injection. The forms in which the novel compositions of the present
invention may be incorporated for administration by injection
include aqueous or oil suspensions, or emulsions, with sesame oil,
corn oil, cottonseed oil, or peanut oil, as well as elixirs,
mannitol, dextrose, or a sterile aqueous solution, and similar
pharmaceutical vehicles. Aqueous solutions in saline are also
conventionally used for injection, but less preferred in the
context of the present invention. Ethanol, glycerol, propylene
glycol, liquid polyethylene glycol, and the like (and suitable
mixtures thereof), cyclodextrin derivatives, and vegetable oils may
also be employed. The proper fluidity can be maintained, for
example, by the use of a coating, such as lecithin, by the
maintenance of the required particle size in the case of dispersion
and by the use of surfactants. The prevention of the action of
microorganisms can be brought about by various antibacterial and
antifungal agents, for example, parabens, chlorobutanol, phenol,
sorbic acid, thimerosal, and the like.
[0253] Sterile injectable solutions are prepared by incorporating
the compound of Formula I in the required amount in the appropriate
solvent with various other ingredients as enumerated above, as
required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilized
active ingredients into a sterile vehicle which contains the basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are vacuum-drying and freeze-drying techniques which
yield a powder of the active ingredient plus any additional desired
ingredient from a previously sterile-filtered solution thereof.
[0254] Compounds of Formula I may be impregnated into a stent by
diffusion, for example, or coated onto the stent such as in a gel
form, for example, using procedures known to one of skill in the
art in light of the present disclosure.
[0255] Oral administration is another route for administration of
the compounds of Formula I. Administration may be via capsule or
enteric coated tablets, or the like. In making the pharmaceutical
compositions that include at least one compound of Formula I, the
active ingredient is usually diluted by an excipient and/or
enclosed within such a carrier that can be in the form of a
capsule, sachet, paper or other container. When the excipient
serves as a diluent, it can be in the form of a solid, semi-solid,
or liquid material (as above), which acts as a vehicle, carrier or
medium for the active ingredient. Thus, the compositions can be in
the form of tablets, pills, powders, lozenges, sachets, cachets,
elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a
solid or in a liquid medium), ointments containing, for example, up
to 10% by weight of the active compound, soft and hard gelatin
capsules, sterile injectable solutions, and sterile packaged
powders.
[0256] Some examples of suitable excipients include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,
calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, sterile water, syrup, and methyl cellulose. The
formulations can additionally include: lubricating agents such as
talc, magnesium stearate, and mineral oil; wetting agents;
emulsifying and suspending agents; preserving agents such as
methyl- and propylhydroxy-benzoates; sweetening agents; and
flavoring agents.
[0257] The compositions of the invention can be formulated so as to
provide quick, sustained or delayed release of the active
ingredient after administration to the patient by employing
procedures known in the art. Controlled release drug delivery
systems for oral administration include osmotic pump systems and
dissolutional systems containing polymer-coated reservoirs or
drug-polymer matrix formulations. Examples of controlled release
systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;
4,902,514; and 5,616,345. Another formulation for use in the
methods of the present invention employs transdermal delivery
devices ("patches"). Such transdermal patches may be used to
provide continuous or discontinuous infusion of the compounds of
the present invention in controlled amounts. The construction and
use of transdermal patches for the delivery of pharmaceutical
agents is well known in the art. See, e.g., U.S. Pat. Nos.
5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed
for continuous, pulsatile, or on demand delivery of pharmaceutical
agents.
[0258] The compositions are preferably formulated in a unit dosage
form. The term "unit dosage forms" refers to physically discrete
units suitable as unitary dosages for human subjects and other
mammals, each unit containing a predetermined quantity of active
material calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical excipient (e.g., a
tablet, capsule, ampoule). The compounds of Formula I are effective
over a wide dosage range and are generally administered in a
pharmaceutically effective amount. Preferably, for oral
administration, each dosage unit contains from 1 mg to 2 g of a
compound of Formula I, and for parenteral administration,
preferably from 0.1 to 700 mg of a compound of Formula I. It will
be understood, however, that the amount of the compound of Formula
I actually administered will be determined by a physician, in the
light of the relevant circumstances, including the condition to be
treated, the chosen route of administration, the actual compound
administered and its relative activity, the age, weight, and
response of the individual patient, the severity of the patient's
symptoms, and the like.
[0259] For preparing solid compositions such as tablets, the
principal active ingredient is mixed with a pharmaceutical
excipient to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention. When
referring to these preformulation compositions as homogeneous, it
is meant that the active ingredient is dispersed evenly throughout
the composition so that the composition may be readily subdivided
into equally effective unit dosage forms such as tablets, pills and
capsules.
[0260] The tablets or pills of the present invention may be coated
or otherwise compounded to provide a dosage form affording the
advantage of prolonged action, or to protect from the acid
conditions of the stomach. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer that serves to
resist disintegration in the stomach and permit the inner component
to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or
coatings, such materials including a number of polymeric acids and
mixtures of polymeric acids with such materials as shellac, cetyl
alcohol, and cellulose acetate.
[0261] Compositions for inhalation or insufflation include
solutions and suspensions in pharmaceutically acceptable, aqueous
or organic solvents, or mixtures thereof, and powders. The liquid
or solid compositions may contain suitable pharmaceutically
acceptable excipients as described supra. Preferably, the
compositions are administered by the oral or nasal respiratory
route for local or systemic effect. Compositions in preferably
pharmaceutically acceptable solvents may be nebulized by use of
inert gases. Nebulized solutions may be inhaled directly from the
nebulizing device or the nebulizing device may be attached to a
facemask tent, or intermittent positive pressure breathing machine.
Solution, suspension, or powder compositions may be administered,
preferably orally or nasally, from devices that deliver the
formulation in an appropriate manner.
[0262] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventor to
function well in the practice of the invention, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention.
EXAMPLE 1
Preparation of a Compound of Formula (3)
Preparation of a Compound of Formula (3) in which R.sup.10 is
2-Methylbenzothiazol-5-yl, Y is Methylene, and Z is Oxygen
##STR00016##
[0264] A mixture of 2-methylbenzothiazol-5-ol (6.0 g, 36 mmol),
(S)-(+)-epichlorohydrin (20 ml, 182 mmol), and potassium carbonate
(20 g, 144 mmol) in acetone (100 ml), was heated to reflux and
allowed to stir overnight. The solution was allowed to cool and
filtered through Celite 512. The filtrate was evaporated under
reduced pressure to yield an oil, which was chromatographed on
silica gel, eluting with 20% ethyl acetate/hexanes, to yield
2-methyl-5-(R)-(oxiran-2-ylmethoxy)benzothiazole as white
solid.
EXAMPLE 2
Preparation of a Compound of Formula (5)
A. Preparation of a Compound of Formula (5) in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 are
Hydrogen, Y is Methylene, Z is --O--, and R.sup.10 is
2-Methylbenzothiazol-5-yl
##STR00017##
[0266] To 2-methyl-5-(oxiran-2-ylmethoxy)benzothiazole (2.21 g, 10
mmol), a compound of formula (3), was added tert-butyl
1-piperazinecarboxylate (1.86 g, 10 mmol), a compound of formula
(4), and ethanol (30 ml). The resulting solution was heated to
85.degree. C. and stirred for 8 hours. The solvent was evaporated
under reduced pressure, and the residue was chromatographed on
silica gel, eluting with 5% methanol/methylene chloride, to yield
tert-butyl
4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarbox-
ylate as a clear oil.
B. Preparation of a Compound of Formula (5) in which R.sup.1,
R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8 are Hydrogen,
R.sup.4 is (S)-Methyl, Y is Methylene, Z is --O--, and R.sup.10 is
2S-Methylbenzothiazol-5-yl
##STR00018##
[0268] Similarly, following the procedure of Example 1A above, but
replacing tert-butyl 1-piperazinecarboxylate with tert-butyl
(3S)-3-methylpiperazinecarboxylate, the following compound of
formula (5) was prepared, tert-butyl
4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](3S)-3-methylpip-
erazinecarboxylate.
C. Preparation of a Compound of Formula (5a) in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 are
Hydrogen, Y is Methylene, Z is --O--, and R.sup.10 is 2
Methoxyphenyl
##STR00019##
[0270] A solution of 2-methoxy-1-(oxiran-2-ylmethoxy)benzene (0.989
g, 1.1 mmol) and N--BOC-4-aminopiperidine (1 g, 5 mmol) in ethanol
(10 ml) was refluxed for 2 hours. The solvent was then removed
under reduced pressure, and the residue flash chromatographed,
eluting with 0-5% methanol/dichloromethane, to provide
N-{1-[(2R)-2-hydroxy-3-(2-methoxyphenoxy)propyl](4-piperidyl)}(tert-butox-
y)carboxamide, a compound of formula (5a).
D. Preparation of Compounds of Formula (5) and (5a), varying
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, R.sup.10, Y, and Z
[0271] Similarly, following the procedure of Example 2A or 2C
above, but optionally replacing tert-butyl 1-piperazinecarboxylate
with other compounds of formula (4), or optionally replacing
N--BOC-4-aminopiperidine with other compounds of formula (4a), and
optionally replacing 2-methyl-5-(oxiran-2-ylmethoxy)benzothiazole
with other compounds of formula (3), or optionally replacing
2-methoxy-1-(oxiran-2-ylmethoxy)benzene with other compounds of
formula (3a), other compounds of formula (5) and (5a) are
prepared.
EXAMPLE 3
Preparation of a Compound of Formula (6)
A. Preparation of a Compound of Formula (6) in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8 are
Hydrogen, Y is Methylene, Z is --O--, and R.sup.10 is
2-Methylbenzothiazol-5-yl
##STR00020##
[0273] A solution of
4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxy-
lic acid tert-butyl ester (2.9 g, 7.1 mmol), a compound of formula
(5), was dissolved in a 4N solution of HCl in dioxane (20 ml) and
allowed to stir at room temperature for 4 hours. The solvent was
evaporated under reduced pressure to yield a white solid. The white
solid was dried under high vacuum, and then dissolved in methanol
(250 ml). AG 1-X8 resin was added and the mixture shaken.
Additional resin was added until a neutral pH was obtained. The
resin beads were removed by filtration, and methanol removed from
the filtrate under reduced pressure, and the residue placed under
high vacuum overnight, to yield
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol as
an oil.
B. Preparation of a Compound of Formula (6) in which R.sup.1,
R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, R.sup.8 are Hydrogen,
R.sup.4 is (S)-Methyl, Y is Methylene, Z is --O--, and R.sup.10 is
2-Methylbenzothiazol-5-yl
##STR00021##
[0275] Similarly, following the procedure of Example 3A above, but
replacing
4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-
-1-carboxylic acid tert-butyl ester with tert-butyl
(3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-3-methylpi-
perazinecarboxylate, the following compound of formula (6), (6'),
was prepared,
(2R)-1-((2S)-2-methylpiperazinyl)-3-(2-methylbenzothiazol-5-ylo-
xy)propan-2-ol.
C. Preparation of a Compound of Formula (6a) in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6R.sup.7, R.sup.8 are
Hydrogen, Y is Methylene, Z is --O--, and R.sup.10 is 2
Methoxyphenyl
##STR00022##
[0277] Similarly, following the procedure of Example 3A above, but
replacing
4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-
-1-carboxylic acid tert-butyl ester with
(tert-butoxy)-N-{1-[2-hydroxy-3-(2-methoxyphenoxy)propyl](4-piperidyl)}ca-
rboxamide, the following compound of formula (6) was prepared,
(2R)-1-(4-aminopiperidyl)-3-(2-methoxyphenoxy)propan-2-ol.
D. Preparation of a Compound of Formula (6), varying R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.10, Y, and Z
[0278] Similarly, following the procedure of Example 3A or 3C
above, but replacing 2-methyl-5-(oxiran-2-ylmethoxy)benzothiazole
with other compounds of formula (5) or (5a), other compounds of
formula (6) or (6a) are prepared.
EXAMPLE 4
A. Preparation of a Compound of Formula I in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are Hydrogen, Q is --N<, X is Butylene, Y is Methylene, T and Z
are --O--, R.sup.9 is Cyclopentyl, and R.sup.10 is
2-Methylbenzothiazol-5-yl
Step 1. Synthesis of a Compound of Formula (7)
##STR00023##
[0280] NaH (560 mg, 13.93 mmol, 60% disp. in mineral oil) was
washed with hexanes (3.times.20 mL) in a pressure tube and toluene
(6 mL,) was added. The solution was cooled to 0.degree. C. and
cyclopentanol (1 g, 11.61 mmol) in toluene (6 mL) was added over 20
min. After stirring at 0.degree. C. for 30 min., 1,4-dibromobutane
(1.39 mL, 11.61 mmol) and KI (250 mg) were added. The solution was
heated to 100.degree. C. for 14 hours. Upon cooling, the reaction
was quenched with NaCl (sat. aq.) and the product extracted with
EtOAc. The organic layer was dried over MgSO.sub.4, filtered, and
concentrated. Purification of the residue via flash column
chromatography afforded (4-bromobutoxy)cyclopentane.
Step 2. Synthesis of the Formula I Compound
##STR00024##
[0282] A solution of (4-bromobutoxy)cyclopentane (400 mg, 1.81
mmol) in EtOH (5 mL) was treated with DIEA (0.64 mL, 3.62 mmol) and
1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as
prepared in Example 3A (557 mg, 1.81 mmol). The solution was
stirred at reflux 15 hours. Upon cooling, the product was
concentrated and purified by flash column chromatography (10%
MeOH/EtOAc) to yield
(2R)-3-[4-(4-cyclopentyloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-y-
loxy)propan-2-ol.
B. Preparation of Other Compounds of Formula I
[0283] Similarly, following the procedure of Example 4A above, but
optionally substituting (4-bromobutoxy)cyclopentane with other
R.sup.9--O--X-Hal ethers, and optionally replacing
1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol with
other compounds of formula (6) or (6a), the following compounds of
Formula I were prepared: [0284]
(2R)-1-[4-(4-indan-2-yloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yl-
oxy)propan-2-ol; [0285]
(2R)-1-[4-(4-cyclohexyloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-yl-
oxy)propan-2-ol; [0286]
(2R)-1-[4-(4-cyclobutoxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-ylox-
y)propan-2-ol; [0287]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[4-(trifluoromethyl)cyclohe-
xyloxy]butyl}piperazinyl)propan-2-ol; [0288]
(2R)-1-(4-{4-[4-(tert-butyl)cyclohexyloxy]butyl}piperazinyl)-3-(2-methylb-
enzothiazol-5-yloxy)propan-2-ol; [0289]
(2R)-1-[4-(4-cyclopentyloxybutyl)piperazinyl]-3-(2-methylbenzothiazol-5-y-
loxy)propan-2-ol; [0290]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-{4-[4-(1,7,7-trimethylbicyclo[2.2-
.1]hept-2-yloxy)butyl]piperazinyl}propan-2-ol; [0291]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-(1,2,3,4-tetrahydronaphthyl-
oxy)butyl)piperazinyl]propan-2-ol; [0292]
(2R)-1-{4-[4-(1-methoxyindan-2-yloxy)butyl]piperazinyl}-3-(2-methylbenzot-
hiazol-5-yloxy)propan-2-ol; and [0293]
(2R)-1-[4-(4-(2H-3,4,5,6-tetrahydropyran-4-yloxy)butyl)piperazinyl]-3-(2--
methylbenzothiazol-5-yloxy)propan-2-ol.
EXAMPLE 5
A. Preparation of a Compound of Formula I in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are Hydrogen, Q is --N<, X is Butylene, Y is Methylene, T and Z
are --O--, R.sup.9 is Phenyl, and R.sup.10 is
2-Methylbenzothiazol-5-yl
##STR00025##
[0295] (4-Chlorobutoxy)benzene (320 mg, 1.39 mmol) in EtOH (17 Ml)
was treated with DIEA (0.48 Ml, 2.78 mmol) and
1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as
prepared in Example 3A (427 mg, 1.39 mmol), then stirred 14 hours
at 88.degree. C. Upon cooling, concentrated in vacuo and purified
on the Isco.TM. (10 g Redisep.TM. columns, 100% EtOAc hold 2 min.,
8 min. gradient to 20% MeOH/EtOAc, hold 10 min) to provide
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-phenoxybutyl)piperazinyl]pr-
opan-2-ol.
B. Preparation of Other Compounds of Formula I
[0296] Similarly, following the procedure of Example 5A above, but
optionally substituting (4-chlorobutoxy)benzene with other
R.sup.9--O--X-Hal ethers, and optionally replacing
1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol with
other compounds of formula (6) or (6a), the following compounds of
Formula I were prepared: [0297]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(3-phenoxypropyl)piperazinyl]p-
ropan-2-ol; [0298]
(2R)-1-{4-[2-(4-fluorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol; [0299]
(2R)-1-{4-[3-(4-fluorophenoxy)propyl]piperazinyl}-3-(2-methylbenzothiazol-
-5-yloxy)propan-2-ol; [0300]
(2R)-1-{4-[2-(4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol; [0301]
(2R)-1-{4-[2-(phenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-5-yloxy)-
propan-2-ol; and [0302]
(2R)-1-{4-[4-(4-chlorophenoxy)butyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol.
EXAMPLE 6
A. Preparation of a Compound of Formula I in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are Hydrogen, Q is --N<, X is Ethylene, Y is Methylene, T and Z
are --O--, R.sup.9 is 2-Methylphenyl, and R.sup.10 is
2-Methylbenzothiazol-5-yl
Step 1. Synthesis of a Compound of Formula (7)
##STR00026##
[0304] 2-Methyl-phenol (1 g, 9.25 mmol) in NaOH (aq) (3.24 mL,
12.96 mmol, 4M soln.) was treated with dibromoethane (2.74 mL, 31.7
mmol) and t-butylammoniumhydrogen sulfate (catalytic), and then
placed in a Robbins.TM. oven at 99.degree. C. for 72 hours. The pH
was then adjusted to .about.8 with NaOH (4M aq. soln.) and the
product extracted with CH.sub.2Cl.sub.2 (.times.3). The combined
organic layer was washed with H.sub.2O (.times.2) and brine, dried
over MgSO.sub.4. The resulting oil taken up in 4:1 hexane/EtOAc and
passed through a plug of silica gel. The plug was then washed with
4:1 hexane/EtOAc and the filtrate concentrated to provide crude
2-bromo-1-(2-methylphenoxy)ethane.
Step 2. Synthesis of the Formula I Compound
##STR00027##
[0306] To a solution of 2-bromo-1-(2-methylphenoxy)ethane (1.09 g,
5.09 mmol, crude) in EtOH (15 mL) was added
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol as
prepared in Example 3A (250 mg, 0.81 mmol) and DIEA (1.5 mL, 8.6
mmol). The solution was stirred at reflux for 14 hours. Upon
cooling, the solution was concentrated to an oil and then purified
on an Isco.TM. (100% EtOAc hold 2 min, 8 min. gradient to 20%
MeOH/EtOAc, hold 10 min) to afford
(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-{4-[2-(2-methylphenoxy)-
ethyl]piperazinyl}propan-2-ol.
B. Preparation of Other Compounds of Formula I
[0307] Similarly, following the procedure of Example 6A above, but
optionally replacing (2-bromo-1-(2-methylphenoxy)ethane with other
R.sup.9--O--X-Hal ethers, and optionally replacing
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol with
other compounds of formula (6) or (6a), the following compounds of
Formula I were prepared: [0308]
(2R)-1-{4-[2-(4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol; [0309]
(2R)-1-{4-[2-(4-trifluoromethoxyphenoxy)ethyl]piperazinyl}-3-(2-methylben-
zothiazol-5-yloxy)propan-2-ol; [0310]
(2R)-1-{4-[2-(2-methoxy-4-chlorophenoxy)ethyl]piperazinyl}-3-(2-methylben-
zothiazol-5-yloxy)propan-2-ol; [0311]
(2R)-1-{4-[2-(3-chloro-4-fluorophenoxy)ethyl]piperazinyl}-3-(2-methylbenz-
othiazol-5-yloxy)propan-2-ol; [0312]
(2R)-1-{4-[2-(4-phenylphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol--
5-yloxy)propan-2-ol; [0313]
(2R)-1-{4-[2-(2-methoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-
-5-yloxy)propan-2-ol; [0314]
(2R)-1-{4-[2-(4-trifluoromethylphenoxy)ethyl]piperazinyl}-3-(2-methylbenz-
othiazol-5-yloxy)propan-2-ol; [0315]
(2R)-1-{4-[2-(3,5-dichlorophenoxy)ethyl]piperazinyl}-3-(2-methylbenzothia-
zol-5-yloxy)propan-2-ol; [0316]
(2R)-1-{4-[2-(3-chloro-4-bromophenoxy)ethyl]piperazinyl}-3-(2-methylbenzo-
thiazol-5-yloxy)propan-2-ol; [0317]
(2R)-1-{4-[2-(4-methoxyphenoxy)ethyl]piperazinyl}-3-(2-methylbenzothiazol-
-5-yloxy)propan-2-ol; [0318]
(2R)-1-{4-[2-(3,5-bis(trifluoromethyl)phenoxy)ethyl]piperazinyl}-3-(2-met-
hylbenzothiazol-5-yloxy)propan-2-ol; [0319]
(2R)-1-{4-[3-(4-trifluoromethylphenoxy)propyl]piperazinyl}-3-(2-methylben-
zothiazol-5-yloxy)propan-2-ol; [0320]
(2R)-1-{4-[4-(4-trifluoromethylphenoxy)butyl]piperazinyl}-3-(2-methylbenz-
othiazol-5-yloxy)propan-2-ol; [0321]
2-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenoxy]acetic acid; [0322]
2-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenoxy]-2-methylpropanoic acid; and [0323]
3-[4-(4-{4-[2-(2R)-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenyl]propanoic acid.
EXAMPLE 7
A. Preparation of a Compound of Formula I in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are Hydrogen, Q is --N<, X is Butylene, Y is Methylene, T and Z
are --O--, R.sup.9 is Indane-5-yl, and R.sup.10 is
2-Methylbenzothiazol-5-yl
Step 1. Synthesis of a Compound of Formula (7)
##STR00028##
[0325] 5-Indanol (1 g, 7.45 mmol) in NaOH (aq) (5.22 mL, 20.88
mmol, 4 M soln.) was treated with dibromobutane (3.38 mL, 28.3
mmol) and t-butylammoniumhydrogensulfate (catalytic). The solution
was placed in a Robbins.TM. oven for 14 hours at 99.degree. C. Upon
cooling, the pH was adjusted to 8 with 4 N NaOH. CH.sub.2Cl.sub.2
was then added and the solution washed with H.sub.2O (.times.2) and
brine. The organic layer was dried over MgSO.sub.4 and concentrated
to an oil. The oil was then dissolved in 4:1 hexane/EtOAc and
passed through a plug of silica gel which was then washed with 4:1
hexane/EtOAc. The filtrate was concentrated to afford
4-bromo-1-indan-5-yloxybutane.
Step 2. Synthesis of the Formula I Compound
##STR00029##
[0327] A solution of 4-bromo-1-indan-5-yloxybutane (934 mg, 3.46
mmol, crude) in EtOH (10 mL) was treated with
(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol as
prepared in Example 3A (250 mg, 0.81 mmol) and DIEA (0.57 mL, 3.3
mmol) and refluxed for 14 hours. Upon cooling to RT, the solution
was then concentrated under reduced pressure and purified via an
Isco.TM. (100% EtOAc 4 min, 10 min gradient to 25% MeOH/EtOAc, hold
6 min.) to afford
(2R)-3-[4-(4-indan-5-yloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yl-
oxy)propan-2-ol.
B. Preparation of Other Compounds of Formula I
[0328] Similarly, following the procedure of Example 7A above, but
optionally replacing 4-bromo-1-indan-5-yloxybutane ethane with
other R.sup.9--O--X-Hal ethers, and optionally replacing
1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol with
other compounds of formula (6) or (6a), the following compounds of
Formula I were prepared: [0329]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-[4-(4-(2-5,6,7,8-tetrahydronaphth-
yloxy)butyl)piperazinyl]propan-2-ol; [0330]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{4-[1-methyl-5-(trifluoromethy-
l)pyrazol-3-yloxy]butyl}piperazinyl)propan-2-ol; [0331]
6-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaziny-
l}butoxy)-2,3a,7a-trihydrobenzo[2,1-b]furan-3-one; [0332] ethyl
2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenyl]acetate; [0333] ethyl
3-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenyl]propanoate; [0334] ethyl
2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenoxy]acetate; [0335] ethyl
2-[4-(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaz-
inyl}butoxy)phenoxy]-2-methylpropanoate; and [0336]
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-(4-{6-[4-(trifluoromethyl)phenoxy-
]hexyl}piperazinyl)propan-2-ol.
EXAMPLE 8
A. Preparation of a Compound of Formula I in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are Hydrogen, Q is --N<, X is a Covalent Bond, Y is Methylene, Z
is --O--, T and R.sup.9 are joined to form
1-Phenyl-2-pyrrolidinone, and R.sup.10 is
2-Methylbenzothiazol-5-yl
Step 1. Synthesis of a Compound of Formula (7)
##STR00030##
[0338] 1-Phenyl-2-pyrrolidinone (1 g, 6.2 mmol) in THF (60 mL,
anhydrous) was cooled to -40.degree. C. and LiHMDS (8 mL, 8 mmol, 1
M soln. in THF) was added. The resulting solution was stirred for
40 min. and tosyl chloride (1.78 g, 9.33 mmol) was then added.
After warming the solution to RT over a 14 hour period, H.sub.2O
added to quench reaction. The solution was then concentrated to
provide an oil. Next, the oil was redissolved in EtOAc and washed
with H.sub.2O and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to an oil once again.
Purified via flash column chromatography (4:1 hexane/EtOAc)
provided 3-chloro-1-phenylpyrrolidin-2-one.
Step 2. Synthesis of the Formula I Compound
##STR00031##
[0340] To a solution of 3-chloro-1-phenylpyrrolidin-2-one (100 mg,
0.51 mmol) in EtOH (10 mL) was added
1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol as
prepared in Example 3A (190 mg, 0.62 mmol) and Et.sub.3N (0.2 mL,
1.43 mmol). The solution was stirred at 85.degree. C. for 60 hours.
Upon cooling, the solution was concentrated to an oil and purified
via flash column chromatography to afford
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-phenylpyrrolidin-2-one.
EXAMPLE 9
A. Preparation of a Compound of Formula I in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are Hydrogen, Q is --N<, X is a Covalent Bond, Y is Methylene, Z
is --O--, T and R.sup.9 are joined to form
1-(4-Chlorophenyl)1-2-pyrrolidinone-4-yl, and R.sup.10 is
2-Methylbenzothiazol-5-yl
Step 1. Synthesis of a Compound of Formula (7)
##STR00032##
[0342] 4-Fluoroaniline (0.7 ml, 7.6 mmol) was added to
2-methylenebutanedioic acid (1.0 g, 7.6 mmol) in a sealed tube. The
mixture was heated to 110 degrees for 3 hours after which a
precipitate formed. The reaction was filtered and the solid was
dissolved in ethyl acetate and concentrated to yield
1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (M+1=223.8).
The product was taken to next step without determining mass.
##STR00033##
[0343] 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid
(unknown amount) was dissolved in 20 ml ethanol and cooled to
0.degree. C. HCl gas was bubbled into the solution until the
solution became red in color. The reaction was allowed to warm to
room temperature and stir overnight. The solvent was removed to
yield ethyl 1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate
(M+1=251.93).
##STR00034##
[0344] To a solution of ethyl
1-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (0.25 g, 1.0
mmol) in ethanol (10 ml) was added lithium chloride (0.085 g, 2.0
mmol) and sodium borohydride (0.080 g, 2.0 mmol). The reaction was
stirred 24 hours at room temperature. The solvent was removed and
30 ml water was added to the residue. The aqueous solution was
acidified with conc. HCl until the pH was 2-3. The acidic solution
was extracted with EtOAc (3.times.75 ml). The organic layer was
then washed with water (100 ml), dried with sodium sulfate and
evaporated. The residue was purified using preparative TLC (15:1
DCM:MeOH) to yield
1-(4-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-2-one (H HNMR). This
was repeated twice.
##STR00035##
[0345] To a cooled solution of
1-(4-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-2-one (0.05 g, 0.25
mmol) in pyridine (3 ml) was added triphenylphosphine (0.130 g, 0.5
mmol). The solution was stirred and carbon tetrabromide (0.08 g,
0.25 mmol) was added in 3 separate portions. The reaction mixture
was then allowed to warm to room temperature and stirred for three
hours. The reaction was quenched with methanol and the solvent
removed. The residue was dissolved in EtOAc (75 ml) and
sequentially washed with ammonium chloride (sat, 2.times.25 ml) and
water (25 ml). The organic layer was concentrated and purified
using preparative tlc (1:1 EtOac:Hexanes) to yield
4-(bromomethyl)-1-(4-fluorophenyl)pyrrolidin-2-one (HNMR).
Step 2. Synthesis of the Formula I Compound
##STR00036##
[0347] A solution of
4-(bromomethyl)-1-(4-fluorophenyl)pyrrolidin-2-one (0.04 g, 0.15
mmol),
(2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol
2.times.HCl (0.09 g, 0.24 mmol), and potassium carbonate (0.150 g,
1.15 mmol) in N,N' dimethylformamide (2 ml) was heated to
70.degree. C. for 16 hours. The solution was filtered and the
filtrate concentrated. The residue was purified using preparative
chromatography (15:1 DCM:MeOH) to yield
4-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]pipera-
zinyl}methyl)-1-(4-fluorophenyl)pyrrolidin-2-one (M+1=498.99).
B. Preparation of Other Compounds of Formula I
[0348] Similarly, following the procedure of Example 8A or 8B
above, but optionally replacing the formula (7) compound with other
R.sup.9-T-X-Hal compounds, and optionally replacing
1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol with
other compounds of formula (6) or (6a), the following compounds of
Formula I were prepared: [0349]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one; [0350]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one; [0351]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-(4-methylphenyl)pyrrolidin-2-one; [0352]
1-(3-fluorophenyl)-3-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl-
]piperazinyl}azolidine-2,5-dione; [0353]
1-[4-(tert-butyl)phenyl]-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-y-
loxy)propyl]piperazinyl}azolidine-2,5-dione; [0354]
1-benzoxazol-2-yl-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)pr-
opyl]piperazinyl}azolidine-2,5-dione; [0355]
1-(4-bromophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)pr-
opyl]piperazinyl}azolidine-2,5-dione; [0356]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
[3-(trifluoromethyl)phenyl]azolidine-2,5-dione; [0357]
1-(4-chlorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)p-
ropyl]piperazinyl}azolidine-2,5-dione; [0358]
1-(2-chlorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)p-
ropyl]piperazinyl}azolidine-2,5-dione; [0359]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
[4-(trifluoromethyl)phenyl]azolidine-2,5-dione; [0360]
1-(4-fluorophenyl)-3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)p-
ropyl]piperazinyl}azolidine-2,5-dione; [0361]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-[4-(trifluoromethoxy)phenyl]azolidine-2,5-dione; [0362]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-(4-vinylphenyl)azolidine-2,5-dione; [0363]
3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}--
1-phenylazolidine-2,5-dione; and [0364]
4-[(4-{(2R)-3-[2-(2-chlorophenyl)benzoxazol-5-yloxy]-2-hydroxypropyl}pipe-
razinyl)methyl]-1-(4-fluorophenyl)pyrrolidin-2-one.
EXAMPLE 10
Preparation of a Compound of Formula I in which R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
Hydrogen, Q is --N<, X is Ethylene, Y is Methylene, T is
--SO.sub.2--NH--, Z is --O--, R.sup.9 is Indane-5-yl, and R.sup.10
is 2-Methylbenzothiazol-5-yl
Step 1. Synthesis of a Compound of Formula (9)
##STR00037##
[0366] To a solution of
(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol
(500 mg, 1.63 mmol) in EtOH (25 mL) was added N-(2-bromoethyl)
phthalimide (435 mg, 1.71 mmol) and Et.sub.3N (0.79 mL, 5.7 mmol).
The reacting solution was shaken at 90.degree. C. for 16 hours.
Upon cooling, the solution was concentrated to an oil and purified
via flash column chromatography (4:1 EtOAc/MeOH) to afford
2-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaziny-
l}ethyl)benzo[c]azolidine-1,3-dione.
Step 2. Synthesis of a Compound of Formula (10)
##STR00038##
[0368] A solution of
2-(2-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}eth-
yl)benzo[c]azoline-1,3-dione (101 mg, 0.21 mmol) in MeOH (0.84 mL)
was treated with hydrazine hydrate (0.07 mL) and stirred at RT for
14 hours. HCl (1 mL, conc) was added and the solution was heated to
88.degree. C. for 14 hours. Upon cooling, the resulting solid was
filtered off and washed with H.sub.2O and EtOAc. The filtrate was
pH adjusted to >12 (NaOH) and extracted with EtOAc. The combined
organic layers were then concentrated to afford
(2R)-1-[4-(2-aminoethyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)prop-
an-2-ol as an oil.
Step 3. Synthesis of the Formula I Compound
##STR00039##
[0370] A solution of
1-[4-(2-aminoethyl)piperazinyl]-3-(2-methylbenzothiazol-5-yloxy)propan-2--
ol (60 mg, 0.171 mmol) in DME (6 mL) was cooled to 0.degree. C. and
benzene sulfonyl chloride (0.022 mL, 0.172 mmol) was added. The
solution was stirred at 0.degree. C. for 5 min and then at RT for
10 min. The reaction mixture was concentrated to an oil and
purified via flash column chromatography (9:1 CHCl.sub.3/MeOH) to
afford
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) (phenylsulfonyl)amine.
B. Preparation of Other Compounds of Formula I
[0371] Similarly, following the procedure of Example 10A above, but
optionally replacing benzene sulfonyl chloride with other
R.sup.9SO.sub.2--Hal compounds, and optionally replacing
(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol
with other compounds of formula (6) or (6a), the following
compounds of Formula I were prepared: [0372]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) [(4-methylphenyl)sulfonyl]amine; [0373]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(4-trifluoromethyl)phenylsulfonyl]amine; [0374]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) [4-chlorophenylsulfonyl]amine; [0375]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) [(4-trifluoromethoxy)phenylsulfonyl]amine; [0376]
(3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
propyl) [(4-trifluoromethyl)phenylsulfonyl]amine; [0377]
(4-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
butyl) [(4-trifluoromethyl)phenylsulfonyl]amine; [0378]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(3-trifluoromethyl)phenylsulfonyl]amine; [0379]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(2,5-dimethyl)phenylsulfonyl]amine; [0380]
{[5-(dimethylamino)naphthyl]sulfonyl}(2-{4-[(2R)-2-hydroxy-3-(2-methylben-
zothiazol-5-yloxy)propyl]piperazinyl}ethyl)amine; [0381]
[(3,4-dimethoxyphenyl)sulfonyl](2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothia-
zol-5-yloxy)propyl]piperazinyl}ethyl)amine; [0382]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl) [(3-methylphenyl)sulfonyl]amine; [0383]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(2,3,5,6-tetramethylphenyl)sulfonyl]amine; [0384]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(2,3,4,5,6-pentafluorophenyl)sulfonyl]amine; [0385]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)[(2,4,6-trimethylphenyl)sulfonyl]amine; [0386]
(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
ethyl)(naphthylsulfonyl)amine; [0387]
{[4-(1,1-dimethylpropyl)phenyl]sulfonyl}(2-{4-[2-hydroxy-3-(2-methylbenzo-
thiazol-5-yloxy)propyl]piperazinyl}ethyl)amine; [0388]
[(4-ethylphenyl)sulfonyl](2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5--
yloxy)propyl]piperazinyl}ethyl)amine; and [0389]
{[4-(tert-butyl)phenyl]sulfonyl}(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothi-
azol-5-yloxy)propyl]piperazinyl}ethyl)amine.
EXAMPLE 11
A. Preparation of a Compound of Formula I in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are Hydrogen, Q is --N<, X is Ethylene, Y is Methylene, T is
--NH--SO.sub.2--, Z is --O--, R.sup.9 is Indane-5-yl, and R.sup.10
is 2-Methylbenzothiazol-5-yl
Step 1--Preparation of a Compound of Formula (13)
##STR00040##
[0391] Aniline (0.98 mL, 10.7 mmol) and Et.sub.3N (1.8 mL, 12.9
mmol) in toluene (25 mL) were treated with
2-chloro-1-ethanesulfonylchloride (1.11 mL, 10.5 mmol). The
exothermic reaction was stirred for 14 hours at room temperature.
After stirring, the solution was diluted with EtOAc and washed with
HCl (.about.10% aq. soln.). The organic layer concentrated and
purified via flash column chromatography (4:1 hexane/EtOAc) to
afford two lots of phenyl(vinylsulfonyl)amine.
Step 2--Preparation of a Compound of Formula I
##STR00041##
[0393] To a solution of phenyl(vinylsulfonyl)amine (141 mg, 0.77
mmol) and DIEA (0.47 mL, 4.9 mmol) in EtOH (7.5 mL) was added
(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol
(470 mg, 1.5 mmol, crude). The solution was heated for 2 hours at
85.degree. C. on a J-Kem.TM. block. Upon cooling, the reaction
mixture was concentrated to an oil and purified via flash column
chromatography (4:1 EtOAc/MeOH) to afford
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl]phenylamine.
B. Preparation of Other Compounds of Formula I
[0394] Similarly, following the procedure of Example 11A above, but
optionally replacing alanine and/or
2-chloro-1-ethanesulfonylchloride with other compounds of formula
(11) or (12), and/or optionally replacing
1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol with
other compounds of formula (6) or (6a), the following compounds of
Formula I were prepared: [0395]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][4-(trifluoromethyl)phenyl]amine; [0396]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][4-(tertbutyl)phenyl]amine; [0397]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][4-(methyl)phenyl]amine; [0398]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][4-(trifluoromethoxy)phenyl]amine; [0399]
[3,5-bis(trifluoromethyl)phenyl][(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzoth-
iazol-5-yloxy)propyl]piperazinyl}ethyl)sulfonyl]amine; [0400]
(4-chlorophenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)pr-
opyl]piperazinyl}ethyl)sulfonyl]amine; [0401]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl]naphthylamine; [0402]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl](2,4,6-trimethylphenyl)amine; [0403]
[(3-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}propyl)sulfonyl][4-(tertbutyl)phenyl]amine; [0404]
(2,5-dimethylphenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-ylox-
y)propyl]piperazinyl}ethyl)sulfonyl]amine; [0405]
(3,4-dimethoxyphenyl)[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-ylo-
xy)propyl]piperazinyl}ethyl)sulfonyl]amine; [0406]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl][3-(trifluoromethyl)phenyl]amine; and [0407]
[(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl-
}ethyl)sulfonyl](2,3,4,5,6-pentafluorophenyl)amine.
EXAMPLE 12
A. Preparation of a Compound of Formula I in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are Hydrogen, Q is --N<, X and Y are Methylene, T is
--NH--SO.sub.2--, Z is --O--, R.sup.9 is Indane-5-yl, R.sup.10 is
2-Methylbenzothiazol-5-yl
Step 1--Preparation of Formula (7')
##STR00042##
[0409] A solution of 2-methylenesuccinic anhydride (500 mg, 4.46
mmol) and aniline (0.4 mL, 4.46 mmol) in CH.sub.3Cl were shaken
overnight. A precipitate formed, which was filtered off, washed
with hexanes, and dried under vacuum to afford
2-[(N-phenylcarbamoyl)methyl]prop-2-enoic acid.
[0410] A suspension of the
2-[(N-phenylcarbamoyl)methyl]prop-2-enoic acid (700 mg, 3.41 mmol)
in Ac.sub.2O (15 mL) was then treated with NaOAc (327 mg, 3.98
mmol) and shaken for 14 hours at 89.degree. C. The resulting clear
solution was dried on a Savant.TM., dissolved in EtOAc and washed
with H.sub.2O and brine. The organic layers were then dried down on
Savant.TM. to yield 3-methylene-1-phenylazolidine-2,5-dione, a
compound of formula (7').
Step 2--Preparation of a Compound of Formula I
##STR00043##
[0412] A solution of 3-methylene-1-phenylazolidine-2,5-dione (250
mg, 1.33 mmol) and
1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol (415
mg, 1.35 mmol) in AcOH (10 mL, glacial) was stirred 14 hours at
50.degree. C. Concentrated in the Savant.TM. and residue taken up
in EtOAc and washed with NaHCO.sub.3 (sat. aq. soln.), H.sub.2O and
brine, dried over MgSO.sub.4, filtered and concentrated.
Purification via flash column chromatography (gradient 5 to 10%
MeOH/EtOAc) afforded
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-phenylazolidine-2,5-dione.
B. Preparation of Other Compounds of Formula I
[0413] Similarly, following the procedure of Example 12A above, but
optionally replacing 3-methylene-1-phenylazolidine-2,5-dione with
other compounds of formula (7') and/or optionally replacing
(2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol
with other compounds of formula (6) or (6a), the following
compounds of Formula I were prepared: [0414]
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-phenylazolidine-2,5-dione; [0415]
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-naphthylazolidine-2,5-dione; [0416]
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-[4-(trifluoromethyl)phenyl]azolidine-2,5-dione; [0417]
1-(4-fluorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-
propyl]piperazinyl}methyl)azolidine-2,5-dione; [0418]
3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)-1-[3-(trifluoromethyl)phenyl]azolidine-2,5-dione; [0419]
1-(3-fluorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-
propyl]piperazinyl}methyl)azolidine-2,5-dione; [0420]
1-[4-(tert-butyl)phenyl]-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5--
yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione; [0421]
1-(4-chlorophenyl)-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-
propyl]piperazinyl}methyl)azolidine-2,5-dione; and [0422]
1-[3-(tert-butyl)-4-chlorophenyl]-3-({4-[(2R)-2-hydroxy-3-(2-methylbenzot-
hiazol-5-yloxy)propyl]piperazinyl}methyl)azolidine-2,5-dione.
EXAMPLE 13
A. Preparation of a Compound of Formula I in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are Hydrogen, Q is --N<, X is Ethylene, Y is Methylene, T is
--C(O)NH--, Z is --O--, R.sup.9 is Indane-5-yl, and R.sup.10 is
2-Methylbenzothiazol-5-yl
Step 1--Preparation of Formula (7)
##STR00044##
[0424] To a cooled (0.degree. C.) solution of 2-bromoethylamine HBr
salt (4.7 g, 23 mmol) in diethyl ether (35 ml) and saturated sodium
bicarbonate (50 ml) was added dropwise a solution of
4-(trifluoromethyl)benzoyl chloride (5.0 g, 24 mmol) in diethyl
ether (15 ml) over one hour. The reaction was stirred vigorously
and allowed to warm to room temperature and then stirred at room
temperature for 48 hours. The ether layer was separated and
concentrated. The product,
N-(2-bromoethyl)[4-(trifluoromethyl)phenyl]carboxamide (M+1=295.9)
was taken to the next step without further purification.
Step 2--Preparation of Formula (7a')
##STR00045##
[0425] A mixture of
N-(2-bromoethyl)[4-(trifluoromethyl)phenyl]carboxamide (0.6 g, 2
mmol), BOC-piperazine (0.38 g, 2 mmol), and potassium carbonate
(0.56 g, 4 mmol) in acetone was heated to reflux for 2 hours. The
reaction was then cooled and concentrated. The product was isolated
using column chromatography (EtOAc:Hexanes 1:1) to yield tert-butyl
4-(2-{[4-(trifluoromethyl)phenyl]carbonylamino}ethyl)piperazinecarboxylat-
e (M+1=402.1)
Step 3--Preparation of Formula (7a)
##STR00046##
[0427]
4-(2-{[4-(trifluoromethyl)phenyl]carbonylamino}ethyl)piperazine
carboxylate (0.2 g, 0.5 mmol) was dissolved in trifluoroacetic acid
(TFA) (10 ml). The solution was allowed to stir at room temperature
for 24 hours. The acid was removed under vacuum and the product,
N-(2-piperazinylethyl)[4-(trifluoromethyl)phenyl]carboxamide was
taken to the next step as a TFA salt.
Step 4--Preparation of Formula (1)
##STR00047##
[0429] To a solution of
N-(2-piperazinylethyl)[4-(trifluoromethyl)phenyl]carboxamide (0.2
g, 0.38 mmol) in ethanol was added diisopropyl ethylamine (0.25 ml,
1.5 mmol) and 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole
(0.09 g, 0.42 mmol). The reaction was heated to 85 degrees for four
hours. The mixture was then concentrated in vacuo and purified
using preparative thin layer chromatography (10:1 DCM:MeOH) to
yield
N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaziny-
l}ethyl)[4-(trifluoromethyl)phenyl]carboxamide (M+1=523.0).
B. Preparation of Other Compounds of Formula I
[0430] Similarly, following the procedure of Example 13A above, but
optionally replacing
N-(2-bromoethyl)[4-(trifluoromethyl)phenyl]carboxamide with other
compounds of formula (7), and/or optionally replacing
5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole with other
compounds of formula (3), the following compounds of Formula I were
prepared: [0431]
(2,6-difluorophenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiaz-
ol-5-yloxy)propyl]piperazinyl}ethyl)carboxamide; [0432]
N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperaziny-
l}ethyl)benzamide; [0433]
(4-chlorophenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)-
propyl]piperazinyl}ethyl)carboxamide; and [0434]
(4-trifluoromethylphenyl)-N-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-
-5-yloxy)propyl]piperazinyl}ethyl)carboxamide.
EXAMPLE 14
Preparation of a Compound of Formula (5b) in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are Hydrogen, Y is Methylene, Z is --O--, and R.sup.10 is
2-Methylbenzothiazol-5-yl
##STR00048##
[0436] To a solution of
5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole (2.0 g, 9.25
mmol) and piperidin-4-one, chloride (1.25 g, 9.25 mmol) in ethanol
was added diisopropylethylamine (1.6 ml, 9.0 mmol). The mixture was
heated to reflux for 16 hours. The solvent was removed and the
residue purified by column chromatography (10:1 DCM:MeOH) followed
by preparative TLC (10:1 DCM:MeOH) to yield
1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperidin-4-one.
EXAMPLE 15
A. Preparation of a Compound of Formula (7b) in which R.sup.9 and T
are joined to form
(3R)-3-Amino-1-(4-Chlorophenyl)Pyrrolidin-2-one
Step 1--Addition of Protected Methionine Group to Substituted
Amine
##STR00049##
[0438] CBZ-d-Methionine (5.4 g, 20 mmol), N-hydroxybenzotriazole
H.sub.2O(HOBt, 3.0 g, 20 mmol),
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU, 7.7 g, 20 mmol),
4-(dimethylamino)-pyridine (DMAP, .about.0.020 g, 0.16 mmol) and
triethylamine (2.8 ml, 20 mmol) were added to a solution of
4-chloroaniline (1.3 g, 10 mmol) in THF. The non-homogeneous
solution was stirred at room temperature for 24 hours. The solvent
was then removed and the residue taken into ethyl acetate
(.about.200 ml) and washed sequentially with NaHCO.sub.3
(3.times.100 ml), 10% citric acid (3.times.100 ml), water
(3.times.100 ml) and saturated NaCl (1.times.75 ml). The organic
layer was then dried with sodium sulfate, filtered, and
concentrated to yield
(2R)--N-(4-chlorophenyl)-4-methylthio-2-[(phenylmethoxy)carbonylamino]but-
anamide (M+1=393.26)
Step 2--Alkylation of Methionine Substituent
##STR00050##
[0440] To neat
(2R)--N-(4-chlorophenyl)-4-methylthio-2-[(phenylmethoxy)carbonylamino]but-
anamide (2.0 g, 5.09 mmol) was added methyl iodide (10 ml, 161
mmol). The solution was allowed to stir for 48 hours. Methyl iodide
was then removed under vacuum to yield
(2R)--N-(4-chlorophenyl)-5-methyl-2-[(phenylmethoxy)carbonylamino]-5-thia-
hexanamide, iodide.
Step 3--Ring Closure to Prepare R.sup.9/X 2-Oxypyrrolidine
Structure
##STR00051##
[0442] To a cooled (0.degree.) solution of
(2R)--N-(4-chlorophenyl)-5-methyl-2-[(phenylmethoxy)carbonylamino]-5-thia-
hexanamide, iodide (0.53 g, 1.0 mmol) in DMF (5.0 ml) and THF (5.0
ml) was added NaH (60% suspension in oil, 0.06 g, 1.5 mmol). The
reaction mixture was warmed to room temperature and then stirred
until the desired product was seen using thin layer chromatography
(EtOAc). The solvent was removed and the product then purified
using preparative chromatography (pure EtOAc) to yield
N-[(3R)-1-(4-chlorophenyl)-2-oxopyrrolidin-3-yl](phenylmethoxy)carboxamid-
e (M+1=366.93)
Step 4--Deprotection of the (7b) Compound
##STR00052##
[0444] To a solution of
N-[(3R)-1-(4-chlorophenyl)-2-oxopyrrolidin-3-yl](phenylmethoxy)carboxamid-
e (0.2 g, 0.58 mmol) in ethanol (10 ml) and cyclohexene (4 ml) was
added palladium hydroxide (40 mg). The reaction was refluxed
vigorously overnight. Palladium was removed by filtration and the
filtrate was concentrated to yield
(3R)-3-amino-1-(4-chlorophenyl)pyrrolidin-2-one.
EXAMPLE 16
A. Preparation of a Compound of Formula I in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are Hydrogen, Q is --NH--CH<, X is a Covalent Bond, Y is
Methylene, -, Z is --O--, R.sup.9 and T are joined to form
(3R)-3-Amino-1-(4-Chlorophenyl)Pyrrolidin-2-one, and R.sup.10 is
2-Methylbenzothiazol-5-yl
##STR00053##
[0446] To a solution of
(3R)-3-amino-1-(4-chlorophenyl)pyrrolidin-2-one as prepared in
Example 14 (0.08 g) in EtOH (3 ml) was added
1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperidin-4-one
as prepared in Example 13 (0.15 g, 0.53 mmol) and sodium
triacetoxyborohydride (0.112 g, 0.53 mmol). The reaction was
stirred at room temperature for 48 hours. The solvent was removed
and the residue purified using preparative TLC (10:1 DCM:MeOH) to
yield
(3R)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-pipe-
ridyl)}amino)-1-(4-chlorophenyl)pyrrolidin-2-one.
B. Preparation of Other Compounds of Formula I
[0447] Similarly, following the procedure of Example 16A above, but
optionally replacing
(3R)-3-amino-1-(4-chlorophenyl)pyrrolidin-2-one with other
compounds of formula (7b), and/or optionally
1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperidin-4-one
with other compounds of formula (5b), the following compounds of
Formula I were prepared: [0448]
(3R)-1-(4-fluorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-y-
loxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one; [0449]
(3R)-1-(4-chlorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-y-
loxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one; [0450]
3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)--
1-(4-chlorophenyl)pyrrolidin-2-one; [0451]
(3R)-1-(2-fluorophenyl)-3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-y-
loxy)propyl](4-piperidyl)}amino)pyrrolidin-2-one; [0452]
3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)--
1-(4-fluorophenyl)pyrrolidin-2-one; [0453]
3-({1-[(2R)-3-(2-fluorophenoxy)-2-hydroxypropyl](4-piperidyl)}amino)(3R)--
1-(2-fluorophenyl)pyrrolidin-2-one; [0454]
3-({1-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl](4-piperidyl-
)}amino)(3R)-1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one; [0455]
3-({1-[3-(2-fluorophenoxy)-(2R)-2-hydroxypropyl](4-piperidyl)}amino)(3R)--
1-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one; [0456]
(3R)-1-(4-chlorophenyl)-3-{4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)p-
ropyl]piperazinyl}pyrrolidin-2-one; and [0457]
4-({4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}-
methyl)(3R)-1-(4-fluorophenyl)pyrrolidin-2-one.
EXAMPLE 17
[0458] Several compounds of Formula I prepared as shown in the
above procedures were characterized by NMR and mass spectrometry.
For example:
(4-Trifluoromethylphenyl)-N-(2-{4-[(2R)-2-Hydroxy-3-(2-Methylbenzothiazol--
5-yloxy)Propyl]Piperazinyl}Ethyl)Carboxamide
[0459] .sup.1H NMR (CDCl.sub.3) .delta. 7.9 (2H, d), 7.7 (2H, d),
7.45 (1H, d), 7.05 (1H, dd), 6.95 (1H, m), 4.18 (1H, m), 4.05 (2H,
m), 3.6 (2H, m), 2.8 (3H, s), 2.8-2.5 (12H, m)
(3R)-1-(4-Fluorophenyl)-3-({1-[(2R)-2-Hydroxy-3-(2-Methylbenzothiazol-5-yl-
oxy)Propyl](4-Piperidyl)}Amino)Pyrrolidin-2-one
[0460] .sup.1H NMR (CDCl.sub.3) .delta. 7.65 (1H, d), 7.6 (2H, m),
7.42 (1H, d), 7.05 (3H, m), 4.15 (1H, m), 4.05 (2H, d), 3.75 (2H,
m), 3.65 (1H, t), 3.05 (1H, m), 2.88 (1H, m), 2.8 (3H, s) 2.7 (1H,
m), 2.4-2.6 (4H, m), 2.18 (1H, m), 1.98 (3H, m), 1.5 (2H, m)
(3R)-3-({1-[(2R)-2-Hydroxy-3-(2-Methylbenzothiazol-5-Yloxy)Propyl](4-Piper-
idyl)}Amino)-1-[4-(Trifluoromethyl)Phenyl]Pyrrolidin-2-one
[0461] .sup.1H NMR (CDCl.sub.3) .delta. 7.8 (2H, d), 7.62 (3H, m),
7.4 (1H, s), 7.0 (1H, dd), 4.4 (1H, m), 4.1 (1H, m), 4.0 (1H, m),
3.8 (2H, m), 3.65 (1H, t), 3.4-3.25 (2H, m), 2.97 (3H, m), 2.8 (3H,
s), 2.9-2.7 (2H, m), 2.55 (1H, m), 2.1 (2H, m), 2.0 (1H, m), 1.75
(2H, m)
4-({4-[(2R)-2-Hydroxy-3-(2-Methylbenzothiazol-5-yloxy)Propyl]piperazinyl}M-
ethyl)-1-(4-Fluorophenyl)Pyrrolidin-2-one
[0462] .sup.1H NMR (CDCl.sub.3) .delta. 7.65 (1H, d), 7.6 (2H, m),
7.45 (1H, s), 7.05 (3H, m), 4.18 (1H, m), 4.05 (2H, m), 3.95 (1H,
t), 3.6 (1H, m), 2.8 (3H, s), 2.7-2.4 (15, mm)
[0463] The following examples illustrate the preparation of
representative pharmaceutical formulations containing a compound of
Formula I, such as those prepared in accordance with Examples 1-16
above.
EXAMPLE 18
[0464] Hard gelatin capsules containing the following ingredients
are prepared:
TABLE-US-00001 Quantity Ingredient (mg/capsule) Active Ingredient
30.0 Starch 305.0 Magnesium stearate 5.0
[0465] The above ingredients are mixed and filled into hard gelatin
capsules.
EXAMPLE 19
[0466] A tablet formula is prepared using the ingredients
below:
TABLE-US-00002 Quantity Ingredient (mg/tablet) Active Ingredient
25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide
10.0 Stearic acid 5.0
[0467] The components are blended and compressed to form
tablets.
EXAMPLE 20
[0468] A dry powder inhaler formulation is prepared containing the
following components:
TABLE-US-00003 Ingredient Weight % Active Ingredient 5 Lactose
95
The active ingredient is mixed with the lactose and the mixture is
added to a dry powder inhaling appliance.
EXAMPLE 21
[0469] Tablets, each containing 30 mg of active ingredient, are
prepared as follows:
TABLE-US-00004 i. Quantity Ingredient (mg/tablet) Active Ingredient
30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg
Polyvinylpyrrolidone 4.0 mg (as 10% solution in sterile water)
Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc
1.0 mg Total 120 mg
[0470] The active ingredient, starch and cellulose are passed
through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution
of polyvinylpyrrolidone is mixed with the resultant powders, which
are then passed through a 16 mesh U.S. sieve. The granules so
produced are dried at 50.degree. C. to 60.degree. C. and passed
through a 16 mesh U.S. sieve. The sodium carboxymethyl starch,
magnesium stearate, and talc, previously passed through a No. 30
mesh U.S. sieve, are then added to the granules which, after
mixing, are compressed on a tablet machine to yield tablets each
weighing 120 mg.
EXAMPLE 22
[0471] Suppositories, each containing 25 mg of active ingredient
are made as follows:
TABLE-US-00005 Ingredient Amount Active Ingredient 25 mg Saturated
fatty acid glycerides to 2,000 mg
[0472] The active ingredient is passed through a No. 60 mesh U.S.
sieve and suspended in the saturated fatty acid glycerides
previously melted using the minimum heat necessary. The mixture is
then poured into a suppository mold of nominal 2.0 g capacity and
allowed to cool.
EXAMPLE 23
[0473] Suspensions, each containing 50 mg of active ingredient per
5.0 mL dose are made as follows:
TABLE-US-00006 Ingredient Amount Active Ingredient 50.0 mg Xanthan
gum 4.0 mg Sodium carboxymethyl cellulose (11%) 50.0 mg
Microcrystalline cellulose (89%) Sucrose 1.75 g Sodium benzoate
10.0 mg Flavor and Color q.v. Purified water to 5.0 mL
[0474] The active ingredient, sucrose, and xanthan gum are blended,
passed through a No. 10 mesh U.S. sieve, and then mixed with a
previously made solution of the microcrystalline cellulose and
sodium carboxymethyl cellulose in water. The sodium benzoate,
flavor, and color are diluted with some of the water and added with
stirring. Sufficient water is then added to produce the required
volume.
EXAMPLE 24
[0475] A subcutaneous formulation may be prepared as follows:
TABLE-US-00007 Ingredient Quantity Active Ingredient 5.0 mg Corn
Oil 1.0 mL
EXAMPLE 25
[0476] An injectable preparation is prepared having the following
composition:
TABLE-US-00008 Ingredients Amount Active ingredient 2.0 mg/ml
Mannitol, USP 50 mg/ml Gluconic acid, USP q.s. (pH 5-6) water
(distilled, sterile) q.s. to 1.0 ml Nitrogen Gas, NF q.s.
EXAMPLE 26
[0477] A topical preparation is prepared having the following
composition:
TABLE-US-00009 Ingredients grams Active ingredient 0.2-10 Span 60
2.0 Tween 60 2.0 Mineral oil 5.0 Petrolatum 0.10 Methyl paraben
0.15 Propyl paraben 0.05 BHA (butylated hydroxy anisole) 0.01 Water
q.s. to 100
[0478] All of the above ingredients, except water, are combined and
heated to 60.degree. C. with stirring. A sufficient quantity of
water at 60.degree. C. is then added with vigorous stirring to
emulsify the ingredients, and water then added q.s. 100 g.
EXAMPLE 25
Sustained Release Composition
TABLE-US-00010 [0479] Weight Preferred Most Preferred Ingredient
Range (%) Range (%) Range (%) Active ingredient 50-95 70-90 75
Microcrystalline cellulose (filler) 1-35 5-15 10.6 Methacrylic acid
copolymer 1-35 5-12.5 10.0 Sodium hydroxide 0.1-1.0 0.2-0.6 0.4
Hydroxypropyl methylcellulose 0.5-5.0 1-3 2.0 Magnesium stearate
0.5-5.0 1-3 2.0
[0480] The sustained release formulations of this invention are
prepared as follows: compound and pH-dependent binder and any
optional excipients are intimately mixed(dry-blended). The
dry-blended mixture is then granulated in the presence of an
aqueous solution of a strong base which is sprayed into the blended
powder. The granulate is dried, screened, mixed with optional
lubricants (such as talc or magnesium stearate), and compressed
into tablets. Preferred aqueous solutions of strong bases are
solutions of alkali metal hydroxides, such as sodium or potassium
hydroxide, preferably sodium hydroxide, in water (optionally
containing up to 25% of water-miscible solvents such as lower
alcohols).
[0481] The resulting tablets may be coated with an optional
film-forming agent, for identification, taste-masking purposes and
to improve ease of swallowing. The film forming agent will
typically be present in an amount ranging from between 2% and 4% of
the tablet weight. Suitable film-forming agents are well known to
the art and include hydroxypropyl methylcellulose, cationic
methacrylate copolymers (dimethylaminoethyl
methacrylate/methyl-butyl methacrylate copolymers--Eudragit.RTM.
E-Rohm. Pharma), and the like. These film-forming agents may
optionally contain colorants, plasticizers, and other supplemental
ingredients.
[0482] The compressed tablets preferably have a hardness sufficient
to withstand 8 Kp compression. The tablet size will depend
primarily upon the amount of compound in the tablet. The tablets
will include from 300 to 1100 mg of compound free base. Preferably,
the tablets will include amounts of compound free base ranging from
400-600 mg, 650-850 mg, and 900-1100 mg.
[0483] In order to influence the dissolution rate, the time during
which the compound containing powder is wet mixed is controlled.
Preferably the total powder mix time, i.e. the time during which
the powder is exposed to sodium hydroxide solution, will range from
1 to 10 minutes and preferably from 2 to 5 minutes. Following
granulation, the particles are removed from the granulator and
placed in a fluid bed dryer for drying at about 60.degree. C.
EXAMPLE 28
Mitochondrial Assays
[0484] Rat heart mitochondria are isolated by the method of
Nedergard and Cannon (Methods in Enzymol. 55, 3, 1979).
[0485] Palmitoyl CoA oxidation--The Palmityl CoA oxidation is
carried out in a total volume of 100 micro liters containing the
following agents: 110 mM KCl, 33 mM Tris buffer at pH 8, 2 mM KPi,
2 mM MgCl.sub.2, 0.1 mM EDTA, 14.7 microM defatted BSA, 0.5 mM
malic acid, 13 mM carnitine, 1 mM ADP, 52 micrograms of
mitochondrial protein, and 16 microM 1-C14 palmitoyl CoA (Sp.
Activity 60 mCi/mmole; 20 microCi/ml, using 5 microliters per
assay). The compounds of this invention are added in a DMSO
solution at the following concentrations: 100 micro molar, 30 micro
molar, and 3 micro molar. In each assay, a DMSO control is used.
After 15 min at 30.degree. C., the enzymatic reaction is
centrifuged (20,000 g for 1 min), and 70 microliters of the
supernatant is added to an activated reverse phase silicic acid
column (approximately 0.5 ml of silicic acid). The column is eluted
with 2 ml of water, and 0.5 ml of the eluent is used for
scintillation counting to determine the amount of C.sup.14 trapped
as C.sup.14 bicarbonate ion.
[0486] The compounds of the invention show activity as fatty acid
oxidation inhibitors in this assay.
EXAMPLE 29
Perfusate
[0487] Langendorff perfusion is conducted using a Krebs-Henseleit
solution containing: (mM) NaCl (118.0), KCl (4.7), KH.sub.2PO.sub.4
(1.2), MgSO.sub.4 (1.2), CaCl.sub.2 (2.5), NaHCO.sub.3 (25.0) and
glucose (5.5 or 11) (Finegan et al. 1996). The working heart
perfusate consists of a Krebs-Henseleit solution with the addition
of palmitate (0.4 or 1.2 mM) pre-bound to 3% bovine serum albumin
(essentially fatty acid free BSA) and insulin (100 .mu.U/ml).
Palmitate is initially dissolved in an ethanol:water mixture
(40%:60%) containing 0.5-0.6 g Na.sub.2CO.sub.3 per g of palmitate.
Following heating to evaporate the ethanol, this mixture is then
added to the 3% BSA-Krebs-Henseleit mixture (without glucose) and
allowed to dialyze (8000 MW cut-off) overnight in 10 volumes of
glucose-free Krebs-Henseleit solution. The next day, glucose is
added to the solution and the mixture is filtered through glass
microfiber filters (GF/C, Whatman, Maidstone, England) and kept on
ice, or refrigerated, prior to use. The perfusate is continuously
oxygenated with a 95% CO.sub.2, 5% O.sub.2 gas mixture while in the
perfusion apparatus to main aerobic conditions.
Heart Perfusion Protocols
[0488] Rats are anesthetized with pentobarbital (60 mg/kg,
intraperitoneally) and hearts are rapidly removed and placed in
ice-cold Krebs-Henseleit solution. The hearts are then rapidly
cannulated via the aortic stump and Langendorff perfusion at
constant pressure (60 mm Hg) is initiated and continued for a
10-min equilibration period. During this equilibration period, the
pulmonary artery is cut, and excess fat and lung tissue removed to
reveal the pulmonary vein. The left atrium is cannulated and
connected to the preload line originating from the oxygenation
chamber. After the 10-min equilibration period, hearts are switched
to working mode (by clamping off the Langendorff line and opening
the preload and afterload lines) and perfused at 37.degree. C.
under aerobic conditions at a constant left atrial preload (11.5 mm
Hg) and aortic afterload (80 mm Hg). The compliance chamber is
filled with air adequate to maintain developed pressure at 50-60 mm
Hg. Perfusate is delivered to the oxygenation chamber via a
peristaltic pump from the reservoir chamber that collected aortic
and coronary flows as well as overflow from the oxygenator.
[0489] Typically, hearts are perfused under aerobic conditions for
60 minutes. Hearts are paced at 300 beats/min throughout each phase
of the perfusion protocol (voltage adjusted as necessary) with the
exception of the initial 5 min of reperfusion when hearts are
allowed to beat spontaneously.
[0490] At the end of the perfusion protocol, hearts are rapidly
frozen using Wollenberger clamps cooled to the temperature of
liquid nitrogen. Frozen tissues are pulverized and the resulting
powders stored at -80.degree. C.
Myocardial Mechanical Function
[0491] Aortic systolic and diastolic pressures are measured using a
Sensonor (Horten Norway) pressure transducer attached to the aortic
outflow line and connected to an AD Instruments data acquisition
system. Cardiac output, aortic flow and coronary flow (cardiac
output minus aortic flow) are measured (ml/min) using in-line
ultrasonic flow probes connected to a Transonic T206 ultrasonic
flow meter. Left ventricular minute work (LV work), calculated as
cardiac output.times.left ventricular developed pressure (aortic
systolic pressure--preload pressure), is used as a continuous index
of mechanical function. Hearts are excluded if LV work decreased
more than 20% during the 60-min period of aerobic perfusion.
Myocardial Oxygen Consumption and Cardiac Efficiency
[0492] Measuring the atrial-venous difference in oxygen content of
the perfusate and multiplying by the cardiac output provides an
index of oxygen consumption. Atrial oxygen content (mmHg) is
measured in perfusate in the preload line or just prior to entering
the left atria. Venous oxygen content is measured from perfusate
exiting the pulmonary artery and passing through in-line O.sub.2
probes and meters Microelectrodes Inc., Bedford, N.H. Cardiac
efficiency is calculated as the cardiac work per oxygen
consumption.
Measurement of Glucose and Fatty Acid Metabolism
[0493] Determining the rate of production of .sup.3H.sub.2O and
.sup.14CO.sub.2 from [.sup.3H/.sup.14C]glucose in the isolated
working rat model allows a direct and continuous measure of the
rates of glycolysis and glucose oxidation. Alternatively, the
measure of the production of .sup.3H.sub.2O from
[5-.sup.3H]palmitate provides a direct and continuous measure of
the rate of palmitate oxidation. Dual labelled substrates allows
for the simultaneous measure of either glycolysis and glucose
oxidation or fatty acid oxidation and glucose oxidation. A 3-ml
sample of perfusate is taken from the injection port of the
recirculating perfusion apparatus at various time-points throughout
the protocol for analysis of .sup.3H.sub.2O and .sup.14CO.sub.2 and
immediately placed under mineral oil until assayed for metabolic
product accumulation. Perfusate is supplemented with
[.sup.3H.sup.14C]glucose or [5-.sup.3H]palmitate to approximate a
specific activity of 20 dpm/mmol. Average rates of glycolysis and
glucose oxidation are calculated from linear cumulative
time-courses of product accumulation between 15 and 60 minutes for
aerobic perfusion. Rates of glycolysis and glucose oxidation are
expressed as .mu.mol glucose metabolized/min/g dry wt.
Measurement of Myocardial Glycolysis
[0494] Rates of glycolysis are measured directly as previously
described (Saddik & Lopaschuk, 1991) from the quantitative
determination of .sup.3H.sub.2O liberated from radiolabeled
[5-.sup.3H]glucose at the enolase step of glycolysis. Perfusate
samples are collected at various time-points throughout the
perfusion protocol. .sup.3H.sub.2O is separated from the perfusate
by passing perfusate samples through columns containing Dowex 1-X 4
anion exchange resin (200-400 mesh). A 90 g/L Dowex in 0.4 M
potassium tetraborate mixture is stirred overnight, after which 2
ml of the suspension is loaded into separation columns and washed
extensively with dH.sub.2O to remove the tetraborate. The columns
are found to exclude 98-99.6% of the total [.sup.3H]glucose (Saddik
& Lopaschuk, 1996). Perfusate samples (100 .mu.l) are loaded
onto the columns and washed with 1.0 ml dH.sub.2O. Effluent is
collected into 5 ml of Ecolite Scintillation Fluid (ICN,
Radiochemicals, Irvine, Calif.) and counted for 5 min in a Beckman
LS 6500 Scintillation Counter with an automatic dual
(.sup.3H.sup.14C) quench correction program. Average rates of
glycolysis for each phase of perfusion are expressed as .mu.mol
glucose metabolized/min/g dry wt as described above.
Measurement of Myocardial Glucose Oxidation
[0495] Glucose oxidation is also determined directly as previously
described (Saddik & Lopaschuk, 1991) by measuring
.sup.14CO.sub.2 from [.sup.14C]glucose liberated at the level of
pyruvate dehydrogenase and in the Krebs cycle. Both .sup.14CO.sub.2
gas exiting the oxygenation chamber and [.sup.14C]bicarbonate
retained in solution are measured. Perfusate samples are collected
at various time-points throughout the perfusion protocol.
.sup.14CO.sub.2 gas is collected by passing the gas exiting the
oxygenator through a hyamine hydroxide trap (20-50 ml depending on
perfusion duration). Perfusate samples (2.times.1 ml), which were
stored under oil to prevent the escape of gas by equilibration with
atmospheric CO.sub.2, are injected into 16.times.150 mm test tubes
containing 1 ml of 9 NH.sub.2SO.sub.4. This process releases
.sup.14CO.sub.2 from the perfusate present as
H.sup.14CO.sub.3.sup.-. These duplicate tubes are sealed with a
rubber stopper attached to a 7-ml scintillation vial containing a
2.times.5 cm piece of filter paper saturated with 250 .mu.l of
hyamine hydroxide. The scintillation vials with filter papers are
then removed and Ecolite Scintillation Fluid (7 ml) added. Samples
are counted by standard procedures as described above. Average
rates of glucose oxidation for each phase of perfusion are
expressed as .mu.mol glucose metabolized/min/g dry wt as described
above.
Measurement of Myocardial Fatty Acid Oxidation
[0496] Rates of palmitate oxidation are measured directly as
previously described (Saddik & Lopaschuk, 1991) from the
quantitative determination of .sup.3H.sub.2O liberated from
radiolabeled [5-.sup.3H]palmitate. .sup.3H.sub.2O is separated from
[5-.sup.3H]palmitate following a chloroform:methanol (1.88 ml of
1:2 v/v) extraction of a 0.5 ml sample of buffer then adding 0.625
ml of chloroform and 0.625 ml of a 2M KCL:HCl solution. The aqueous
phase is removed and treated with a mixture of chloroform, methanol
and KCl:HCl (1:1:0.9 v/v). Duplicate samples are taken from the
aqueous phase for liquid scintillation counting and rates of
oxidation are determined taking into account a dilution factor.
This results in >99% extraction and separation of .sup.3H.sub.2O
from [5-.sup.3H]palmitate. Average rates of glucose oxidation for
each phase of perfusion are expressed as .mu.mol glucose
metabolized/min/g dry wt as described above.
Dry to Wet Ratios
[0497] Frozen ventricles are pulverized at the temperature of
liquid nitrogen with a mortar and pestle. Dry to wet determinations
are made by weighing a small amount of frozen heart tissue and
re-weighing that same tissue after 24-48 hr of air drying and
taking the ratio of the two weights. From this ratio, total dry
tissue can be calculated. This ratio is used to normalize, on a per
g dry weight basis, rates of glycolysis, glucose oxidation and
glycogen turnover as well as metabolite contents.
[0498] The compounds of the invention showed activity as fatty acid
oxidation inhibitors in the above assays.
REFERENCES
[0499] 1. Finegan B A, Gandhi M, Lopaschuk G D, Clanachan A S,
1996. Antecedent ischemia reverses effects of adenosine on
glycolysis and mechanical function of working hearts. American
Journal of Physiology 271: H2116-25. [0500] 2. Saddik M, Lopaschuk
G. D., 1991. Myocardial triglyceride turnover and contribution to
energy substrate utilization in isolated working rat hearts.
Journal of Biological Chemistry 266: 8162-8170.
[0501] All patents and publications cited above are hereby
incorporated by reference.
* * * * *