U.S. patent application number 10/598686 was filed with the patent office on 2007-09-06 for compounds and methods for treating dyslipidemia.
Invention is credited to Michael Gregory Bell, Guoqing Cao, Ana Maria Escribano, Maria Carmen Fernandez, Nathan Bryan Mantlo, Eva Maria Martin de la Nava, Ana Isabel Mateo Herranz, Daniel Ray Mayhugh, Xiadong Wang.
Application Number | 20070208003 10/598686 |
Document ID | / |
Family ID | 34963426 |
Filed Date | 2007-09-06 |
United States Patent
Application |
20070208003 |
Kind Code |
A1 |
Bell; Michael Gregory ; et
al. |
September 6, 2007 |
COMPOUNDS AND METHODS FOR TREATING DYSLIPIDEMIA
Abstract
The present invention discloses compounds of formula I ##STR1##
wherein A, n, m, j, q, y, W, X, Y, Z, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, and R.sup.6 are as defined herein and their
pharmaceutical compositions and methods of use are disclosed as
useful for treating dyslipidemia and its sequelae.
Inventors: |
Bell; Michael Gregory;
(Indianapolis, IN) ; Cao; Guoqing; (Carmel,
IN) ; Escribano; Ana Maria; (Alcobendas, ES) ;
Fernandez; Maria Carmen; (Alcobendas, ES) ; Mantlo;
Nathan Bryan; (Brownsburg, IN) ; Martin de la Nava;
Eva Maria; (Alcobendas, ES) ; Mateo Herranz; Ana
Isabel; (Alcobendas, ES) ; Mayhugh; Daniel Ray;
(Carmel, IN) ; Wang; Xiadong; (Carmel,
IN) |
Correspondence
Address: |
ELI LILLY & COMPANY
PATENT DIVISION
P.O. BOX 6288
INDIANAPOLIS
IN
46206-6288
US
|
Family ID: |
34963426 |
Appl. No.: |
10/598686 |
Filed: |
March 17, 2005 |
PCT Filed: |
March 17, 2005 |
PCT NO: |
PCT/US05/09294 |
371 Date: |
September 8, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60557134 |
Mar 26, 2004 |
|
|
|
60621162 |
Oct 22, 2004 |
|
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Current U.S.
Class: |
514/215 ;
540/576; 540/577 |
Current CPC
Class: |
C07D 471/04 20130101;
A61P 9/10 20180101; C07D 487/04 20130101; C07D 495/04 20130101;
A61P 3/06 20180101; A61P 3/04 20180101; A61P 3/00 20180101; A61P
9/00 20180101; A61P 43/00 20180101 |
Class at
Publication: |
514/215 ;
540/576; 540/577 |
International
Class: |
A61K 31/55 20060101
A61K031/55; C07D 498/02 20060101 C07D498/02; C07D 487/02 20060101
C07D487/02 |
Claims
1. A compound of formula I ##STR78## wherein n is 0, 1, 2, or 3; m
is 0, 1, 2, 3, 4, 5 or 6; j is 1 or 2; q is 0, 1, or 2; W, X, Y and
Z are each independently CH, C, N, S, or O with appropriate single
or double bonds and/or hydrogen atoms to complete valency
requirements; Ring A is a five or six member ring wherein one of W,
X, Y or Z may be absent; provided that ring A is not phenyl; K is a
bond, C.dbd.O, or S(O).sub.p; p is 0, 1 or 2; R.sup.1 is selected
from a group consisting of hydroxy, hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkylheterocyclic, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkylcycloalkyl; C.sub.1-C.sub.6 alkylaryl, aryl,
heterocyclyl, C.sub.2-C.sub.6 alkylalcohol, --OC.sub.1-C.sub.6
alkyl, --O-aryl, --OC.sub.2-C.sub.6 alkenyl, --OC.sub.1-C.sub.6
haloalkyl, --OC.sub.1-C.sub.6 alkylheterocyclic, --OC.sub.3-C.sub.8
cycloalkyl, --OC.sub.1-C.sub.6 alkylcycloalkyl, --NR.sup.7R.sup.8,
--OC.sub.1-C.sub.6 alkylaryl, --O-heterocyclic,
--OC.sub.1-C.sub.6alkylCO.sub.2R.sup.11,
--OC.sub.2-C.sub.6alkylalcohol,
--OC.sub.1-C.sub.6alkylNR.sup.7R.sup.8, --OC.sub.2-C.sub.6
alkylcyano, CONR.sup.11R.sup.12, NR.sup.11 SO.sub.2R.sup.12,
NR.sup.11COR.sup.12, C.sub.0-C.sub.3 alkylNR.sup.11R.sup.12,
C.sub.1-C.sub.3 alkylCOR.sup.11, C.sub.0-C.sub.6 alkylCOOR.sup.11
and; provided that R.sup.1 is not hydroxy when K is S(O).sub.p, CO,
and/or when n and K are both zero; and wherein each cycloalkyl,
aryl or heterocyclic group is optionally substituted with 1 to 3
groups independently selected from oxo, hydroxy, halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkylalcohol, --OC.sub.2-C.sub.6alkylalcohol,
C.sub.1-C.sub.6 haloalkoxy, CONR.sup.11R.sup.13,
NR.sup.11SO.sub.2R.sup.12, NR.sup.11COR.sup.12, C.sub.0-C.sub.3
alkylNR.sup.11R.sup.12, C.sub.1-C.sub.3 alkylCOR.sup.11,
C.sub.0-C.sub.6 alkylCOOR.sup.11, C.sub.0-C.sub.6 alkylcyano,
--OC.sub.2-C.sub.6alkylcyano, C.sub.1-C.sub.6 alkylcycloalkyl,
phenyl, --OC.sub.1-C.sub.6 alkylcycloalkyl, --OC.sub.1-C.sub.6
alkylaryl, --OC.sub.1-C.sub.6 alkylheterocyclic, and
C.sub.1-C.sub.6 alkylaryl; R.sup.2 is independently selected from
the group consisting of hydrogen, halo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, OC.sub.1-C.sub.6 haloalkyl, OC.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkylaryl, aryl, C.sub.0-C.sub.6
alkylNR.sup.7R.sup.8, heteroaryl, heterocyclyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.6 alkylcycloalkyl and C.sub.1-C.sub.6
alkylheterocyclyl; wherein each cycloalkyl, aryl, or heterocyclic
is optionally substituted with 1 to 3 groups independently selected
from oxo, hydroxy, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alcohol,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, CONR.sup.11R.sup.12, NR.sup.11SO.sub.2R.sup.12,
NR.sup.11COR.sup.12, C.sub.0-C.sub.3 alkylNR.sup.11R.sup.12,
C.sub.1-C.sub.3 alkylCOR.sup.11, C.sub.0-C.sub.6 alkylCOOR.sup.11,
cyano, and phenyl, and wherein two R.sup.2 groups may combine to
form a 3, 4 or 5 member spirocycle, or a five or six member
optionally substituted fused carbocyclic or heterocyclic ring;
R.sup.3 is hydrogen, C.sub.1-C.sub.6 alkyl, aryl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkylaryl,
C.sub.1-C.sub.6 alkylheterocyclic, C.sub.3-C.sub.8 cycloalkyl, or
C.sub.1-C.sub.6 alkylcycloalkyl; R.sup.4 is a group represented by
the formula --NR.sup.9R.sup.10; R.sup.5 is selected from the group
consisting of hydrogen, halogen, hydroxy, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
--OC.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkylcycloalkyl,
C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6 alkylheterocyclic, aryl,
C.sub.1-C.sub.6 alkylaryl, heteroaryl, --O-aryl, --OC.sub.2-C.sub.6
alkenyl, --OC.sub.1-C.sub.6 haloalkyl, --NR.sup.7R.sup.8, and
--OC.sub.1-C.sub.6 alkylaryl; and wherein when q is 1, 2 or 3, two
adjacent R.sup.5 groups may combine to form a fused 5 or 6 member
optionally substituted carbocyclic or heterocyclic ring; R.sup.6 is
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, --OC.sub.1-C.sub.6
alkyl, --O-aryl, --OC.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6
haloalkyl, --OC.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkylNR.sup.7R.sup.8, C.sub.3-C.sub.8 cycloalkyl, and
C.sub.1-C.sub.6 alkylcycloalkyl; R.sup.7 and R.sup.5 are
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.6 alkylcycloalkyl, C.sub.1-C.sub.6
alkylheterocyclic, heterocyclic, aryl, C.sub.1-C.sub.6 alkylaryl,
hydroxy, oxo, COOH, C(O)OC.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkylalcohol, C.sub.1-C.sub.6 alkylamine,
C.sub.2-C.sub.6 alkenylaryl, C.sub.2-C.sub.6 alkynylaryl,
C.sub.1-C.sub.6 alkyl-O--C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkyl-NR.sup.11--C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkylcyano, C.sub.1-C.sub.6 alkylCONR.sup.7R.sup.8, C.sub.1-C.sub.6
alkylNR.sup.7R.sup.8, C.sub.1-C.sub.6alkylNR.sup.11COR.sup.12
wherein each alkyl, cycloalkyl, heterocyclic, or aryl group is
optionally substituted with 1-3 groups independently selected from
hydroxy, oxo, amino, halogen, C.sub.1-C.sub.6 alkylcycloalkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkylheterocyclic,
C.sub.1-C.sub.6 haloalkyl, COOH, C(O)OC.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylalcohol, and
C.sub.1-C.sub.6 alkylamine and NR.sup.11R.sup.12; or R.sup.7 and
R.sup.8 combine to form a nitrogen containing heterocyclic ring
which may have 0, 1, or 2 additional hetero-atoms selected from
oxygen, nitrogen or sulfur and may be optionally substituted with
oxo, or C.sub.1-C.sub.6 alkyl; R.sup.9 is the group C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkylcycloalkyl, aryl, heterocyclic,
C.sub.1-C.sub.6 alkylheterocyclic, COR.sup.7, CO.sub.2R.sup.7,
C.sub.0-C.sub.3 alkylCONR.sup.7R.sup.8, C.sub.0-C.sub.3
alkylS(O).sub.pNR.sup.7R.sup.8, or C.sub.0-C.sub.3
alkylS(O).sub.pR.sup.7 wherein R.sup.7 is as defined above, and
wherein each alkyl, cycloalkyl, aryl, and heterocyclic is
optionally substituted with one to two groups independently
selected from halo, hydroxy, oxo, COOH, C(O)OC.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylalcohol, C.sub.1-C.sub.6 alkylamine,
C.sub.1-C.sub.6 alkylaryl, C.sub.2-C.sub.6 alkenylaryl,
C.sub.2-C.sub.6 alkynylaryl, C.sub.1-C.sub.6 alkylheterocyclic,
--NR.sup.7R.sup.8, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6
alkylcycloalkyl, C.sub.1-C.sub.6 alkyl-O--C.sub.1-C.sub.6
alkylaryl, C.sub.1-C.sub.6 alkyl-NR.sup.2--C.sub.1-C.sub.6
alkylaryl, C.sub.1-C.sub.6 alkylcyano, C.sub.1-C.sub.6
alkylCONR.sup.7R.sup.8, C.sub.1-C.sub.6 alkylNR.sup.7R.sup.8,
C.sub.1-C.sub.6 alkylCO.sub.2R.sup.11,
C.sub.1-C.sub.6alkylNR.sup.11COR.sup.12, and aryl, wherein each
cycloalkyl or aryl group is optionally substituted with halo,
hydroxy, oxo, amino, COOH, C(O)OC.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylalcohol, and C.sub.1-C.sub.6 alkylamine;
R.sup.10 is selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkylaryl, C.sub.2-C.sub.6 alkenylaryl,
C.sub.2-C.sub.6 alkynylaryl, C.sub.1-C.sub.6 haloalkylaryl,
C.sub.1-C.sub.6 alkylheterocyclic, C.sub.2-C.sub.6
alkenylheterocyclic, C.sub.1-C.sub.6 alkylcycloalkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6
alkyl-O--C.sub.1-C.sub.6 alkylaryl, and wherein each cycloalkyl,
aryl, or heterocyclic group is optionally substituted with 1-3
groups independently selected from the group consisting of hydroxy,
oxo, --SC.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, halogen, C.sub.1-C.sub.6 alkoxy, aryloxy,
C.sub.1-C.sub.6 alkenyloxy, C.sub.1-C.sub.6 haloalkoxyalkyl,
C.sub.0-C.sub.6 alkylNR.sup.11R.sup.12, --OC.sub.1-C.sub.6
alkylaryl, nitro, cyano, --OC.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkylalcohol, and C.sub.1-C.sub.6 alkylalcohol;
R.sup.11 and R.sup.12 are independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkenyl, C.sub.3-C.sub.8 cycloalkyl, heterocyclic, aryl, and
C.sub.1-C.sub.6 alkylaryl, wherein each aryl group is optionally
substituted with 1-3 groups independently selected from halogen,
C.sub.1-C.sub.6 alkylheterocyclic, and C.sub.1-C.sub.6 haloalkyl,
or R.sup.11 and R.sup.12 combine to form a nitrogen containing
heterocyclic ring which may have 0, 1, or 2 additional heteroatoms
selected from oxygen, nitrogen or sulfur and is optionally
substituted with oxo, or C.sub.1-C.sub.6 alkyl; or a
pharmaceutically acceptable salt, enantiomer, racemate,
diastereomer or mixture of diastereomers thereof.
2. A compound according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof, wherein n is 0, and K is C.dbd.O, wherein
R.sup.1 is selected from a group consisting of hydroxy, hydrogen,
--C.sub.1-C.sub.6 alkyl, --C.sub.0-C.sub.6 alkylcycloalkyl,
--C.sub.0-C.sub.6 alkylheterocyclic, --C.sub.1-C.sub.6 haloalkyl
--OC.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylaryl,
--OC.sub.1-C.sub.6 alkyl, --OC.sub.3-C.sub.8 cycloalkyl
--OC.sub.1-C.sub.6 alkylcycloalkyl, --OC.sub.1-C.sub.6
alkylcycloalkylNR.sup.7R.sup.8, C.sub.1-C.sub.6 alkoxy,
--OC.sub.0-C.sub.6 alkylaryl, --OC.sub.1-C.sub.6haloalkyl,
OC.sub.1-C.sub.6alkylcyano, OC.sub.1-C.sub.6alkylCO.sub.2R.sup.11,
--OC.sub.1-C.sub.6alkylhydroxy, --OC.sub.3-C.sub.8
cycloalkylCO.sub.2R.sup.11, --OC.sub.1-C.sub.6 alkylNR.sup.7R.sup.8
and --OC.sub.1-C.sub.6 alkylheterocyclic and wherein each
cycloalkyl, aryl, or heterocyclic is optionally substituted with 1
or 2 groups selected from halogen, C.sub.0-C.sub.3 alkylalcohol,
C.sub.0-C.sub.3 alkylamine, C.sub.0-C.sub.3 alkylCOOH, CONH.sub.2,
C.sub.0-C.sub.3alkylcyano, and C(O)OC.sub.1-C.sub.3 alkyl.
3. A compound according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof, wherein R.sup.4 is NR.sup.9R.sup.10 and
R.sup.9 is a heterocyclic group optionally substituted with one or
two groups independently selected from hydroxy, halo, amino,
C(O)OC.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylalcohol,
C.sub.1-C.sub.6 alkylamine, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkylCONR.sup.7R.sup.3, C.sub.1-C.sub.6 alkylcyano,
C.sub.1-C.sub.6 alkylCO.sub.2R.sup.11, C.sub.1-C.sub.6
alkylNR.sup.7R.sup.8 and C.sub.1-C.sub.6 alkylcycloalkyl.
4. A compound of claim 1, or a pharmaceutically acceptable salt,
enantiomer, racemate, diastereomer, or mixture of diastereomers
thereof, wherein j is 2.
5. A compound according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof, wherein n, m, and q are independently 0, or
1.
6. A compound according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof, wherein the A ring is selected from the
group consisting of pyridine, pyrazine, thiophene, pyrazole
isoxazole, oxazole, and thiazole.
7. A compound according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof, wherein the A ring is pyridine.
8. A compound according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof, wherein the A ring is thiophene.
9. A compound according to claim 1 or a pharmaceutically acceptable
salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof, wherein each R.sup.3 is hydrogen and R.sup.4
is NR.sup.9R.sup.10 and R.sup.9 is selected from the group
consisting of: ##STR79## ##STR80## wherein R is independently H,
OH, NR.sup.7R.sup.8 or C.sub.1-C.sub.3 alkyl wherein the
C.sub.1-C.sub.3 alkyl group is optionally substituted with OH,
halo, cyano, CONR.sup.7R.sup.8, CO.sub.2R.sup.11, or
NR.sup.7R.sup.8.
10. A compound according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof, wherein R.sup.3 is hydrogen and R.sup.4 is
NR.sup.9R.sup.10 selected from the group consisting of: ##STR81##
##STR82## wherein R.sup.7 is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkylcycloalkyl,
C.sub.1-C.sub.6 alkyheterocyclic, heterocyclic, aryl,
C.sub.1-C.sub.6 alkylaryl, O--C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, wherein each cycloalkyl, heterocyclic or
aryl group is optionally substituted with a group selected from
hydroxy, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkylalcohol,
C.sub.1-C.sub.3 alkylNH.sub.2, C.sub.1-C.sub.3 haloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.3alkylamine, and
C.sub.1-C.sub.3 alkylcycloalkyl.
11. A compound according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof, wherein R.sup.4 is NR.sup.9R.sup.10 and
R.sup.9 is COOR.sup.7.
12. A compound according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof, wherein R.sup.4 is NR.sup.9R.sup.10 and
R.sup.9 is CONR.sup.7R.sup.8.
13. A compound according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof wherein R.sup.4 is NR.sup.9R.sup.10 and
R.sup.9 is S(O).sub.2NR.sup.7R.sup.8.
14. A compound selected from the group consisting of:
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-thie-
no[3,4-b]azepine-1-carboxylic acid isopropyl ester,
8-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-3-methyl-5,6,7,8-tetrah-
ydro-thieno[3,2-b]azepine-4-carboxylic acid isopropyl ester,
8-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-bromo-5,6,7,8-tetrahy-
dro-thieno[3,2-b]azepine-4-carboxylic acid isopropyl ester,
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-5,6,7,8-tetrahydro-pyri-
do[2,3-b]azepine-9-carboxylic acid isopropyl ester,
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-pyri-
do[3,4-b]azepine-1-carboxylic acid isopropyl ester,
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-pyri-
do[4,3-b]azepine-1-carboxylic acid isopropyl ester,
9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-6,7,8,9-tetrahydro-pyri-
do[3,2-b]azepine-5-carboxylic acid isopropyl ester,
9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-6,7,8-
,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl
ester,
9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-3-trifluoromethyl-6,7,8-
,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl
ester,
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-thie-
no[3,4-b]azepine-1-carboxylic acid isopropyl ester,
8-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-3-methyl-5,6,7,8-tetrah-
ydro-thieno[3,2-b]azepine-4-carboxylic acid isopropyl ester,
4-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-1-methyl-4,5,6,7-tetrah-
ydro-1H-1,2,8-triaza-azulene-8-carboxylic acid isopropyl ester,
9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-chloro-6,7,8,9-tetrahyd-
ro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester,
9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-methoxy-6,7,8,9-tetrahy-
dro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester,
9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-bromo-6,7,8,9-tetrahydr-
o-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester,
9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-dimethylamino-6,7,8,9-t-
etrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester,
9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-methyl-6,7,8,9-tetrahyd-
ro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester,
9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-cyano-6,7,8,9-tetrahydr-
o-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester,
9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-3-chloro-2-methoxy-6,7,8,-
9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl
ester,
9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-3-chloro-2-ethoxy-6,7,8,9-
-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester,
9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)amino]-2-methyl-3-trifluorometh-
yl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
isopropyl ester,
9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)amino]-2-methyl-3-trifl-
uoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic
acid tert-butyl ester,
9-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-2-m-
ethyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxyl-
ic acid isopropyl ester,
9-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-2-m-
ethyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxyl-
ic acid tert-butyl ester,
(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-2-methyl-3-trifluor-
omethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine,
(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopropylmethyl-2-methyl-3-trifluor-
omethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine,
(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-5-pyridin-3-ylmethyl-3-trifluo-
romethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-(2-methyl-2H-tetr-
azol-5-yl)-amine,
(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-5-pyridin-4-ylmethyl-3-trifluo-
romethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-(2-methyl-2H-tetr-
azol-5-yl)-amine,
3-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-
-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepin-5-ylmet-
hyl}-benzoic acid,
4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-
-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepin-5-ylmet-
hyl}-benzoic acid,
5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-
-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepin-5-yl}-3-
,3-dimethyl-pentanoic acid,
(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepin-5-ylme-
thyl}-cyclohexyl)-acetic acid,
(3,5-Bis-trifluoromethyl-benzyl)-(5-ethyl-2-methyl-3-trifluoromethyl-6,7,-
8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-(2-methyl-2H-tetrazol-5-yl)-am-
ine,
5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepin-5--
ylmethyl}-thiophene-2-carboxylic acid,
2-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-
-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepin-5-yl}-e-
thanol,
(5-Benzyl-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-pyrido-
[3,2-b]azepin-9-yl)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-
-5-yl)-amine,
(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(2-methyl-5--
thiazol-2-ylmethyl-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]az-
epin-9-yl)-amine,
9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2--
methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxy-
lic acid tetrahydro-furan-3-yl ester,
(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-5-pyridin-4-ylmethyl-3-trifluo-
romethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-carbamic
acid methyl ester,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-(2-methyl-5-pyridin-4-ylmethyl-3-tri-
fluoromethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-acetamide
or a pharmaceutically acceptable salt, enantiomer or diastereomer
or mixture thereof.
15. A method of regulating CETP activity comprising administering a
compound of formula I according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer or mixture of
diastereomers thereof to a patient in need thereof.
16. A method of treating dyslipidemia comprising administering a
compound of formula I, according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate diastereomer, mixture of
diastereomers thereof, to a patient in need thereof.
17. A method of treating artherosclerosis comprising administering
a compound of formula I according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof to a patient.
18. A method according to claim 15, wherein the regulation of CETP
activity results in a decrease in LDL-cholesterol.
19. A method of lowering plasma LDL-cholesterol in a mammal
comprising administering a therapeutically effective dose of a
compound of formula I, according to claim 1, or a pharmaceutically
acceptable salt, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof to a patient in need thereof.
20. A method of treating the pathological sequelae due to high
levels of plasma LDL-cholesterol in a mammal comprising
administering an effective dose of a compound of formula I,
pharmaceutically acceptable salt, enantiomer, racemate,
diastereomer, or mixture of diastereomers to a patient in need
thereof.
21. A pharmaceutical composition comprising a compound according to
claim 1, or a pharmaceutically acceptable salt, enantiomer,
racemate, diastereomer, or mixture of diastereomers thereof, and a
carrier, diluent and/or excipient.
22. (canceled)
23. A method according to claim 15, wherein the regulation of CETP
activity results in an increase in plasma HDL-cholesterol
levels.
24. A method of treating cardiovascular diseases comprising
administering a compound of formula I according to claim 1, or a
pharmaceutically acceptable salt enantiomer, racemate,
diastereomer, or mixture of diastereomers thereof to a patient.
Description
FIELD OF THE INVENTION
[0001] The current invention relates to the fields of medicinal
organic chemistry, pharmacology, and medicine. Further, the current
invention relates to a group of compounds that demonstrate utility
for treating pathological states due to dyslipidemia.
BACKGROUND OF THE INVENTION
[0002] Coronary heart disease (CHD) is one of the major causes of
morbidity and mortality worldwide. Despite attempts to modify risk
factors such as obesity, smoking, lack of exercise, and treatment
of dyslipidemia with dietary modification or drug therapy, CHD
remains the most common cause of death in the U.S. Over 50% of all
CHD deaths are due to underlying atherosclerotic coronary heart
disease.
[0003] Dyslipidemia is a major risk factor for CHD. Low plasma
levels of high density lipoprotein (HDL) cholesterol with either
normal or elevated levels of low density (LDL) cholesterol is a
significant risk factor for developing atherosclerosis and
associated coronary artery disease in humans. Indeed, several
studies on lipoprotein profiles of CHD patients have shown that
about 50% of the CHD patients have cholesterol levels that are
considered to be in the normal range (<200 mg/dl). Furthermore,
these studies found low HDL cholesterol in about 40% of the
normo-cholesterolemic CHD patients as compared to the general
population reported in the National Health and Nutrition
Examination Survey. Since low levels of HDL cholesterol increase
the risk of atherosclerosis, methods for elevating plasma HDL
cholesterol would be therapeutically beneficial for the treatment
of cardiovascular disease including, but not limited to,
atherosclerosis, CHD, stroke, and peripheral vascular disease.
[0004] Cholesterol ester transfer protein (CETP) is a 74 KD
glycoprotein that facilitates the exchange of cholesterol esters in
HDL for triglycerides in triglyceride-rich lipoproteins (A. R. Tall
et. al., (1999) 1999 George Lyman Duss Memorial Lecture: Lipid
transfer proteins, HDL metabolism and athero genesis. Arterio.
Thromb. Vasc. Biol. 20:1185-1188.). The net result of CETP activity
is a lowering of HDL cholesterol and an increase in LDL
cholesterol. This effect on lipoprotein profile is believed to be
proatherogenic, especially in subjects whose lipid profile
constitutes an increased risk for CHD. Niacin can significantly
increase HDL, but has serious toleration issues that reduce
compliance. Fibrates and the HMG CoA reductase inhibitors raise HDL
cholesterol only modestly (.about.10-12%). As a result, there is a
significant unmet medical need for a well-tolerated agent that can
significantly elevate plasma HDL levels, thereby reversing or
slowing the progression of atherosclerosis.
[0005] CETP is expressed in multiple tissues and secreted into
plasma, where it associates with HDL (X. C. Jiang et. al., (1991)
Mammalian adipose tissue and muscle are major sources of lipid
transfer protein mRNA. J. Biol. Chem. 266:4631-4639). Humans and
monkeys, which express CETP, have relatively low HDL cholesterol,
whereas mice and rats do not express CETP and carry nearly all
their cholesterol in HDL. Further more, transgenic expression of
CETP in mice results in significantly reduced HDL cholesterol
levels and development of severe atherosclerosis compared to
control mice (K. R. Marotti et. al., (1993) Severe atherosclerosis
in transgenic mice expressing simian cholesteryl ester transfer
protein. Nature: 364, 73-75). Expression of human CETP in Dahl
salt-sensitive hypertensive rats led to spontaneous combined
hyperlipidemia, coronary heart disease and decreased survival (V.
L. M. Herrera et. al., (1999) Spontaneous combined hyperlipidemia,
coronary heart disease and decreased survival in Dahl
salt-sensitive hypertensive rats transgenic for human cholesteryl
ester transfer protein. Nature Medicine: 5, 1383-1389).
[0006] Antibodies either directly injected into the plasma or
generated through vaccine injection can effectively inhibit CETP
activity in hamsters and rabbits resulting in elevated HDL
cholesterol (C. W. Rittershaus, (1999) Vaccine-induced antibodies
inhibit CETP activity in vivo and reduce aortic lesions in a rabbit
model of atherosclerosis. Furthermore, antibody neutralization of
CETP in rabbits has been shown to be anti-atherogenic (Arterio.
Thromb. Vasc. Biol. 20, 2106-2112; G. F. Evans et. al., (1994)
Inhibition of cholesteryl ester transfer protein in
normocholesterolemic and hypercholesterolemic hamsters: effects on
HDL subspecies, quantity, and apolipoprotein distribution. J. Lipid
Research. 35, 1634-1645). However, antibody and/or vaccine therapy
is not currently a viable option for the treatment of large
populations of patients in need of treatment for dyslipidemia and
resultant or associated disease state manifestations.
[0007] Cholesterol ester transfer protein (CETP) catalyzes the
exchange of neutral lipid between HDL and apoB-containing
lipoprotein particles. As a net result of this exchange, HDL
cholesterol is reduced and LDL particles are further enriched with
cholesterol, resulting in LDL cholesterol elevation and formation
of small dense LDL particles, which are believed to be more
atherogenic. CETP inhibition (small molecule, antibody, anti-sense
oligo etc.) effectively elevates HDL cholesterol and also reduces
LDL cholesterol in animal models as well as in humans (Whitlock, M.
et al., J. of Clin. Invest., 1989, Vol. 84, 129-137, Hirochi, O. et
al., Nature, 2000, Vol. 406, 203-207, Grooth, G. et al.,
Circulation, 2002; 105:2159-2165, Clark, R. et al., Arterioscler
Thromb Vasc Biol. 2004; 24:1-9, Brousseau M. et al., New Engl. J.
Med., 2004, Vol 350:1505-1515). Further, CETP inhibition leads to
the formation of less-dense LDL particles-a benefit in addition to
LDL cholesterol lowering (Brousseau M. et al., New Engl. J. Med.,
2004, Vol. 350:1505-1515). Thus, administration of CETP inhibitors
to humans in need thereof would significantly elevate HDL
cholesterol level and reduce LDL cholesterol levels and increase
LDL particle size, all of which are believed to benefit patients
exposed to atherosclerotic risks.
[0008] There have been several reports of small molecule CETP
inhibitors. Barrret et. al. (J. Am Chem. Soc., 188, 7863, (1996))
and Kuo et al. (J. Am. Chem. Soc., 117, 10629, (1995)) describe
cyclopropan-containing CETP inhibitors. Pietz onka et al. (Biorg.
Med. Chem. Lett. 6, 1951 (1996)) describe phosphanate-containing
analogs as CETP inhibitors. Coval et al. (Bioorg. Med. Chem. Lett.
5, 605, (1995)) describe Wiedendiol-A and -B related sesquiterpines
as CETP inhibitors. Japanese Patent Application No. 10287662-A
describes polycyclic, non-amine containing, polyhydroxylic natural
compounds possessing CETP inhibition properties. Lee et al. (J.
Antibiotics, 49, 693-96 (1996)) describe CETP inhibitors derived
from an insect fungus. Busch et al. (Lipids, 25, 216-220 (1990))
describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and
Zillversmit (J. Lipid Res., 35, 836-47 (1982)) describe that
p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl
mercurithiosalicylate inhibit CETP. Connolly et al. (Biochem.
Biophys. Res. Comm. 223, 42-47 (1996)) describe other cysteine
modification reagents as CETP inhibitors. Xia et al. Describe
1,3,5-triazines as CETP inhibitors (Bioorg. Med. Chem. Lett., 6,
919-22 (1996)). Bisgaier et al. (Lipids, 29, 811-8 (1994) describe
4-phenyl-5-tridecyl-4H-1,2,4-triazole-thiol as a CETP inhibitor.
Oomura et al., disclose non-peptidic tetracyclic and hexacyclic
phenols as CETP inhibitors in Japanese Patent Application No.
10287662.
[0009] U.S. Pat. No. 6,586,448 B1 describes
4-caboxamino-2-substituted-1,2,3,4-tetrahydroquinolines of formula
I ##STR2## and prodrugs thereof, and pharmaceutically acceptable
salts of said compounds and said prodrugs; 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 as defined therein. Similarly, PCT patent applications WO
03/063868A1, WO 0017164, No. 0017165, and WO 40017166, discloses
variously, formulations, methods of preparation and methods of use
of tetrahydroquinoline compounds generally related to that of U.S.
Pat. No. 6,586,448 B1 from which it derives or is a divisional
application thereof.
[0010] European Patent Application No. 818448 by Schmidt et al.
describes tetrahydroquinoline derivatives as cholesteryl ester
transfer protein inhibitors. European Patent Application No.
818197, Schmek et al., describe pyridines with fused heterocycles
as cholesteryl ester transfer protein inhibitors. Brandes et al. in
German Patent Application No. 19627430 describe bicyclic condensed
pyridine derivatives as cholesteryl ester transfer protein
inhibitors. In U.S. Pat. No. 6,207,671 Schmidt et al., describe
substituted pyridine compounds as CETP inhibitors. In WO Patent
Application No. 09839299, and WO Patent application No. 03028727 by
Muller-gliemann et al. and Erfinder/Anmelder respectively, describe
quinoline derivatives as cholesteryl ester transfer protein
inhibitors.
[0011] The above disclosures notwithstanding, a great need remains
for effective compounds useful as CETP inhibitors to treat
conditions caused by, associated with or exacerbated by
dyslipidemia.
SUMMARY OF THE INVENTION
[0012] The present invention provides a compound of formula I
##STR3## wherein n is 0, 1, 2, or 3; m is 0, 1, 2, 3, 4, 5 or 6; j
is 1 or 2; q is 0, 1, or 2; W, X, Y and Z are each independently
CH, C, N, S, or O with appropriate single or double bonds and/or
hydrogen atoms to complete valency requirements; Ring A is a five
or six member ring wherein one of W, X, Y or Z may be absent;
provided that ring A is not phenyl; K is a bond, C.dbd.O, or
S(O).sub.p; p is 0, 1 or 2; R.sup.1 is selected from a group
consisting of hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkylheterocyclic, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6
alkylcycloalkyl; C.sub.1-C.sub.6 alkylaryl, aryl, heterocyclyl,
C.sub.2-C.sub.6 alkylalcohol, --OC.sub.1-C.sub.6 alkyl, --O-aryl,
--OC.sub.2-C.sub.6 alkenyl, --OC.sub.1-C.sub.6 haloalkyl,
--OC.sub.1-C.sub.6 alkylheterocyclic, --OC.sub.3-C.sub.8
cycloalkyl, --OC.sub.1-C.sub.6 alkylcycloalkyl, --NR.sup.7R.sup.8,
--OC.sub.1-C.sub.6 alkylaryl, --O-heterocyclic,
--OC.sub.1-C.sub.6alkylCO.sub.2R.sup.11,
--OC.sub.2-C.sub.6alkylalcohol,
--OC.sub.1-C.sub.6alkylNR.sup.7R.sup.8, --OC.sub.2-C.sub.6cyano,
CONR.sup.11R.sup.12, NR.sup.11SO.sub.2R.sup.12,
NR.sup.11COR.sup.12, C.sub.0-C.sub.3 alkylNR.sup.11R.sup.12,
C.sub.1-C.sub.3 alkylCOR.sup.11, C.sub.0-C.sub.6 alkylCOOR.sup.11
and; provided that R.sup.1 is not hydroxy when K is S(O).sub.p, CO,
and/or when n and K are both zero; and wherein each cycloalkyl,
aryl or heterocyclic group is optionally substituted with 1 to 3
groups independently selected from oxo, hydroxy, halo,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkylalcohol, --OC.sub.2-C.sub.6alkylalcohol,
C.sub.1-C.sub.6 haloalkoxy, CONR.sup.11R.sup.12,
NR.sup.11SO.sub.2R.sup.12, NR.sup.11COR.sup.12, C.sub.0-C.sub.3
alkylNR.sup.11R.sup.12, C.sub.1-C.sub.3 alkylCOR.sup.11,
C.sub.0-C.sub.6 alkylCOOR.sup.11, C.sub.0-C.sub.6 alkylcyano,
--OC.sub.2-C.sub.6alkylcyano, C.sub.1-C.sub.6 alkylcycloalkyl,
phenyl, --OC.sub.1-C.sub.6 alkylcycloalkyl, --OC.sub.1-C.sub.6
alkylaryl, --OC.sub.1-C.sub.6 alkylheterocyclic, and
C.sub.1-C.sub.6 alkylaryl; R.sup.2 is independently selected from
the group consisting of hydrogen, halo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, OC.sub.1-C.sub.6 haloalkyl, OC.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkylaryl, aryl, C.sub.0-C.sub.6
alkylNR.sup.7R.sup.8, heteroaryl, heterocyclyl, C.sub.3-C.sub.9
cycloalkyl, C.sub.1-C.sub.6 alkylcycloalkyl and C.sub.1-C.sub.6
alkylheterocyclyl; wherein each cycloalkyl, aryl, or heterocyclic
is optionally substituted with 1 to 3 groups independently selected
from oxo, hydroxy, halo, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alcohol,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, CONR.sup.11R.sup.12, NR.sup.11SO.sub.2R.sup.12,
NR.sup.11COR.sup.12, C.sub.0-C.sub.3 alkylNR.sup.11R.sup.12,
C.sub.1-C.sub.3 alkylCOR.sup.11, C.sub.0-C.sub.6 alkylCOOR.sup.11,
cyano, and phenyl, and wherein two R.sup.2 groups may combine to
form a 3, 4 or 5 member spirocycle, or a five or six member
optionally substituted fused carbocyclic or heterocyclic ring;
R.sup.3 is hydrogen, C.sub.1-C.sub.6 alkyl, aryl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkylaryl,
C.sub.1-C.sub.6 alkylheterocyclic, C.sub.3-C.sub.8 cycloalkyl, or
C.sub.1-C.sub.6 alkylcycloalkyl; R.sup.4 is a group represented by
the formula --NR.sup.9R.sup.10; R.sup.5 is selected from the group
consisting of hydrogen, halogen, hydroxy, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
--OC.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkylcycloalkyl,
C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6 alkylheterocyclic, aryl,
C.sub.1-C.sub.6 alkylaryl, heteroaryl, --O-aryl, --OC.sub.2-C.sub.6
alkenyl, --OC.sub.1-C.sub.6 haloalkyl, --NR.sup.7R.sup.8, and
--OC.sub.1-C.sub.6 alkylaryl; and wherein when q is 1, 2 or 3, two
adjacent R.sup.5 groups may combine to form a fused 5 or 6 member
optionally substituted carbocyclic or heterocyclic ring; R.sup.6 is
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, --OC.sub.1-C.sub.6
alkyl, --O-aryl, --OC.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6
haloalkyl, --OC.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkylNR.sup.7R.sup.8, C.sub.3-C.sub.8 cycloalkyl, and
C.sub.1-C.sub.6 alkylcycloalkyl; R.sup.7 and R.sup.8 are
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.6 alkylcycloalkyl, C.sub.1-C.sub.6
alkylheterocyclic, heterocyclic, aryl, C.sub.1-C.sub.6 alkylaryl,
hydroxy, oxo, COOH, C(O)OC.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkylalcohol, C.sub.1-C.sub.6 alkylamine,
C.sub.2-C.sub.6 alkenylaryl, C.sub.2-C.sub.6 alkynylaryl,
C.sub.1-C.sub.6 alkyl-O--C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkyl-NR.sup.11--C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkylcyano, C.sub.1-C.sub.6 alkylCONR.sup.7R.sup.8, C.sub.1-C.sub.6
alkylNR.sup.7R.sup.8, C.sub.1-C.sub.6alkylNR.sup.11COR.sup.12
wherein each alkyl, cycloalkyl, heterocyclic, or aryl group is
optionally substituted with 1-3 groups independently selected from
hydroxy, oxo, amino, halogen, C.sub.1-C.sub.6 alkylcycloalkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkylheterocyclic,
C.sub.1-C.sub.6 haloalkyl, COOH, C(O)OC.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylalcohol, and
C.sub.1-C.sub.6 alkylamine and NR.sup.11R.sup.12; or R.sup.7 and
R.sup.8 combine to form a nitrogen containing heterocyclic ring
which may have 0, 1, or 2 additional hetero-atoms selected from
oxygen, nitrogen or sulfur and may be optionally substituted with
oxo, or C.sub.1-C.sub.6 alkyl; R.sup.9 is the group C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkylcycloalkyl, aryl, heterocyclic,
C.sub.1-C.sub.6 alkylheterocyclic, COR.sup.7, CO.sub.2R.sup.7,
C.sub.0-C.sub.3 alkylCONR.sup.7R.sup.8, C.sub.0-C.sub.3
alkylS(O).sub.pNR.sup.7R.sup.8, or C.sub.0-C.sub.3
alkylS(O).sub.pR.sup.7 wherein R.sup.7 is as defined above, and
wherein each alkyl, cycloalkyl, aryl, and heterocyclic is
optionally substituted with one to two groups independently
selected from halo, hydroxy, oxo, COOH, C(O)OC.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylalcohol, C.sub.1-C.sub.6 alkylamine,
C.sub.1-C.sub.6 alkylaryl, C.sub.2-C.sub.6 alkenylaryl,
C.sub.2-C.sub.6 alkylnylaryl, C.sub.1-C.sub.6 alkylheterocyclic,
--NR.sup.7R.sup.8, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6
alkylcycloalkyl, C.sub.1-C.sub.6 alkyl-O--C.sub.1-C.sub.6
alkylaryl, C.sub.1-C.sub.6 alkyl-NR.sup.2--C.sub.1-C.sub.6
alkylaryl, C.sub.1-C.sub.6 alkylcyano, C.sub.1-C.sub.6
alkylCONR.sup.7R.sup.8, C.sub.1-C.sub.6 alkylNR.sup.7R.sup.8,
C.sub.1-C.sub.6alkylNR.sup.11COR.sup.12, and aryl, wherein each
cycloalkyl or aryl group is optionally substituted with halo,
hydroxy, oxo, amino, COOH, C(O)OC.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylalcohol, and C.sub.1-C.sub.6 alkylamine;
R.sup.10 is selected from the group consisting of aryl,
C.sub.1-C.sub.6 alkylaryl, C.sub.2-C.sub.6 alkenylaryl,
C.sub.2-C.sub.6 alkynylaryl, C.sub.1-C.sub.6 haloalkylaryl,
C.sub.1-C.sub.6 alkylheterocyclic, C.sub.2-C.sub.6
alkenylheterocyclic, C.sub.1-C.sub.6 alkylcycloalkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6
alkyl-O--C.sub.1-C.sub.6 alkylaryl, and wherein each cycloalkyl,
aryl, or heterocyclic group is optionally substituted with 1-3
groups independently selected from the group consisting of hydroxy,
oxo, --SC.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkynyl, C.sub.1-C.sub.6
haloalkyl, halogen, C.sub.1-C.sub.6 alkoxy, aryloxy,
C.sub.1-C.sub.6 alkenyloxy, C.sub.1-C.sub.6 haloalkoxyalkyl,
C.sub.0-C.sub.6 alkylNR.sup.11R.sup.12, --OC.sub.1-C.sub.6
alkylaryl, nitro, cyano, --OC.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkylalcohol, and C.sub.1-C.sub.6 alkylalcohol;
R.sup.11 and R.sup.12 are independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkenyl, C.sub.3-C.sub.8 cycloalkyl, heterocyclic, aryl, and
C.sub.1-C.sub.6 alkylaryl, wherein each aryl group is optionally
substituted with 1-3 groups independently selected from halogen,
C.sub.1-C.sub.6 alkylheterocyclic, and C.sub.1-C.sub.6 haloalkyl,
or R.sup.11 and R.sup.12 combine to form a nitrogen containing
heterocyclic ring which may have 0, 1, or 2 additional heteroatoms
selected from oxygen, nitrogen or sulfur and is optionally
substituted with oxo, or C.sub.1-C.sub.6 alkyl; or a
pharmaceutically acceptable salt, solvate, enantiomer, racemate,
diastereomer or mixture of diastereomers thereof.
[0013] The present invention also provides a method for modulating
or regulating CETP activity comprising the use of a compound of
formula I or a pharmaceutically acceptable salt, solvate,
enantiomer, racemate, diastereomer or mixture of diastereomers
thereof, for the treatment, prevention or amelioration of CETP
mediated diseases.
[0014] The present invention provides a method for treating or
preventing dyslipidemia comprising administering a compound of
formula I, pharmaceutically acceptable salt, solvate, enantiomer,
racemate, diastereomer, mixture of diastereomers, or prodrug
thereof, to a patient in need thereof.
[0015] The present invention provides a method for treating or
preventing CHD comprising administering a compound of formula I,
pharmaceutically acceptable salt, solvate, enantiomer, racemate,
diastereomer, mixture of diastereomers, or prodrug thereof, to a
patient in need thereof.
[0016] The present invention provides a method for treating and/or
preventing artherosclerosis comprising administering a compound of
formula I, pharmaceutically acceptable salt, solvate, enantiomer,
racemate diastereomer, mixture of diastereomers, or prodrug
thereof, to a patient in need thereof.
[0017] The present invention provides a method for treating and/or
preventing diseases related to abnormal CETP activity comprising
administering a compound of formula I, pharmaceutically acceptable
salt, solvate, enantiomer, racemate diastereomer, mixture of
diastereomers, or prodrug thereof, to a patient in need
thereof.
[0018] The present invention provides a method for raising the
ratio of plasma HDL-cholesterol to plasma LDL-cholesterol in a
mammal comprising administering a therapeutically effective dose of
a compound of formula I, pharmaceutically acceptable salt, solvate,
enantiomer, racemate, diastereomer, mixture of diastereomers, or
prodrug thereof, to a patient in need thereof.
[0019] The present invention provides a method of raising the level
of plasma HDL-cholesterol in a mammal comprising administering a
therapeutically effective dose of a compound of formula I,
pharmaceutically acceptable salt, solvate, enantiomer, racemate,
diastereomer, mixture of diastereomers, or prodrug thereof, to a
patient in need thereof.
[0020] The present invention provides a method of lowering the
level of plasma LDL-cholesterol in a mammal comprising
administering a therapeutically effective dose of a compound of
formula I, pharmaceutically acceptable salt, solvate, enantiomer,
racemate, diastereomer, mixture of diastereomers, or prodrug
thereof, to a patient in need thereof.
[0021] The present invention also provides a pharmaceutical
composition comprising a compound of formula I or a
pharmaceutically acceptable salt, solvate, enantiomer, racemate,
diastereomer or mixture of diastereomers thereof, and a
carrier.
[0022] The present invention also provides a method of treating
and/or preventing the pathological sequelae due to low levels of
plasma HDL and/or high levels of LDL-cholesterol in a mammal
comprising administering an effective dose of a compound of formula
I, pharmaceutically acceptable salt, solvate, enantiomer, racemate,
diastereomer, or mixture of diastereomers, thereof, to a patient in
need thereof.
[0023] The present invention also relates to the use of a compound
of formula I for the manufacture of a medicament for treating
and/or preventing atherosclerosis in a mammal comprising
administering an effective dose of a compound of formula I,
pharmaceutically acceptable salt, solvate, enantiomer, racemate,
diastereomer, mixture of diastereomers, or prodrug thereof, to a
patient in need thereof.
[0024] The present invention also provides a combination therapy
involving a compound of formula I and one or more other effective
cardio protective agents such as, for example, statins, leptin,
and/or other LXR, CETP, ABC A1 or lipid regulating agents useful
for the treatment and/or prevention of dyslipidemia and/or
artherosclerosis.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The current invention provides novel compounds of formula I
useful in modulating CETP activity.
[0026] The terms "modulation" or "regulating" would include, but
not be limited to, up-regulation, down-regulation, inhibition,
agonism, antagonism of the CETP receptor as appropriate to achieve
HDL raising, or LDL lowering and the resulting biological sequelae
from such intervention.
[0027] The phrase "diseases" or "diseases related to abnormal
activity CETP" or "diseases mediated by CETP activity" refers to
pathological states where atherosclerosis and/or other
cardiovascular diseases are prone because of dyslipidemia and/or
other risk factors and are therefore beneficially affected by
modulation, particularly down-regulation, of CETP activity. These
diseases include but are not limited to hyperlipidemia and its
sequelae such as atherosclerosis, CHD, elevated blood pressure,
CHF, stroke, hypertension, hypertriglyceremia, diabetes, obesity,
inflammatory diseases including but not limited to dermatitis,
arthritis, and pain, and diseases of the central nervous system
including but not limited to dementia, cognitive disorders such as,
for example, Alzheimer's disease.
[0028] The term "treatment" bears its usual meaning which includes
prohibiting, inhibiting, ameliorating, halting, restraining,
slowing or reversing the progression, or reducing the severity of a
pathological symptom related to or resultant from the modulation of
CETP activity, especially as related to raising plasma levels of
HDL, or lowering LDL-cholesterol levels or raising the HDL/LDL
ratio or controlling atherosclerosis, hyperlipidemia and/or
hypercholesterolemia.
[0029] Generally, one of skill in the art is aware that valency
must be conserved (complete) for all stable molecules. Therefore,
the necessary implication that hydrogen atoms are necessary and
available to complete valency in all structures including formula I
unless expressly indicated otherwise, is imputed to the general
knowledge of one of skill in the art.
[0030] General chemical terms used in the description of compounds
herein described bear their usual meanings. For example, the term
"C.sub.1-6 alkyl," or "(C.sub.1-C.sub.6)alkyl" or "C.sub.1-C.sub.6
alkyl" refers to a straight or branched aliphatic chain of 1 to 6
carbon atoms including but not limited to methyl, ethyl, propyl,
iso-propyl, n-butyl, pentyl, and hexyl. Unless otherwise stated,
the term "alkyl" means C.sub.1-C.sub.6 alkyl. Similarly, the term
"C.sub.0-C.sub.6 alkyl" implies an alkyl group as indicated wherein
when the term C.sub.0 applies, the alkyl group is not present, and
the remaining groups attach directly to the substrate. For example
C.sub.0-C.sub.6 alkylcyano is the cyano group when C.sub.0 applies.
The invention also contemplates that the term C.sub.1-C.sub.6 alkyl
or C.sub.2-C.sub.6 alkenyl or similar terms also encompass the
specified alkyl or alkenyl or similar group, which may be chiral,
regio or steroisomeric. Such chiral or regio or stereo isomeric
groups are also objects of the present invention.
[0031] The term "alkylaryl" refers to an alkyl group substituted by
an aryl group. For example, C.sub.1-C.sub.6 alkylaryl indicates
that a C.sub.1-C.sub.6 alkyl group is attached to the aryl group,
and that the resulting C.sub.1-C.sub.6 alkylaryl is attached to the
nucleus via the alkyl group. Preferred alkylaryl groups include
phenylethyl (phenethyl), and benzyl.
[0032] The term "substituted phenyl" or "optionally substituted
phenyl" refers to a phenyl group having one or more substituents
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, hydroxy, COR.sup.7, --COOR.sup.7,
C.sub.0-C.sub.6 alkylNR.sup.7R.sup.8, nitro, chloro, fluoro, bromo,
iodo, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6 haloalkoxyalkyl,
and C.sub.0-C.sub.6 alkylheterocyclic.
[0033] The term "optionally substituted carbocyclic or heterocyclic
ring" refers to a saturated or unsaturated, aromatic or
non-aromatic five or six member ring having optional substituents
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, hydroxy, COR.sup.7, --COOR.sup.7,
C.sub.0-C.sub.6 alkylNR.sup.7R.sup.8, nitro, chloro, fluoro, bromo,
iodo, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6 haloalkoxyalkyl,
and C.sub.0-C.sub.6 alkylheterocyclic.
[0034] The term "aryl" refers to a substituted or unsubstituted
aromatic or heteroaromatic, or heterocyclic radical. Illustrative
aryl groups include but is not limited to napthyl, quinolyl,
tetrahydroquinolyl, indazolyl, pyrimidinyl, triazinyl, pyrazine,
pyridazinyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,
tetrahydrofuranyl, pyranyl, tetrazolyl, imidazolyl, 1,2,3-trazolyl,
1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl,
isoxazolyl, isothiazolyl, pyrazolyl, imidazopyridine,
benzimidazolyl, triazolone-yl, imidazolone-yl, imidazolidinone-yl,
2-furyl, 3-furyl, 2-thienyl 3-thienyl, 1-pyrrolyl, 2-pyrrolyl,
3-pyrrolyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-naphthyl,
2-naphthyl, 2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5-benzofuryl,
6-benzofuryl, 7-benzofuryl, 2-benzothienyl, 3-benzothienyl,
4-benzothienyl, 5-benzothienyl, 6-benzothienyl, 7-benzothienyl,
1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl,
tetrazole, imidazole, isoxazole, pyrazole, 7-indolyl, and isomers
thereof. As used herein the term aryl also encompasses the benzyl
group.
[0035] The term "C.sub.3-C.sub.8 cycloalkyl" or similar terms refer
to a saturated carbocyclic ring having from 3 to 8 carbon atoms
where the term "cycloalkyl" is used a carbocyclic ring having 3 to
8 carbon atoms is implied.
[0036] The term "carbocycle" as used herein refers to a cyclic
group having only carbon and appropriate number of hydrogen atoms.
The term encompasses groups such as cycloalkyl, cycloalkene,
cycloalkylene, naphthyl, phenyl and the like.
[0037] The term "heterocycle", "heterocyclyl", or "heterocyclic"
refers to a 5, 6, 7, 8, 9 or 10 member saturated, partially
unsaturated, or aromatic, mono-cyclic or a bicyclic ring containing
1-5 heteroatoms selected from N, S or O, wherein said heterocycle
is optionally substituted at carbon or nitrogen atom(s) unless
otherwise specified. Most preferred heterocyclic groups include
pyridinyl, pyrrolidinyl, piperidinyl, hexamethyleneimino,
morpholino, thiophene, indolyl, quinolyl, isoquinolyl, and
tetrazolyl.
[0038] As a corollary, the term "alkylheterocyclic" or
"alkylheterocycle" is understood to mean that the alkyl group is
attached to the heterocycle and the point of attachment to the
molecular backbone or nucleus is the alkyl group. The term "alkyl"
without a qualifier implies a C.sub.1-C.sub.6 alkyl group.
[0039] The term "haloalkoxyalkyl" as used herein include for
example trifluoromethoxy, pentafluoroethoxy, trifluoroethoxy
(OCH.sub.2CF.sub.3) and the like.
[0040] The term "Prodrugs" describes derivatives of the compounds
of the invention that have chemically or metabolically cleavable
groups and become by solvolysis or under physiological conditions
the compounds of the invention, which are pharmaceutically active,
in vivo. Derivatives of the compounds of this invention have
activity in both their acid and base derivative forms, but the acid
derivative form often offers advantages of solubility, tissue
compatibility, or delayed release in a mammalian organism (see,
Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier,
Amsterdam 1985). Prodrugs include acid derivatives, such as, esters
prepared by reaction of the parent acidic compound with a suitable
alcohol, or amides prepared by reaction of the parent acid compound
with a suitable amine. Simple aliphatic esters (e.g., methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl) or aromatic
esters derived from acidic groups pendent on the compounds of this
invention are preferred prodrugs. Other preferred esters include
morpholinoethyloxy, diethylglycolamide and
diethylaminocarbonylmethoxy. In some cases it is desirable to
prepare double ester type prodrugs such as (acyloxy) alkyl esters
or ((alkoxycarbonyl)oxy)alkyl esters.
[0041] As used herein, the term "protecting group" refers to a
group useful for masking reactive sites in a molecule to enhance
the reactivity of another group or allow reaction at another
desired site or sites following which the protecting group may be
removed. Protecting groups are usually used to protect or mask
groups including but not limited to --OH, --NH, and --COOH.
Suitable protecting groups are known to one of skill in the art and
are described in Protecting groups in Organic Synthesis, 3.sup.rd
edition, Greene, T. W.; Wuts, P. G. M. Eds., John Wiley and Sons,
New York, 1999.
[0042] As used herein, the term "solvate" is a form of the compound
of the invention wherein a crystal or crystals of a compound of the
invention have been formed from a stoichiometric or
non-stoichiometric amount of the compound of formula I and a
solvent. Typical solvating solvents include for example, water,
methanol, ethanol, acetone and dimethylformamide.
[0043] In those instances where a compound of the invention
possesses acidic or basic functional groups, various salts may be
formed which are more water soluble and/or more physiologically
suitable than the parent compound. Representative pharmaceutically
acceptable salts, include but are not limited to, the alkali and
alkaline earth salts such as lithium, sodium, potassium, calcium,
magnesium, aluminum and the like. Salts are conveniently prepared
from the free acid by treating the acid in solution with a base or
by exposing the acid to an ion-exchange resin.
[0044] Included within the definition of pharmaceutically
acceptable salts are the relatively non-toxic, inorganic and
organic base or acid addition salts of compounds of the present
invention. Base addition salts include for example, ammonium,
quaternary ammonium, and amine cations, derived from nitrogenous
bases of sufficient basicity to form salts with the compounds of
this invention (see, for example, S. M. Berge, et al.,
"Pharmaceutical Salts," J. Phar. Sci., 66: 1-19 (1977)). Moreover,
the basic group(s) of the compound of the invention may be reacted
with suitable organic or inorganic acids to form salts such as
acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, hydrobromide, camsylate, carbonate,
clavulanate, citrate, chloride, edetate, edisylate, estolate,
esylate, fluoride, fumarate, gluceptate, gluconate, glutamate,
glycolylarsanilate, hexylresorcinate, hydrochloride,
hydroxynaphthoate, hydroiodide, isothionate, lactate, lactobionate,
laureate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate,
oxalate, palmitate, pantothenate, phosphate, polygalacturonate,
salicylate, stearate, subacetate, succinate, tannate, tartrate,
tosylate, trifluoroacetate, trifluoromethane sulfonate, and
valerate. Preferred salts for the purpose of the invention include
the hydrochloride salt, the hydrobromide salt, the bisulfate salt,
the methane sulfonic acid salt, the p-toluenesulfonic acid salt,
bitartrate, the acetate and the citrate salt.
[0045] A compound of the invention as illustrated by formula I may
occur as any one of its positional isomers, stereochemical isomers
or regio-isomers, all of which are objects of the invention.
Certain compounds of the invention may possess one or more chiral
centers, and thus, may exist in optically active forms. Likewise,
when the compounds contain an alkenyl or alkenylene group, there
exist the possibility of cis- and trans-isomeric forms of the
compounds. The R- and S-isomers and mixtures thereof, including
racemic mixtures as well as mixtures of enantiomers or cis- and
trans-isomers, are contemplated by and within the purview of this
invention. Additional asymmetric carbon atoms can be present in a
substituent group such as an alkyl group. All such isomers as well
as the mixtures thereof are intended to be included in the
invention. If a particular stereoisomer is desired, it can be
prepared by methods well known in the art by using stereo-specific
reactions with starting materials that contain the asymmetric
centers and are already resolved. Alternatively desired
stereoisomers may be prepared by methods that lead to mixtures of
the stereoisomers and subsequent resolution by known methods. For
example, a racemic mixture may be reacted with a single enantiomer
of some other compound i.e. a chiral resolving agent. This changes
the racemic form into a mixture of stereoisomers and diastereomers,
because they have different melting points, different boiling
points, and different solubilities and can be separated by
conventional means, such as crystallization.
Preferred Embodiments of the Invention
Preferred n, m, p, j and q
[0046] Preferably n is 0, or 1.
[0047] Preferably m is 0, 1, 2 or 3. More preferably m is 0, 1 or
2.
[0048] Preferably p is 1, or 2.
[0049] Preferably j is 1 or 2. More preferably j is 1.
[0050] Preferably, q is 0, 1 or 2. More preferably q is 0 or 1.
Preferred A Ring
[0051] A preferred a ring is selected from the group consisting of
pyridine, pyrimidine, pyrazine, pyridazine, 1,2,5-triazine,
thiophene, furan, pyrrole, pyrazole, isoxazole, isothiazole,
imidazole, oxazole, thiazole, and 1,2,3-triazole. More preferred is
an A ring selected from the group consisting of pyridine, pyrazine,
thiophene, pyrazole, isoxazole, oxazole, and thiazole. Most
preferred A-ring is pyridine.
Preferred R.sup.1
[0052] A preferred R.sup.1 groups is selected from the group
consisting of hydroxy, hydrogen, --C.sub.1-C.sub.6 alkyl,
--C.sub.0-C.sub.6 alkylcycloalkyl, --C.sub.0-C.sub.6
alkylheterocyclic, --C.sub.1-C.sub.6 haloalkyl --OC.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 alkylaryl, --OC.sub.1-C.sub.6 alkyl,
--OC.sub.3-C.sub.8 cycloalkyl --OC.sub.1-C.sub.6 alkylcycloalkyl,
--OC.sub.1-C.sub.6 alkylcycloalkylNR.sup.7R.sup.8, C.sub.1-C.sub.6
alkoxy, --OC.sub.0-C.sub.6 alkylaryl, --OC.sub.1-C.sub.6haloalkyl,
OC.sub.1-C.sub.6alkylcyano, OC.sub.1-C.sub.6alkylCO.sub.2R.sup.11,
--OC.sub.1-C.sub.6alkylhydroxy, --OC.sub.3-C.sub.9
cycloalkylCO.sub.2R.sup.11, --OC.sub.1-C.sub.6 alkylNR.sup.7R.sup.8
and --OC.sub.1-C.sub.6 alkylheterocyclic provided that when K is
S(O).sub.pR.sup.7, R.sup.1 is not hydrogen; and wherein each alkyl,
cycloalkyl, aryl, or heterocyclic is optionally substituted with 1
or 2 groups selected from halogen, C.sub.0-C.sub.3 alkylalcohol,
C.sub.0-C.sub.3 alkylamine, C.sub.0-C.sub.3 alkylCOOH,
C.sub.0-C.sub.3alkylCONH.sub.2, C.sub.0-C.sub.3alkylcyano, and
C(O)OC.sub.1-C.sub.3 alkyl. More preferred is an R.sup.1 group
selected from hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkylaryl, --C.sub.1-C.sub.6 alkylcycloalkyl,
--C.sub.1-C.sub.6 alkylheterocyclic --OC.sub.1-C.sub.6 alkyl,
--OC.sub.0-C.sub.6 alkylaryl, --OC.sub.1-C.sub.6 alkylcycloalkyl,
--OC.sub.1-C.sub.6alkylcyano, --OC.sub.1-C.sub.6 alkylheterocyclic,
--OC.sub.1-C.sub.6 alkylhydroxy, --OC.sub.1-C.sub.6
alkylNR.sup.7R.sup.8, --OC.sub.1-C.sub.6alkylCO.sub.2R.sup.11,
heterocyclic, cycloalkyl, and --OC.sub.0-C.sub.6
alkylcycloalkylNR.sup.7R.sup.8 wherein each alkyl, cycloalkyl,
heterocyclic and aryl groups are each optionally substituted as
described herein. Most preferred is an R.sup.1 group represented by
--OC.sub.1-C.sub.6 alkyl
Preferred R.sup.2
[0053] A preferred R.sup.2 groups is selected from the group
consisting of hydrogen, C.sub.1-C.sub.6 alkyl, hydroxy,
C.sub.1-C.sub.6 haloalkyl, halo, C.sub.1-C.sub.6 alkylhalide,
--C.sub.1-C.sub.6 alkylcycloaryl, --C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkylaryl, --OC.sub.1-C.sub.6 alkyl,
--OC.sub.1-C.sub.6 haloalkyl, --OC.sub.1-C.sub.5 alkylcycloalkyl,
C.sub.0-C.sub.6 alkylNR.sup.7R.sup.8, --OC.sub.1-C.sub.6 alkylaryl,
--C.sub.1-C.sub.6 alkylheterocyclic, and --OC.sub.1-C.sub.6
alkylheterocyclic. More preferred is an R.sup.2 group selected from
hydroxy, C.sub.1-C.sub.6 alkyl, halo, --C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkylaryl and C.sub.1-C.sub.6 alkoxyalkyl. Most
preferred is an R.sup.2 group represented by hydrogen or
C.sub.1-C.sub.6 alkyl, or C.sub.3-C.sub.8 cycloalkyl.
Preferred R.sup.3 Groups
[0054] Preferably each R.sup.3 is hydrogen.
Preferred R.sup.4 Groups
[0055] A preferred R.sup.4 group is NR.sup.9R.sup.10. It is
understood by one of skill in the art that the carbon atom to which
R.sup.4 is attached also has a hydrogen substituent to complete
valency requirements. Preferably, the group --NR.sup.9R.sup.10 is
represented by a group selected from the group consisting of:
##STR4## ##STR5## wherein R.sup.7 is as defined above.
[0056] Also preferred are R.sup.9 groups selected from the group
consisting of CO.sub.2R.sup.7, CONR.sup.7R.sup.8,
S(O).sub.2NR.sup.7R.sup.8, or S(O)R.sup.7 wherein R.sup.7 is as
defined above.
[0057] More preferably, R.sup.4 is NR.sup.9R.sup.10, wherein
R.sup.10 is a mono or di-substituted haloalkylbenzyl, and R.sup.9
is heterocyclic selected from the group consisting of: ##STR6##
##STR7## wherein R is H, OH, NR.sup.7R.sup.8 or C.sub.1-C.sub.3
alkyl wherein C.sub.1-C.sub.3 alkyl group is optionally substituted
with OH, halo, cyano, CC)NR.sup.7R.sup.8, CO.sub.2R.sup.11 or
NH.sub.2, NR.sub.7R.sub.8 Preferred R.sup.5 Groups
[0058] R.sup.5 is preferably selected from a group consisting of
hydrogen, halogen, hydroxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkenyl, C.sub.1-C.sub.6
alkylheterocyclic, C.sub.1-C.sub.6 alkylaryl, aryl,
--OC.sub.1-C.sub.6 alkyl, aryloxy (--O-aryl), --OC.sub.2-C.sub.6
alkenyl, --OC.sub.1-C.sub.6 haloalkyl,
--NR.sup.7R.sup.8--CH.sub.2NR.sup.7R.sup.8, --NH.sub.2, --CN,
--COOH, and NO.sub.2;
[0059] More preferably, R.sup.5 is at each occurrence is
independently selected from the group consisting of hydrogen,
halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 haloalkyl,
--NR7R8-O C.sub.1-C.sub.3 alkyl, and C.sub.1-C.sub.3
haloalkoxy.
Preferred R.sup.6
[0060] R.sup.6 is preferably selected from a group consisting of
hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkenyl, C.sub.0-C.sub.6 alkylheterocyclic,
C.sub.1-C.sub.6 alkylaryl, aryl, C.sub.2-C.sub.6 alkoxy, aryloxy,
--OC.sub.2-C.sub.6 alkenyl, --CH.sub.2NR.sup.7R.sup.8, --NH.sub.2,
and NO.sub.2.
More preferably, R.sup.6 is at each occurrence independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.6
alkyl, and optionally substituted cycloalkyl.
Preferred R.sup.7 and R.sup.8
[0061] Preferred R.sup.7 and R.sup.8 are independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkylaryl, and
C.sub.1-C.sub.6alkylheterocyclic, wherein each aryl group is
optionally substituted with 1-3 groups independently selected from
C.sub.1-C.sub.6 alkyl, halo, and C.sub.1-C.sub.6 haloalkyl.
Preferred R.sup.11 and R.sup.12
[0062] Preferred R.sup.1 and R.sup.12 are independently selected
from a group consisting of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkylaryl, and
C.sub.1-C.sub.6alkylheterocyclic, wherein each aryl group is
optionally substituted with 1-3 groups independently selected from
C.sub.1-C.sub.6 alkyl, halo, and C.sub.1-C.sub.6 haloalkyl.
[0063] A most preferred compound of the invention is a compound
selected from the group consisting of: [0064]
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-thie-
no[3,4-b]azepine-1-carboxylic acid isopropyl ester, [0065]
8-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-3-methyl-5,6,7,8-tetrah-
ydro-thieno[3,2-b]azepine-4-carboxylic acid isopropyl ester, [0066]
8-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-bromo-5,6,7,8-tetrahy-
dro-thieno[3,2-b]azepine-4-carboxylic acid isopropyl ester, [0067]
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-5,6,7,8-tetrahydro-pyri-
do[2,3-b]azepine-9-carboxylic acid isopropyl ester, [0068]
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-pyri-
do[3,4-b]azepine-1-carboxylic acid isopropyl ester, [0069]
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-pyri-
do[4,3-b]azepine-1-carboxylic acid isopropyl ester, [0070]
9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-6,7,8,9-tetrahydro-pyri-
do[3,2-b]azepine-5-carboxylic acid isopropyl ester, [0071]
9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-6,7,8-
,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl
ester, [0072]
9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-3-trifluorometh-
yl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
isopropyl ester, [0073]
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-thie-
no[3,4-b]azepine-1-carboxylic acid isopropyl ester, [0074]
8-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-3-methyl-5,6,7,8-tetrah-
ydro-thieno[3,2-b]azepine-4-carboxylic acid isopropyl ester, [0075]
4-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-1-methyl-4,5,6,7-tetrah-
ydro-1H-1,2,8-triaza-azulene-8-carboxylic acid isopropyl ester,
[0076]
9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-chloro-6,7,8,9-tetrahyd-
ro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester, [0077]
9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-methoxy-6,7,8,9-tetrahy-
dro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester, [0078]
9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-bromo-6,7,8,9-tetrahydr-
o-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester, [0079]
9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-dimethylamino-6,7,8,9-t-
etrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester,
[0080]
9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-methyl-6,7,8,9-tetrahyd-
ro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester, [0081]
9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-cyano-6,7,8,9-tetrahydr-
o-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester, [0082]
9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-3-chloro-2-methoxy-6,7,8,-
9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl
ester, [0083]
9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-3-chloro-2-ethoxy-
-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
isopropyl ester, [0084]
9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)amino]-2-methyl-3-trifluorometh-
yl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
isopropyl ester, [0085]
9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)amino]-2-methyl-3-trifluorometh-
yl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
tert-butyl ester, [0086]
9-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-2-m-
ethyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxyl-
ic acid isopropyl ester, [0087]
9-[(3,5-Bis-trifluoro-ethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-2-m-
ethyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxyl-
ic acid tert-butyl ester, [0088]
(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-2-methyl-3-trifluor-
omethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine, [0089]
(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopropylmethyl-2-methyl-3-trifluor-
omethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine, [0090]
(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-5-pyridin-3-ylmethyl-3-trifluo-
romethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-(2-methyl-2H-tetr-
azol-5-yl)-amine, [0091]
(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-5-pyridin-4-ylmethyl-3-trifluo-
romethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-(2-methyl-2H-tetr-
azol-5-yl)-amine, [0092]
3-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-
-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepin-5-ylmet-
hyl}-benzoic acid, [0093]
4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-amino]--
2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepin-5-ylmeth-
yl}-benzoic acid, [0094]
5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-amino]--
2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepin-5-yl}-3,-
3-dimethyl-pentanoic acid, [0095]
(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepin-5-ylme-
thyl}-cyclohexyl)-acetic acid, [0096]
(3,5-Bis-trifluoromethyl-benzyl)-(5-ethyl-2-methyl-3-trifluoromethyl-6,7,-
8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-(2-methyl-2H-tetrazol-5-yl)-am-
ine, [0097]
5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-
-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepin-5-ylmet-
hyl}-thiophene-2-carboxylic acid, [0098]
2-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-
-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepin-5-yl}-e-
thanol, [0099]
(5-Benzyl-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]a-
zepin-9-yl)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mine, [0100]
(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(2-methyl-5--
thiazol-2-ylmethyl-3-trifluoromethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]az-
epin-9-yl)-amine, [0101]
9-[(3,5-Bis-trifluoro-ethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2--
methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxy-
lic acid tetrahydro-furan-3-yl ester, [0102]
(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-5-pyridin-4-ylmethyl-3-trifluo-
romethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-carbamic
acid methyl ester, [0103]
N-(3,5-Bis-trifluoromethyl-benzyl)-N-(2-methyl-5-pyridin-4-ylmethyl-3-tri-
fluoromethyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-9-yl)-acetamide
or a pharmaceutically acceptable salt, solvate enantiomer or
diastereomer or mixture thereof.
[0104] The positional isomers and geometric isomers associated with
the asymmetric carbon atoms of compounds of formula I are also
contemplated to be within the scope of the current invention as
useful for the treatment of diseases related to CETP
modulation.
Synthesis of Compounds of the Invention
[0105] The compounds of the instant invention can be synthesized as
exemplified in the following schemes. Aryl amino ester
intermediates of Formula 1 can be chemically prepared, for example,
by following the synthetic routes set forth in the Schemes below.
However, the following discussion is not intended to be limiting to
the scope of the present invention in any way. The reagents and
starting materials are readily available to one of ordinary skill
in the art. Other necessary reagents and starting materials may be
made by procedures which are selected from standard techniques of
organic and heterocyclic chemistry, techniques which are analogous
to the syntheses of known structurally similar intermediates or
starting materials and the procedures described in the preparations
and examples below, including any novel procedures. Such known
procedures include, but are not limited to, esterification of a
carboxylic acid, hydrolysis of a nitrile to a carboxylic acid, and
subsequent esterification. In addition, one of ordinary skill will
appreciate that many of the necessary reagents or starting
materials can be readily obtained from commercial suppliers or
custom synthesis groups. The R, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, W, X, Y, Z, etc, used within this section for the
purpose of illustrating the various methods of synthesizing
compounds of the invention are not necessarily synonymous in scope
or meaning with similar groups used in the generic structure for
compounds of formula I, assuming W, X, Y, Z do not all equal
carbon. However, groups in similar positions are co-extensive in
scope and meaning compared to groups occupying similar positions as
defined for the generic structure of compounds of formula I.
##STR8##
[0106] Synthetic scheme 1 shows preparation of compounds of formula
I wherein j is 1 and n is 0. For example, substituted
heteroarylamino esters 1 that are either commercially available or
prepared as set forth in the literature or in Schemes 1a to 1d can
be protected with tosyl chloride, isopropyl chloroformate, or other
suitable protecting group to provide 2. The compound 2 may in turn
be alkylated with appropriately substituted, or unsubstituted
3-bromopropanoic acid esters 11 thus affording 3. Dieckmann
condensation-cyclization of intermediate 3 yields N-protected
heteroarylazepine 4, which is subjected to acid hydrolysis and
decarboxylation to afford heteroarylazepin-5-one derivatives 5.
Removal of the protecting group, if necessary, with acid (e.g. PPA
(polyphosphoric acid)), TMSI (trimethylsilyliodide), or HCl
provides the intermediate heteroarylazepin-5-one 6. Alternatively,
utilizing the same conditions to effect 7 to 8, one can proceed
directly to 8 without deprotection.
[0107] N-acylation of 6 by treatment with an appropriately
substituted aryl or alkyl chloroformate in the presence of an
organic base such as pyridine affords carbamates of structure 7.
Alternatively, treatment of 6 with an acid chloride or an
appropriate activated ester, such as those generated in-situ from
the reaction of an appropriately substituted aryl or alkyl
carboxylic acid affords compounds of formula 7.
[0108] Generation of urea derivatives from 6 is accomplished by
treatment with a carbamoyl chloride in the presence of base such as
pyridine and DMAP (dimethylamino pyridine) or an alternative base
such as NaH in DMF. Alternatively, treatment with phosgene, or
carbodiimide (CDI) reagent such as cyclohexylcarbodiimide or analog
thereof, followed by the addition of an appropriately
di-substituted amine will afford ureas of structure 7. Formation of
sulfonamide derivatives from 6 can be accomplished by reaction with
appropriately substituted sulfonyl chlorides in the presence of a
base.
[0109] Conversion of ketone 7 to 10 may be performed through direct
reductive amination with an appropriately substituted alkylamine or
aryl amine to afford compound 9. Alternatively, compound 9 may be
prepared through formation of the amine derivate 8 by reduction of
an intermediate oxime, followed by alkylation with an appropriately
substituted benzylic halide, mesylate or tosylate, or by reductive
alkylation with the appropriate aldehyde or ketone in the presence
of a reducing reagent such as NaCNBH.sub.3. Compound 9 is converted
to 10 (a compound of the invention) by acylation with an
appropriately substituted symmetrical anhydride or acid halides to
afford amides. Reaction of compound 9 with chloroformates affords
the corresponding carbamates, Reaction of 9 with isocyanates,
carbamoyl chlorides, or appropriately substituted sulfonyl
chlorides affords the corresponding urea or sulfonamides
respectively.
[0110] The intermediate compound (I) may be prepared as shown and
described in schemes 1a through 1d below: ##STR9##
[0111] In scheme 1a, the nucleophilic aromatic substitution occurs
by methods known in the art, (Wells, K. M. et al. Tetrahedron
Letters, 1996, 37(36), 6439-6442). The appropriately substituted
amine 14, such as benzylamine, is dissolved in a suitable solvent,
such as DMF or DMSO. A base such as cesium carbonate is added. The
appropriately substituted fluoro heterobenzoate or
heterobenzonitrile 13 (R.sup.6.dbd.CN or CO.sub.2R.sup.3), such as
methyl fluoronicotinate ester is also added. The reaction proceeds
at 0.degree. C. to elevated (up to about 150.degree. C.)
temperatures in anywhere from ten minutes to several days depending
on the stability of the starting materials. The product of
structure 15 (R.sup.6.dbd.CN) or 1 (R.sup.6.dbd.CO.sub.2R.sub.3)
can then be isolated by a standard aqueous workup, followed by
normal phase chromatographic methods or recrystallization
techniques commonly employed in the art. ##STR10##
[0112] In scheme 1b, the N-Aryl coupling occurs by methods known in
the art, (Hartwig, J. F. et al. Angew. Chem., Int. Ed. Engl. 1998,
37, 2046-2067). The appropriately substituted amine 14 is dissolved
in a suitable solvent, such as DMF. A base, such as cesium
carbonate or sodium tert-butoxide, the appropriately substituted
halogenated heterobenzoate or heterobenzonitrile 16 (R.sup.6.dbd.CN
or CO.sub.2R.sup.3), and a suitable catalyst complex, such as
palladium acetate and diphenyl phospino ferrocene ligand are added.
The reaction proceeds at 0.degree. C. to elevated temperatures (up
to 150.degree. C.) in anywhere from ten minutes to several days
depending on the stability of the starting materials. The product
of structure 15 (R.sup.6.dbd.CN) or 1 (R.sup.6.dbd.CO.sub.2R.sup.3)
can then be isolated by a standard aqueous workup, followed by
normal phase chromatographic methods or recrystallization
techniques commonly employed in the art. ##STR11##
[0113] In scheme 1c, the carbonylation occurs by methods known in
the art, (Heck, Palladium Reagents in Organic Synthesis; Academic
Press: New York, 1985, p. 348-358). The appropriately substituted
heteroaryl bromide 17 is dissolved in a suitable solvent, such as
DMF, followed by addition of a base, such as cesium carbonate or
sodium tert-butoxide/A suitable catalyst complex, such as palladium
acetate and diphenyl phospino ferrocene, an appropriate alcohol
(R.sup.3--OH) are added. The reaction mixture is then saturated
with carbon monoxide. The reaction proceeds at 0.degree. C. to
elevated temperatures (up to about 150.degree. C.) in anywhere from
ten minutes to several days depending on the stability of the
starting materials. The reaction may also be preformed under
pressure using procedures known to one of skill in the art. The
product of structure 1 may then be isolated by a standard aqueous
workup, optionally followed by normal phase chromatographic methods
or recrystallization techniques commonly employed in, the art.
##STR12##
[0114] In scheme 1d, the aromatic carboxylation occurs by methods
known in the art, (Boger, D. L. et al., Journal of Organic
Chemistry, 1994, 59(17), 4943-4949, Volpin et al., Organomet.
Reactions, 1975, 5, 313-386). The appropriately substituted
heteroaryl bromide 17 is dissolved in a suitable solvent, such as
diethyl ether or tetrahydrofuran. An alkyl lithium, such as n-butyl
lithium or tert-butyl lithium or magnesium turnings is added. The
resulting anion is quenched with a suitable carbon dioxide source,
such as dry ice, or dimethyl carbonate. The reaction proceeds at
-78.degree. C. to room temperature in anywhere from about five
minutes to several hours depending on the stability of the starting
materials. The product of structure 1 can then be isolated by a
standard aqueous workup, followed by normal phase chromatographic
methods or recrystallization techniques commonly employed in the
art. ##STR13##
[0115] In scheme 2, the ring nitrogen of compound 6 can be
alkylated by methods known in the art (Tetrahedron, 2002, 58 (43),
8719-8727) such as by treating the appropriately substituted
heterobenzazapine, 6, with a base such as sodium carbonate or
sodium hydride, and an alkylating agent, such as methyl
bromoacetate or chloroacetonitrile, to afford the intermediate 18.
The final product 21 can then be obtained according to the
procedure described in scheme 1.
[0116] Compounds of the invention wherein j is 2, i.e.
heterobenzazacines may be prepared following the procedure of
scheme 3 below: ##STR14##
[0117] Under conditions similar to those of Scheme 1,
heterobenzazacine compounds of formula I (30) are prepared
utilizing the steps outlined in Scheme 3. By using an appropriately
substituted bromo propionate 22, followed by a Dieckmann
condensation-cyclization, the heterobenzazacin-ones 24 may be
synthesized. Further elaborations of 24 to final products 30
proceed according to Scheme 1. ##STR15##
[0118] In Scheme 4, the lower nitrogen can be alkylated by methods
known in the art (Tetrahedron, 2002, 58 (43), 8719-8727) such as by
treating the appropriately substituted heterobenzazapine 26, with
base and an alkylating agent, such as methyl bromoacetate or
chloroacetonitrile, to afford intermediate 31. The final product 34
may then be obtained according to the procedure described in Scheme
1.
[0119] Compounds of formula I wherein neither R.sup.4 nor R.sup.3
is hydrogen and both R.sup.4 and R.sup.3 are not NR.sup.9R.sup.10
may also be prepared as shown below in scheme 5 for j is 1.
##STR16##
[0120] Installation of substituents alpha to the carbonyl of
1-heterobenzazapin-5-one 5 can be accomplished for example
according to the method outlined in scheme 5 by enolate formation
followed by alkylation with an appropriate alkyl halide. Conversion
of 35 to 36 is as described, for example in Scheme 1. ##STR17##
[0121] As shown in Scheme 6, amine 9 can be treated with for
example cyanogen bromide or N-cyano imidazole in the presence or
absence of base to form the N-cyano derivative 37. The synthesis of
imidazole 38, tetrazole 39, triazole 40 and oxadiazole 41 is
illustrated in the scheme. Tetrazole 39 can be alkylated using the
appropriate alcohol under Mitsunobu conditions, or with the
appropriate alkyl iodide, mesylate, or the like in the presence of
base to provide 42. Triazole 40 can be alkylated using an
appropriate alkyl iodide, mesylate, or the like in the presence of
base to afford 43. ##STR18##
[0122] As shown in scheme 7 compound 9 can be transformed to 44 by
reaction with diketene or a .alpha.-haloketone, further treatment
with hydroxylamine hydrochloride can afford isoxazole 45.
Alternatively 45 can react with hydrazine in a solvent such as
ethanol to afford pyrazole 47 that can be alkylated or acylated to
give rise compound 48. Or alternatively compound 45 can be
converted into the oxazole 49 by treatment with sodium azide and
methanesulfonic acid. ##STR19## ##STR20##
[0123] As shown in scheme 8, secondary amine 9 can be transformed
in the acyl chloride 50 by treatment with triphosgene. Compound 50
may be converted into the oxadiazole 51 by reaction with an
appropriate amidoxime. Alternatively 50 can be reacting with
hydrazine to yield compound 53, that after treatment with an
appropriate acyl chloride in a presence of ammonia can yield
triazole 56 or in the presence of acid such as sulfuric acid and
water can give rise the oxadiazole 57. Compound 50 can be treated
with ammonia to yield the ureido derivative 53 that can be
transformed into oxazole 55 by reaction with an .alpha.-haloketone
in the presence of a base. Alternatively compound 53 can be first
converted to the corresponding thioamide with Lawesson's reagent
and after reaction with a .alpha.-haloketone can afford the
thiazole 54. ##STR21##
[0124] As shown in scheme 9, compound 59 may be hydrolyzed to the
corresponding amine 60, and may be further acylated using standard
procedures by one skilled in the art to provide 64. Alternatively,
60 can be treated with triphosgene or trichloromethylchoroformate
to provide 61. Compound 61 can afford compound 59 by reaction with
the appropriate alcohols.
Assay
[0125] The following assay protocol and result(s) thereof
demonstrating the utility and efficacy of the compounds and/or
methods of the current invention are given for the purpose of
illustration and are not meant to be limiting in any way.
In Vitro Cetp Inhibitor Assay: Spa Assay
[0126] An in vitro Scintillation proximity assay (SPA) has been
used to test the ability of compounds of this invention to inhibit
the transfer of radiolabeled cholesterol esters between HDL and
LDL. This assay monitors the inhibition of the transfer of
[.sup.3H]cholesterol esters from HDL (Amersham) to biotinylated LDL
(Amersham) by a CETP source. CETP produced by AV-12 cells that have
been created to express human CETP has been used to mediate the
transfer. After 30 minutes incubation in which the radiolabeled
cholesterol ester is transferred in a HEPES-NaCl based buffer, the
reaction is stopped and the biotinylated LDL is bound to
streptavidin/scintillant coated SPA beads (Amersham). Then the
radioactive signal is measured in a Packard 96-well scintillation
TopCounter with window settings fully open. A decrease in
radioactive signal represents the ability of compounds of the
invention to inhibit the activity of CETP.
[0127] Alternatively, additional CETP sources can be used to
mediate the transfer of radiolabeled cholesterol ester in this
assay Endogenous CETP from human plasma, CETP from mice made to
express human CETP, and endogenous CETP from hamsters can be used
as the CETP source in this assay.
[0128] Alternatively, other sources may be used as the buffer. In
addition to the HEPES-NaCl based buffer that has been used in this
assay, human plasma, mouse plasma or a Tris-buffer that is high in
albumin may be used as the buffer in which the transfer of
radiolabeled cholesterol esters from HDL to LDL may occur.
[0129] Alternatively, other sources of radioactivity may be used to
track the CETP activity in this assay. In yet another alternative,
radiolabeled-LDL may be used in this assay.
[0130] Compounds of the present invention tested have shown
inhibition of CETP activity below about 100 micromolar when
subjected to the SPA assay procedure above.
Assay of Cetp Activity In Vivo.
[0131] Syrian Golden Hamsters, which express endogenous CETP, are
used to assess the activity of the compounds in vivo. Test
compounds are administered orally in selected aqueous or oil based
vehicles for up to one week. At various times after dosing, ranging
from 4 h to 48 h, blood can be obtained. CETP activity is
determined by a method similar to that described for the in vitro
CETP activity assay, except that plasma from treated animals is
used as the CETP source in the assay.
[0132] A strain of transgenic mice that express human CETP
(Taconic, Germantown, N.Y.) are used to test compounds of this
invention. Test compounds are administered orally in selected
aqueous or oil based vehicles for up to one week. At various times
after dosing, ranging from 4 h to 48 h, blood can be obtained. CETP
activity is determined by a method similar to that described for
the in vitro CETP activity assay, except that plasma from treated
animals is used as the CETP source in the assay.
[0133] Alternatively, a strain of transgenic mice that express both
human CETP and human apolipoprotein A-1 (Taconic, Germantown, N.Y.)
are used to test compounds of this invention. Test compounds are
administered orally in selected aqueous or oil based vehicles for
up to one week. At various times after dosing, ranging from 4 h to
48 h, blood is obtained. CETP activity is determined by a method
similar to that described for the in vitro CETP activity assay,
except that plasma from treated animals is used as the CETP source
in the assay.
Assay of Plasma Lipids In Vivo.
[0134] Activity of compounds of this invention in vivo can be
determined by the level of elevation of HDL cholesterol relative to
control by a given amount of compound in a CETP-containing animal
species. A strain of transgenic mice that express both human CETP
and human apolipoprotein A-1 (Taconic, Germantown, N.Y.) is used to
test compounds of this invention. Test compounds are administered
once orally in selected aqueous or oil based vehicles. At various
times after dosing, ranging from 4 h to 24 h, blood is obtained.
Blood is allowed to clot and serum is obtained by centrifugation.
HDL cholesterol levels in the serum is determined by HDL-C plus
reagents (Roche/Hitachi, Indianapolis, Ind.) with a clinical
chemistry analyzer (Roche/Hitachi, Indianapolis, Ind.). Additional
serum lipids can be analyzed by enzymatic methods. Lipids in the
VLDL, LDL and HDL fractions are analyzed by enzymatic methods after
precipitation or size exclusion chromatography. An example of the
elevation of HDL cholesterol levels at 8 hr are summarized in table
1 TABLE-US-00001 TABLE 1 Elevation of HDL cholesterol levels at 8
hr Compound Single Oral % HDL of Example Dose cholesterol No.
(mg/kg) increase 14 30 91
[0135] The efficacy of compounds of the invention in vivo can also
be determined utilizing Syrian Golden Hamsters. The compounds can
be tested in hamsters made hypercholesterolemic by feeding a high
fat high cholesterol diet for a minimum of two weeks or in
non-hypercholesterolemic hamsters fed normal chow for two weeks.
Test compounds can be administered orally in selected aqueous or
oil based vehicles for up to 1 week. Serum can be obtained and
lipids can be analyzed by enzymatic methods. Lipids in the VLDL,
LDL and HDL fractions are analyzed by enzymatic methods after
precipitation or size exclusion chromatography.
[0136] Alternatively, a strain of transgenic mice that express
human CETP (Taconic, Germantown, N.Y.) are used to test the
efficacy of the compounds of this invention. The hCETP mice can be
made hypercholesterolemic by feeding a high fat chow diet such as
TD 88051, as described by Nishina et al. (J Lipid Res., 31, 859-869
(1990)) for at least two weeks before the start of the study. Test
compounds can be administered orally in selected aqueous or oil
based vehicles for up to 1 week. Serum can be obtained and lipids
can be analyzed by enzymatic methods. Lipids in the VLDL, LDL and
HDL fractions are analyzed by enzymatic methods after precipitation
or size exclusion chromatography.
Method of Treatment
[0137] As used herein, the term "effective amount" means an amount
of compound of the present invention, i.e., formula I, which is
capable of alleviating the symptoms of the various pathological
conditions herein described. The specific dose of a compound
administered according to this invention will, of course, be
determined by the particular circumstances surrounding the case
including, for example, the compound administered, the route of
administration, the state of being of the patient, and the
pathological condition being treated. A typical daily dose will
contain a nontoxic dosage level of from about 0.01 mg to about 100
mg/day of a compound of the present invention. Preferred daily
doses generally will be from about 1 mg to about 250 mg/day.
[0138] The compounds of this invention can be administered by a
variety of routes including oral, rectal, transdermal,
subcutaneous, intravenous, intramuscular, and intranasal. These
compounds preferably are formulated prior to administration, the
selection of which will be decided by the attending physician.
Thus, another aspect of the present invention is a pharmaceutical
composition comprising an effective amount of a compound of Formula
I, or a pharmaceutically acceptable salt thereof, solvate, prodrug,
enantiomer or prodrug thereof, and a pharmaceutically acceptable
carrier, diluent, or excipient.
[0139] The total active ingredients in such formulations comprises
from 0.1% to 99.9% by weight of the formulation. By
"pharmaceutically acceptable" it is meant the carrier, diluent,
excipients and salt must be compatible with the other ingredients
of the formulation, and not deleterious to the recipient
thereof.
[0140] Pharmaceutical formulations of the present invention can be
prepared by procedures known in the art using well-known and
readily available ingredients. For example, the compounds of
formula I can be formulated with common excipients, diluents, or
carriers, and formed into tablets, capsules, suspensions, powders,
and the like. Examples of excipients, diluents, and carriers that
are suitable for such formulations include the following: fillers
and extenders such as starch, sugars, mannitol, and silicic
derivatives; binding agents such as carboxymethyl cellulose and
other cellulose derivatives, alginates, gelatin, and
polyvinyl-pyrrolidone; moisturizing agents such as glycerol;
disintegrating agents such as calcium carbonate and sodium
bicarbonate; agents for retarding dissolution such as paraffin;
resorption accelerators such as quaternary ammonium compounds;
surface active agents such as cetyl alcohol, glycerol monostearate;
adsorptive carriers such as kaolin and bentonite; and lubricants
such as talc, calcium and magnesium stearate, and solid polyethyl
glycols.
[0141] The compounds also can be formulated as elixirs or solutions
for convenient oral administration or as solutions appropriate for
parenteral administration, for example, by intramuscular,
subcutaneous or intravenous routes. Additionally, the compounds are
well suited to formulation as sustained release dosage forms and
the like. The formulations can be so constituted that they release
the active ingredient only or preferably in a particular
physiological location, possibly over a period of time. The
coatings, envelopes, and protective matrices may be made, for
example, from polymeric substances or waxes.
[0142] Compounds of formula I, generally, will be administered in a
convenient formulation as determined by the attending physician.
The following formulation examples are only illustrative and are
not intended to limit the scope of the present invention.
Formulations
[0143] In the formulations which follow, "Active Ingredient" means
a compound of formula I, a salt, solvate, racemate, enantiomer
diastereomer or mixture of diastereomers, or prodrug thereof, or a
combination of a compound of formula I and other effective agent
for the treatment or prevention of dyslipidemia or
atherosclerosis.
Formulation 1: Gelatin Capsules
[0144] Hard gelatin capsules are prepared using the following:
TABLE-US-00002 Ingredient Quantity (mg/capsule) Active ingredient
0.1-1000 Starch, NF 0-650 Starch flowable powder 0-650 Silicone
fluid 350 centistokes 0-15
[0145] The formulation above may be changed in compliance with the
reasonable variations provided.
[0146] A tablet formulation is prepared using the ingredients
below:
[0147] Formulation 2: Tablets TABLE-US-00003 Ingredient Quantity
(mg/tablet) Active ingredient 2.5-1000 Cellulose, microcrystalline
200-650 Silicon dioxide, fumed 10-650 Stearate acid 5-15
The components are blended and compressed to form tablets.
[0148] Alternatively, tablets each containing 2.5-1000 mg of active
ingredient are made up as follows:
[0149] Formulation 3: Tablets TABLE-US-00004 Ingredient Quantity
(mg/tablet) Active ingredient 25-1000 Starch 45 Cellulose,
microcrystalline 35 Polyvinylpyrrolidone 4 (as 10% solution in
water) Sodium carboxymethyl cellulose 4.5 Magnesium stearate 0.5
Talc 1
[0150] The active ingredient, starch, and cellulose are passed
through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution
of polyvinylpyrrolidone is mixed with the resultant powders that
are then passed through a No. 14 mesh U.S. sieve. The granules so
produced are dried at 50-60.degree. C. and passed through a No. 18
mesh U.S. sieve. The sodium carboxymethyl starch, magnesium
stearate, and talc, previously passed through a No. 60 U.S. sieve,
are then added to the granules, which after mixing, are compressed
on a tablet machine to yield tablets.
[0151] Suspensions each containing 0.1-1000 mg of medicament per 5
ml dose are made as follows:
[0152] Formulation 4: Suspensions TABLE-US-00005 Quantity
Ingredient (mg/5 ml) Active ingredient 0.1-1000 mg Sodium
carboxymethyl cellulose 50 mg Syrup 1.25 mg Benzoic acid solution
0.10 mL Flavor q.v. Color q.v. Purified water to 5 mL
[0153] The medicament is passed through a No. 45 mesh U.S. sieve
and mixed with the sodium carboxymethyl cellulose and syrup to form
a smooth paste. The benzoic acid solution, flavor, and color are
diluted with some of the water and added, with stirring. Sufficient
water is then added to produce the required volume.
[0154] An aerosol solution is prepared containing the following
ingredients:
[0155] Formulation 5: Aerosol TABLE-US-00006 Quantity Ingredient (%
by weight) Active ingredient 0.25 Ethanol 25.75 Propellant 22
(Chlorodifluoromethane) 70.00
[0156] The active ingredient is mixed with ethanol and the mixture
added to a portion of the propellant 22, cooled to 30 C, and
transferred to a filling device. The required amount is then fed to
a stainless steel container and diluted with the remaining
propellant. The valve units are then fitted to the container.
[0157] Formulation 6: Intravenous Solution TABLE-US-00007
Ingredient Quantity Active ingredient 50 mg Isotonic saline 1,000
mL
[0158] The solution of the above ingredients is intravenously
administered to a patient at a rate of about 1 mL per minute.
EXAMPLES
[0159] The following examples are illustrative of compounds made or
compounds that could be made by one of skill in the art following
the teachings disclosed herein and known to one of skill in the art
and requiring minimal experimentation. The disclosed examples
should in no way limit the scope of the claims.
Example 1
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-thien-
o[3,4-b]azepine-1-carboxylic acid isopropyl ester
[0160] ##STR22##
Step 1. Preparation of
4-Isopropoxycarbonylamino-thiophene-3-carboxylic acid methyl
ester
[0161] ##STR23##
[0162] Combine methyl 3-aminothiophene-4-carboxylate hydrochloride
(3.26 g, 16.8 mmol) and isopropyl chloroformate (1.0 N in toluene,
50.5 ml) in dichloromethane (100 ml) and add 2 N NaOH (100 mL).
Stir the reaction mixture at room temperature for 4 h. Adjust to pH
2 to 4 by adding 1 N HCl. After separating the layers, extract the
aqueous layer with dichloromethane (100 ml). Wash the combined
organic phases with brine (3.times.200 ml), dry over
Na.sub.2SO.sub.4, filter, and concentrate. Purify using silica gel
column chromatography (gradient eluent, 0-20% ethyl acetate in
hexane) to provide 4-isopropoxycarbonylamino-thiophene-3-carboxylic
acid methyl ester (3.15 g, 77%) as an oil. MS (ES+): 244 (M+H).
Step 2. Preparation of
4-[Isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-thiophene-3-carbo-
xylic acid methyl ester
[0163] ##STR24##
[0164] Suspend NaH (60% in mineral oil, 0.508 g, 12.7 mmol) in
anhydrous DMF (50 ml) and cool the mixture to 0.degree. C. Inject a
solution of 4-isopropoxycarbonylamino-thiophene-3-carboxylic acid
methyl ester (3.10 g, 12.7 mmol) in DMF (50 ml) dropwise and then
warm up the mixture to room temperature for an hour. Add methyl
4-bromobutyrate (3.57 g, 19.1 mmol), and then stir for 4 h at room
temperature. Dilute the reaction mixture with ethyl acetate (200
mL) and wash with aqueous HCl (200 ml). Extract the aqueous portion
with more ethyl acetate (100 ml). Combine the organic layers, wash
with brine (3.times.300 ml), dry over Na.sub.2SO.sub.4, filter and
concentrate. Purify using silica gel column chromatography
(gradient eluent, 0-20% ethyl acetate in hexane) to provide
4[isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-thiophene--
3-carboxylic acid methyl ester (2.38 g, 55%) as an oil. MS (ES+):
344 (M+H).
Step 3. Preparation of
5-Oxo-2,3,4,5-tetrahydro-thieno[3,4-b]azepine-1,4-dicarboxylic acid
1-isopropyl ester 4-methyl ester
[0165] ##STR25##
[0166] Inject a solution of
4-[isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-thiophene-3-carbo-
xylic acid methyl ester (2.30 g, 6.70 mmol) in toluene (100 ml)
dropwise to a preheated solution of potassium t-butoxide (1.53 g,
13.4 mmol) in toluene (100 ml) at 70.degree. C. After the addition
is complete, cool the mixture down to room temperature. Pour the
reaction mixture into ice water (100 ml) and adjust the pH by
adding 1 N HCl (15 ml). Separate the organic layer and extract the
aqueous portion with ethyl acetate (2.times.100 ml). Combine the
organic layers, wash with brine (3.times.300 ml), dry over
Na.sub.2SO.sub.4, filter, and evaporate the solvents in vacuo.
Purify using silica gel column chromatography (gradient eluent,
0-10% ethyl acetate in hexane) to give
5-oxo-2,3,4,5-tetrahydro-thieno[3,4-b]azepine-1,4-dicarboxylic acid
1-isopropyl ester 4-methyl ester (1.68 g, 80%) as an oil. MS (ES+):
312 (M+H); (ES-): 310 (M-H).
Step 4. Preparation of
5-Oxo-2,3,4,5-tetrahydro-thieno[3,4-b]azepine-1-carboxylic acid
isopropyl ester
[0167] ##STR26##
[0168] Add LiCl (0.300 g, 7.18 mmol) in one portion to a mixture of
5-oxo-2,3,4,5-tetrahydro-thieno[3,4-b]azepine-1,4-dicarboxylic acid
1-isopropyl ester 4-methyl ester (0.930 g, 2.99 mmol) in DMSO (24
ml) and water (2 drops). Heat the mixture at 160.degree. C. for 2
h. Cool the reaction to room temperature and partition between
ethyl acetate (50 ml) and brine (50 ml). Separate the organic
layer, wash with brine (3.times.50 ml), dry over Na.sub.2SO.sub.4,
filter, and concentrate to an oil. Purify using silica gel column
chromatography (gradient eluent, 0-15% EtOAc in hexane) to give
5-oxo-2,3,4,5-tetrahydro-thieno[3,4-b]azepine-1-carboxylic acid
isopropyl ester (0.272 g, 36%) as an oil. MS (ES+): 254 (M+H).
Step 5. Preparation of
5-(3,5-Bis-trifluoromethyl-benzylamino)-2,3,4,5-tetrahydro-thieno[3,4-b]a-
zepine-1-carboxylic acid isopropyl ester
[0169] ##STR27##
[0170] Inject titanium(IV)isopropoxide (0.390 ml, 1.33 mmol) to a
mixture of
5-oxo-2,3,4,5-tetrahydro-thieno[3,4-b]azepine-1-carboxylic acid
isopropyl ester (0.269 g, 1.06 mmol) and
3,5-bis(trifluoromethyl)benzylamine (0.258 g, 1.06 mmol), and stir
at room temperature for 16 h. Inject a solution of NaCNBH.sub.3
(0.266 g, 4.24 mmol) in methanol (10 ml) to the reaction mixture
and continue to stir at room temperature overnight. Treat the
mixture with 0.1 N NaOH (25 ml) for 10 min, and then filter through
a Celite.RTM. pad. Wash the filtered residue thoroughly with ethyl
acetate. Separate the organic layer, wash with brine (3.times.50
ml), dry over Na.sub.2SO.sub.4, filter, and concentrate to provide
crude
5-(3,5-bis-trifluoromethyl-benzylamino)-2,3,4,5-tetrahydro-thieno[3,4-b]a-
zepine-1-carboxylic acid isopropyl ester (0.518 g) which was
elaborated without further purification. MS (ES+): 481 (M+H).
Step 6. Preparation of
5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-thie-
no[3,4-b]azepine-1-carboxylic acid isopropyl ester
[0171] ##STR28##
[0172] Inject acetic anhydride (0.40 ml, 4.24 mmol) dropwise to a
solution of crude
5-(3,5-bis-trifluoromethyl-benzylamino)-2,3,4,5-tetrahydro-thieno[3,4-b]a-
zepine-1-carboxylic acid isopropyl ester (0.277 g, 0.577 mmol) and
pyridine (0.40 ml, 4.96 mmol) in dichloromethane (4 ml) at room
temperature. Stir the mixture at room temperature for 16 h. Dilute
the reaction mixture with ethyl acetate (50 mL), and wash with
aqueous HCl (50 ml) and brine (3.times.50 ml). Dry over
Na.sub.2SO.sub.4, filter, and concentrate to an oil. Purify using
silica gel column chromatography (gradient eluent, 0-30% ethyl
acetate in hexane) to provide the title compound (230 mg, white
crystalline). MS (ES+): 523 (M+H).
Example 2
8-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-3-methyl-5,6,7,8-tetrahy-
dro-thieno[3,2-b]azepine-4-carboxylic acid isopropyl ester
[0173] ##STR29##
[0174] Prepare the title compound by essentially following the
procedures described in Example 1, Steps 1-6, by replacing methyl
3-aminothiophene-4-carboxylate hydrochloride with methyl
3-amino-4-methylthiophene-2-carboxylate in Example 1, Step 1. MS
(ES+): 537 (M+H).
Example 3
4-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-1-methyl-4,5,6,7-tetrahy-
dro-1H-1,2,8-triaza-azulene-8-carboxylic acid isopropyl ester
[0175] ##STR30##
[0176] Prepare the title compound by essentially following the
procedures described in Example 1, Steps 1-6, by replacing methyl
3-aminothiophene-4-carboxylate hydrochloride with
5-amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester in
Example 1, Step 1. MS (ES+): 521 (M+H).
Example 4
Synthesis of
(+/-)-9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-chloro-6,7,8,9-te-
trahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester
[0177] ##STR31##
Step 1. Preparation of 6-chloro-3-nitro-pyridine-2-carbonitrile
[0178] ##STR32##
[0179] Combine 2,6-dichloro-3-nitro-pyridine (5.0 g, 25.9 mmol) and
copper (1) cyanide (2.55 g, 28.5 mmol) in N-methylpyrrolidinone (19
mL) and heat at 180.degree. C. for 15 min. Cool the reaction
mixture to room temperature, pour onto ice-water, and stir for 10
min. Separate the water and extract the oil with boiling toluene
and then with ethyl acetate. Dry over sodium sulfate, filter, and
concentrate under reduced pressure. Triturate the solid with
diethyl ether and filter to afford the title compound (1.76 g,
39%). .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 7.78 (d, J=8.9 Hz,
1H), 8.54 (d, J=8.9 Hz, 1H).
Step 2. Preparation of 3-amino-6-chloro-pyridine-2-carboxylic acid
amide
[0180] ##STR33##
[0181] Combine 6-chloro-3-nitro-pyridine-2-carbonitrile (1.0 g,
5.45 mmol) and tin (II) chloride (5.0 g, 21.8 mmol) in ethanol (10
mL) and heat at 90.degree. C. for 3 h. Evaporate the solvent under
reduced pressure, suspend the residue in ethyl acetate and add a
saturated solution of sodium bicarbonate until pH=7 and then a
solution of 2 N sodium hydroxide until pH=8 to 9. Filter the
precipitate through Celite.RTM. and extract the filtrate with ethyl
acetate several times. Combine the organic layers, dry over sodium
sulfate, filter, and concentrate under reduced pressure to afford
the title compound (0.87 g, 93%). MS (ES+): 172 (M+H).
Step 3. Preparation of 3-amino-6-chloro-pyridine-2-carboxylic acid
methyl ester hydrochloride
[0182] ##STR34##
[0183] Combine 3-amino-6-chloro-pyridine-2-carboxylic acid amide
(0.87 g, 5.09 mmol) and 35% hydrochloric acid (5 mL) and heat at
110.degree. C. for 5 h. Evaporate the solvent under reduced
pressure until dryness to afford
3-amino-6-chloro-pyridine-2-carboxylic acid hydrochloride (1.22 g,
98%). MS (ES+): 246 (M+H). Suspend
3-amino-6-chloro-pyridine-2-carboxylic acid hydrochloride (1.2 g,
4.89 mmol) in methanol (10 mL), add thionyl chloride (0.85 mL, 6.36
mmol) dropwise at room temperature and stir the mixture at
100.degree. C. for 24 h. Remove the solvent under reduced pressure
to afford the title compound (1.21 g, 95%). MS (ES+): 260
(M+H).
Step 4. Preparation of
6-chloro-3-isopropoxycarbonylamino-pyridine-2-carboxylic acid
methyl ester
[0184] ##STR35##
[0185] Add isopropyl chloroformate (3.43 mL, 3.53 mmol, 1.0 M in
toluene) dropwise to a solution of
3-amino-6-chloro-pyridine-2-carboxylic acid methyl ester (600 mg,
3.21 mmol) and pyridine (0.508 mL, 6.42 mmol) in dichloromethane (6
mL) at 0.degree. C. under an atmosphere of nitrogen and stir at
room temperature for 30 min. Add water and separate the layers.
Extract the aqueous layer with dichloromethane. Dry the organic
layers over anhydrous sodium sulfate, filter, and remove the
solvent under reduced pressure, to afford the title compound (717
mg, 82%). .sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 1.27 (d, J=6.5
Hz, 6H); 3.97 (s, 3H); 4.98 (sp, J=6.0 Hz, 1H); 7.43 (d, J=8.9 Hz,
1H), 8.87 (d, J=8.9 Hz, 1H); 10.2 (bs, 1H).
Step 5. Preparation of
6-chloro-[(3-ethoxycarbonyl-propyl)-3-isopropoxycarbonyl-amino]-pyridine--
2-carboxylic acid methyl ester
[0186] ##STR36##
[0187] Add a solution of
6-chloro-3-isopropoxycarbonylamino-pyridine-2-carboxylic acid
methyl ester (1.0 g, 3.68 mmol) in dimethylformamide (2 mL) to a
suspension of sodium hydride 60% in mineral oil (0.176 g, 4.42
mmol) in dry dimethylformamide (5 mL) at 0.degree. C. under an
atmosphere of nitrogen. Stir for 30 min at room temperature, cool
to 0.degree. C. and add ethyl 4-bromobutyrate (0.665 mL, 4.42
mmol). Stir the mixture at room temperature for 18 h. Pour the
reaction mixture onto ice water and extract with diethyl ether Dry
the organic layer over anhydrous sodium sulfate, filter, and remove
the solvent under reduced pressure. Purify the residue by flash
chromatography, eluting with hexanes/ethyl acetate, to provide the
title compound (696 mg, 49%). MS (ES+): 387 (M+H).
Step 6. Preparation of
2-chloro-9-oxo-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic
acid isopropyl ester
[0188] ##STR37##
[0189] Add potassium tert-butoxide (1.9 M in tetrahydrofuran, 1.71
mL, 0.171 mmol) to a solution of
6-chloro-[(3-ethoxycarbonyl-propyl)-3-isopropoxycarbonyl-amino]-pyridine--
2-carboxylic acid methyl ester (330 mg, 0.855 mmol) in toluene (15
mL) at 0.degree. C. Remove the bath and stir the reaction mixture
at room temperature for 15 min. Add a saturated solution of
ammonium chloride and extract with ethyl acetate. Dry the organic
layer over anhydrous sodium sulfate, filter, and remove the solvent
under reduced pressure. Dissolve the residue in dimethylsulfoxide
(1.5 mL) and add water (1 drop) followed by addition of lithium
chloride (128 mg, 3.02 mmol) and heat the resulting solution at
160.degree. C. for 2 h. Cool the mixture to room temperature and
pour onto brine. Extract the mixture with ethyl acetate and purify
the residue over a silica gel cartridge eluting with hexanes/ethyl
acetate (4:1), to afford the title compound (168 mg, 33%). MS
(ES+): 331 (M+H). Also obtain
2-methoxy-9-oxo-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic
acid isopropyl ester (20 mg, 6%). MS (ES+): 279 (M+H).
Step 7. Preparation of
9-[acetyl-(3,5-bis-trifluoromethyl-benzyl)amino]-2-chloro-6,7,8,9-tetrahy-
dro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester
[0190] ##STR38##
[0191] Add 3,5-bis(trifluoromethyl)benzylamine (190 mg, 0.623 mmol)
followed by titanium isopropoxide (226 mg, 0.794 mmol) to
2-chloro-9-oxo-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic
acid isopropyl ester (160 mg, 0.567 mmol) at room temperature under
an atmosphere of nitrogen and stir the solution for 15 h. Add
methanol (2 mL) and sodium borohydride (33 mg, 0.851 mmol) and stir
the mixture at room temperature for 30 min. Add 0.1 M sodium
hydroxide (12 mL), stir for 1 h, filter through Celite.RTM. and
wash the residue with diethyl ether and then with dichloromethane.
Separate the organic layer and dry over anhydrous sodium sulfate.
Filter and remove the solvent under reduced pressure. Dissolve the
residue in dichloromethane (2 mL), add acetic anhydride (0.107 mL,
1.08 mmol), followed by pyridine (0.085 mL, 1.08 mmol), and stir at
room temperature for 15 h. Dilute with ethyl acetate (3 mL) and
wash with brine. Separate the organic layer, dry over sodium
sulfate, and filter. Remove the solvent under reduced pressure and
purify the residue by silica gel chromatography, eluting with ethyl
acetate/hexanes to afford the title compound (37 mg, 31%). MS
(ES+): 552 (M+H).
Example 5
Synthesis of
(+/-)-9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-methoxy-6,7,8,9-t-
etrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl
ester
[0192] ##STR39##
[0193] Prepare the title compound by essentially following the
procedures described in Example 4, Step 7, by replacing
2-chloro-9-oxo-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic
acid isopropyl ester with
2-methoxy-9-oxo-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic
acid isopropyl ester (minor product from Example 4, Step 6). MS
(ES+): 548 (M+H).
Example 6
Synthesis of
(+/-)-9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-bromo-6,7,8,9-tet-
rahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester
[0194] ##STR40##
Step 1. Preparation of 3-amino-pyridine-2-carboxylic acid methyl
ester
[0195] ##STR41##
[0196] Add dropwise a solution of trimethylsilyl diazomethane (2.0
M in toluene, 7.24 mL, 14.48 mmol) to a solution of
3-amino-pyridine-2-carboxylic acid (1.0 g, 7.24 mmol) in ethyl
acetate (5 mL) and methanol (5 mL) at room temperature. After the
addition is complete, remove the solvent under reduced pressure.
Suspend the residue in water (5 mL), add a saturated solution of
sodium bicarbonate, and extract with ethyl acetate. Separate the
organic layer, dry over sodium sulfate, and filter. Remove the
solvent under reduced pressure to afford the title compound (590
mg, 54%). MS (ES+): 153 (M+H).
Step 2. Preparation of 3-amino-6-bromo-pyridine-2-carboxylic acid
methyl ester
[0197] ##STR42##
[0198] Add a solution of 2 M sulfuric acid (2 mL) to a suspension
of 3-amino-pyridine-2-carboxylic acid methyl ester (0.59 g, 3.88
mmol) in water (10 mL) and stir the mixture until the precipitate
is dissolved. Add dropwise a solution of bromine (0.199 mL, 3.88
mmol) in acetic acid (1.5 mL). Add a solution of 2 M sodium
hydroxide until pH=6 and extract with ethyl acetate. Separate the
organic layer and extract with ethyl acetate. Dry the combined
organic layers over anhydrous sodium sulfate, filter, and remove
the solvent under reduced pressure. Purify the residue using silica
gel chromatography eluting with ethyl acetate/hexanes to afford the
title compound (0.616 g, 69%). .sup.1H-NMR (CDCl.sub.3, 300 MHz):
.delta. 3.90 (s, 3H); 6.90 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.5 Hz,
1H).
Step 3. Preparation of
6-bromo-3-isopropoxycarbonylamino-pyridine-2-carboxylic acid methyl
ester
[0199] ##STR43##
[0200] Prepare the title compound by essentially following the
procedure described in Example 4, step 4, by replacing
3-amino-6-chloro-pyridine-2-carboxylic acid methyl ester with
3-amino-6-bromo-pyridine-2-carboxylic acid methyl ester and
stirring the mixture for 1 h at room temperature. MS (ES+): 316,
318 (M+H).
Step 4. Preparation of
(+/-)-9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-bromo-6,7,8,9-tet-
rahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester
[0201] ##STR44##
[0202] Prepare the title compound by essentially following the
procedures described in Example 4, Steps 5-7, by replacing
6-chloro-3-isopropoxycarbonylamino-pyridine-2-carboxylic acid
methyl ester with
6-bromo-3-isopropoxycarbonylamino-pyridine-2-carboxylic acid methyl
ester in Example 4, Step 5. MS (ES+): 595, 597 (M+H).
Example 7
(+/-)-9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-dimethylamino-6,7,-
8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl
ester
[0203] ##STR45##
[0204] Add N,N-dimethylamine (40% in water, 0.4 mL) to a solution
of
(+/-)-9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-chloro-6,7,8,9-te-
trahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester (45
mg, 0.082 mmol) in dimethylsulfoxide (0.12 mL) and heat the mixture
at 100.degree. C. in a sealed tube for 20 h. Cool the reaction
mixture to room temperature, add water, and extract with ethyl
acetate. Dry the organic layer over anhydrous sodium sulfate,
filter, and remove the solvent under reduced pressure.
Chromatograph the residue over a silica gel cartridge, eluting with
hexanes/ethyl acetate to provide the title compound (39 mg, 85%).
MS (ES+): 561 (M+H).
Example 8
(+/-)-9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-methyl-6,7,8,9-tet-
rahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester
[0205] ##STR46##
[0206] Add 1,1'-bis(diphenylphosphino)(II) chloride, complex with
dichloromethane (10 mg, 0.012 mmol) to a suspension of
(+/-)-9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-chloro-6,7,8,9-te-
trahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester (44
mg, 0.080 mmol), methyl boronic acid (15 mg, 0.24 mmol) and cesium
fluoride (42 mg, 0.28 mmol) in dry dioxane (1 mL) and heat the
mixture at 80.degree. C. in a sealed tube for 15 h. Cool the
reaction mixture to room temperature, add water, and extract with
dichloromethane. Dry the organic layer over anhydrous sodium
sulfate, filter, and remove the solvent under reduced pressure.
Chromatograph the residue over silica gel cartridge, eluting with
hexanes/ethyl acetate to provide the title compound (34 mg, 79%).
MS (ES+): 532 (M+H).
Example 9
(+/-)-9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-cyano-6,7,8,9-tetr-
ahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester
[0207] ##STR47##
[0208] Combine
(+/-)-9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-chloro-6,7,8,9-te-
trahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester (45
mg, 0.081 mmol), zinc (II) cyanide (19 mg, 0.162 mmol) and
tetrakis(triphenylphosphine) palladium (0) (9 mg, 0.0081 mmol) in
dry dimethylformamide (1 mL) and heat at 120.degree. C. for 15 h.
Then add more zinc (II) cyanide (19 mg, 0.162 mmol) and
tetrakis(triphenylphosphine) palladium (0) (9 mg, 0.0081 mmol) and
stir the mixture for 48 h. Cool to room temperature, add water, and
extract with ethyl acetate. Separate the organic layer, dry over
sodium sulfate, filter and remove the solvent under reduced
pressure. Purify the residue using silica gel chromatography,
eluting with ethyl acetate/hexanes to afford the title compound (10
mg, 23%). MS (ES+): 543 (M+H).
Example 10
(+/-)-9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-3-chloro-2-methoxy-6-
,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl
ester
[0209] ##STR48##
Step 1. Preparation of 5-Chloro-3-nitro-pyridine-2-carbonitrile
[0210] ##STR49##
[0211] Add 3-nitro-5-chloro-pyridin-2-ol (3.9 g, 22.3 mmol) to a
mixture of phosphorous oxychloride (4.17 mL) and dimethylformamide
(10 mL). Heat the resulting mixture at 110.degree. C. for 30 min.
Cool the reaction mixture to room temperature and pour onto
ice-water. Add sodium bicarbonate slowly until neutralization
occurs and extract with ethyl acetate. Dry the organic layer over
anhydrous sodium sulfate, filter, and remove the solvent under
reduced pressure. Dissolve the residue in N-methyl pyrrolidinone (4
mL), add copper (I) cyanide (2.39 g, 26.7 mmol) and heat at
160.degree. C. for 15 min. Cool the reaction mixture to room
temperature and pour onto ice water and ethyl acetate. Add a
saturated solution of sodium bicarbonate, separate the organic
layer, and extract the aqueous layer with ethyl acetate. Dry the
combined organic layers over sodium sulfate, filter, and
concentrate under reduced pressure. Purify the residue using silica
gel chromatography, eluting with ethyl acetate/hexanes 1:3 to
afford the title compound (1.01 g, 26%). .sup.1H-NMR (CDCl.sub.3,
300 MHz): .delta. 8.61 (s, 1H), 8.95 (s, 1H).
Step 2. Preparation of 3-Amino-5-chloro-pyridine-2-carboxylic acid
methyl ester
[0212] ##STR50##
[0213] Heat at 90.degree. C. a mixture of
5-chloro-3-nitro-pyridine-2-carbonitrile (1.0 g, 5.90 mmol) and tin
(II) chloride (6.79 g, 29.5 mmol) in ethanol (10 mL) for 3 h.
Evaporate the solvent under reduced pressure, add a solution of 35%
hydrochloric acid (5 mL) and reflux the mixture for 6 h.
Concentrate the reaction in vacuo to dryness and dissolve the
resulting residue in methanol (20 mL). Add thionyl chloride (0.95
mL, 7.08 mmol) at room temperature and heat the mixture at
90.degree. C. for 24 h. Remove the solvent under reduced pressure,
add ethyl acetate, and wash with a saturated solution of sodium
bicarbonate. Separate the organic layer, dry over sodium sulfate,
filter, and concentrate under reduced pressure. Purify the residue
using silica gel chromatography, eluting with ethyl acetate to
afford the title compound (0.77 g, 70%). .sup.1H-NMR (CDCl.sub.3,
300 MHz): .delta. 3.97 (s, 3H); 5.85 (bs, 2H); 7.06 (d, J=2.0 Hz,
1H), 7.97 (d, J=2.0 Hz, 1H).
Step 3. Preparation of
3-Amino-6-bromo-5-chloro-pyridine-2-carboxylic acid methyl
ester
[0214] ##STR51##
[0215] Prepare the title compound by essentially following the
procedure described in Example 6, Step 2 by replacing
3-amino-pyridine-2-carboxylic acid methyl ester with
3-amino-5-chloro-pyridine-2-carboxylic acid methyl ester (2.15
mmol) and using 25 mL of sulfuric acid. .sup.1H-NMR (CDCl.sub.3,
300 MHz): .delta. 3.90 (s, 3H); 5.83 (bs, 2H); 7.13 (s, 1H).
Step 4. Preparation of
6-Bromo-5-chloro-3-isopropoxycarbonylamino-pyridine-2-carboxylic
acid methyl ester
[0216] ##STR52##
[0217] Prepare the title compound by essentially following the
procedure described in Example 4, Step 4 by replacing
3-amino-6-chloro-pyridine-2-carboxylic acid methyl ester with
3-amino-6-bromo-5-chloro-pyridine-2-carboxylic acid methyl ester.
.sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 1.27 (d, J=6.5 Hz, 6H);
3.96 (s, 3H); 4.98 (septuplet, J=6.5 Hz, 1H); 9.03 (s, 1H); 10.24
(bs, 1H).
Step 5. Preparation of
6-Bromo-5-chloro-[(3-ethoxycarbonyl-propyl)-3-isopropoxycarbonyl-amino]-p-
yridine-2-carboxylic acid methyl ester
[0218] ##STR53##
[0219] Prepare the title compound by essentially following the
procedure described in Example 4, Step 5 by replacing
6-chloro-3-isopropoxycarbonylamino-pyridine-2-carboxylic acid
methyl ester with
6-bromo-5-chloro-3-isopropoxycarbonylamino-pyridine-2-carboxylic
acid methyl ester. MS (ES+): 464, 466 (M+H).
Step 6. Preparation of
3-Chloro-2-methoxy-9-oxo-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carbox-
ylic acid isopropyl ester
[0220] ##STR54##
[0221] Prepare the title compound by essentially following the
procedure described in Example 4, Step 6 by replacing
6-chloro-[(3-ethoxycarbonyl-propyl)-3-isopropoxycarbonyl-amino]-pyridine--
2-carboxylic acid methyl ester with
6-bromo-5-chloro-[(3-ethoxycarbonyl-propyl)-3-isopropoxycarbonyl-amino]-p-
yridine-2-carboxylic acid methyl ester. MS (ES+): 313 (M+H).
3-Chloro-2-ethoxy-9-oxo-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxy-
lic acid isopropyl ester is also obtained during this process. MS
(ES+): 327 (M+H).
Step 7. Preparation of
(+/-)-9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-3-chloro-2-methoxy--
6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl
ester
[0222] ##STR55##
[0223] Prepare the title compound by essentially following the
procedure described in Example 4, Step 7 by replacing
2-chloro-9-oxo-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic
acid isopropyl ester with
3-chloro-2-methoxy-9-oxo-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carbox-
ylic acid isopropyl ester. MS (ES+): 582 (M+H).
Example 11
(+/-)-9-[Acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-3-chloro-2-ethoxy-6,-
7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl
ester
[0224] ##STR56##
[0225] Prepare the title compound by essentially following the
procedure described in Example 4, Step 7 by replacing
2-chloro-9-oxo-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic
acid isopropyl ester with
3-chloro-2-ethoxy-9-oxo-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxy-
lic acid isopropyl ester. MS (ES+): 596 (M+H).
Example 12
(+/-)-9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)amino]-2-methyl-3-trifluor-
omethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
isopropyl ester
[0226] ##STR57##
Step 1. Preparation of
2-Chloro-3-nitro-5-trifluoromethyl-pyridine
[0227] ##STR58##
[0228] Add 3-nitro-5-trifluoromethyl-pyridin-2-ol (10.0 g, 48 mmol)
to a mixture of phosphorous oxychloride (27 mL) and
dimethylformamide (1.5 mL). Heat the resulting mixture at
110.degree. C. for 30 min. Cool the reaction mixture to room
temperature and pour onto ice-water. Add sodium carbonate slowly to
pH=7 and extract with dichloromethane. Dry the organic layer over
anhydrous sodium sulfate, filter, and remove the solvent under
reduced pressure to afford the title compound (10.6 g, 86%).
.sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta. 9.10 (s, 1H); 8.82 (s,
1H).
Step 2. Preparation of
3-Nitro-5-trifluoromethyl-pyridin-2-carbonitrile
[0229] ##STR59##
[0230] Add copper (I) cyanide (3.87 g, 43.28 mmol) to a solution of
2-chloro-3-nitro-5-trifluoromethylpyridine (10.5 g, 43.28 mmol) in
N-methyl-2-pyrrolidinone (17 mL) and heat the mixture at
175.degree. C. for 15 min. Cool the reaction mixture to room
temperature, add ice, and stir for 15 min. Filter the precipitate
through Celite.RTM., washing with ethyl acetate and methanol.
Separate the organic layer and extract the aqueous with ethyl
acetate. Dry the combined organic layers over anhydrous sodium
sulfate, filter, and remove the solvent under reduced pressure.
Purify the residue using silica gel chromatography, eluting with
ethyl acetate/hexanes to afford the title compound (5.30 g, 56%).
.sup.1H-NMR (CDCl.sub.3, 300 MHz): .delta. 9.30 (s, 1H); 8.85 (s,
1H).
Step 3. Preparation of
3-Amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl
ester
[0231] ##STR60##
[0232] Prepare the title compound by essentially following the
procedure described in Example 10, Step 2, by replacing
5-chloro-2-nitro-pyridine-2-carbonitrile with
3-nitro-5-trifluoromethyl-pyridin-2-carbonitrile. After removing
the ethanol under vacuum, suspend the solid in ethyl acetate,
filter through Celite.RTM., and wash with a saturated solution of
sodium bicarbonate. Combine the organic layers, dry over sodium
sulfate, filter, and remove the solvent under vacuum. Then, follow
the procedure described in Example 10, Step 2. MS (ES+): 221
(M+H).
Step 4. Preparation of
3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl
ester
[0233] ##STR61##
[0234] Prepare the title compound by essentially following the
procedure described in Example 6, Step 2, by replacing
3-amino-pyridine-2-carboxylic acid methyl ester with
3-amino-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester
(9.54 mmol) and using 80 mL of sulfuric acid. MS (ES+): 300, 302
(M+H).
Step 5. Preparation of
3-Amino-6-methyl-5-trifluoromethyl-pyridine-2-carboxylic acid
methyl ester
[0235] ##STR62##
[0236] Prepare the title compound by essentially following the
procedure described in Example 8, by replacing
(+/-)-9-[acetyl-(3,5-bis-trifluoromethylbenzyl)amino]-2-chloro-6,7,8,9-te-
trahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl ester
with 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid
methyl ester. MS (ES+): 235 (M+H).
Step 6. Preparation of
3-Isopropoxycarbonylamino-6-methyl-5-trifluoromethyl-pyridine-2-carboxyli-
c acid methyl ester
[0237] ##STR63##
[0238] Prepare the title compound by essentially following the
procedure described in Example 4, Step 4, by replacing
3-amino-6-chloro-pyridine-2-carboxylic acid methyl ester with
3-amino-6-methyl-5-trifluoromethyl-pyridine-2-carboxylic acid
methyl ester and stirring the mixture at room temperature for 2 h.
MS (ES+): 321 (M+H).
Step 7. Preparation of
3-[Isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-6-methyl-5-triflu-
oromethyl-pyridine-2-carboxylic acid methyl ester
[0239] ##STR64##
[0240] Add cesium carbonate (0.84 g, 2.56 mmol) followed by methyl
4-bromobutyrate (0.21 mL, 1.53 mmol) to a solution of
3-isopropoxycarbonylamino-6-methyl-5-trifluoromethyl-pyridine-2-carboxyli-
c acid methyl ester (410 mg, 1.28 mmol) in dimethylformamide (2 mL)
at room temperature under nitrogen atmosphere and stir the mixture
at 80.degree. C. for 15 h. Cool the mixture to room temperature,
add water, and extract with ethyl acetate. Dry the organic layer
over anhydrous sodium sulfate, filter, and remove the solvent under
reduced pressure. Purify the residue by flash chromatography,
eluting with hexanes/ethyl acetate, to provide the title compound
(330 mg, 61%). MS (ES+): 582 (M+H).
Step 8. Preparation of
2-Methyl-9-oxo-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine--
5-carboxylic acid isopropyl ester
[0241] ##STR65##
[0242] Prepare the title compound by essentially following the
procedure described in Example 4, Step 6, by replacing
6-chloro-[(3-ethoxycarbonyl-propyl)-3-isopropoxycarbonyl-amino]-pyridine--
2-carboxylic acid methyl ester with
3-[isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-6-methyl-5-triflu-
oromethyl-pyridine-2-carboxylic acid methyl ester. MS (ES+): 331
(M+H).
Step 9.
(+/-)-9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)amino]-2-methyl-3--
trifluoro
methyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
isopropyl ester
[0243] ##STR66##
[0244] Prepare the title compound by essentially following the
procedures described in Example 4, Step 7, by replacing
2-chloro-9-oxo-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic
acid isopropyl ester with
2-methyl-9-oxo-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine--
5-carboxylic acid isopropyl ester. Besides the title compound,
9-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2-methyl-3-trifluoromet-
hyl-6,7-dihydro-pyrido[3b]-azepine-5-carboxylic acid isopropyl
ester is also obtained in this reaction. Dissolve the residue in
methanol (1 mL), add platinum (II) oxide (2 mg) and stir the
mixture under hydrogen atmosphere for 4 h. Filter the residue
through Celite.RTM., wash with dichloromethane, and remove the
residue under reduced pressure. Purify the residue by flash
chromatography, eluting with ethyl acetate/hexanes to afford the
title compound (18.5 mg, 26%). MS (ES+): 600 (M+H).
Example 13
(+/-)-9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)amino]-2-methyl-3-trifluor-
omethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
tert-butyl ester
[0245] ##STR67##
Step 1. Preparation of
2-Methyl-9-oxo-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine
[0246] ##STR68##
[0247] Add iodotrimethylsilane (0.071 mL, 0.484 mmol) to a solution
of
2-methyl-9-oxo-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine--
5-carboxylic acid isopropyl ester (80 mg, 0.242 mmol) (Example 12,
Step 8) in chloroform (2 mL) at 0.degree. C. Remove the ice bath
and stir the mixture at room temperature for 3 h and at reflux
temperature for 24 h. Concentrate under vacuum, dissolve the
residue in dichloromethane, and wash with an aqueous solution of
sodium thiosulfite. Separate the organic layer, dry over sodium
sulfate, and remove the solvent under reduced pressure. Purify the
residue using silica gel chromatography, eluting with ethyl
acetate/hexanes to afford the title compound (31 mg, 52%). MS
(ES+): 245 (M+H).
Step 2. Preparation of
2-Methyl-9-oxo-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine--
5-carboxylic acid tert-butyl ester
[0248] ##STR69##
[0249] Add tert-butoxycarbonyl dicarbonate (33 mg, 0.147 mmol),
diisopropylethyl amine (0.41 mL, 0.271 mmol) and
4,4-dimethylaminopiridine (32 mg, 0.061 mmol) to a solution of
2-methyl-9-oxo-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine
(30 mg, 0.13 mmol) in dichloromethane (1 mL) and stir the mixture
at room temperature for 20 h. Add water and extract with
dichloromethane, dry over sodium sulfate, filter, and remove the
solvent under reduced pressure. Purify the residue using silica gel
chromatography, eluting with ethyl acetate/hexane to afford the
title compound (30 mg, 70%). MS (ES+): 245 (M-Boc).
Step 3. Preparation of
(+/-)-9-(3,5-Bis-trifluoromethyl-benzyl)amino-2-methyl-3-trifluoromethyl--
6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
tert-butyl ester
[0250] ##STR70##
[0251] Add 3,5-bis(trifluoromethyl)benzylamine (565 mg, 2.26 mmol)
followed by titanium isopropoxide (642 mg, 2.26 mmol) to
2-methyl-9-oxo-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine--
5-carboxylic acid tert-butyl ester (380 mg, 1.13 mmol) at room
temperature under an atmosphere of nitrogen and stir the solution
for 20 h. Add methanol (1 mL) and sodium borohydride (85 mg, 2-26
mmol) and stir the mixture at room temperature for 3 h. Add 0.1M
sodium hydroxide and stir for 30 min. Filter through Celite.RTM.
and wash the residue with ethyl acetate. Separate the organic layer
and extract the aqueous portion with ethyl acetate. Dry the organic
layers over anhydrous sodium sulfate, filter, and remove the
solvent under reduced pressure. Dissolve the residue in methanol (3
mL), add 10% palladium on carbon (20 mg) and stir the mixture under
an atmosphere of hydrogen for 4 h. Filter the crude material over
Celite.RTM., washing with methanol and dichloromethane. Remove the
solvent under reduced pressure and purify the residue using silica
gel chromatography, eluting with ethyl acetate/hexanes to afford
the title compound (578 mg, 89%). MS (ES+): 572 (M+H).
Step 4.
(+/-)-9-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)amino]-2-methyl-3--
trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic
acid tert-butyl ester
[0252] ##STR71##
[0253] Add acetyl chloride (0.006 mL, 0.084 mmol) followed by
pyridine (0.011 mL, 0.14 mmol) to a solution of
(3,5-bis-trifluoromethyl-benzyl)amino-2-methyl-3-trifluoromethyl-6,7,8,9--
tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid tert-butyl ester
(16 mg, 0.028 mmol) in dichloromethane (0.5 mL) and stir at room
temperature for 15 h. Remove the solvent under reduced pressure and
purify the residue using silica gel chromatography, eluting with
ethyl acetate/hexanes 1:4 to afford the title compound (10 mg,
59%). MS (ES+): 614 (M+H).
Example 14
(+/-)-9-[(3,5-Bis-trifloromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]-
-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carb-
oxylic acid isopropyl ester
[0254] ##STR72##
Step 1.
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-cyano-amino]-2-methyl-3--
trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic
acid isopropyl ester
[0255] ##STR73##
[0256] Combine
(+/-)-9-(3,5-bis-trifluoromethyl-benzyl)amino-2-methyl-3-trifluoromethyl--
6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid isopropyl
ester (130 mg, 0.233 mmol) and cyanogen bromide (76 mg, 0.699 mmol)
in diethyl ether (1.5 mL) and stir at room temperature for 15 h.
Remove the solvent in vacuo and purify the resulting residue using
silica gel chromatography, eluting with ethyl acetate to afford the
title compound (121 mg, 89%). MS (ES+): 583 (M+H).
Step 2. Preparation of
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amin-
o]-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-ca-
rboxylic acid isopropyl ester
[0257] ##STR74##
[0258] Combine
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-amino-cyano]-2-methyl-3-trifluo-
romethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
isopropyl ester (120 mg, 0-268 mmol), sodium azide (17 mg, 0.258
mmol), and triethyl amine hydrochloride (37 mg, 0.268 mmol) in dry
toluene (3 mL) under a nitrogen atmosphere and heat at 120.degree.
C. for 7 h. Cool the reaction to room temperature, dilute with
ethyl acetate, and wash with 1 N hydrochloric acid. Separate the
organic layer, dry over anhydrous sodium sulfate, filter, and
remove the solvent under reduced pressure to afford
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-2H-tetrazol-5-yl)-amino]-2-meth-
yl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic
acid isopropyl ester (110 mg). Add triphenylphosphine (110 mg,
0.176 mmol), methanol (22 mg, 0.704 mmol) and
diisopropylazodicarboxylate (0.031 mL, 0.176 mmol) to a solution of
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-2H-tetrazol-5-yl)-amino]-2-meth-
yl-3-trifluoromethyl-6,7,8,9-tetra-hydro-pyrido[3,2-b]azepine-5-carboxylic
acid isopropyl ester in dry dichloromethane (1 mL) and stir the
mixture for 15 h at room temperature. Remove the solvent under
vacuum and purify the residue using a silica gel cartridge, eluting
with ethyl acetate/hexanes 1:6 to afford the title compound (12 mg,
7%). MS (ES+): 640 (M+H).
Example 15
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino-
]-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-car-
boxylic acid tert-butyl ester
[0259] ##STR75##
Step 1. Preparation of
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-cyano-amino]-2-methyl-3-trifluo-
romethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
tert-butyl ester
[0260] ##STR76##
[0261] Prepare the title compound by essentially following the
procedures described in Example 14, Step 1, by replacing
(+/-)-9-(3,5-bis-trifluoromethyl-benzyl)-amino-2-methyl-3-trifluoromethyl-
-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
isopropyl ester with
(+/-)-9-(3,5-bis-trifluoromethyl-benzyl)amino-2-methyl-3-trifluorome-
thyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
tert-butyl ester. MS (ES+): 597 (M+H).
Step 2.
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-y-
l)-amino]-2-methyl-3-trifluoromethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepi-
ne-5-carboxylic acid tert-butyl ester
[0262] ##STR77##
[0263] Prepare the title compound by essentially following the
procedures described in Example 14, Step 2, by replacing
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-amino-cyano]-2-methyl-3-trifluo-
romethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
isopropyl ester with
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-2-methyl-3-trifluo-
romethyl-6,7,8,9-tetrahydro-pyrido[3,2-b]azepine-5-carboxylic acid
tert-butyl ester. MS (ES+): 654 (M+H).
* * * * *