U.S. patent application number 12/763344 was filed with the patent office on 2010-08-12 for compounds and methods for treating dyslipidemia.
Invention is credited to Xinchao Chen, Christopher Lawrence Cioffi, Sean Richard Dinn, Ana Maria Escribano, Maria Carmen Fernandez, Todd Fields, Robert Jason Herr, Nathan Bryan Mantlo, Eva Maria Martin De La Nava, Ana Isabel Mateo Herranz, Saravanan Parthasarathy, Xiaodong Wang.
Application Number | 20100204207 12/763344 |
Document ID | / |
Family ID | 35056992 |
Filed Date | 2010-08-12 |
United States Patent
Application |
20100204207 |
Kind Code |
A1 |
Chen; Xinchao ; et
al. |
August 12, 2010 |
Compounds and Methods for Treating Dyslipidemia
Abstract
Compounds of Formula (I): wherein n, m, p, q, Y, R1, R2, R3a,
R3b, R4, R5, and R6 are as defined herein and their pharmaceutical
compositions and methods of use are disclosed. ##STR00001##
Inventors: |
Chen; Xinchao; (Schenectady,
NY) ; Cioffi; Christopher Lawrence; (Troy, NY)
; Dinn; Sean Richard; (Delmar, NY) ; Escribano;
Ana Maria; (Alcobendas-Madrid, ES) ; Fernandez; Maria
Carmen; (Alcobendas-Madrid, ES) ; Fields; Todd;
(Indianapolis, IN) ; Herr; Robert Jason;
(Voorheesville, NY) ; Mantlo; Nathan Bryan;
(Brownsburg, IN) ; Martin De La Nava; Eva Maria;
(Alcobendas-Madrid, ES) ; Mateo Herranz; Ana Isabel;
(Alcobendas-Madrid, ES) ; Parthasarathy; Saravanan;
(Carmel, IN) ; Wang; Xiaodong; (Millbrae,
CA) |
Correspondence
Address: |
ELI LILLY & COMPANY
PATENT DIVISION, P.O. BOX 6288
INDIANAPOLIS
IN
46206-6288
US
|
Family ID: |
35056992 |
Appl. No.: |
12/763344 |
Filed: |
April 20, 2010 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11570542 |
Dec 13, 2006 |
|
|
|
PCT/US05/22389 |
Jun 23, 2005 |
|
|
|
12763344 |
|
|
|
|
60664862 |
Mar 24, 2005 |
|
|
|
60627241 |
Nov 12, 2004 |
|
|
|
60582708 |
Jun 24, 2004 |
|
|
|
Current U.S.
Class: |
514/215 ;
514/213.01; 514/217; 540/586; 540/593 |
Current CPC
Class: |
C07D 491/04 20130101;
C07D 403/14 20130101; C07D 417/12 20130101; C07D 401/14 20130101;
A61P 43/00 20180101; C07D 405/14 20130101; C07D 413/12 20130101;
A61P 9/00 20180101; A61P 3/06 20180101; A61P 9/10 20180101; A61P
3/00 20180101; C07D 403/12 20130101; C07D 401/12 20130101 |
Class at
Publication: |
514/215 ;
540/593; 540/586; 514/217; 514/213.01 |
International
Class: |
A61K 31/55 20060101
A61K031/55; C07D 403/12 20060101 C07D403/12; C07D 417/12 20060101
C07D417/12; C07D 491/048 20060101 C07D491/048; C07D 405/14 20060101
C07D405/14; C07D 413/12 20060101 C07D413/12; C07D 401/14 20060101
C07D401/14; A61P 3/00 20060101 A61P003/00; A61P 9/10 20060101
A61P009/10 |
Claims
1. A compound of Formula I ##STR00431## wherein n is 0, 1, 2, or 3;
m is 0, 1, 2, or 3; p is 1 or 2; q is 0, 1, 2, 3, or 4; Y is a
bond, C.dbd.O, or S(O).sub.t; wherein t is 0, 1, or 2; R.sup.1 is
selected from a group consisting of: hydroxy, C.sub.1-C.sub.6
alkyl, aryl, 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,
heterocyclyl, C.sub.1-C.sub.6 alkylalcohol, C.sub.1-C.sub.6 alkoxy,
aryloxy, --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
and --OC.sub.1-C.sub.6 alkylaryl, --O-heterocyclic,
--OC.sub.1-C.sub.6 alkylheterocyclic, C.sub.I-C.sub.6
alkyl-O--C(O)NR.sup.7R.sup.8, C.sub.1-C.sub.6
alkyl-NR.sup.7C(O)NR.sup.7R.sup.8, and C.sub.0-C.sub.6
alkylCOOR.sup.11; provided that R.sup.1 is not hydroxy when Y is
S(O).sub.t; and wherein each cycloalkyl, aryl and heterocyclic
group is optionally substituted with 1 to 3 groups independently
selected from oxo, hydroxy, halogen, 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,
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, 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; each R.sup.2 is
bound only to a carbon atom and is a group independently selected
from the group consisting of: hydrogen, hydroxy, halogen, oxo,
C.sub.2-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,
CONR.sup.11R.sup.12, --NR.sup.11SO.sub.2R.sup.12,
--NR.sup.11COR.sup.12, C.sub.0-C.sub.6 alkylNR.sup.11R.sup.12,
C.sub.0-C.sub.6 alkylCOR.sup.1, C.sub.0-C.sub.6 alkylCOOR.sup.11,
cyano, nitro, C.sub.0-C.sub.6 alkylcycloalkyl, phenyl,
C.sub.0-C.sub.6 alkylaryl, heterocyclyl, C.sub.3-C.sub.8
cycloalkyl, and C.sub.1-C.sub.6 haloalkyl; and wherein two
independently selected R.sup.2 groups are optionally
gem-disubstituted; R.sup.3a and R.sup.3b are independently selected
from the group consisting of: hydrogen, halogen, 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, and C.sub.1-C.sub.6 haloalkyl; R.sup.4 is a
group represented by the formula --NR.sup.4aR.sup.4b wherein;
R.sup.4a is a heterocyclic, C.sub.1-C.sub.6 alkylheterocyclic, or
C.sub.2-C.sub.6 alkenylheterocyclic group wherein each heterocyclic
group is optionally substituted with 1 to 3 groups independently
selected from the group consisting of: oxo, hydroxyl, halogen,
--NR.sup.11R.sup.12, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkenyl, C.sub.0-C.sub.6 alkylCN, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylalcohol, C.sub.1-C.sub.6 haloalkyl,
--OC(O)NR.sup.11R.sup.12, C.sub.1-C.sub.6 alkylNR.sup.11R.sup.12
wherein the C.sub.1-C.sub.6 alkyl group is optionally substituted
with --OR.sup.10 or C(O)OR.sup.10, C.sub.0-C.sub.6 alkylNO.sub.2,
C.sub.0-C.sub.6 alkylNR.sup.11SO.sub.2R.sup.12, C.sub.0-C.sub.6
alkylC(O)NR.sup.11R.sup.12, C.sub.0-C.sub.6
alkylNR.sup.11C(O)R.sup.12, C.sub.0-C.sub.6
alkylNR.sup.11C(O)OR.sup.12, C.sub.0-C.sub.6
alkylNR.sup.11C(O)NR.sup.10R.sup.12, C.sub.0-C.sub.6
alkylNR.sup.11CHR.sup.10CO.sub.2R.sup.12, C.sub.0-C.sub.6
alkylC(O)OR.sup.11, C.sub.0-C.sub.6 alkylSO.sub.2NR.sup.11R.sup.12,
C.sub.0-C.sub.6 alkylS(O).sub.tR.sup.11, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.6 alkylcycloalkyl, and C.sub.0-C.sub.6
alkylheterocyclic wherein the heterocycle of the C.sub.0-C.sub.6
alkylheterocyclic group is optionally substituted with halo,
C.sub.1-C.sub.6 alkyl, oxo, --CO.sub.2R.sup.11 and
--NR.sup.11R.sup.12; and R.sup.4b is selected from the group
consisting of: 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, C.sub.2-C.sub.6 alkenylheterocyclic,
C.sub.1-C.sub.6 alkylcycloalkyl, C.sub.1-C.sub.6
alkyl-O--C.sub.1-C.sub.6 alkylaryl, 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,
C.sub.1-C.sub.6 haloalkylalcohol, and C.sub.1-C.sub.6 alkyl
alcohol; R.sup.5 is selected from a group consisting of: hydrogen,
hydroxy, halogen, 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, aryloxy,
--OC.sub.2-C.sub.6 alkenyl, --OC.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6 alkylheterocyclic,
C.sub.2-C.sub.6 alkenylaryl, C.sub.2-C.sub.6 alkenylheterocyclic,
aryl, heterocyclic, cyano, nitro, C.sub.0-C.sub.6
alkylNR.sup.7R.sup.8, C.sub.0-C.sub.6 alkylCOR.sup.7,
C.sub.0-C.sub.6 alkylCO.sub.2R.sup.7, C.sub.0-C.sub.6
alkylCONR.sup.7R.sup.8, CONR.sup.7SO.sub.2R.sup.8,
--NR.sup.7SO.sub.2R.sup.8, --NR.sup.7COR.sup.8,
--N.dbd.CR.sup.7R.sup.8, --OCONR.sup.7R.sup.8, --S(O).sub.tR.sup.7,
--SO.sub.2NR.sup.7R.sup.8, C.sub.0-C.sub.5CH.sub.2OH,
--OC.sub.1-C.sub.6 alkylheterocyclic, and --OC.sub.1-C.sub.6
alkylaryl wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl,
aryl and heterocyclic group or subgroup is optionally substituted
with oxo, alkyloxy, aryloxy; and wherein any two R.sup.5 groups may
combine to form an optionally substituted 5, 6, or 7-member fused
ring with the phenyl ring (A-ring) to which they are attached,
wherein the 5, 6, or 7-member fused ring is saturated, partially
unsaturated, or fully unsaturated and optionally contains 1, 2, or
3 heteroatoms independently selected from O, N, and S; R.sup.6 is
independently selected from a group consisting of: hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, hydroxy, COR.sup.7,
C.sub.1-C.sub.6 alkoxy, aryloxy, --OC.sub.2-C.sub.6 alkenyl,
--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, heterocyclic, aryl, C.sub.1-C.sub.6
alkyl-O--C(O)NR.sup.7R.sup.8, C.sub.1-C.sub.6
alkyl-NR.sup.7C(O)NR.sup.7R.sup.8 and C.sub.1-C.sub.6
alkylcycloalkyl; R.sup.7 and R.sup.8 are each independently
selected from a group consisting of: hydrogen, 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, --O-aryl,
--OC.sub.3-C.sub.8 cycloalkyl, --O-heterocyclic, --NR.sup.7R.sup.8,
--C.sub.1-C.sub.6 alkylcycloalkyl, --OC.sub.1-C.sub.6
alkylcycloalkyl, --OC.sub.1-C.sub.6 alkylheterocyclic,
C.sub.1-C.sub.6 alkylheterocyclic, --O C.sub.1-C.sub.6 alkylaryl,
C.sub.3-C.sub.8 cycloalkyl, heterocyclic, aryl, and C.sub.1-C.sub.6
alkylaryl, wherein each alkyl, cycloalkyl, heterocyclic or aryl
group is optionally substituted with 1-3 groups independently
selected from hydroxy, CN, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, and
--NR.sup.11R.sup.12, or R.sup.7 and R.sup.8 combine to form a
nitrogen containing heterocyclic ring which having 0, 1, or 2
additional heteroatoms selected from oxygen, nitrogen and sulfur
and wherein the nitrogen-containing heterocycle is optionally
substituted with oxo or C.sub.1-C.sub.6 alkyl; R.sup.10, R.sup.11
and R.sup.12 are independently selected from a 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, C.sub.1-C.sub.6
alkylaryl, wherein each alkyl, aryl, cycloalkyl, and heterocyclic
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, C.sub.1-C.sub.6 alkyl,
COR.sup.7, and --SO.sub.2R.sup.7; or a pharmaceutically acceptable
salt, solvate, enantiomer, racemate, diastereomer or mixture of
diastereomers thereof.
2. A compound of claim 1 wherein p is 1.
3. A compound according to claim 1 wherein n, m, and q are
independently 0, or 1.
4. A compound according to claim 1 wherein p is 1, n is 0, Y is
C(O), and 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,
C.sub.0-C.sub.6 alkylaryl, --Oaryl, --OC.sub.1-C.sub.6 haloalkyl,
--OC.sub.1-C.sub.6 alkylcycloalkyl, --OC.sub.3-C.sub.8 cycloalkyl,
--OC.sub.1-C.sub.6 alkylcycloalkylNR.sup.7R.sup.8,
--OC.sub.1-C.sub.6 alkyl, --OC.sub.0-C.sub.6 alkylaryl,
--OC.sub.1-C.sub.6 alkylcyano, --OC.sub.1-C.sub.6
alkylCO.sub.2R.sup.11, --OC.sub.3-C.sub.8
cycloalkylCO.sub.2R.sup.11, --OC.sub.1-C.sub.6 alkylhydroxy,
--OC.sub.1-C.sub.6 alkylNR.sup.7R.sup.8 and --OC.sub.1-C.sub.6
alkylheterocyclic; 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.3
alkylCONH.sub.2, C.sub.0-C.sub.3 alkylcyano, and C.sub.0-C.sub.3
alkylC(O)OC.sub.1-C.sub.3 alkyl.
5. A compound according to claim 1 wherein p is 1, n is 0, Y is a
bond, and R.sup.1 is selected from a group consisting of:
C.sub.1-C.sub.6 alkyl, C.sub.0-C.sub.6 alkylcycloalkyl,
C.sub.1-C.sub.6 alkylheterocyclic, C.sub.2-C.sub.6 haloalkyl,
C.sub.0-C.sub.6 alkylaryl, C.sub.1-C.sub.6
alkylcycloalkylNR.sup.7R.sup.8, C.sub.1-C.sub.6 alkylcyano,
C.sub.1-C.sub.6 alkylCO.sub.2R.sup.11, C.sub.1-C.sub.6
alkylcycloalkylCO.sub.2R.sup.11, C.sub.1-C.sub.6 alkylalcohol, and
C.sub.1-C.sub.6 alkylNR.sup.7R.sup.8; 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.3 alkylCONH.sub.2, and C.sub.0-C.sub.3
alkylcyano.
6. A compound compound according to claim 1 wherein p is 1,
R.sup.3a and R.sup.3b are both hydrogen and R.sup.4 is
NR.sup.4aR.sup.4b; wherein R.sup.4b is 3,5-bistrifluoromethylbenzyl
and R.sup.4a is selected from the group consisting of: ##STR00432##
##STR00433## wherein each R is independently selected from the
group consisting of: halogen, C.sub.0-C.sub.6 alkylalcohol,
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy
C.sub.0-C.sub.6 alkylcycloalkyl, C.sub.0-C6 alkylheterocyclic,
C.sub.1-C.sub.6 alkylCN, C.sub.1-C.sub.6 haloalkyl, C.sub.0-C.sub.6
alkylNR.sup.11R.sup.12, C.sub.1-C.sub.6 alkylC(O)NR.sup.11R.sup.12,
and C.sub.1-C.sub.6 alkylC(O)OR.sup.11.
7. A compound selected from the group consisting of:
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid tetrahydro-pyran-4-yl ester,
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-7-methyl--
8-trifluoromethyl-2,3,4,
5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetrazol-2-yl}-ethanol,
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-et-
hanol,
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-
-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-car-
boxylic acid isopropyl ester, (+/-)-Isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3-
,4, 5-tetrahydrobenzo[b]azepine-1-carboxylate, (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-8-c-
hloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate, (+/-)
isopropyl
-6-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-2,3,6,7,8,9-
-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylate,
(+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(5-methyl-1H-pyrazol-3-yl)-amino]-8-ch-
loro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate,
+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(5-methyl-isoxazol-5-yl)-amino]-8-chlo-
ro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate,)
(S)-6-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-21.sup.-1-tetrazol-5-yl-
)-amino]-4-methyl-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-c-
arboxylic acid isopropyl ester, (S)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-8,9-
-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate,
(S)-isopropyl
5-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl-
]-amino}-8,9-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate,
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid tert-butyl ester,
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-1,2,3,5,6,7,8,9-
-octahydro-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amin-
e,
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-3,5,6,7,8,9-h-
exahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-y-
l)-amine,
(S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-
-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl)-3-
,3-dimethyl-pentanoic acid,
(S)-5-(9-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetraz-
ol-5-yl]-amino}-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl)-
-3,3-dimethyl-pentanoic acid,
(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-2,3,4,5,7,8,9,10-oc-
tahydro-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine,
(S)-6-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol--
5-yl]-amino)-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carbox-
ylic acid isopropyl ester,
(S)-6-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol--
5-yl]-amino}-4-methyl-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene--
10-carboxylic acid isopropyl ester,
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5,carboxylic
acid 2-carboxy-2-methyl-propyl ester,
(S)-1-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-ami-
no]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-3-f-
uran-2-ylmethoxy)-propan-2-one,
2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]--
7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-1-pheny-
l-ethanol,
2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-y-
l)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-y-
l) -2-phenyl-ethanol,
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-
-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cy-
clohexyl)-acetic acid methyl ester,
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-
-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cy-
clohexyl)-acetic acid,
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine,
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine hydrochloride,
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-3-ylmethyl-8-tri-
fluoromethyl-2;3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine,
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-eth-
anol,
(S)5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-
)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}--
thiophene-2-carboxylic acid,
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(5-pyrid-
in-4-ylmethyl-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl-
)-amine,
(S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-
-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmet-
hyl}-cyclohexyl)-acetic acid,
(S)-2-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl}-ethanol,
(S)-9-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benz-
yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxy-
lic acid tert-butyl ester,
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(5-benzyl-3,5,6,7,8,9-hexahydro--
1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(3,5-bis-trifluoromethyl-benzyl)-a-
mine,
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-be-
nzyl)-[5-(3,3,3-trifluoro-propyl)-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyc-
lohepta[f]inden-9-yl]-amine,
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-2,3,4,5,7,8,9,10-octahydro-naphtho[2,3-b]azepin-1-yl}-3,3-dimethyl-pe-
ntanoic acid,
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-11-methyl-2,3,4-
,5,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol--
5-yl)-amine,
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-thiophene-2-carboxylic acid,
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1,7-dimethyl-8-trifluoromethyl-2,3,-
4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine,
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-1-thiazol-2-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]aze-
pin-5-yl)-amine,
(S)-(3,5-Bis-trifluoromethyl-benzyl)-[7-methyl-1-(1-methyl-1H-imidazol-2--
ylmethyl)-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(2--
methyl-2H-tetrazol-5-amine,
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl},
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-ylmethyl-
-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-
-tetrazol-5-yl)-amine,
(S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmet-
hyl}-piperidin-1-yl)-acetic acid ethyl ester,
(S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmet-
hyl}-piperidin-1-yl)-acetic acid,
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyrrolidin-2-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine,
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-[1-(2-benzyloxy-ethyl)-7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(3,5-bis-trif-
luoromethyl-benzyl)-amine,
(S)-2-{5-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-b-
enzyl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-
-1-yl}-ethanol,
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-(7-methyl-1-thiazol-2-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-be-
nzo[b]azepin-5-yl)-amine,
(S)-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-e-
thoxy)-acetic acid,
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-[7-methy-
l-1-(2H-tetrazol-5-ylmethyl)-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo-
[b]azepin-5-yl]-amine,
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 2-amino-ethyl ester,
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 2-carboxy-2-methyl-propyl ester,
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-(1-cyclopropylmethyl-7-methyl-8-tri
fluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine,
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-(1-cyclopropylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-ben-
zo[b]azepin-5-yl)-amine hydrochloride, and pharmaceutically
acceptable salt, solvate, enantiomer, racemate, diastereomer or
mixture of diastereomers thereof.
8. A method of modulating CETP activity comprising administering a
therapeutically effective composition comprising a compound of
Formula I, or a pharmaceutically acceptable salt, solvate,
enantiomer, racemate, diastereomer or mixture of diastereomers
thereof to a patient in need thereof.
9. The method of claim 8 wherein modulation of CETP activity
results in a decrease in LDL-cholesterol.
10. A method of treating or preventing dyslipidemia comprising
administering a therapeutically effective composition comprising a
compound of Formula I, or a pharmaceutically acceptable salt,
solvate, enantiomer, racemate diastereomer, mixture of
diastereomers thereof, to a patient in need thereof.
11. A method of treating or preventing atherosclerosis comprising
administering a therapeutically effective composition comprising a
compound of Formula I, or a pharmaceutically acceptable salt,
solvate, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof to a patient.
12. A method of lowering plasma LDL-cholesterol in a mammal
comprising administering a therapeutically effective dose of a
compound of Formula I, or a pharmaceutically acceptable salt,
solvate, enantiomer, racemate, diastereomer, or mixture of
diastereomers thereof to said mammal.
13. A method of treating and/or preventing the pathological
sequelae due to high levels 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, or mixture of diastereomers to
said mammal.
14. A pharmaceutical composition comprising a compound according to
claim 1 and at least one of: a carrier, diluent, and excipient.
15. Use of a compound according to claim 1 for the manufacture of a
medicament for treating or preventing atherosclerosis in a mammal
comprising administering an effective dose of a compound of Formula
I, or a pharmaceutically acceptable salt, solvate, enantiomer,
racemate; diastereomer, or mixture of diastereomers thereof to said
mammal.
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 and methods 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-cholesterolernic 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 diseases 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 atherogenesis. 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
pro-atherogenic, 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. Furthermore, transgenic expression of
CETP in mice results in significantly reduced HDL cholesterol
levels and developed 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 spbntaneous 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. Vasa 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] 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. Pietzonka 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.
[0008] U.S. Pat. No. 6,586,448 B1 describes
4-carboxamino-2-substituted-1,2,3,4-tetrahydroquinolines of the
following structure:
##STR00002##
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 00/17164, WO 00/17165, and WO
00/17166, disclose variously, formulations, methods of preparation
and methods of use of compounds tetrahydroquinoline compounds
generally related to those in U.S. Pat. No. 6,586,448 B1 from which
it derives as a divisional application.
[0009] European Patent Application No. 818448 by Schmidt et al.
describes certain tetrahydroquinoline derivatives as cholesteryl
ester transfer protein inhibitors. European Patent Application No.
818197 by 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 PCT Patent
Applications WO 03/028727 by Muller-Gliemann et al. and WO 98/39299
by Gielen et al. certain quinoline derivatives are described as
cholesteryl ester transfer protein inhibitors.
[0010] The above disclosures notwithstanding, a great need remains,
particularly for affluent western societies for effective compounds
useful to treat conditions caused by, associated with, or
exacerbated by dyslipidemia.
SUMMARY OF THE INVENTION
[0011] The present invention provides a compound of Formula I
##STR00003##
wherein [0012] n is 0, 1, 2, or 3; [0013] m is 0, 1, 2, or 3;
[0014] p is 1 or 2; [0015] q is 0, 1, 2, 3, or 4; [0016] Y is a
bond, C.dbd.O, or S(O).sub.t; wherein t is 0, 1, or 2;
[0017] R.sup.1 is selected from a group consisting of: hydroxy,
C.sub.1-C.sub.6 alkyl, aryl, 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, heterocyclyl, C.sub.1-C.sub.6
alkylalcohol, C.sub.1-C.sub.6 alkoxy, aryloxy, --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 and
--OC.sub.1-C.sub.6 alkylaryl, --O-heterocyclic, --OC.sub.1-C.sub.6
alkylheterocyclic, C.sub.1-C.sub.6 alkyl-O--C(O)NR.sup.7R.sup.8,
C.sub.1-C.sub.6 alkyl-NR.sup.7C(O)NR.sup.7R.sup.8, and
C.sub.0-C.sub.6 alkylCOOR.sup.11; provided that R.sup.1 is not
hydroxy when Y is S(O).sub.t; and wherein each cycloalkyl, aryl and
heterocyclic group is optionally substituted with 1 to 3 groups
independently selected from oxo, hydroxy, halogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkene, 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, 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, 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;
[0018] Each R.sup.2 is bound only to a carbon atom and is or are if
more than one independently selected from the group consisting of:
hydrogen, hydroxy, halogen, oxo, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkene, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkyl, CONR.sup.11R.sup.12,
--NR.sup.11COR.sup.12, --NR.sup.11COR.sup.12, C.sub.0-C.sub.6
alkylNR.sup.11R.sup.12, C.sub.0-C.sub.6 alkylCOR.sup.11,
C.sub.0-C.sub.6COOR.sup.11, cyano, nitro, C.sub.0-C.sub.6
alkylcycloalkyl, phenyl, C.sub.0-C.sub.6 alkylaryl, heterocyclyl,
C.sub.3-C.sub.8 cycloalkyl, and C.sub.1-C.sub.6 haloalkyl; and
wherein two independently selected R.sup.2 groups are optionally
gem-disubstituted;
[0019] R.sup.3a and R.sup.3b are independently selected from the
group consisting of: hydrogen, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkene, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, and C.sub.1-C.sub.6 haloalkyl;
[0020] R.sup.4 is a group represented by the formula
--NR.sup.4aR.sup.4b; wherein, [0021] R.sup.4a is a heterocyclic,
C.sub.1-C.sub.6 alkylheterocyclic, or C.sub.2-C.sub.6
alkenylheterocyclic group wherein each heterocyclic group is
optionally substituted with 1 to 3 groups independently selected
from the group consisting of: hydroxyl, halogen, oxo,
--NR.sup.11R.sup.12, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.0-C.sub.6 alkylCN, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylalcohol, C.sub.1-C.sub.6 haloalkyl,
--OC(O)NR.sup.11R.sup.12, C.sub.1-C.sub.6 alkylNR.sup.11R.sup.12
wherein the C.sub.1-C.sub.6 alkyl group is optionally substituted
with --OR.sup.10 or C(O)OR.sup.10, C.sub.0-C.sub.6 alkylNO.sub.2,
C.sub.0-C.sub.6 alkylNR.sup.11SO.sub.2R.sup.12, C.sub.0-C.sub.6
alkylC(O)NR.sup.11R.sup.12, C.sub.0-C.sub.6
alkylNR.sup.11C(O)R.sup.12, C.sub.0-C.sub.6
alkylNR.sup.11C(O)OR.sup.12, C.sub.0-C.sub.6
alkylNR.sup.11C(O)NR.sup.10R.sup.12, C.sub.0-C.sub.6
alkylNR.sup.11CHR.sup.10CO.sub.2R.sup.12, C.sub.0-C.sub.6
alkylC(O)OR.sup.11, C.sub.0-C.sub.6 alkylSO.sub.2NR.sup.11R.sup.12,
C.sub.0-C.sub.6 alkylS(O).sub.tR.sup.11, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.6 alkylcycloalkyl, and C.sub.0-C.sub.6
alkylheterocyclic wherein the heterocycle of the C.sub.0-C.sub.6
alkylheterocyclic group is optionally substituted with halo,
C.sub.1-C.sub.6 alkyl, oxo, --CO.sub.2R.sup.11 and
--NR.sup.11R.sup.12; and
[0022] R.sup.4b is selected from the group consisting of:
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,
C.sub.2-C.sub.6 alkenylheterocyclic, C.sub.1-C.sub.6
alkylcycloalkyl, and C.sub.1-C.sub.6 alkyl-O--C.sub.1-C.sub.6
alkylaryl, 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, C.sub.1-C.sub.6
haloalkylalcohol, and C.sub.1-C.sub.6 alkyl alcohol;
[0023] R.sup.5 is selected from a group consisting of: hydrogen,
hydroxy, halogen, 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, aryloxy,
--OC.sub.2-C.sub.6 alkenyl, --OC.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6 alkylheterocyclic,
C.sub.2-C.sub.6 alkenylaryl, C.sub.2-C.sub.6 alkenylheterocyclic,
aryl, heterocyclic, cyano, nitro, C.sub.0-C.sub.6
alkylNR.sup.7R.sup.8, C.sub.0-C.sub.6 alkylCOR.sup.7,
C.sub.0-C.sub.6 alkylCO.sub.2R.sup.7, C.sub.0-C.sub.6
alkylCONR.sup.7R.sup.8, CONR.sup.7SO.sub.2R.sup.8,
--NR.sup.7SO.sub.2R.sup.8, --NR.sup.7COR.sup.8,
--N.dbd.CR.sup.7R.sup.8, --OCONR.sup.7R.sup.8, --S(O).sub.tR.sup.7,
--SO.sub.2NR.sup.7R.sup.8, C.sub.0-C.sub.5CH.sub.2OH,
--OC.sub.1-C.sub.6 alkylheterocyclic, and --OC.sub.1-C.sub.6
alkylaryl wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl,
aryl and heterocyclic group or subgroup is optionally substituted
with oxo, alkyloxy, aryloxy; and wherein any two R.sup.5 groups may
combine to form an optionally substituted 5, 6, or 7-member fused
ring with the phenyl ring (A-ring) to which they are attached,
wherein the 5, 6, or 7-member fused ring is saturated, partially
unsaturated, or fully unsaturated and optionally contains 1, 2, or
3 heteroatoms independently selected from O, N, and S;
[0024] R.sup.6 is independently selected from a group consisting
of: hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
hydroxy, COR.sup.7, C.sub.1-C.sub.6 alkoxy, aryloxy,
--OC.sub.2-C.sub.6 alkenyl, --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,
heterocyclic, aryl, C.sub.1-C.sub.6 alkyl-O--C(O)NR.sup.7R.sup.8,
C.sub.1-C.sub.6 alkyl-NR.sup.7C(O)NR.sup.7R.sup.8 and
C.sub.1-C.sub.6 alkylcycloalkyl;
[0025] R.sup.7 and R.sup.8 are each independently selected from a
group consisting of: hydrogen, 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, --O-aryl,
--OC.sub.3-C.sub.8 cycloalkyl, --O-heterocyclic, --NR.sup.7R.sup.8,
C.sub.1-C.sub.6 alkylcycloalkyl, --OC.sub.1-C.sub.6
alkylcycloalkyl, --OC.sub.1-C.sub.6 alkylheterocyclic,
C.sub.1-C.sub.6 alkylheterocyclic, --OC.sub.1-C.sub.6 alkylaryl,
C.sub.3-C.sub.8 cycloalkyl, heterocyclic, aryl, and C.sub.1-C.sub.6
alkylaryl, wherein each alkyl, cycloalkyl, heterocyclic or aryl
group is optionally substituted with 1-3 groups independently
selected from hydroxy, --CN, halogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, 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 heteroatoms selected from oxygen, nitrogen and sulfur
and wherein the nitrogen-containing heterocycle is optionally
substituted with oxo, or C.sub.1-C.sub.6 alkyl;
[0026] R.sup.10, R.sup.11, and R.sup.12 are independently selected
from a 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, C.sub.1-C.sub.6 alkylaryl, wherein each alkyl, aryl,
cycloalkyl, and heterocyclic 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,
C.sub.1-C.sub.6 alkyl, COR.sup.7, and --SO.sub.2R.sup.7;
[0027] or a pharmaceutically acceptable salt, solvate, enantiomer,
racemate, diastereomer or mixture of diastereomers thereof.
[0028] The present invention also provides a method for modulating
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.
[0029] The present invention provides a method for treating or
preventing dyslipidemia comprising administering a compound of
Formula I, or a pharmaceutically acceptable salt, solvate,
enantiomer, racemate, diastereomer, or mixture of diastereomers, or
prodrug thereof, to a patient in need thereof.
[0030] 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.
[0031] The present invention provides a method for treating and/or
preventing atherosclerosis comprising administering a compound of
Formula I, or a pharmaceutically acceptable salt, solvate,
enantiomer, racemate diastereomer, mixture of diastereomers, or
prodrug thereof, to a patient in need thereof.
[0032] The present invention provides a method for treating and/or
preventing diseases related to abnormal CEPT activity comprising
administering a compound of Formula I, or a pharmaceutically
acceptable salt, solvate, enantiomer, racemate diastereomer,
mixture of diastereomers, or prodrug thereof, to a patient in need
thereof.
[0033] The present invention provides a method of 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, or a pharmaceutically acceptable salt,
solvate, enantiomer, racemate, diastereomer, mixture of
diastereomers, or prodrug thereof, to a patient in need
thereof.
[0034] 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, or a
pharmaceutically acceptable salt, solvate, enantiomer, racemate,
diastereomer, mixture of diastereomers, or prodrug thereof, to a
patient in need thereof.
[0035] 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, or a pharmaceutically acceptable salt, solvate,
enantiomer, racemate, diastereomer, mixture of diastereomers, or
prodrug thereof, to a patient in need thereof.
[0036] 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.
[0037] 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, or a pharmaceutically acceptable salt, solvate, enantiomer,
racemate, diastereomer, or mixture of diastereomers, thereof, to a
patient in need thereof.
[0038] 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, or a
pharmaceutically acceptable salt, solvate, enantiomer, racemate,
diastereomer, mixture of diastereomers, or prodrug thereof, to a
patient in need thereof.
[0039] The present invention also provides a combination therapy
involving a compound of Formula I and one or more other 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 atherosclerosis.
DETAILED DESCRIPTION OF THE INVENTION
[0040] The current invention provides novel compounds of Formula I
useful in modulating CETP activity.
[0041] The term "modulation" 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.
[0042] The phrase "diseases" or "diseases related to CETP
modulation" or "diseases mediated by CETP activity" refers to
pathological states where atherosclerosis and cardiovascular
diseases are prone because of dyslipidemia and/or other risk
factors and are therefore beneficially affected by down-regulation
or modulation 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 Alzheimer's disease.
[0043] 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.
[0044] 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.
[0045] 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 group sans carbon attach directly to the rest of the
referenced molecule or group.
[0046] The terms alkenyl and alkynyl, for example, a
C.sub.2-C.sub.6 alkenyl group or a C.sub.2-C.sub.6 alkynyl group as
used herein mean that the respective groups can include 1, 2, or 3
double bonds or triple bonds, respectively. If more than one double
or triple bond is present in the group, the double and triple bonds
can be conjugated or non-conjugated.
[0047] 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 stereoisomeric groups are also within the scope of the present
invention.
[0048] The term alkylaryl refers to an alkyl group substituted with
an aryl group. For example, C.sub.1-C.sub.6 alkylaryl indicates
that an aryl group is attached to a C.sub.1-C.sub.6 alkyl group and
that the resulting C.sub.1-C.sub.6 alkylaryl is attached to the
rest of the referenced molecule or group via the alkyl group.
[0049] 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, --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,
C.sub.0-C.sub.6 alkylheterocyclic.
[0050] The terms "optionally substituted 5-7 member carbocyclic" or
"optionally substituted 5-7 member heterocyclic" whether written in
the conjunctive or disjunctive style, or in single or in compound
sentences, mean a carbocyclic or heterocyclic 5-7 member ring that
is optionally substituted with 1-3 groups independently selected
from the group consisting of hydroxy, halogen, C.sub.1-C.sub.6
haloalkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkylaryl,
C.sub.1-C.sub.6 alkylheterocyclic, aryl, heterocyclic,
C.sub.0-C.sub.3 alkylcyano, nitro, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl C.sub.1-C.sub.6 alkoxy, aryloxy,
--OC.sub.2-C.sub.6 alkenyl, --OC.sub.1-C.sub.6 haloalkyl,
C.sub.0-C.sub.6 alkylNR.sup.7R.sup.8, C.sub.0-C.sub.6
alkylCOR.sup.7, C.sub.0-C.sub.6 alkylCO.sub.2R.sup.7,
C.sub.0-C.sub.6 alkylCONR.sup.7R.sup.8, CONR.sup.7SO.sub.2R.sup.8,
--NR.sup.7SO.sub.2R.sup.8, --NR.sup.7COR.sup.8,
--N.dbd.CR.sup.7R.sup.8, --OCONR.sup.7R.sup.8,
--S(O).sub.0-2R.sup.7, --SO.sub.2NR.sup.7R.sup.8,
C.sub.0-C.sub.5CH.sub.2OH, --OC.sub.1-C.sub.6 alkylheterocyclic,
and --OC.sub.1-C.sub.6 alkylaryl.
[0051] The term "optionally substituted" in general means that the
subject group may be substituted, where possible, with 1-3 groups
independently selected from the group consisting of hydroxy,
halogen, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkylaryl, C.sub.1-C.sub.6 alkylheterocyclic, aryl,
heterocyclic, C.sub.0-C.sub.3 alkylcyano, nitro, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl C.sub.1-C.sub.6 alkoxy, aryloxy,
--OC.sub.2-C.sub.6 alkenyl, --OC.sub.1-C.sub.6 haloalkyl,
--C.sub.0-C.sub.6 alkylNR.sup.7R.sup.8, C.sub.0-C.sub.6
alkylCOR.sup.7, C.sub.0-C.sub.6 alkylCO.sub.2R.sup.7,
C.sub.0-C.sub.6 alkylCONR.sup.7R.sup.8, CONR.sup.7SO.sub.2R.sup.8,
--NR.sup.7SO.sub.2R.sup.8, --NR.sup.7COR.sup.8,
--N.dbd.CR.sup.7R.sup.8, --OCONR.sup.7R.sup.8,
--S(O).sub.0-2R.sup.7, --SO.sub.2NR.sup.7R.sup.8,
C.sub.0-C.sub.5CH.sub.2OH, --OC.sub.1-C.sub.6 alkylheterocyclic,
and --OC.sub.1-C.sub.6 alkylaryl. Where an optionally substituted
group is claimed or disclosed, it should be noticed that both the
substituted and unsubstituted versions of the subject group are
within the purview of the invention unless otherwise indicated.
[0052] The term "aryl" refers to a substituted or unsubstituted
aromatic or heteroaromatic, or heterocyclic radical (heteroarylaryl
groups are subsumed in this term). 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,
benziniidazolyl, 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-benzothieny, 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.
[0053] 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.
[0054] The term "heterocycle", "heterocyclyl", or "heterocyclic"
refers to a 5, 6, or 7 member saturated, partially unsaturated or
aromatic mono-cyclic or a fused 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
pyrolidinyl, piperidinyl, hexamethyleneimmino, morpholino,
thiomorpholino, benzthiophene, indolyl, quinolyl, isoquinolyl,
tetrazolyl, and pyridinyl. 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 rest of the referenced molecule or group.
[0055] The term "haloalkyl" as used herein refers to an alkyl (as
noted above) substituted with one or more halo atoms selected from
F, Br, Cl, and I.
[0056] The term "haloalkoxyalkyl" as used herein include for
example trifluoromethoxy, pentafluoroethoxy, trifluoroethoxy
(OCH.sub.2CF.sub.3), and the like.
[0057] 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 die 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.
[0058] 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.
[0059] 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, non-limiting, solvating solvents include for
example, water, methanol, ethanol, acetone and dimethylformamide.
The term "hydrate" may be used when the solvent is water.
[0060] 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.
[0061] 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 groups) 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, carnsylate, 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.
[0062] 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 included within the scope 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 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
##STR00004##
[0063] Preferred n, m, p, and q
[0064] Preferably n is 0, or 1. More preferably, n is 0.
[0065] Preferably m is 0, or 1.
[0066] Preferably p is 1 or 2.
[0067] Preferably, q is 0, 1, 2, or 3. More preferably q is 2 or
3.
[0068] Preferably Y is a bond or C(O), or S(O).sub.t; Where t=0, 1,
or 2.
Preferred R.sup.1
[0069] A preferred R.sup.1 group 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, C.sub.0-C.sub.6 alkylaryl, --Oaryl,
--OC.sub.1-C.sub.6 haloalkyl, --OC.sub.1-C.sub.6 alkylcycloalkyl,
--OC.sub.3-C.sub.8 cycloalkyl, --C.sub.1-C.sub.6
aLkylcycloalkylNR.sup.7R.sup.8, --OC.sub.1-C.sub.6 alkyl,
--OC.sub.0-C.sub.6 alkylaryl, --OC.sub.1-C.sub.6 alkylcyano,
--OC.sub.1-C.sub.6 alkylCO.sub.2R.sup.11, --OC.sub.3-C.sub.8
cycloalkylCO.sub.2R.sup.11, --OC.sub.1-C.sub.6alkylhydroxy,
--OC.sub.1-C.sub.6 alkylNR.sup.7R.sup.8 and --OC.sub.1-C.sub.6
alkylheterocyclic, provided that R.sup.1 is not --OH when Y is
S(O).sub.1; 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.3
alkylCONH.sub.2, C.sub.0-C.sub.3 alkylcyano, and C.sub.0-C.sub.3
alkylC(O)OC.sub.1-C.sub.3 alkyl.
[0070] When p is 1, a more preferred R.sup.1 group is selected from
the group consisting of: hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl,
C.sub.0-C.sub.6 alkylaryl, C.sub.1-C.sub.6 alkylcycloalkyl,
C.sub.0-C.sub.6 alkylheterocyclic, C.sub.3-C.sub.8cycloalkyl,
--OC.sub.1-C.sub.6 alkyl, --OC.sub.1-C.sub.6 alkylcycloalkyl,
--OC.sub.1-C.sub.6 alkylhydroxy, --OC.sub.1-C.sub.6
alkylNR.sup.7R.sup.8, and --OC.sub.1-C.sub.6 alkylCO.sub.2R.sup.11,
provided that R.sup.1 is not --OH when Y is S(O).sub.t; wherein
each alkyl, cycloalkyl, heterocyclic and aryl groups are each
optionally substituted as described above.
[0071] When p is 1, a still more preferred R.sup.1 is a group
represented by C.sub.1-C.sub.6 alkyl, C.sub.0-C.sub.6 alkylaryl,
C.sub.0-C.sub.6 alkylheterocyclic, C.sub.0-C.sub.6 alkylcycloalkyl,
--OC.sub.1-C.sub.6 alkyl 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.3b alkylCONH.sub.2, C.sub.0-C.sub.3 alkylcyano, and
C.sub.0-C.sub.3 alkylC(O)OC.sub.1-C.sub.3 alkyl.
Preferred R.sup.2
[0072] A preferred R.sup.2 group is selected from the group
consisting of: hydrogen, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkylcycloalkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.6 alkylaryl and C.sub.0-C.sub.6
alkylNR.sup.7R.sup.8.
[0073] When p is 1, a more preferred R.sup.2 group is represented
by hydrogen.
Preferred R.sup.3 Groups
[0074] Preferred R.sup.3a and R.sup.3b groups are independently
selected from the group consisting of: hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl. More
preferably, R.sup.3a and R.sup.3b are independently selected from
hydrogen and C.sub.1-C.sub.6 alkyl.
Preferred R.sup.4 Groups
[0075] A preferred R.sup.4 group is NR.sup.4aR.sup.4b.
[0076] Also preferred, is an R.sup.4a group selected from the group
consisting of:
##STR00005## ##STR00006##
wherein R is independently selected from the group consisting of:
halogen, C.sub.0-C.sub.6 alkylalcohol, hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy C.sub.0-C.sub.6 alkylcycloalkyl ,
C.sub.0-C.sub.6 alkylheterocyclic, C.sub.1-C.sub.6 alkylCN,
C.sub.1-C.sub.6 haloalkyl, C.sub.0-C.sub.6
alkylNR.sub.11R.sup.12C.sub.1-C.sub.6 alkylC(O)NR.sup.11R.sup.12,
and C.sub.1-C.sub.6 alkylC(O)OR.sup.11. Still more preferred is an
R group independently selected from the group consisting of:
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkylNH.sub.2, and
C.sub.2-C.sub.6 alkylalcohol.
[0077] Preferably, R.sup.4b is selected from C.sub.1-C.sub.6
alkylaryl, C.sub.1-C.sub.6 alkylheterocyclic, wherein the
heterocyclic and aryl groups are optionally substituted with 1-3
groups selected from the group consisting of: hydroxy, oxo, cyano,
--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, and --OC.sub.1-C.sub.6 alkyl. More preferably, R.sup.4b is
benzyl mono or disubstituted with C.sub.1-C.sub.6 haloalkyl. Still
more preferably R.sup.4b is 3,5-bistrifluorobenzyl.
Preferred R.sup.5 Groups
[0078] R.sup.5 is preferably selected from a group consisting of:
hydrogen, halogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, --OC.sub.1-C.sub.6 alkyl, --Oaryl, --OC.sub.2-C.sub.6
alkenyl, --OC.sub.1-C.sub.6 haloalkyl, CH.sub.2NR.sup.7R.sup.8,
--NH.sub.2, --N(C.sub.1-C.sub.4 alkyl).sub.2, --CN, and --NO.sub.2.
Also preferred are any two R.sup.5 groups which combine to form an
optionally substituted 5, 6, or 7-member ring fused with the phenyl
ring to which they are attached, wherein the 5, 6, or 7-member ring
is saturated, partially unsaturated, or fully unsaturated and
optionally contains 1, 2, or 3 heteroatoms independently selected
from O, N, and S. Optional substituents for the 5, 6, or 7-member
fused ring discussed above include preferably, halogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, aryloxy, --OC.sub.2-C.sub.6 alkenyl, --OC.sub.1-C.sub.6
haloalkyl, --CH.sub.2NR.sup.7R.sup.8, --NH.sub.2,
--N(C.sub.1-C.sub.4 alkyl).sub.2, --CN, and --NO.sub.2.
Preferred R.sup.6 Groups
[0079] Preferred R.sup.6 groups are independently selected from a
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,
C.sub.1-C.sub.6 alkylhydroxy, phenyl, and C.sub.1-C.sub.6
alkoxy.
Preferred R.sup.7 and R.sup.8
[0080] Preferred R.sup.7 and R.sup.8 groups 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.6 alkylheterocyclic, wherein each aryl group is
optionally substituted with 1-3 groups independently selected from
C.sub.1-C.sub.6 alkyl, halogen, and C.sub.1-C.sub.6 haloalkyl.
Preferred R.sup.11 and R.sup.12
[0081] Preferred R.sup.11 and R.sup.12 groups 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.6 alkylheterocyclic, wherein each aryl group is
optionally substituted with 1-3 groups independently selected from
C.sub.1-C.sub.6 alkyl, halogen, and C.sub.1-C.sub.6 haloalkyl.
[0082] A particularly preferred compound of the invention is
selected from the group consisting of: [0083]
(S)-(3,5-Bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-triflu-
oromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-
-5-yl)amine, [0084]
5-[(3,5-Bis-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl-amino]-7-methyl-8-t-
rifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid
isopropyl ester, [0085]
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid ethyl ester, [0086]
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid isopropyl ester, [0087]
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid tert-butyl ester, [0088]
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 1-ethyl-propyl ester, [0089]
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid cyclopentyl ester, [0090]
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 1-ethyl-2-methyl-propyl ester, [0091]
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid tetrahydro-pyran-4-yl ester, [0092]
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetraz-
ol-2-yl}-ethanol, [0093]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-ethyl-7-methyl-8-trifluoromethyl--
2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-ami-
ne, [0094]
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-
-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-
-ylmethyl}-cyclohexyl)-acetic acid, [0095]
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-3,-
3-dimethyl-pentanoic acid, [0096]
(S)-2-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-eth-
anol, [0097]
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,2-d-
ifluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxyli-
c acid isopropyl ester, [0098]
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5--
carboxylic acid isopropyl ester, [0099] (+/-)-Isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3-
,4,5-tetrahydrobenzo[b]azepine-1-carboxylate, [0100]
(+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-8-c-
hloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate, [0101] (+/-)
isopropyl-6-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-2,-
3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylate,
[0102]
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-1-tetrazol-5-yl)-amino]-2,3-
,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
isopropyl ester, [0103]
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl-ester, [0104] (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(5-methyl-1H-pyrazol-3-yl)-amino]-8-ch-
loro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate, [0105]
+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(5-methyl-isoxazol-5-yl)-amino]-8-chlo-
ro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate, [0106]
(+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-9-m-
ethyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate,
[0107]
(S)-6-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-
)-amino]-4-methyl-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-c-
arboxylic acid isopropyl ester, [0108] (S)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-8,9-
-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate, [0109]
(S)-isopropyl
5-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl-
]-amino}-8,9-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate,
[0110]
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-
)-amino]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid tert-butyl ester, [0111]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-1,2,3,5,6,7,8,9-
-octahydro-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amin-
e, [0112]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-3,5,6,-
7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine, [0113]
(S)-5-(9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl}-3,3-dimeth-
yl-pentanoic acid, [0114]
(S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetraz-
ol-5-yl]-amino}-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl)-
-3,3-dimethyl-pentanoic acid, [0115]
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester, [0116]
(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-2,3,4,5,7,8,9,10-oc-
tahydro-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine,
[0117]
5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-2,3,4,5,7,8,9,10-octahydro-naphtho[2,3-b]azepine-1-carboxylic
acid isopropyl ester, [0118]
(S)-9-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol--
5-yl)-amino}-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxyl-
ic acid isopropyl ester, [0119]
(R)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester, [0120]
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester, [0121]
(S)-6-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol--
5-yl]-amino}-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carbox-
ylic acid isopropyl ester, [0122]
(S)-6-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol--
5-yl]amino}-4-methyl-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-1-
0-carboxylic acid isopropyl ester, [0123]
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid 2-methoxycarbonyl-2-methyl-propyl ester, [0124]
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid 2-carboxy-2-methyl-propyl ester, [0125]
(S)-1-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-ami-
no]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-3-f-
uran-2-ylmethoxy)-propan-2-one, [0126]
2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]--
7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-1-pheny-
l-ethanol, [0127]
2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]--
7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)
-2-phenyl-ethanol, [0128]
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-benzoic acid methyl ester, [0129]
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-benzoic acid, [0130]
(S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-benzoic acid methyl ester, [0131]
(S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-benzoic acid, [0132]
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-be-
nzoic acid, [0133]
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-
-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cy-
clohexyl)-acetic acid methyl ester, [0134]
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-
-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cy-
clohexyl)-acetic acid, [0135]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine, [0136]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine hydrochloride, [0137]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-3-ylmethyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine, [0138]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7-methyl-8-trif-
luoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetraz-
ol-5-yl)-amine, [0139]
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-eth-
anol, [0140]
(S)-(2-{5-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-eth-
yl)-carbamic acid text-butyl ester, [0141]
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethy-
l}-benzoic acid, [0142]
(S)5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-thiop-
hene-2-carboxylic acid, [0143]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(5-pyrid-
in-4-ylmethyl-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl-
)-amine, [0144]
(S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-cyc-
lohexyl)-acetic acid, [0145]
(S)-2-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl}-ethanol,
[0146]
(S)-9-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluorometh-
yl-benzyl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5--
carboxylic acid tert-butyl ester, [0147]
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(5-benzyl-3,5,6,7,8,9-hexahydro--
1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(3,5-bis-trifluoromethyl-benzyl)-a-
mine, [0148]
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-[5-(3,3,3-trifluoro-propyl)-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohep-
ta[f]inden-9-yl]-amine, [0149]
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-2,3,4,5,7,8,9,10-octahydro-naphtho[2,3-b]azepin-1-yl}-3,3-dimethyl-pe-
ntanoic acid, [0150]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-11-methyl-2,3,4-
,5,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol--
5-yl)-amine, [0151]
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-thiophene-2-carboxylic acid, [0152]
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-2-methyl-propionic acid ethyl ester, [0153]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1,7-dimethyl-8-trifluoromethyl-2,3,-
4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine,
[0154]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(-
7-methyl-1-thiazol-2-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benz-
o[b]azepin-5-yl)-amine, [0155]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-[7-methyl-1-(1-methyl-1H-imidazol-2--
ylmethyl)-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(2--
methyl-2H-tetrazol-5-amine, [0156]
(S)-(1-Benzyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]az-
epin-5-yl)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ine, [0157]
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}, [0158] (S)-(4-
{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-
-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-ph-
enyl)-acetic acid, [0159]
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-bu-
tyric acid, [0160]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-ylmethyl-8-t-
rifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tet-
razol-5-yl)-amine, [0161]
(S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmet-
hyl}-piperidin-1-yl)-acetic acid ethyl ester, [0162]
(S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmet-
hyl}-piperidin-1-yl)-acetic acid, [0163]
(S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-2--
methyl-propionic acid, [0164]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyrrolidin-2-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine, [0165]
(S)-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl
-acetic acid, [0166]
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-[1-(2-benzyloxy-ethyl)-7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(3,5-bis-trif-
luoromethyl-benzyl)-amine, [0167]
(S)-2-{5-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-b-
enzyl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-
-1-yl}-ethanol, [0168]
(S)-5-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benz-
yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-
-carboxylic acid tert-butyl ester, [0169]
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl)-(3,5-bis-trifluoromethyl-benzyl)-
-(7-methyl-1-thiazol-2-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-be-
nzo[a]azepin-5-yl)-amine,
[0170]
(S)-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol--
5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin--
1-yl}-ethoxy)-acetic acid, [0171] (S)-Acetic acid
2-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino)-
-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-ethyl
ester, [0172]
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-[7-methy-
l-1-(2H-tetrazol-5-ylmethyl)-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo-
[b]azepin-5-yl]-amine, [0173]
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 2-amino-ethyl ester, [0174]
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 2-carboxy-2-methyl-propyl ester, [0175]
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl)-(3,5-bis-trifluoromethyl-benzyl)-
-(1-cyclopropylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-ben-
zo[b]azepin-5-yl)-amine, [0176]
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-(1-cyclopropylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-ben-
zo[b]azepin-5-yl)-amine hydrochloride, and pharmaceutically
acceptable salts solvate, enantiomer, racemate, diastereomer or
mixture of diastereomers thereof.
[0177] The geometric isomers associated with the double bonds and
the optical isomers associated with 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
[0178] The compounds of the instant invention can be synthesized as
exemplified in the following Schemes, Examples, and procedures.
Anthranilatc 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
limit the scope of the present invention in any way because one of
skill in the art is able to extrapolate without undue
experimentation from the Schemes and Examples herein to other
specific compounds within the scope of the invention. Many of the
reagents and starting materials can be readily obtained from
commercial suppliers and are readily available to one of ordinary
skill in the art. Other 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 similar reagents or starting materials,
and the procedures described in the preparations and Examples
below, including any novel procedures. This includes, but is not
limited to, esterification of a carboxylic acid, hydrolysis of a
nitrile to a carboxylic acid, and subsequent esterification. The R,
R1, R2, R3, R4, R5, R6, etc, designations used within this section
for the purpose of illustrating the various methods of synthesizing
compounds of the invention and/or illustrating variability of
substituents at the pendent position are not necessarily synonymous
in scope or meaning with similar groups used in the generic
structure for compounds of Formula I. However, groups in final
compounds of the schemes occupying 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.
##STR00007##
[0179] In intermediate preparation Scheme 1, 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 is dissolved in a suitable solvent,
such as DMF or DMSO, with a base, such as cesium carbonate, and the
appropriately substituted benzonitrile or fluoro benzoate (R6=CN or
CO.sub.2R3). The reaction proceeds at 0.degree. C. to elevated
temperatures (up to or about 150.degree. C.) in anywhere from ten
minutes to several days depending on the stability of the starting
materials and/or reaction conditions. The product of structure 4
(R6=CN) or 1 (R6=CO.sub.2R3) can then be isolated by a standard
aqueous workup, followed by normal phase chromatographic methods or
recrystallization techniques commonly employed in the art.
##STR00008##
[0180] In intermediate preparation Scheme 2, 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 is dissolved in a suitable solvent, such as DMF,
with a base, such as cesium carbonate or sodium tert-butoxide, the
appropriately substituted benzonitrile or haloalkyl benzoate (R6=CN
or CO.sub.2R3), and a suitable catalyst complex, such as palladium
acetate and diphenyl phospino ferrocene. The reaction proceeds at
0.degree. C. to elevated temperatures in anywhere from ten minutes
to several days depending on the stability of the starting
materials. The product of structure 4 (R6=CN) or 1 (R6=CO.sub.2R3)
can then be isolated by a standard aqueous workup, followed by
normal phase chromatographic methods or recrystallization
techniques commonly employed in the art.
##STR00009##
[0181] In intermediate preparation Scheme 3, 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 aryl bromide is dissolved in a suitable
solvent, such as DMF, with 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
(R3-OH) and saturated with carbon monoxide. The reaction proceeds
at 0.degree. C. to elevated temperatures (up to or about
150.degree. C.) in anywhere from ten minutes to several days
depending on the stability of the starting materials and/or
reaction conditions. 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.
##STR00010##
[0182] In intermediate preparation Scheme 4, 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 aryl bromide is dissolved in a suitable solvent, such
as diethyl ether or tetrahydrofuran, with an alkyllithium, such as
n-butyl lithium or tert-butyl lithium or magnesium turnings. The
resulting anion is quenched with a suitable carbon dioxide source,
such as dry ice, or dimethyl carbonate. The reaction proceeds at
about -78.degree. C. to about 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.
##STR00011##
[0183] Synthetic Scheme 5 shows preparation of exemplary precursor
compounds for Formula I. For example, substituted acylamino esters
1 that are either commercially available or prepared as set forth
in the literature or in Schemes 1 to 4 can be protected with tosyl
chloride, isopropyl chloroformate, or other suitable protecting
group to provide 54. The compound 54 may in turn be alkylated with
appropriately substituted, or unsubstituted 3-bromoethylesters 55
thus affording 56. Dieckmann condensation-cyclization of
intermediate 56 yields N-protected benzazepinone 57, which is
subjected to acid hydrolysis and decarboxylation to afford ketone
derivatives 58. Removal of the protecting group, if necessary, with
acid (e.g. PPA (polyphosphoric acid)), TMSI (trimethylsilyliodide),
or HCl provides the intermediate 59. N-acylation of 59 by treatment
with an appropriately substituted aryl or alkyl chloroformate in
the presence of an organic base such as pyridine affords carbamates
of structure 64. Alternatively, treatment of 59 with an acid
chloride or an appropriate activated ester, affords compounds of
formula 64. The intermediate benzazepin-5-ones may be reduced with
a reducing agent such as sodium borohydride in an appropriate
solvent, such as tetrahydrofuran or methanol, to achieve the
benzylic alcohol 65 as shown in Scheme 5.
##STR00012##
[0184] Compounds of Formula I may be prepared as shown in Schemes 6
and 7, in which reductive amination chemistry is utilized.
Formation of a Schiff base of benzazepin-5-ones 64 with a
heterocyclic amine is followed by treatment with a reducing agent
such as sodium borohydride in an appropriate solvent, such as
tetrahydrofuran or methanol, to achieve the heterocyclic amine
adducts. Further elaboration by reaction with an activated benzylic
reagent in the presence of base or the use of a Mitsunobu-type
displacement reaction affords the corresponding product, a compound
of the invention. Alternatively, the benzazepin-5-ones (64) may be
reduced to the corresponding carbinol intermediate with a reducing
agent such as sodium borohydride in an appropriate solvent, such as
tetrahydrofuran or methanol. These adducts may be converted
directly to provide disubstituted amine products using the
Mitsunobu protocol, or initially converted to activated templates
such as a mesylate, tosylate or bromide and displaced with the
heterocyclic-substituted benzylamine to achieve trisubstituted
amine products as shown in Scheme 6. A preferred group of potential
heterocyclic R-A substituents has been described supra.
##STR00013##
[0185] A reverse procedure for forming the disubstituted amine is
shown in Scheme 7. Formation of a Schiff base of benzazepin-5-ones
(64) with a benzylic amine is followed by treatment with a reducing
agent such as sodium borohydride in an appropriate solvent, such as
tetrahydrofuran or methanol, to achieve the disubstitued benzylic
amine adduct 69. Further elaboration by reaction with an activated
heterocylic reagent in the presence of base (or alternatively,
Schiff base formation with a heteroaromatic aldehyde followed by
reduction) provides a secondary route to disubstituted amine
products 67.
##STR00014## ##STR00015##
[0186] Compounds of Formula I may also be prepared by
transformation of pendant functionality as shown in Scheme 8.
Disubstituted amine products, such as, 68 in which the moiety R-A
corresponds to reactive functionality such as cyano, carboxylate,
and the like may be transformed into heterocyclic moieties such as
71 in intermediate stages of synthesis or at the end of the
synthetic preparation. Also, the order of N-substitution may be
reversed as shown above. Procedures for transforming pendant
functionalities wherein R-A corresponds to reactive functionality
such as nitrile, carboxylate, etc are known to one of skill in the
art and may be found in general organic and/or heterocyclic
chemistry reference text such as but not limited to Comprehensive
Organic Transformations, 2.sup.nd, ed., by Richard Larock,
Wiley-VCH, Publishers, New York.
##STR00016## ##STR00017##
[0187] Scheme 8a shows a few examples of transformation reactions
to illustrate inter-conversion of functionalities as means of
preparing compounds of the invention. Detailed procedures are
disclosed in the examples, known to one of skill in the art or may
be readily sourced from reference sources by one of skill in the
art.
##STR00018##
[0188] Compounds of the Formula I may also be prepared as shown in
Schemes 9 and 10, in which the intermediate benzazepin-5-ones are
transformed into benzylic amine adducts. This may be achieved by a
number of methods, including reductive amination with a primary
amine surrogate (such as, hydroxylamine, hydrazine, ammonium
chloride, benzophenoneimine, among others), to provide a primary
amine, as shown in Scheme 9, or may be incorporated into the ring
construction sequence, as shown in Scheme 10, by chemistry known to
one of ordinary skill in the art (Hadden, M.; Nieuwenhuyzen, M.;
Potts, D.; Stevenson, P. J.; Thompson, N. Tetrahedron 2001, 57,
5615; Crousse, B.; Begue, J.-P.; Bonnet-Delpon, D. J Org Chem 2000,
65, 5009). Schiff base formation by treatment of the amine with a
benzaldehyde is followed by treatment with a reducing agent such as
sodium borohydride in an appropriate solvent, such as
tetrahydrofuran or methanol, to achieve the benzylic amine adducts
(or alternatively, displacement of an activated benzylic substrate,
such as a mesylate, tosylate or bromide) provides the benzylamine
product. This is followed by treatment with an activated heteroaryl
(heterocyclic aryl) substrate, such as a mesylate, tosylate or
bromide in the presence of a base to produce dibenzylic products,
as shown in Scheme 9. In a reverse fashion, formation of a Schiff
base of benzazepine-5-amines with a heteroaromatic aldehyde,
followed by treatment with a reducing agent such as sodium
borohydride in an appropriate solvent, such as tetrahydrofuran or
methanol (or alternatively, displacement of an appropriately
activated heteroaryl substrate, such as a mesylate, tosylate or
bromide) achieves the benzylic heteroaromatic amine adduct. This is
followed by treatment with an activated benzylic substrate, such as
a mesylate, tosylate, or bromide, in the presence of a base to
produce dibenzylic products, as shown in Scheme 9.
##STR00019##
[0189] In Scheme 10, compound 64 can be treated with a base, such
as sodium hydride or lithium diisopropylamide or lithium
bis(trimethylsilyl)amide, in a solvent, such as DMF or
tetrahydrofuran. Alkylation with the appropriately substituted
halide or mesylate or tosylate may form compound 79 where R3a and
R3b can be the same or different. Conversion of 79 to 67 is as
described, for example in scheme 9.
##STR00020##
[0190] As shown in Scheme 11, compound 73d may be hydrolyzed to the
corresponding amine 80, and may be further acylated using standard
procedures known or determined by one skilled in the art to provide
73d. Or alternatively, 80 can be treated with triphosgene or
trichloromethylchoroformate to provide 81. Compound 81 can afford
compound 73d by reaction with the appropriate alcohols. Also,
compound 80 can be alkylated by methods known in the art such as
treating 80 with base and an alkyl halide, tosylate or the like, to
afford 82. Alternatively compound 82 can be obtained using
reductive amination conditions.
##STR00021##
[0191] As shown in Scheme 12, tetrazole 83 can be alkylated with
the appropriate protected aminoalcohol under Mitsunobu conditions
or with the appropriate protected aminoalkylbromide, iodide,
mesylate, or the like in the presence of base to provide a
protected aminoalkyltetrazole 84. Removal of the protecting group,
P1, using methods well known in the art can yield compound 85.
Alternatively, tetrazole 83 can be alkylated with the appropriate
alkylcyano bromide or with the appropriate acrylonitrile under
Michael reaction conditions. Cyano derivative 86 can be then
reduced to the corresponding amine 85. Tetrazole 83 can be
alkylated using the appropriate alcohol under Mitsunobu conditions,
or with the appropriate alkyl halide or the like in the presence of
base to provide 87. Removal of P1 (protecting group) using methods
well known in the art can yield compound 88. Alternatively
hydroxyalkyltetrazole 88 can be obtained by alkylation of 83 with
the corresponding halide in the presence of base.
##STR00022##
[0192] As shown in Scheme 14, compound 89 can be oxidized to
compound 90 with ruthenium oxide in presence of sodium periodate.
Compound 90 can be converted to 91 as is described, for example in
scheme 9. Deprotection of tertbutoxycarbonyl group by methods well
known in the art, can afford amide 92. Alkylation of 92 with the
appropriate alkyl halide or tosylate or the like in presence of a
base, can give rise compound 93.
##STR00023##
[0193] As shown in Scheme 15, iodoaryl derivative 94 can be
transformed in ketone 95 by lithium exchange reaction followed by
addition of a Weinreb amide. Then conversion of compound 95 in the
aldehyde 96 and oxidation to the corresponding carboxylic acid can
afford compound 97. Hydrolisis of amino protecting group and
reductive amination reaction can give rise to compound 99, which
can be cyclize to compound 100. Finally compound 93 can be obtained
as is described in scheme 14.
Assay
[0194] 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
[0195] An in vitro Scintillation Proximity Assay (SPA) has been
used to evaluate 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. The CETP source for this assay can
be produced by AV-12 cells that have been created to express human
CETP. The radiolabeled cholesterol ester is transferred in a
HEPES-NaCl based buffer, after thirty minutes incubation the
reaction is stopped and the biotinylated LDL is bound to
streptavidin/scintillant coated SPA beads (Amersham). The
radioactive signal is measured in a Packard 96-well scintillation
TopCounter with window settings fully open. A decrease in
radioactive signal from the LDL relative to a standard indicates
the ability of compounds to inhibit the activity of CETP. Preferred
compounds of the invention evaluated according to this assay
protocol exhibit CETP inhibition at concentrations of less than 100
micromolar.
[0196] Alternatively, other CETP sources can be used to mediate the
transfer of radiolabeled cholesterol ester in this assay. For
example, endogenous CETP from human plasma, CETP from mice that
express human CETP, and endogenous CETP from hamsters can be used
as the CETP source in this assay.
[0197] Buffers other than HEPES-NaCl based buffer can be used in
this assay, for example, human plasma, mouse plasma or a
Tris-buffer that is high in albumin may be used.
[0198] It will be understood by those skilled in the art that other
sources of radioactivity may be used to track the CETP activity in
this assay.
[0199] Additionally, radio labeled-LDL may be used in this
assay.
In Vivo Assay of CETP Activity
[0200] Syrian Golden Hamsters, which express endogenous CETP, can
be 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/plasma can be obtained. The CETP activity
can be determined by a method similar to that described above for
the in vitro CETP activity assay, with the modification that plasma
from the treated animals is used as the CETP source in the
assay.
[0201] A strain of transgenic mice that express human CETP
(Taconic, Germantown, N.Y.) can also be used to test compounds of
this invention. Test compounds can be 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/plasma
can be obtained. The CETP activity can be determined by a method
similar to that described above for the in vitro CETP activity
assay, with the modification that plasma from the treated animals
is used as the CETP source in the assay.
[0202] Alternatively, a strain of transgenic mice that express both
human CETP and human apolipoprotein A-1 (Taconic, Germantown, N.Y.)
can be used to test compounds of this invention. Test compounds can
be 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/plasma is obtained. CETP activity can be determined
by a method similar to that described for the in vitro CETP
activity assay, with the modification that plasma from the treated
animals is used as the CETP source in the assay.
In Vivo Assay of Plasma Lipids
[0203] Activity of compounds of this invention in vivo can be
evaluated by comparing the level of elevation of HDL cholesterol
relative to a control by a given amount of a 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.) can be used to evaluate compounds of this
invention. Test compounds are administered to the animals once
orally in selected aqueous or oil based vehicles. At various times
after dosing, ranging from 4 h to 24 h, blood is obtained. The
blood is allowed to clot, and serum is obtained from the clotted
blood by centrifugation. The HDL cholesterol levels in the serum
can be determined by known procedures using 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 after administration
are summarized in Table 1.
TABLE-US-00001 TABLE 1 Elevation of HDL cholesterol levels at 8 hr
Single Oral Dose % HDL cholesterol Compound of Example No. (mg/kg)
increase 3 30 71 16 30 82 17 30 73 18 30 105 20 30 72 25 30 142 27
30 128 30 30 54 31 30 114 32 30 128 33 30 354 50 30 127 73 30 374
77 30 229 89 30 186 94 30 154 129 30 92 139 30 130 141 30 74 142 30
90 148 30 224 151 30 165 153 30 165 154 30 99 165 30 177 166 30 102
170 30 95 175 30 100 178 30 128 185 30 155 187 30 124 191 30 91 192
30 102 196 30 126 200 30 153 201 30 147 202 30 206
[0204] The efficacy of compounds of the invention in vivo can also
be evaluated 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 from the animals can be
obtained, and lipids can be analyzed by enzymatic methods. Lipids
in the VLDL, LDL and HDL fractions can be analyzed by known
enzymatic methods after precipitation or size exclusion
chromatography.
[0205] Alternatively, a strain of transgenic mice that expresses
human CETP (Taconic, Germantown, N.Y.) can be 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 to the animals in selected
aqueous or oil based vehicles for up to 1 week. Serum can be
obtained from the animals. Lipids from the serum 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
[0206] 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. A 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, but not limited to: 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 1000 mg/day of a compound of the present
invention. Preferred daily doses generally will be from about 1 mg
to about 250 mg/day.
[0207] The compounds of this invention may 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. The total active ingredients in
such formulations comprises from 0.1% to 99.9% by weight of the
formulation.
[0208] The term "pharmaceutically acceptable" as used herein means
that the carrier, diluent, excipients and salt are compatible with
the other ingredients of the formulation and not deleterious to the
recipient thereof.
[0209] Pharmaceutical formulations of the present invention may 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. Non limiting 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.
[0210] The compounds also may 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.
[0211] 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
[0212] Compounds of the invention may be formulated following one
or more of the formulation examples, procedures, protocols or
mixing ratios below. In the formulations which follow, the term
"Active Ingredient" as used herein means a compound of Formula I, a
salt, solvate, racemate, enantiomer diastereomer, mixture of
diastereomers, prodrug thereof, or a combination of a compound of
Formula I and other effective agents for the treatment or
prevention of dyslipidemia, atherosclerosis, or other co-morbid
conditions and symptoms.
Formulation 1: Gelatin Capsules
[0213] Hard gelatin capsules can be prepared according to 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
[0214] The formulation above may be changed in compliance with the
reasonable variations provided.
Formulation 2: Tablets
[0215] A tablet formulation, each tablet containing 2.5-1,000 mgs
of active ingredient, can be prepared using the ingredients
below:
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.
Formulation 3: Tablets
[0216] Alternatively, tablets, each containing 25-1000 mg of active
ingredient, can be prepared according to the following:
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
[0217] The active ingredient, starch, and cellulose are passed
through a No. 45 mesh U.S. sieve and thoroughly blended. The
solution of polyvinylpyrrolidone is mixed with the blended powders.
The blended powders are then passed through a No. 14 mesh U.S.
sieve and pelletized or formed into granules. The granules so
produced are dried at 50.degree.-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.
Formulation 4: Suspensions
[0218] A suspensions containing 0.1-1000 mg of medicament per 5 ml
dose can be prepared as follows:
TABLE-US-00005 Ingredient Quantity (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
[0219] The active ingredient is passed through a No. 45 mesh U.S.
sieve and then blended with the sodium carboxymethyl cellulose and
syrup to form a smooth paste. The benzoic acid solution, flavor,
and color are diluted with an amount of purified water and added,
with stirring to the paste. Sufficient purified water is then added
to provide the suspension with the desired volume (or
concentration).
Formulation 5: Aerosol
[0220] An aerosol solution can be prepared as follows:
TABLE-US-00006 Ingredient Quantity (% by weight) Active ingredient
0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane) 70.00
[0221] The active ingredient is mixed with ethanol and the mixture
added to a portion of the propellant 22, cooled to 30.degree. C.,
and transferred to a filling device. The desired amount is then fed
to a stainless steel container and diluted with the remaining
propellant. The valve units are then fitted to the container.
Formulation 6: Intravenous Solution
[0222] A solution suitable for intravenous administration can be
prepared as follows:
TABLE-US-00007 Ingredient Quantity Active ingredient 50 mg Isotonic
saline 1,000 mL
[0223] A solution comparing the above ingredients can be
intravenously administered to a patient at a rate of about 1 mL per
minute or as prescribed by a physician.
Examples
[0224] Compounds of the invention may be prepared following or in
analogy to one or more of the Examples and procedure below.
Example 1
Synthesis of (+/-)-Isopropyl
5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-bro-
mo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00024##
[0225] Step 1. Preparation of Methyl
5-bromo-2-isopropoxycarbonylaminobenzoate
##STR00025##
[0227] Add isopropyl chloroformate (36.9 mL, 36.9 mmol, 1.0 M in
toluene) dropwise to a solution of methyl 2-amino-5-bromobenzoate
(5.0 g, 24.6 mmol) and pyridine (80.0 mL, 36.9 mmol) in
dichloromethane (80 mL) at room temperature under an atmosphere of
nitrogen and stir for 1.5 h. Pour the reaction into water (100 mL)
and separate the layers. Extract the aqueous layer with
dichloromethane (2.times.40 mL) and combine the organic extracts
and wash with 2 N hydrochloric acid, saturated sodium hydrogen
carbonate, and brine (80 mL each). Dry the organic layer over
anhydrous sodium sulfate, filter, and remove the solvent under
reduced pressure to afford the title compound as a pale yellow
solid (6.68 g, 86%). .sup.1H NMR (CDCl.sub.3) .delta. 1.31 (d,
J=6.3 Hz, 6H), 3.92 (s, 3H), 5.03 (septet, J=6.3 Hz, 1H), 7.61 (dd,
J=1.9, 8.5 Hz, 1H), 8.11 (d; J=1.9 Hz, 1H), 8.40 (d, J=8.5 Hz, 1H),
10.31 (br s, 1H). ESI MS m/z 316
[C.sub.12H.sub.14BrNO.sub.4+H].sup.+.
Step 2. Preparation of Methyl
5-bromo-2-[isopropoxycarbonyl-(3-methoxycarbonylpropyl)amino]benzoate
##STR00026##
[0229] Heat a suspension of methyl
5-bromo-2-isopropoxycarbonylaminobenzoate (10.0 g, 31.6 mmol),
methyl 4-bromobutyrate (22.9 g, 126 mmol) and cesium carbonate
(41.6 g, 126 mmol) in N,N-dimethylformamide (150 mL) under nitrogen
at 80.degree. C. for 24 h. Cool the mixture to room temperature and
pour into water (200 mL). Extract with ethyl acetate (3.times.100
mL) and wash the organic extracts with water (3.times.100 mL) and
brine (100 mL). Dry the organic layer over anhydrous sodium
sulfate, filter, and remove the solvent under reduced pressure.
Chromatograph the residue over silica gel, eluting with
hexanes/ethyl acetate (60:40), to provide the title compound as a
colorless oil (11.8 g, 89%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 1.05-1.07 (m, 4H), 1.30-1.32 (m, 2H), 1.89-1.94 (m, 2H),
2.38-2.44 (m, 2H), 3.46-3.60 (m, 1H), 3.65 (s, 3H), 3.68-3.79 (m,
1H), 3.86 (s, 3H), 4.85-5.01 (m, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.62
(dd, J=1.7, 8.4 Hz, 1H), 8.07 (brs, 1H); ESI MS m/z 416
[C.sub.17H.sub.22BrNO.sub.6+H].sup.+.
Step 3. Preparation of (+/-)-Isopropyl
7-bromo-5-oxo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00027##
[0231] Add a solution of methyl
5-bromo-2-1methoxycarbonylpropyl)amino]benzoate (11.7 g, 28.1 mmol)
in toluene (100 mL) to a suspension of potassium tert-butoxide
(6.31 g, 56.2 mmol) in toluene (100 mL) at 70.degree. C. under an
atmosphere of nitrogen over a period of 30 min. After 15 min, cool
the mixture to room temperature and pour the suspension into ice
water (500 mL). Adjust the pH of the solution to pH=3 with 2 N
hydrochloric acid (25 mL) and separate the layers. Extract the
aqueous layer with ethyl acetate (3.times.200 mL) and combine the
organic extracts. Dry the organic layer over anhydrous sodium
sulfate, filter, and remove the solvent under reduced pressure to
provide
(+/-)-1-isopropyl-4-methyl-7-bromo-5-oxo-2,3,4,5-tetrahydrobenzo[b]azepin-
e-1,4-dicarboxylate as an orange oil (10.5 g, 98% crude). Dissolve
(+/-)-1-isopropyl-4-methyl-7-bromo-5-oxo-2,3,4,5-tetrahydrobenzo[b]azepin-
e-1,4-dicarboxylate (10.5 g, 27.3 mmol) in glacial acetic acid (100
mL) and add water (10 mL) followed by concentrated hydrochloric
acid (35 mL) and heat the resulting solution at reflux for 1 h.
Cool the mixture to room temperature and pour into ice water (500
mL). Adjust the to pH=8 with potassium hydroxide (85 g) in water
(200 mL), and extract the mixture with ethyl acetate (3.times.150
mL) and combine the organic extracts. Dry the organic layer over
anhydrous sodium sulfate, filter, and remove the solvent under
reduced pressure. Dissolve the crude material (12.0 g) in
dichloromethane (30 mL) and cool to 0.degree. C. To the solution
add pyridine (2.0 mL, 25.5 mmol) followed by dropwise addition of
1.0 M solution of isopropyl chloroformate in toluene (19.1 mL, 19.1
mmol) and stir for 1.5 h. Pour the reaction into water (100 mL) and
separate the layers. Extract the aqueous layer with dichloromethane
(2.times.40 mL) and combine the organic extracts and wash with 2 N
hydrochloric acid, saturated sodium hydrogen carbonate, and brine
(80 mL each). Dry the organic layer over anhydrous sodium sulfate,
filter, and remove the solvent under reduced pressure.
Chromatograph the residue over silica gel eluting with
hexanes/ethyl acetate (60:40), to afford the title compound as a
yellow solid (3.5 g, 40% over three steps). NMR (CDCl.sub.3, 300
MHz) .delta. 1.30 (d, J=6.2 Hz, 6H), 2.09-2.21 (m, 2H), 2.75-2.79
(m, 2H), 3.75-3.80 (m, 2H), 5.05 (septet, J=6.2 Hz, 1H), 7.38 (m,
1H), 7.61 (dd, J=1.9, 8.5 Hz, 1H), 7.67 (m, 1H), 7.98 (d, J=8.5 Hz,
1H); ESI MS m/z 326 [C.sub.14H.sub.16BrNO.sub.3+H].sup.+.
Step 4. Preparation of (+/-)-Isopropyl
5-(3,5-bistrifluoromethylbenzylamino)-7-bromo-2,3,4,5-tetrahydrobenzo[b]a-
zepine-1-carboxylate
##STR00028##
[0233] Add 3,5-bis(trifluoromethyl)benzylamine (3.23 g, 13.31 mmol)
followed by titanium isopropoxide (3.69 mL, 12.35 mmol) to a
solution of isopropyl 7-bromo-5-oxo-2,3,4,5-tetrahydro
benzo[b]azepine-1-carboxylate (3.10 g, 9.50 mmol) in anhydrous
tetrahydrofuran (30 mL) at room temperature under an atmosphere of
nitrogen and stir the solution for 16 h. Dilute the solution with
methanol (30 mL) and slowly add sodium borohydride (0.539 g, 14.25
mmol) over a period of 15 min, then stir at room temperature for
3.5 h. Quench the reaction with the addition of 2 N NaOH (50 mL)
and water (50 mL) and stir for 30 min. Filter the mixture and wash
the solids with ethyl acetate/ethanol (4:1, 3.times.100 mL).
Separate the filtrate and wash the organic layer with 2 N NaOH, 2 N
hydrochloric acid, and brine (50 mL each). Dry the organic layer
over anhydrous sodium sulfate, filter, and remove the solvent under
reduced pressure to afford the title compound as an orange oil
(5.08 g, 96%), which is of sufficient purity to use for subsequent
chemistry without additional purification.
Step 5. Preparation of (+/-)-Isopropyl
5-[(3,5-bistrifluoromethylbenzyl)cyanoamino]-7-bromo-2,3,4,5-tetrahydrobe-
nzo[b]azepine-1-carboxylate
##STR00029##
[0235] Add a solution of 1-cyanoimidazole in N,N-dimethylacetamide
to a solution of isopropyl
5-(3,5-bistrifluoromethylbenzylamino)-7-bromo-2,3,4,5-tetrahydrobenzo[b]a-
zepine-1-carboxylate in N,N-dimethylacetamide at room temperature
under nitrogen and heat the mixture to 100.degree. C. Pour the
cooled mixture into water and extract with methylene chloride. Dry
the organic layer over anhydrous sodium sulfate, filter, and remove
the solvent under reduced pressure. Chromatograph the residue over
silica gel to afford the title compound.
Step 6. Preparation of (+/-)-Isopropyl
5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-bromo-2,3,4,-
5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00030##
[0237] Add a solution of (+/-)-isopropyl
5-[(3,5-bistrifluoromethylbenzyl)-cyanoamino]-7-bromo-2,3,4,5-tetrahydrob-
enzo[b]azepine-1-carboxylate in anhydrous N,N-dimethylformamide
dropwise to a stirred suspension of sodium azide and ammonium
chloride in anhydrous N,N-dimethylformamide and heat the resulting
yellow mixture at 110.degree. C. under nitrogen. Dilute the cooled
mixture with water and 2 N NaOH and wash with diethyl ether.
Acidify with 5 N HCl, collect the precipitate and wash with water
to provide the title compound.
Step 7. Preparation of (+/-)-Isopropyl
5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-bro-
mo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00031##
[0239] Add tri-n-butylphosphine to a solution of (+/-)-isopropyl
5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-bromo-2,3,4,-
5-tetrahydrobenzo[b]azepine-1-carboxylate, methanol and
1,1'-(azocarbonyl)dipiperidine (ADDP) in toluene at 0.degree. C.
under nitrogen and warm to room temperature. Dilute the mixture
with ethyl acetate, wash with 2 N HCl and brine and dry over sodium
sulfate. Remove the solvents under reduced pressure and purify the
residue by flash column chromatography on silica gel to provide the
title compound.
Example 2
Synthesis of (+/-)-Isopropyl
5-[(3,5-bistrifluoromethylbenzyl)-(3-methylisothiazol-5-yl)amino]-7-bromo-
-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00032##
[0240] Step 1. Preparation of (+/-)-Isopropyl
7-bromo-5-(3-methylisothiazol-5-ylamino)-2,3,4,5-tetrahydrobenzo[b]azepin-
e-1-carboxylate
##STR00033##
[0242] Add titanium isopropoxide to a stirring solution of
5-amino-3-methylisothiazole hydrochloride and isopropyl
7-bromo-5-oxo-2,3,4,5-tetrahydro benzo[b]azepine-1-carboxylate
(Example 1, Step 3) in anhydrous tetrahydrofuran at room
temperature under nitrogen. After the appropriate stirring time,
dilute the solution with methanol and slowly add sodium
borohydride, and stir at room temperature. After an appropriate
stirring time, dilute the reaction with addition of 2 N NaOH and
water and stir for 30 min. Remove the solids by vacuum filtration
and wash the solids with ethyl acetate/ethanol (4;1). Separate the
filtrate and wash the organic layer with 2 N NaOH, 2 N hydrochloric
acid, and brine. Dry the organic layer over anhydrous sodium
sulfate and remove the solvent under reduced pressure to afford the
title compound.
Step 2. Preparation of (+/-)-Isopropyl
5-[(3,5-bistrifluoromethylbenzyl)-(3-methylisothiazol-5-yl)amino]-7-bromo-
-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00034##
[0244] Add sodium hydride to a stirring solution of isopropyl
7-bromo-5-(3-methylisothiazol-5-ylamino)-2,3,4,5-tetrahydrobenzo[b]azepin-
e-1-carboxylate in anhydrous tetrahydrofuran at room temperature
under nitrogen. After the appropriate stirring time, treat the
mixture with 3,5-bis(trifluoromethyl)benzyl bromide and continue
stirring for an appropriate time. Dilute the mixture with ethyl
acetate, wash with water and brine and dry over sodium sulfate.
Remove the solvents under reduced pressure and purify the residue
by flash column chromatography on silica gel to provide the title
compound.
Example 3
Synthesis of
(S)-(3,5-Bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-triflu-
oromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-
-5-yl)amine
##STR00035##
[0245] Step 1. Preparation of Methyl
2-nitro-4-trifluoromethylbenzoate
##STR00036##
[0247] Add concentrated sulfuric acid (120 mL) dropwise to a
solution of 2-nitro-4-trifluoromethylbenzoic acid (200 g, 850 mmol)
in methanol (2 L) at room temperature under nitrogen and heat the
mixture at reflux for 48 h. Cool the solution to room temperature
and remove most of the solvent by evaporation at 45.degree. C.
under reduced pressure. Pour the turbid residue onto ice/water (2
L) and extract with ethyl acetate (2.times.1 L). Wash the combined
organic extracts with brine (1 L), dry over anhydrous magnesium
sulfate, filter and remove the solvent under reduced pressure to
provide the title compound as a yellow oil (212.2 g, >99%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .quadrature. 8.21 (s, 1H), 7.95
(d, J=1.13 Hz, 1H), 7.90 (s, 1H), 3.97 (s, 3H).
Step 2. Preparation of Methyl 2-amino-4-trifluoromethylbenzoate
##STR00037##
[0249] Add a solution of methyl 2-nitro-4-trifluoromethylbenzoate
(106 g, 425 mmol) in ethyl acetate (2.2 L) to a slurry of 10%
palladium on carbon (11.0 g) in ethyl acetate (200 mL) and stir the
suspension at room temperature under an atmosphere of hydrogen at
60 psi for 3 h. Filter the suspension through a pad of Celite.RTM.
and wash the pad with additional ethyl acetate. Remove the solvents
under reduced pressure and purify the residue by column
chromatography on silica gel, eluting with isohexane/ethyl acetate
(9:1), to provide the title compound as a white crystalline solid
(84 g, 95%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.93 (d,
J=8.48 Hz, 1H), 7.06 (s, 1H), 6.78 (s, 1H), 4.86 (s, 3H), 3.89 s,
3H),
Step 3. Preparation of methyl
2-amino-5-iodo-4-trifluoromethylbenzoate
##STR00038##
[0251] Add a solution of methyl 2-amino-4-trifluoromethylbenzoate
(178 g, 812 mmol) in ethanol (3.3 L) to a suspension of iodine
(206.1 g, 812 mmol) and silver(II) sulfate (253 g, 812 mmol) in
ethanol (5 L) at room temperature under an atmosphere of nitrogen
and stir for 2 h. Filter the suspension through a pad of a
Celite.RTM., wash the pad with additional ethanol (2 L) and remove
the solvents from the combined filtrates under reduced pressure at
40.degree. C. Dissolve the residue in ethyl acetate (7.5 L) and
wash with saturated sodium bicarbonate solution (3.times.1.5 L),
water (3.times.1.5 L) and brine (2 L). Dry the organic phase over
anhydrous magnesium sulfate, filter and remove the solvent under
reduced pressure to give the title compound as a pale brown
crystalline solid (276.0 g, 99%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.quadrature. 8.39 (1H, s), 6.99 (1H, s), 5.93 (2H, s), 3.90 (3H,
s).
Step 4. Preparation of Methyl
2-amino-5-methyl-4-trifluoromethylbenzoate
##STR00039##
[0253] Add cesium fluoride (184.3 g, 1.21 mol), methyl boronic acid
(63.7 g, 1.05 mol, 3 mol equiv.) and
bis(diphenylphosphinoferrocene)palladium(II) chloride (27.83 g,
35.1 mmol) to a solution of methyl
2-amino-5-iodo-4-trifluoromethylbenzoate (121 g, 351 mmol) in
anhydrous 1,4-dioxane (2.5 L) at room temperature under an
atmosphere of nitrogen and heat the mixture at 80.degree. C. for 3
h. Allow the mixture to cool to room temperature then partition
between ethyl acetate (2.5 L) and water (2.5 L) and filter through
a pad of Celite.RTM. to remove the fine black suspension. Extract
the aqueous phase with ethyl acetate (2.times.100 mL) and wash the
combined organic extracts with brine (1 L). Dry over anhydrous
magnesium sulfate, filter and remove the solvent under reduced
pressure at 45.degree. C. to give a red oil. Purify the residue by
column chromatography on silica gel, eluting with isohexane/ethyl
acetate (9:1), to give the title compound as a pale yellow
crystalline solid (75.25 g, 92%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.quadrature. 7.73 (s, 1H), 6.93 (s, 1H), 5.70 (s, 2H), 3.90 (s,
3H), 2.33 (s, 3H).
Step 5. Preparation of methyl
2-(N-Isopropoxycarbonyl)amino-5-methyl-4-trifluromethylbenzoate
##STR00040##
[0255] Add isopropyl chloroformate (900 mL, 900 mmol, 1 M in
toluene) dropwise to a solution of methyl
2-amino-5-methyl-4-trifluoromethylbenzoate (200 g, 858 mmol) and
pyridine (170 mL, 2.14 mol) in anhydrous dichloromethane (2 L) at
0-5.degree. C. under an atmosphere of nitrogen, keeping the
internal reaction temperature below 5.degree. C. during the
addition. Allow the solution/suspension to warm to room temperature
and stir for 2 h. Add 1 M HCl (2 L) and stir the mixture for 10
min. Collect the organic phase and wash with brine (1 L), dry over
anhydrous magnesium sulfate, filter and remove the solvents under
reduced pressure at 45.degree. C. to give the title compound as a
yellow crystalline solid (283 g, >99%). .sup.1H NMR (300 MHz,
CDCl.sub.3) .quadrature. 10.25 (s, 1H), 8.80 (s, 1H), 7.88 (s, 1H),
4.97-5.09 (m, 1H), 3.95 (s, 3H), 2.43 (d, J=1.32 Hz, 3H), 1.27 -
1.35 (m, 6H).
Step 6. Preparation of Methyl
2-{N-isopropoxycarbonyl-N-(3-methoxycarbonylpropyl)}amino-5-methyl-4-trif-
luoromethylbenzoate
##STR00041##
[0257] Add cesium carbonate (504 g, 1.55 mol, 2.5 mol equiv.) and
methyl 4-bromobutyrate (100 mL, 800 mmol) to a solution of methyl
2-(N-isopropoxycarbonyl)amino-5-methyl-4-trifluoromethylbenzoate
(204 g, 618 mmol) in anhydrous N,N-dimethylformamide (2.4 L) at
room temperature under an atmosphere of nitrogen and heat the
suspension at 55.degree. C. for 2.5 h. Pour the cooled mixture into
ice/water (7.5 L) and stir for 1 h. Filter the suspension and wash
the filter pad with water (3.times.1 L) and pull dry. Dry at
40.degree. C. under vacuum to provide the title compound as a cream
solid (261.3 g, 96%). .sup.1H NMR (300 MHz, dimethyl
sulfoxide-d.sub.6) at 80.degree. C. .quadrature. 7.84 (s, 1H),
7.57(s, 1H), 3.76-3.84 (m, 3H), 3.52-3.65 (m, 5H), 2.33 (t, J=7.25
Hz, 2H), 1.72-1.83 (m, 2H), 1.09 (d, J=4.71 Hz, 6H).
Step 7. Preparation of (+/-)-1-Isopropyl
4-methyl-7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepi-
ne-1,4-dicarboxylate
##STR00042##
[0259] Add a solution of methyl
2-{N-isopropoxycarbonyl-N-(3-methoxycarbonylpropyl)}amino-5-methyl-4-trif-
luoromethylbenzoate (130 g, 310 mmol) in tetrahydrofuran (3.7 L) to
a solution of potassium tert-butoxide (618 mL, 618 mmol, 1 M in
tetrahydrofuran) in tetrahydrofuran (3.7 L) at room temperature
under an atmosphere of nitrogen over a period of 2 h. Stir for 1 h
and acidify the mixture to neutral pH with 1 M HCl (600 mL).
Extract with dichloromethane (2.times.4 L) and wash the combined
organic extracts with brine (3.times.1 L). Dry over anhydrous
magnesium sulfate, filter and remove the solvents under reduced
pressure. Purify the residue by column chromatography on silica
gel, eluting with isohexane/ethyl acetate (9:1), to give the title
compound as a pale yellow solid (99.7 g, 83%). LC MS m/z 410
(M+Na).sup.+.
Step 8. Preparation of Isopropyl
7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carb-
oxylate
##STR00043##
[0261] Add 5 M HCl (2.115 L) to a solution of
(+/-)-1-isopropyl-4-methyl-7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetra-
hydrobenzo[b]azepine-1,4-dicarboxylate (197.2 g, 509 mmol) in
glacial acetic acid (500 mL) at room temperature under an
atmosphere of nitrogen and heat the stirred mixture at
87-88.degree. C. for 24 h. Allow the mixture to cool to room
temperature with stirring and filter the suspension. Wash the
collected solids with water and pull dry. Dry under vacuum at
45.degree. C. to give the title compound as a cream solid (145.4 g,
87%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.74 (s, 2H),
5.03-5.09 (m, 1H), 3.79 (t, J=6.24 Hz, 2H), 2.77 (t, J=6.72 Hz,
2H), 2.49 (d, J=1.47 Hz, 3H), 2.10-2.20 (m, J=6.72, 6.72, 6.72,
6.72 Hz, 2H), 1.27 (d, J=3.91 Hz, 6H).
Step 9. Preparation of
7-Methyl-8-trifluoromethyl-1,2,3,4-tetrahydrobenzo[b]azepin-5-one
##STR00044##
[0263] Heat a degassed mixture of isopropyl
7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carb-
oxylate (6.68 g, 20.28 mmol) and sodium chloride (37.5 g) in water
(7 mL) and dimethyl sulfoxide (180 mL) at reflux under nitrogen for
5 h. Dilute the cooled mixture with water (500 mL) and extract with
ethyl acetate (2.times.300 mL). Wash the combined organic extracts
with brine (200 mL), dry over anhydrous sodium sulfate and filter.
Remove the solvents under reduced pressure and purify the residue
by column chromatography on silica gel, eluting with ethyl
acetate/hexanes (1:4), to afford the title compound as a yellow
solid (3.94 g, 80%). ESI MS m/z 242 (M-H).sup.-.
Step 10. Preparation of tert-Butyl
7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carb-
oxylate
##STR00045##
[0265] Add di-tert-butyl dicarbonate (6.67 g, 30.58 mmol),
diisopropylethylamine (5.32 mL, 30.58 mmol) and 4-DMAP (374 mg, 3.1
mmol) to a solution of
7-methyl-8-trifluoromethyl-1,2,3,4-tetrahydrobenzo[b]azepin-5-one
(2.48 g, 10.19 mmol) in dichloromethane (50 mL) under nitrogen at
0.degree. C. and warm the mixture to room temperature. Stir the
mixture for 24 h and dilute with dichloromethane (50 mL). Wash the
mixture with 2 N HCl (2.times.20 mL) and brine (20 mL) and dry over
anhydrous sodium sulfate and filter. Remove the solvents under
reduced pressure and purify the residue by column chromatography on
silica gel, eluting with ethyl acetate/hexanes (1:3), to provide
the title compound as an off-white solid (2.20 g, 63%). ESI MS m/z
(243 (M-Boc).sup.-.
Step 11. Preparation of (R)-ten-Butyl
5-hydroxy-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1--
carboxylate
##STR00046##
[0267] Add a solution of borane dimethylsulfide complex (3.8 mL,
7.58 mmol, 2 M in tetrahydrofuran) dropwise to a solution of
(S)-2-methyl-CBS-oxazaborolidine (9.5 mL, 9.48 mmol, 1 M in
toluene) in dichloromethane (20 mL) at -30.degree. C. under
nitrogen. Stir the mixture for 30 min and add a solution of
ten-butyl
7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carb-
oxylate (2.17 g, 6.32 mmol) in dichloromethane (20 mL) dropwise and
warm the mixture slowly to 0.degree. C. Pour the mixture into
methanol (200 mL) at -20.degree. C. and slowly warm the stirring
mixture to room temperature over 1 h. Remove the solvents under
reduced pressure and purify the residue by column chromatography on
silica gel, eluting with ethyl acetate/hexanes (1:2), to provide
the title compound as a colorless oil (1.65 g, 76%). APCI MS m/z
345 (M+H).sup.+.
Step 12. Preparation of (S)-tert-Butyl
5-azido-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-ca-
rboxylate
##STR00047##
[0269] Heat a mixture of (R)-tert-butyl
5-hydroxy-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1--
carboxylate (1.60 g, 4.65 mmol), diphenylphosphoryl azide (DPPA,
1.4 mL, 6.50 mmol) and DBU (1.0 mL, 6.50 mmol) in toluene (20 mL)
at 65.degree. C. under nitrogen for 12 h. Add silica gel to the
cooled mixture and remove the solvents under reduced pressure.
Purify the residue by column chromatography, eluting with ethyl
acetate/hexanes (1:2), to provide the title compound as a colorless
oil (1.45 g, 85%). APCI MS m/z 356 (M-N.sub.2).sup.-.
Step 13. Preparation of (S)-tert-Butyl
5-amino-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-ca-
rboxylate
##STR00048##
[0271] Shake a mixture of (S)-tert-butyl
5-azido-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-ca-
rboxylate (1.44 g, 3.89 mmol) and 5% palladium on charcoal (0.15 g,
50% wet) in methanol (50 mL) under 20 psi of hydrogen in a Parr
bottle at room temperature for 12 h. Filter the mixture through
Celite.RTM. and remove the solvents under reduced pressure to
provide the title compound as a colorless oil (1.30 g, >99%),
which is used in the next step without further purification. APCI
MS m/z 344 (M+H).sup.+.
Step 14. Preparation of (S)-tert-butyl
5-(3,5-bistrifluoromethylbenzylamino)-7-methyl-8-trifluoromethyl-2,3,4,5--
tetrahydrobenzo[b]azepine-1-carboxylate
##STR00049##
[0273] Add 3,5-bistrifluoromethylbenzaldehyde (909 mg, 3.75 mmol)
to a solution of (S)-tert-butyl
5-amino-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-ca-
rboxylate (1.29 g, 3.75 mmol) in methanol (20 mL) at room
temperature under nitrogen and stir for 2 h. Add sodium borohydride
(283 mg, 7.5 mmol) and stir the mixture for 2 h. Remove the
solvents under reduced pressure and dilute the residue with
dichloromethane (50 mL) and water (50 mL). Collect the organic
layer and extract the aqueous layer with dichloromethane
(3.times.30 mL). Wash the combined organic extracts with water (20
mL) and brine (20 mL) and dry over anhydrous sodium sulfate. Filter
and remove the solvents under reduced pressure to provide the title
compound as an amber oil (2.09 g, 98%), which is used in the next
step without purification. APCI MS m/z 570 (M+H).sup.+.
Step 15. Preparation of (S)-tert-butyl
5-[(3,5-bistrifluoromethylbenzyl)cyanoamino]-7-methyl-8-trifluoromethyl-2-
,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00050##
[0275] Add cyanogen bromide (1.21 mL, 6.04 mmol, 5 M solution in
acetonitrile) to a solution of (S)-tert-butyl
5-(3,5-bistrifluoromethylbenzylamino)-7-methyl-8-trifluoromethyl-2,3,4,5--
tetrahydrobenzo[b]azepine-1-carboxylate (2.30 g, 4.03 mmol) and
diisopropylethylamine (1.05 mL, 6.04 mmol) in tetrahydrofuran (50
mL) at room temperature under nitrogen and heat the mixture at
50.degree. C. for 12 h. Add silica gel to the cooled mixture and
remove the solvents under reduced pressure. Purify the residue by
column chromatography on silica gel, eluting with ethyl
acetate/hexanes (2:3), to provide the title compound as a colorless
oil (2.10 g, >99%), which is used in the next step without
further purification: APCI MS m/z 496 (M+H-Boc).sup.+.
Step 16. Preparation of (S)-tent-Butyl
5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-methyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00051##
[0277] Heat a mixture of (S)-tent-butyl
5-[(3,5-bistrifluoromethylbenzyl)cyanoamino]-7-methyl-8-trifluoromethyl-2-
,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.0 g, 3.36 mmol),
triethylamine hydrochloride (694 mg, 5.04 mmol) and sodium azide
(328 mg, 5.04 mmol) in anhydrous toluene (20 mL) at reflux under
nitrogen for 12 h. Dilute the cooled mixture with ethyl acetate
(100 mL) and wash with 2 N HCl (2.times.50 mL), water (50 mL) and
brine (50 mL) and dry over anhydrous sodium sulfate. Filter and
remove the solvent under reduced pressure to provide the title
compound as an off-white foam (2.12 g, >99%), which is used in
the next step without purification. ESI MS m/z 637 (M-H).sup.-.
Step 17. Preparation of (S)-tert-Butyl
5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-met-
hyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00052##
[0279] Add diisopropyl azodicarboxylate (0.56 mL, 3.94 mmol) to a
solution of (S)-tent-butyl
5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-methyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.10
g, 3.29 mmol) and triphenylphosphine (1.03 g, 3.94 mmol) in
methanol (0.20 mL, 4.94 mmol) and toluene (30 mL) at 0.degree. C.
under nitrogen. Warm the mixture to room temperature and stir for
12 h. Add silica gel, remove the solvents under reduced pressure
and purify the residue by column chromatography on silica gel,
eluting with ethyl acetate/hexanes (1:3), to provide the title
compound as a colorless oil (2.04 g, 95%). APCI MS m/z 653
(M+H).sup.+.
Step 18. Preparation of
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
##STR00053##
[0281] Add trifluoroacetic acid (10 mL) to a solution of
(S)-tert-butyl
5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-met-
hyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
(2.04 g, 3.13 mmol) in methylene chloride (50 mL) at 0.degree. C.
under nitrogen. Warm the mixture to room temperature, stir for 8 h
and pour the mixture into saturated aqueous sodium bicarbonate
solution (200 mL). Extract the mixture with methylene chloride (200
mL) and wash the combined organic extracts with brine (50 mL), dry
over anhydrous sodium sulfate and filter. Remove the solvent under
reduced pressure to provide the title compound as a colorless oil
(1.73 g, >99%), which is used in the next step without
purification. APCI MS m/z 553 (M+H).sup.+.
Step 19. Preparation of
(S)-(3,5-Bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-triflu-
oromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-
-5-yl)amine
##STR00054##
[0283] Add cyclopentanecarboxaldehyde (462 mg, 4.71 mmol) to a
solution of
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
(520 mg, 0.941 mmol) in acetic acid (1 mL) and 1,2-diehloroethane
(10 mL) at room temperature under nitrogen and stir for 1 h. Add
sodium triacetoxy borohydride (998 mg, 4.71 mmol) and stir for 5
min. Dilute the mixture with methylene chloride (30 mL) and wash
with saturated aqueous sodium bicarbonate solution (2.times.10 mL).
Extract the combined aqueous washes with methylene chloride (20 mL)
and wash the combined organic extracts with brined (20 mL) and dry
over anhydrous sodium sulfate. Remove the solvents under reduced
pressure and purify the residue by column chromatography on silica
gel, eluting with ethyl acetate/hexanes (1:2), to provide the title
compound as a colorless oil (420 mg, 70%). APCI MS m/z 635
(M+H).sup.+.
[0284] Alternative preparation of methyl
2-(N-isopropoxycarbonyl)amino-5-methyl-4-trifluromethylbenzoate.
##STR00055##
Step 1. Preparation of
2-Iodo-4-methyl-5-trifluoromethylphenylamine
##STR00056##
[0286] Add a solution of iodine monochloride (27.8 g, 171 mmol) in
dichloromethane (180 mL) to a solution of
4-methyl-3-trifluoromethylaniline (25.0 g, 143 mmol) and sodium
bicarbonate (14.4 g, 171 mmol) in methanol (180 mL) and
dichloromethane (730 mL) at room temperature under nitrogen. Stir
the mixture for 3 h and dilute the cooled mixture with aqueous
sodium metabisulfite (500 mL). Collect the organic phase, and
extract the aqueous phase with methylene chloride (200 mL). Wash
the combined organic extracts with brine (250 mL), dry over
anhydrous sodium sulfate and filter. Remove the solvent under
reduced pressure to provide a brown oil, which crystallizes upon
standing to afford the title compound as brown needles (44.4 g,
>99%), which is used in the next step without purification. APCI
MS m/z 302 (M+H).sup.+.
Step 2. Preparation of isopropyl
(2-iodo-4-methyl-5-trifluoromethylphenyl)carbamate
##STR00057##
[0288] Add a solution of isopropyl chloroformate (99.6 mL, 99.6
mmol, 1 M in toluene) dropwise to a solution of
2-iodo-4-methyl-5-trifluoromethylphenylamine (27.26 g, 90.55 mmol)
and pyridine (14.6 mL, 181.1 mmol) in dichloromethane (350 mL) at
5.degree. C. under an atmosphere of nitrogen and warm the mixture
to room temperature. Stir for 3 h and wash the mixture with 2 N HCl
(100 mL) and brine (100 mL). Dry over anhydrous sodium sulfate,
filter and remove the solvent under reduced pressure to afford the
title compound as a tan solid (33.59 g, 96%), which is used in the
next step without purification. APCI MS m/z 388 (M+H).sup.+.
Step 3. Preparation of methyl
2-(N-isopropoxycarbonyl)amino-5-methyl-4-trifluromethylbenzoate
##STR00058##
[0290] Add tetrakis(triphenylphosphine)palladium(0) (8.53 g, 7.4
mmol) to a solution of isopropyl
(2-iodo-4-methyl-5-trifluoromethylphenyl)carbamate (28.59 g, 73.8
mmol) and triethylamine (10.3 mL, 73.8 mmol) in methanol (75 mL)
and acetonitrile (150 mL) at room temperature under nitrogen in a
stirred Parr high pressure reaction vessel and charge the unit to
20 psi of carbon monoxide. Heat the mixture to 60.degree. C. and
stir the mixture for 18 h, periodically recharging the vessel to
20-30 psi of carbon monoxide. Add silica gel to the cooled mixture
and remove the solvents under reduced pressure. Purify the residue
using column chromatography on silica gel, eluting with ethyl
acetate/hexanes (1:9), to provide the title compound as an orange
solid (19.80 g, 84%): APCI MS m/z 320 (M+H).sup.+.
Example 4
Synthesis of
5-[(3,5-Bis-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-7-methyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid ethyl ester
##STR00059##
[0291] Step 1. Preparation of
5-[(3,5-Bis-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-7-methyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid tert-butyl ester
##STR00060##
[0293] The titled compound was prepared using procedures analogous
to those used in Example 1, Steps 4 to 6 and substituting
tert-butyl
7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carb-
oxylate (Example 3, step 10) for isopropyl
7-bromo-5-oxo-2,3,4,5-tetrahydro benzo[b]azepine-1-carboxylate in
Example 1, Step 4. MS (ES+): 637. (M-H).
Step 2. Preparation of
(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetr-
ahydro-1H-benzo[b]azepin-5-yl)-(1H-tetrazol-5-yl)-amine
##STR00061##
[0295] Add dichloromethane (5 mL) and trifluoroacetic acid (5 mL)
to
5-[(3,5-bis-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-7-methyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid tert-butyl ester (0.18 g, 0.24 mmol). After stirring for 1-2
h, neutralize the reaction with sodium carbonate. Wash the organic
phase with water (5 mL) and brine (5 mL). Dry the organics over
sodium sulfate and filter. Chromatograph the crude material,
eluting with ethyl acetate/hexane (20-60%) to provide the title
compound (0.13 g, 85%) as an oil. MS (ES+): 539 (M+H).
Step 3. Preparation of
5-[(3,5-Bis-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-7-methyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid ethyl ester
##STR00062##
[0297] Add ethyl chloroformate (0.24 mmol) and pyridine (0.24 mmol)
to a dichloromethane (5 mL) solution of
(3,5-bis-trifluoromethyl-benzyl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetr-
ahydro-1H-benzo[b]azepin-5-yl)-(1H-tetrazol-5-yl)-amine (0.045 g,
0.08 mmol). After stirring 14 h, wash the reaction with 5% HCl (3
mL), water (3 mL) and brine (3 mL). Dry the organic portion over
sodium sulfate and filter. Chromatograph the crude product, eluting
with ethyl acetate/hexane (20-60%), to provide the title compound
(0.01 g, 20%) as an oil: MS (ES+): 611 (M+H).
##STR00063##
[0298] Additional compounds could be prepared following procedures
described in Example 4 by replacing ethyl chloroformate with the
appropriate reagent.
TABLE-US-00008 Example # Reagent R5 5 Isopropyl Isopropyl
chloroformate 6 1,1,1-trifluoro-2-propyl 1,1,1-trifluoro-2-
chloroformate propyl 7 2-butyl chloroformate 2-butyl 8 Cyclobutyl
cyclobutyl chloroformate 9 Cyclopentyl cyclopentyl chloroformate 10
Cyclohexyl cyclohexyl chloroformate 11 3-pentyl chloroformate
3-pentyl 12 3-methyl-2-butyl 3-methyl-2-butyl chloroformate 13
(S)-(+)- (S)-(+)- tetrahydrofuran-3-yl tetrahydroruran-3-yl
chloroformate 14 (R)-(-)-tetrahydrofuran- (R)-(-)- 3-yl
chloroformate tetrahydrofuran-3-yl
Example 15
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid ethyl ester
##STR00064##
[0300] Add ethyl chloroformate (0.0223 mL, 0.233 mmol) dropwise to
a solution of
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
(0.0430 g, 0.0778 mmol) (Example 3, Step 18) and pyridine (0.0190
mL, 0.233 mmol) in dichloromethane (1 mL) at room temperature under
an atmosphere of nitrogen and stir for 2 h. Dilute the reaction
mixture with ethyl acetate (10 mL) and wash with 1.0 N hydrochloric
acid (10 mL) and water (3.times.10 mL). Dry the organic layer over
anhydrous sodium sulfate, filter, and remove the solvent under
reduced pressure. Purify the residue using column chromatography on
silica gel, eluting with ethyl acetate/hexanes (0-20%), to provide
the title compound (0.0320 g, 65%). MS (ES+): 625 (M+H).
Example 16
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid isopropyl ester
##STR00065##
[0302] Prepare the titled compound by essentially following the
procedures described in Example 15, by substituting ethyl
chloroformate with isopropyl chloroformate MS (ES+): 639 (M+H):
Example 17
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid tert-butyl ester
##STR00066##
[0304] Prepare the titled compound by essentially following the
procedures described in Example 3, Step 17. MS (ES+): 675
(M+Na)
Example 18
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 1-ethyl-propyl ester
##STR00067##
[0306] To a mixture of pentan-3-ol (0.117 ml, 1.08 mmol)
di-isopropyl ethyl amine (0.189 ml, 1.08 mmol) in dichloromethane
at 0.degree. C. with 20% phosgene in toluene (0.480 nil, 0.905
mmol). Stir the mixture at 0.degree. C. for 10 minutes, and then
warm up to room temperature for an hour. Add a solution of
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(0.100 mg, 0.181 mmol) (Example 3, Step 18)) in dichloromethane
(1.00 ml) followed by pyridine (0.0730 ml, 0.905 mmol). Continue
the reaction at room temperature overnight. Dilute the mixture with
dichloromethane (5.05 ml), wash with 1N hydrochloric acid (5.00 ml)
and water (3.times.5.00 ml), dry over Na.sub.2SO.sub.4 and
concentrated. Purify by silica gel chromatography (gradient eluent,
0-25% ethyl acetate in hexane) to provide the titled compound
(0.0710 g, 59%). MS (ES+): 667 (M+H).
Example 19
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid cyclopentyl ester
##STR00068##
[0308] The title compound can be prepared following the procedures
described in Example 18 by replacing pentan-3-ol with
cyclobutanol.
Example 20
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid cyclopentyl ester
##STR00069##
[0310] Prepare the title compound by following the procedures
described in Example 18 by replacing pentan-3-ol with
cyclopentanol. MS (ES+): 665 (M+H).
Example 21
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid cyclopentyl ester
##STR00070##
[0312] The title compound can be prepared following the procedures
described in Example 18 by replacing pentan-3-ol with
cyclohexanol.
Example 22
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 2,2,2-trifluoro-1-methyl-ethyl ester
##STR00071##
[0314] The title compound can be prepared following the procedures
described in Example 18 by replacing pentan-3-ol with
1,1,1-trifluoro-propan-2-ol.
Example 23
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid sec-butyl ester
##STR00072##
[0316] The title compound can be prepared following the procedures
described in Example 18 by replacing pentan-3-ol with
butan-2-ol.
Example 24
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 1,2-dimethyl-propyl ester
##STR00073##
[0318] The title compound may be prepared by following the
procedures described in Example 18 by replacing pentan-3-ol with
3-methyl-butan-2-ol.
Example 25
Synthesis of
(+/-)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbox-
ylic acid 1-ethyl-2-methyl-propyl ester
##STR00074##
[0320] Prepare the title compound by essentially following the
procedures described in Example 18 by replacing pentan-3-ol with
2-methyl-pentan-3-ol. MS (ES+): 681 (M+H).
Example 26
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid tetrahydro-pyran-4-yl ester
##STR00075##
[0322] Prepare the title compound by essentially following the
procedures described in Example 18 by replacing pentan-3-ol with
tetrahydro-4H-pyran-4-ol. MS (ES+): 681 (M+H).
Example 27
Synthesis of
(S)-2-(5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cydopentylmethyl-7-methyl-8-
-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetrazo-
l-2-yl}-ethanol
##STR00076##
[0323] Step 1. Preparation of
(S)-5-{(3,5-Bis-trifluoromethyl-benzyl)-(2-(2-hydroxy-ethyl)-2H-tetrazol--
5-yl)-amino}-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-
-1-carboxylic acid tert-butyl ester
##STR00077##
[0325] Dissolve (S)-tert-Butyl
5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino)-7-methyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
(Example 3, Step 16) (0.252 g, 0.395 mmole) in DMF (4 mL), add
potassium carbonate (0.0929 g, 0.672 mmole) in one portion. Inject
2-bromoethanol (0.0420 mL, 0.593 mmole) dropwise. Stir at room
temperature overnight. Partition the reaction mixture between ethyl
acetate (50 mL) and water (50 mL). Extract aqueous back with more
ethyl acetate (20 mL). Combine organic layers, Dry over sodium
sulfate, filter and concentrate the solution. Chromatograph the
residue over silica gel, eluting with ethyl acetate/hexanes
(0-100%), to provide the title compound as a colorless oil (0.0700
g, 26%). MS (ES+): 705 (M+Na).
Step 2. Preparation of
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-8-trifluoromethyl-2,-
3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetrazol-2-yl}-ethanol
##STR00078##
[0327] Add trifluoroacetic acid (2 mL) to a solution of
(S)-5-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol--
5-yl]-amino)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-
-1-carboxylic acid tert-butyl ester (0.0650 g, 0.0952 mmol) in
methylene chloride (2 mL) at room temperature, stir for 1 h.
Evaporate solvents and partition the residue between saturated
aqueous sodium bicarbonate solution (10 mL). Extract the mixture
with methylene chloride (10 mL). Separate two layers and dry over
anhydrous sodium sulfate end filter. Remove the solvent under
reduced pressure. Chromatograph the residue over silica gel,
eluting with ethyl acetate/hexanes (0-100%), to provide the title
compound as a colorless oil (0.0340 g, 62%). MS (ES+): 583
(M+H).
Step 3. Preparation of
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetraz-
ol-2-yl}-ethanol
##STR00079##
[0329] Prepare the title compound by essentially following the
procedures described in Example 3, Step 19 by replacing
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
with
(S)-2-{5-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-8-trifluoromethyl-2,3-
,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetrazol-2-yl}-ethanol.
MS (ES+): 665 (M+H).
[0330] Examples 28-29 can be prepared following the procedures as
essentially described in Example 3, Step 19, using
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) and the corresponding aldehyde as starting
materials.
Example 28
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclobutylmethyl-7-methyl-8-trifl-
uoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazo-
l-5-yl)-amine
##STR00080##
[0331] Example 29
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclohexylmethyl-7-methyl-8-trifl-
uoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazo-
l-5-yl)-amine
##STR00081##
[0332] Example 30
Synthesis of (S)-(3,5-Bis
-trifluoromethyl-benzyl)-(1-ethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetr-
ahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
##STR00082##
[0334] Prepare the title compound by essentially following the
procedures described in Example 3, Step 19 using
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) and replacing cyclopentanecarboxaldehyde with
acetaldehyde. MS (ES+): 681 (M+H).
Example 31
Synthesis of
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-
-cyclohexyl)-acetic acid
##STR00083##
[0335] Step 1. Preparation of
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-
-cyclohexyl)-acetic acid benzyl ester
##STR00084##
[0337] Prepare the title compound by essentially following the
procedures described in Example 3, Step 19 by replacing
cyclopentanecarboxaldehyde with (4-formyl-cyclohexyl)-acetic acid
benzyl ester. MS (ES+): 797 (M+H).
Step 2. Preparation of
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-
-cyclohexyl)-acetic acid
##STR00085##
[0339] Heat the mixture of
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-
-cyclohexyl)-acetic acid benzyl ester (0.0340 g, 0.0427 mmol) in
5.0 N NaOH (1 mL) and methanol (1 mL) at 60.degree. C. for 2 h.
Evaporate the solvents and re-dissolve in water (10 mL). Adjust to
pH=2 by adding 5.0 N HCl. Extract with ethyl acetate (2.times.10
mL). Combine organic layers, dry over anhydrous sodium sulfate and
filter. Remove the solvent under reduced pressure. Chromatograph
the residue over silica gel, eluting with ethyl acetate/hexanes
(0-50%), to provide the title compound as a colorless oil (0.0200
g, 67%). MS(ES+): MS(ES+): 707 (M+H).
Example 32
Synthesis of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-3,-
3-dimethyl-pentanoic acid
##STR00086##
[0340] Step 1. Preparation of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-3,-
3-dimethyl-pentanoic acid methyl ester
##STR00087##
[0342] Prepare the title compound by essentially following the
procedures described in Example 3, Step 19 by replacing
cyclopentanecarboxaldehyde with 3,3-dimethyl-5-oxo-pentanoic acid
methyl ester (Example 74, Step 2). MS (ES+): 695 (M+H).
Step 2. Preparation of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-3,-
3-dimethyl-pentanoic acid
##STR00088##
[0344] Heat the mixture of (0.0400 g, 0.0576 mmol) in 2.0 N NaOH
(0.350 mL) and methanol (1 mL) at 50.degree. C. for 2 h. Evaporate
the solvents and re-dissolve in water (10 mL). Adjust to pH=2 by
adding 5.0 N HCl. Extract with ethyl acetate (2.times.10 mL).
Combine organic layers, dry over anhydrous sodium sulfate and
filter. Remove the solvent under reduced pressure. Chromatograph
the residue over silica gel, eluting with ethyl acetate/hexanes
(0-50%), to provide the title compound as a colorless oil (0.0310
g, 79%). MS(ES+): 681 (M+H).
Example 33
Synthesis is of
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-et-
hanol
##STR00089##
[0345] Step 1. Preparation of
(S)-[1-(2-Benzyloxy-ethyl)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro--
1H-benzo[b]azepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetr-
azol-5-yl)-amine
##STR00090##
[0347] Prepare the title compound by essentially following the
procedures described in Example 3, Step 19 by replacing
cyclopentanecarboxaldehyde with benzyloxy-acetaldehyde. MS (ES+):
687 (M+H).
Step 2. Preparation of
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-et-
hanol
##STR00091##
[0349] Stir a mixture of
(S)-[1-(2-Benzyloxy-ethyl)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro--
1H-benzo[b]azepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetr-
azol-5-yl)-amine (0.420 g, 0.612 mmol) and 10% palladium on
charcoal (0.210 g) in ethanol (50 mL) under a hydrogen balloon at
room temperature for 3 h. Filter the mixture through Celite.RTM.
and remove the solvents under reduced pressure to provide the title
compound as a colorless foam (0.350 g, 97%). MS (ES+): 597
(M+H).
Example 34
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyli-
c acid tert-butyl ester
##STR00092##
[0350] Step 1. Preparation of
2-Amino-4-trifluoromethyl-5-vinyl-benzoic acid methyl ester
##STR00093##
[0352] Add tetrakis palladium(triphenylphosphine(0) (5.00 g, 4.33
mmol) to a mixture of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid
methyl ester (Example 3, Step 3) (17.25 g, 49.99 mmol) and
tributyl(vinyl)tin (16.10 mL, 55.14 mmol) in toluene (500 mL) and
heat at reflux for 14 h. Allow the reaction to cool to room
temperature dilute the mixture with ethyl acetate (1 L). Wash the
mixture with saturated aqueous potassium fluoride solution
(3.times.300 mL), then water (300 mL), followed by brine (500 mL).
Dry the organic layer over anhydrous sodium sulfate, filter, and
remove the solvents under reduced pressure. Purify the residue by
column chromatography on silica gel, eluting with ethyl
acetate/hexanes (0 to 15%), to provide the title compound as a pale
yellow solid (8.73 g, 71%): TLC R.sub.f0.52 (3:1 hexanes/ethyl
acetate); .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 3.89 (s, 3H),
5.21-5.30 (m, 1H), 5.60-5.71 (m, 1H), 5.98 (bs, 2H), 6.83-7.02 (m,
2H), 8.19 (s, 1H).
Step 2. Preparation of
2-Isopropoxycarbonylamino-4-trifluoromethyl-5-vinyl-benzoic acid
methyl ester
##STR00094##
[0354] Add a 1.0 M solution of isopropyl chloroformate in toluene
(183.0 mL, 183.0 mmol) to a 0.degree. C. cooled solution of
2-amino-4-trifluoromethyl-5-vinyl-benzoic acid methyl ester (34.47
g, 140.58 mmol) and pyridine (35.0 mL, 429.20 mmol) in methylene
chloride (500 mL). Allow the mixture to stir for 2 h at 0.degree.
C. then 16 h at room temperature under an atmosphere of N.sub.2.
Wash the mixture with saturated aqueous sodium bicarbonate solution
(2.times.200 mL) followed by aqueous 2 N HCl solution (2.times.200
mL). Wash the combined organic extracts with brine (20 mL) and dry
over anhydrous sodium sulfate. Remove the solvents under reduced
pressure and purify the residue by column chromatography on silica
gel, eluting with ethyl acetate/hexanes (0 to 15%), to provide the
title compound as an off-white solid (40.50 g, 87%): TLC
R.sub.f0.62 (3:1 hexanes/ethyl acetate); .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 1.32-1.33 (m, 6H), 3.89 (s, 3H), 5.21-5.27 (m,
1H), 5.41-5.44 (m, 1H), 5.63-5.70 (m, 1H), 7.03-7.11 (m, 1H), 8.23
(s, 1H), 8.89 (s, 1H), 10.32 (bs, 1H).
Step 3. Preparation of
5-Ethyl-2-isopropoxycarbonylamino-4-trifluoromethyl-benzoic acid
methyl ester
##STR00095##
[0356] Add 10% palladium on carbon (4.06 g, 12.22 mmol) to a
solution of
2-isopropoxycarbonylamino-4-trifluoromethyl-5-vinyl-benzoic acid
methyl ester (40.48 g, 122.19 mmol) in methanol (350 mL) in a Parr
bottle. Subject the mixture to a hydrogen atmosphere at a pressure
of 30 psi at room temperature with shaking on a Parr shaker
apparatus for 2 h. Filter the mixture through Celite and remove the
solvent under reduced pressure to provide the title compound as a
white solid (39.07 g, 96%): TLC R.sub.f0.62 (3:1 hexanes/ethyl
acetate); .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.13-1.42 (m,
9H), 2.71-2.80 (m, 2H), 3.89 (s, 3H), 5.21-5.27 (m, 1H), 7.98 (s,
1H), 8.81 (s, 1H), 10.23 (bs, 1H).
Step 4. Preparation of
5-Ethyl-2-[isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-4-trifluo-
romethyl-benzoic acid methyl ester
##STR00096##
[0358] Add 4-bromo-butyric acid methyl ester (74.30 g, 410.46 mmol)
to a mixture of
5-ethyl-2-isopropoxycarbonylamino-4-trifluoromethyl-benzoic acid
methyl ester (39.05 g, 117.16 mmol) and cesium carbonate (114.65 g,
351.88 mmol) in N,N-dimethylformamide (800 mL). Heat the mixture at
90.degree. C. for 4 h and the allow it to cool to room temperature.
Filter the mixture through Celite then dilute the mixture with
water (2 L) and ethyl acetate (2 L). Wash the organic layer with
water (500 mL) and brine (500 mL). Dry the organic layer over
anhydrous sodium sulfate and filter. Remove the solvents under
reduced pressure and purify the resulting residue by column
chromatography on silica gel, eluting with ethyl acetate/hexanes (0
to 15%), to provide the title compound as a white solid (39.75 g,
78%): TLC R.sub.f0.42 (3:1 hexanes/ethyl acetate); .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.0-1.10 (m, 3H), 1.22-1.32 (m, 6H),
1.78-1.89 (m, 2H), 2.37-2.40 (m, 2H), 2.82-2.89 (m, 2H), 3.41-3.80
(m, 5H), 3.89 (s, 3H), 4.78-5.02 (m, 1H), 7.43 (s, 1H), 7.91 (s,
1H).
Step 5. Preparation of
7-Ethyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1,4-di-
carboxylic acid 1-isopropyl ester 4-methyl ester
##STR00097##
[0360] To a 0.degree. C. cooled solution of
5-ethyl-2-[isopropoxycarbonyl-(3-methoxycarbonyl-propyl)-amino]-4-trifluo-
romethyl-benzoic acid methyl ester (39.72 g, 91.64 mmol) in toluene
add potassium tert-butoxide (24.68 g, 219.92 mmol). Stir the
mixture at room temperature for 30 min under an atmosphere of
N.sub.2. Quench the mixture with 2 N HCl (150 mL) and dilute with
ethyl acetate (1.5 L). Wash with water (2.times.400 mL) and brine
(500 mL). Dry the organic layer over anhydrous sodium sulfate and
filter through Celite to provide the title compound as a yellow
viscous oil (31.25 g, 85%): TLC R.sub.f0.63 (3:1 hexanes/ethyl
acetate); .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.0-1.40 (m,
9H), 2.31-2.55 (m, 2H), 2.88-2.94 (m, 1H), 3.75 (s, 3H), 3.89 (s,
31.3), 4.89-4.93 (m, 1H), 5.11-5.12 (m, 1H), 7.43 (s, 1H), 7.91 (s,
1H).
Step 6. Preparation of
7-Ethyl-8-trifluoromethyl-1,2,3,4-tetrahydro-benzo[b]azepin-5-one
##STR00098##
[0362] Heat a mixture of
7-ethyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1,4-di-
carboxylic acid 1-isopropyl ester 4-methyl ester (23.55 g, 58.61
mmol), sodium chloride (52.50 g), and water (10.0 mL) in
dimethylsulfoxide (500 mL) at reflux for 46 h. Allow the mixture to
cool to room temperature and dilute it with water (200 mL) and
ethyl acetate (200 mL). Wash the organic layer with water (350 mL).
Dry the organic layer over anhydrous sodium sulfate and filter.
Remove the solvents under reduced pressure and purify the resulting
residue by column chromatography on silica gel, eluting with ethyl
acetate/hexanes (0 to 15%), to provide the title compound as a
yellow solid (9.17 g, 61%)TLC R.sub.f0.32 (3:1 hexanes/ethyl
acetate); .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.10-1.23 (m,
3H), 2.13-2.21 (m, 2H), 2.63-2.71 (m, 2H), 2.83-2.92 (m,2H),
3.22-3.31 (m, 2H), 4.74 (bs, 1H), 7.03 (s, 1H), 7.68 (s, 1H).
Step 7. Preparation of
7-Ethyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carb-
oxylic acid tert-butyl ester
##STR00099##
[0364] Add di-tert-butyl dicarbonate (21.12 g, mmol) to a mixture
of ethyl-8-trifluoromethyl-1,2,3,4-tetrahydro-benzo[b]azepin-5-one
(8.30 g, 32.26 mmol), di-isopropylethylamine (20.0 mL, 114.18
mmol), and dimethylaminopyridine (0.395 g) in tetrahydrofuran (300
mL) at room temperature. Stir the mixture for 16 h under an
atmosphere of N.sub.2. Dilute the mixture with aqueous saturated
sodium bicarbonate solution (100 mL) and ethyl acetate (1 L). Wash
the organic layer with brine (500 mL) and dry it over anhydrous
sodium sulfate and filter. Remove the solvents under reduced
pressure and purify the resulting residue by column chromatography
on silica gel, eluting with ethyl acetate/hexanes (0 to 15%), to
provide the title compound as a white gum (8.66 g, 75%): TLC
R.sub.f0.69 (3:1 hexanes/ethyl acetate); .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 1.19-1.25 (m, 3H), 1.45 (s, 11H), 2.19-2.22 (m,
2H), 2.74-2.83 (m, 2H), 3.43-3.55 (m, 2H), 7.62-7.65 (bs, 1H), 7.80
(s, 1H).
Step 8. Preparation of
(R)-7-Ethyl-5-hydroxy-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-
e-1-carboxylic acid tert-butyl ester
##STR00100##
[0366] Add a solution of borane dimethylsulfide complex (16.0 mL,
16.0 mmol, 1 M in tetrahydrofuran) dropwise to a solution of
(S)-2-methyl-CBS-oxazaborolidine (7.50 mL, 7.50 mmol, 1 M in
toluene) in dichloromethane (100 mL) at -30.degree. C. under
nitrogen. Stir the mixture for 30 min and add a solution of
tert-butyl
7-ethyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carbo-
xylate (8.60 g, 24.0 mmol) in dichloromethane (50 mL) dropwise and
warm the mixture slowly to 0.degree. C. over a period of 6 h. Pour
the mixture into methanol (200 mL) at -20.degree. C. and slowly
warm the stirring mixture to room temperature over 1 h. Remove the
solvents under reduced pressure and purify the residue, by column
chromatography on silica gel, eluting with ethyl acetate/hexanes (0
to 15%), to provide the title compound as a colorless oil (7.62 g,
88%): TLC R.sub.f0.49 (3:1 hexanes/ethyl acetate); .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 1.21-2.30 (m, 19H), 2.83-2.89 (m,
2H), 4.78-4.80 (m, 1H), 7.31-7.45 (m, 2H); Chiral HPLC (OD Column)
91.6% ee; APCI MS m/z 360 (M+H).sup.+.
Step 9. Preparation of
(S)-5-Azido-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine--
1-carboxylic acid tert-butyl ester
##STR00101##
[0368] Heat a mixture of
(R)-7-ethyl-5-hydroxy-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-
e-1-carboxylic acid tert-butyl ester (7.59 g, 21.12 mmol),
diphenylphosphoryl azide (DPPA, 5.50 mL, 25.64 mmol) and DBU (3.95
mL, 26.41 mmol) in toluene (200 mL) at 65.degree. C. under nitrogen
for 12 h. Add silica gel to the cooled mixture and remove the
solvents under reduced pressure. Purify the residue by column
chromatography, eluting with ethyl acetate/hexanes (1:2), to
provide the title compound as a colorless oil (5.79 g, 71%):
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.21-2.30 (m, 18H),
2.83-2.89 (m, 2H), 4.78-4.80 (m, 1H), 7.31-7.45 (in, 2H); APCI MS
m/z 356 (M-N2)-.
Step 10. Preparation of
(S)-5-Amino-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine--
1-carboxylic acid tert-butyl ester
##STR00102##
[0370] Shake a mixture of
(S)-5-amino-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine--
1-carboxylic acid tert-butyl ester (5.75 g, 14.96 mmol) and 5%
palladium on charcoal (0.630 g, 50% wet) in ethanol (200 mL) under
25 psi of hydrogen in a Parr bottle at room temperature for 2 h.
Filter the mixture through Celite.RTM. and remove the solvents
under reduced pressure to provide the title compound as a colorless
oil (4.93 g, >99%), which is used in the next step without
further purification. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
1.21-2.30 (m, 19H), 2.83-2.89 (m, 3H), 4.78-4.80 (m, 1H), 7.31-7.45
(m, 2H); APCI MS m/z 359 (M+H).sup.+.
Step 11. Preparation of
(S)-5-(3,5-Bis-trifluoromethyl-benzylamino)-7-ethyl-8-trifluoromethyl-2,3-
,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl
ester
##STR00103##
[0372] Add 3,5-bistrifluoromethylbenzaldehyde (4.30 g, 24.22 mmol)
to a solution of
(S)-5-amino-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine--
1-carboxylic acid tert-butyl ester (4.91 g, 13.70 mmol) in
dichloromethane (100 mL) and glacial acetic acid (6 mL) at room
temperature under nitrogen and stir for 2 h. Add sodium
triacetoxyborohydride (6.01 g, 28.35 mmol) and stir the mixture for
2 h. Remove the solvents under reduced pressure and dilute the
residue with dichloromethane (50 mL) and water (50 mL). Collect the
organic layer and extract the aqueous layer with dichloromethane
(3.times.30 mL). Wash the combined organic extracts with water (20
mL) and brine (20 mL) and dry over anhydrous sodium sulfate. Filter
and remove the solvents under reduced pressure to provide the title
compound as an amber oil (6.58 g, 75%), which is used in the next
step without purification. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 1.21-2.30 (m, 19H), 2.83-2.89 (m, 2H), 4.78-4.80 (m, 3H),
6.89-7.60 (m, 3H), 7.70-7.91 (m, 2H); APCI MS m/z 585 (M+H)+.
Step 12. Preparation of
(S)-5-[(3,5-bistrifluoromethylbenzyl)cyanoamino]-7-ethyl-8-trifluoromethy-
l-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid tert-butyl
ester
##STR00104##
[0374] Add cyanogen bromide (0.352 g, 3.33 mmol) to a solution of
(S)-5-(3,5-Bis-trifluoromethyl-benzylamino)-7-ethyl-8-trifluoromethyl-2,3-
,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester
(0.647 g, 1.11 mmol) and diisopropylethylamine (0.679 mL, 3.89
mmol) in tetrahydrofuran (3 mL) at room temperature under nitrogen
and heat the mixture at 65-70.degree. C. for 16 hours and then for
another 90.degree. C. 16 h. Partition the cooled mixture between
dichloromethane (40 mL) and brine (40 mL), separated layers.
Extract aqueous with more dichloromethane (40 mL). Combine organic
layers, dry over anhydrous sodium sulfate, filter and concentrated
under reduced pressure. Purify the residue by column chromatography
on silica gel, eluting with ethyl acetate/hexanes (0-20%), to
provide the title compound (0.517 g, 76%), MS (ES+): 627
(M+NH.sub.4), 632 (M+Na).
Step 13. Preparation of
(S)-5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-ethyl-8--
trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid
tert-butyl ester
##STR00105##
[0376] Heat a mixture of
(S)-5-[(3,5-bistrifluoromethylbenzyl)cyanoamino]-7-ethyl-8-trifluoromethy-
l-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid tert-butyl
ester (0.510 g, 0.837 mmol), azidotributyltin (0.344 mL, 1.26 mmol)
in anhydrous toluene (20 mL) at 100.degree. C. under nitrogen for
16 h. Dilute the cooled mixture with ethyl acetate (50 mL) and wash
with aqueous NaF (50 mL) and brine (50 mL). Dry over anhydrous
sodium sulfate. Filter and remove the solvent under reduced
pressure. Purify the residue by column chromatography on silica
gel, eluting with ethyl acetate/hexanes (0-60%), to provide the
title compound (0.432 g, 79%), MS (ES+): 653 (M+H).
Step 14. Preparation of
(S)-5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-
-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic
acid tert-butyl ester
##STR00106##
[0378] Add diethyl azodicarboxylate (0.0.240 mL, 1.32 mmol) to a
solution of
(S)-5-[(3,5-bistrifluoromethylbenzyl)cyanoamino]-7-ethyl-8-trifluorome-
thyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid tert-butyl
ester (0.430 g, 0.659 mmol), triphenylphosphine (0.262 g, 0.989
mmol) and methanol (0.133 mL, 3.30 mmol) in dichloromethane (6 mL)
at room temperature under nitrogen. Stir for 2 h. Evaporate the
solvent on a rota-vapor. Purify the residue by column
chromatography on silica gel, eluting with ethyl acetate/hexanes
(0-30%), to provide the title compound (0.386 g, 88%). MS (ES+):
689 (M+Na).
Example 35
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine.-1-carboxyl-
ic acid isopropyl ester
##STR00107##
[0379] Step 1. Preparation of
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-ethyl-8-
-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
##STR00108##
[0381] Add trifluoroacetic acid (1 mL) to a solution of
(S)-5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-
-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic
acid tert-butyl ester (2.04 g, 3.13 mmol) in dichloromethane (1
mL). Stir for 30 minutes at room temperature. Dilute the mixture
with dicloromethane (40 mL) and wash with saturated aqueous sodium
bicarbonate solution (40 mL). Dry organic layer over anhydrous
sodium sulfate and filter. Remove the solvent under reduced
pressure. Purify the residue by column chromatography on silica
gel, eluting with ethyl acetate/hexanes (0-30%), to provide the
title compound (0.318 g, 98%). MS (ES+): 567 (M+H).
Step 2. Preparation of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyli-
c acid isopropyl ester
##STR00109##
[0383] The title compound can be prepared using procedures
analogous to those used in Example 15 by replacing
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
with
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-ethyl-8-
-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
and ethyl chloroformate with isopropyl chloroformate
[0384] The following Examples 36-43 can be prepared using the same
procedures as generally described in Examples 18-25 by replacing
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
(Example 3, Step 18) with
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-ethyl-8-
-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
(Example 35, Step 1).
Example 36
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyli-
c acid 1-ethyl-propyl ester
##STR00110##
[0385] Example 37
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyli-
c acid cyclopentyl ester
##STR00111##
[0386] Example 38
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyli-
c acid cyclopentyl ester
##STR00112##
[0387] Example 39
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyli-
c acid cyclopentyl ester
##STR00113##
[0388] Example 40
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyli-
c acid 2,2,2-trifluoro-1-methyl-ethyl ester
##STR00114##
[0389] Example 41
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyli-
c acid sec-butyl ester
##STR00115##
[0390] Example 42
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyli-
c acid 1,2-dimethyl-propyl ester
##STR00116##
[0391] Example 43
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyli-
c acid 1-ethyl-2-methyl-propyl ester
##STR00117##
[0392] Example 44
Synthesis of
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino)-2,2-d-
ifluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxyli-
c acid isopropyl ester
##STR00118##
[0393] Step 1. Preparation of
2,2-Difluoro-9-oxo-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-
-5-carboxylic acid isopropyl ester
##STR00119##
[0395] The title compound can be prepared using procedures
analogous to those used in Example 3, Steps 1-3 (alternative
preparation of
methyl-2-(N-isopropoxycarbonyl)amino-5-methyl-4-trifluoromethylbenzoate)
starting with 2,2-difluoro-benzo[1,3]dioxol-5-ylamine and then
proceeding with Example 3, Steps 6-8.
Step 2. Preparation of
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,2-d-
ifluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxyli-
c acid isopropyl ester
##STR00120##
[0397] The title compound can be prepared using procedures
analogous to those used in Example 1, Steps 4-6, starting with
2,2-difluoro-9-oxo-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-
-5-carboxylic acid isopropyl ester.
Example 45
Synthesis of
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5--
carboxylic acid isopropyl ester
##STR00121##
[0399] The title compound can be prepared using procedures
analogous to those used in Example 1, Step 7, starting with
9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,2-difluor-
o-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester.
Example 46
Synthesis of (+/-)-Isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3-
,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00122##
[0400] Step 1. Preparation of (+/-) Isopropyl
5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b-
]azepine-1-carboxylate
##STR00123##
[0402] Prepare the titled compound by following the procedures as
essentially described in Example 1, Step 1-4, by replacing methyl
2-amino-5-bromobenzoate with methyl-2-amino-4-chlorobenzoate in
Example 1, Step 1.
Step 2. Preparation of (+/-)-Isopropyl
5-[(3.5-bistrifluoromethyl-benzyl)-cyano-amino]-8-chloro-2,3,4,5-tetrahyd-
robenzo[b]azepine-1-carboxylate
##STR00124##
[0404] Add a solution of cyanogen bromide (68 mg, 0.63 mmol) in
ether (2.6 mL) to a solution of isopropyl
5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b-
]azepine-1-carboxylate (512 mg, 1.0 mmol) in ether (2.6 mL). Stir
the mixture overnight at room temperature. Filter off the resulting
solid and wash with ether. Wash the filtrate with water, dry over
anhydrous sodium sulfate, filter and remove the solvent under
reduced pressure. Purify the residue by flash chromatography,
eluting with hexanes/ethyl acetate, to afford the title compound
(204 mg, 38%): MS (ES+): 534 (M+H).
Step 3. Preparation of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3-
,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00125##
[0406] Add azidotributyltin (0.19 mL, 0.68 mmol) to a solution of
(+/-)-isopropyl
5-(3,5-bistrifluoromethyl-benzyl)-cyano-amino]-8-chloro-2,3,4,5-tetrahydr-
obenzo[b]azepine-1-carboxylate (180 mg, 0.34 mmol) in toluene (3.6
mL). Stir the mixture at 80.degree. C. overnight. Cool down the
mixture to room temperature; add ethyl acetate and 1 N HCl (8.2 mL)
and stir at room temperature for 1 h. Separate the layers, wash the
organic phase with saturated KF, then with brine, dry over
anhydrous sodium sulfate, filter and remove the solvent under
reduced pressure. Purify the residue by flash chromatography,
eluting with dichloromethane/methanol, and then by reverse phase
purification to provide 198 mg (quantitative) of the title
compound. MS (ES-): 575 (M-H).
Example 47
Synthesis of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-8-c-
hloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00126##
[0408] Add sodium carbonate (36 mg, 0.34 mmol) and methyl iodide
(0.021 mL, 0.34 mmol) to a solution of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3-
,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (98 mg, 0.17 mmol) in
dimethylformamide/acetone (1:1) (1 mL). Stir the reaction mixture
at room temperature overnight. Then add water and dichloromethane.
Separate the layers and wash the organic phase with brine. 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 afford the
title compound (70 mg, 70%). MS (ES+): 591 (M+H).
Example 48
Synthesis of (+/-)
isopropyl-6-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-2,-
3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylate
##STR00127##
[0409] Step 1. Preparation of
2-Hydroxyamino-N-indan-4-yl-acetamide
##STR00128##
[0411] To a solution of chloral hydrate (5.46 g, 33 mmol) and
anhydrous sodium sulfate (25.6 g, 180 mmol) in water (92 mL) add a
mixture of hydroxylamine sulfate (25.6 g, 156 mmol), 4-aminoindane
(4 g, 30 mmol), concentrated hydrochloric acid (3.1 mL) in water
(30.8 mL). Heat the mixture up to 45.degree. C. for 90 min, to
52.degree. C. over 45 min and to 75.degree. C. for 60 min. Cool the
mixture to room temperature and filter the solid. Wash the solid
with water and hexane. Dry the solid under vacuum to yield the
title compound (5.54 g, 90%). MS (ES-): 203 (M-H).
Step 2. Preparation of
1,6,7,8-Tetrahydro-1-aza-as-indacene-2,3-dione
##STR00129##
[0413] Add 2-Hydroxyamino-N-indan-4-yl-acetamide (5.54 g, 27.1
mmol) in small portions at 80.degree. C. to methanesulfonic acid
(21 mL). Stir the mixture at this temperature for 25 min. Cool to
room temperature, pour into ice water and filter the precipitate.
Dissolve the solid in warmed 1 N NaOH, and neutralize with acetic
acid. Filter the resulting solid and acidify the filtrate with
concentrated HCl. Filter the precipitate and wash with water. Dry
the solid to yield the title compound (3.80 g, 72%). MS (ES-): 186
(M-H).
Step 3. Preparation of 4-Amino-indan-5-carboxylic acid methyl
ester
##STR00130##
[0415] Add 30% aqueous hydrogen peroxide solution (5 mL) in water
(44 mL) to a solution of
1,6,7,8-Tetrahydro-1-aza-as-indacene-2,3-dione (3.80 mg, 20.3 mmol)
and NaOH (5.03 g, 126 mmol) in water (97 mL) over a period of 30
minutes, stir the mixture at room temperature for 1 h. Acidulate
with 1 N hydrochloric acid, filter the solid, wash with water and
dry to afford 4-amino-indan-5-carboxylic acid (3.13 g, 87%).
Dissolve 4-amino-indan-5-carboxylic acid (3.07 g, 17.3 mmol) in
ethyl acetate (87 mL) and ethanol (87 mL) and add (trimethylsilyl)
diazomethane (17.3 mL., 34.6 mmol, 2 M in hexanes) at room
temperature and stir the solution for 1 h. Remove the solvent under
reduced pressure. Purify the residue by flash chromatography,
eluting with hexanes/ethyl acetate, to afford the title compound
(2.50 g, 76%). .sup.1H NMR (MeOD, 300 MHz) .delta. 2.12
(quintuplet, J=7.6 Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.5
Hz, 2H), 3.83 (s, 3H), 6.53 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz,
1H). MS (ES+): 192 (M+H).
Step 4. Preparation of 4-Isopropoxycarbonylamino-indan-5-carboxylic
acid methyl ester
##STR00131##
[0417] Add isopropyl chloroformate (2.22 mL, 2.22 mmol, 1.0 M in
toluene) dropwise to a solution of 4-amino-indan-5-carboxylic acid
methyl ester (425 mg, 2.22 mmol) and pyridine (0.44 mL, 5.5 mmol)
in dichloromethane (4.4 mL) at 0.degree. C. under an atmosphere of
nitrogen and stir at room temperature for 24 h. Add 1 M HCl 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 (576 mg, 93%). .sup.1H NMR (MeOD) .delta.
1.37 (d, J=6.5 Hz, 6H), 2.16 (quintuplet, J=7.7 Hz, 2H), 2.97 (t,
J=7.3 Hz, 2H), 3.05 (t, J=7.3 Hz, 2H), 3.94 (s, 3H), 4.97 (m, 1H),
7.22 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H). MS (ES+): 278
(M+H).
Step 5. Preparation of
4-[(3-Ethoxycarbonyl-propyl)-isopropoxycarbonyl-amino]-indan-5-carboxylic
acid methyl ester
##STR00132##
[0419] Add a solution of
4-isopropoxycarbonylamino-indan-5-carboxylic acid methyl ester (570
mg, 2.1 mmol) in dimethylformamide (8.2 mL) to a suspension of
sodium hydride 60% dispersion mineral oil (82 mg, 2.1 mmol) in
dimethylformamide (8.2 mL) at 0.degree. C. under an atmosphere of
nitrogen and allow to reach room temperature over 1 h. Add ethyl
4-bromobutyrate (0.44 mL, 3.09 mmol) and stir at room temperature
for 14 h, then heat at 65.degree. C. for 2 h. Cool the mixture to
room temperature, dilute with ethyl acetate, wash with 1 M HCl,
water, and brine. 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 (651 mg, 81%).
.sup.1H NMR (MeOD, 300 MHz) .delta. 1.03-1.34 (m, 9H), 1.85 (m,
2H), 2.10 (m, 2H), 2.30 (m, 2H), 2.82-3.01 (m, 4H), 3.32 (m, 1H),
3.68 (m, 1H), 3.86 (s, 3H), 4.08 (m, 2H), 4.91(m, 1H), 7.19 (d,
J=7.7 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H). MS (ES+): 392 (M+H).
Step 6. Preparation of
6-Oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic
acid isopropyl ester
##STR00133##
[0421] Add a solution of
4-[(3-ethoxycarbonyl-propyl)-isopropoxycarbonyl-amino]-indan-5-carboxylic
acid methyl ester (510 mg, 1.30 mmol) in tetrahydrofuran (20.4 mL)
to a solution of potassium tert-butoxide (2.60 mL, 2.60 mmol, 1 M
in tetrahydrofuran) in tetrahydrofuran (18 mL) at room temperature
under an atmosphere of nitrogen. After 30 min, pour the mixture
into ice/water. Treat the aqueous phase with 1 M HCl to pH neutral
and extract with dichloromethane. Dry the organic layer over
anhydrous sodium sulfate, filter, and remove the solvent under
reduced pressure. Dissolve the former crude in dimethyl sulfoxide
(11 mL and add water (2 drops) followed by addition of lithium
chloride (134 mg, 3.2 mmol) and heat the resulting solution at
160.degree. C. for 30 minutes. Cool the mixture to room temperature
and pour into brine. Extract the mixture with ethyl acetate. Dry
the organic layers over anhydrous sodium sulfate, filter and remove
the solvent under reduced pressure. Purify the residue by flash
chromatography, eluting with hexanes/ethyl acetate, to afford the
title compound (302 mg, 81% over two steps). MS (ES+): 288
(M+H).
Step 7. Preparation of (+/-)
isopropyl-6-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-2,-
3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylate
##STR00134##
[0423] Add 3,5-bis(trifluoromethyl)benzylamine (349 mg, 1.15 mmol)
followed by titanium isopropoxide (414 mg, 1.46 mmol) to
6-oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic
acid isopropyl ester (300 mg, 1.04 mmol) at room temperature under
an atmosphere of nitrogen and stir the solution for 14 h. Add
methanol (4.3 mL) and sodium borohydride (59 mg, 1.56 mmol) and
stir the mixture under nitrogen at room temperature for 45 min. Add
0.1 M NaOH and stir for 30 min. Filter through Celite.RTM. and wash
the residue with ethyl acetate. Separate the organic layer and
extract the aqueous with ethyl acetate. Wash the organic layer with
brine and dry the organic layers over anhydrous sodium sulfate.
Filter and remove the solvent under reduced pressure. Purify the
residue by flash chromatography, eluting with hexanes/ethyl
acetate, to afford
(+/-)isopropyl-6-(3,5-bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahy-
dro-1H-10-aza-cyclohepta[e]indene-10-carboxylate (443 mg, 83%).
[0424] The titled compound was prepared in a manner analogous to
the procedure for the preparation of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3-
,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 46, from Step
2 to Step 3) by replacing (+/-)-isopropyl
5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b-
]azepine-1-carboxylate with (+/-)-isopropyl
6-(3,5-bis-trifluoromethyl-benzylamino]-2,3,6,7,8,9-hexahydro-1H-10-aza-c-
yclohepta[e]indene-10-carboxylate (prepared above) in Example 46
Step 2. MS (ES-): 581 (M-H).
Example 49
Synthesis of
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6-
,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
isopropyl ester
##STR00135##
[0425] Step 1. Preparation of
2-Hydroxyimino-N-indan-5-yl-acetamide
##STR00136##
[0427] To a solution of chloral hydrate (5.56 g, 33.53 mmol) and
anhydrous sodium sulfate (28.58 g, 201.20 mmol) in water (90 mL)
add a mixture of hydroxylamine sulfate (25.63 g, 156.16 mmol),
5-aminoindane (4 g, 30.03 mmol), concentrated hydrochloric acid
(3.14 mL) in water (30 mL). Heat the mixture at 45.degree. C. for 1
h and at 75.degree. C. for 2 h. Cool the mixture to room
temperature and filter the solid. Wash the solid with water and
ethyl ether. Dry the solid under vacuum to yield the title compound
(4.98 g, 81%). .sup.1H NMR (dimethyl sulfoxide-d.sub.6, 300 MHz)
.delta. 1.90 (quintuplet, J=7.8 Hz, 2H), 2.72 (q, J=7.8 Hz, 4H),
7.06 (d, J=8.2 Hz, 1H), 7.28 (dd, J=1.5, 8.2 Hz, 1H), 7.49 (bs,
1H), 9.94 (s, 1H), 12.02 (s, 1H). MS (ES-): 203 (M-H).
Step 2. Preparation of
1,5,6,7-Tetrahydro-1-aza-s-indacene-2,3-dione
##STR00137##
[0429] Add 2-hydroxyimino-N-indan-5-yl-acetamide (4.66 g, 22.84
mmol) in small portions at 65.degree. C. to concentrated sulfuric
acid (22 mL) and heat the mixture at 80.degree. C. for 15 minutes.
Cool to room temperature, pour into ice water (200 mL) and filter
the precipitate.
[0430] Dissolve the solid in warmed ethanol and leave to cool
overnight. Filter the precipitate and wash with ethyl ether. Dry
the solid to yield the title compound (3.3 g, 77%). .sup.1H NMR
(dimethyl sulfoxide-d.sub.6, 300 MHz) .delta. 1.98 (quintuplet,
J=7.7 Hz, 2H), 2.76 (t, J=7.7 Hz, 2H), 2.85 (t, J=7.7 Hz, 2H), 6.74
(s, 1H), 7.28 (s, 1H). MS (ES-): 186 (M-H).
Step 3. Preparation of 6-Amino-indan-5-carboxylic acid methyl
ester
##STR00138##
[0432] Add 30% aqueous hydrogen peroxide solution (3 mL) to a
solution of 1,5,6,7-tetrahydro-1-aza-s-indacene-2,3-dione (2.18 g,
11.66 mmol) in 2 N NaOH (23 mL) over a period of 5 minutes, stir
the mixture at room temperature for 3 h. Add 1 N hydrochloric acid
to pH=5 and extract with ethyl acetate (3.times.20 mL). Wash with
brine, dry the organic layer over anhydrous sodium sulfate, filter
and remove the solvent under reduced pressure to afford
6-amino-indan-5-carboxylic acid (1.7 g, 86%). Dissolve in ethyl
acetate (2 mL) and ethanol (2 mL) and add (trimethylsilyl)
diazomethane (9.6 mL, 19.2 mmol, 2 M in hexane) at room temperature
and stir the solution for 16 h. Remove the solvent under reduced
pressure. Chromatograph the residue over silica gel, eluting with
hexanes/ethyl acetate (9:1), to afford the title compound (1.19 g,
66%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 2.05 (quintuplet,
J=7.3 Hz, 2H), 2.80 (q, J=7.7 Hz, 4H), 6.59 (s, 1H), 7.69 (s, 1H).
MS (ES+): 192 (M+H).
Step 4. Preparation of
9-Oxo-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester
##STR00139##
[0434] Prepare the titled compound by following the procedure as
essentially described for the preparation of
methyl-5-bromo-2-[isopropoxycarbonyl-(3-methoxycarbonylpropyl)amino]benzo-
ate (Example 1, Steps 1 and 2) and followed by the procedure
described for the preparation of
6-Oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic
acid isopropyl ester (Example 48, Step 6) by replacing methyl
2-amino-5-bromobenzoate with 6-amino-indan-5-carboxylic acid methyl
ester in Example 1, Step 1. MS (ES+): 288 (M+H).
Step 5. Preparation of
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6-
,7,8,9-hexahydro-1H-5- aza-cyclohepta[f]indene-5-carboxylic acid
isopropyl Ester
##STR00140##
[0436] Add 3,5-bis(trifluoromethyl)benzylamine (187 mg, 0.77 mmol)
followed by titanium isopropoxide (835 mg, 2.94 mmol) to
9-oxo-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester (200 mg, 0.7 mmol) at room temperature under
an atmosphere of nitrogen and stir the solution for 3 days. Add
methanol (3 mL) and sodium borohydride (40 mg, 1.05 mmol) and stir
the mixture under nitrogen at room temperature for 16 h. Add sodium
bicarbonate saturated solution, filter through Celite.RTM. and wash
the residue with ethyl acetate. Separate organic layer, extract
aqueous with ethyl acetate. Wash organic layer with brine and dry
the organic layers over anhydrous sodium sulfate. Filter and remove
the solvent under reduced pressure. Purify the residue by silica
cartridge, eluting with hexanes/ethyl acetate 9:1, to afford
(+/-)-isopropyl-9-(3,5-bis-trifluoromethyl-benzylamino)-2,3,6,7,8,-
9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylate (220
mg).
[0437] The titled compound was prepared in a manner analogous to
the procedure for the preparation of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3-
,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 46, from Step
2 to Step 3) by replacing isopropyl
5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b-
]azepine-1-carboxylate with
(+/-)-isopropyl-9-(3,5-bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexah-
ydro-1H-5-aza-cyclohepta[f]indene-5-carboxylate (prepared above) in
Example 46 Step 2. MS (ES-): 581 (M-H).
Example 50
Synthesis of
(+/-)-9[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester
##STR00141##
[0439] To a solution of (+/-)-isopropyl
9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9-
-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylate (Example 49)
(48 mg, 0.082 mmol) and methanol (0.015 mL, 0.36 mmol) in
dichloromethane (1 mL) at room temperature, under nitrogen
atmosphere, add triphenyl phosphine (22 mg, 0.082 mmol) in one
portion. Add diethyl azodicarboxylate (0.015 mL, 0.082 mmol). The
reaction mixture was allowed to stir at room temperature overnight.
Add methanol (0.015 mL, 0.36 mmol), triphenyl phosphine (22 mg,
0.082 mmol) and diethyl azodicarboxylate (0.015 mL, 0.082 mmol).
After stirring for 6 h, remove the solvents under reduced pressure.
Purify the residue by flash chromatography, eluting with
hexanes/ethyl acetate, to afford the title compound (25 mg, 51%).
MS (ES+): 597 (M+H).
Example 51
Synthesis of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(5-methyl-1H-pyrazol-3-yl)-amino]-8-ch-
loro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00142##
[0440] Step 1. Preparation of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-8-chloro-2,3,4,-
5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00143##
[0442] To a solution of isopropyl
5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b-
]azepine-1-carboxylate (Example 46, Step 1) (200 mg, 0.39 mmol) and
4-dimethylaminopyridine (6 mg, 0.049 mmol) in dry tetrahydrofuran
(1.4 mL) at 0.degree. C. under a nitrogen atmosphere, add a
solution of diketene (0.033 mL, 0.43 mmol) in dry tetrahydrofuran
(0.4 mL). After stirring 1.5 h at 0.degree. C., remove the solvent
under reduced pressure. Purify the by flash chromatography, eluting
with hexanes/ethyl acetate, to afford the title compound (169 mg,
73%). MS (ES+): 593 (M+H).
Step 2. Preparation of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(5-methyl-1H-pyrazol-3-yl)-amino)-8-ch-
loro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00144##
[0444] Add cold (ice bath) absolute EtOH (1 mL) slowly to a cooled
0.degree. C. stirred mixture of
(+/-)-5-[(3,5-bistrifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-8-chloro--
2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester
(118 mg, 0.20 mmol) and phosphorus pentoxide (511 mg, 3.6 mmol).
Then, add hydrazine hydrate (0.062 mL, 2.0 mmol) dropwise while
keeping the mixture cooled at 0.degree. C. Heat at 100.degree. C.
overnight in a sealed tube. Cool down the mixture and remove the
solvents under reduce pressure. Partition the residue between water
and dichloromethane. Separate the layers, and dry organic phase
over anhydrous magnesium sulfate, filter and concentrate in vacuo.
Purify the residue by flash chromatography, eluting with
hexanes/ethyl acetate, and then by a SCX cartridge to afford the
title compound (25 mg, 21%). MS (ES+): 589 (M+H).
Example 52
Synthesis of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(5-methyl-isoxazol-5-yl)-amino]-8-chlo-
ro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00145##
[0446] Add hydroxylamine hydrochloride (39 mg, 0.55 mmol) and
sodium acetate (1.5 mg, 0.018 mmol). to a solution of compound
(+/-)-5-[(3,5-bistrifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-8-chloro--
2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester
(Example 51, Step 1) (218 mg, 0.37 mmol) in methanol (1.8 mL) at
0.degree. C., Heat the reaction mixture under reflux overnight.
Cool and remove the solvents under reduce pressure. Dilute the
residue with ethyl acetate and brine. Separate the layers and dry
the organic phase over magnesium sulfate, filter and concentrate in
vacuo. Purify the residue by flash chromatography, eluting with
hexanes/ethyl acetate to afford the title compound (85 mg, 39%). MS
(ES+): 590 (M+H).
Example 53
Synthesis of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-9-m-
ethyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00146##
[0447] Step 1. Preparation of
7-methyl-6-trifluoromethyl-1H-indole,2,3-dione
##STR00147##
[0449] To a solution of chloral hydrate (6.08 g, 36.74 mmol) and
anhydrous sodium sulfate (28.5 g, 200.4 mmol) in water (102 mL) add
a mixture of hydroxylamine sulfate (28.5 g, 173.68 mmol),
2-methyl-3-trifluoromethyl-phenylamine (5.85 g, 33.4 mmol),
concentrated hydrochloric acid (3.5 mL) in water (34 mL). Heat the
mixture at 35.degree. C. for 1 h, then heat up to 52.degree. C. for
90 min and at 75.degree. C. for 1 h. Cool the mixture to room
temperature and filter the solid. Wash the solid with water and
hexane. Dry the solid under vacuum to afford
2-hydroxyimino-N-(2-methyl-3-trifluoromethyl-phenyl)-acetamide: MS
(ES+): 245 (M-H). Add the former crude in small portions at
60.degree. C. to concentrated sulfuric acid (44 mL) and heat the
mixture at 80.degree. C. for 1 h. Cool to room temperature, pour
into ice water (100 mL) and filter the precipitate. Wash the solid
with cool water twice. Dry the solid to afford the title compound
(3.54 g, 46% two steps). MS (ES-): 228 (M-H).
Step 2. Preparation of 2-Amino-3-methyl-4-trifluoromethyl-benzoic
acid
##STR00148##
[0451] Add 30% aqueous hydrogen peroxide solution (3.8 mL) in water
(33 mL) to solution of
7-methyl-6-trifluoromethyl-1H-indole,2,3-dione (3.54 g, 15.46 mmol)
and NaOH (3.83 g, 95.84 mmol) in water (74 mL) slowly. Then stir
the mixture at room temperature for 1 h. Add 1 N hydrochloric acid
to acidulate the mixture. Filter the resulting solid and wash with
water. Dry the solid to afford the title compound (1.7 g, 50%). MS
(ES+): 218 (M-H).
Step 3. Preparation of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-cyano-amino]-9-methyl-8-trifluormethyl-
-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00149##
[0453] Prepare isopropyl
5-(3,5-bistrifluoromethyl-benzylamino)-9-methyl-8-trifluormethyl-2,3,4,5--
tetrahydrobenzo[b]azepine-1-carboxylate following procedures as
generally described for Example 48, Step 3 to 7, using
2-amino-3-methyl-4-trifluoromethyl-benzoic acid.
[0454] To a suspension of sodium hydride 60% in mineral oil (32 mg,
0.81 mmol) in dry dimethyl sulfoxide (3 mL), add isopropyl
5-(3,5-bistrifluoromethyl-benzylamino)-9-methyl-8-trifluormethyl-2,3,4,5--
tetrahydrobenzo[b]azepine-1-carboxylate (300 mg, 0.54 mmol) and dry
dimethylformamide (2 mL). Add cyanogen bromide (176 mg, 1.62 mmol)
and stir the reaction mixture at room temperature overnight. Add
sodium hydride 60% in mineral oil (32 mg, 0.81 mmol) and cyanogen
bromide (176 mg, 1.62 mmol) and stir at room temperature for one
hour. Add additional sodium hydride 60% in mineral oil (32 mg, 0.81
mmol) and cyanogen bromide (176 mg, 1.62 mmol) and stir one hour.
Add water and ethyl acetate. Separate the layers and dry the
organic phase over anhydrous magnesium sulfate, filter and remove
the solvent under reduced pressure. Purify the residue by flash
chromatography, eluting with hexanes/ethyl acetate, to afford the
titled compound (124 mg, 40%). MS (ES+): 582 (M+H).
Step 4. Preparation of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-9-methyl-8-t-
rifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00150##
[0456] Add sodium azide (42 mg, 0.64 mmol) and triethylamine
hydrochloride (88 mg, 0.64 mmol) to a solution of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-cyano-amino]-9-methyl-8-trifluormethyl-
-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (124 mg, 0.21
mmol) in toluene (2 mL). Stir the mixture at 110.degree. C.
overnight. Cool down the mixture to room temperature, add 1 N HCl
(5 mL) and dichloromethane. Separate the layers, dry the organic
phase over anhydrous magnesium sulfate, filter and remove the
solvent under reduced pressure to provide 117 mg (89%) of the title
compound. MS (ES-): 623 (M-H).
Step 5. Preparation of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-9-m-
ethyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00151##
[0458] To a solution of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-9-methyl-8-t-
rifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (87
mg, 0.139 mmol), methanol (0.564 mL, 13.9 mmol), triphenyl
phosphine (73 mg, 0.278 mmol) in dry dichloromethane (3.4 mL) at
0.degree. C., under nitrogen, add diethyl azodicarboxylate (0.128
mL, 0.278 mmol). Stir the reaction mixture at room temperature for
3 h. Remove the solvents under reduced pressure and purify the
residue by flash chromatography, eluting with hexanes/ethyl acetate
to afford the title compound (47 mg, 53%). MS (ES+): 639 (M+H).
Example 54
Synthesis of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7,9-
-methyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00152##
[0460] To a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,-
4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 148, Step 2) (0.12 mmol) in dichloromethane (5 mL) add
pyridine (0.37 mmol) followed by isopropyl chloroformate (0.37
mmol) as a 1.0 M solution in toluene. After stirring at room
temperature for 14 h dilute the reaction with dichloromethane (10
mL) and water (10 mL). Acidify the aqueous by dropwise addition of
5M HCl. Separate the organics and wash the aqueous with
dichloromethane (2.times.5 mL). Dry the combined organics over
sodium sulfate, filtered, and remove solvent. Chromatograph the
mixture over silica gel using ethyl acetate/hexane (5-30%). This
affords the title compound as a colorless foam. MS (ES+): 653
(M+H).
Example 55
Synthesis of
(S)-6-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-4-methyl-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxyl-
ic acid isopropyl ester
##STR00153##
[0461] Step 1. Preparation of 4-Amino-7-bromo-indan-5-carboxylic
acid methyl ester
##STR00154##
[0463] Add N-bromosuccinimide (1.99 g, 11.2 mmol) to
4-amino-indan-5-carboxylic acid methyl ester (2.15 g, 11.2 mmol)
(Example 48, Step 3) in acetic acid (13 mL). Stir the mixture at
room temperature for 48 h. Pour the mixture into ice water and add
ethyl acetate. Separate the layers and wash the organic phase with
saturated NaHCO.sub.3 and brine and dry over sodium sulfate. Remove
the solvent under reduced pressure to afford the title compound
(3.10 g, quantitative). MS (ES+): 271 (M+H).
Step 2. Preparation of
4-Bromo-6-oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carb-
oxylic acid isopropyl ester
##STR00155##
[0465] Prepare the title compound by essentially following the
procedure described in Example 3, Steps 5-8 by replacing methyl
2-amino-5-methyl-4-trifluoromethylbenzoate with
4-amino-7-bromo-indan-5-carboxylic acid methyl ester in Example 3,
Step 5. MS (ES+): 366, 368 (M+H).
Step 3. Preparation of
(S)-6-(3,5-Bis-trifluoromethyl-benzylamino)-4-bromo-2,3,6,7,8,9-hexahydro-
-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl
ester
##STR00156##
[0467] Prepare the title compound by essentially following the
procedure described in Example 3, Steps 11-14 by replacing
tert-butyl-7-methyl-5-oxo-8-trifluoromethyl-2,3-4,5-tetrahydrobenzo[b]aze-
pine-1-carboxylate with
4-Bromo-6-oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carb-
oxylic acid isopropyl ester in Example 3, Step 11. MS (ES+): 593,
595 (M+H).
Step 4. Preparation of
(S)-6-(3,5-Bis-trifluoromethyl-benzylamino)-4-methyl-2,3,6,7,8,9-hexahydr-
o-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl
ester
##STR00157##
[0469] Add cesium carbonate (383 mg, 2.52 mmol), methyl boronic
acid (76 mg, 1.26 mmol) and
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (69 mg, 0.084 mmol) to a
solution of
(S)-6-(3,5-bis-trifluoromethyl-benzylamino)-4-bromo-2,3,6,7,8,9-hexahydro-
-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester
(500 mg, 0.84 mmol) in dioxane (7 mL). Stir the mixture under
nitrogen at 110.degree. C. for 2 h. Cool down the mixture to room
temperature and filter over Celite.RTM. washing with
dichloromethane. Evaporate the solvent and purify the crude by
chromatography, eluting with hexane/ethyl acetate (90/10) to afford
the title compound (355 mg, 0.67 mmol, 80%). MS (ES+): 529
(M+H).
Step 5. Preparation of
(S)-6-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-4-methy-
l-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic
acid isopropyl ester
##STR00158##
[0471] Prepare the title compound by essentially following the
procedure described in Example 3, Steps 15-16 by replacing
(S)-tert-butyl
5-(3,5-bistrifluoromethylbenzylamino)-7methyl-8-trifluoromethyl-2,3,4,5-t-
etrahydrobenzo[b]azepine-1-carboxylate with
(S)-6-(3,5-Bis-trifluoromethyl-benzylamino)-4-methyl-2,3,6,7,8,9-hexahydr-
o-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester
in Example 3, Step 15. MS (ES+): 597 (M+H).
Step 6. Preparation of
(S)-6-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-4-methyl-2,3.6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxyl-
ic acid isopropyl ester
##STR00159##
[0473] Prepare the title compound by essentially following the
procedure described in Example 3, Step 17 by replacing
(S)-tort-butyl
5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-methyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxilate with
(S)-6-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-4-methy-
l-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic
acid isopropyl ester in Example 3, Step 17. MS (ES+): 611
(M+H).
Example 56
Synthesis of (S)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-8,9-
-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00160##
[0474] Step 1. Preparation of 2-Amino-4-bromo-3-methyl-benzoic
acid
##STR00161##
[0476] Prepare the titled compound by following the procedure as
essentially described for the preparation of
2-Amino-3-methyl-4-trifluoromethyl-benzoic acid (Example 53, from
Step 1 to Step 2) by replacing
2-methyl-3-trifluoromethyl-phenylamine with
3-bromo-2-methyl-phenylamine in Step 1. MS (ES-): 229 (M-H).
Step 2. Preparation of methyl 2-amino-4-bromo-3-methylbenzoate
##STR00162##
[0478] Add (trimethylsilyl)diazomethane (16.5 mL, 33 mmol, 2 M in
hexane) to a solution of 2-amino-4-bromo-3-methyl-benzoic acid (3.8
g, 16.5 mmol) in ethyl acetate (50 mL) and ethanol (50 mL) at room
temperature and stir the solution for 16 h. Remove the solvent
under reduced pressure. Chromatograph the residue over silica gel,
eluting with hexanes/ethyl acetate, to afford the title compound
(3.54 g, 88%). MS (ES+): 245 (M+H).
Step 3. Preparation of
8-bromo-9-methyl-5-oxo-2.3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid isopropyl ester
##STR00163##
[0480] Prepare the titled compound by following the procedure as
essentially described for the preparation of isopropyl
7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5
tetrahydrobenzo[b]azepine-1-carboxylate (Example 3, Steps 5 to 8)
by replacing methyl 2-amino-5-methyl-4-trifluoromethylbenzoate with
methyl 2-amino-4-bromo-3-methylbenzoate in Step 5. MS (ES+): 341
(M+H).
Step 4. Preparation of 8,
9-dimethyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid isopropyl ester
##STR00164##
[0482] Add cesium carbonate (456 mg, 3.0 mmol), methyl boronic acid
(90 mg, 1.5 mmol) and
[1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II)
complex with dichloromethane (1:1) (82 mg, 0.1 mmol) to a solution
of
8-bromo-9-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid isopropyl ester (341 mg, 1.0 mmol) in dioxane (8 mL). Stir the
mixture under nitrogen at 110.degree. C. for 1 h and 30 min. Cool
down the mixture to room temperature and filter over Celite.RTM.
washing with ethyl acetate. Evaporate the solvent and purify the
crude by chromatography, eluting with hexane/ethyl acetate to
afford the title compound (239 mg, 87%). MS (ES+): 276 (M+H).
Step 5. Preparation of (S) isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8,9-dimethyl-
-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00165##
[0484] Prepare the titled compound by following the procedure as
essentially described for the preparation of (S)-tent-Butyl
5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-methyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
(Example 3, Steps 11-16) by replacing tert-butyl
7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carb-
oxylate with 8,
9-dimethyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid isopropyl ester in Step 11. MS (ES-): 569 (M-H).
Step 6. Preparation of (S) isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-8,9-
-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00166##
[0486] Prepare the titled compound by following the procedure as
essentially described for the preparation of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-9-m-
ethyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
(Example 53, Step 5) by replacing (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-9-methyl-8-t-
rifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with
(S) isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8,-
9-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate MS
(ES+): 585 (M+H).
Example 57
Synthesis of (S)-isopropyl
5-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol-5-yl-
]-amino}-8,9-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
##STR00167##
[0488] Add potassium carbonate (58 mg, 0.42 mmol) and
2-bromoethanol (0.038 mL, 0.53 mmol) to a solution of (S)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8,9-dimethyl-
-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate "(Example 56, Step
5) (120 mg, 0.21 mmol) in DMF (0.4 mL) at room temperature in a
tube. Seal the tube and stir the mixture at 50.degree. C. for 3 h.
Cool the mixture at room temperature and add water and ethyl
acetate. Separate the layers, dry the organic phase over anhydrous
Na.sub.2SO.sub.4, filter and remove the solvent under reduced
pressure. Purify the residue by flash chromatography, eluting with
hexane/ethyl acetate, to provide 58 mg (45%) of the title compound.
MS (ES+): 615 (M+H).
Example 58
Synthesis of
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-4-met-
hyl-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester
##STR00168##
[0489] Step 1. Preparation of methyl
6-amino-1-methyl-indan-5-carboxylate
##STR00169##
[0491] Add N-bromosuccinimide (1.87 g, 10.5 mmol) to methyl
6-amino-indan-5-carboxylate (1.82 g, 9.53 mmol) (Example 49, Step
3) in acetic acid (9.3 mL). Stir the mixture at room temperature
for 1 h. Pour the mixture into ice water and add ethyl acetate.
Separate the layers and wash the organic phase with saturated
NaHCO3 and brine and dry over sodium sulfate. Remove the solvent
under reduced pressure. Purify with silica gel cartiridge, eluting
with hexanes/ethyl acetate to afford methyl 5-amino-1-bromo-indan
carboxylate (2.45 g, 95%): MS (ES+): 271, 272 (M+H). Add methyl
boronic acid (1.6 g, 26.7 mmol), cesium fluoride (4.6 g, 30.22
mmol) and 1-bis(diphenylphosphinoferrocene)palladium chloride (727
mg, 0.89 mmol) to methyl 5-amino-1-bromo-indan carboxylate (2.40 g,
8.89 mmol) in dioxane (60 ml), and stir at 90.degree. C. for 12 h.
Partition between water and ethyl acetate. Extract with more ethyl
acetate and then combine the organic phases. Dry over sodium
sulfate and remove the solvent under reduced pressure. Purify with
silica gel cartiridge, eluting with hexanes/ethyl acetate to afford
the titled compound (1.73 g, 95%). MS (ES+): 206 (M+H).
Step 2. Preparation of
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-4-met-
hyl-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester
##STR00170##
[0493] The titled compound can be prepared in a manner analogous to
the procedure for the preparation of (+/-)-isopropyl
5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3-
,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 46, Steps 1
to 3) by replacing methyl-2-amino-4-chlorobenzoate with methyl
6-amino-1-methyl-indan-5-carboxylatein Example 46, Step 1.
Example 59
Synthesis of
(+/-)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-4-methyl-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxyl-
ic acid
##STR00171##
[0495] The title compound can be prepared in a mauler analogous to
the procedure set forth in preparation of
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester (Example 50) by replacing
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino)-2,3,6-
,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
isopropyl ester with
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-4-met-
hyl-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester (Example 58).
Example 60
Synthesis of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7-
,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
tert-butyl ester
##STR00172##
[0497] Prepare the title compound by following the procedure as
essentiatly described for the preparation of (S)-tert-Butyl
5-[(3,5-bistrifluoromethylbenzyl)-(2H-tetrazol-5-yl)amino]-7-methyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
(Example 3, steps 5 to 16) by replacing Methyl
2-amino-5-methyl-4-trifluoromethylbenzoate (Example 3, step 4) with
6-Amino-indan-5-carboxylic acid methyl ester (Example 49, step 3)
in Example 3, step 5. MS (ES-): 595 (M-H).
[0498] Examples 61 to 63 can be prepared following the procedures
described in Example 4 by replacing
5-[(3,5-bis-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino)-7-methyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid tert-butyl ester with
(S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7-
,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
tert-butyl ester (Example 60) in Example 4, Step 2, and ethyl
chloroformate by the appropriate chloroformate in Example 4, Step
3.
Example 61
Synthesis of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7-
,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
1-ethyl-propyl ester
##STR00173##
[0499] Example 62
Synthesis of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7-
,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
cyclopentyl ester
##STR00174##
[0500] Example 63
Synthesis of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7-
,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
1-ethyl-2-methyl-propyl ester
##STR00175##
[0501] Example 64
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-1,2,3,5,6,7,8,9-
-octahydro-5-aza-cyclohepta[f]inden-9-yl)-(2H-tetrazol-5-yl)-amine
##STR00176##
[0503] The title compound can be prepared by removing the tBOC of
(S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7-
,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
tert-butyl ester (Example 60) as essentially described in Example
4, Step 2, and then stirring
(S)-(3,5-bis-trifluoromethyl-benzyl)-(1,2,3,5,6,7,8,9-octahydro-5-aza-cyc-
lohepta[f]indene-9-yl)-(1H-tetrazol-5-yl)-amine with cyclopentane
carboxaldehyde (1-5 eq) in the presence of acetic acid (1-5 eq) and
sodium triacetoxyborohydride (1-5 eq) or sodium borohydride (1-5
eq).
Example 65
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-
-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid tert-butyl ester
##STR00177##
[0505] Prepare the title compound by essentially following the
procedure described in Example 3, Steps 5-17 for the preparation of
(S)-tort-Butyl
5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-met-
hyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
by replacing methyl 2-amino-5-methyl-4-trifluoromethylbenzoate
(Example 3, step 4) with 6-amino-indan-5-caboxylic acid methyl
ester (Example 49, Step 3) in Example 3, Step 5. MS (ES+): 611
(M+H)
Example 66
Synthesis of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid 1-ethyl-propyl ester
##STR00178##
[0507] The titled compound can be prepared in a manner analogous to
the procedure set forth in preparation of Example 50
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester by replacing isopropyl
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6-
,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylate with
(S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino)-4-methy-
l-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid 1-ethyl-propyl ester (Example 61).
Example 67
Synthesis of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid cyclopentyl ester
##STR00179##
[0509] The titled compound can be prepared in a manner analogous to
the procedure set forth in preparation of Example 50
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester by replacing isopropyl
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino)-2,3,6-
,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylate with
(S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino)-4-methy-
l-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid cyclopentyl ester (Example 62).
Example 68
Synthesis of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid 1-ethyl-2-methyl-propyl ester
##STR00180##
[0511] The titled compound can be prepared in a manner analogous to
the procedure set forth in preparation of Example 50
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester by replacing isopropyl
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6-
,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylate with
(S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-4-methy-
l-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid 1-ethyl-2-methyl-propyl ester (Example 63).
[0512] Examples 69 to 70 can be prepared following the procedures
described in Example 3, Steps 18-19 by replacing (S)-tert-butyl
5[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-meth-
yl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
with
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid tert-butyl ester (Example 65) in Example 3, Step 18, and using
the corresponding aldehyde in Example 3, Step 19.
Example 69
Synthesis
(S)-4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-
-5-yl)-amino]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]inden-5-ylmethyl-
}-cyclohexanecarboxylic acid
##STR00181##
[0513] Example 70
Synthesis of
(S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]inden-5-yl}-3,3-dimethyl--
pentanoic acid
##STR00182##
[0514] Example 71
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-1,2,3,5,6,7,8,9-
-octahydro-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amin-
e
##STR00183##
[0516] Prepare the title compound by essentially following the
procedure described in Example 3, Steps 18-19 by replacing
(S)-tert-butyl
5[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-meth-
yl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
with
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid tert-butyl ester (Example 65) in Example 3, Step 18. MS (ES+):
593 (M+H).
Example 72
Synthesis of
9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-ethyl-2H-tetrazol-5-yl)-amino]-2,3-
,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
isopropyl ester
##STR00184##
[0518] The titled compound can be prepared in a manner analogous to
the procedure set forth in preparation of Example 50,
(+/-)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester by replacing methanol with ethanol.
Example 73
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-3,5,6,7,8,9-hex-
ahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-
-amine
##STR00185##
[0519] Step1 . Preparation of
1,3-Dihydro-isobenzofuran-5-ylamine
##STR00186##
[0521] To a solution of 1,3-dihydro-isobenzofuran (83.2 mmol) in
sulfuric acid (75 mL), cooled in an ice bath, add a solution of
potassium nitrate (83.2 mmol) in sulfuric acid (25 mL) dropwise.
After stirring for 30 min, pour the reaction mixture over ice and
collect the resulting precipitate on a glass frit. Wash the
precipitate with water (200 mL) and dry under vacuum. Dissolve the
precipitate in ethanol (250 mL) and add tin chloride dihydrate
(273.6 mmol). After heating at 70.degree. C. for 2 h, dilute with
water (200 mL), cool to room temperature, and neutralize the
reaction with 5 N NaOH. Extract the mixture with ethyl acetate
(3.times.200 mL) and dry the organic portion over sodium sulfate.
Remove the solvent in vacuo to afford the title compound as a tan
solid. .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 3.50 (bs, 2H),
5.02 (s, 4H), 6.56 (d, J=2.4 Hz, 1H), 6.60 (dd, J=2.4, 8.0 Hz, 1H),
7.01 (d, J=8.0 Hz, 1H).
Step 2. Preparation of
6-Iodo-1,3-dihydro-isobenzofuran-5-ylamine
##STR00187##
[0523] Dropwise, add a 1.0 M solution of iodine monochloride (64
mmol) to a solution of 1,3-dihydro-isobenzofuran-5-ylamine (64
mmol) in dichloromethane (200 mL), methanol (50 mL) and sodium
bicarbonate (96 mmol). After stirring for 1 h, quench the reaction
with aqueous sodium metabisulfite (100 mL). Separate the organic
phase and wash the aqueous with dichloromethane (2.times.100 mL).
Combine the organics and dry over sodium sulfate. Filter the
reaction and remove solvent under vacuum. Chromatograph (0-20%
ethyl acetate/hexane) the crude mixture over silica gel to give the
title compound as a tan solid. .sup.1H NMR (CDCl.sub.3, 400 MHz):
.quadrature. 4.10 (bs, 2H), 4.97 (s, 4H), 6.63 (s, 1H), 7.49 (s,
1H).
Step 3. Preparation of
6-Amino-1,3-dihydro-isobenzofuran-5-carboxylic acid methyl
ester
##STR00188##
[0525] Add palladium (II) acetate (2.8 mmol),
1,1-bis(diphenylphosphino)ferrocene (2.8 mmol), potassium carbonate
(86.1 mmol), and triethyl amine (28.7 trump to a solution of
6-iodo-1,3-dihydro-isobenzofuran-5-ylamine (28.7 mmol) in
acetonitrile (150 mL) and methanol (75 mL). Using a balloon of
carbon monoxide, vacuum purge the reaction mixture several times,
then heat to 70.degree. C. After heating under a balloon of carbon
monoxide for 1.5 h, cool the reaction to room temperature. Dilute
the reaction with ethyl acetate (500 mL), wash with water
(3.times.100 mL), followed by brine. Dry the organic phase over
sodium sulfate, filter, and remove the solvent under vacuum.
Chromatograph the product over silica gel, eluting with ethyl
acetate/hexane (5-35%) to provide the title compound as an off
white solid. .sup.1H NMR (CDCl.sub.3, 400 MHz) .quadrature. 3.85
(s, 3H), 4.97 (s, 4H), 6.54 (s, 1H), 7.71 (s, 1H).
Step 4. Preparation of
(S)-9-(3,5-Bis-trifluoromethyl-benzylamino)-1,3,6,7,8,9-hexahydro-2-oxa-5-
-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester
##STR00189##
[0527] Prepare the titled compound by following the procedure as
essentially described in the synthesis of (S) tert-butyl
5-(3,5-Bistrifluoromethylbenzylamino)-(7-methyl-8-trifluoromethyl-2,3,4,5-
-tetrahydrobenzo[b]azepine-1-carboxylate Example 3, Steps 5 to 14
and substituting methyl 2-amino-5-methyl-4-trifluoromethylbenzoate
with 6-amino-1,3-dihydro-isobenzofuran-5-carboxylic acid methyl
ester in Example 3, Step S. MS (ES+): 531.2 (M+H).
Step 5. Preparation of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-cyano-amino)-1,3,6,7,8,9-hexahydr-
o-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl
ester
##STR00190##
[0529] To a solution of
(S)-9-(3,5-bis-trifluoromethyl-benzylamino)-1,3,6,7,8,9-hexahydro-2-oxa-5-
-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.75
mmol) in tetrahydrofuran (7 mL) and diisopropyl ethylamine (5.25
mmol), add cyanogenbromide (5.25 mmol) and heat to 65.degree. C.
After stirring overnight, cool to room temperature and dilute with
ethyl acetate (10 mL). Wash the organic portion with water (10 mL),
followed by brine (10 mL). Dry the organic portion over sodium
sulfate, filter, and remove solvent under vacuum. Chromatograph the
product over silica gel, eluting with ethyl acetate/hexane (5-35%)
to afford the title compound as an oil. MS (ES+): 554.2 (M-H).
Step 6. Preparation of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-1,3,6,7-
,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid
tert-butyl ester
##STR00191##
[0531] To a solution of
(S)-9-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-1,3,6,7,8,9-hexahydr-
o-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl
ester (1.61 mmol) in toluene (10 mL), add azidotributyltin (3.22
mmol) and heat to 100.degree. C. After stirring for 12 h, cool the
reaction to room temperature and quench with methanol (1 mL).
Dilute the reaction mixture with ethyl acetate (100 mL) and wash
with aqueous sodium fluoride (50 mL) and brine (50 mL). Dry the
organic portion over sodium sulfate, filter, and remove the solvent
under vacuum. Chromatograph the product over silica gel, eluting
with methanol/dichloromethane (1-5%) to afford the title compound
as a colorless foam. MS (ES+): 597.3 (M-H).
Step 7. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-az-
a-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
##STR00192##
[0533] To a solution of
(S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-1,3,6,7-
,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid
tert-butyl ester (1.17 mmol) in dichloromethane (20 mL), add
methanol (5.85 mmol) and triphenylphosphine (3.51 mmol). To this
solution, add diethyl azodicarboxylate (3.51 mmol) dropwise at room
temperature. After stirring for 12 h, remove the solvent under
vacuum and chromatograph the intermediate over silica gel eluting
with ethyl acetate/hexane (2-35%) to afford
(S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-
)-amino)-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxyli-
c acid tert-butyl ester as a colorless oil. To this intermediate in
dichloromethane (5 mL), add TFA (2 mL). After stirring for 2 h,
quench the reaction with aqueous sodium carbonate (5 mL) and dilute
with dichloromethane (10 mL). Separate the organic portion, dry
over sodium sulfate, filter, and remove the solvent under vacuum.
This provides the title compound as a crude oil that is further
used without purification.
Step 8. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-3,5,6,7,8,9-hex-
ahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-
-amine
##STR00193##
[0535] To a solution of
(S)-(3,5-bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-az-
a-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.195
mmol) dichloroethane (5 mL), add cyclopentanecarbaldehyde (0.780
mmol) along with a catalytic amount of acetic acid. Add sodium
triacetoxyborohydride (0.975 mmol) and stir at room temperature
overnight. Quench the reaction with aqueous sodium carbonate (5 mL)
and dilute with dichloromethane (5 mL). Dry the organic portion,
filter, and remove the solvent under vacuum. Chromatograph the
product over silica gel eluting With ethyl acetate/hexane (5-35%)
to afford the title compound as a colorless foam. MS (ES+): 595.2
(M+H).
Example 74
Synthesis of
(S)-5-{9-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl}-3,3-dimethy-
l-pentanoic acid
##STR00194##
[0536] Step 1: Preparation of 3,3-Dimethylpentanedioic acid
monomethyl ester
##STR00195##
[0538] Combine 3,3-dimethylglutaric anhydride (1.00 g, 7.03 mmol)
and sodium methoxide (2.5 mL, 14.1 mmol, 30 wt % in methanol) in
methanol (20 mL) and heat at reflux for 3 h. Cool the reaction to
room temperature and pour into ice water (100 mL). Add diethyl
ether (25 mL) and adjust the pH of the mixture to pH=2 with 2 N HCl
(10 mL) and separate the layers. Extract the aqueous layer with
diethyl ether (25 mL) and combine the organic layers, dry over
sodium sulfate, filter and remove the solvent under reduced
pressure to afford 3,3-dimethylpentanedioic acid monomethyl ester
as a colorless oil (0.827 g, 68%): .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 1.14 (s, 6H), 2.46 (s, 2H), 2.48 (s, 2H), 3.67 (s,
3H), 10.9 (br s, 1H); APCI MS (Negative mode) m/z 173
[C.sub.8H.sub.14O.sub.4-H].sup.-.
Step 2. Preparation of 3,3-Dimethyl-5-oxo-pentanoic acid methyl
ester
##STR00196##
[0540] Use the procedure as describe in Journal of Fluorine
Chemistry, (1992), 56, 373-383, to prepare the titled compound from
3,3-dimethylpentanedioic acid monomethyl ester.
Step 3. Preparation of
(S)-5-(9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl)
-3,3-dimethyl-pentanoic acid methyl ester
##STR00197##
[0542] To a solution of
(S)-(3,5-bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-az-
a-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.195
mmol) in dichloroethane (5 mL), add 3,3-dimethyl-5-oxo-pentanoic
acid methyl ester (0.585 mmol) along with a catalytic amount of
acetic acid. To this stirred solution add sodium
triacetoxyborohydride (0.975 mmol). After stirring for 12 h, quench
the reaction with aqueous sodium carbonate (5 mL) and dilute with
dichloromethane (5 mL). Dry the organic portion, filter, and remove
the solvent under vacuum. Chromatograph the product over silica
gel, eluting with ethyl acetate/hexane (2-35%) to afford the title
compound as a colorless oil. MS (ES+): 655.2 (M+H).
Step 4. Preparation of
(S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino)-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl)-3,3-dimeth-
yl-pentanoic acid
##STR00198##
[0544] To a solution of
(S)-5-{9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino)-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl)-3,3-dimeth-
yl-pentanoic acid methyl ester (0.113 mmol) in methanol (3 mL), add
5 N NaOH (2 mL) and heat to 60.degree. C. After stirring for 6 h,
cool the reaction to room temperature, dilute with water (10 mL)
and neutralize with 5 M HCl. Extract the organics with ethyl
acetate (2.times.20 mL). Combine the organic portions, dry over
sodium sulfate, filter, and remove the solvent under vacuum.
Chromatograph the product over silica gel, eluting with ethyl
acetate/hexane (20-60%) to afford the title compound as a colorless
foam. MS (ES+): 641.3 (M+H).
Example 75
Synthesis of
(S)-5-(9-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetraz-
ol-5-yl]-amino}-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl)-
-3,3-dimethyl-pentanoic acid
##STR00199##
[0545] Step 1. Preparation of
(S)-9-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-tert-butoxy-ethyl)-2H-tetra-
zol-5-yl]-amino}-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-c-
arboxylic acid tert-butyl ester
##STR00200##
[0547] To a solution of
(S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-1,3,6,7-
,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid
tert-butyl ester (Example 73, Step 6) (0.167 mmol) in
dichloromethane (20 mL), add 2-tert-butoxy-ethanol (0.835 mmol) and
triphenylphosphine (0.501 mmol). To this solution, add diethyl
azodicarboxylate (0.501 mmol) dropwise at room temperature. After
stirring for 12 h, remove the solvent under vacuum. Chromatograph
the intermediate over silica gel, eluting with ethyl acetate/hexane
(2-35%) to afford the title compound as an oil. MS (ES+): 699
(M+14).
Step 2.
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro--
1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-amino]-tetrazol-2-yl}-ethanol
##STR00201##
[0549] Dissolve
(S)-9-{(3,5-bis-trifluoromethyl-benzyl)-[2-(2-tert-butoxy-ethyl)-2H-tetra-
zol-5-yl]-amino}-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-c-
arboxylic acid tert-butyl ester (0.140 mmol) in 4 M hydrochloric
acid/dioxane (10 mL). After stirring overnight at room temperature,
neutralize the reaction with aqueous sodium carbonate and dilute
with ethyl acetate (20 mL). Dry the organic portion over sodium
sulfate, filter, and remove the solvent under vacuum. Chromatograph
the product over silica gel eluting with ethyl acetate/hexane
(10-40%) to provide the title compound as an oil.
Step 3. Preparation of
(S)-5-(9-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetraz-
ol-5-yl]-amino}-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl)-
-3,3-dimethyl-pentanoic acid
##STR00202##
[0551] Prepare the title compound by following the procedure as
essentially described for the synthesis of
(S)-5-{9-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl}-3,3-dimeth-
yl-pentanoic acid (Example 74, Steps 1-4), starting with
2-{5-[(3,5-bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5--
aza-cyclohepta[f]inden-9-yl)-amino]-tetrazol-2-yl)-ethanol. MS
(ES+): 671.3 (M.sub.+H).
Example 76
Synthesis of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester
##STR00203##
[0553] Prepare the title compound by following the procedure as
essentially described in the synthesis of (+/-)-isopropyl
5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-bro-
mo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 1),
starling with 6-amino-1,3-dihydro-isobenzofuran-5-carboxylic acid
methyl ester (Example 73, Step 3). MS(ES+): 599 (M+H)
Example 77
Synthesis of
(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-2,3,4,5,7,8,9,10-oc-
tahydro-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-
yl)-amine
##STR00204##
[0554] Step 1. Preparation of
5,6,7,8-Tetrahydro-naphthalen-2-ylamine
##STR00205##
[0556] To a stirred solution of tetralin (0.30 mol), cooled in an
ice bath, add a mixture of sulfuric acid (25 mL) and nitric acid
(0.60 mol) dropwise over 30 minutes. After stirring an additional
30 minutes at 0.degree. C., pour the mixture over ice and extract
the organics with dichloromethane (3.times.200 mL). Wash the
combined organic portions with sodium carbonate (200 mL) and dry
over sodium sulfate. Filter, remove the solvent under vacuum, and
chromatograph the product over silica gel, eluting with ethyl
acetate/hexane (0-20%). This provides the nitro intermediate as an
oil. Dissolve this intermediate in ethanol (200 mL) and add RaNi
(catalytic). Vacuum purge the mixture several times with hydrogen.
After stirring 48 h at room temperature under a balloon of
hydrogen, filter the mixture through Celite.RTM.. Remove the
solvent under vacuum and chromatograph the product over silica gel
eluting with ethyl acetate/hexane (0-25%), to afford the title
compound as an oil. .sup.1H NMR (CDCl.sub.3, 400 MHz) .quadrature.
1.80 (m, 4H), 2.68 (m, 4H), 3.39 (bs, 2H), 6.44 (m, 1H), 6.49 (m,
1H), 6.87 (d, J=8.0 Hz, 1H).
Step 2. Preparation of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,4,5,7,8,9,10-octahydro-naphtho[2,3-b]azepine-1-carboxylic
acid tert-butyl ester
##STR00206##
[0558] Prepare the title compound by following the procedure as
essentially described for the synthesis of
(S)-(3,5-bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-3,5,6,7,8,9-hex-
ahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-
-amine starting with 5,6,7,8-tetrahydro-naphthalen-2-ylamine.
Step 3. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(2,3,4,5-
,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-amine
##STR00207##
[0560] To a solution of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,4,5,7,8,9,10-octahydro-naphtho[2,3-b]azepine-1-carboxylic
acid tert-butyl ester (0.67 mmol) in dichloromethane (18 mL) add
trifluoroacetic acid (2 mL). After stirring at room temperature for
1 h, quench with concentrated sodium carbonate (10 mL) and dilute
with dichloromethane (20 mL) and water (20 mL). Seperate the
organic phase and wash the aqueous with dichloromethane (2.times.10
mL). Dry the combined organics over sodium sulfate, filter, and
remove solvent under vacuum. Chromatograph the product over silica
gel eluting with ethyl acetate/hexane (5-30%) to afford the title
compound as a colorless foam. MS(ES+): 525 (M+H).
Step 4. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-2,3,4,5,7,8,9,1-
0-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amin-
e
##STR00208##
[0562] Prepare the title compound by following the procedure as
essentially described for the synthesis of
(S)-(3,5-bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-3,5,6,7,8,9-hex-
ahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-
-amine in starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(2,3,4,5-
,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-amine. MS (ES+):
607.2 (M+H).
Example 78
Synthesis of
5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,-
3,4,5,7,8,9,10-octahydro-naphtho[2,3-b]azepine-1-carboxylic acid
isopropyl ester
##STR00209##
[0564] The title compound can be prepared using procedures
analogous to those used in the synthesis of (+/-)-isopropyl
5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-bro-
mo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 1),
starting with 3-amino-5,6,7,8-tetrahydro-naphthalene-2-carboxylic
acid methyl ester.
3-amino-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl
ester could be prepared using procedures as described in Example
73, Steps 2 and 3 starting with
5,6,7,8-tetrahydro-naphthalen-2-ylamine.
Example 79
Synthesis of
(S)-9-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol--
5-yl]-amino}-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxyl-
ic acid isopropyl ester
##STR00210##
[0565] Step 1. Preparation of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7-
,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
isopropyl ester
##STR00211##
[0567] Prepare the title compound by essentially following the
procedure described in Example 3, Step 11-16, by replacing
tent-butyl-7-methyl-5-oxo-8-trifluoromethyl-2,3-4,5-tetrahydrobenzo[b]aze-
pine-1-carboxylate with
9-oxo-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester (Example 49, Step 4) in Example 3, Step 11. MS
(ES-): 581 (M-H).
Step 2. Preparation of
(S)-9-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol--
5-yl]-amino}-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxyl-
ic acid isopropyl ester
##STR00212##
[0569] Add potassium carbonate (40 mg, 0.29 mmol) and bromoethanol
(0.018 mL, 0.26 mmol) to a solution of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7-
,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
isopropyl ester (50 mg, 0.086 mmol) in dimethylformamide (0.3 mL).
Stir at room temperature for 18 hrs in a sealed tube. Then add
bromoethanol (0.018 mL, 0.26 mmol) and stir for 2 hrs. Add a 1N
solution of hydrochloric acid and extract with dichloromethane. Dry
the organic phase over anhydrous sodium sulfate, filter and
concentrate in vacuo. Purify the residue using silica gel
cartridge, eluting with ethyl acetate/hexanes to afford the title
compound (26 mg, 49%). MS (ES+): 627 (M+H).
Example 80
Synthesis of
(R)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester
##STR00213##
[0571] The title compound is obtained by chiral resolution of
Example 50 on a Chiralpak AD (20.times.250 mm), flow rate 10-12
mL/min (15 min). Gradient: 10-30% propan-2-ol in hexane 0.05% TFA,
R.sub.f=5.2 min, wavelength: 215.16, e.e. >98%. MS (ES+): 597
(M+H).
Example 81
Synthesis of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid isopropyl ester
##STR00214##
[0573] The title compound is obtained by chiral resolution of
Example 50 on a Chiralpak AD (20.times.250 mm), flow rate 10-12
mL/min (15 min). Gradient: 10-30% propan-2-ol in hexane 0.05% TFA,
R.sub.f=11.2 min, wavelength: 215.16, e.e. >98%. MS (ES+): 597
(M+H).
Example 82
Synthesis of
(S)-6-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol--
5-yl]-amino}-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carbox-
ylic acid isopropyl ester
##STR00215##
[0575] Prepare the title compound by essentially following the
procedure described in Example 79, Step 2 by replacing
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7-
,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
isopropyl ester with
(S)-6-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino)-4-methy-
l-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic
acid isopropyl ester (Example 55, Step 5) in Example 79, Step 2. MS
(ES+): 641 (M+H).
Example 83
Synthesis of
(S)-6-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol--
5-yl]-amino}-4-methyl-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene--
10-carboxylic acid isopropyl ester
##STR00216##
[0576] Step 1. Preparation of
(S)-6-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7-
,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid
isopropyl ester
##STR00217##
[0578] Prepare the title compound by essentially following the
procedure described in Example 3, Step 11-16, by replacing
tert-butyl-7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]aze-
pine-1-carboxylate with
6-Oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic
acid isopropyl ester (Example 48, Step 6) in Example 3, Step 11. MS
(ES+): 581 (M-H).
Step 2. Preparation of
(S)-6-{(3,5-Bis-trifluoromethyl-benzyl)-[2-(2-hydroxy-ethyl)-2H-tetrazol--
5-yl]-amino}-4-methyl-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene--
10-carboxylic acid isopropyl ester
##STR00218##
[0580] Prepare the title compound by essentially following the
procedure described in Example 79, Step 2 by replacing
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7-
,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid
isopropyl ester with
(S)-6-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-2,3,6,7-
,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid
isopropyl ester in Example 79, Step 2. MS (ES+): 627 (M+H).
Example 84
Synthesis of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid 2-methoxycarbonyl-2-methyl-propyl ester
##STR00219##
[0581] Step 1. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(1,2,3,5-
,6,7,8,9-octahydro-5-aza-cyclohepta[f]inden-9-yl)-amine
##STR00220##
[0583] Prepare the title compound by essentially following the
procedure described in Example 3, Step 18, by replacing
(S)-tert-Butyl
5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-met-
hyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
with
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid tert-butyl ester (Example 65) in Example 3, Step 18. MS (ES+):
511 (M+H).
Step 2. Preparation of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid 2-methoxycarbonyl-2-methyl-propyl ester
##STR00221##
[0585] Add a 20% solution of phosgene in toluene (0.43 mL, 0.78
mmol) to a mixture of 3-hydroxy-2,2-dimethyl-propionic acid methyl
ester (0.12 mL, 0.96 mmol) and diisopropylethylamine (0.16 mL, 0.96
mmol) in dichloromethane (1.8 mL) at 0.degree. C. under nitrogen.
Stir the mixture at 0.degree. C. for 10 minutes, then at room
temperature for 1 h. To the former solution add a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(1,2,3,5-
,6,7,8,9-octahydro-5-aza-cyclohepta[f]inden-9-yl)-amine (80 mg,
0.16 mmol) in dichloromethane (1.8 mL) followed by pyridine (0.064
mL, 0.78 mmol). Stir the mixture at room temperature for 1 h.
Dilute with dichloromethane. Wash with HCl 1 M and water. Dry
organic layers over anhydrous sodium sulphate and evaporate the
solvent. Purify the residue by chromatography (elution with
hexane/ethyl acetate) to afford the title compound (78 mg, 73%). MS
(ES+): 669 (M+H).
Example 85
Synthesis of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid 2-carboxy-2-methyl-propyl ester
##STR00222##
[0587] Add aqueous 5 M NaOH (2.4 mL, 12 mind) to a solution of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic
acid 2-methoxycarbonyl-2-methyl-propyl ester (86 mg, 0.13 mmol) in
metanol (3.4 mL). Heat the mixture at 60.degree. C. for 1 h. Cool
down to room temperature. Dilute with water and neutralize with 2 M
HCl. Extract aqueous phase with ethyl acetate. Dry organic layers
with anhydrous sodium sulphate and evaporate the solvent. Purify
the residue by chromatography (elution with
dichloromethane/methanol) to afford the title compound (62 mg,
73%). MS (ES+): 655 (M+H).
Example 86
Synthesis of
(S)-1-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-ami-
no]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-3-f-
uran-2-ylmethoxy)-propan-2-one
##STR00223##
[0588] Step 1. Preparation of
(S)-1-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-ami-
no]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-3-f-
uran-2-ylmethoxy)-propan-2-ol
##STR00224##
[0590] Add furfuryl glycidyl ether (0.068 mL, 0.50 mmol) followed
by Ytterbium (III) trifluoromethanesulfonate hydrate (0.012 g, 0.02
mmol) to a solution of
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]amine
(Example 3, Step 18) (0.055 g, 0.10 mmol) in acetonitrile (1 mL).
After, stirring at room temperature for 3 days remove the solvent
under vacuum. Dilute with ethyl acetate (20 mL), wash with water,
brine, dry and concentrate under reduced pressure. Purify by silica
gel column (gradient eluent, 0-50% ethyl acetate in hexane) to
obtain the title compound (0.043 g, 61%). mass spectrum: MS (ES+):
707 (M+H).
Step 2. Preparation of
(S)-1-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-ami-
no]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-3-f-
uran-2-ylmethoxy)-propan-2-one
##STR00225##
[0592] To a mixture of pyridinium chlorochromate (0.037 g, 0.17
mmol), sodium acetate (0.014 g, 0.17 mmol) and 4 A0 molecular
sieves (0.10 g) in dichloromethane (1 mL) at room temperature, was
added
(S)-1-{5-[(3,5-bis-tifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amin-
o)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-3-fu-
ran-2-ylmethoxy)-propan-2-ol (0.041 g, 0.058 mmol) in
dicholormethane (1 mL). Allow the reaction mixture to stir at room
temperature for 60 min and dilute with ether. Filter and remove the
solvent under reduced pressure. Purify the residue by flash
chromatography, eluting with hexanes/ethyl acetate (gradient
eluent, 0-30% ethyl acetate in hexane), to provide the title
compound (0.026 g, 65%). MS (ES+): 705 (M+H).
Example 87
Synthesis of
2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]--
7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-1-pheny-
l-ethanol and
2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]--
7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-2-pheny-
l-ethanol
##STR00226##
[0594] Prepare the title compound by essentially following the
procedure described in Example 86, Step 1, using,
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
(Example 3, Step 18)(0.055 g, 0.10 mmol), styrene oxide (0.057 mL,
0.50 mmol) and Ytterbium (III) trifluoromethanesulfonate hydrate
(0.012 g, 0.02 mmol) to give the mixture of two separable
regioisomers by column. Purify by silica gel column (gradient
eluent, 0-40% ethyl acetate in hexane) to provide isomer-1:
2-{5-((3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]--
7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-1-pheny-
l-ethanol (0.015 g, 22%). MS (ES+): 673 (M+H), and isomer-2:
2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-amino]--
7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-2-pheny-
l-ethanol (0.012 g, 18%). MS (ES+): 673 (M+H).
##STR00227##
Example 88
Synthesis of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-benzoic acid methyl ester
##STR00228##
[0596] Add 4-formylbenzoic acid methyl ester (133 mg, 0.815 mmol)
to a solution of
(S)-(3,5-bis-trifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-
-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
(Example 3, Step 18) (150 mg, 0.272 mmol) in acetic acid (1 mL) and
1,2-dichloroethane (10 mL) at room temperature under nitrogen and
stir for 2 h. Add sodium triacetoxy borohydride (231 mg, 1.08 mmol)
and stir for 3 h. Dilute the mixture with methylene chloride (30
mL) and wash with saturated aqueous sodium bicarbonate solution
(2.times.10 mL). Extract the combined aqueous washes with methylene
chloride (20 mL) and wash the combined organic extracts with brined
(20 mL) and dry over anhydrous sodium sulfate. Remove the solvents
under reduced pressure and purify the residue by column
chromatography on silica gel, eluting with ethyl acetate/hexanes
(1:2), to provide the title compound as a white solid (100 mg,
52%): mp 71-74.degree. C. dec; .sup.1H NMR (CDCl3, 300 MHz) .delta.
1.61-1.65 (m, 2H), 2.02-2.22 (m, 2H), 2.29 (s, 3H), 2.71-2.80 (m,
1H), 3.02-3.11 (m, 1H), 3.89 (s, 3H), 4.18 (s, 3H), 4.22-4.40 (m,
2H), 4.89-5.10 (m, 2H), 5.55-5.60 (m, 1H), 6.90 (s, 1H), 7.21 (s,
1H), 7.45-7.49 (m, 2H), 7.65-7.70 (m, 2H), 7.75-7.80 (m, 1H),
7.97-7.81 (m, 2H); ESI MS m/z 701 [C32H29F9N6O2+H]+; HPLC 98.3%, tR
19.6 min.
Example 89
Synthesis of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-benzoic acid
##STR00229##
[0598] Add 5 N sodium hydroxide solution (0.5 mL) to a solution of
(S)-4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo{b]azepin-1-ylmeth-
yl}-benzoic acid methyl ester (70 mg, 0.100 mmol) in methanol (1
mL) and heat at 60.degree. C. for 4 h. After the reaction cools to
room temperature, acidify to pH 4 with 2 N hydrochloric acid
solution and extract the aqueous mixture with ethyl acetate
(3.times.10 mL). Wash the organic layer with water and brine (10 mL
each). Dry the organic layer over anhydrous sodium sulfate, filter
and remove the solvent under reduced pressure to provide the title
compound as a white solid (62 mg, 90%). mp 95-98.degree. C.;
.sup.1H NMR (CDCl3, 300 MHz) .delta. 1.63-1.71 (m, 2H), 1.99-2.05
(m, 2H), 2.29 (s, 3H), 2.75-2.84 (m, 1H), 2.98-3.10 (m, 1H), 4.15
(s, 3H), 4.31-4.50 (m, 2H), 4.82-5.12 (m, 2H), 5.51-5.60 (m, 1H),
6.95 (s, 1H), 7.31-7.37 (m, 1H), 7.51-7.60 (m, 2H), 7.65 -7.70 (m,
2H), 7.78-7.82 (m, 1H), 8.10-8.17 (m, 2H); ESI MS m/z 687
[C31H27F9N6O2+H]+; HPLC 98.1%, tR 17.0 min.
Example 90
Synthesis of
(S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-benzoic acid methyl ester
##STR00230##
[0600] Add 3-formylbenzoic acid methyl ester (133 mg, 0.815 mmol)
to a solution of
(S)-(3,5-bis-trifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-
-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
(Example 3, Step 18) (150 mg, 0.272 mmol) in acetic acid (1 mL) and
1,2-dichloroethane (10 mL) at room temperature under nitrogen and
stir for 2 h. Add sodium triacetoxy borohydride (231 mg, 1.08 mmol)
and stir for 3 h. Dilute the mixture with methylene chloride (30
mL) and wash with saturated aqueous sodium bicarbonate solution
(2.times.10 mL). Extract the combined aqueous washes with methylene
chloride (20 mL) and wash the combined organic extracts with brined
(20 mL) and dry over anhydrous sodium sulfate. Remove the solvents
under reduced pressure and purify the residue by column
chromatography on silica gel, eluting with ethyl acetate/hexanes
(1:2), to provide the title compound as a white solid (101 mg,
53%): mp 62-65.degree. C. dec; .sup.1H NMR (CDCl3, 300 MHz) .delta.
1.50-1.70 (m, 2H), 2.07-2.25 (m, 2H), 2.29 (s, 3H), 2.73-2.85 (m,
1H), 2.95-3.09 (m, 1H), 3.89 (s, 3H), 4.18 (s, 3H), 4.31-4.40 (m,
2H), 4.81-5.02 (m, 2H), 6.93 (s, 1H), 7.31-7.42 (m, 2H), 7.55-7.63
(m, 4H), 7.79-7.82 (m, 1H), 7.89-7.92 (m, 1H), 8.10 (s, 1H); ESI MS
in/z 701 [C32H29F9N6O2+H]+; HPLC 97.6%, tR 19.7 min.
Example 91
Synthesis of
(S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-benzoic acid
##STR00231##
[0602] Add 5 N sodium hydroxide solution (0.5 mL) to a solution of
(S)-3-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-benzoic acid methyl ester (70 mg, 0.100 mmol) in methanol (1
mL) and heat at 60.degree. C. for 4 h. After the reaction cools to
room temperature, acidify to pH 4 with 2 N hydrochloric acid
solution and extract the aqueous mixture with ethyl acetate
(3.times.10 mL). Wash the organic layer with water and brine (10 mL
each). Dry the organic layer over anhydrous sodium sulfate, filter
and remove the solvent under reduced pressure to provide the title
compound as a white solid (67 mg, >99%): mp 83-86.degree. C.;
.sup.1H NMR (CDCl3, 300 MHz) .delta. 1.51-1.71 (m, 2H), 2.00-2.12
(m, 2H), 2.29 (s, 3H), 2.78-2.85 (m, 1H), 3.02-3.09 (m, 1H), 4.17
(s, 3H), 4.31-4.43 (m, 2H), 4.86-5.16 (m, 2H), 5.51-5.60 (m, 1H),
6.98 (s, 1H), 7.25 (s, 1H), 7.43-7.49 (m, 1H), 7.60-7.82 (m, 4H),
7.99-8.03 (m, 1H), 8.15 (s, 1H); ESI MS m/z 687 [C31H27F9N6O2+H]+;
HPLC 97.6%, tR 17.0 min.
Example 92
Synthesis of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-be-
nzoic acid
##STR00232##
[0603] Step 1. Preparation of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-be-
nzoic acid methyl ester
##STR00233##
[0605] Combine tris(dibenzylideneacetone)dipalladium (0) (16 mg,
0.018 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl
(14 mg, 0.036 mmol) and sodium t-butoxide (43 mg, 0.452 mmol) in
toluene (5 mL) and purge this suspension with nitrogen at room
temperature for 5 min. Add
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-met-
hyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
(Example 3, Step 18) (100 mg, 0.181 mmol) followed by
methyl-4-iodobenzoate (47 mg, 0.181 mmol) and heat this mixture at
100.degree. C. under nitrogen for 2 h. Cool the mixture to room
temperature, dilute with dichloromethane, filter through
Celite.RTM., and concentrate under reduced pressure. Chromatograph
the residue over silica gel, eluting with hexanes/ethyl acetate
(20:1 to 1:2), to provide the title compound as an off-white solid
(50 mg, 40%). mp 101-105.degree. C.; TLC Rf 0.50 (3:1 hexanes/ethyl
acetate); 1H NMR (CDCl3, 300 MHz) .delta. 1.72-1.89 (m, 1H),
2.00-2.32 (m, 3H), 2.29 (s, 3H), 3.33-3.40 (m, 1H), 3.89 (s, 3H),
3.99-4.09 (m, 1H), 4.19 (s, 3H), 4.69-5.33 (m, 3H), 6.68-6.73 (m,
2H), 7.15 (s, 1H), 7.45 (s, 1H), 7.62-7.72 (m, 2H), 7.79 (s, 1H),
7.96-8.05 (m, 2H); ESI MS m/z 687 [C31H27F9N6O2+H]+.
Step 2. Preparation of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-be-
nzoic acid
##STR00234##
[0607] Add 5 N sodium hydroxide solution (0.5 mL) to a solution of
(S)-4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-be-
nzoic acid methyl ester (40 mg, 0.058 mmol) in methanol (1 mL) and
heat at 60.degree. C. for 4 h. After the reaction cools to room
temperature, acidify to pH 4 with 2 N hydrochloric acid solution
and extract the aqueous mixture with ethyl acetate (3.times.10 mL).
Wash the organic layer with water and brine (10 mL each). Dry the
organic layer over anhydrous sodium sulfate, filter and remove the
solvent under reduced pressure to provide the title compound as an
off-white solid (20 mg, 51%). mp 101-105.degree. C.; .sup.1H NMR
(CDCl3, 300 MHz) .delta. 1.75-1.91 (m, 1H), 2.05-2.36 (m, 3H), 2.29
(s, 3H), 3.35-3.43 (m, 1H) 3.99-4.09 (m, 1H), 4.19 (s, 3H),
4.70-5.35 (m, 3H), 6.70-6.75 (m, 2H), 7.20 (s, 1H), 7.47 (s, 1H),
7.63-7.72 (m, 2H), 7.80 (s, 1H), 7.96-8.10 (m, 2H); ESI MS m/z 673
[C30H25F9N6O2+H]+.
Example 93
Synthesis of
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-
-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cy-
clohexyl)-acetic acid methyl ester
##STR00235##
[0608] Step 1. Preparation of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-7-methyl-8-
-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-cathoxylic
acid tert-butyl ester
##STR00236##
[0610] To a solution of
(S)-5-(3,5-bis-trifluoromethyl-benzylamino)-7-methyl-8-trifluoromethyl-2,-
3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester
(Example 3, Step 14) (1.0 g, 1.75 mmol) and 4-dimethylaminopyridine
(25 mg, 0.21 mmol) in dry tetrahydrofuran (10 mL) at 0.degree. C.
under a nitrogen atmosphere, add diketene (0.147 mL, 1.93 mmol).
After stirring 1.5 h at 0.degree. C., remove the solvent under
reduced pressure. Purify the by flash chromatography, eluting with
hexanes/ethyl acetate (20:1 to 1:2), to provide the title compound
as an off-white solid (1.12 g, 97%). TLC Rf 0.40 (3:1 hexanes/ethyl
acetate); .sup.1H NMR (CDCl3, 300 MHz) .delta. 1.10-2.10 (m, 1311),
2.29 (s, 3H), 2.52 (s, 3H), 3.41-3.53 (m, 1H), 4.14-4.54 (m, 4H),
4.89-5.12 (m, 1H), 5.57-5.69 (m, 1H), 6.89 (s, 1H), 7.24-7.92 (m,
4H).
Step 2. Preparation of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-
-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid tert-butyl ester
##STR00237##
[0612] To a solution of compound
(S)-5-[(3,5-bis-trifluoromethyl-benzyl)-(3-oxo-butyryl)-amino]-7-methyl-8-
-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid tert-butyl ester (600 mg, 0.916 mmol) in methanol (5 mL) at
0.degree. C., add hydroxylamine hydrochloride (96 mg, 1.37 mmol)
and sodium acetate (3 mg, 0.046 mmol). Heat the reaction mixture
under reflux for 4 h. Cool and remove the solvents under reduced
pressure. Dilute the residue with ethyl acetate and brine. Separate
the layers and dry the organic phase over sodium sulfate, filter
and concentrate under reduced pressure. Purify the residue by flash
chromatography, eluting with hexanes/ethyl acetate (20:1 to 3:1) to
afford the title compound as an off-white solid (100 mg, 17%).
.sup.1H NMR (CDCl3, 300 MHz) .delta. 1.10-2.10 (m, 16H), 2.21 (s,
3H), 2.54 (s, 3H), 4.22-4.83 (m, 3H), 6.89-6.92 (m, 1H), 7.36-7.89
(m, 4H); ESI MS m/z 652 [C30H30F9N3O3+H]+.
Step 3. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-(7-methyl-8-
-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
##STR00238##
[0614] Add trifluoroacetic acid (10 mL) to a solution of
(S)-5-[(3,5-bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-
-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid tert-butyl ester (140 mg, 0.458 mmol) in methylene chloride (5
mL) at 0.degree. C. under nitrogen. Warm the mixture to room
temperature, stir for 4 h and pour the mixture into saturated
aqueous sodium bicarbonate solution (20 mL). Extract the mixture
with methylene chloride (20 mL) and wash the combined organic
extracts with brine (10 mL), dry over anhydrous sodium sulfate and
filter. Remove the solvent under reduced pressure to provide the
title compound as a colorless oil (90 mg, 76%), which is used in
the next step without purification: ESI MS m/z 552
[C25H22F9N3O+H]+.
Step 4. Preparation of
4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7--
methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cyc-
lohexyl)-acetic acid methyl ester
##STR00239##
[0616] Add (4-formyl-cyclohexyl)-acetic acid methyl ester (68 mg,
0.368 mmol) to a solution of
(S)-(3,5-bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-(7-methyl-8-
-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(80 mg, 0.122 mmol) in acetic acid (0.5 mL) and 1,2-dichloroethane
(5 mL) at room temperature under nitrogen and stir for 2 h. Add
sodium triacetoxy borohydride (103 mg, 0.488 mmol) and stir for 3
h. Dilute the mixture with methylene chloride (30 mL) and wash with
saturated aqueous sodium bicarbonate solution (2.times.10 mL).
Extract the combined aqueous washes with methylene chloride (20 mL)
and wash the combined organic extracts with brined (20 mL) and dry
over anhydrous sodium sulfate. Remove the solvents under reduced
pressure and purify the residue by column chromatography on silica
gel, eluting with ethyl acetate/hexanes (1:2), to provide the title
compound as a colorless semi-solid (73 mg, 85%). .sup.1H NMR
(CDCl3, 300 MHz) .delta. 0.72-2.34 (m, 21H), 2.60-2.65 (m, 1H),
2.82-2.90 (m, 1H), 3.00-3.10 (m, 2H), 3.89 (s, 3H), 4.60-4.89 (m,
3H), 5.12-5.18 (m, 1H), 6.89 (s, 1H), 7.15 (s, 1H), 7.68-7.71 (m,
3H), 7.82 (s, 1H); ESI MS m/z 720 (C35H38F9N3O3+H]+; HPLC 96.1%, tR
22.1 min.
Example 94
Synthesis of
(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-
-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cy-
clohexyl)-acetic acid
##STR00240##
[0618] Add 5 N sodium hydroxide solution (2 mL) to a solution of
(4-(5-[(3,5-bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-
-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cy-
clohexyl)-acetic acid methyl ester (63 mg, 0.088 mmol) in methanol
(5 mL) and heat at 60.degree. C. for 4 h. After the reaction cools
to room temperature, acidify to pH 4 with 2 N hydrochloric acid
solution and extract the aqueous mixture with ethyl acetate
(3.times.10 mL). Wash the organic layer with water and brine (10 mL
each). Dry the organic layer over anhydrous sodium sulfate, filter
and remove the solvent under reduced pressure to provide the title
compound as an off-white solid (58 mg, 95%). .sup.1H NMR (CDCl3,
300 MHz) .delta. 0.78-2.45 (m, 22H), 2.63-3.10 (m, 4H), 4.61-4.82
(m, 3H), 5.12-5.19 (m, 1H), 6.89 (s, 1H), 7.12-7.33 (m, 2H),
7.62-7.81 (m, 3H); ESI MS m/z 706 [C34H36F9N3O3+H]+; HPLC 96.3%, tR
18.9 min.
Example 95
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine
##STR00241##
[0620] Prepare the title compound by essentially following the
procedure described in Example 3, Step 19, using
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) and replacing cyclopentanecarboxaldehyde with
4-pyridine-carboxaldehyde. MS (ES+): 644 (M+H).
Example 96
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine hydrochloride
##STR00242##
[0622] Add 1.0 N HCl in ethyl ether (0.0500 mL) to a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine (0.0230 mg, 0.0357 mmole) in ethyl ether (0.500
mL), stir for 10 minutes. Evaporate the solvent to provide the
title compound. MS (ES+): 644 (M+H).
Example 97
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-3-ylmethyl-8-tri-
fluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine
##STR00243##
[0624] Prepare the title compound by essentially following the
procedure described in Example 3, Step 19, using
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) and replacing cyclopentanecarboxaldehyde with
3-pyridine-carboxaldehyde. MS (ES+): 644 (M+H).
Example 98
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7-methyl-8-trif-
luoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetraz-
ol-5-yl)-amine
##STR00244##
[0626] Prepare the title compound by essentially following the
procedure described in Example 3, Step 19, using
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) and replacing cyclopentanecarboxaldehyde with
cyclopropanecarboxaldehyde. MS (ES+): 607 (M+H).
Example 99
Synthesis of
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)
-ethanol
##STR00245##
[0628] Prepare the title compound by essentially following the
procedure described in Example 33 by replacing
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) with
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-ethyl-
-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 35, Step 1). MS (ES+): 611 (M+H).
Example 100
Synthesis of
(S)-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-et-
hyl)-carbamic acid tert-butyl ester
##STR00246##
[0630] Prepare the title compound by essentially following the
procedures described in Example 3, Step 19, by replacing
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) with
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-ethyl-
-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo(b)azepin-5-yl)-amine
(Example 35, Step 1), and replacing cyclopentanecarboxaldehyde with
(2-oxo-ethyl)-carbamic acid tert-butyl ester. MS (ES+): 710
(M+H).
Example 101
Synthesis of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethy-
l}-benzoic acid
##STR00247##
[0632] Prepare the title compound by essentially following the
procedures described in Example 3, Step 19 by replacing
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) with
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-ethyl-
-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 35, Step 1), and replacing cyclopentanecarboxaldehyde with
4-carboxybenzaldehyde. MS (ES+): 701 (M+H).
Example 102
Synthesis of
(S)5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-thiop-
hene-2-carboxylic acid
##STR00248##
[0634] To a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-az-
a-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 73, Step 7) (0.16 mmol) in dichloroethane (5 mL), add
5-formyl-thiophene-2-carboxylic acid (0.63 mmol) followed by acetic
acid (cat.). Add NaB(OAc).sub.3H (0.78 mmol) and stir the mixture
at room temperature for 14 h. Dilute the reaction with
dichloromethane (10 mL) and quench with water (5 mL). Separate the
organics and wash the aqueous with dichloromethane (2.times.10 mL).
Dry the combined organics over Na.sub.2SO.sub.4, filter; and remove
the solvent under vacuum. Chromatograph the product over silica gel
eluting with MeOH/DCM (1-5%) to provide the title compound as a
colorless foam. MS (ES+): 651 (M-H).
Example 103
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(5-pyrid-
in-4-ylmethyl-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl-
)-amine
##STR00249##
[0636] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-thio-
phene-2-carboxylic acid (Example 102), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-az-
a-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 73, Step 7) and 4-pyridine carboxaldehyde. MS (ES +): 604
(M+H).
Example 104
Synthesis of
(S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]
inden-5-ylmethyl}-cyclohexyl)-acetic acid
##STR00250##
[0637] Step 1. Preparation of
(S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-cyc-
lohexyl)-acetic acid benzyl ester
##STR00251##
[0639] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl)-thiop-
hene-2-carboxylic acid (Example 102), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-az-
a-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 73, Step 7) and (4-Formyl-cyclohexyl)-acetic acid benzyl
ester. MS: 757 (M+H).
Step 2. Preparation of
(S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl)-cyc-
lohexyl)-acetic acid
##STR00252##
[0641] To a solution of
(S)-(4-(9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino)-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-cyc-
lohexyl)-acetic acid benzyl ester (0.07 mmol) in methanol (5 mL),
add NaOH (3 mL of 5N) and heat to 60.degree. C. for 2 h. After
cooling to room temperature, dilute with water (20 mL) and
neutralize using 5 M HCl. Extract the organic phase using ethyl
acetate (3.times.10 mL). Dry the combined organics over sodium
sulfate, filter, and remove solvent under vacuum, to provide the
title compound as a colorless foam. MS (ES+): 667 (M+H).
Example 105
Synthesis of
(S)-2-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl}-ethanol
##STR00253##
[0642] Step 1. Preparation of
(S)-[5-(2-Benzyloxy-ethyl)-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohept-
a[f]inden-9-yl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-y-
l)-amine
##STR00254##
[0644] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-1-tetrazol-5-yl)--
amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-th-
iophene-2-carboxylic acid (Example 102), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-az-
a-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 73, Step 7) and benzyloxy-acetaldehyde.
Step 2. Preparation of
(S)-2-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl)-ethanol
##STR00255##
[0646] Purge a solution of
(S)-[5-(2-Benzyloxy-ethyl)-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohept-
a[f]inden-9-yl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-y-
l)-amine (0.14 mmol) in methanol (20 mL) with nitrogen and add a
catalytic amount of Pd/C. Purge the resulting mixture with hydrogen
and stir at room temperature for 5 h. Purge the reaction with
nitrogen, filter through Celite.RTM., and wash with methanol (50
mL). Remove solvent under vacuum. Chromatograph the crude product
over silica gel, eluting with ethyl acetate/hexane (5-100%) to
provide the title compound as a colorless foam. MS (ES+): 557
(M+H).
Example 106
Synthesis of
(S)-9-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benz-
yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxy-
lic acid tert-butyl ester
##STR00256##
[0647] Step 1. Preparation of
(S)-9-((3,5-Bis-trifluoromethyl-benzyl)-{2-[2-(1,3-dioxo-1,3-dihydro-isoi-
ndol-2-yl)-ethyl]-2H-tetrazol-5-yl)-amino)-1,3,6,7,8,9-hexahydro-2-oxa-5-a-
za-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester
##STR00257##
[0649] To a solution of
(S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-1,3,6,7-
,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid
tert-butyl ester (Example 72, Step 6) (0.84 mmol) and
N-(2-Hydroxyethyl)phthalimide (2.51 mmol) in dichloromethane (10
mL), add triphenylphosphine (2.51 mmol) followed by dropwise
addition of diethylazodicarboxylate (2.51 mmol). After stirring at
room temperature for 14 h, remove the solvent under vacuum.
Chromatograph over silica gel eluting with ethyl acetate/hexane
(5-50%) to provide the title compound as a colorless foam. MS
(ES+): 772 (M+H).
Step 2. Preparation of
(S)-9-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benz-
yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxy-
lic acid tert-butyl ester
##STR00258##
[0651] Add hydrazine monohydrate (1.94 mmol) to a solution of
(S)-9-((3,5-Bis-trifluoromethyl-benzyl)-{2-[2-(1,3-dioxo-1,3-dihydro-isoi-
ndol-2-yl)-ethyl]-2H-tetrazol-5-yl}-amino)-1,3,6,7,8,9-hexahydro-2-oxa-5-a-
za-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (0.13
mmol) in methanol (5 mL). After heating the mixture at 60.degree.
C. for 4 h cool to room temperature and stir for 14 h. Remove
solvent under vacuum. Chromatograph over silica gel eluting with
methanol/dichloromethane (0-5%) to provide the title compound as a
colorless foam. MS (ES+): 642 (M+H).
Example 107
Synthesis of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(5-benzyl-3,5,6,7,8,9-hexahydro--
1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(3,5-bis-trifluoromethyl-benzyl)-a-
mine
##STR00259##
[0652] Step 1. Preparation of
(S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-amino]-tetrazol-2-yl}-ethyl)-isoindole-
-1,3-dione
##STR00260##
[0654] To a solution of
(S)-9-((3,5-Bis-trifluoromethyl-benzyl)-{2-[2-(1,3-dioxo-1,3-dihydro-isoi-
ndol-2-yl)-ethyl]-2H-tetrazol-5-yl}-amino)-1,3,6,7,8,9-hexahydro-2-oxa-5-a-
za-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (Example
106, Step 1) (0.39 mmol) in dichloromethane (5 mL), add
trifluoroacetic acid (2 mL). After stirring at room temperature for
3 h, quench the reaction with concentrated sodium carbonate, dilute
with dichloromethane (20 mL), and water (20 mL). Separate the
organic phase and wash the aqueous with dichloromethane (2.times.10
mL). Dry the combined organics over sodium sulfate, filter, and
remove solvent under vacuum. Chromatograph the product over silica
gel eluting with ethyl acetate/hexane (10-50%) to provide the title
intermediate as a colorless foam. MS(ES+): 730 (M+59).
Step 2. Preparation of
(S)-2-(2-{5-[(5-Benzyl-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]-
inden-9-yl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-ethyl)--
isoindole-1,3-dione
##STR00261##
[0656] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-thio-
phene-2-carboxylic acid (Example 102), starting with
(S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-amino]-tetrazol-2-yl)-ethyl)-isoindole-
-1,3-dione and benzaldehyde. MS(ES+): 762 (M+H).
Step 3. Preparation of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(5-benzyl-3,5,6,7,8,9-hexahydro--
1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(3,5-bis-trifluoromethyl-benzyl)-a-
mine
##STR00262##
[0658] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-9-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benz-
yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxy-
lic acid tert-butyl ester (Example 106, Step 2) starting with
(S)-2-(2-{5-[(5-Benzyl-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]-
inden-9-yl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-ethyl)--
isoindole-1,3-dione. MS(ES+): 632 (M+H).
Example 108
Synthesis of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-[5-(3,3,3-trifluoro-propyl)-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohep-
ta[f]inden-9-yl]-amine
##STR00263##
[0660] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(5-benzyl-3,5,6,7,8,9-hexahydro--
1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(3,5-bis-trifluoromethyl-benzyl)-a-
mine (Example 107) starting with
(S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-amino]-tetrazol-2-yl}-ethyl)-isoindole-
-1,3-dione and 3,3,3-Trifluoro-propionaldehyde in Example 107, Step
2. MS(ES+): 638 (M+H).
Example 109
Synthesis of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-2,3,4,5,7,8,9,10-octahydro-naphtho[2,3-b]azepin-1-yl}-3,3-dimethyl-pe-
ntanoic acid
##STR00264##
[0662] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl}-3,3-dimeth-
yl-pentanoic acid (Example 74) by replacing
(S)-(3,5-bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-az-
a-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(2,3,4,5-
,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-amine (Example
77, Step 3) in Example 74, Step 3. MS(ES+): 653 (M+H).
Example 110
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-11-methyl-2,3,4-
,5,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol--
5-yl)-amine
##STR00265##
[0663] Step 1. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(11-methyl-2,3,4,5,7,8,9,10-octahydr-
o-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
##STR00266##
[0665] To a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(2,3,4,5-
,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-amine (Example
77, Step 3) (0.19 mmol) in dichloromethane (5 mL), add sodium
bicarbonate (0.28 mmol) and methanol (2 mL). Add a 1.0 M solution
of Wine monochloride (0.28 mmol) in dichloromethane dropwise. After
stirring for 1 h at room temperature, quench the reaction with
concentrated aqueous sodium metabisulfite. Dilute with
dichloromethane (20 mL) and water (20 mL). Separate the organic
phase and wash the aqueous with dichloromethane (2.times.10 mL).
Dry the combined organics over sodium sulfate, filter, and remove
solvent under vacuum. Dissolve the crude intermediate in dioxane (5
mL) and purge with nitrogen. To this solution add palladium acetate
(0.04 mmol), diphenylphosphinoferrocene (0.04 mmol), cesium
fluoride (0.76 mmol), and methylboronic acid (0.76 mmol). Heat the
mixture at 60.degree. C. for 4 h, then cool to room temperature and
remove the solvent under vacuum. Chromatograph the product over
silica gel eluting with ethyl acetate/hexane (5-25%) to afford the
title compound. MS(ES+): 539 (M+H).
Step 2. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-11-methyl-2,3,4-
,5,7,8,9,10-octahydro-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol--
5-yl)-amine
##STR00267##
[0667] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-thio-
phene-2-carboxylic acid (Example 102), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(11-methyl-2,3,4,5,7,8,9,10-octahydr-
o-1H-naphtho[2,3-b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
and cyclopentanecarboxaldehyde. MS(ES+): 621 (M+H).
Example 111
Synthesis of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-thiophene-2-carboxylic acid
##STR00268##
[0669] To a solution of
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
(Example 3, Step 18) (0.10 mmol) in dichloroethane (5 mL), add
5-Formyl-thiophene-2-carboxylic acid (0.4 mmol) followed by acetic
acid (cat.). Add NaB(OAc).sub.3H (0.5 mmol) and stir the mixture at
room temperature for 14 h. Dilute the reaction with dichloromethane
(10 mL) and quench with water (5 mL). Separate the organics and
wash the aqueous with dichloromethane (2.times.10 mL). Dry the
combined organics over Na.sub.2SO.sub.4, filter, and remove the
solvent under vacuum. Chromatograph the product over silica gel
eluting with MeOH/DCM (1-5%) to provide the ale compound as a
colorless foam. MS(ES+): 693 (M+H).
##STR00269##
[0670] Prepare Examples 112-119 by essentially following the
procedures described in the synthesis of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-thiophene-2-carboxylic acid (Example 111) by replacing
5-formyl-thiophene-2-carboxylic acid with the appropriate
aldehyde.
TABLE-US-00009 Example # Reagent R 112 2-Methyl-3-oxo-
2-methyl-propionic propionic acid ethyl acid ethyl ester; ester 113
formaldehyde methyl 114 2- thiazol-2-ylmethyl
thiazolecarboxaldehyde 115 1-Methyl-1H- 1-methyl-1H- imidazole-2-
imidazol-2- carbaldehyde ylmethyl 116 Benzaldehyde benzyl 117
(4-Formyl-phenyl)- 4-phenylacetic acid acetic acid 118
4-Oxo-butyric acid butyric acid 119 Oxo-acetic acid ethyl acetic
acid ethyl ester ester
Example 120
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-ylmethyl-8-t-
rifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tet-
razol-5-yl)-amine
##STR00270##
[0671] Step 1. Preparation of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-piperidine-1-carboxylic acid tert-butyl ester
##STR00271##
[0673] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-thiophene-2-carboxylic acid. (Example 111) starting with (S)-
(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-tr-
ifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
(Example 3, Step 18) and 4-Formyl-piperidine-1-carboxylic acid
tert-butyl ester. MS(ES+): 750 (M+H).
Step 2. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-ylmethyl-8-t-
rifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tet-
razol-5-yl)-amine
##STR00272##
[0675] To a solution of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-piperidine-1-carboxylic acid tert-butyl ester (0.09) in
dichloromethane (10 mL), add trifluoroacetic acid (2 mL). After
stirring for 1 h at room temperature, quench the reaction with
concentrated sodium carbonate (10 mL) and dilute with
dichloromethane (20 mL) and water (20 mL). Separate the organics
and wash the aqueous with dichloromethane (2.times.10 mL). Dry the
combined organics over sodium sulfate, filter, and remove solvent
under vacuum. Chromatograph the reaction over silica gel eluting
with methanol/dichloromethane (0-5%) to afford the title compound
as a colorless foam. MS(ES+); 650 (M+H).
Example 121
Synthesis of
(S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmet-
hyl}-piperidin-1-yl)-acetic acid ethyl ester
##STR00273##
[0677] To a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-ylmethyl-8-t-
rifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tet-
razol-5-yl)-amine (Example 120) (0.18 mmol) in DMF (3 mL), add
bromo-acetic acid ethyl ester (0.54 mmol) and cesium carbonate
(0.90 mmol). After heating the mixture at 50.degree. C. for 30
minutes, cool to room temperature and dilute the reaction with
water (15 mL) and extract with ethyl acetate (3.times.10 mL). Dry
the combined organic phases over sodium sulfate, filter, and remove
solvent under vacuum. Chromatograph the product over silica gel,
eluting with ethyl acetate/hexane (5-50%), to give the title
compound as a colorless foam. MS(ES+): 736 (M+H).
Example 122
Synthesis of
(S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1ylmeth-
yl}-piperidin-1-yl)-acetic acid
##STR00274##
[0679] To a solution of
(S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmet-
hyl}-piperidin-1-yl)-acetic acid ethyl ester (0.11 mmol) in
methanol (5 mL), add 5.0 N sodium hydroxide (2 mL). After heating
at 60.degree. C. for 6 h cool to room temperature and dilute with
water (20 mL). Extract the organics with ethyl acetate (3.times.10
mL). Dry the combined organic phases over sodium sulfate, filter,
and remove solvent under vacuum, to afford the title compound as a
colorless foam. MS(ES+): 708 (M+H).
Example 123
Synthesis of
(S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-2--
methyl-propionic acid
##STR00275##
[0681] To a solution of
(S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-2--
methyl-propionic acid ethyl ester (Example 112) (0.04 mmol) in
methanol (5 mL), add 5.0 N sodium hydroxide (2 mL). After heating
at 60.degree. C. for 6 h cool to room temperature and dilute with
water (20 mL). Extract the organics with ethyl acetate (3.times.10
mL). Dry the combined organic phases over sodium sulfate, filter,
and remove solvent under vacuum, to afford the title compound as a
mixture of diastereomers. MS(ES+): 639 (M+H).
Example 124
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyrrolidin-2-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine
##STR00276##
[0682] Step 1. Preparation of
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-pyrrolidine-1-carboxylic acid tert-butyl ester
##STR00277##
[0684] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-thiophene-2-carboxylic acid (Example 111) starting with
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
(Example 3, Step 18) and (R)-(-)-2-formyl-pyrrolidine-1-carboxylic
acid tert-butyl ester. MS(ES+): 736 (M+H).
Step 2. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-pyrrolidin-2-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine
##STR00278##
[0686] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-ylmethyl-8-t-
rifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tet-
razol-5-yl)-amine (Example 120, Step 2) starting with
(S)-2-(5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-pyrrolidine-1-carboxylic acid tert-butyl ester. MS(ES+): 636
(M+H).
Example 125
Synthesis of
(S)-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-7-methyl-8-trifluoromethyl-2,3,4.5-tetrahydro-benzo[b]azepin-1-yl)-acet-
ic acid
##STR00279##
[0688] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-2--
methyl-propionic acid (Example 123) starting with
(S)-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-acet-
ic acid ethyl ester (Example 119). MS(ES+): 611 (M+H)
Example 126
Synthesis of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(1-(2-benzyloxy-ethyl)-7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(3,5-bis-trif-
luoromethyl-benzyl)-amine
##STR00280##
[0689] Step 1. Preparation of
(S)-5-((3,5-Bis-trifluoromethyl-benzyl)-{2-[2-(1,3-dioxo-1,3-dihydro-isoi-
ndol-2-yl)-ethyl]-2H-tetrazol-5-yl}-amino)-7-methyl-8-trifluoromethyl-2,3,-
4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid, tert-butyl
ester
##STR00281##
[0691] Prepare the title compound by essentially following the
procedures described for the synthesis of
(S)-9-((3,5-Bis-trifluoromethyl-benzyl)-{2-[2-(1,3-dioxo-1,3-dihydro-isoi-
ndol-2-yl)-ethyl]-2H-tetrazol-5-yl}-amino)-1,3,6,7,8,9-hexahydro-2-oxa-5-a-
za-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (Example
106, Step 1), starting with
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino)-7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid tert-butyl ester (Example 3, Step 16). MS(ES+): 812 (M+H).
Step 2. Preparation of
(S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-8-trifluoromethyl-
-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]tetrazol-2-yl}-ethyl)-is-
oindole-1,3-dione
##STR00282##
[0693] To a solution of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-({2-[2-(1,3-dioxo-1,3-dihydro-iso-
indol-2-yl)-ethyl]-2H-tetrazol-5-yl}-amino)-7-methyl-8-trifluoromethyl-2,3-
,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester
(0.12 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (1
mL). After stirring at room temperature for 1 h, quench the
reaction with concentrated sodium carbonate (10 mL), and dilute
with water (10 mL) and dichloromethane (20 mL). Separate the
organic phase and wash the aqueous with dichloromethane (2.times.10
mL). Dry the combined organics over sodium sulfate, filter, and
remove solvent under vacuum, to provide the title compound as a
colorless foam. MS(ES+): 712 (M+H).
Step 3. Preparation of
(S)-2-(2-{5-[[1-(2-Benzyloxy-ethyl)-7-methyl-8-trifluoromethyl-2,3,4,5-te-
trahydro-1H-benzo[b]azepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-t-
etrazol-2-yl) -ethyl)-isoindole-1,3-dione
##STR00283##
[0695] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-thiophene-2-carboxylic acid (Example 111) starting with
(S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-8-trifluoromethyl-
-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetrazol-2-yl)
-ethyl)-isoindole-1,3-dione and benzyloxy-acetaldehyde. MS(ES+):
846 (M+H).
Step 4. Preparation of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(1-(2-benzyloxy-ethyl)-7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(3,5-bis-trif-
luoromethyl-benzyl)-amine
##STR00284##
[0697] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-9-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benz-
yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxy-
lic acid tert-butyl ester (Example 106, Step 2) starting with
(S)-2-(2-{5-[[1-(2-Benzyloxy-ethyl)-7-methyl-8-trifluoromethyl-2,3,4,5-te-
trahydro-1H-benzo[b]azepin-5-yl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-t-
etrazol-2-yl}-ethyl)-isoindole-1,3-dione. MS(ES+): 716 (M+H).
Example 127
Synthesis of
(S)-2-{5-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-b-
enzyl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-
-1-yl}-ethanol
##STR00285##
[0698] Step 1. Preparation of
(S)-2-[2-(5-{(3,5-Bis-trifluoromethyl-benzyl)-[1-(2-hydroxy-ethyl)-7-meth-
yl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino}-tet-
razol-2-yl)-ethyl]-isoindole-1,3-dione
##STR00286##
[0700] To a solution of
(S)-2-(2-{5-[[1-(2-Benzyloxy-ethyl)-7-methyl-8-trifluoromethyl-2,3,4,5-te-
trahydro-1H-benzo[b]azepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-t-
etrazol-2-yl}-ethyl)-isoindole-1,3-dione (Example 126, Step 3)
(0.09 mmol) in methanol (20 mL), add a catalytic amount of 10% Pd/C
after purging with nitrogen. Purge the reaction with a balloon of
hydrogen and stir under a balloon of hydrogen for 14 h. Purge the
reaction with nitrogen and filter through Celite.RTM.. Collect the
filtrate and remove solvent under vacuum. Chromatograph the
reaction over silica gel eluting with ethyl acetate/hexane (15-45%)
to afford the title compound.
Step 2. Preparation of
(S)-2-{5-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-b-
enzyl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-
-1-yl}-ethanol
##STR00287##
[0702] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-9-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benz-
yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxy-
lic acid tert-butyl ester (Example 106, Step 2) starting with
(S)-2-[2-(5-{(3,5-Bis-trifluoromethyl-benzyl)-[1-(2-hydroxy-ethyl)-7-meth-
yl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-amino}-tet-
razol-2-yl)-ethyl]-isoindole-1,3-dione. MS(ES+): 626 (M+H).
Example 128
Synthesis of
(S)-5-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benz-
yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-
-carboxylic acid tert-butyl ester
##STR00288##
[0704] Prepare the title compound uby essentially following the
procedures described in the synthesis of
(S)-9-[[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benz-
yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxy-
lic acid tert-butyl ester (Example 106) starting with
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino)-7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid tert-butyl ester (Example 3, Step 16). MS(ES+): 682 (M+H).
Example 129
Synthesis of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-(7-methyl-1-thiazol-2-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-be-
nzo[b]azepin-5-yl)-amine
##STR00289##
[0706] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(5-benzyl-3,5,6,7,8,9-hexahydro--
1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(3,5-bis-trifluoromethyl-benzyl)-a-
mine (Example 107) starting with
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid tert-butyl ester (Example 3, Step 16) and using
thiazole-2-carboxaldehyde in place of benzaldehyde. MS(ES+): 679
(M+H).
Example 130
Synthesis of
(S)-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-e-
thoxy)-acetic acid.
##STR00290##
[0707] Step 1. Preparation of
(S)-[1-(2-Benzyloxy-ethyl)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro--
1H-benzo[b]azepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetr-
azol-5-yl)-amine
##STR00291##
[0709] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-thio-
phene-2-carboxylic acid (Example 102), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) and benzyloxy-acetaldehyde. MS(ES+): 687
(M+H).
Step 2. Preparation of
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-et-
hanol
##STR00292##
[0711] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-2-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl]-ethanol.
(Example 105, Step 2) starting with
(S)-[1-(2-Benzyloxy-ethyl)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro--
1H-benzo[b]azepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetr-
azol-5-yl)-amine. MS(ES+): 597 (M+H).
Step 3. Preparation of
(S)-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-e-
thoxy)-acetic acid
##STR00293##
[0713] To a solution of
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)
-ethanol (0.17 mmol) in tetrahydrofuran (5 mL), add potassium
hydride (0.67 mmol) at room temperature. After stirring for 30
minutes add bromoacetic acid (0.25 mmol) as a solution in
tetrahydrofuran (1 mL). After stirring an additional 0.5 h, quench
the reaction with wet tetrahydrofuran (2 mL), dilute with water (1
mL), and ethyl acetate (5 mL). Neutralize the reaction with 5M HCl,
separate the organic phase, and wash the aqueous with ethyl acetate
(2.times.5 mL). Dry the combined organic phases over sodium
sulfate, filter, and remove solvent under vacuum. Chromatograph the
product over silica gel, eluting with methanol/dichloromethane
(0.5-4%) to afford the title compound as a colorless foam. MS(ES+):
655 (M+H).
Example 131
Synthesis of (S)-Acetic acid
2-{(5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-ethyl
ester
##STR00294##
[0715] To a solution of
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-et-
hanol (Example 130, Step 2) (0.12 mmol) in dichloromethane (5 mL),
add pyridine (0.47 mmol) followed by acetyl chloride (0.47 mmol).
After stirring at room temperature for 14 h, quench the reaction
with water (5 mL) and dilute with dichloromethane (5 mL). Separate
the organic phase and wash the aqueous with dichloromethane
(2.times.5 mL). Dry the combined organics over sodium sulfate,
filter, and remove solvent under vacuum. Chromatograph the product
over silica gel, eluting with ethyl acetate/hexane (5-40%), to
afford the title compound as a colorless foam. MS(ES+): 639
(M+H).
Example 132
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-[7-methy-
l-1-(2H-tetrazol-5-ylmethyl)-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo-
[b]azepin-5-yl}-amine
##STR00295##
[0716] Step 1. Preparation of
(S)-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-acet-
onitrile
##STR00296##
[0718] To a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) (0.09 mmol) in dimethylformamide (3 mL), add
bromoacetonitrile (0.36 mmol) and cesium carbonate (0.36 mmol).
After stirring the reaction at 60.degree. C. for 6 h, cool to room
temperature and dilute with water (20 mL) and ethyl acetate (30
mL). Separate the organic phase and wash the aqueous with ethyl
acetate (2.times.10 mL). Dry the combined organics over sodium
sulfate, filter, and remove solvent under vacuum. Chromatograph the
product over silica gel, eluting with ethyl acetate/hexane (5-40%),
to afford the title compound as a colorless foam. MS(ES+): 592
(M+H).
Step 2. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-[7-methy-
l-1-(2H-tetrazol-5-ylmethyl)-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo-
[b]azepin-5-yl]-amine
##STR00297##
[0720] To a solution of
(S)-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-acet-
onitrile (0.1 mmol) in toluene (6 mL), add azidotributyltin (0.1
mmol) and heat at 100.degree. C. After heating for 14 h, cool to
room temperature and dilute with ethyl acetate (20 mL). Wash the
reaction with concentrated sodium fluoride (2.times.20 mL), dry the
organic phase over sodium sulfate, filter, and remove solvent under
vacuum. Chromatograph the product over silica gel, eluting with
methanol/dichloromethane (0.5-5%), to afford the title compound as
a colorless foam. MS(ES+): 633 (M+H).
Example 133
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 2-amino-ethyl ester
##STR00298##
[0721] Step 1. Preparation of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl
chloride
##STR00299##
[0723] To a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) (0.91 mmol) in toluene (5 mL), add phosgene
(0.91 mmol) as a 1.93 M solution in toluene. Next, add
diisopropylethylamine (0.96 mmol) dropwise at room temperature.
After stirring at room temperature for 1 h, dilute the reaction
with ethyl acetate (10 mL) and wash with water (5 mL). Dry the
organic phase over sodium sulfate, filter, and remove solvent under
a stream of nitrogen. Chromatograph the product over silica gel,
eluting with ethyl acetate/hexane (5-25%), to afford the title
compound as a colorless foam. MS(ES+): 615 (M+H).
Step 2. Preparation of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 2-amino-ethyl ester
##STR00300##
[0725] To a solution of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl
chloride (0.08 mmol) in dimethylformamide (3 mL), add
(2-Hydroxy-ethyl)-carbamic acid tert-butyl ester (0.24 mmol) and
dimethylaminopyridine (0.08 mmol). Next, add sodium hydride (0.24
mmol) and stir at room temperature for 0.5 h. Quench the reaction
with water (15 mL) and dilute with ethyl acetate (10 mL). Separate
the organic phase and wash the aqueous with ethyl acetate
(2.times.10 mL). Dry the combined organics over sodium sulfate,
filter, and remove solvent under vacuum. Dissolve the crude
5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7--
methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid 2-tert-butoxycarbonylamino-ethyl ester intermediate in
dichloromethane (5 mL) and add trifluoroacetic acid (2 mL). After
stirring for 1 h, quench the reaction with concentrated sodium
carbonate (5 mL). Dilute the reaction with dichloromethane (10 mL)
and water (10 mL). Separate the organic phase and wash the aqueous
with dichloromethane (2.times.10 mL). Dry the combined organics
over sodium sulfate, filter, and remove the solvent under vacuum.
Chromatograph the product over silica gel, eluting with
methanol/dichloromethane (0-5%), to afford the title compound as a
colorless foam. MS(ES+): 640 (M+H).
Example 134
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 2-carboxy-2-methyl-propyl ester
##STR00301##
[0726] Step 1. Preparation of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 2-methoxycarbonyl-2-methyl-propyl ester
##STR00302##
[0728] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 2-amino-ethyl ester (Example 133), replacing
(2-Hydroxy-ethyl)-carbamic acid tert-butyl ester with
3-Hydroxy-2,2-dimethyl-propionic acid methyl ester in Example 133,
Step 2. MS(ES+): 711 (M+H).
Step 2. Preparation of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 2-carboxy-2-methyl-propyl ester
##STR00303##
[0730] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-2--
methyl-propionic acid (Example 123) starting with
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 2-methoxycarbonyl-2-methyl-propyl ester. MS(ES+): 697
(M+H).
Example 135
Synthesis of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-(1-cyclopropylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-ben-
zo[b]azepin-5-yl)-amine
##STR00304##
[0731] Step 1. Preparation of
(S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7-meth-
yl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino}-tet-
razol-2-yl}-ethyl)-isoindole-1,3-dione
##STR00305##
[0733] Prepare the title compound by essentially following the
procedures described in Example 3, Step 19 by replacing
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
with
(S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-8-trifluoromethyl-
-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino)-tetrazol-2-yl)-ethyl)-i-
soindole-1,3-dione (Example 126, Step 2), and replacing
cyclopentanecarboxaldehyde with cyclopropanecarboxaldehyde. MS
(ES+): 766 (M+H).
Step 2. Preparation of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-(1-cyclopropylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-ben-
zo[b]azepin-5-yl)-amine
##STR00306##
[0735] Heat the mixture of
(S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7-meth-
yl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tet-
razol-2-yl}-ethyl)-isoindole-1,3-dione (0.140 g, 0.183 mmol) and
hydrazine hydrate (0.114 mL, 3.66 mmol) in methanol (2 mL) at
60.degree. C. overnight. Evaporate the solvents. Chromatograph the
residue over silica gel, eluting with ethyl acetate/hexanes
(0-100%), to provide the title compound as a colorless oil (0.0700
g, 60%). MS (ES+): 636 (M+H).
Example 136
Synthesis of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-(1-cyclopropylmethyl-7
-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amin-
e hydrochloride
##STR00307##
[0737] Add 1.0 N HCl in ethyl ether (0.0500 mL) to a solution of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-(1-cyclopropylmethyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-ben-
zo[b]azepin-5-yl)-amino (0.0300 mg, 0.0472 mmole) in ethyl ether
(0.500 mL), stir for 10 minutes. Evaporate the solvent to provide
the title compound as white powder. MS (ES+): 636 (M+H).
Example 137
Synthesis of
(+/-)-5-[(3,5-Bis-trifluoromethyl-benzyl)-pyridin-3-yl-amino]-7-methyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-benzazepine-1-carboxylic acid
isopropyl ester
##STR00308##
[0738] Step 1. Preparation of
(+/-)-7-Methyl-5-(pyridin-3-ylamino)-8-trifluoromethyl-2,3,4,5-tetrahydro-
benzo[b]azepine-1-carboxylic acid isopropyl ester
##STR00309##
[0740] Add isopropyl
7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carb-
oxylate (Example 3, Step 8) (1.16 g, 3.52 mmol), 3-aminopyridine
(465 mg, 5.10 mmol), p-toluenesulfonic acid (210 mg, 1.10 mmol) and
toluene (8.0 mL) to a sealed tube and stir vigorously for 4 days at
130.degree. C. Evaporate the toluene, dissolve the residue with
MeOH (10.0 mL), and add sodium borohydride (146 mg, 3.86 mmol)
portionwise. Reflux overnight and evaporate the MeOH. Partition the
resulting residue between water (10 mL) and EtOAc (10 mL). Wash the
organic layer with 2-mL portions of water and brine, dry
(MgSO.sub.4), and concentrate. Purify via column chromatography
(silica gel; 30% to 70% EtOAc:hexanes to 100% EtOAc gradient) to
give 189 mg (13%) of the title compound as a white solid. APCI MS
m/z 408 [M+H].sup.+.
Step 2. Preparation of (+/-)
5-[(3,5-Bis-trifluoromethyl-benzoyl)-pyridin-3-yl-amino]-7-methyl-8-trifl-
uoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid
isopropyl ester
##STR00310##
[0742] Add 3,5-bis(trifluoromethyl)-benzoyl chloride (0.220 mL,
1.22 mmol) and triethylamine (0.180 mL, 1.29 mmol) over a 24 h
period to a solution of
7-methyl-5-(pyridin-3-ylamino)-8-trifluoromethyl-2,3,4,5-tetrahydroben-
zo[b]azepine-1-carboxylic acid isopropyl ester (114 mg, 0.280 mmol)
in chloroform (1.9 mL) at 70.degree. C. Allow the reaction to cool,
dilute with methylene chloride (20 mL) and wash sequentially with
10% HCl, saturated aqueous sodium bicarbonate, water, and then
brine. Dry (MgSO.sub.4), concentrate, and purify via column
chromatography (silica gel; 20% to 40% EtOAc:hexanes) to give 92 mg
(51%) of the title compound as a white solid APCI MS raz 648
[M+H].sup.+.
Step 3. Preparation of
(+/-)-5-[(3,5-Bis-trifluoromethyl-benzyl)-pyridin-3-yl-amino]-7-methyl-8--
trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid
isopropyl ester
##STR00311##
[0744] Add a solution of borane-THF complex in THF (1.0 M, 0.2 mL,
0.2 mmol) to
5-[(3,5-Bis-trifluoromethyl-benzoyl)-pyridin-3-yl-amino]-7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic
acid isopropyl ester (90.1 mg, 0.139 mmol) in THF (1.6 mL). Heat in
a sealed tube (70.degree. C.) for 14 h. Add saturated aqueous
sodium bicarbonate (5 mL) and extract with EtOAc (3.times.5 mL).
Dry (MgSO.sub.4), concentrate, and purify via column chromatography
(silica gel; 10% to 20% to 25% EtOAc:hexanes) to give 19 mg (22%)
of the title compound as a yellow solid. APCI MS m/z 634
[M+H].sup.+.
Example 138
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-phenyl-amino]-7-methyl-8-trifluor-
omethyl-2,3,4,5-tetrahydrobenzo[b]zepine-1-carboxylic acid
tert-butyl ester
##STR00312##
[0746] Add (S)-tert-butyl
5-(3,5-bis-trifluoromethylbenzylamino)-7-methyl-8-trifluoromethyl-2,3,4,5-
-tetrahydrobenzo[b]azepine-1-carboxylate (Example 3, Step 14) (307
mg, 0.538 mmol), sodium t-butoxide (103 mg, 1.07 mmol),
bromobenzene (65.0 .quadrature.L, 0.617 mmol), palladium acetate
(2.4 mg, 0.011 mmol), Q-Phos (15.3 mg, 0.022 mmol), and toluene
(5.4 mL) to a sealed tube and heat at 130.degree. C. for 24 h.
Quench with water (20 mL) and extract with EtOAc (2.times.20 mL).
Dry (MgSO4), concentrate, and purify via column chromatography
(silica gel; 5% to 10% to 20% EtOAc:hexanes) to give 180 mg (52%)
of the title compound as a white solid. APCI MS ink 648 [M+H]+.
Example 139
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-[7-methyl-1-(tetrahydro-pyran-4-yl)--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(2-methyl-2H--
tetrazol-5-yl)-amine
##STR00313##
[0748] Add sodium triacetoxyborohydride (0.153 g, 0.724 mmol)
portionwise to a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) (0.100 g, 0.181 mmol), tetrahydro-4-pyranone
(0.054 g, 0.543 mmol) and glacial acetic acid (1 mL) in
acetonitrile (10 mL) at room temperature under an atmosphere of
nitrogen and stir for 24 h. Quench the reaction with saturated
sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL).
Separate the layers and wash the organic layer with saturated
sodium bicarbonate and brine (20 mL each). Dry the organic layer
over sodium sulfate, filter and remove the solvent wider reduced
pressure. Purify the residue using flash column chromatography on
silica gel, eluting with hexanes/ethyl acetate (80:20), to provide
the title compound as an off-white solid (0.070 g, 61%). .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. 0.87-0.95 (m, 1H), 1.24-1.34 (m,
1H), 1.61-2.10 (m, 6H), 2.30 (s, 3H), 2.75-2.90 (m, 1H), 3.15-3.22
(m, 1H), 3.41-3.62 (m, 3H), 3.96-4.10 (m, 2H), 4.14 (s, 3H),
4.75-4.95 (m, 2H), 5.37-5.50 (m, 1H), 6.96 (s, 1H), 7.20 (s, 1H),
7.30 (s, 1H), 7.65 (s, 1H), 7.72 (s, 1H); ESI MS m/z 637
[C.sub.28H.sub.29F.sub.9N.sub.6O+H].sup.+.
Example 140
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-isopropyl-7-methyl-8-trifluoromet-
hyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-
-amine
##STR00314##
[0750] Prepare the title compound by essentially following the
procedure described for the preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-(tetrahydro-pyran-4-yl)--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(2-methyl-2H--
tetrazol-5-yl)-amine (Example 139), by substituting
tetrahydro-4-pyranone with acetone. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. 1.10-1.31 (m, 6H), 1.55-1.87 (in, 2H), 1.90-2.15 (m,
1H), 2.10-2.20 (m, 4H), 2.78-2.90 (m, 1H), 3.00-3.13 (m, 1H),
3.64-3.80 (m, 1H), 4.14, (s, 3H), 4.72-4.93 (m, 2H), 5.32-5.43 (m,
1H), 6.81 (s, 1H), 7.19 (s, 1H), 7.56 (s, 2H), 7.71 (s, 1H); ESI MS
m/z 595 [C.sub.26H.sub.27F.sub.9N.sub.6+H].sup.+.
Example 141
Synthesis of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-2-hydroxy-benzoic acid
##STR00315##
[0751] Step 1. Preparation of 5-formyl-2-hydroxy-benzoic acid
methyl ester
##STR00316##
[0753] Heat a mixture of 5-formyl-2-hydroxy-benzoic acid (5.0 g,
30.09 mmol) concentrated sulfuric acid (5 mL) in methanol (100 mL)
at reflux for 24 h. Cool the mixture to room temperature and
concentrate under reduced pressure. Purify the resulting residue by
chromatography over silica gel, eluting with hexanes/ethyl acetate
(80:20), to provide the title compound as a colorless oil (4.28 g,
79%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 3.88 (s, 3H), 4.52
(bs, 1H), 7.05 (d, J=8.56 Hz, 1H), 7.84 (d, J=8.56 Hz, 1H), 8.40
(s, 1H), 9.85 (s, 1H); TLC Rf=0.34 (3:1 Hexanes/Ethyl Acetate).
Step 2.
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-
-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-
-ylmethyl}-2-hydroxy-benzoic acid methyl ester
##STR00317##
[0755] Add sodium triacetoxyborohydride (0.115 g, 0.543 mmol)
portionwise to a solution of
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) (0.200 g, 0.362 mmol),
5-formyl-2-hydroxy-benzoic acid methyl ester (0.195 g, 1.08 mmol)
and glacial acetic acid (1 mL) in acetonitrile (10 mL) at room
temperature under an atmosphere of nitrogen and stir for 24 h.
Quench the reaction with saturated sodium bicarbonate (5 mL) and
dilute with dichloromethane (15 mL). Separate the layers and wash
the organic layer with saturated sodium bicarbonate and brine (20
mL each). Dry the organic layer over sodium sulfate, filter and
remove the solvent under reduced pressure. Purify the residue using
flash column chromatography on silica gel, eluting with
hexanes/ethyl acetate (80:20), to provide the title compound as an
off-white foam (0.155 g, 60%). .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 10.63 (s, 1H), 7.89 (s, 1H), 7.67 (s, (s, 1H), 7.56 (m,
2H), 7.28 (s, 1H), 6.96 (m, 2H), 556 (m, 1H), 4.85-4.98 (m, 2H),
4.14 (s, 3H), 3.89 (s, 3H), 2.95-3.00 (m, 1H), 2.73-2.80 (m, 1H),
2.30 (s, 3H), 2.00-2.13 (m, 2H), 1.43-1.72 (m, 2H), 1.21-1.34 (m,
3H); ESI MS m/z 717
[C.sub.32H.sub.29F.sub.9N.sub.6O.sub.3+H].sup.+.
Step 3. Preparation of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-2-hydroxy-benzoic acid
##STR00318##
[0757] Add 2 N sodium hydroxide solution (2 mL) to a solution of
(S)-5-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-2-hydroxy-benzoic acid methyl ester (0.100 g, 0.139 mmol) in
methanol (5 mL) and heat at 60.degree. C. for 4 h. After the
reaction cools to room temperature, acidify to pH 4 with 2 N
hydrochloric acid solution and extract the aqueous mixture with
ethyl acetate (3.times.10 mL). Wash the organic layer with water
and brine (10 mL each). Dry the organic layer over anhydrous sodium
sulfate, filter and remove the solvent under reduced pressure to
provide the title compound as a white solid (0.076 g, 78%). NMR
(CDCl.sub.3, 300 MHz) .delta. 1.23-1.32 (m, 2H), 1.51-1.52 (m, 2H),
1.94-2.05 (m, 1H), 2.25 (s, 3H), 2.65-2.71 (m, 1H), 2.95-3.04 (m,
1H), 4.10-4.21 (m, 5H), 4.76-5.03 (m, 2H), 5.50-5.61 (m, 1H),
6.68-6.89 (m, 2H), 7.31-7.40 (m, 2H), 7.49-7.62 (m, 2H), 7.70 (s,
1H), 7.98 (s, 1H), 10.43 (s, 1H); ESI MS m/z 703
[C.sub.31H.sub.27F.sub.9N.sub.6O.sub.3+H].sup.+.
Example 142
Synthesis of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-nicotinic acid hydrochloride
##STR00319##
[0758] Step 1. Preparation of 5-Formyl-nicotinic acid methyl
ester
##STR00320##
[0760] Subject a mixture of methyl-5-bromonicotinate (1.0 g, 4.63
mmol), triethylsilane (0.807 g, 6.94 mmol),
tetrakis(triphenylphosphino)palladium (0) (0.531 g, 0.460 mmol),
and triethylamine (1.03 g, 10.18 mmol) in acetonitrile (10 mL) to
an atmosphere of carbon monoxide gas (20 psi) heated at 60.degree.
C. for 5 h. Cool the reaction to room temperature and then absorb
directly onto silica gel. Purify the residue by chromatography over
silica gel, eluting with hexanes/ethyl acetate (80:20), to provide
the title compound as an oil (0.114 g, 15%). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 3.90 (s, 3H), 7.35-7.50 (m, 1H),
8.32-8.42 (m, 1H), 8.77-8.90 (m, 1H), 9.23 (s, 1H); TLC Rf=0.37
(4:1 Hexanes/Ethyl Acetate).
Step 2. Preparation of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-nicotinic acid methyl ester
##STR00321##
[0762] Add sodium triacetoxyborohydride (0.153 g, 0.724 mmol)
portionwise to a solution of
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) (0.100 g, 0.181 mmol), 5-formyl-nicotinic acid
methyl ester (0.089 g, 0.543 mmol) and glacial acetic acid (1 mL)
in acetonitrile (10 mL) at room temperature under an atmosphere of
nitrogen and stir for 24 h. Quench the reaction with saturated
sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL).
Separate the layers and wash the organic layer with saturated
sodium bicarbonate and brine (20 mL each). Dry the organic layer
over sodium sulfate, filter and remove the solvent under reduced
pressure. Purify the residue using flash column chromatography on
silica gel, eluting with hexanes/ethyl acetate (80:20), to provide
(the title compound as an off-white foam (0.113 g, 90%). .sup.1H
NMR (CDCl.sub.3, 30 MHz) .delta. 1.21-1.43 (m, 1H), 1.61-1.71 (m,
1H), 2.04-2.13 (m, 2H), 2.32 (s, 3H), 2.71-2.83 (in, 1H), 3.10-3.18
(m, 1H), 3.89 (s, 3H), 4.14 (s, 3H), 4.32-4.50 (m, 2H), 4.83-5.10
(m, 2H), 5.64-5.0 (m,1H), 6.89 (s, 1H), 7.21 (s, 1H), 7.65 (s, 2H),
7.72 (s, 1H), 8.35 (s, 1H), 8.83 (s, 1H), 9.12 (s, 1H); ESI MS m/z
702 [C.sub.31H.sub.28F.sub.9N.sub.7O.sub.2+H].sup.+
Step 3. Preparation of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-nicotinic acid hydrochloride
##STR00322##
[0764] Add 2 N sodium hydroxide solution (2 mL) to a solution of
(S)-5-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-nicotinic acid methyl ester (0.090 g, 0.128 mmol) in methanol
(5 mL) and heat at 60.degree. C. for 4 h. After the reaction cools
to room temperature, acidify to pH 4 with 2 N hydrochloric acid
solution and extract the aqueous mixture with ethyl acetate
(3.times.10 mL). Wash the organic layer with water and brine (10 mL
each). Dry the organic layer over anhydrous, sodium sulfate, filter
and remove the solvent under reduced pressure to provide the title
compound as a white solid (0.076 g, 78%). .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 1.23-2.34 (m, 1H), 1.57-1.64 (m, 2H), 2.03-2.13
(m, 2H), 2.32 (s, 3H), 2.67-2.73 (m, 1H), 3.04-3.14 (m, 1H), 4.14
(s, 3H), 4.32-4.56 (m, 2H), 4.89-5.10 (m, 2H), 5.67-5.70 (m, 1H),
6.89 (s, 1H), 7.23-7.30 (m, 1H), 7.60-7.70 (m, 3H), 8.45 (s, 1H),
8.89 (s, 1H), 9.22 (s, 1H); ESI MS m/z 688
[C.sub.30H.sub.26F.sub.9N.sub.7O.sub.2+H].sup.+.
Example 143
Synthesis of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-2-fluoro-benzoic acid
##STR00323##
[0765] Step 1. Preparation of 2-Fluoro-5-methyl-benzoic acid methyl
ester
##STR00324##
[0767] Heat a mixture of 2-fluoro-5-methyl-benzoic acid (1.0 g,
6.48 mmol), iodomethane (1.38 g, 9.73 mmol), and potassium
carbonate (2.68 g, 19.44 mmol) in acetone (20 mL) at reflux
overnight. Cool the reaction and filter through Celite.RTM..
Concentrate the filtrate under reduced pressure to provide the
title compound as a colorless gum (0.895 g, 82%). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 2.32 (s, 3H), 3.89 (s, 3H), 6.95-7.10
(m, 1H), 7.20-7.30 (m, 1H), 7.75-7.80 (m, 1H); TLC Rf=0.45 (2:1
Hexanes/Ethyl Acetate).
Step 2. Preparation of 2-Fluoro-5-formyl-benzoic acid methyl
ester
##STR00325##
[0769] Add N-bromosuccinimide (2.46 g, 13.86 mmol) and benzoyl
peroxide (0:152 g, 0.630 mmol) to a solution of
2-fluoro-5-methyl-benzoic acid methyl ester (1.06 g, 6.30 mmol) in
carbon tetrachloride (50 mL). Heat the mixture at reflux for 4 h.
Cool the mixture to room temperature and wash with saturated
aqueous sodium bicarbonate solution (10 mL) and brine (10 mL). Dry
the organic layer over anhydrous sodium sulfate, filter, and
concentrate under reduced pressure. Dissolve the resulting residue
in dimethylsulfoxide (30 mL) and heat at reflux for 16 h. Cool the
mixture to room temperature and dilute with water (100 mL) and
ethyl acetate (100 mL). Extract the aqueous layer with ethyl
acetate (3.times.100 mL). Wash the combined organic layers with
water (3.times.100 mL), followed by brine (100 mL). Dry the organic
layer over anhydrous sodium sulfate, filter and concentrate. Purify
the residue by chromatography over silica gel, eluting with
hexanes/ethyl acetate (80:20), to provide the title compound as a
tan solid (0.228 g, 20%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.
3.89 (s, 3H), 7.31-7.44 (m, 1H), 8.05-8.12 (m,1H), 8.44-8.53 (m,
1H), 10.00 (s, 1H); TLC Rf=0.65 (3:1 Hexanes/Ethyl Acetate).
Step 3. Preparation of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl]-2-fluoro-benzoic acid methyl ester
##STR00326##
[0771] Add sodium triacetoxyborohydride (0.153 g, 0.724 mmol)
portionwise to a solution of
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) (0.100 g, 0.181 mmol),
2-fluoro-5-formyl-benzoic acid methyl ester (0.100 g, 0.543 mmol)
and glacial acetic acid (1 mL) in acetonitrile (10 mL) at room
temperature under an atmosphere of nitrogen and stir for 24 h.
Quench the reaction with saturated sodium bicarbonate (5 mL) and
dilute with dichloromethane (15 mL). Separate the layers and wash
the organic layer with saturated sodium bicarbonate and brine (20
mL each). Dry the organic layer over sodium sulfate, filter and
remove the solvent under reduced pressure. Purify the residue using
flash column chromatography on silica gel, eluting with
hexanes/ethyl acetate (80:20), to provide the title compound as a
white foam (0.120 g, 92%), .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. 1.23-1.34 (m, 2H), 1.64-1.72 (m, 2H), 2.10-2.20 (m, 1H),
2.32 (s, 3H), 2.76-2.80 (m, 1H), 2.94-3.02 (m, 1H), 3.89 (s, 3H),
4.14 (s, 3H), 4.23-4.54 (m, 2H), 4.76-5.02 (m, 2H), 5.62-5.70 (m,
1H), 6.90 (s, 1H), 7.10 (m, 1H), 7.35-7.43 (m, 2H), 7.56-7.80 (m,
2H), 7.89-7.92 (m, 1H); ESI MS m/z 719
[C.sub.32H.sub.28F.sub.10N.sub.6O.sub.2+H].sup.+.
Step 4. Preparation of
(S)-5-(5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-2-fluoro-benzoic acid
##STR00327##
[0773] Add 2 N sodium hydroxide solution (2 mL) to a solution of
(S)-5-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl)-2-fluoro-benzoic acid methyl ester (0.120 g, 0.167 mmol) in
methanol (5 mL) and heat at 60.degree. C. for 4 h. After the
reaction cools to room temperature, acidify to pH 4 with 2 N
hydrochloric acid solution and extract the aqueous mixture with
ethyl acetate (3.times.10 mL). Wash the organic layer with water
and brine (10 mL each). Dry the organic layer over anhydrous sodium
sulfate, filter and remove the solvent under reduced pressure to
provide the title compound as a white solid (0.116 g, 98%). .sup.1H
NMR (CDCl.sub.3, 300 MHz) .delta. 1.60-1.85 (m, 2H), 2.01-2.10 (m,
2H), 2.32 (s, 3H), 2.75-2.84 (m, 1H), 2.97-3.01 (m, 1H), 4.10-4.11
(m, 1H), 4.14 (s, 3H), 4.20-4.35 (m, 2H), 4.76-5.10 (m, 2H),
5.65-5.70 (m, 1H), 6.89 (s, 1H), 7.10-7.15 (m, 1H), 7.32-7.40 (m,
2H), 7.56-7.60 (m, 2H), 7.67 (s, 1H), 8.10(s, 11H); ESI MS m/z 705
[C.sub.31H.sub.26F.sub.10N.sub.6O.sub.2+H).sup.+.
Example 144
Synthesis of
(S)-1-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-2--
ethyl-butan-1-one
##STR00328##
[0775] Add 2-ethyl-butyryl chloride (0.014 g, 0.108 mmol) dropwise
under an atmosphere of nitrogen to a 0.degree. C. cooled solution
of
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
(Example 3, Step 18) (0.060 g, 0.108 mmol) and pyridine (0.010 g,
0.108 mmol) in methylene chloride (5 mL). After stirring for 1 h,
wash the reaction with saturated aqueous sodium bicarbonate
solution (10 mL), 2N aqueous hydrogen chloride solution (10 mL),
and brine (10 mL). Dry the organic layer over anhydrous sodium
sulfate, filter, and concentrate under reduced pressure to afford
the title compound as a colorless gum (0.075 g, 98%). .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta. 0.71-2.16 (m, 16H), 2.34-2.43 (m,
1H), 2.43 (s, 3H), 2.50-2.41 (m, 1H), 4.14 (s, 3H), 4.25-4.67 (m,
2H), 6.89 (bs, 1H), 7.43 (s, 1H), 7.75 (s, 2H), 7.85 (s, 1H); ESI
MS m/z 651 [C.sub.29H.sub.31F.sub.9N.sub.6O+H].sup.+.
Example 145
Synthesis of
(S)-1-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-et-
hanone:
##STR00329##
[0777] Prepare the title compound by essentially following the
procedures described for the preparation of
(S)-1-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo(b)azepin-1-yl}-2--
ethyl-butan-1-one (Example 144), by substituting 2-ethyl-butyryl
chloride with acetyl chloride. .sup.1H NMR (CDCl3, 300 MHz) .delta.
0.75-2.123 (m, 8H), 2.43 (s, 3H), 2.50-2.41 (m, 1H), 4.14 (s, 3H),
4.25-4.67 (m, 2H), 5.21-5.50 (m, 1H), 6.89 (bs, 1H), 7.43 (s, 1H),
7.75 (s, 2H), 7.85 (s, 1H); ESI MS m/z 595 [C25H23F9N6O+H]+.
Example 146
Synthesis of
(S)-(5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-cycl-
ohexyl-methanone
##STR00330##
[0779] Prepare the title compound by essentially following the
procedures described for the preparation of
(S)-1-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-2--
ethyl-butan-1-one (Example 144), by substituting 2-ethyl-butyryl
chloride with cyclohexanecarbonyl chloride. .sup.1H NMR (CDCl3, 300
MHz) .delta. 0.75-2.123 (m, 16H), 2.43 (s, 3H), 2.50-2.41 (m, 1H),
4.14 (s, 3H), 4.25-4.67 (n, 2H), 5.21-5.50 (m, 1H), 6.89 (bs, 1H),
7.43 (s, 1H), 7.75 (s, 2H), 7.85 (s, 1H); ESI MS m/z 663
[C30H31F9N6O+H]+.
Example 147
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-yl-8-trifluo-
romethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol--
5-yl)-amine
##STR00331##
[0780] Step 1. Preparation of
(S)-[1-(1-Benzyl-piperidin-4-yl)-7-methyl-8-trifluoromethyl-2,3,4,5-tetra-
hydro-1H-benzo[b]azepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2-
H-tetrazol-5-yl)-amine
##STR00332##
[0782] Add sodium triacetoxyborohydride (0.153 g, 0.724 mmol)
portionwise to a solution of
(S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b)azepin-5-yl)-amine
(Example 3, Step 18) (0.200 g, 0.362 mmol),
1-benzyl-piperidin-4-one (0.206 g, 1.09 mmol) and glacial acetic
acid (1 mL) in acetonitrile (10 mL) at room temperature under an
atmosphere of nitrogen and stir for 24 h. Quench the reaction with
saturated sodium bicarbonate (5 mL) and dilute with dichloromethane
(15 mL). Separate the layers and wash the organic layer with
saturated sodium bicarbonate and brine (20 mL each). Dry the
organic layer over sodium sulfate, filter and remove the solvent
under reduced pressure. Purify the residue using flash column
chromatography on silica gel, eluting with hexanes/ethyl acetate
(80:20), to provide the title compound as an off-white solid (0.070
g, 61%). .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 1.63-2.13 (m,
8H), 2.34 (s, 3H), 2.82-3.0 (m, 3H), 3.10-3.22 (m, 1H), 3.33-3.41
(m, 1H), 3.50 (s, 2H), 4.09-4.13 (m, 1H), 4.14 (s, 3H), 4.74-4.97
(m, 2H), 5.34-5.49 (m, 1H), 6.89 (s, 1H), 7.32 (s, 1H), 7.41 (s,
5H), 7.60 (s, 2H), 7.71 (s, 1H); ESI MS m/z 726
[C.sub.35H.sub.36F.sub.9N.sub.7+H].sup.+.
Step 2. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7-methyl-1-piperidin-4-yl-8-trifluo-
romethyl-2,3,4,5-tetrahydro-1H-benzor[b]azepin-5-yl)-(2-methyl-2H-tetrazol-
-5-yl)-amine
##STR00333##
[0784] Subject a mixture of
(S)-[1-(1-benzyl-piperidin-4-yl)-7-methyl-8-trifluoromethyl-2,3,4,5-tetra-
hydro-1H-benzo[b]azepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2-
H-tetrazol-5-yl)-amine (0.130 g, 0.179 mmol) and palladium on
carbon (10% by weight, wet, 0.050 g) in methanol (10mL) to an
atmosphere of hydrogen gas (35 psi) at room temperature on a Parr
shaker apparatus. After 5 h, filter the mixture through celite and
the concentrate the filtrate under reduced pressure. Purify the
resulting residue using flash column chromatography on silica gel,
eluting with hexanes/ethyl acetate (80:20), to provide the title
compound as white solid (0.055 g, 48%): .sup.1H NMR (CDCl.sub.3,
300 MHz) .delta. 1.63-2.13 (m, 10H), 2.34 (s, 3H), 2.82-3.0 (m,
31-1), 3.10-3.22 (m, 1H), 3.33-3.41 (m, 1H), 4.09-4.13 (m, 1H),
4.14 (s, 3H), 4.74-4.97 (m, 2H), 5.12 (bs, 1H), 5.34-5.49 (m, 1H),
6.89 (s, 1H), 7.32 (s, 1H), 7.60.(s, 1H), 7.71 (s, 1H); ESI MS m/z
726 [C.sub.28H.sub.30F.sub.9N.sub.7+H].sup.+.
Example 148
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7,9-dimethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine
##STR00334##
[0785] Step 1. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(9-bromo-7-methyl-8-trifluoromethyl--
2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-ami-
ne
##STR00335##
[0787] Add N-bromosuccinimide (1.10 g, 6.19 mmol) in one portion to
a solution of
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
(2.85 g, 5.16 mmol) (Example 3, Step 18) in acetic acid (25 mL) at
room temperature. Stir for 2 hours. Evaporate the solvent under
reduced pressure. Partition the residue between ethyl acetate (250
mL) and aqueous Na.sub.2CO.sub.3 (250 mL). Separate the layers, dry
over Na.sub.2SO.sub.4, filter and concentrate. Purify the residue
by column chromatography on silica gel, eluting with ethyl
acetate/hexanes (0-30%), to provide the title compound as an
off-white solid (2.99 g, 92%). MS (ES+): 631, 633 (M+H).
Step 2. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,-
4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
##STR00336##
[0789] Add cesium fluoride (2.44 g, 16.1 mmol) to a mixture of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(9-bromo-7-methyl-8-trifluoromethyl--
2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-ami-
ne and methyl boronic acid (0.820 g, 13.8 mmol) in dioxane (50.0
mL). Purge the mixture with nitrogen for 15 min. Add
1,1'-bis(diphenylphosphino)ferrocene palladium (II) chloride,
complex with dichloromethane (0.290 g, 0.355 mmol) under nitrogen.
Heat the reaction mixture for 3 h. Cool down to room temperature
and then evaporate the solvent under reduced pressure. Partition
the residue between ethyl acetate (100 mL) and water (100 mL).
Separate the layers and extract the aqueous with more ethyl acetate
(2.times.50 mL). Combine the organic layers, dry over
Na.sub.2SO.sub.4, filter and concentrate. Purify the residue by
column chromatography on silica gel, eluting with ethyl
acetate/hexanes (0-35%), to provide the title compound as an
off-white solid (2.16 g, 83%). MS (ES+): 567 (M+H).
Step 3. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7,9-dimethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine
##STR00337##
[0791] Prepare the title compound by essentially following the
procedure described in Example 3, Step 19 by replacing
cyclopentanecarboxaldehyde with cyclopropanecarboxaldehyde, and
(S)-(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)amine
with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,-
4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine.
MS (ES+): 621 (M+H).
Example 149
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7,9-dimethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine hydrochloride
##STR00338##
[0793] Dissolve
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7,9-dimethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine (Example 148) (0.0210 g, 0.0338 mmol) in ethyl
ether (0.5 mL). Add HCl in ether (1.0 N, 0.0338 mL). Evaporate the
solvent and then triturate the residue with hexane to provide an
off-white powder. MS (ES+): 621 (M+H).
Example 150
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopentylmethyl-7,9-dimethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-y)-amine
##STR00339##
[0795] Prepare the title compound by essentially following the
procedure described in Example 148, Step 3 by replacing
cyclopropanecarboxaldehyde with cyclopentanecarboxaldehyde. MS
(ES+): 649 (M+H).
Example 151
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-1-pyridin-4-ylmethyl-8-
-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-t-
etrazol-5-yl)-amine
##STR00340##
[0797] Prepare the title compound by essentially following the
procedure described in Example 148, Step 3 by replacing
cyclopropanecarboxaldehyde with pyridine-4-carbaldehyde and
1,2-dichloroethane with acetonitrile. MS (ES+): 658 (M+H).
Example 152
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(1-ethyl-7,9-dimethyl-8-trifluoromet-
hyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-
-amine
##STR00341##
[0799] Prepare the title compound by essentially following the
procedure described in Example 148, Step 3 by replacing
cyclopropanecarboxaldehyde with acetaldehyde. MS (ES+): 595
(M+H).
Example 153
Synthesis of
(S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-y-
lmethyl}-cyclohexyl)-acetic acid
##STR00342##
[0800] Step 1. Preparation of
(S)-(4-(5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-y-
lmethyl}-cyclohexyl)-acetic acid methyl ester
##STR00343##
[0802] Prepare the title compound by essentially following the
procedure described in Example 148, Step 3 by replacing
cyclopropanecarboxaldehyde with (4-formyl-cyclohexyl)-acetic acid
methyl ester. MS (ES+): 735 (M+H).
Step 2. Preparation of
(S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-y-
lmethyl}-cyclohexyl)-acetic acid
##STR00344##
[0804] Heat the mixture of
(S)-(4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-y-
lmethyl}-cyclohexyl)-acetic acid methyl ester (0.0950 g, 0.129
mmol) in 5.0 N NaOH (1 mL) and methanol (2 mL) under reflux for 2
h. Evaporate the solvents and re-dissolve in water (10 mL). Adjust
to pH=7 by adding 2.0 N HCl. Extract with ethyl acetate (2.times.10
mL). Combine organic layers, dry over anhydrous sodium sulfate and
filter. Remove the solvent under reduced pressure. Chromatograph
the residue over silica gel, eluting with ethyl acetate/hexanes
(0-100%), to provide the title compound as a white foam (0.0620 g,
67%). MS (ES+): 721 (M+H); 719 (M-H).
Example 154
Synthesis of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
}-3,3dimethyl-pentanoic acid
##STR00345##
[0805] Step 1. Preparation of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
}-3,3-dimethyl-pentanoic acid methyl ester
##STR00346##
[0807] Prepare the title compound by essentially following the
procedure described in Example 148, Step 3 by replacing
cyclopropanecarboxaldehydc with 3,3-Dimethyl-5-oxo-pentanoic acid
methyl ester. MS (ES+): 709 (M+H).
Step 2. Preparation of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
}-3,3-dimethyl-pentanoic acid
##STR00347##
[0809] Heat the mixture of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
}-3,3-dimethyl-pentanoic acid methyl ester (0.120 g, 0.169 mmol) in
5.0 N NaOH (1 mL) and methanol (5 mL) under reflux for 2 h.
Evaporate the solvents and re-dissolve in water (10 mL). Adjust to
pH=4 by adding 4.0 N HCl. Extract with ethyl acetate (2.times.10
mL). Combine the organic layers, dry over anhydrous sodium sulfate
and filter. Remove the solvent under reduced pressure.
Chromatograph the residue over silica gel, eluting with ethyl
acetate/hexanes (0-100%), to provide the title compound as white
foam (0.104 g, 88%). MS (ES+): 695 (M+H); 693 (M-H).
Example 155
Synthesis of
(S)-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}--
oxo-accticacid_methyl ester
##STR00348##
[0811] Dissolve
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,-
4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 148, Step 2) (0.200 g, 0.353 mmol) in dichloromethane (4
mL), cool the solution down with an ice-water bath. Add pyridine
(0.143 mL, 1.77 mmol) followed by chloro-oxo-acetic acid methyl
ester (0.162 mL, 1.77 mmol) dropwise. Warm up the reaction to room
temperature and stir overnight. Dilute the reaction mixture with
more dichloromethane (10 mL), and wash with aqueous NaHCO.sub.3 (10
mL). Extract back the aqueous layer with dichloromethane (10 mL).
Combine the organic layers, dry over anhydrous sodium sulfate and
filter. Remove the solvent under reduced pressure. Chromatograph
the residue over silica gel, eluting with ethyl acetate/hexanes
(0-30%), to provide the title compound (0.187 g, 81%). MS (ES+):
653 (M+H).
Example 156
Synthesis of
(S)-5-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
)-5-oxo-pentanoic acid methyl ester
##STR00349##
[0813] Prepare the title compound by essentially following the
procedure described in Example 155 by replacing chloro-oxo-acetic
acid methyl ester with 4-chlorocarbonyl-butyric acid methyl ester.
MS (ES+): 695 (M+H).
Example 157
Synthesis of
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
}-ethanol
##STR00350##
[0815] Prepare the title compound by essentially following the
procedures described in Example 33, by replacing
(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
with
(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,4,5--
tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine.
MS (ES+): 611 (M+H).
Example 158
Synthesis of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-(1-cyclopropylmethyl-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-
-benzo[b]azepin-5-yl)-amine
##STR00351##
[0816] Step 1. Preparation of
(S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluorome-
thyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]
-tetrazol-2-yl}-ethyl)-isoindole-1,3-dione
##STR00352##
[0818] Prepare the title compound by essentially following the
procedure described in Example 148, Step 1 and 2, by replacing
(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
with
2-(2-{5-[(3,5-bis-trifluoromethyl-benzyl)-(7-methyl-8-trifluoromethyl-2,3-
,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetrazol-2-yl}-ethyl)-isoin-
dole-1,3-dione (Example 126, Step 2). MS (ES+): 726 (M+H).
Step 2. Preparation of
(S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7,9-di-
methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino1-
.sub.7tetrazol-2-yl}-ethyl)-isoindole-1,3-dione
##STR00353##
[0820] Prepare the title compound by essentially following the
procedure described in Example 148, Step 3, by replacing
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,-
4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
with
(S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-triflu-
oromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-tetrazol-2-yl}-
-ethyl)-isoindole-1,3-dione. MS (ES+): 780 (M+H).
Step 3. Preparation of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-(1-cyclopropylmethyl-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-
-benzo[b]azepin-5-yl)-amine
##STR00354##
[0822] Heat the mixture of
(S)-2-(2-(5-[(3,5-Bis-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7,9-di-
methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amino]-
-tetrazol-2-yl}-ethyl)-isoindole-1,3-dione (0.175 g, 0.224 mmol)
and hydrazine hydrate (0.1 ml) in methanol (2.0 mL) at 60.degree.
C. overnight. Cool down to room temperature. Remove the precipitate
by filtration and evaporate the solvent to provide the title
compound (0.143 g, 98%). MS (ES+): 650 (M+H).
Example 159
Synthesis of (S)-tert-butyl
4-{5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7,-
9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepin-1-ylmethyl}--
piperidine-4-carboxylate
##STR00355##
[0824] Add sodium triacetoxyborohydride (0.374 g, 1.76 mmol)
portionwise to a solution of
(S)-(3,5-bistrifluoromethylbenzyl)-(7,9-dimethyl-8-trifluoromethyl-2,3,4,-
5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 148, Step 2) (0.250 g 0.441 mmol),
tert-butyl-4-formylpiperidine-1-carboxylate (0.282 g, 1.32 mmol)
and glacial acetic acid (0.2 mL) in 1,2-dichloroethane (3 mL) at
room temperature under an atmosphere of nitrogen and stir for 24 h.
Quench the reaction with saturated sodium bicarbonate (5 mL) and
dilute with dichloromethane (15 mL). Separate the layers and wash
the organic layer with saturated sodium bicarbonate and brine (20
mL each). Dry the organic layer over sodium sulfate, filter and
remove the solvent under reduced pressure. Purify the residue using
flash column chromatography on silica gel, eluting with
hexanes/ethyl acetate (80:20), to provide the title compound as a
white crushable foam (0.272 g, 81%). .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.87-1.14 (m, 3H), 1.24-1.34 (m, 1H), 1.45 (s, 9H),
1.61-1.97 (m, 7H), 2.30-2.33 (m, 6H), 2.65-2.75 (m, 2H), 2.86-2.89
(m, 2H), 2.95-3.11 (m, 1H), 3.25-3.28 (m, 1H), 4.13 (s, 3H),
4.81-4.88 (m, 1H), 5.21 (br s, 1H), 5.60 (br s, 1H), 6.57 (s, 1H),
7.77 (s, 3H); ESI MS m/z 764
[C.sub.35H.sub.42F.sub.9N.sub.7O.sub.2+H].sup.+.
Example 160
Synthesis of
(S)-(3,5-bistrifluoromethylbenzyl)-(7,9-dimethyl-1-piperidin-4-ylmethyl-8-
-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-t-
etrazol-5-yl)-amine
##STR00356##
[0826] Add trifluoroacetic acid (1.7 mL) slowly to a solution of
(S)-tert-butyl
4-{5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7,-
9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepin-1-ylmethyl}--
piperidine-1-carboxylate (Example 159) (0.251 g, 0.329 mmol) in
dichloromethane (4 mL) at 0.degree. C. under an atmosphere of
nitrogen and stir for 4.5 h. Pour the reaction into saturated
sodium bicarbonate (25 mL) and dilute with dichloromethane (15 mL).
Separate the layers and extract the aqueous layer with
dichloromethane (10 mL). Combine the organic layers, wash with
saturated sodium bicarbonate (25 mL), dry over sodium sulfate,
filter and remove the solvent under reduced pressure. Purify the
residue using flash column chromatography on silica gel, eluting
with dichloromethane/methanol/concentrated ammonium hydroxide
(90:10:1), to provide the title compound as a white solid (0.101 g,
46%): .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1.01-1.11 (., 2H),
1.47-1.66 (m, 3H), 1.73-1.95 (m, 5H), 2.34 (s, 6H), 2.55-2.60 (m,
2H), 2.84-2.87 (m, 2H), 2.98-3.09 (m, 3H), 3.25 (br s, 1H), 4.13
(m, 3H), 4.73-4.96 (m, 1H), 5.12 (br s, 1H), 5.56 (br s, 1H), 6.58
(s, 1H), 7.77 (s, 3H); ESI MS m/z 664
[C.sub.30H.sub.34F.sub.9N.sub.7+H].sup.+.
Example 161
Synthesis of
(S)-(3,5-bistrifluoromethylbenzyl)-[7,9-dimethyl-1-(1-methylpiperidin-4-y-
lmethyl)-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(2-m-
ethyl-2H-tetrazol-5-yl)-amine
##STR00357##
[0828] Add glacial acetic acid (0.25 mL) over 25 minutes to a
solution of
(S)-(3,5-bistrifluoromethylbenzyl)-(7,9-dimethyl-1-piperidin-4-ylmethyl-8-
-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-t-
etrazol-5-yl)-amine (Example 160) (0.038 g, 0.057 mmol), 37%
aqueous formaldehyde (0.014 mL, 0.189 mmol) and sodium
cyanoborohydride (0.011 g, 0.172 mmol) in acetonitrile (2.5 mL) at
room temperature under an atmosphere of nitrogen and stir for 18 h.
Dilute the reaction with dichloromethane (20 mL) and wash with 2 N
sodium hydroxide and brine (10 mL each). Dry the organic layer over
sodium sulfate, filter and remove the solvent under reduced
pressure. Purify the residue using flash column chromatography on
silica gel, eluting with dichloromethane/methanol/concentrated
ammonium hydroxide (90:10:1), to provide the title compound as a
white crushable foam (0.028 g, 72%). .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 1.15-1.70 (m, 4H), 1.83-2.06 (m, 7H), 2.33-2.35 (m,
9H), 2.76-3.03 (m, 5H), 3.24 (br s, 1H), 4.13 (m, 3H), 4.80-4.87
(m, 1H), 5.14 (br s, 1H), 5.58 (br s, 1H), 6.58 (m, 1H), 7.77-7.78
(m, 3H); ESI MS m/z 678
[C.sub.31H.sub.36F.sub.9N.sub.7+H].sup.+.
Example 162
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(5-pyrid-
in-4-ylmethyl-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl-
)-amine Hydrochloride
##STR00358##
[0830] To a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(5-pyrid-
in-4-ylmethyl-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl-
)-amine (Example 103) in diethyl ethyl ether, add HCl as a 1.0 M
solution in diethyl ether. Remove solvent under a slow stream of
nitrogen followed by vacuum to obtain the title compound as an off
white solid. MS (ES+): 580 (M+H).
Example 163
Synthesis of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-
-(5-thiazol-2-ylmethyl-3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]i-
nden-9-yl)-amine
##STR00359##
[0832] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-[2-(2-Amino-ethyl)-2H-tetrazol-5-yl]-(5-benzyl-3,5,6,7,8,9-hexahydro--
1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(3,5-b is
-trifluoromethyl-benzyl)-amine (Example 107) starting with
(S)-2-(2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-amino]-tetrazol-2-yl}-ethyl)-isoindole-
-1,3-dione (Example 107, Step 1) and replacing benzaldehyde with
thiazole-2-carbaldehyde in Example 107, Step 2. MS (ES+): 637
(M-H).
Example 164
Synthesis of
(S)-1-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-yl)-2-ethyl-bu-
tan-1-one
##STR00360##
[0834] Add pyridine (0.35 mmol) followed by 2-ethyl-butyryl
chloride (0.35 mmol) to a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-az-
a-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 73, Step 7) (0.17 mmol) in dichloromethane (3 mL). After
stirring at room temperature for 14 h, dilute the reaction with
dichloromethane (10 mL) followed by water (10 mL). Separate the
organic phase and wash the aqueous with dichloromethane (2.times.10
mL). Dry the combined organics over sodium sulfate, filter, and
remove solvent in vacuuo. Chromatograph the crude product over
silica gel using ethyl acetate/hexane (10-50%) to elute to obtain
the title compound as a colorless foam. MS (ES+): 611 (M+H).
Example 165
Synthesis of
(S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-4-methyl-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylme-
thyl}-cyclohexyl)-acetic acid
##STR00361##
[0835] Step 1. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-bromo-3,5,6,7,8,9-hexahydro-1H-2--
oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
##STR00362##
[0837] To a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-az-
a-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 73, Step 7) (2.64 mmol) in chloroform (20 mL), add
N-bromosuccinamide (2.9 mmol) along with sodium bicarbonate (5.28
mmol). After stirring the mixture at room temperature for 20
minutes, add water (20 mL) and dilute the mixture with
dichloromethane (20 mL). Separate the organics and wash the aqueous
with dichloromethane (2.times.10 mL). Dry the combined organics
over sodium sulfate, filter, and remove solvent under vacuum.
Chromatograph the crude intermediate over silica gel eluting with
ethyl acetate/hexane to obtain the title compound as an off white
solid. MS (ES+): 593 (M+H).
Step 2. Preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
##STR00363##
[0839] To a solution of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-bromo-3,5,6,7,8,9-hexahydro-1H-2--
oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(2.16 mmol) in dioxane (150 mL), add
bis(diphenylphosphinoferrocene)palladium(II) chloride (0.22 mmol)
followed by cesium fluoride (9.32 mmol) and methylboronic acid
(6.48 mmol). Heat the mixture under nitrogen to 95.degree. C. After
heating for 2 h, cool the reaction mixture to room temperature and
dilute with ethyl acetate (50 mL) and water (50 mL). Separate the
organics and wash the aqueous with ethyl acetate (2.times.20 mL).
Dry the combined organics over sodium sulfate, filter, and remove
the solvent under vacuum. Chromatograph the crude product over
silica gel, eluting with ethyl acetate/hexane (10-45%) to obtain
the title compound as an off white solid. MS (ES+): 527 (M+H).
Step 3. Preparation of
(S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino)-4-methyl-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylme-
thyl}-cyclohexyl)-acetic acid methyl ester.
##STR00364##
[0841] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)5-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-thioph-
ene-2-carboxylic acid (Example 102), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
and replacing 5-formyl-thiophene-2-carboxylic acid with
(4-formyl-cyclohexyl)-acetic acid methyl ester.
Step 4. Synthesis of
(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-4-methyl-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl-
}-cyclohexyl)-acetic acid
##STR00365##
[0843] To a solution of
(S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-4-methyl-1,3,6,7,8,9-hexahydro-2-aza-cyclohepta[f]inden-5-ylmethyl]--
cyclohexyl)-acetic acid methyl ester (0.15 mmol) in methanol (5
mL), add 5 N sodium hydroxide (3 mL). Heat the mixture to
60.degree. C. for 2 h, then cool to room temperature and dilute
with water (20 mL). Neutralize the reaction with 5M HCl and extract
the organics with ethyl acetate (3.times.10 mL). Dry the combined
organics over sodium sulfate, filter, and remove the solvent under
vacuum. Chromatograph the product over silica gel, eluting with
ethyl acetate/hexane (10-70%) to obtain the title compound as a
colorless foam. MS (ES+): 681 (M+H).
Example 166
Synthesis of
(S)-4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-4-methyl-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmet-
hyl}-benzoic acid
##STR00366##
[0845] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-4-methyl-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylme-
thyl}-cyclohexyl)-acetic acid (Example 165), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
and replacing (4-formyl-cyclohexyl)-acetic acid methyl ester with
4-formyl-benzoic acid methyl ester in Example 165, step 3. MS
(ES+): 661 (M+H).
Example 167
Synthesis of
(S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-4-methyl-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmet-
hyl)-thiophene-2-carboxylic acid
##STR00367##
[0847] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-(4-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-a-
mino]-4-methyl-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylme-
thyl}-cyclohexyl)-acetic acid (Example 165), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
and replacing (4-formyl-cyclohexyl)-acetic acid methyl ester with
5-Formyl-thiophene-2-carboxylic acid in Example 165, Step 3. MS
(ES+): 665 (M-H).
Example 168
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-methyl-5-pyridin-3-ylmethyl-3,5,6-
,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetr-
azol-5-yl)-amine
##STR00368##
[0849] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl
}-thiophene-2-carboxylic acid (Example 102), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 165, Step 2) and replacing 5-formyl-thiophene-2-carboxylic
acid with pyridine-3-carbaldehyde. MS (ES+): 618 (M+H).
Example 169
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopropylmethyl-4-methyl-3,5,6,-
7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine
##STR00369##
[0851] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-thiop-
hene-2-carboxylic acid (Example 102), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 165, Step 2) and replacing 5-formyl-thiophene-2-carboxylic
acid with cyclopropanecarboxaldehyde. MS (ES+): 581 (M+H).
Example 170
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-4-methyl-3,5,6,-
7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetra-
zol-5-yl)-amine
##STR00370##
[0853] Prepare the title compound uby essentially following the
procedures described in the synthesis of
(S)5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-thiop-
hene-2-carboxylic acid (Example 102), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 165, Step 2) and replacing 5-formyl-thiophene-2-carboxylic
acid with cyclopentanecarboxaldehyde. MS (ES+): 609 (M+H).
Example 171
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclobutylmethyl-4-methyl-3,5,6,7-
,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetraz-
ol-5-yl)-amine
##STR00371##
[0855] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-thio-
phene-2-carboxylic acid (Example 102), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 165, Step 2) and replacing 5-formyl-thiophene-2-carboxylic
acid with cyclobutanecarboxaldehyde. MS (ES+): 595 (M+H).
Example 172
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclobutyl-4-methyl-3,5,6,7,8,9-h-
exahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-y-
l)-amine
##STR00372##
[0857] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-thiop-
hene-2-carboxylic acid (Example 102), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 165, Step 2) and replacing 5-formyl-thiophene-2-carboxylic
acid with cyclobutanone. MS (ES+): 581 (M+H).
Example 173
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-[4-methyl-5-(tetrahydro-pyran-4-yl)--
3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl]-(2-methyl-2H-
-tetrazol-5-yl)-amine
##STR00373##
[0859] Prepare the title compound by essentially following the
procedures described in the synthesis of (S)5-55
9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-1,-
3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl)-thiophene-2-
-carboxylic acid (Example 102), starting with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 165, Step 2) and replacing 5-formyl-thiophene-2-carboxylic
acid with tetrahydro-pyran-4-one. MS (ES+): 611 (M+H).
Example 174
Synthesis of
(S)-(3-Chloro-5-trifluoromethyl-benzyl)-(5-cyclopropylmethyl-4-methyl-3,5-
,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine
##STR00374##
[0860] Step 1. Preparation of
(S)-(3-Chloro-5-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-
-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
##STR00375##
[0862] Prepare the title compound by essentially following the
procedures described for the preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-az-
a-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 73) by replacing 3-Chloro-5-trifluoromethyl-benzaldehyde
for 3,5-bis-trifluoromethylbenzaldehyde in Example 73, Step 4. MS
(ES+): 579 (M+H).
Step 2. Preparation of
(S)-(3-Chloro-5-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1-
H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
##STR00376##
[0864] Prepare the title compound by essentially following the
procedures described in the preparation of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1H-2-
-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
(Example 165 Steps 1 and 2), starting with
(S)-(3-Chloro-5-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-
-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine. MS
(ES+): 491 (M-H).
Step 3. Preparation of
(S)-(3-Chloro-5-trifluoromethyl-benzyl)-(5-cyclopropylmethyl-4-methyl-3,5-
,6,7,
8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-t-
etrazol-5-yl)-amine
##STR00377##
[0866] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)5-{9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]inden-5-ylmethyl}-thiop-
hene-2-carboxylic acid (Example 102), starting with
(S)-(3-Chloro-5-trifluoromethyl-benzyl)-(4-methyl-3,5,6,7,8,9-hexahydro-1-
H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine
and replacing 5-formyl-thiophene-2-carboxylic acid with
cyclopropane carboxyaldehyde. MS (ES+): 547 (M+H).
Example 175
Synthesis of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-cy-
clohexanecarboxylic acid
##STR00378##
[0867] Step 1. Preparation of
(S)-4-(5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-cy-
clohexanecarboxylic acid ethyl ester
##STR00379##
[0869] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-(3,5-Bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-triflu-
oromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-
-5-yl)amine (Example 3 step 19) by replacing
cyclopentanecarboxaldehyde with 4-oxo-cyclohexanecarboxylic acid
ethyl ester. Isolate the title compound by chromatography over
silica gel, eluting with ethyl acetate/hexane. MS (ES+): 707
(M+H).
Step 2. Preparation of
(S)-4-(5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-cy-
clohexanecarboxylic acid
##STR00380##
[0871] To a solution of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-cy-
clohexanecarboxylic acid ethyl ester (0.14 mmol) in methanol (5
mL), add 5N sodium hydroxide (14 mmol). After heating the mixture
at 60.degree. C. for 2 h, cool to room temperature and dilute with
water (20 mL). Neutralize the mixture using 5M HCl and extract the
organics using ethyl actate (3.times.5 mL). Dry the combined
organics over sodium sulfate, filter, and remove the solvent under
vacuum. Chromatograph the crude product over silica gel, eluting
with methanol/dichloromethane (0-5%) to obtain the separated cis
and trans isomers. MS (ES+): 679 (M+H).
Example 176
Synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 4-carboxy-cyclohexyl ester
##STR00381##
[0872] Step 1. Preparation of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 4-methoxycarbonyl-cyclohexyl ester
##STR00382##
[0874] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 1-ethyl-propyl ester (Example 18), by replacing pentan-3-ol
with 4-hydroxy-cyclohexanecarboxylic acid methyl ester. MS (ES+):
737 (M+H).
Step 2. Preparation of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 4-carboxy-cyclohexyl ester
##STR00383##
[0876] To a solution of
(S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxyl-
ic acid 4-methoxycarbonyl-cyclohexyl ester (0.14 mmol) in methanol
(5 mL), add 5N sodium hydroxide (14 mmol). After heating the
mixture at 60.degree. C. for 2 h, cool to room temperature and
dilute with water (20 mL). Neutralize the mixture using 5M HCl and
extract the organics using ethyl actate (3.times.5 mL). Dry the
combined organics over sodium sulfate, filter, and remove the
solvent under vacuum. Chromatograph the crude product over silica
gel, eluting with methanol/dichloromethane (0-5%) to obtain the
separated cis and trans isomers. MS (ES+): 723 (M+H).
Example 177
Synthesis of
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-ca-
rboxylic acid tert-butyl ester
##STR00384##
[0878] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-(3,5-Bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-triflu-
oromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-
-5-yl)amine (Example 3, Steps 1-3) (alternative preparation of
methyl-2-(N-isoproposycarbonyl)amino-5-methyl-4-trifluoromethylbezoate)
starting with 2,2-difluoro-benzo[1,3]diozol-5-ylaminc and then
proceeding with Example 3, Steps 6-17. MS (ES+): 543 (M+H).
Example 178
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(5-cyclopentylmethyl-2,2-difluoro-6,-
7,8,9-tetrahydro-5H-1,3-dioxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H--
tetrazol-5-yl)-amine
##STR00385##
[0880] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-(3,5-Bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-triflu-
oromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-
-5-yl)amine (Example 3, Steps 18-19) by replacing (S)-tert-butyl
5-[(3,5-bistrifluoromethylbenzyl)-(2-methyl-2H-tetrazol-5-yl)amino]-7-met-
hyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate
with
(S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino-
]-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cyclohepta[f]indene-5-ca-
rboxylic acid tert-butyl ester (Example 177). MS (ES+): 525
(M+H).
Example 179
Synthesis of
(S)-5-(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbox-
ylic acid tert-butyl ester
##STR00386##
[0881] Step 1. Preparation of
(S)-5-(3-fluoro-5-trifluoromethyl-benzylamino)-7-methyl-8-trifluoromethyl-
-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl
ester
##STR00387##
[0883] Add sodium triacetoxyborohydride (0.40 g, 1.89 mmol) to a
mixture of 3-fluoro-5-trifluoromethyl benzaldehyde (0.096 mL, 0.69
mmol), acetic acid (0.030 mL, 0.625 mmol)) and (S)-tert-Butyl
5-amino-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-ca-
rboxylate (Example 3, Step 13) (0.215 g, 0.63 mmol) in
dichloroethane (3.0 mL). Stir the mixture at room temperature under
an atmosphere of nitrogen for 20 h. Add a saturated solution of
sodium bicarbonate, separate the layers and extract the aqueous
layer with dichloromethane. Dry the combined organic layers over
anhydrous sodium sulfate, filter, and remove the solvent under
reduced pressure. Purify the residue by flash chromatography,
eluting with hexanes/ethyl acetate (gradient eluent, 0-30% ethyl
acetate in hexane), to afford the title compound (0.32 g, 98%). MS
(ES+): 521 (M+H).
Step 2. Preparation of
(S)-5-[cyano-(3-fluoro-5-trifluoromethyl-benzylamino)-7-methyl-8-trifluor-
omethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid
tert-butyl ester
##STR00388##
[0885] Add cyanogen bromide (0.20 g, 1.88 mmol) followed by
N,N-diisopropyl ethylamine (0.43 mL, 2.48 mmol) to a solution of
(S)-5(3-fluoro-5-trifluoromethyl acid tert-butyl ester (0.32 g,
0.62 mmol) in THF (2 mL). After stirring at 65.degree. C. for 12 h
remove the solvent under vacuum. Dilute with ether (20 mL), wash
with water, brine, dry and concentrate under reduced pressure.
Chromatograph the product over silica gel, eluting with ethyl
acetate/hexane (gradient eluent, 0-50% ethyl acetate in hexane) to
obtain the title compound (0.32 g, 91%). MS (ES+): 546 (M+H).
Step 3. Preparation of
(S)-5-(3-fluoro-5-trifluoromethyl-benzyl)-(1H-tetrazol-5yl)-amino]-7-meth-
yl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepinc-1-carboxylic
acid tert-butyl ester
##STR00389##
[0887] Prepare the title compound by stirring
(S)-5-[cyano-(3-fluoro-5-trifluoromethyl-benzylamino)-7-methyl-8-trifluor-
omethyl-2,3,4,5-tetrahydro-benzo[b)azepine-1-carboxylic acid
tert-butyl ester (0.31 g, 0.57 mmol) with sodium azide (0.11 g,
1.70 mmol) and triethylamine hydrochloride (0.31 g, 2.28 mmol) in
anhydrous toluene (3 mL) and heat at 110.degree. C. for 16 h.
Dilute the cooled mixture with water and 0.1 N HCl to bring the pH
to 6-7 and extract with EtOAc (3.times.15 mL). Combine the organic
layers and wash with water and brine, dry over sodium sulfate,
filter, and concentrate under reduced pressure to give a residue.
Purify the residue by chromatography (elution with 5% methanol in
EtOAc) to afford the title compound (0.27 g, 81%). MS (ES+): 589
(M+H).
Step 4. Preparation of
(S)-5(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxy-
lic acid tert-butyl ester
##STR00390##
[0889] To a solution of
(S)-5-(3-fluoro-5-trifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-7-met-
hyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid tert-butyl ester (0.19 g, 0.32 mmol) and methanol (0.065 mL,
1.61 mmol) in dichloromethane (2 mL) at room temperature, under
nitrogen atmosphere, add in one portion triphenyl phosphine (0.084
g, 0.32 mmol) followed by addition of DEAD (0.06 mL, 0.32 mmol).
Allow the reaction mixture to stir at room temperature overnight.
Remove the solvent under reduced pressure. Purify the residue by
flash chromatography, eluting with hexanes/ethyl acetate (elution
with 30% EtOAc in hexane), to afford the title compound (0.18 g,
93%). MS (ES+): 503 (M.sup.+-Boc+H).
Example s 180-185
##STR00391##
[0891] Prepare Examples 180-185, in the table below, by essentially
following the procedure describe in the synthesis of
(S)-5(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxy-
lic acid tert-butyl ester (Example 179, Steps 1.4), by replacing
3-fluoro-5-trifluoromethyl benzaldehyde in Step 1 with the
appropriate reagent.
TABLE-US-00010 Example # Reagent MS (ES+) Example 180 ##STR00392##
3,5-dichloro benzaldehyde 585 (M + H) Example 181 ##STR00393##
3-trifluoromethoxy benzaldehyde 601 (M + H) Example 182
##STR00394## 2-fluoro-3-chloro-5-trifluoromethyl benzaldehyde 635
(M - H) Example 183 ##STR00395## 4-trifluoromethyl-3-pyridine
carboxaldehyde 608 (M + Na) Example 184 ##STR00396##
3-methyl-5-trifluoromethyl benzaldehyde 499 (M - Boc + H) Example
185 ##STR00397## 3-chloro-5-trifluoromethyl benzaldehyde 519 (M -
Boc + H)
Example 186
Synthesis of
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine
##STR00398##
[0892] Step 1. Preparation of
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-me-
thyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-yl)-amine
##STR00399##
[0894] Add trifluoroacetic acid (0.37 mL) to a solution of
(S)-5-(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbox-
ylic acid tert-butyl ester (Example 179, Step 4) (0.14 g, 0.24
mmol) in methylene chloride (2 mL) at room temperature under
nitrogen. Stit the reaction for 1 h and pour the mixture into
saturated aqueous sodium bicarbonate solution (20 mL). Extract the
mixture with methylene chloride (2.times.20 mL) and wash the
Combined organic extracts with brine (50 mL), dry over anhydrous
sodium sulfate and filter. Remove the solvent under reduced
pressure to provide the title compound as a colorless oil. Purify
the residue by column chromatography on silica gel, eluting with
ethyl acetate/hexanes (0-30%), to provide the title compound (0.12
g, 98%). MS (ES+): 503 (M+H).
Step 2. Preparation of
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine
##STR00400##
[0896] Add pyridine-4-carboxaldehyde (0.065 mL, 0.69 mmol) to a
solution of
(5)-(3-fluoro-5-trifluoromethyl-benzyl)-2-methyl-2H-tetrazol-5-yl)-(7--
methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-yl)-amine
(0.12 g, 0.23 mmol) in 1,2-dichloroethane (10 mL) and acetic acid
(0.02 mL) at room temperature under nitrogen and stir for 5 min.
Add sodium triacetoxy borohydride (0.29 g, 1.38 mmol) and stir for
12 h. Dilute the mixture with methylene chloride (30 mL) and wash
with saturated aqueous sodium bicarbonate solution (2.times.10 mL).
Extract the combined aqueous washes with methylene chloride (20 mL)
and wash the combined organic extracts with brine (20 mL) and dry
over anhydrous sodium sulfate. Remove the solvents under reduced
pressure and purify by silica gel column (gradient eluent, 0-5%
MeOH in ethyl acetate) to give the title compound (0.12 g, 87%). MS
(ES+): 594 (M+H).
Example 187
Synthesis of
(S)-(3,5-Dichloro-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8-trifluoromethy-
l-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-a-
mine
##STR00401##
[0898] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine (Example 186) by replacing
(S)-5(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxy-
lic acid tert-butyl ester with
(S)-5-[(3,5-Dichloro-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl--
8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid tert-butyl ester (Example 180) in Example 186, Step 1. MS
(ES+): 576 (M+H)
Example 188
Synthesis of
(S)-(7-Methyl-1-pyridin-4-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1-
H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-(3-trifluoromethoxy-ben-
zyl)-amine
##STR00402##
[0900] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine (Example 186) by replacing
(S)-5(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxy-
lic acid tert-butyl ester with
(S)-7-Methyl-5-[(2-methyl-211-tetrazol-5-yl)-(3-trifluoromethoxy-benzyl)--
amino)-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic
acid tert-butyl ester (Example 181) in Example 186, Step 1. MS
(ES+): 592 (M+H).
Example 189
Synthesis of
(S)-(7-Methyl-1-pyridin-4-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1-
H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-(6-trifluoromethyl-pyri-
din-3-ylmethyl)-amine
##STR00403##
[0902] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine (Example 186) by replacing
(S(-5(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxy-
lic acid tent-butyl ester with
(S)-7-Methyl-5-[(2-methyl-2H-tetrazol-5-yl)-(6-trifluoromethyl-pyridin-3--
ylmethyl)-amino)-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-ca-
rboxylic acid tert-butyl ester (Example 183) in Example 186, Step
1. MS (ES+): 577 (M+H).
Example 190
Synthesis of
(S)-(7-Methyl-1-pyridin-4-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1-
H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-(3-methyl-5-trifluorome-
thyl-benzyl)-amine
##STR00404##
[0904] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine (Example 186) by replacing
(S)-5(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxy-
lic acid tert-butyl ester with
(S)-7-Methyl-5-[(2-methyl-2H-tetrazol-5-yl)-(3-methyl-5-trifluoromethyl-b-
enzyl)-amino]-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbo-
xylic acid tert-butyl ester (Example 184) in Example 186, Step 1.
MS (ES+): 590 (M+H).
Example 191
Synthesis of
(S)-(3-Chloro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine
##STR00405##
[0906] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine (Example 186) by replacing
(S)-5(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amin-
o]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxy-
lic acid tert-butyl ester with
(S)-5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbo-
xylic acid tert-butyl ester (Example 185) in Example 186, Step 1.
MS (ES+): 610 (M+H).
Example 192
Synthesis of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-benzonitrile
##STR00406##
[0908] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3,5-bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-triflu-
oromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-
-5-yl)amine (Example 3, Step 19) by replacing
cyclopentanecarboxaldehyde with 4-cyanobenzaldehyde. MS (ES+): 668
(M+H).
Example 193
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methy-
l-1-[4-(1H-tetrazol-5-yl)-benzyl]-8-trifluoromethyl-2,3,4,5-tetrahydro-1H--
benzo[b]azepin-5-yl}-amine
##STR00407##
[0910] Heat a mixture of
(S)-4-(5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-benzonitrile (Example 192) (0.13 g, 0.19 mmol), sodium azide
(0.04 g, 0.60 mmol) and triethylamine hydrochloride (0.08 g, 0.60
mmol) in anhydrous toluene (5 mL) at 110.degree. C. under nitrogen
for 20 h. Dilute the cooled mixture with ethyl acetate (50 mL) and
wash with aqueous 0.1 N HCl (10 mL) and brine (10 mL). Dry over
anhydrous sodium sulfate. Filter and remove the solvent under
reduced pressure. Purify the residue by column chromatography on
silica gel, eluting with MeOH/EtOAc (0-20%), to provide the title
compound (0.12 g, 82%). MS (ES+): 711 (M+H).
Example 194
Synthesis of
(S)-2-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo(b)azepin-1-ylmeth-
yl}-benzonitrile
##STR00408##
[0912] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3,5-bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-triflu-
oromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-
-5-yl)amine (Example 3, Step 19) by replacing
cyclopentanecarboxaldehyde with 2-cyanobenzaldehyde. MS (ES+): 668
(M+H).
Example 195
Synthesis of
(S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmeth-
yl}-benzonitrile
##STR00409##
[0914] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3,5-bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-triflu-
oromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-
-5-yl)amine (Example 3, Step 19) by replacing
cyclopentanecarboxaldehyde with 3-cyanobenzaldehyde. MS (ES+): 668
(M+H).
Example 196
Synthesis of
(S)-(3-Chloro-5-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7-methyl-8-t-
rifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tet-
razol-5-yl)-amine
##STR00410##
[0916] Prepare the title compound by essentially following the
procedures described in the synthesis of
(S)-(3-Chloro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-y)-amine (Example 191) by replacing
pyridine-4-carboxaldehyde with cyclopropane carboxaldehyde. MS
(ES+): 573 (M+H).
Example 197
Synthesis of
(S)-(4-{5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-
)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
methyl}-cyclohexyl)-acetic acid
##STR00411##
[0917] Step 1. Preparation of
(S)-(4-{5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-
)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
methyl}-cyclohexyl)-acetic acid methyl ester
##STR00412##
[0919] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3-Chloro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol -5-yl)-amine (Example 191) by replacing
pyridine-4-carboxaldehyde with (4-formyl-cyclohexyl)acetic acid
methyl ester. MS (ES+): 687 (M+H).
Step 2. Preparation of
(S)-(4-{5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-
)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
methyl}-cyclohexyl)-acetic acid
##STR00413##
[0921] To a solution of
(S)-(4-(5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-
)-amino)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
methyl}-cyclohexyl)-acetic acid methyl ester (0.1 mmol) in methanol
(1 mL), add 4N sodium hydroxide (0.4 mL). Heat the mixture at
60.degree. C. for 3 h. Dilute the cooled mixture with water and 1N
HCl to bring the pH to 6-7 and extract with CH.sub.2Cl.sub.2
(3.times.15 mL). Combine the organic layers and wash with water and
brine, dry over sodium sulfate, filter, and concentrate under
reduced pressure to give a residue. Purify the residue by
chromatography (elution with 5%-20% methanol in EtOAc) to afford
the title compound. MS (ES+): 673 (M+H).
Example 198
Synthesis of
(S)-4-{7-Methyl-5-[(2-methyl-2H-tetrazol-5-yl)-(3-methyl-5-trifluoromethy-
l-benzyl)-amino]-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-
-cyclohexanecarboxylic acid
##STR00414##
[0923] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-cy-
clohexanecarboxylic acid (Example 175) by replacing
(S)-(3,5-Bistrifluoromethylbenzyl)-(1-cyclopentylmethyl-7-methyl-8-triflu-
oromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-
-5-yl)amine with
(S)-(2-Methyl-2H-tetrazol-5-yl)-(3-methyl-5-trifluoromethyl-benzyl)-(7-me-
thyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
in Example 175, Step 1. MS (ES+): 639 (M+H).
Example 199
Synthesis of
(S)-(3-chloro-5-trifluoromethyl-benzyl)-(7,9-dimethyl-1-pyridin-4-ylmethy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2-
H-tetrazol-5-yl)-amine
##STR00415##
[0924] Step 1. Preparation of
(S)-(2-Methyl-2H-tetrazol-5-yl)-(3-methyl-5-trifluoromethyl-benzyl)-(7-me-
thyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine
##STR00416##
[0926] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-me-
thyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-yl)-amine
(Example 186, Step 1) by replacing
(S)-5-(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-ami-
no]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbox-
ylic acid tert-butyl ester with
(S)-5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbo-
xylic acid tert-butyl ester (Example 185). MS (ES+): 519 (M+H).
Step 2. Preparation of
(S)-(9-bromo-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]aze-
pin-5-yl)-(3-chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)--
amine
##STR00417##
[0928] Stir
(S)-(3-chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-me-
thyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-yl)-amine
(0.53 g, 1.02 mmol) with N-bromosuccinimide (0.22 g, 1.22 mmol) in
acetic acid (2 mL) at room temperature for 2 h. Evaporate the
solvent under reduced pressure. Dilute the residue with water and
neutralize with saturated NaHCO.sub.3 and extract with EtOAc
(3.times.25 mL). Combine the organic layers and wash with water and
brine, dry over sodium sulfate, filter, and concentrate under
reduced pressure to give a residue. Purify the residue by flash
chromatography, eluting with hexane/ethyl acetate (5-40% EtOAc in
hexane), to provide the title compound (0.49 g, 83%). MS (ES+): 599
(M+H).
Step 3. Preparation of
(S)-(3-chloro-5-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2-
,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amin-
e
##STR00418##
[0930] Add a solution of
(S)-(9-bromo-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]aze-
pin-5-yl)-(3-chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)--
amine (0.39 g, 0.65 mmol) in dioxane (5 mL) to a mixture of
methylboronic acid (0.12 g, 1.96 mmol), palladium
diphenylphosphinoferrocene dichloride (0.05 g, 0.06 mmol), and
cessium fluoride (0.35 g, 2.32 mmol), then purge with nitrogen and
stir for 15 min. at room temperature, then at 100.degree. C. for 4
h. After completion, cool the reaction to room temperature, dilute
with ethyl acetate (50 mL) and wash with water and brine (10 mL
each). Dry the organic layer over sodium sulfate, filter, and
remove the solvent under reduced pressure. Purify the residue using
flash column chromatography on silica gel, eluting with
hexanes/ethyl acetate (0-30% EtOAc in hexane), to provide the title
compound as a white solid (0.32 g, 90%). MS (ES+): 533 (M+H).
Step 4. Preparation of
(S)-(3-chloro-5-trifluoromethyl-benzyl)-(7,9-dimethyl-1-pyridin-4-ylmethy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2-
H-tetrazol-5-yl)-amine
##STR00419##
[0932] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine (Example 186, Step 2) by using
(S)-(3-chloro-5-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-2-
,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amin-
e (0.08 g, 0.15 mmol) and pyridine-4-carboxaldehyde (0.045 mL, 0.45
mmol) in dichloroethane (2 mL) at room temperature for 15 h to
afford the title compound. Purification by silica gel column
(gradient eluent, 0-5% MeOH in ethyl acetate) provides the title
compound (0.09 g 91%). MS (ES+): 624 (M+H).
Example 200
Synthesis of
(S)-(3-Chloro-5-trifluoromethyl-benzyl)-(1-cyclopropylmethyl-7,9-dimethyl-
-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-
-tetrazol-5-yl)-amine
##STR00420##
[0934] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3-chloro-5-trifluoromethyl-benzyl)-(7,9-dimethyl-1-pyridin-4-ylmethy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2-
H-tetrazol-5-yl)-amine (Example 199) by replacing
pyridine-4-carboxaldehyde with cyclopropane carboxaldehyde. MS
(ES+): 587 (M+H).
Example 201
Synthesis of
(S)-(4-(5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-
)-amino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin--
1-ylmethyl}-cyclohexyl)-acetic acid
##STR00421##
[0935] Step 1. Preparation of
(S)-(4-{5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-
)-amino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin--
1-ylmethyl)-cyclohexyl)-acetic acid methyl ester
##STR00422##
[0937] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3-chloro-5-trifluoromethyl-benzyl)-(7,9-dimethyl-1-pyridin-4-ylmethy-
l-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2-
H-tetrazol-5-yl)-amine (Example 199) by replacing
pyridine-4-carboxaldehyde with (4-formyl-cyclohexyl)-acetic acid
methyl ester. MS (ES+): 701 (M+H).
Step 2. Preparation of
(S)-(4-{5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-
)-amino)-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin--
1-ylmethyl}-cyclohexyl)-acetic acid
##STR00423##
[0939] To a solution of
(S)-(4-{5-[(3-Chloro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl-
)-amino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin--
1-ylmethyl}-cyclohexyl)-acetic acid methyl ester (0.1 mmol) in
methanol (1 mL), add 4N sodium hydroxide (0.5 mL). Heat the mixture
at 60.degree. C. for 3 h. Dilute the cooled mixture with water and
1N HCl to bring the pH to 6-7 and extract with CH.sub.2Cl.sub.2
(3.times.15 mL). Combine the organic layers, dry over sodium
sulfate, filter, and concentrate under reduced pressure to give a
residue. Purify the residue by chromatography (elution with 5%-10%
methanol in EtOAc) to afford the title compound. MS (ES+): 687
(M+H).
Example 202
Synthesis of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
methyl}-benzoic acid
##STR00424##
[0940] Step 1. Preparation of
(S)-4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
methyl}-benzoic acid methyl ester
##STR00425##
[0942] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine (Example 186, Step 2) by replacing
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-me-
thyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-yl)-amine
with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-
-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-am-
ine (Example 148, Step 2) and pyridine-4-carboxaldehyde with
4-formyl methyl benzoate. MS (ES+): 715 (M+H).
Step 2. Preparation of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino}-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
methyl}-benzoic acid
##STR00426##
[0944] To a solution of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
methyl}-benzoic acid methyl ester (0.1 mmol) in methanol (1 mL),
add 4N sodium hydroxide (0.5 mL). Heat the mixture at 60.degree. C.
for 3 h. Dilute the cooled mixture with water and 1N HCl to bring
the pH to 6-7 and extract with CH.sub.2Cl.sub.2 (3.times.15 mL).
Combine the organic layers, dry over sodium sulfate, filter, and
concentrate under reduced pressure to give a residue. Purify the
residue by chromatography (elution with 5% methanol in EtOAc) to
afford the title compound. MS (ES+): 701 (M+H).
Example 203
Synthesis of
(S)-3-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
methyl }-benzoic acid
##STR00427##
[0946] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
methyl}-benzoic acid (Example 202) by replacing 4-formyl methyl
benzoate with 3-formyl methyl benzoate in Example 202, Step 1. MS
(ES.sub.+): 701 (M+H).
Example 204
Synthesis of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
}-butyric acid
##STR00428##
[0948] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
methyl}-benzoic acid (Example 202) by replacing 4-formyl methyl
benzoate with succinic semialdehyde in Example 202, Step 1. MS
(ES+): 653 (M+H).
Example 205
Synthesis of
(S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-am-
ino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl-
methyl}-benzonitrile
##STR00429##
[0950] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(7-methyl-1-pyridin-4-ylmethyl-8--
trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-te-
trazol-5-yl)-amine (Example 186, Step 2) by replacing
(S)-(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-me-
thyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine-5-yl)-amine
with
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-8-trifluoromethyl-
-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-am-
ine (Example 148, Step 2) and pyridine-4-carboxaldehyde with
4-cyanobenzaldehyde. MS (ES+): 682 (M+H).
Example 206
Synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(7,9-dimethyl-1-[4-(1H-tetrazol-5-yl-
)-benzyl]-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}-(2--
methyl-2H-tetrazol-5-yl)-amine
##STR00430##
[0952] Prepare the title compound by essentially following the
procedure described in the synthesis of
(S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-{7-methy-
l-1-[4-(1H-tetrazol-5-yl)-benzyl}-8-trifluoromethyl-2,3,4,5-tetrahydro-1H--
benzo[b]azepin-5-yl}-amine (Example 193). MS (ES+): 725 (M+H).
* * * * *