U.S. patent application number 14/126579 was filed with the patent office on 2014-05-08 for cycloalkyl-fused tetrahydroquinolines as crth2 receptor modulators.
This patent application is currently assigned to Merck Sharp & Dohme Corp.. The applicant listed for this patent is Robert G. Aslanian, Purakkattle Johny Biju, Jason Brubaker, John W. Butcher, Joshua T. Close, Li Dong, Xianhai Huang, Ying Huang, Joon O. Jung, Rachel Nicola MacCoss, Michelle Martinez, Kevin D. McCormick, Anandan Palani, Scott L. Peterson, Ning Shao, Phieng Siliphaivanh, Hongjun Zhang, Wei Zhou. Invention is credited to Robert G. Aslanian, Purakkattle Johny Biju, Jason Brubaker, John W. Butcher, Joshua T. Close, Li Dong, Xianhai Huang, Ying Huang, Joon O. Jung, Rachel Nicola MacCoss, Michelle Martinez, Kevin D. McCormick, Anandan Palani, Scott L. Peterson, Ning Shao, Phieng Siliphaivanh, Hongjun Zhang, Wei Zhou.
Application Number | 20140128367 14/126579 |
Document ID | / |
Family ID | 47357455 |
Filed Date | 2014-05-08 |
United States Patent
Application |
20140128367 |
Kind Code |
A1 |
Huang; Xianhai ; et
al. |
May 8, 2014 |
CYCLOALKYL-FUSED TETRAHYDROQUINOLINES AS CRTH2 RECEPTOR
MODULATORS
Abstract
The invention provides certain cycloalkyl-fused
tetrahydroquinolines of the Formula (I), and their pharmaceutically
acceptable salts and esters, wherein R.sup.1, R.sup.2, R.sup.7,
R.sup.8a, E, Y, Z, n, u, and t are as defined herein. The invention
also provides pharmaceutical compositions comprising such
compounds, and methods of using the compounds for treating diseases
or conditions associated with uncontrolled or inappropriate
stimulation of CRTH.sub.2 function. ##STR00001##
Inventors: |
Huang; Xianhai; (Warren,
NJ) ; Brubaker; Jason; (Cambridge, MA) ;
Peterson; Scott L.; (Salem, MA) ; Butcher; John
W.; (Berlin, MA) ; Close; Joshua T.;
(Franklin, MA) ; Martinez; Michelle; (Medford,
MA) ; MacCoss; Rachel Nicola; (Oxford, GB) ;
Jung; Joon O.; (Newton, MA) ; Siliphaivanh;
Phieng; (Newton, MA) ; Zhang; Hongjun;
(Newton, MA) ; Aslanian; Robert G.; (Rockaway,
NJ) ; Biju; Purakkattle Johny; (Piscataway, NJ)
; Dong; Li; (Roselle Park, NJ) ; Huang; Ying;
(Berkeley Heights, NJ) ; McCormick; Kevin D.;
(Baking Ridge, NJ) ; Palani; Anandan;
(Bridgewater, NJ) ; Shao; Ning; (Watchung, NJ)
; Zhou; Wei; (Scotch Plains, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Huang; Xianhai
Brubaker; Jason
Peterson; Scott L.
Butcher; John W.
Close; Joshua T.
Martinez; Michelle
MacCoss; Rachel Nicola
Jung; Joon O.
Siliphaivanh; Phieng
Zhang; Hongjun
Aslanian; Robert G.
Biju; Purakkattle Johny
Dong; Li
Huang; Ying
McCormick; Kevin D.
Palani; Anandan
Shao; Ning
Zhou; Wei |
Warren
Cambridge
Salem
Berlin
Franklin
Medford
Oxford
Newton
Newton
Newton
Rockaway
Piscataway
Roselle Park
Berkeley Heights
Baking Ridge
Bridgewater
Watchung
Scotch Plains |
NJ
MA
MA
MA
MA
MA
MA
MA
MA
NJ
NJ
NJ
NJ
NJ
NJ
NJ
NJ |
US
US
US
US
US
US
GB
US
US
US
US
US
US
US
US
US
US
US |
|
|
Assignee: |
Merck Sharp & Dohme
Corp.
Rahway
NJ
|
Family ID: |
47357455 |
Appl. No.: |
14/126579 |
Filed: |
June 14, 2012 |
PCT Filed: |
June 14, 2012 |
PCT NO: |
PCT/US2012/042336 |
371 Date: |
December 16, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61498345 |
Jun 17, 2011 |
|
|
|
Current U.S.
Class: |
514/210.18 ;
514/232.8; 514/252.04; 514/256; 514/269; 514/274; 514/290; 544/126;
544/238; 544/298; 544/316; 544/333; 546/79 |
Current CPC
Class: |
C07D 413/12 20130101;
C07D 401/04 20130101; C07D 417/10 20130101; C07D 413/04 20130101;
C07D 401/12 20130101; A61P 29/00 20180101; A61K 31/501 20130101;
A61K 31/506 20130101; C07D 221/16 20130101; A61P 11/02 20180101;
C07D 401/06 20130101; A61K 31/5377 20130101; A61P 11/00 20180101;
A61P 43/00 20180101; C07D 417/12 20130101; A61P 11/06 20180101;
C07D 409/12 20130101; A61P 37/08 20180101; C07D 405/12 20130101;
C07D 401/10 20130101; C07D 405/06 20130101; A61K 31/473
20130101 |
Class at
Publication: |
514/210.18 ;
546/79; 514/290; 544/126; 514/232.8; 544/333; 514/256; 544/316;
514/274; 544/238; 514/252.04; 544/298; 514/269 |
International
Class: |
C07D 221/16 20060101
C07D221/16; A61K 31/5377 20060101 A61K031/5377; C07D 401/12
20060101 C07D401/12; A61K 31/506 20060101 A61K031/506; A61K 31/501
20060101 A61K031/501; A61K 31/473 20060101 A61K031/473; C07D 401/10
20060101 C07D401/10 |
Claims
1. A compound of the Formula (I) ##STR00557## or a pharmaceutically
acceptable salt or ester thereof, wherein R.sup.1 is (i) H, (ii)
C.sub.1-C.sub.4 alkyl, (iii) C.sub.3-C.sub.4 alkenyl, (iv)
C.sub.3-C.sub.7 cycloalkyl, (v) --(C.sub.1-C.sub.3
alkylene)-R.sup.9 wherein R.sup.9 is C.sub.3-C.sub.7 cycloalkyl,
phenyl or a 5- to 6-membered heteroaryl containing 1 to 2
heteroatoms selected from the group consisting of N, O, and S, (vi)
phenyl, (vii) --C(O)--R.sup.5, wherein R.sup.5 is C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, phenyl, (viii) or a group of the
formula ##STR00558## wherein v is 1, 2, or 3; R.sup.2 is (i)
-Q-W--V, wherein Q is --C(O)--, --C(O)O--, --C(O)N(H)--,
--C(O)N(C.sub.1-C.sub.6 alkyl)-, --CH.sub.2--, or --S(O).sub.2--; W
is (a) C.sub.1-C.sub.8 alkylene, wherein said alkylene of W is
unsubstituted or substituted by 1 to 2 fluoro; (b) --CH.dbd.CH--,
or (c) a phenylene of the formula ##STR00559## wherein said
phenylene is unsubstituted or substituted by 1 to 2 halo; V is (a)
--CO.sub.2H, (b) tetrazolyl, or (c) a group of the formula
##STR00560## wherein R.sup.V1 is selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, and phenyl;
(ii) -M-CO.sub.2H, wherein M is ##STR00561## wherein w is 0, 1, 2,
or 3; X.sup.A is S or O; X.sup.B is N or C(H); with the proviso
that when R.sup.1 is --C(O)--R.sup.5, then R.sup.2 is
--CH.sub.2--W--V; Y is --C(O)--, --S(O).sub.2--, or a group of the
formula ##STR00562## wherein X.sup.A1 is S or O; and X.sup.B1 is N
or C(H); Z is (i) absent, (ii) --(C.sub.1-C.sub.6) alkylene-, (iii)
--O--, (iv) --O--(C.sub.1-C.sub.6 alkylene)-, wherein said
--O--(C.sub.1-C.sub.6 alkylene)- of Z is unsubstituted or
substituted by 1 to 3 fluoro, (v) --N(H)--, or (vi) a group of the
formula ##STR00563## wherein r is 1, 2, 3, or 4; E is (i) phenyl,
(ii) naphthyl, (iii) tetrahydronapthyl, (iv) indanyl, (v) 5- to
10-membered mono- or bicyclic heteroaryl containing one to three
heteroatoms selected from the group consisting of N, O, and S, (vi)
5- to 10-membered mono- or bicyclic heterocyclenyl containing one
to three heteroatoms selected from the group consisting of N, O,
and S, wherein said phenyl, napthyl, tetrahydronapthyl, indanyl, 5-
to 10-membered heteroaryl, or 5- to 10-membered heterocyclenyl of E
is unsubstituted or substituted by one to three R.sup.4 moieties,
wherein each R.sup.4 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 alkoxy, --CN, halo,
hydroxyl, C.sub.1-C.sub.3 fluoroalkyl, --O--(C.sub.1-C.sub.3
fluoroalkyl), --S--(C.sub.1-C.sub.3 alkyl), --S--(C.sub.1-C.sub.3
fluoroalkyl), C.sub.3-C.sub.7 cycloalkyl, R.sup.4a, --O--R.sup.4a,
or 5- to 6-membered heterocyclyl containing 1 or 2 heteroatom
selected from the group consisting of N, O, and S; R.sup.4a is
phenyl or a 5 to 6-membered heteroaryl ring containing one to two
heteroatoms selected from the group consisting of N, O, and S;
wherein R.sup.4a is unsubstituted or substituted by one to two
moieties independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 alkoxy, halo, --CN,
C.sub.1-C.sub.3 fluoroalkyl, --O--(C.sub.1-C.sub.3 fluoroalkyl),
--S--(C.sub.1-C.sub.3 fluoroalkyl), and
--SO.sub.2--(C.sub.1-C.sub.3 alkyl), or, wherein two R.sup.4
moieties are substituted on vicinal carbon atoms of E, the two
R.sup.4 moieties together with the carbon atoms to which they are
attached form a dioxolane ring; (vii) C.sub.3-C.sub.7 cycloalkyl,
or (viii) C.sub.1-C.sub.6 alkyl, n is 0, 1, or 2; each occurrence
of R.sup.7 is independently halo, C.sub.1-C.sub.3 fluoroalkyl,
hydroxy(C.sub.1-C.sub.3 alkyl), --CN, phenyl, or a 5- to 6-membered
heteroaryl containing 1 to 2 heteroatoms selected from the group
consisting of N, O, and S, wherein said phenyl or heteroaryl of
R.sup.7 is independently unsubstituted or substituted with 1 to 2
halo; t is 0, 1, 2, or 3; each occurrence of R.sup.8 is
independently C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, or
fluoro; u is 0, 1, or 2; and R.sup.8a is H or C.sub.1-C.sub.6
alkyl.
2. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is -Q-W--V; Q is --C(O)--, --C(O)O--,
--C(O)N(CH.sub.3)-- or --CH.sub.2--; W is C.sub.1-C.sub.4 alkylene;
and V is --CO.sub.2H.
3. The compound of claim 2 or a pharmaceutically acceptable salt
thereof, wherein the group -Q-W--V is selected from the group
consisting of: ##STR00564##
4. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.7
cycloalkyl, --CH.sub.2--(C.sub.3-C.sub.7 cycloalkyl), or
phenyl.
5. The compound of claim 4 or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is methyl, ethyl, cyclopropyl, cyclobutyl,
--CH.sub.2-cyclopropyl, or phenyl.
6. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein Y is --C(O)-- or ##STR00565##
7. The compound of claim 6 or a pharmaceutically acceptable salt
thereof, wherein Y is --C(O)--.
8. The compound of claim 7 or a pharmaceutically acceptable salt
thereof, wherein the group --Y--Z is selected from the group
consisting of --C(O)--, --C(O)O--CH.sub.2--,
--C(O)O--C(H)(CH.sub.3)--, and ##STR00566##
9. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein E is phenyl, thienyl, ##STR00567## wherein E is
unsubstituted or substituted by one to two moieties independently
selected from the group consisting of methyl, fluoro,
trifluoromethoxy, --O-phenyl, and thiazolyl.
10. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein the compound has the Formula (IB) ##STR00568##
wherein R.sup.1 is H, C.sub.1-C.sub.4 alkyl, cyclopropyl,
cyclobutyl, --CH.sub.2-cyclopropyl, --CH.sub.2-cyclobutyl, or
phenyl; Q is --C(O)--, --C(O)O--, --C(O)N(CH.sub.3)--, or
--CH.sub.2--; m is 1 or 2; Y is --C(O)-- or ##STR00569## Z is
absent, --(C.sub.1-C.sub.3) alkylene-, --OCH.sub.2--,
--OCH(CH.sub.3)--, or a group of the formula ##STR00570## E is
phenyl, thienyl, ##STR00571## wherein E is unsubstituted or
substituted by one to two R.sup.4 moieties independently selected
from the group consisting of C.sub.1-C.sub.3 alkyl, fluoro,
trifluoromethoxy, --S--CF.sub.3, --O-phenyl, and thiazolyl; n is 0
or 1; each occurrence of R.sup.7 is independently chloro or fluoro;
and t is 0, 1, or 2.
11. The compound of claim 10 or a pharmaceutically acceptable salt
thereof, wherein the compound has the Formula (IC) ##STR00572##
wherein Q is --C(O)--, --C(O)O--, or --CH.sub.2--; m is 1 or 2; Z
is absent or --OCH.sub.2--; each occurrence of R.sup.4 is
independently C.sub.1-C.sub.3 alkyl, fluoro, trifluoromethoxy, or
--S--CF.sub.3; v is 0, 1, or 2; n is 0 or 1; each occurrence of
R.sup.7 is independently chloro or fluoro; and t is 0, 1, or 2.
12. The compound of claim 11 or a pharmaceutically acceptable salt
thereof, wherein the group ##STR00573## is selected from the group
consisting of: ##STR00574##
13. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein the compound is selected from the group consisting
of:
4-[{cis,cis-4-[(Benzyloxy)carbonyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta-
[b]quinolin-9-yl}(cyclopropyl)amino]-4-oxobutanoic acid;
4-[{cis,cis-4-[(benzyloxy)carbonyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta-
[b]quinolin-9-yl}(phenyl)amino]-4-oxobutanoic acid;
4-{ethyl[cis,cis-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-2,3,3a,4,9,9a-h-
exahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobutanoic acid;
4-{cyclopropyl[cis,cis-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-2,3,3a,4,-
9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobutanoic
acid;
4-[{cis,cis-4-[(benzyloxy)carbonyl]-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-c-
yclopenta[b]quinolin-9-yl}(cyclopropyl)amino]-4-oxobutanoic acid;
4-{cyclopropyl[cis,cis-6-fluoro-4-[(4-phenoxyphenyl)carbonyl]-2,3,3a,4,9,-
9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl}amino)-4-oxobutanoic
acid;
4-{cyclopropyl[cis,cis-3-{[4-(trifluoromethoxy)phenyl]carbonyl}-1,2,2a,3,-
8,8a-hexahydrocyclobuta[b]quinolin-8-yl]amino}-4-oxobutanoic acid;
({cyclopropyl[cis,cis-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-2,3,3a,4,9-
,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]carbamoyl}oxy)acetic
acid; 3-(phenylmethyl)
cis,cis-8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-5-fluoro-2,2a,8,8a-te-
trahydrocyclobuta[b]quinoline-3(1H)-carboxylate; 4-(phenylmethyl)
cis,cis-9-[(3-carboxy-1-oxopropyl)cyclopropylamino]-6-chloro-1,2,3,3a,9,9-
a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate;
4-(phenylmethyl)cis,cis-9-[(3-carboxy-1-oxopropyl)cyclopropylamino]-7-flu-
oro-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate;
4-[cyclopropyl[(cis,cis)-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoro-
methoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic
acid;
4-[[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]-1H-cy-
clopenta[b]quinolin-9-yl]methylamino]-4-oxobutanoic acid;
4-[(cyclobutylmethyl)[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorometh-
oxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic
acid;
4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-(3-phenoxybenzoyl)-1H-cy-
clopenta[b]quinolin-9-yl]amino]-4-oxo-butanoic acid;
4-(cyclopropyl(cis,cis-4-(thiophene-2-carbonyl)-2,3,3a,4,9,9a-hexahydro-1-
H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid;
[[[[cis,cis-6-chloro-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorometh-
oxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]carbonyl]oxy]a-
cetic acid;
4-[cyclopropyl[cis,cis-5-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluorome-
thoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid;
deuterated-4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoro-
methoxy)benzoyl]-1H-cyclopenta[b]quinolin-9(R)-yl-(d)]amino]-4-oxobutanoic
acid; 4-[[(cis,
cis)-6-chloro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]-1H--
cyclopenta[b]quinolin-9-yl]cyclobutylamino]-4-oxobutanoic acid;
4-[[(cis,
cis)-6-chloro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]-1H--
cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic acid;
4-[[(cis,
cis)-6-chloro-2,3,3a,4,9,9a-hexahydro-4-[(trans-2-phenylcyclopropyl)carbo-
nyl]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid; 4-[cyclobutyl[(cis,
cis)-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]-1H-cyclopent-
a[b]quinolin-9-yl]amino]-4-oxobutanoic acid; 4-[[(cis,
cis)-6-chloro-2,3,3a,4,9,9a-hexahydro-4-[(1,2,3,4-tetrahydro-1-naphthalen-
yl)carbonyl]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid; 4-[[(cis,
cis)-6-chloro-4-[(2,3-dihydro-1H-inden-2-yl)carbonyl]-2,3,3a,4,9,9a-hexah-
ydro-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid; 4-[[(cis,
cis)-6-chloro-2,3,3a,4,9,9a-hexahydro-4-[(1,2,3,4-tetrahydro-2--
naphthalenyl)carbonyl]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-o-
xobutanoic acid;
4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[3-(5-thiazolyl)benzoyl]-
-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic acid;
4-[(2,4-difluorophenyl)methyl](cis,
cis)-9-[[(carboxymethoxy)carbonyl]cyclopropylamino]-1,2,3,3a,9,9a-hexahyd-
ro-4H-cyclopenta[b]quinoline-4-carboxylate;
4-[1-(4-fluorophenyl)ethyl](cis,cis)-9-[(3-carboxy-1-oxopropyl)cyclopropy-
lamino]-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate;
4-(1,2,3,4-tetrahydro-2-naphthalenyl)(cis,
cis)-9-[(3-carboxy-1-oxopropyl)cyclopropylamino]-7-fluoro-1,2,3,3a,9,9a-h-
exahydro-4H-cyclopenta[b]quinoline-4-carboxylate;
4-[cyclopropyl[(cis,
cis)-6-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoromethoxy)benzoyl]cycl-
obuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid;
3-(phenylmethyl)(cis,cis)-8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-5-c-
hloro-2,2a,8,8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate;
4-[[(cis,cis)-5-chloro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoromethoxy)ben-
zoyl]cyclobuta[b]quinolin-8-yl]cyclopropylamino]-4-oxobutanoic
acid;
3-(phenylmethyl)(cis,cis)-8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-2,2-
a,8,8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate;
4-[cyclopropyl[(cis,cis)-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoromethoxy)b-
enzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid;
4-(phenylmethyl)(cis,cis)-9-[[(carboxymethoxy)carbonyl]cyclopropylamino]--
1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate;
4-(phenylmethyl)(cis,cis)-9-[[(carboxymethoxy)carbonyl]cyclopropylamino]--
7-fluoro-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate;
[[[cyclopropyl[(cis,cis)-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoromethoxy)b-
enzoyl]cyclobuta[b]quinolin-8-yl]amino]carbonyl]oxy]acetic acid;
[[[cyclopropyl[(cis,cis)-3-(3,4-difluorobenzoyl)-1,2,2a,3,8,8a-hexahydroc-
yclobuta[b]quinolin-8-yl]amino]carbonyl]oxy]acetic acid;
[[[cyclopropyl[(cis,cis)-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoro-
methoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]carbonyl]oxy]acetic
acid;
4-(phenylmethyl)(cis,cis)-9-[[(2(S)-carboxy-1-azetidinyl)carbonyl]c-
yclopropylamino]-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carbo-
xylate;
N-[[cyclopropyl[(cis,cis)-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorom-
ethoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]carbonyl]-N-methylglyc-
ine;
[[[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[5-[[4-(trifluoromet-
hoxy)phenyl]methyl]-1,3,4-oxadiazol-2-yl]-1H-cyclopenta[b]quinoline-9-yl]a-
mino]carbonyl]oxy]acetic acid;
2-[ethyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]--
1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxazolecarboxylic acid;
3-(phenylmethyl)
cis,cis-8-[(3-carboxypropyl)cyclopropylamino]-5-fluoro-2,2a,8,8a-tetrahyd-
rocyclobuta[b]quinoline-3(1H)-carboxylate;
4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)ben-
zoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]butanoic acid;
4-[cyclopropyl[cis,cis-5-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluorome-
thoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]butanoic acid;
4-[cyclopropyl[(cis,cis)-2,3,3a,4,9,9a-hexahydro-4-[4-[(trifluoromethyl)t-
hio]benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic
acid;
4-(ethyl((cis,cis)-3-(4-(trifluoromethylthio)benzoyl)-1,2,2a,3,8,8a-hexah-
ydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
4-(ethyl((cis,cis)-3-(4-ethylbenzoyl)-1,2,2a,3,8,8a-hexahydrocyclobuta[b]-
quinolin-8-yl)amino)-4-oxobutanoic acid; 3-(phenylmethyl)
8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-5,6-difluoro-2,2a,8,8a-tetrah-
ydro-cyclobuta[b]quinoline-3(1H)-carboxylate;
4-[cyclopropyl[(cis,cis)-5,6-dichloro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifl-
uoromethoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic
acid;
4-(cyclopropyl((cis,cis)-5,6-difluoro-3-(4-(trifluoromethoxy)benzoyl)-1,2-
,2a,3,8,8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic
acid;
4-[cyclopropyl[(cis,cis)-6-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoro-
methoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxo-butanoic
acid;
(R)-1-(((cis,cis)-3-(benzyloxycarbonyl)-5,6-difluoro-1,2,2a,3,8,8a-hexahy-
drocyclobuta[b]quinolin-8-yl)(cyclopropyl)carbamoyl)azetidine-2-carboxylic
acid;
4-(cyclopropyl(cis,cis-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,-
3,8,8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic
acid;
4-(ethyl(cis,cis-6-fluoro-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,3,8-
,8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
4-(ethyl(cis,cis-7-fluoro-4-(4-((trifluoromethyl)thio)benzoyl)-2,3,3a,4,9-
,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid;
4-(cyclopropyl(cis,cis-7-fluoro-4-(4-((trifluoromethyl)thio)benzoyl)-2,3,-
3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid; and
4-(cyclopropyl(cis,cis-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-
-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)butanoic
acid
14. The compound of claim 1 or a pharmaceutically acceptable salt
thereof, wherein the compound is selected from the group consisting
of:
4-{cyclopropyl[cis,cis-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-2,3,3a,4,-
9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobutanoic
acid;
4-[cyclopropyl[cis,cis-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorome-
thoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic
acid;
4-[[cis,cis-6-chloro-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorometh-
oxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid;
4-[cyclopropyl[cis,cis-5-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifl-
uoromethoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic
acid;
4-[cyclopropyl[cis,cis-6-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluorome-
thoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid;
3-(phenylmethyl)(cis,cis)-8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-5-c-
hloro-2,2a,8,8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate;
3-(phenylmethyl)(cis,cis)-8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-2,2-
a,8,8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate;
4-[cyclopropyl[cis,cis-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoromethoxy)ben-
zoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid;
[[[cyclopropyl[cis,cis-3-(3,4-difluorobenzoyl)-1,2,2a,3,8,8a-hexahydrocyc-
lobuta[b]quinolin-8-yl]amino]carbonyl]oxy]acetic acid;
3-(phenylmethyl)
cis,cis-8-[(3-carboxypropyl)cyclopropylamino]-5-fluoro-2,2a,8,8a-tetrahyd-
rocyclobuta[b]quinoline-3(1H)-carboxylate;
4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)ben-
zoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]butanoic acid;
4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-[(trifluoromethyl)thi-
o]benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic acid;
and
(R)-1-((cis,cis-3-(benzyloxycarbonyl)-5,6-difluoro-1,2,2a,3,8,8a-hexahydr-
ocyclobuta[b]quinolin-8-yl)(cyclopropyl)carbamoyl)azetidine-2-carboxylic
acid;
4-(cyclopropyl(cis,cis-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,-
3,8,8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic
acid;
4-(ethyl(cis,cis-6-fluoro-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,3,8-
,8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
4-(ethyl(cis,cis-7-fluoro-4-(4-((trifluoromethyl)thio)benzoyl)-2,3,3a,4,9-
,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid;
4-(cyclopropyl(cis,cis-7-fluoro-4-(4-((trifluoromethyl)thio)benzoyl)-2,3,-
3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid; and
4-(cyclopropyl(cis,cis-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-
-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)butanoic
acid;
15. A pharmaceutical formulation comprising a therapeutically
effective amount of the compound of claim 1 or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier.
16. A method for treating a disease or condition associated with
uncontrolled or inappropriate stimulation of CRTH.sub.2 function
comprising administering to a patient in need of such treatment a
therapeutically amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof.
17. The method according to claim 16, wherein the disease or
condition is asthma, allergic rhinitis, or COPD.
18. A method for treating a disease or condition associated with
uncontrolled or inappropriate stimulation of CRTH.sub.2 function
comprising administering to a patient in need of such treatment a
therapeutically amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof and an additional
therapeutic agent.
19. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to certain cycloalkyl-fused
tetrahydroquinolines of the Formula (I) (also referred to herein as
the "compounds of the Formula (I)"), compositions comprising such
compounds, and methods of using such compounds for treating an
inflammatory disease, or other disorder mediated by the
chemoattractant receptor-homologous molecule expressed on
T-helper-type-2 cells (CRTH.sub.2).
BACKGROUND OF THE INVENTION
[0002] Prostaglandin D.sub.2 (PGD.sub.2) belongs to a class of
chemical mediators which cells synthesize in response to stimuli,
such as local tissue damage or hormonal stimuli, or by cellular
activation pathways. Cells synthesize PGD.sub.2 from arachidonic
acid by cyclooxygenase and other specific synthases in the
pathway.
[0003] Upon stimulation, mast cells release PGD.sub.2 in major
amounts and this release plays a major role in the etiology of
respiratory disease, such as asthma and congestion. PGD.sub.2
achieves this effect by binding with either of two G-protein
coupled receptors, which are the D-prostanoid (DP) receptor and the
CRTH.sub.2 receptor. TH-2 cells, eosinophils, and basophils express
the CRTH.sub.2 receptor, which mediates the chemoattractant effect
of PGD.sub.2.
[0004] Scientific studies support a clear role for PGD.sub.2 in an
allergic inflammatory response. PGD.sub.2 is found at high levels
in the bronchoalveolar lavage of asthmatics. Inhalation of
PGD.sub.2 enhances eosinophilic and lymphocytic airway inflammation
in allergic animal models. Evidence obtained by studying CRTH.sub.2
knockout mice demonstrates that PGD.sub.2 achieves this enhancement
by binding to the CRTH.sub.2 receptor. Hence, CRTH.sub.2 receptor
antagonists would be expected to reduce the allergic inflammatory
response caused by PGD.sub.2, and these compounds would be useful
in the treatment or prevention of allergic/immune disorders.
[0005] Current drugs of choice for the treatment of chronic
inflammatory airway disease, such as asthma or COPD, are synthetic
glucocorticoids; examples of these compounds currently indicated
for treating these disorders include fluticasone and mometasone.
The difficulty with treating patients with this class of compounds
is that the compounds possess a number of systemic side-effects;
these include adrenal suppression, altered bone metabolism and
growth suppression in children. These side effects limit the dose
that can be administered on a daily basis to the patient. While a
non-steroidal class of therapeutics that inhibit
bronchoconstriction exists (CysLT.sub.1 antagonists), this class of
compounds has limited efficacy in achieving the endpoints of
reducing inflammatory and improving in lung function when compared
to the glucocorticoids. Therefore, a therapeutic that combines the
efficacy of inhaled glucocorticoids without the side effects would
be advantageous.
SUMMARY OF THE INVENTION
[0006] The present invention provides novel compounds of the
Formula (I) as described below and pharmaceutically acceptable
salts or esters thereof as well as pharmaceutical compositions
containing them. The compounds of Formula (I) are useful in the
treatment and prevention of diseases and disorders associated with
uncontrolled or inappropriate stimulation of CRTH.sub.2 function
such as asthma.
BRIEF DESCRIPTION OF THE FIGURE
[0007] FIG. 1 shows a perspective view calculated from the
crystallographic coordinates of a single crystal X-ray of a
monotoluene solvate of
4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,-
3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid, compound 17.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0008] The terms used herein have their ordinary meaning and the
meaning of such terms is independent at each occurrence thereof.
That notwithstanding and except where stated otherwise, the
following definitions apply throughout the specification and
claims. Chemical names, common names, and chemical structures may
be used interchangeably to describe the same structure. If a
chemical compound is referred to using both a chemical structure
and a chemical name, and an ambiguity exists between the structure
and the name, the structure predominates. These definitions apply
regardless of whether a term is used by itself or in combination
with other terms, unless otherwise indicated. Hence, the definition
of "alkyl" applies to "alkyl" as well as the "alkyl" portions of
"fluoroalkyl," "--O-alkyl," etc.
[0009] As used herein, and throughout this disclosure, the
following terms, unless otherwise indicated, shall be understood to
have the following meanings:
[0010] A "patient" is a human or non-human mammal. In one
embodiment, a patient is a human. In another embodiment, a patient
is a chimpanzee.
[0011] The term "therapeutically effective amount" as used herein,
refers to an amount of the compound of Formula (I) and/or an
additional therapeutic agent, or a composition thereof that is
effective in producing the desired therapeutic, ameliorative,
inhibitory or preventative effect when administered to a patient
suffering from a disease or disorder associated with uncontrolled
or inappropriate stimulation of CRTH.sub.2 function. In the
combination therapies of the present invention, a therapeutically
effective amount can refer to each individual agent or to the
combination as a whole, wherein the amounts of all agents
administered are together effective, but wherein the component
agent of the combination may not be present individually in an
effective amount.
[0012] The term "preventing," as used herein with respect to
disease or disorder associated with uncontrolled or inappropriate
stimulation of CRTH.sub.2 function, refers to reducing the
likelihood of disease or disorder associated with uncontrolled or
inappropriate stimulation of CRTH.sub.2 function.
[0013] The term "alkyl," as used herein, refers to an aliphatic
hydrocarbon group having one of its hydrogen atoms replaced with a
bond. An alkyl group may be straight or branched and contain from
about 1 to about 20 carbon atoms. In one embodiment, an alkyl group
contains from about 1 to about 12 carbon atoms. In different
embodiments, an alkyl group contains from 1 to 6 carbon atoms
(C.sub.1-C.sub.6 alkyl), 1 to 4 carbon atoms (C.sub.1-C.sub.4
alkyl), or from 1 to 3 carbon atoms (C.sub.1-C.sub.3 alkyl).
Non-limiting examples of alkyl groups include methyl, ethyl,
n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,
n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. In
one embodiment, an alkyl group is linear. In another embodiment, an
alkyl group is branched. Unless otherwise indicated, an alkyl group
is unsubstituted.
[0014] The term "alkylene," as used herein, refers to an alkyl
group, as defined above, wherein one of the alkyl group's hydrogen
atoms has been replaced with a bond. Non-limiting examples of
alkylene groups include --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH(CH.sub.3)CH.sub.2CH.sub.2--, --CH(CH.sub.3)-- and
--CH.sub.2CH(CH.sub.3)CH.sub.2--. In one embodiment, an alkylene
group has from 1 to about 6 carbon atoms (C.sub.1-C.sub.6
alkylene). In another embodiment, an alkylene group has from 1 to 3
carbon atoms C.sub.1-C.sub.3 alkylene). In another embodiment, an
alkylene group is branched. In another embodiment, an alkylene
group is linear. In one embodiment, an alkylene group is
--CH.sub.2--. The term "C.sub.1-C.sub.3 alkylene" refers to an
alkylene group having from 1 to 3 carbon atoms. Unless otherwise
indicated, an alkylene group is unsubstituted.
[0015] The term "alkenyl," as used herein, refers to an aliphatic
hydrocarbon group containing at least one carbon-carbon double bond
and having one of its hydrogen atoms replaced with a bond. An
alkenyl group may be straight or branched and contain from about 2
to about 15 carbon atoms. In one embodiment, an alkenyl group
contains from about 2 to 4 carbon atoms. Non-limiting examples of
alkenyl groups include ethenyl, propenyl, n-butenyl,
3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. The term
"C.sub.2-C.sub.6 alkenyl" refers to an alkenyl group having from 2
to 6 carbon atoms. The term "C.sub.2-C.sub.4 alkenyl" refers to an
alkenyl group having from 2 to 4 carbon atoms. Unless otherwise
indicated, an alkenyl group is unsubstituted.
[0016] The term "alkoxy" as used herein, refers to an --O-alkyl
group, wherein an alkyl group is as defined above. Non-limiting
examples of alkoxy groups include methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy and t-butoxy. An alkoxy group is bonded via
its oxygen atom.
[0017] The term "aryl," as used herein, refers to an aromatic
monocyclic or multicyclic ring system comprising from about 6 to
about 14 carbon atoms. In one embodiment, an aryl group contains
from about 6 to 10 carbon atoms (C.sub.6-C.sub.10 aryl). In another
embodiment an aryl group is phenyl. Non-limiting examples of aryl
groups include phenyl and naphthyl. Unless otherwise indicated, an
aryl group is unsubstituted.
[0018] The term "cycloalkyl," as used herein, refers to a
non-aromatic mono- or multicyclic ring system comprising from about
3 to about 10 ring carbon atoms. In one embodiment, a cycloalkyl
contains from about 5 to 10 ring carbon atoms. In another
embodiment, a cycloalkyl contains from 3 to 7 ring atoms
(C.sub.3-C.sub.7 cycloalkyl). In another embodiment, a cycloalkyl
contains from 3 to 6 ring atoms (C.sub.3-C.sub.7 cycloalkyl). In
another embodiment, a cycloalkyl contains from about 5 to about 6
ring atoms. Non-limiting examples of monocyclic cycloalkyls include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl. Non-limiting examples of multicyclic cycloalkyls
include 1-decalinyl, norbornyl and adamantyl. Unless otherwise
indicated, a cycloalkyl group is unsubstituted.
[0019] The term "halo," as used herein, means --F, --Cl, --Br or
--I. In one embodiment, a halo group is --F or --Cl. In another
embodiment, a halo group is --F.
[0020] The term "fluoroalkyl," as used herein, refers to an alkyl
group as defined above, wherein one or more of the alkyl group's
hydrogen atoms has been replaced with a fluorine. In one
embodiment, a fluoroalkyl group has from 1 to 6 carbon atoms. In
another embodiment, a fluoroalkyl group is substituted with from 1
to 3 F atoms. Non-limiting examples of fluoroalkyl groups include
--CH.sub.2F, --CHF.sub.2, and --CF.sub.3. The term "C.sub.1-C.sub.3
fluoroalkyl" refers to a fluoroalkyl group having from 1 to 3
carbon atoms.
[0021] The term "heteroaryl," as used herein, refers to an aromatic
monocyclic or multicyclic ring system comprising about 5 to about
14 ring atoms, wherein from 1 to 4 of the ring atoms is
independently O, N or S and the remaining ring atoms are carbon
atoms. In one embodiment, a heteroaryl group has 5 to 10 ring
atoms. In another embodiment, a heteroaryl group is monocyclic and
has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is
bicyclic. A heteroaryl group is joined via a ring carbon atom, and
any nitrogen atom of a heteroaryl can be optionally oxidized to the
corresponding N-oxide. The term "heteroaryl" also encompasses a
heteroaryl group, as defined above, which is fused to a benzene
ring. Non-limiting examples of heteroaryls include pyridyl,
pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including
N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl,
oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl,
1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,
phthalazinyl, oxindolyl, imidazo[1,2-a]pyridinyl,
imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,
benzimidazolyl, benzothienyl, quinolinyl, imidazolyl,
benzimidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,
pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,
1,2,4-triazinyl, benzothiazolyl and the like. In one embodiment, a
heteroaryl group is a 5-membered heteroaryl. In another embodiment,
a heteroaryl group is a 6-membered heteroaryl. In another
embodiment, a heteroaryl group comprises a 5- to 6-membered
heteroaryl group fused to a benzene ring. Unless otherwise
indicated, a heteroaryl group is unsubstituted.
[0022] The term "heterocyclyl," as used herein, refers to a
non-aromatic saturated monocyclic or multicyclic ring system
comprising 3 to about 11 ring atoms, wherein from 1 to 4 of the
ring atoms are independently O, S, or N, and the remainder of the
ring atoms are carbon atoms. A heterocyclyl group can be joined via
a ring carbon or ring nitrogen atom. In one embodiment, a
heterocyclyl group is monocyclic and has from about 3 to about 7
ring atoms. In another embodiment, a heterocyclyl group is
monocyclic has from about 4 to about 7 ring atoms. In another
embodiment, a heterocyclyl group is bicyclic and has from about 7
to about 11 ring atoms. In still another embodiment, a heterocyclyl
group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a
heterocyclyl group is monocyclic. In another embodiment, a
heterocyclyl group is bicyclic. The term "heterocyclyl" also
encompasses a heterocyclyl group, as defined above, which is fused
to an aryl (e.g., benzene) or heteroaryl ring. The nitrogen or
sulfur atom of the heterocyclyl can be optionally oxidized to the
corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting
examples of monocyclic heterocyclyl rings include oxetanyl,
piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,
thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,
tetrahydrothiophenyl, delta-lactam, delta-lactone, and the
like.
[0023] In one embodiment, a heterocyclyl group is a 5- to
6-membered monocyclic heterocyclyl. In another embodiment, a
heterocyclyl group is a 5-membered monocyclic heterocyclyl. In
another embodiment, a heterocyclyl group is a 6-membered monocyclic
heterocyclyl. The term "5- to 6-membered heterocyclyl" refers to a
monocyclic heterocyclyl group having from 5 to 6 ring atoms. Unless
otherwise indicated, a heterocyclyl group is unsubstituted.
[0024] "Heterocyclenyl" means a non-aromatic monocyclic or
multicyclic ring system comprising about 3 to about 10 ring atoms,
preferably about 5 to about 10 ring atoms, in which one or more of
the atoms in the ring system is an element other than carbon, for
example nitrogen, oxygen or sulfur atom, alone or in combination,
and which contains at least one carbon-carbon double bond or
carbon-nitrogen double bond. In specific embodiments of the ring
system, from 1 to 4 of the ring atoms are independently O, S, or N,
and the remainder of the ring atoms are carbon atoms. There are no
adjacent oxygen and/or sulfur atoms present in the ring system.
Preferred heterocyclenyl rings contain about 5 to about 6 ring
atoms. The prefix aza, oxa or thia before the heterocyclenyl root
name means that at least a nitrogen, oxygen or sulfur atom
respectively is present as a ring atom. Unless otherwise indicated,
a heterocyclenyl group is unsubstituted. The nitrogen or sulfur
atom of the heterocyclenyl can be optionally oxidized to the
corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting
examples of suitable heterocyclenyl groups include
1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl,
1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,
1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,
2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,
dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,
dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,
dihydrothiophenyl, dihydrothiopyranyl, and the like."
[0025] The term "substituted" means that one or more hydrogens on
the atoms of the designated are replaced with a selection from the
indicated group, provided that the atoms' normal valencies under
the existing circumstances are not exceeded, and that the
substitution results in a stable compound. Combinations of
substituents and/or variables are permissible only if such
combinations result in stable compounds. By "stable compound" or
"stable structure" is meant a compound that is sufficiently robust
to survive isolation to a useful degree of purity from a reaction
mixture, and formulation into an efficacious therapeutic agent.
[0026] Esters of the compounds of the invention are also
contemplated herein. For example, if a compound of Formula (I)
contains a carboxylic acid functional group, a prodrug can comprise
an ester formed by the replacement of the hydrogen atom of the acid
group with a group such as, for example, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.6)alkoxymethyl, (C.sub.2-C.sub.12)alkanoyloxymethyl,
1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,
1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,
1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,
1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon
atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon
atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon
atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl, and
the like. Such esters may antagonize CRTH.sub.2 themselves and/or
can function as prodrugs of the corresponding carboxylic acids. In
one embodiment, the esters are C.sub.1-C.sub.6 alkyl esters (e.g.,
C.sub.1-C.sub.3 alkyl esters). In another embodiment, the esters
are C.sub.1-C.sub.3 alkoxymethyl esters (e.g., methoxymethyl
esters).
[0027] When any substituent or variable occurs more than one time
in any constituent or the compound of Formula (I), its definition
on each occurrence is independent of its definition at every other
occurrence, unless otherwise indicated.
[0028] The term "in purified form," as used herein, refers to the
physical state of a compound after the compound is isolated from a
synthetic process (e.g., from a reaction mixture), a natural
source, or a combination thereof. The term "in purified form," also
refers to the physical state of a compound after the compound is
obtained from a purification process or processes described herein
or well-known to the skilled artisan (e.g., chromatography,
recrystallization and the like), in sufficient purity to be
characterizable by standard analytical techniques described herein
or well-known to the skilled artisan.
[0029] It should also be noted that any carbon as well as
heteroatom with unsatisfied valences in the text, schemes, examples
and tables herein is assumed to have the sufficient number of
hydrogen atom(s) to satisfy the valences.
[0030] One or more compounds of the invention may exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like, and it is
intended that the invention embrace both solvated and unsolvated
forms. "Solvate" means a physical association of a compound of this
invention with one or more solvent molecules. This physical
association involves varying degrees of ionic and covalent bonding,
including hydrogen bonding. In certain instances the solvate will
be capable of isolation, for example when one or more solvent
molecules are incorporated in the crystal lattice of the
crystalline solid. "Solvate" encompasses both solution-phase and
isolatable solvates. Non-limiting examples of suitable solvates
include ethanolates, methanolates, and the like. "Hydrate" is a
solvate wherein the solvent molecule is H.sub.2O.
[0031] The compounds of Formula (I) may contain one or more
stereogenic centers and can thus occur as racemates, racemic
mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers. Additional asymmetric centers may be
present depending upon the nature of the various substituents on
the molecule. Each such asymmetric center will independently
produce two optical isomers and it is intended that all of the
possible optical isomers and diastereomers in mixtures and as pure
or partially purified compounds are included within the ambit of
this invention. Any formulas, structures or names of compounds
described in this specification that do not specify a particular
stereochemistry are meant to encompass any and all existing isomers
as described above and mixtures thereof in any proportion. When
stereochemistry is specified, the invention is meant to encompass
that particular isomer in pure form or as part of a mixture with
other isomers in any proportion.
[0032] The independent syntheses of these diastereomers or their
chromatographic separations may be achieved as known in the art by
appropriate modification of the methodology disclosed herein. Their
absolute stereochemistry may be determined by the x-ray
crystallography of crystalline products or crystalline
intermediates which are derivatized, if necessary, with a reagent
containing an asymmetric center of known absolute configuration. If
desired, racemic mixtures of the compounds may be separated so that
the individual enantiomers are isolated. The separation can be
carried out by methods well known in the art, such as the coupling
of a racemic mixture of compounds to an enantiomerically pure
compound to form a diastereomeric mixture, followed by separation
of the individual diastereomers by standard methods, such as
fractional crystallization or chromatography. The coupling reaction
is often the formation of salts using an enantiomerically pure acid
or base. The diasteromeric derivatives may then be converted to the
pure enantiomers by cleavage of the added chiral residue. The
racemic mixture of the compounds can also be separated directly by
chromatographic methods utilizing chiral stationary phases, e.g.,
such as the supercritical fluid chromatography, which methods are
well known in the art. Alternatively, any enantiomer of a compound
may be obtained by stereoselective synthesis using optically pure
starting materials or reagents of known configuration by methods
well known in the art.
[0033] It is also possible that the compounds of Formula (I) may
exist in different tautomeric forms, and all such forms are
embraced within the scope of the invention.
[0034] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds (including those of
the salts and solvates of the compounds as well as the salts,
solvates and esters of the prodrugs), such as those which may exist
due to asymmetric carbons on various substituents, including
enantiomeric forms (which may exist even in the absence of
asymmetric carbons), rotameric forms, atropisomers, and
diastereomeric forms, are contemplated within the scope of this
invention. Individual stereoisomers of the compounds of the
invention may, for example, be substantially free of other isomers,
or may be admixed, for example, as racemates or with all other, or
other selected, stereoisomers. The chiral centers of the present
invention can have the S or R configuration as defined by the IUPAC
1974 Recommendations.
[0035] The compounds of Formula (I) can form salts which are also
within the scope of this invention. Reference to a compound of
Formula (I) herein is understood to include reference to salts
thereof, unless otherwise indicated. The term "salt(s)", as
employed herein, denotes acidic salts formed with inorganic and/or
organic acids, as well as basic salts formed with inorganic and/or
organic bases. In addition, when a compound of Formula (I) contains
both a basic moiety, such as, but not limited to a pyridine or
imidazole, and an acidic moiety, such as, but not limited to a
carboxylic acid, zwitterions ("inner salts") may be formed and are
included within the term "salt(s)" as used herein. Such acidic and
basic salts used within the scope of the invention are
pharmaceutically acceptable (i.e., non-toxic, physiologically
acceptable) salts. Salts of the compounds of Formula (I) may be
formed, for example, by reacting a compound of Formula (I) with an
amount of acid or base, such as an equivalent amount, in a medium
such as one in which the salt precipitates or in an aqueous medium
followed by lyophilization.
[0036] Exemplary acid addition salts include acetates, ascorbates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, fumarates,
hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,
methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates, propionates, salicylates, succinates, sulfates,
tartarates, thiocyanates, toluenesulfonates (also known as
tosylates,) and the like. Additionally, acids which are generally
considered suitable for the formation of pharmaceutically useful
salts from basic pharmaceutical compounds are discussed, for
example, by P. Stahl et al, Camille G. (eds.) Handbook of
Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:
Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences
(1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics
(1986) 33 201-217; Anderson et al, The Practice of Medicinal
Chemistry (1996), Academic Press, New York; and in The Orange Book
(Food & Drug Administration, Washington, D.C. on their
website). These disclosures are incorporated herein by
reference.
[0037] Exemplary basic salts include ammonium salts, alkali metal
salts such as sodium, lithium, and potassium salts, alkaline earth
metal salts such as calcium and magnesium salts, salts with organic
bases (for example, organic amines) such as dicyclohexylamines,
t-butyl amines, and salts with amino acids such as arginine, lysine
and the like. Basic nitrogen-containing groups may be quarternized
with agents such as lower alkyl halides (e.g., methyl, ethyl, and
butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.,
dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g.,
decyl, lauryl, and stearyl chlorides, bromides and iodides),
aralkyl halides (e.g., benzyl and phenethyl bromides), and
others.
[0038] The present invention further includes the compounds of
Formula (I) in all their isolated forms. For example, the
above-identified compounds are intended to encompass all forms of
the compounds such as, any solvates, hydrates, stereoisomers, and
tautomers thereof.
[0039] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0040] In the compounds of generic Formula (I), the atoms may
exhibit their natural isotopic abundances, or one or more of the
atoms may be artificially enriched in a particular isotope having
the same atomic number, but an atomic mass or mass number different
from the atomic mass or mass number predominantly found in nature.
The present invention is meant to include all suitable isotopic
variations of the compounds of generic Formula (I). For example,
different isotopic forms of hydrogen (H) include protium (.sup.1H)
and deuterium (.sup.2H). Protium is the predominant hydrogen
isotope found in nature. Enriching for deuterium may afford certain
therapeutic advantages, such as increasing in vivo half-life or
reducing dosage requirements, or may provide a compound useful as a
standard for characterization of biological samples.
Isotopically-enriched compounds within generic Formula (I) can be
prepared without undue experimentation by conventional techniques
well known to those skilled in the art or by processes analogous to
those described in the Schemes and Examples herein using
appropriate isotopically-enriched reagents and/or
intermediates.
Compounds of the Invention
[0041] In embodiment no. 1, the present invention provides a
compound of the Formula (I):
##STR00002## [0042] or a pharmaceutically acceptable salt or ester
thereof, wherein [0043] R.sup.1 is [0044] (i) H, [0045] (ii)
C.sub.1-C.sub.4 alkyl, [0046] (iii) C.sub.2-C.sub.4 alkenyl, [0047]
(iv) C.sub.3-C.sub.7 cycloalkyl, [0048] (v) --(C.sub.1-C.sub.3
alkylene)-R.sup.9 wherein R.sup.9 is C.sub.3-C.sub.7 cycloalkyl,
phenyl or a 5- to 6-membered heteroaryl containing 1 to 2
heteroatoms selected from the group consisting of N, O, and S,
[0049] (vi) phenyl, [0050] (vii) --C(O)--R.sup.5, wherein R.sup.5
is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, phenyl,
[0051] (viii) or a group of the formula
[0051] ##STR00003## wherein v is 1, 2, or 3; [0052] R.sup.2 is
[0053] (i) -Q-W--V, wherein [0054] Q is --C(O)--, --C(O)O--,
--C(O)N(H)--, --C(O)N(C.sub.1-C.sub.6 alkyl)-, --CH.sub.2--, or
--S(O).sub.2--; [0055] W is [0056] (a) C.sub.1-C.sub.8 alkylene,
wherein said alkylene of W is unsubstituted or substituted by 1 to
2 fluoro; [0057] (b) --CH.dbd.CH--, or [0058] (c) a phenylene of
the formula
[0058] ##STR00004## wherein said phenylene is unsubstituted or
substituted by 1 to 2 halo; [0059] V is [0060] (a) --CO.sub.2H, or
[0061] (b) tetrazolyl, or [0062] (c) a group of the formula
[0062] ##STR00005## wherein R.sup.V1 is selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
and phenyl; [0063] (ii) -M-CO.sub.2H, wherein [0064] M is
[0064] ##STR00006## wherein w is 0, 1, 2, or 3; [0065] X.sup.A is S
or O; [0066] X.sup.B is N or C(H); [0067] with the proviso that
when R.sup.1 is --C(O)--R.sup.5, then R.sup.2 is --CH.sub.2--W--V;
[0068] Y is --C(O)--, --S(O).sub.2--, or a group of the formula
[0068] ##STR00007## [0069] wherein X.sup.A1 is S or O; and [0070]
X.sup.B1 is N or C(H); [0071] Z is [0072] (i) absent, [0073] (ii)
--(C.sub.1-C.sub.6) alkylene-, [0074] (iii) --O--, [0075] (iv)
--O--(C.sub.1-C.sub.6 alkylene)-, wherein said
--O--(C.sub.1-C.sub.6 alkylene)- of Z is unsubstituted or
substituted by 1 to 3 fluoro, [0076] (v) --N(H)--, or [0077] (vi) a
group of the formula
[0077] ##STR00008## wherein r is 1, 2, 3, or 4; [0078] E is [0079]
(i) phenyl, [0080] (ii) naphthyl, [0081] (iii) tetrahydronapthyl,
[0082] (iv) indanyl, [0083] (v) 5- to 10-membered mono- or bicyclic
heteroaryl containing one to three heteroatoms selected from the
group consisting of N, O, and S, [0084] (vi) 5- to 10-membered
mono- or bicyclic heterocyclenyl containing one to three
heteroatoms selected from the group consisting of N, O, and S,
[0085] wherein said phenyl, napthyl, tetrahydronapthyl, indanyl, 5-
to 10-membered heteroaryl, or 5- to 10-membered heterocyclenyl of E
is unsubstituted or substituted by one to three R.sup.4 moieties,
wherein [0086] each R.sup.4 is selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 alkoxy, --CN, halo,
hydroxyl, C.sub.1-C.sub.3 fluoroalkyl, --O--(C.sub.1-C.sub.3
fluoroalkyl), --S--(C.sub.1-C.sub.3 alkyl), --S--(C.sub.1-C.sub.3
fluoroalkyl), C.sub.3-C.sub.7 cycloalkyl, R.sup.4a, --O--R.sup.4a,
or 5- to 6-membered heterocyclyl containing 1 or 2 heteroatom
selected from the group consisting of N, O, and S; [0087] R.sup.4a
K is phenyl or a 5 to 6-membered heteroaryl ring containing one to
two heteroatoms selected from the group consisting of N, O, and S;
[0088] wherein R.sup.4a is unsubstituted or substituted by one to
two moieties independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 alkoxy, halo, --CN,
C.sub.1-C.sub.3 fluoroalkyl, --O--(C.sub.1-C.sub.3 fluoroalkyl),
--S--(C.sub.1-C.sub.3 fluoroalkyl), and
--SO.sub.2--(C.sub.1-C.sub.3 alkyl), [0089] or, wherein two R.sup.4
moieties are substituted on vicinal carbon atoms of E, the two
R.sup.4 moieties together with the carbon atoms to which they are
attached form a dioxolane ring; [0090] (vii) C.sub.3-C.sub.7
cycloalkyl, or [0091] (viii) C.sub.1-C.sub.6 alkyl; [0092] n is 0,
1, or 2; [0093] each occurrence of R.sup.7 is independently halo,
C.sub.1-C.sub.3 fluoroalkyl, hydroxy(C.sub.1-C.sub.3 alkyl), --CN,
phenyl, or a 5- to 6-membered heteroaryl containing 1 to 2
heteroatoms selected from the group consisting of N, O, and S,
wherein said phenyl or heteroaryl of R.sup.7 is independently
unsubstituted or substituted with 1 to 2 halo; [0094] t is 0, 1, 2,
or 3; [0095] each occurrence of R.sup.8 is independently
C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.3 alkenyl, or fluoro; [0096] u
is 0, 1, or 2; and [0097] R.sup.8a is H or C.sub.1-C.sub.6
alkyl.
[0098] The compounds of Formulae (IA'), (IA''), (IB), (IB'),
(IB''), (IC), (IC'), and (IC'') as are described in detail below,
are embodiments of the compound of Formula (I).
[0099] Described below are further embodiments of the compound of
Formula (I).
[0100] In embodiment no. 2, R.sup.1 is C.sub.1-C.sub.4 alkyl,
C.sub.3-C.sub.7 cycloalkyl, or --(C.sub.1-C.sub.3
alkylene)-R.sup.9, wherein R.sup.9 is C.sub.3-C.sub.7 cycloalkyl,
and the remaining variables are as set forth in embodiment no.
1.
[0101] In embodiment no. 3, R.sup.1 is methyl, ethyl, cyclopropyl,
cyclobutyl, --CH.sub.2-cyclopropyl, or phenyl, and the remaining
variables are as set forth in embodiment no. 1.
[0102] In embodiment no 4,
[0103] R.sup.2 is -Q-W--V;
[0104] Q is --C(O)--, --C(O)O--, --C(O)N(CH.sub.3)-- or
--CH.sub.2--;
[0105] W is C.sub.1-C.sub.4 alkylene; and
[0106] V is --CO.sub.2H; and the remaining variables are as set
forth in any one of embodiment nos. 1-3.
[0107] In embodiment no. 5, the group -Q-W--V is selected from the
group consisting of:
##STR00009##
and the remaining variables are as set forth in any one of
embodiment nos. 1-3.
[0108] In embodiment no. 6,
[0109] R.sup.2 is -Q-W--V;
[0110] Q is --C(O)--;
[0111] W is C.sub.1-C.sub.4 alkylene; and
[0112] V is a group of the formula
##STR00010##
wherein R.sup.V1 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.6 cycloalkyl; and the
remaining variables are as set forth in any one of embodiment nos.
1-3.
[0113] In embodiment no 7,
[0114] W is --CH.sub.2CH.sub.2--; and
[0115] R.sup.V1 is selected from the group consisting of methyl and
cyclopropyl; and the remaining variables are as set forth in
embodiment no. 6.
[0116] In embodiment no. 8, Y is --C(O)-- or
##STR00011##
and the remaining variables are as set forth in any one of
embodiment nos. 1-7.
[0117] In embodiment no. 9, Y is --C(O)--, and the remaining
variables are as described are as set forth in any one of
embodiment nos. 1-7.
[0118] In embodiment no. 10, Y is --Y--Z is selected from the group
consisting of --C(O)--, --C(O)O--CH.sub.2--,
--C(O)O--C(H)(CH.sub.3)--, and
##STR00012##
the remaining variables are as set forth in any one of embodiment
nos. 1-7.
[0119] In embodiment no. 11, E is phenyl, thienyl,
##STR00013##
wherein E is unsubstituted or substituted by one to two moieties
independently selected from the group consisting of methyl, fluoro,
trifluoromethoxy, --O-phenyl, and thiazolyl, and the remaining
variables are as set forth in any one of embodiment nos. 1-10.
[0120] In embodiment no. 12, said ester is a C.sub.1-C.sub.6 alkyl
carboxylic acid ester, and the remaining variables are as described
in any one of embodiment nos. 1-11. For example, when V is
--CO.sub.2H, said ester can be a methyl carboxylic acid ester,
i.e., --CO.sub.2CH.sub.3, or ethyl carboxylic acid ester, i.e.,
--CO.sub.2CH.sub.2CH.sub.3.
[0121] In embodiment no. 13, each occurrence of R.sup.7 is
independently chloro or fluoro; and t is 0, 1, or 2, and the
remaining variables are as set forth in any one of embodiment nos.
1-12.
[0122] In embodiment no. 14, n is 0 (such that a cyclobutyl ring is
formed) or 1, and the remaining variables are as set forth in any
one of embodiment nos. 1-11.
[0123] In embodiment no. 15, n is 0 or 1, R.sup.8 is methyl, and
the remaining variables are as set forth in any one of embodiment
nos. 1-14.
[0124] In embodiment no. 16, R.sup.8a is H or methyl, and the
remaining variables are as set forth in any one of embodiment nos.
1-15.
[0125] In embodiment no. 17, R.sup.8a is H, and the remaining
variables are as set forth in any one of embodiment nos. 1-15.
[0126] In embodiment no. 18, the bond joining the substituent
N(R.sup.1)(R.sup.2) to the tetrahydroquinoline in the tricyclic
core of Formula (I) and the bond on the vicinal carbon atom which
joins the cycloalkyl ring to the tetrahydroquinoline are on the
same side of the plane of the tetrahydroquinoline, or are cis to
each other. In addition, the bonds joining the cycloalkyl ring to
the tetrahydroquinoline are on the same side of the plane of the
tetrahydroquinoline, or are cis to each other. Such a configuration
in the central tricyclic core of the compound of the Formula (I) is
referred to hereinafter as a "cis, cis" configuration. The
variables are as set forth in any one of embodiment nos. 1-17.
[0127] In one embodiment of a compound having a cis,cis
configuration, i.e., embodiment no. 19, the compound of the Formula
(I) has the Formula (IA')
##STR00014##
and the variables R.sup.1, R.sup.2, R.sup.7, R.sup.8, R.sup.8a, Y,
Z, E, n, u, and t are as set forth in any one of embodiment nos.
1-17.
[0128] In embodiment no 20, the compound of the Formula (I) has the
Formula (IA'')
##STR00015##
and the variables R.sup.1, R.sup.2, R.sup.7, R.sup.8, R.sup.8a, Y,
Z, E, n, u, and t are as set forth in any one of embodiment nos.
1-17.
[0129] In embodiment no. 21, the present invention provides a
compound of the Formula (I) as described in any one of embodiment
nos. 1-11 and 13-20, or a pharmaceutically acceptable salt
thereof.
[0130] In embodiment no. 22, the compound of the Formula (I) has
the Formula (IB)
##STR00016##
wherein [0131] R.sup.1 is H, C.sub.1-C.sub.4 alkyl, cyclopropyl,
cyclobutyl, --CH.sub.2-cyclopropyl, --CH.sub.2-cyclobutyl, or
phenyl; [0132] Q is --C(O)--, --C(O)O--, --C(O)N(CH.sub.3)--, or
--CH.sub.2--; m is 1 or 2; [0133] Y is --C(O)-- or
[0133] ##STR00017## [0134] Z is absent, --(C.sub.1-C.sub.3)
alkylene-, --OCH.sub.2--, --OCH(CH.sub.3)--, or a group of the
formula
[0134] ##STR00018## [0135] E is phenyl, thienyl,
[0135] ##STR00019## wherein E is unsubstituted or substituted by
one to two R.sup.4 moieties independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, fluoro, trifluoromethoxy,
--S--CF.sub.3, --O-phenyl, and thiazolyl; [0136] n is 0 or 1;
[0137] each occurrence of R.sup.7 is independently chloro or
fluoro; and [0138] t is 0, 1, or 2.
[0139] In embodiment no. 23, R.sup.1 is H, C.sub.1-C.sub.2 alkyl,
cyclopropyl, cyclobutyl, --CH.sub.2-cyclopropyl, or
--CH.sub.2-cyclobutyl, and the remaining variables are as set forth
in embodiment no. 22.
[0140] In embodiment no. 24, R' is cyclopropyl and the remaining
variables are as set forth in embodiment no. 22.
[0141] In embodiment no. 25, the group
##STR00020##
(wherein the truncated bond joins with the nitrogen atom bearing
R.sup.1) is selected from the group consisting of
##STR00021##
and the remaining variables are as set forth in any one of
embodiment nos. 22-24.
[0142] In embodiment no. 26, n is 1, and the remaining variables
are as set forth in any one of embodiment nos. 22-25.
[0143] In embodiment no. 27, n is 0, and the remaining variables
are as set forth in any one of embodiment nos. 22-25.
[0144] In embodiment no. 28, Y is --C(O)--, Z is absent, and the
remaining variables are as set forth in any one of embodiment nos.
22-27.
[0145] In embodiment no. 29, Y is --C(O)--, Z is
--(C.sub.1-C.sub.3) alkylene-, and the remaining variables are as
set forth in any one of embodiment nos. 22-27.
[0146] In embodiment no. 30, Y is
##STR00022##
Z is absent, and the remaining variables are as set forth in any
one of embodiment nos. 22-27.
[0147] In embodiment no. 31, the bond joining the group
##STR00023##
to the central piperidine ring and the bonds joining the
cycloalkane ring to the piperidine ring in the compound of Formula
(IB) are disposed in a cis, cis configuration, and the variables
R.sup.1, R.sup.7, Q, Y, Z, E, m, n, and t are as set forth in any
one of embodiment nos. 22-30. For instance, in one alternative, the
compound of the Formula (IB) has the Formula (IB')
##STR00024##
In another alternative, the compound of the Formula (IB) has the
Formula (IB'')
##STR00025##
[0148] In embodiment no. 32, the compound of the Formula (I) has
the Formula (IC)
##STR00026##
wherein
Q is --C(O)--, --C(O)O--, or --CH.sub.2--;
[0149] m is 1 or 2; Z is absent or --OCH.sub.2--; each occurrence
of R.sup.4 is independently C.sub.1-C.sub.3 alkyl, fluoro,
trifluoromethoxy, or --S--CF.sub.3; v is 0, 1, or 2; n is 0 or 1;
each occurrence of R.sup.7 is independently chloro or fluoro; and t
is 0, 1, or 2.
[0150] In embodiment no. 33, the group
##STR00027##
is selected from the group consisting of:
##STR00028##
and the remaining variables are as set forth for embodiment no.
32.
[0151] In embodiment no. 34, Z is absent and the remaining
variables are as set forth for any one of embodiment nos. 32 and
33.
[0152] In embodiment no. 35, Z is --OCH.sub.2-- and the remaining
variables are as set forth for any one of embodiment nos. 32 and
33.
[0153] In embodiment no. 36, n is 1 and the remaining variables are
as set forth for any one of embodiment nos. 32-35.
[0154] In embodiment, no. 37, the bond joining the group
##STR00029##
to the central piperidine ring and the bonds joining the
cycloalkane ring to the piperidine ring in the compound of Formula
(IC) are disposed in a cis, cis configuration, and the variables
R.sup.4, R.sup.7, Q, m, n, t, and v are as described in any one of
embodiment nos. 32-36. For instance, in one alternative, the
compound of the Formula (IC) has the Formula (IC')
##STR00030##
In another alternative, the compound of the Formula (IC) has the
Formula (IC'')
##STR00031##
[0155] In embodiment no. 38, the compound has the Formula (IC'),
wherein
[0156] Q is --C(O)-- or --CH.sub.2--;
[0157] m is 2;
[0158] R.sup.7 is F;
[0159] t is 0 or 1
[0160] R.sup.4 is --OCF.sub.3 or halo;
[0161] v is 0 or 1; and
[0162] Z is absent (such that the carbonyl of Y is directly bonded
to the phenyl of E).
[0163] In embodiment no. 39, the compound has the Formula (I),
wherein [0164] Z is [0165] (i) absent, [0166] (ii)
--(C.sub.1-C.sub.6) alkylene-, [0167] (iii) --O--, [0168] (iv)
--O--(C.sub.1-C.sub.6 alkylene)-, [0169] (v) --N(H)--, or [0170]
(vi) a group of the formula
[0170] ##STR00032## wherein r is 1, 2, 3, or 4; [0171] E is [0172]
(i) phenyl, [0173] (ii) naphthyl, [0174] (iii) tetrahydronapthyl,
[0175] (iv) indanyl, [0176] (v) 5- to 10-membered mono- or bicyclic
heteroaryl containing one to three heteroatoms selected from the
group consisting of N, O, and S, [0177] (vi) 5- to 10-membered
mono- or bicyclic heterocyclenyl containing one to three
heteroatoms selected from the group consisting of N, O, and S,
[0178] wherein said phenyl, napthyl, tetrahydronapthyl, indanyl, 5-
to 10-membered heteroaryl, or 5- to 10-membered heterocyclenyl of E
is unsubstituted or substituted by one to three R.sup.4 moieties,
wherein [0179] each R.sup.4 is selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 alkoxy, --CN, halo,
C.sub.1-C.sub.3 fluoroalkyl, --O--(C.sub.1-C.sub.3 fluoroalkyl),
--S--(C.sub.1-C.sub.3 fluoroalkyl), C.sub.3-C.sub.7 cycloalkyl,
R.sup.4a, --O--R.sup.4a, or 5- to 6-membered heterocyclyl
containing 1 or 2 heteroatom selected from the group consisting of
N, O, and S; [0180] R.sup.4a is phenyl or a 5 to 6-membered
heteroaryl ring containing one to two heteroatoms selected from the
group consisting of N, O, and S; [0181] wherein R.sup.4a is
unsubstituted or substituted by one to two moieties independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3 alkoxy, halo, --CN, C.sub.1-C.sub.3 fluoroalkyl,
--O--(C.sub.1-C.sub.3 fluoroalkyl), --S--(C.sub.1-C.sub.3
fluoroalkyl), and --SO.sub.2--(C.sub.1-C.sub.3 alkyl), [0182] or,
wherein two R.sup.4 moieties are substituted on vicinal carbon
atoms of E, the two R.sup.4 moieties together with the carbon atoms
to which they are attached form a dioxolane ring; [0183] (vii)
C.sub.3-C.sub.7 cycloalkyl, or [0184] (viii) C.sub.1-C.sub.6 alkyl;
[0185] each occurrence of R.sup.7 is independently halo,
C.sub.1-C.sub.3 fluoroalkyl, --CN, phenyl, or a 5- to 6-membered
heteroaryl containing 1 to 2 heteroatoms selected from the group
consisting of N, O, and S, wherein said phenyl or heteroaryl of
R.sup.7 is independently unsubstituted or substituted with 1 to 2
halo; and [0186] the remaining variables are as described in
embodiment no. 1.
[0187] In embodiment no. 40, the invention also provides any one of
the compounds specified in Tables A and B in the Examples section
below, which tables include compounds 7, 9, 9A, 9B, 10, 11, 11A,
11B, 11C, 12, 12B, 12C, 12D, 12E, 13, 13C, 13D, 13E, 14, 14C, 14D,
14E, 14F, 14G, 14H, 14i, 14K, 14L, 14N, 14o, 14P, 15, 16, 16A, 16B,
16C, 16D, 16E, 17, 17G, 17H, 17i, 17J, 17K, 17L, 17M, 17N, 17o,
17P, 17Q, 17R, 17S, 17T, 17U, 17V, 17W, 17.times., 17Y, 17Z, 17AA,
17AB, 17AC, 17AD, 17AE, 17AF, 17AG, 17AH, 17Ai, 17AJ, 17AK, 17AL,
17AM, 17AN, 17Ao, 17AP, 17AQ, 17AR, 17AS, 17AT, 17AU, 17AV, 17AW,
17AX, 17AY, 17AZ, 17BA, 17BB, 17BC, 17BD, 17BE, 17BF, 17BG, 17BH,
17Bi, 17BJ, 17BK, 17BL, 17BM, 17BN, 17Bo, 17BP, 17BQ, 17BR, 17BS,
17BT, 17BU, 17BV, 17BW, 17BX, 17BY, 17BZ, 17CA, 17CB, 17CC, 17CD,
17CE, 17CF, 17CG, 17CH, 17Ci, 17CJ, 17CK, 17CL, 17CM, 17CN, 17Co,
17CP, 17CQ, 17CR, 17CS, 17CT, 17CU, 17CV, 17CW, 17CX, 17CY, 17CZ,
17DA, 17 DB, 17DC, 17DD, 17DE, 17DF, 17DG, 17DH, 17Di, 17DJ, 17DK,
17DL, 17DN, 17Do, 18, 18C, 18D, 18E, 18F, 18G, 18H, 18i, 18J, 18K,
18L, 18M, 18N, 18o, 18P, 18Q, 18R, 18S, 18T, 19, 20, 21, 21A, 21B,
21C, 21D, 21E, 21F, 21G, 21H, 21i, 21J, 21K, 21L, 22, 22A, 22D,
22E, 22F, 22G, 22H, 22i, 22J, 22K, 22L, 22M, 22N, 22o, 22P, 22Q,
22R,22S, 22T, 22U, 22V, 22W, 22.times., 22Y, 23, 23B, 23C, 23D,
23E, 23F, 23G, 23H, 23i, 24, 24B, 24C, 24D, 25, 26, 27, 27A, 27B,
27C, 27D, 27E, 27F, 27G, 27H, 27i, 27J, 27K, 27L, 27M, 27N, 27o,
27P, 27Q, 27R, 27S, 28, 29, 30, 31, 32, 32C, 32D, 32E, 32F, 32G,
32H, 32i, 32J, 32K, 32L, 32M, 32N, 32o, 32P, 32Q, 32R, 32S, 32T,
32U, 33, 34, 35, 35D, 35E, 35F, 35G, 35H, 35i, 35J, 35K, 36, 36A,
36B, 36C, 37, 38, 38D, 38E, 38F, 38G, 39, 40, 41, 42, 43, 43B, 43C,
44, 44B, 44C, 44D, 44E, 44F, 45, 46, 47, 47D, 47E, 47F, 47G, 48,
48C, 49, 49B, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,
63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,
80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,
97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110,
111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123,
124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136,
137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149,
150, 151, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 163,
164, 165, 166, 167, 168, 169, 170, 171, 172, 173, and 174, or a
pharmaceutically acceptable salt thereof. The structures of these
compounds are set forth in the Examples section below.
[0188] In embodiment no. 41, the invention provides a compound
selected from the group consisting of: [0189]
4-[{cis,cis-4-[(benzyloxy)carbonyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta-
[b]quinolin-9-yl}(cyclopropyl)amino]-4-oxobutanoic acid; [0190]
4-[{cis,cis-4-[(benzyloxy)carbonyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta-
[b]quinolin-9-yl}(phenyl)amino]-4-oxobutanoic acid; [0191]
4-{ethyl[cis,cis-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-2,3,3a,4,9,9a-h-
exahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobutanoic acid;
[0192]
4-{cyclopropyl[cis,cis-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-2,3,3a,4,-
9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobutanoic
acid; [0193]
4-[{cis,cis-4-[(benzyloxy)carbonyl]-6-fluoro-2,3,3a,4,9,9a-hexahyd-
ro-1H-cyclopenta[b]quinolin-9-yl}(cyclopropyl)amino]-4-oxobutanoic
acid; [0194]
4-{cyclopropyl[cis,cis-6-fluoro-4-[(4-phenoxyphenyl)carbonyl]-2,3,-
3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobutanoic
acid; [0195]
4-{cyclopropyl[cis,cis-3-{[4-(trifluoromethoxy)phenyl]carbonyl}-1,2,2a,3,-
8,8a-hexahydrocyclobuta[b]quinolin-8-yl]amino}-4-oxobutanoic acid;
[0196]
({cyclopropyl[cis,cis-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-2,3,3a,4,9-
,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]carbamoyl}oxy)acetic
acid; [0197] 3-(phenylmethyl)
cis,cis-8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-5-fluoro-2,2a,8,8a-te-
trahydrocyclobuta[b]quinoline-3(1H)-carboxylate; [0198]
4-(phenylmethyl)
cis,cis-9-[(3-carboxy-1-oxopropyl)cyclopropylamino]-6-chloro-1,2,3,3a,9,9-
a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate; [0199]
4-(phenylmethyl)
cis,cis-9-[(3-carboxy-1-oxopropyl)cyclopropylamino]-7-fluoro-1,2,3,3a,9,9-
a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate; [0200]
4-[cyclopropyl[(cis,
cis)-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]-1H--
cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic acid; [0201]
4-[[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]-1H-cy-
clopenta[b]quinolin-9-yl]methylamino]-4-oxobutanoic acid; [0202]
4-[(cyclobutylmethyl)[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorometh-
oxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic
acid; [0203]
4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-(3-phenoxybenzoyl-
)-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxo-butanoic acid; [0204]
4-(cyclopropyl(cis,cis-4-(thiophene-2-carbonyl)-2,3,3a,4,9,9a-hexahydro-1-
H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid; [0205]
[[[[cis,cis-6-chloro-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorometh-
oxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]carbonyl]oxy]a-
cetic acid; [0206]
4-[cyclopropyl[cis,cis-5-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluorome-
thoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid;
[0207]
deuterated-4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoro-
methoxy)benzoyl]-1H-cyclopenta[b]quinolin-9(R)-yl-(d)]amino]-4-oxobutanoic
acid; [0208] 4-[[(cis,
cis)-6-chloro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]-1H--
cyclopenta[b]quinolin-9-yl]cyclobutylamino]-4-oxobutanoic acid;
[0209] 4-[[(cis,
cis)-6-chloro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)be-
nzoyl]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid; [0210] 4-[[(cis,
cis)-6-chloro-2,3,3a,4,9,9a-hexahydro-4-[(trans-2-phenylcyclopropyl)carbo-
nyl]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid; [0211] 4-[cyclobutyl[(cis,
cis)-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]-1H-cyclopent-
a[b]quinolin-9-yl]amino]-4-oxobutanoic acid; [0212] 4-[[(cis,
cis)-6-chloro-2,3,3a,4,9,9a-hexahydro-4-[(1,2,3,4-tetrahydro-1-naphthalen-
yl)carbonyl]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid; [0213] 4-[[(cis,
cis)-6-chloro-4-[(2,3-dihydro-1H-inden-2-yl)carbonyl]-2,3,3a,4,9,9a-hexah-
ydro-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid; [0214] 4-[[(cis,
cis)-6-chloro-2,3,3a,4,9,9a-hexahydro-4-[(1,2,3,4-tetrahydro-2-naphthalen-
yl)carbonyl]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid; [0215]
4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[3-(5-thiazolyl)benzoyl]-
-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic acid; [0216]
4-[(2,4-difluorophenyl)methyl] (cis,
cis)-9-[[(carboxymethoxy)carbonyl]cyclopropylamino]-1,2,3,3a,9,9a-hexahyd-
ro-4H-cyclopenta[b]quinoline-4-carboxylate; [0217]
4-[1-(4-fluorophenyl)ethyl](cis,cis)-9-[(3-carboxy-1-oxopropyl)cyclopropy-
lamino]-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate;
[0218]
4-(1,2,3,4-tetrahydro-2-naphthalenyl)(cis,cis)-9-[(3-carboxy-1-oxo-
propyl)cyclopropylamino]-7-fluoro-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]-
quinoline-4-carboxylate; [0219]
4-[cyclopropyl[(cis,cis)-6-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoro-
methoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic
acid; [0220]
3-(phenylmethyl)(cis,cis)-8-[(3-carboxy-1-oxopropyl)cyclopropylami-
no]-5-chloro-2,2a,8,8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate;
[0221]
4-[[(cis,cis)-5-chloro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluorometh-
oxy)benzoyl]cyclobuta[b]quinolin-8-yl]cyclopropylamino]-4-oxobutanoic
acid; [0222]
3-(phenylmethyl)(cis,cis)-8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-2,2-
a,8,8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate; [0223]
4-[cyclopropyl[(cis,cis)-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoromethoxy)b-
enzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid; [0224]
4-(phenylmethyl)(cis,cis)-9-[[(carboxymethoxy)carbonyl]cyclopropylamino]--
1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate;
[0225]
4-(phenylmethyl)(cis,cis)-9-[[(carboxymethoxy)carbonyl]cyclopropylamino]--
7-fluoro-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate;
[0226]
[[[cyclopropyl[(cis,cis)-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluorome-
thoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]carbonyl]oxy]acetic
acid; [0227]
[[[cyclopropyl[(cis,cis)-3-(3,4-difluorobenzoyl)-1,2,2a,3,8,8a-hex-
ahydrocyclobuta[b]quinolin-8-yl]amino]carbonyl]oxy]acetic acid;
[0228]
[[[cyclopropyl[(cis,cis)-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoro-
methoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]carbonyl]oxy]acetic
acid; [0229]
4-(phenylmethyl)(cis,cis)-9-[[(2(S)-carboxy-1-azetidinyl)carbonyl]cyclopr-
opylamino]-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate-
; [0230]
N--[[cyclopropyl[(cis,cis)-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluor-
omethoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]carbonyl]-N-methylgl-
ycine; [0231]
[[[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[5-[[4-(trifluoromethoxy-
)phenyl]methyl]-1,3,4-oxadiazol-2-yl]-1H-cyclopenta[b]quinoline-9-yl]amino-
]carbonyl]oxy]acetic acid; [0232]
2-[ethyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]--
1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxazolecarboxylic acid;
[0233] 3-(phenylmethyl)
cis,cis-8-[(3-carboxypropyl)cyclopropylamino]-5-fluoro-2,2a,8,8a-tetrahyd-
rocyclobuta[b]quinoline-3(1H)-carboxylate; [0234]
4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)ben-
zoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]butanoic acid; [0235]
4-[cyclopropyl[cis,cis-5-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluorome-
thoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]butanoic acid; [0236]
4-[cyclopropyl[(cis,cis)-2,3,3a,4,9,9a-hexahydro-4-[4-[(trifluoromethyl)t-
hio]benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic
acid; [0237]
4-(ethyl((cis,cis)-3-(4-(trifluoromethylthio)benzoyl)-1,2,2a,3,8,8-
a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
[0238]
4-(ethyl((cis,cis)-3-(4-ethylbenzoyl)-1,2,2a,3,8,8a-hexahydrocyclobuta[b]-
quinolin-8-yl)amino)-4-oxobutanoic acid; [0239] 3-(phenylmethyl)
8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-5,6-difluoro-2,2a,8,8a-tetrah-
ydro-cyclobuta[b]quinoline-3(1H)-carboxylate; [0240]
4-[cyclopropyl[(cis,cis)-5,6-dichloro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifl-
uoromethoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic
acid; [0241]
4-(cyclopropyl((cis,cis)-5,6-difluoro-3-(4-(trifluoromethoxy)benzo-
yl)-1,2,2a,3,8,8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic
acid; [0242]
4-[cyclopropyl[(cis,cis)-6-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoro-
methoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxo-butanoic
acid; and [0243]
(R)-1-(((cis,cis)-3-(benzyloxycarbonyl)-5,6-difluoro-1,2,2a,3,8,8a-hexahy-
drocyclobuta[b]quinolin-8-yl)(cyclopropyl)carbamoyl)azetidine-2-carboxylic
acid; [0244]
4-(cyclopropyl(cis,cis-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,3,8,8a-
-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
[0245]
4-(ethyl(cis,cis-6-fluoro-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,3,8-
,8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
[0246]
4-(ethyl(cis,cis-7-fluoro-4-(4-((trifluoromethyl)thio)benzoyl)-2,3,3a,4,9-
,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid; [0247]
4-(cyclopropyl(cis,cis-7-fluoro-4-(4-((trifluoromethyl)thio)benzoy-
l)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutan-
oic acid; and [0248]
4-(cyclopropyl(cis,cis-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,-
9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)butanoic
acid;
[0249] or a pharmaceutically acceptable salt thereof.
[0250] In embodiment no. 42, the invention provides a compound
selected from the group consisting of: [0251]
4-{cyclopropyl[cis,cis-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-2,3,3a,4,-
9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobutanoic
acid; [0252]
4-[cyclopropyl[cis,cis-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trif-
luoromethoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic
acid; [0253]
4-[[cis,cis-6-chloro-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorometh-
oxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid; [0254]
4-[cyclopropyl[cis,cis-5-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluorome-
thoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid;
[0255]
4-[cyclopropyl[cis,cis-6-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluorome-
thoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid;
[0256]
3-(phenylmethyl)(cis,cis)-8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-5-c-
hloro-2,2a,8,8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate;
[0257]
3-(phenylmethyl)(cis,cis)-8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-2,2-
a,8,8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate; [0258]
4-[cyclopropyl[cis,cis-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoromethoxy)ben-
zoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid; [0259]
[[[cyclopropyl[cis,cis-3-(3,4-difluorobenzoyl)-1,2,2a,3,8,8a-hexahydrocyc-
lobuta[b]quinolin-8-yl]amino]carbonyl]oxy]acetic acid; [0260]
3-(phenylmethyl)
cis,cis-8-[(3-carboxypropyl)cyclopropylamino]-5-fluoro-2,2a,8,8a-tetrahyd-
rocyclobuta[b]quinoline-3(1H)-carboxylate; [0261]
4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)ben-
zoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]butanoic acid; [0262]
4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-[(trifluoromethyl)thi-
o]benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic acid;
[0263]
(R)-1-((cis,cis-3-(benzyloxycarbonyl)-5,6-difluoro-1,2,2a,3,8,8a-hexahydr-
ocyclobuta[b]quinolin-8-yl)(cyclopropyl)carbamoyl)azetidine-2-carboxylic
acid; [0264]
4-(cyclopropyl(cis,cis-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,3,8,8a-
-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
[0265]
4-(ethyl(cis,cis-6-fluoro-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,3,8-
,8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
[0266]
4-(ethyl(cis,cis-7-fluoro-4-(4-((trifluoromethyl)thio)benzoyl)-2,3,3a,4,9-
,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid; [0267]
4-(cyclopropyl(cis,cis-7-fluoro-4-(4-((trifluoromethyl)thio)benzoy-
l)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutan-
oic acid; and [0268]
4-(cyclopropyl(cis,cis-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,-
9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)butanoic acid;
[0269] or a pharmaceutically acceptable salt thereof.
[0270] In embodiment no. 43, the invention provides a compound
selected from the group consisting of: [0271]
4-{cyclopropyl[cis,cis-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-2,3,3a,4,-
9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobutanoic
acid; [0272]
4-{cyclopropyl[[(3aS,9aR)-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-
-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9(R)-yl]amino}-4-oxobuta-
noic acid; [0273]
4-{cyclopropyl[[(3aR,9aS)-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-2,3,3a-
,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9(S)-yl]amino}-4-oxobutanoic
acid; [0274]
4-[cyclopropyl[cis,cis-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorome-
thoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic
acid; [0275]
4-[cyclopropyl[(3aS,9aR)-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(tr-
ifluoromethoxy)benzoyl]-1H-cyclopenta[b]quinolin-9(R)-yl]amino]-4-oxobutan-
oic acid; [0276]
4-[cyclopropyl[(3aR,9aS)-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoro-
methoxy)benzoyl]-1H-cyclopenta[b]quinolin-9(S)-yl]amino]-4-oxobutanoic
acid; [0277]
4-[[cis,cis-6-chloro-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorometh-
oxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid; [0278]
4-[[(3aS,9aR)-6-chloro-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorome-
thoxy)benzoyl]-1H-cyclopenta[b]quinolin-9(R)-yl]cyclopropylamino]-4-oxobut-
anoic acid; [0279]
4-[[(3aR,9aS)-6-chloro-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorome-
thoxy)benzoyl]-1H-cyclopenta[b]quinolin-9(S)-yl]cyclopropylamino]-4-oxobut-
anoic acid; [0280]
4-[cyclopropyl[cis,cis-5-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluorome-
thoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid;
[0281]
4-[cyclopropyl[(2aS,8aR)-5-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoro-
methoxy)benzoyl]cyclobuta[b]quinolin-8(R)-yl]amino]-4-oxobutanoic
acid; [0282]
4-[cyclopropyl[(2aR,8aS)-5-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(tr-
ifluoromethoxy)benzoyl]cyclobuta[b]quinolin-8(S)-yl]amino]-4-oxobutanoic
acid; [0283]
4-[cyclopropyl[cis,cis-6-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluorome-
thoxy)benzoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid;
[0284]
4-[cyclopropyl[(2aS,8aR)-6-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoro-
methoxy)benzoyl]cyclobuta[b]quinolin-8(R)-yl]amino]-4-oxobutanoic
acid; [0285]
4-[cyclopropyl[(2aR,8aS)-6-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(tr-
ifluoromethoxy)benzoyl]cyclobuta[b]quinolin-8(S)-yl]amino]-4-oxobutanoic
acid; [0286]
3-(phenylmethyl)(cis,cis)-8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-5-c-
hloro-2,2a,8,8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate;
[0287] 3-(phenylmethyl)
(2aS,8aR)-8(R)-[(3-carboxy-1-oxopropyl)cyclopropylamino]-5-chloro-2,2a,8,-
8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate; [0288]
3-(phenylmethyl)
(2aR,8aS)-8(S)-[(3-carboxy-1-oxopropyl)cyclopropylamino]-5-chloro-2,2a,8,-
8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate; [0289]
3-(phenylmethyl)(cis,cis)-8-[(3-carboxy-1-oxopropyl)cyclopropylamino]-2,2-
a,8,8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate; [0290]
3-(phenylmethyl)
(2aS,8aR)-8(R)-[(3-carboxy-1-oxopropyl)cyclopropylamino]-2,2a,8,8a-tetrah-
ydrocyclobuta[b]quinoline-3(1H)-carboxylate; [0291]
3-(phenylmethyl)
(2aR,8aS)-8(S)-[(3-carboxy-1-oxopropyl)cyclopropylamino]-2,2a,8,8a-tetrah-
ydrocyclobuta[b]quinoline-3(1H)-carboxylate; [0292]
4-[cyclopropyl[cis,cis-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoromethoxy)ben-
zoyl]cyclobuta[b]quinolin-8-yl]amino]-4-oxobutanoic acid; [0293]
4-[cyclopropyl[(2aS,8aR)-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoromethoxy)b-
enzoyl]cyclobuta[b]quinolin-8(R)-yl]amino]-4-oxobutanoic acid;
[0294]
4-[cyclopropyl[(2aR,8aS-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoromethoxy)be-
nzoyl]cyclobuta[b]quinolin-8(S)-yl]amino]-4-oxobutanoic acid;
[0295]
[[[cyclopropyl[cis,cis-3-(3,4-difluorobenzoyl)-1,2,2a,3,8,8a-hexahydrocyc-
lobuta[b]quinolin-8-yl]amino]carbonyl]oxy]acetic acid; [0296]
[[[cyclopropyl[(2aS,8aR)-3-(3,4-difluorobenzoyl)-1,2,2a,3,8,8a-hexahydroc-
yclobuta[b]quinolin-8(R)-yl]amino]carbonyl]oxy]acetic acid; [0297]
[[[cyclopropyl[(2aR,8aS)-3-(3,4-difluorobenzoyl)-1,2,2a,3,8,8a-hexahydroc-
yclobuta[b]quinolin-8(S)-yl]amino]carbonyl]oxy]acetic acid; [0298]
3-(phenylmethyl)
cis,cis-8-[(3-carboxypropyl)cyclopropylamino]-5-fluoro-2,2a,8,8a-tetrahyd-
rocyclobuta[b]quinoline-3(1H)-carboxylate; [0299] 3-(phenylmethyl)
(2aS,8aR)-8(R)-[(3-carboxypropyl)cyclopropylamino]-5-fluoro-2,2a,8,8a-tet-
rahydrocyclobuta[b]quinoline-3(1H)-carboxylate; [0300]
3-(phenylmethyl)
(2aR,8aS)-8(S)-[(3-carboxypropyl)cyclopropylamino]-5-fluoro-2,2a,8,8a-tet-
rahydrocyclobuta[b]quinoline-3(1H)-carboxylate; [0301]
4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)ben-
zoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]butanoic acid; [0302]
4-[cyclopropyl[(3aS,9aR)-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)b-
enzoyl]-1H-cyclopenta[b]quinolin-9(R)-yl]amino]butanoic acid;
[0303]
4-[cyclopropyl[(3aR,9aS)-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)b-
enzoyl]-1H-cyclopenta[b]quinolin-9(S)-yl]amino]butanoic acid;
[0304]
4-[cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-[(trifluoromethyl)thi-
o]benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic acid;
[0305]
4-[cyclopropyl[(3aS,9aR)-2,3,3a,4,9,9a-hexahydro-4-[4-[(trifluoromethyl)t-
hio]benzoyl]-1H-cyclopenta[b]quinolin-9(R)-yl]amino]-4-oxobutanoic
acid; [0306]
4-[cyclopropyl[(3aR,9aS)-2,3,3a,4,9,9a-hexahydro-4-[4-[(trifluorom-
ethyl)thio]benzoyl]-1H-cyclopenta[b]quinolin-9(S)-yl]amino]-4-oxobutanoic
acid; [0307]
(R)-1-((cis,cis-3-(benzyloxycarbonyl)-5,6-difluoro-1,2,2a,3,8,8a-hexahydr-
ocyclobuta[b]quinolin-8-yl)(cyclopropyl)carbamoyl)azetidine-2-carboxylic
acid; [0308]
(R)-1-(((2aS,8aR)-3-(benzyloxycarbonyl)-5,6-difluoro-1,2,2a,3,8,8a-hexahy-
drocyclobuta[b]quinolin-8(R)-yl)(cyclopropyl)carbamoyl)azetidine-2-carboxy-
lic acid; [0309]
(R)-1-(((2aR,8aS)-3-(benzyloxycarbonyl)-5,6-difluoro-1,2,2a,3,8,8a-hexahy-
drocyclobuta[b]quinolin-8(S)-yl)(cyclopropyl)carbamoyl)azetidine-2-carboxy-
lic acid; [0310]
4-(cyclopropyl(cis,cis-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,3,8,8a-
-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
[0311]
4-(cyclopropyl((2aS,8aR)-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,3,8,-
8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
[0312]
4-(cyclopropyl((2aR,8aS)-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,3,8,-
8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
[0313]
4-(ethyl(cis,cis-6-fluoro-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,3,8-
,8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
[0314]
4-(ethyl((2aS,8aR)-6-fluoro-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,3-
,8,8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
[0315]
4-(ethyl((2aR,8aS)-6-fluoro-3-(4-((trifluoromethyl)thio)benzoyl)-1,2,2a,3-
,8,8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic acid;
[0316]
4-(ethyl(cis,cis-7-fluoro-4-(4-((trifluoromethyl)thio)benzoyl)-2,3,3a,4,9-
,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid; [0317]
4-(ethyl((3aS,9aR)-7-fluoro-4-(4-((trifluoromethyl)thio)benzoyl)-2-
,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid; [0318]
4-(ethyl((3aR,9aS)-7-fluoro-4-(4-((trifluoromethyl)thio)benzoyl)-2,3,3a,4-
,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid; [0319]
4-(cyclopropyl(cis,cis-7-fluoro-4-(4-((trifluoromethyl)thio)benzoy-
l)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutan-
oic acid; [0320]
4-(cyclopropyl((3aS,9aR)-7-fluoro-4-(4-((trifluoromethyl)thio)benzoyl)-2,-
3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid; [0321]
4-(cyclopropyl((3aR,9aS)-7-fluoro-4-(4-((trifluoromethyl)thio)benzoyl)-2,-
3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid; and [0322]
4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,-
3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)butanoic
acid; [0323] or a pharmaceutically acceptable salt thereof.
[0324] In embodiment no. 44, the invention provides a compound
selected from the group consisting of: [0325]
4-{cyclopropyl[[(3aS,9aR)-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-2,3,3a-
,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9(R)-yl]amino}-4-oxobutanoic
acid; [0326]
4-[cyclopropyl[(3aS,9aR)-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoro-
methoxy)benzoyl]-1H-cyclopenta[b]quinolin-9(R)-yl]amino]-4-oxobutanoic
acid; [0327]
4-[[(3aS,9aR)-6-chloro-7-fluoro-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorome-
thoxy)benzoyl]-1H-cyclopenta[b]quinolin-9(R)-yl]cyclopropylamino]-4-oxobut-
anoic acid; [0328]
4-[cyclopropyl[(2aS,8aR)-6-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(trifluoro-
methoxy)benzoyl]cyclobuta[b]quinolin-8(R)-yl]amino]-4-oxobutanoic
acid; [0329]
4-[cyclopropyl[(2aR,8aS)-6-fluoro-1,2,2a,3,8,8a-hexahydro-3-[4-(tr-
ifluoromethoxy)benzoyl]cyclobuta[b]quinolin-8(S)-yl]amino]-4-oxobutanoic
acid; [0330]
4-(ethyl((3aS,9aR)-7-fluoro-4-(4-((trifluoromethyl)thio)benzoyl)-2,3,3a,4-
,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid; [0331]
4-[cyclopropyl[(3aS,9aR)-2,3,3a,4,9,9a-hexahydro-4-[4-[(trifluorom-
ethyl)thio]benzoyl]-1H-cyclopenta[b]quinolin-9(R)-yl]amino]-4-oxobutanoic
acid; and [0332]
4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,-
3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)butanoic
acid; [0333] or a pharmaceutically acceptable salt thereof.
[0334] The invention also provides a compound of Formula (I) or a
pharmaceutically acceptable salt thereof in purified form.
Compositions and Administration
[0335] This invention is also directed to pharmaceutical
compositions which comprise a therapeutically effective amount of
the compound of Formula (I), or a pharmaceutically acceptable salt
of said compound and a pharmaceutically acceptable carrier.
[0336] A preferred dosage is about 0.001 to 100 mg/kg of body
weight/day of the compound of Formula (I). An especially preferred
dosage is about 0.01 to 10 mg/kg of body weight/day of a compound
of Formula (I), or a pharmaceutically acceptable salt of said
compound.
[0337] The term "pharmaceutical composition" is also intended to
encompass both the bulk composition and individual dosage units
comprised of more than one (e.g., two) pharmaceutically active
agents such as, for example, a compound of the present invention
and an additional therapeutic agent selected from the lists of the
additional agents described herein below, along with any
pharmaceutically inactive excipients. The bulk composition and each
individual dosage unit can contain fixed amounts of the aforesaid
"more than one pharmaceutically active agents". The bulk
composition is material that has not yet been formed into
individual dosage units. An illustrative dosage unit is an oral
dosage unit such as tablets, pills and the like. Similarly, the
herein-described method of treating a patient by administering a
pharmaceutical composition of the present invention is also
intended to encompass the administration of the afore-said bulk
composition and individual dosage units.
[0338] For preparing pharmaceutical compositions from the compounds
described by this invention, inert, pharmaceutically acceptable
carriers can be either solid or liquid. Solid form preparations
include powders, tablets, dispersible granules, capsules, cachets
and suppositories. The powders and tablets may be comprised of from
about 5 to about 95 percent active ingredient. Suitable solid
carriers are known in the art, e.g., magnesium carbonate, magnesium
stearate, talc, sugar or lactose. Tablets, powders, cachets and
capsules can be used as solid dosage forms suitable for oral
administration. Examples of pharmaceutically acceptable carriers
and methods of manufacture for various compositions may be found in
A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18.sup.th
Edition, (1990), Mack Publishing Co., Easton, Pa.
[0339] Liquid form preparations include solutions, suspensions and
emulsions. Examples of materials useful for forming such liquid
form preparations include water or water-propylene glycol solutions
for parenteral injection, or sweeteners and opacifiers for oral
solutions, suspensions and emulsions. Liquid form preparations may
also include solutions or suspensions for intranasal
administration.
[0340] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas, e.g., nitrogen.
[0341] Also included are solid form preparations that are intended
to be converted, shortly before use, to liquid form preparations
for either oral or parenteral administration. Such liquid forms
include solutions, suspensions and emulsions.
[0342] The compounds of the invention can also be deliverable
transdermally. The transdermal compositions can take the form of
creams, lotions, aerosols and/or emulsions and can be included in a
transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
[0343] The compounds of this invention may also be delivered
subcutaneously.
[0344] Preferably the compound is administered orally.
[0345] Preferably, the pharmaceutical preparation is in a unit
dosage form. In such form, the preparation is subdivided into
suitably sized unit doses containing appropriate quantities of the
active component, e.g., an effective amount to achieve the desired
purpose.
[0346] The quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 0.001 mg to about
100 mg per kg body weight of a mammal, preferably from about 0.01
mg to about 10 mg per kg. The actual dosage employed may be varied
depending upon the requirements of the patient and the severity of
the condition being treated. Determination of the proper dosage
regimen for a particular situation is within the skill of the art.
For convenience, the total daily dosage may be divided and
administered in portions during the day as required.
[0347] The compositions of the invention can further comprise one
or more additional therapeutic agents, as discussed in further
detail below. Accordingly, in one embodiment, the present invention
provides compositions comprising: (i) a compound of Formula (I) or
a pharmaceutically acceptable salt thereof; (ii) one or more
additional therapeutic agents, that are not compounds of Formula
(I); and (iii) a pharmaceutically acceptable carrier, wherein the
amounts in the composition are together effective to treat one of
the disease or conditions discussed above.
Uses of the Compounds
[0348] The compounds of Formula (I) bind to CRTH.sub.2 and,
therefore, are useful in characterizing tissues containing
CRTH.sub.2, and in identifying further compounds which bind to
CRTH.sub.2. The general value of the compounds of the invention in
binding the CRTH.sub.2 receptor can be determined, for example,
using the radioligand binding assay described below in the Examples
section.
[0349] The compounds of Formula (I) can also be useful as
modulators of CRTH.sub.2 receptor function. In some embodiments,
compounds of Formula (I) are antagonists of the CRTH.sub.2
receptor. The general value of the compounds of the invention in
antagonizing CRTH.sub.2 receptor function can be determined, for
example, using the chemiluminescent-based cAMP assay, the
.beta.-Arrestin assay, or the eosinophil shape change assay
described below in the Examples section.
[0350] While not being bound by any specific theory, Applicants
believe that the compounds of Formula (I) are useful in treating
the symptoms of diseases or conditions associated with uncontrolled
or inappropriate stimulation of CRTH.sub.2 function because of
their ability to antagonize the CRTH.sub.2 receptor. Accordingly,
in one embodiment, the invention provides a method for treating a
disease or conditions associated with uncontrolled or inappropriate
stimulation of CRTH.sub.2 function, comprising administering a
therapeutically effective amount of a compound of Formula (I) to a
patient in need of such treatment.
[0351] Diseases or conditions associated with uncontrolled or
inappropriate stimulation of CRTH.sub.2 function include (but are
not limited to) asthma, congestion, allergic rhinitis, atopic
dermatitis, chronic obstructive pulmonary disease ("COPD"),
dermatitis, inflammatory bowel disease, rheumatoid arthritis,
allergic nephritis, conjunctivitis, bronchial asthma, fold allergy,
systemic mast cell disorder, anaphylactic shock, urticaria, eczema,
itching, inflammation, ischemia-reperfusion injury, cerebrovascular
disorders, pleuritis, ulcerative colitis, eosinophil-related
diseases, such as Churg-Strauss syndrome and sinusitis, and
basophile-related diseases, such as basophilic leukemia and
basophilic leukocytosis, in humans and other mammals. Examples of
cerebrovascular disorders include stroke.
[0352] In certain embodiments, the present invention provides a
method for treating asthma, congestion, allergic rhinitis or COPD
which comprises administering a therapeutically effective dose of a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof to a patient in need of such treatment. In a specific
embodiment, the disease or condition being treated is asthma. In
another embodiment, the disease or condition being treated is
COPD.
[0353] In addition, compounds of the Formula (I) which act as
CRTH.sub.2 receptor antagonists can inhibit prostanoid-induced
smooth muscle contraction by antagonizing contractile prostanoids
or mimicking relaxing prostanoids and hence may be used in the
treatment of dysmenorrhea, premature labor and eosinophil related
disorders.
[0354] In another embodiment, the present invention provides a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof for use in the manufacture of a medicament for treating a
disease or condition selected from the group consisting of asthma,
congestion, allergic rhinitis, atopic dermatitis, COPD, dermatitis,
inflammatory bowel disease, rheumatoid arthritis, allergic
nephritis, conjunctivitis, bronchial asthma, food allergy, systemic
mast cell disorder, anaphylactic shock, urticaria, eczema, itching,
inflammation, ischemia-reperfusion injury, cerebrovascular
disorders, pleuritis, ulcerative colitis, eosinophil-related
diseases, such as Churg-Strauss syndrome and sinusitis, and
basophile-related diseases, such as basophilic leukemia and
basophilic leukocytosis.
[0355] In another embodiment, the present invention provides a
compound of Formula (I) or a pharmaceutically acceptable salt
thereof for use in treating a disease or condition from the group
consisting of asthma, congestion, allergic rhinitis, atopic
dermatitis, COPD, dermatitis, inflammatory bowel disease,
rheumatoid arthritis, allergic nephritis, conjunctivitis, bronchial
asthma, food allergy, systemic mast cell disorder, anaphylactic
shock, urticaria, eczema, itching, inflammation,
ischemia-reperfusion injury, cerebrovascular disorders, pleuritis,
ulcerative colitis, eosinophil-related diseases, such as
Churg-Strauss syndrome and sinusitis, and basophile-related
diseases, such as basophilic leukemia and basophilic
leukocytosis.
Combination Therapy
[0356] The compounds of Formula (I) or their pharmaceutically
acceptable salts may be used in combination, either in a single
formulation or co-administered as separate formulations with at
least one additional therapeutic agent to treat or prevent the
diseases and conditions described herein. These additional
therapeutic agents include, but are not limited to: (1) a DP
receptor antagonist, such as S-5751 and laropiprant; (2) a
corticosteroid, such as triamcinolone acetonide, budesonide,
beclomethasone, fluticasone and mometasone; (3) a 132-adrenergic
agonist, such as salmeterol, formoterol, arformoterol, terbutaline,
metaproterenol, albuterol and the like; (4) a leukotriene modifier,
including a leukotriene receptor antagonist, such as montelukast,
zafirlukast, pranlukast, or a lipooxygenase inhibitor including
5-lipooxygenase inhibitors and FLAP (5-lipooxygenase activating
protein) inhibitors, such as zileuton; (5) an antihistamine such as
bromopheniramine, chlorpheniramine, dexchlorpheniramine,
triprolidine, clemastine, diphenhydramine, diphenylpyraline,
tripelennamine, hydroxyzine, methdilazine, promethazine,
trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine
pyrilamine, astemizole, terfenadine, loratadine, cetirizine,
fexofenadine, descarboethoxyloratadine, and the like; (6) a
decongestant, including phenylephrine, phenylpropanolamine,
pseudophedrine, oxymetazoline, ephinephrine, naphazoline,
xylometazoline, propylhexedrine, or levo-desoxyephedrine; (7) an
antiitussive, including codeine, hydrocodone, caramiphen,
carbetapentane, or dextramethorphan; (8) another prostaglandin
ligand, including prostaglandin F agonist such as latanoprost;
misoprostol, enprostil, rioprostil, ornoprostol or rosaprostol; (9)
a diuretic; (10) non-steroidal antiinflammatory agents (NSAIDs),
such as propionic acid derivatives (alminoprofen, benoxaprofen,
bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,
flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen,
naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic
acid, and tioxaprofen), acetic acid derivatives (indomethacin,
acemetacin, alclofenac, clidanac, diclofenac, fenclofenac,
fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac,
sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic
acid derivatives (flufenamic acid, meclofenamic acid, mefenamic
acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid
derivatives (diflunisal and flufenisal), oxicams (isoxicam,
piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic
acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon,
feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (11)
cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and
rofecoxib; (12) inhibitors of phosphodiesterase type IV (PDE-IV)
e.g., Ariflo, roflumilast; (13) antagonists of the chemokine
receptors, especially CCR-1, CCR-2, and CCR-3; (14) cholesterol
lowering agents such as HMG-CoA reductase inhibitors (lovastatin,
simvastatin and pravastatin, fluvastatin, atorvastatin, and other
statins), sequestrants (cholestyramine and colestipol), nicotinic
acid, fenofibric acid derivatives (gemfibrozil, clofibrat,
fenofibrate and benzafibrate), and probucol; (15) anti-diabetic
agents such as insulin, sulfonylureas, biguanides (metformin),
.alpha.-glucosidase inhibitors (acarbose) and glitazones
(troglitazone, pioglitazone, englitazone, rosiglitazone and the
like); (16) preparations of interferon beta (interferon beta-1a,
interferon beta-1b); (17) anticholinergic agents, such as
muscarinic antagonists (ipratropium bromide and tiotropium
bromide), as well as selective muscarinic M3 antagonists; (18)
steroids such as beclomethasone, methylprednisolone, betamethasone,
prednisone, dexamethasone, and hydrocortisone; (19) triptans
commonly used for the treatment of migraine such as sumitriptan and
rizatriptan; (20) alendronate and other treatments for
osteoporosis; (21) other compounds such as 5-aminosalicylic acid
and prodrugs thereof, antimetabolites such as azathioprine and
6-mercaptopurine, cytotoxic cancer chemotherapeutic agents,
bradykinin (BK2) antagonists such as FK-3657, TP receptor
antagonists such as seratrodast, neurokinin antagonists (NK1/NK2),
VLA-4 antagonists, such as those described in U.S. Pat. No.
5,510,332, WO97/03094, WO97/02289, WO96/40781, WO96/22966,
WO96/20216, WO96/01644, WO96/06108, WO95/15973 and WO96/31206. In
addition, the invention encompasses a method of treating
prostaglandin D2 mediated diseases comprising: administration to a
patient in need of such treatment a non-toxic therapeutically
effective amount of a compound of Formula (I), optionally
co-administered with one or more of such ingredients as listed
immediately above.
[0357] When administering a combination therapy to a patient in
need of such administration, the therapeutic agents in the
combination, or a pharmaceutical composition or compositions
comprising the therapeutic agents, may be administered in any order
such as, for example, sequentially, concurrently, together,
simultaneously and the like.
[0358] In one embodiment, the compound of Formula (I) is
administered during a time when the additional therapeutic agent(s)
exert their prophylactic or therapeutic effect, or vice versa.
[0359] In another embodiment, the compound of Formula (I) and the
additional therapeutic agent(s) are administered in doses commonly
employed when such agents are used as monotherapy for treating the
disorder.
[0360] In another embodiment, the compound of Formula (I) and the
additional therapeutic agent(s) are administered in doses lower
than the doses commonly employed when such agents are used as
monotherapy for treating the disorder.
[0361] In one embodiment, the compound of Formula (I) and the
additional therapeutic agent(s) are present in the same
composition, which is suitable for oral administration.
[0362] The compound of Formula (I) and the additional therapeutic
agent(s) can act additively or synergistically. A synergistic
combination may allow the use of lower dosages of one or more
agents and/or less frequent administration of one or more agents of
a combination therapy. A lower dosage or less frequent
administration of one or more agents may lower toxicity of the
therapy without reducing the efficacy of the therapy.
[0363] The doses and dosage regimen of the additional therapeutic
agent(s) used in the combination therapies of the present invention
for the treatment or prevention of a disease or disorder can be
determined by the attending clinician, taking into consideration
the approved doses and dosage regimen in the package insert; the
age, sex and general health of the patient; and the type and
severity of the viral infection or related disease or disorder.
[0364] Another aspect of this invention is a kit comprising a
therapeutically effective amount of the compound of Formula (I) or
a pharmaceutically acceptable salt of said compound, optionally at
least one additional therapeutic agent listed above and a
pharmaceutically acceptable carrier, vehicle or diluent.
Methods of Preparing the Compounds of Formula (I)
[0365] In general, the compounds in the invention may be produced
by a variety of processes known to those skilled in the art and by
know, processes analogous thereto. The invention disclosed herein
is exemplified by the following preparations and examples which
should not be construed to limit the scope of the disclosure.
Alternative mechanistic pathways and analogous structures will be
apparent to those skilled in the art. The practitioner is not
limited to these methods. Illustrative general synthetic methods
are set out below and then specific compounds of the Formula (I)
are prepared in the Examples.
[0366] One skilled in the art will recognize that one route will be
optimized depending on the choice of appendage substituents.
Additionally, one skilled in the art will recognize that in some
cases the order of steps has to be controlled to avoid functional
group incompatability.
[0367] The prepared compounds may be analyzed for their composition
and purity as well as characterized by standard analytical
techniques such as, for example, elemental analysis, NMR, mass
spectroscopy and IR spectra.
[0368] One skilled in the art will recognize that reagents and
solvents actually used may be selected from several reagents and
solvents well known in the art to be effective equivalents. Hence,
when a specific solvent or reagent is mentioned, it is meant to be
an illustrative example of the conditions desirable for that
particular reaction scheme or for the preparation described
below.
[0369] Where NMR data are presented, .sup.1H spectra were obtained
on either a Varian VXR-400 (400 MHz, 1H), Varian Gemini-300 (300
MHz), Varian Mercury VX-400 (400 MHz), Bruker-Biospin AV-500 (500
MHz) or Bruker Avance DRX-500 (500 MHz), and chemical shifts are
reported as ppm with number of protons and multiplicities indicated
parenthetically. Where LC/MS data are presented, analyses was
performed using a 1200 series Agilent 6140 Quadrupole LCMS with a
1.8 .mu.M Zorbax SB-C18 column (10-95% of MeCN--H.sub.2O with 0.1%
TFA over 2.7 min, 1 mL/min) or with an Applied Biosystems API-150
mass spectrometer and Gemini C18 column (50.times.4.6 mm, 10-95%
CH.sub.3CN--H.sub.2O with 0.05% TFA over 5 min, 1 mL/min).
[0370] Preparative chiral HPLC separations were generally carried
out using supercritical fluid chromatography by eluting a chiral
column such as OJ-H, (4.6.times.250 mm, Chiral Technologies, Inc.,
West Chester, Pa.) with a mobile phase of isopropanol and
supercritical CO.sub.2.
[0371] The following solvents, reagents, protecting groups,
moieties, and other designations may be referred to by their
abbreviations in parenthesis:
[0372] Me=methyl; Et=ethyl; Pr=propyl; iPr--isopropyl; Bu=butyl;
t-Bu=tert-butyl; Ph=phenyl, and Ac=acetyl
[0373] .mu.l=microliters
[0374] AcOEt or EtOAc=ethyl acetate
[0375] AcOH or HOAc=acetic acid
[0376] aq=aqueous
[0377] Ar=aryl
[0378] atm=atmosphere
[0379] 9-BBN=9-borabicyclo[3.3.1]nonane
[0380] Bn=benzyl
[0381] Boc or BOC=tert-butoxycarbonyl
[0382] Bz=benzoyl
[0383] Boc=tert-butoxycarbonyl
[0384] cat=catalyst or catalytic
[0385] Cbz or CBZ=benyzloxycarbonyl
[0386] DBU=1,8-Diaza-7-bicyclo[5.4.0]undecene
[0387] DCM=dichloromethane
[0388] DCE=dichloroethane
[0389] DMAP=4-Dimethylaminopyridine
[0390] DIBAL=diisobutylaluminum hydride
[0391] DIPEA or Hunig's Base=N,N-diisopropylethylamine
[0392] DME=1,2-dimethoxyethane
[0393] DMF=dimethylformamide
[0394] DMS=dimethylsulfide
[0395] DMSO=dimethyl sulfoxide
[0396] EDCI or
DEC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
[0397] ee=enantiomeric excess
[0398] EDTA=ethylenediaminetetraacetic acid
[0399] Et.sub.2O=diethyl ether
[0400] g=grams
[0401] h=hour
[0402] HMDS=1,1,1,3,3,3-hexamethyldisilazane
[0403] HATU=N,N,N,N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium
hexafluorophosphate
[0404] HOBt=1-hydroxybenzotriazole
[0405] Im=imidazole
[0406] LAH=lithium aluminum hydride
[0407] LDA=lithium diisopropylamide
[0408] LCMS=liquid chromatography mass spectrometry
[0409] LG=leaving group
[0410] min=minute
[0411] mg=milligrams
[0412] mL=milliliters
[0413] mmol=millimoles
[0414] MeOH: methanol
[0415] MS=mass spectrometry
[0416] NBS=N-bromosuccimide
[0417] NMR=nuclear magnetic resonance spectroscopy
[0418] PG=protecting group
[0419] Pyr=pyridine
[0420] RT or rt=room temperature (ambient, about 25.degree. C.)
[0421] sat=saturated
[0422] SFC=supercritical fluid chromatography
[0423] SM=starting material
[0424] TBSCl=t-butyldimethylsilyl chloride
[0425] TBS=t-butyldimethyl silyl
[0426] TFA=trifluoroacetic acid
[0427] TFAA=trifluoroacetic anhydride
[0428] THF=tetrahydrofuran
[0429] TLC=thin layer chromatography
[0430] TMS=trimethylsilyl
[0431] Tos or Ts=p-toluenesulfonyl (tosyl)
[0432] Tol=toluene
[0433] IBMX==3-Isobutyl-1-methylxanthine
[0434] HBSS=Hank's balanced salt solution
[0435] HEPES=1-[4-(2-Hydroxyethyl)-1-piperazinyl]ethane-2-sulfonic
acid
[0436] The compounds of this invention can be prepared through the
general approach outlined in the following schemes. These schemes
are being provided to illustrate the present invention. To assist
one in this endeavor, the ordinary practitioner would have full
knowledge of literature sources such as Chemical Abstracts;
Beilstein, Protective Groups in Organic Synthesis 2.sup.nd Edition
T. W. Greene, P. G. M. Wuts 1991, Wiley and Sons; Comprehensive
Organic Transformations, Advanced Organic Chemistry etc.
##STR00033## ##STR00034## ##STR00035##
[0437] As shown in Scheme 1 above, compounds of the Formula (I) can
be prepared from substituted 4-methoxyquinolines a1. Compounds b1
are prepared from a1 in the presence of allylMgBr and CbzCl. The
alkene in b1 is used as a key functional group to provide primary
alcohol c1 with 2-4 carbon length linkers. The primary alcohols are
then converted to iodides d1 before they are cyclized under basic
conditions to provide ketones e1. Compounds h1 are obtained from e1
by reductive amination, acylation and hydrolysis. Analogs based on
g1 can be synthesized by hydrogenation followed by acylation,
carbamate, or urea formation before hydrolysis to give final acids
k1.
##STR00036##
[0438] For cyclopentyl fused ring compounds, a second route can
also be employed as shown Scheme 2 above and Scheme 3 below.
Starting from substituted anilines, ethyl
2-oxocyclopentanecarboxylate is condensed with substituted anilines
to give the esters (a2). The esters (a2) are hydrolyzed to acids
(b2) which undergo Friedel-Crafts reaction to give cyclized
products c2. Cbz intermediate d2 and acylated product e2 can be
synthesized from c2. Following a similar process as described above
for e1-h1 and g1 to k1, further analogs such as h2 and j2 can be
prepared from e2. Tertiary amine analogs j2 can be prepared from f2
by reductive amination followed by hydrolysis.
##STR00037##
[0439] The starting materials and reagents used in preparing
compounds described below are either available from commercial
suppliers such as Aldrich Chemical Co. (Wisconsin, USA) and Acros
Organics Co. (New Jersey, USA) or were prepared by literature
methods known to those skilled in the art.
[0440] Where the stereodesignations of the specifically exemplified
compounds in the tables below specify "racemic, cis, cis", this
description means that the compound is racemic and has a structure
wherein the bonds joining the tetrahydroquinoline ring in the core
to the cycloalkyl ring have a cis configuration, and that the bond
joining the --N(R')(R.sup.2) group to the tetrahydroquinoline ring
and the adjacent bond also has a cis configuration. By way of
example, where an example indicates that the isolated compound has
the structure:
##STR00038##
and has a stereodesignation indicated as "racemic, cis, cis", this
designation means that the isolated compound is a racemic mixture
of the following enantiomers:
##STR00039##
[0441] Where the stereodesignations of the specifically exemplified
compounds in the tables below specify "cis, cis, single enantiomer"
or "cis, cis, enantiopure," this designation means that the
isolated compound is a single enantiomer or is enriched in a single
enantiomer as compared to the other enantiomer. Furthermore, this
description means that the compound has a structure wherein the
bonds joining the tetrahydroquinoline ring in the core to the
cycloalkyl ring have a cis configuration, and that the bond joining
the --N(R.sup.1)(R.sup.2) group to the tetrahydroquinoline ring and
the adjacent bond also has a cis configuration.
[0442] These examples are being provided to further illustrate the
present invention. They are for illustrative purposes only; the
scope of the invention is not to be considered limited in any way
thereby.
EXAMPLES
Example 1
Preparation of Racemic Benzyl
cis,cis-9-(cyclopropylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quin-
oline-4-carboxylate (1E)
Step 1: Benzyl
2-allyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate
##STR00040##
[0444] A solution of allylmagnesium bromide (1.00 M in
tetrahydrofuran, 101 mL, 101 mmol, 2.00 equiv) was added to a
solution of 4-methoxy quinoline (8.00 g, 50.3 mmol, 1 equiv) in
tetrahydrofuran (335 mL) at -78.degree. C. The reaction mixture was
stirred at -78.degree. C. for 1 h, then benzyl chloroformate (14.35
mL, 101.0 mmol, 2.00 equiv) was added via syringe over 5 min. The
reaction mixture was stirred for an additional 15 minutes at
-78.degree. C., then the cooling bath was removed and the reaction
mixture was allowed to warm to 23.degree. C. After 1 h, added
methanol (40 mL). After stirring for 5 min, aqueous hydrochloric
acid solution (2 N, 20 mL) was added and the mixture was stirred
for 10 min. The mixture was then concentrated by rotary evaporation
to remove most of the tetrahydrofuran and methanol, and the residue
was partitioned between ethyl acetate and water. The organic phase
was washed with brine, and the washed solution was dried over
sodium sulfate. The dried solution was filtered, and the filtrate
was concentrated. The residue was purified by flash-column
chromatography (5% ethyl acetate-hexanes, grading to 20% ethyl
acetate-hexanes) to afford 1A as a colorless oil. [M+H].sup.+:
322.2.
Step 2: Benzyl
2-(3-hydroxypropyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate
##STR00041##
[0446] A solution of 9-borabicyclo[3.3.1]nonane (0.4 M in hexanes,
224 mL, 90 mmol, 2 equiv) was added to a solution of benzyl
2-allyl-4-oxo-3,4-dihydroquinoline-[(21])-carboxylate (13.7 g, 42.6
mmol, 1 equiv) in tetrahydrofuran (213 mL) at 0.degree. C. After
the addition was complete, the cooling bath was removed and the
reaction mixture was stirred for 15 h. The reaction mixture was
then cooled to 0.degree. C., and aqueous sodium hydroxide solution
(5 M, 85 mL, 10 equiv) was added by addition funnel over 10
minutes. After the addition was complete, aqueous hydrogen peroxide
solution (30% by weight, 174 mL, 40 equiv) was added by addition
funnel over 10 minutes. After the addition was complete, the
cooling bath was removed and the biphasic reaction mixture was
stirred for 45 minutes. The mixture was then partitioned between
ethyl acetate and saturated aqueous sodium chloride solution. The
layers were separated, and the organic phase was washed with an
additional portion of saturated aqueous sodium chloride solution.
The washed solution was dried over sodium sulfate, and the dried
solution was then filtered. The filtrate was concentrated, and the
residue was dissolved in 1,2-dichloroethane (213 mL). Manganese
dioxide (18.5 g, 213 mmol, 5.00 equiv) was added, and the reaction
mixture was heated to 80.degree. C. After stirring for 2 h at
80.degree. C., the reaction mixture was cooled to 23.degree. C. and
filtered through Celite.RTM.. The filtrate was concentrated, and
the residue was purified by flash-column chromatography (50% ethyl
acetate-hexanes, grading to ethyl acetate) to afford 1B as a
colorless oil. [M+H].sup.+: 340.2.
Step 3: Benzyl
2-(3-iodopropyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate
##STR00042##
[0448] Iodine (12.5 g, 49.4 mmol, 1.30 equiv) was added to a
solution of benzyl
2-(3-hydroxypropyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate
(12.9 g, 38.0 mmol, 1 equiv), triphenylphosphine (13.0 g, 49.4
mmol, 1.30 equiv), and imidazole (6.47 g, 95.0 mmol, 1 equiv) in
dichloromethane (380 mL) at 23.degree. C. After stirring for 15
minutes, the reaction mixture was partitioned between
dichloromethane and water. The organic phase was dried over sodium
sulfate, and the dried solution was filtered. The filtrate was
concentrated, and the residue was purified by flash-column
chromatography (hexanes, grading to 30% ethyl acetate-hexanes) to
afford 1C as a colorless oil. [M+H].sup.+: 450.1.
Step 4: Racemic Benzyl
cis-9-oxo-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate
##STR00043##
[0450] A solution of sodium bis(trimethylsilyl)amide in
tetrahydrofuran (1.0 M, 39.4 mL, 39.4 mmol, 1.10 equiv) was added
to a solution of benzyl
2-(3-iodopropyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (16.1
g, 35.8 mmol, 1 equiv) in tetrahydrofuran (716 mL) at -78.degree.
C. The reaction mixture was stirred at -78.degree. C. for 1 h, then
the cooling bath was removed and the reaction mixture was allowed
to warm. After stirring for 40 min, water was added (300 mL), and
the reaction mixture was concentrated by rotary evaporation to
remove most of the tetrahydrofuran. The residue was partitioned
between ethyl acetate and water. The organic phase was washed with
saturated aqueous sodium chloride solution, and the washed solution
was dried over sodium sulfate. The dried solution was filtered, and
the filtrate was concentrated. The residue was purified by
flash-column chromatography (hexanes, grading to 40% ethyl
acetate-hexanes) to afford 1D as a colorless oil. [M+H].sup.+:
322.2.
Step 5: Racemic Benzyl
cis,cis-9-(cyclopropylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quin-
oline-4-carboxylate
##STR00044##
[0452] Titanium (IV) ethoxide (4.84 mL, 23.3 mmol, 2.50 equiv) was
added to a solution of benzyl
cis-9-oxo-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate
(3.00 g, 9.34 mmol, 1 equiv) and cyclopropylamine (1.83 mL, 23.3
mmol, 2.50 equiv) in tetrahydrofuran. The reaction vessel was
sealed and heated to 60.degree. C. After stirring for 16 h, the
reaction mixture was cooled to 23.degree. C. and poured over
saturated aqueous sodium chloride solution (50 mL). The biphasic
mixture was stirred for 5 min, then filtered through Celite.RTM.
with the aid of ethyl acetate. The filtrate was partitioned between
ethyl acetate and brine, and the organic phase was then dried over
sodium sulfate. The dried solution was filtered, and the filtrate
was concentrated. The residue was dissolved in methanol (30 mL) and
tetrahydrofuran (60 mL), and the solution was cooled to 0.degree.
C. Sodium borohydride (855 mg, 22.6 mmol, 2.50 equiv) was added to
the cooled solution. After stirring for 15 min at 0.degree. C., the
cooling bath was removed, and the reaction mixture was partitioned
between ethyl acetate and saturated aqueous sodium bicarbonate
solution. The organic layer was washed with saturated aqueous
sodium chloride solution, and the washed solution was dried over
sodium sulfate. The dried solution was filtered, and the filtrate
was concentrated to afford 1E. [M+H].sup.+: 363.3.
Example 2
Preparation of Racemic Benzyl
cis,cis-9-amino-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carbo-
xylate (2)
##STR00045##
[0454] Sodium cyanoborohydride (78 mg, 1.2 mmol, 2.0 equiv) was
added to a mixture of benzyl
cis-9-oxo-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate
(200 mg, 0.622 mmol, 1 equiv) and ammonium acetate (480 mg, 6.22
mmol, 10 equiv) in methanol (6.2 mL). The reaction vessel was
sealed and heated to 70.degree. C. After stirring at 70.degree. C.
for 90 min, the reaction mixture was cooled to 23.degree. C. and
partitioned between ethyl acetate and saturated aqueous sodium
bicarbonate solution. The organic layer was washed with saturated
aqueous sodium chloride solution, and the washed solution was dried
over sodium sulfate. The dried solution was filtered, and the
filtrate was concentrated. The residue was purified by flash-column
chromatography (50% ethyl acetate-hexanes, grading to ethyl
acetate, then flushing with 10% methanol-dichloromethane) to afford
2.
Example 3
Preparation of Racemic Benzyl
cis,cis-9-(acetylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-
-4-carboxylate (3)
##STR00046##
[0456] Acetic anhydride (0.250 mL, 2.65 mmol, 5.00 equiv) was added
to a solution of benzyl
cis,cis-9-amino-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carbo-
xylate 2 (171 mg, 0.530 mmol, 1 equiv) and
N,N-diisopropylethylamine (0.278 mL, 1.59 mmol, 3.00 equiv) in
dioxane (5.3 mL) at 23.degree. C. The reaction mixture was stirred
for 10 min, and then was partitioned between ethyl acetate and
aqueous hydrochloric acid solution (1 N). The organic layer was
washed with saturated aqueous sodium chloride solution, and the
washed solution was dried over sodium sulfate. The dried solution
was filtered, and the filtrate was concentrated to afford 3.
[M+H].sup.+: 365.2.
Example 4
Preparation of Racemic Benzyl
cis,cis-9-(cyclobutylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quino-
line-4-carboxylate (4A)
##STR00047##
[0458] Benzyl
cis,cis-9-(cyclobutylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quino-
line-4-carboxylate 4A was prepared from benzyl
cis-9-oxo-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate
using a procedure similar to that used for Example 1, Step 5,
substituting cyclobutylamine and acetic acid for ammonium acetate.
[M+H].sup.+: 377.3.
Example 5
Preparation of Racemic Benzyl
cis,cis-9-(isopropylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinol-
ine-4-carboxylate
##STR00048##
[0460] Benzyl
cis,cis-9-(isopropylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinol-
ine-4-carboxylate 5A was prepared from racemic benzyl
cis-9-oxo-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate
using a procedure similar to that used in Example 1, Step 5.
[M+H].sup.+: 365.3.
Example 6
Preparation of Racemic Benzyl
cis,cis-9-(cyclopropylamino)-6-fluoro-1,2,3,3a,9,9a-hexahydro-4H-cyclopen-
ta[b]quinoline-4-carboxylate (6D)
Step 1: 2-[(3-Fluorophenyl)amino]cyclopentanecarboxylic acid
(6A)
##STR00049##
[0462] Sodium hydroxide (96 mL, 478 mmol, 5 M in water, 5 equiv.)
was added to a mixture of ethyl
2-[(3-fluorophenyl)amino]cyclopentanecarboxylate (reported by
Micovic et al., Synthesis, 1991, 1043-1045) (24.0 g, 96 mmol, 1
equiv) in dioxane (95 mL). The reaction was heated to 100.degree.
C. and stirred for one hour. The reaction mixture was then cooled
to 23.degree. C. and acidified to pH=3 with 2N HCl. The reaction
mixture was then partitioned between ethyl acetate and water. The
organic layer was washed with saturated aqueous sodium chloride
solution, and the washed solution was dried over sodium sulfate.
The dried solution was filtered, and the filtrate was concentrated
to afford 6A as a mixture of cis and trans isomers. [M+H].sup.+:
224.1.
Step 2: Racemic
cis-6-Fluoro-1,2,3,3a,4,9a-hexahydro-9H-cyclopenta[b]quinolin-9-one
(6B)
##STR00050##
[0464] Eaton's reagent (100 mL, 630 mmol, 6.6 equiv.) was added to
2-[(3-fluorophenyl)amino]cyclopentanecarboxylic acid 6A (21.3 g, 95
mmol, 1 equiv). The mixture was heated to 70.degree. C. and stirred
for one hour. The reaction mixture was then cooled to 23.degree. C.
and quenched with the addition of wet ice. The mixture was then
neutralized to pH=10 with the portionwise addition of solid sodium
hydroxide pellets. The reaction mixture was then partitioned
between ethyl acetate and water. The organic layer was washed with
saturated aqueous sodium chloride solution, and the washed solution
was dried over sodium sulfate. The dried solution was filtered, and
the filtrate was concentrated. The filtrate was purified by
flash-column chromatography (hexanes, grading to 50% ethyl
acetate-hexanes) to afford 6B. [M+H].sup.+: 206.2.
Step 3: Racemic Benzyl
cis-6-fluoro-9-oxo-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-ca-
rboxylate (6C)
##STR00051##
[0466] Phosgene (20% in toluene, 1.0 g, 2.2 mmol, 1.5 equiv) was
added to a solution of
cis-6-fluoro-1,2,3,3a,4,9a-hexahydro-9H-cyclopenta[b]quinolin-9-one
6B (300 mg, 1.5 mmol, 1 equiv) and diisopropyl ethylamine (380 uL,
2.2 mmol, 1.5 equiv) in THF (14.6 mL). After stirring at 23.degree.
C. for two hours the solution was treated with benzyl alcohol (450
.mu.L, 4.4 mmol, 3 equiv) and sodium hydride (60% in mineral oil,
230 mg, 5.9 mmol, 4 equiv). After stirring at 23.degree. C. for 12
hours the reaction was neutralized to pH=7 with 1 N HCl. The
reaction mixture was then partitioned between ethyl acetate and
water. The organic layer was washed with saturated aqueous sodium
chloride solution, and the washed solution was dried over sodium
sulfate. The dried solution was filtered, and the filtrate was
concentrated. The filtrate was purified by flash-column
chromatography (hexanes, grading to 50% ethyl acetate-hexanes) to
afford 6C. [M+H].sup.+: 340.2.
Step 4: Racemic Benzyl
cis,cis-9-(cyclopropylamino)-6-fluoro-1,2,3,3a,9,9a-hexahydro-4H-cyclopen-
ta[b]quinoline-4-carboxylate (6D)
##STR00052##
[0468] Benzyl
cis,cis-9-(cyclopropylamino)-6-fluoro-1,2,3,3a,9,9a-hexahydro-4H-cyclopen-
ta[b]quinoline-4-carboxylate 6D was prepared from benzyl
cis-6-fluoro-9-oxo-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-ca-
rboxylate using a procedure similar to that used in Example 1, Step
5. [M+H].sup.+: 381.2.
Example 7
Preparation of Racemic
4-[{cis,cis-4-[(Benzyloxy)carbonyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta-
[b]quinolin-9-yl}(cyclopropyl)amino]-4-oxobutanoic acid (7)
Step 1: Racemic Benzyl
cis,cis-9-[cyclopropyl(4-methoxy-4-oxobutanoyl)amino]-1,2,3,3a,9,9a-hexah-
ydro-4H-cyclopenta[b]quinoline-4-carboxylate (7A)
##STR00053##
[0470] Methyl 4-chloro-4-oxobutanoate (1.54 mL, 12.3 mmol, 2.50
equiv) was added to a solution of benzyl
cis,cis-9-(cyclopropylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quin-
oline-4-carboxylate (1E) (1.78 g, 4.91 mmol, 1 equiv) and
N,N-diisopropylethylamine (2.57 mL, 14.7 mmol, 3.00 equiv) in
dioxane (33 mL) at 23.degree. C. (used a 23.degree. C. water bath
to control the exotherm that was observed during the addition). The
reaction mixture was stirred for 1 h, and then it was partitioned
between ethyl acetate and aqueous hydrochloric acid solution (1 N).
The organic layer was washed sequentially with aqueous sodium
hydroxide solution (1 N) and saturated aqueous sodium chloride
solution, and the washed organic layer was dried over sodium
sulfate. The dried solution was filtered, and the filtrate was
concentrated. The residue was purified by flash-column
chromatography (20% ethyl acetate-hexanes, grading to ethyl
acetate) to afford 7A. [M+H].sup.+: 477.2.
Step 2: Racemic
4-[{cis,cis-4-[(Benzyloxy)carbonyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta-
[b]quinolin-9-yl}(cyclopropybamino)amino]-4-oxobutanoic acid
(7)
##STR00054##
[0472] Aqueous sodium hydroxide solution (1 N, 0.168 mL, 0.168
mmol, 4.0 equiv) was added to a solution of benzyl
cis,cis-9-[cyclopropyl(4-methoxy-4-oxobutanoyl)amino]-1,2,3,3a,9,9a-hexah-
ydro-4H-cyclopenta[b]quinoline-4-carboxylate 7A (20 mg, 0.42 mmol,
1 equiv) in dioxane (0.42 mL). The reaction vessel was sealed and
heated to 80.degree. C. After stirring for 1 h at 80.degree. C.,
the reaction mixture was cooled to 23.degree. C. and partitioned
between ethyl acetate and aqueous hydrochloric acid solution. The
organic layer was washed with saturated aqueous sodium chloride
solution, and the washed solution was dried over sodium sulfate.
The dried solution was filtered, and the filtrate was concentrated
to afford 7 as a white solid. [M+H].sup.+: 463.3.
Example 8
Preparation of Enantiomerically Pure
1,2,3,3a,4,9a-hexahydro-9H-cyclopenta[b]quinolin-9-one (8)
##STR00055##
[0473] Step 1
[0474] Isobutyl chloroformate (1.5 mL, 11.5 mmol) was added to a
solution of i-Pr.sub.2NEt (2.3 mL, 13 mmol) and
(1S,2R)-2-(benzyloxycarbonyl)-cyclopentane-carboxylic acid 8A,
(Small Molecules, Inc., Hoboken, New Jersey) (2.15 g, 8.70 mmol) in
acetone (35 mL) at 0.degree. C. The resulting solution was stirred
at 0.degree. C. for 1 h. A solution of NaN.sub.3 (1.40 g, 21.0
mmol) in 14 mL of water was added. The resulting mixture was
stirred at room temperature for another hour. DCM was added to the
reaction mixture. The aqueous layer was separated and extracted
with DCM. The organic extracts were combined and washed with brine,
dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue
was dissolved in toluene (50 mL), and benzyl alcohol (1.5 mL, 14.5
mmol) and Et.sub.3N (2.4 mL, 17.1 mmol) were added. The resulting
mixture was heated at 130.degree. C. for 1 h. The reaction mixture
was cooled to room temperature, diluted with EtOAc, and washed with
1 N HCl. The aqueous layer was separated, and extracted with EtOAc.
The organic extracts were combined and washed with brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified over a silica gel column (80 g), eluting with 10% EtOAc in
hexanes, followed by 15% EtOAc in hexanes to give 3.14 g of product
8B as a white solid (95%).
Step 2
[0475] 10% Pd on carbon (3 g) was added to a solution of compound
8B (3.14 g, 10.2 mmol) in MeOH (45 mL). The resulting mixture was
placed under 1 atm of hydrogen and stirred at room temperature
overnight. The mixture was filtered through a pad of Celite.RTM.,
and the filtrate was concentrated in vacuo to give 1.4 g of the
desired product 8C as a white solid (100%).
Step 3
[0476] Compound 8C (1.0 g, 7.8 mmol), iodobenzene (1.76 g, 8.7
mmol), CuI (148 mg, 0.78 mmol), Cs.sub.2CO.sub.3 (7.64 g, 23.4
mmol) were mixed in DMF (12 mL) in a sealed tube. The content was
evacuated and refilled with nitrogen three times.
2-Isobutyrylcyclohexanone (0.26 mL, 1.6 mmol) was added to the
mixture with a syringe via a septum. The septum was replaced with a
screwed cap, and the sealed tube was heated at 50.degree. C.
overnight. The reaction mixture was cooled to room temperature and
checked with TLC. EtOAc and water were added to the mixture. The
aqueous layer was separated and washed with EtOAc. The EtOAc layers
were combined and extracted with 1 N NaOH three times to make sure
that the desired product is retained in the basic water layer. The
aqueous layer was treated with 1 N HCl carefully to adjust the pH
to between 4 and 5. The resulting aqueous layer was then extracted
with EtOAc. The combined organic extracts were washed with brine,
dried (MgSO.sub.4), filtered and concentrated in vacuo to give 1.24
g (77%) desired product 8D as a brown oil.
Step 4
[0477] Thionyl chloride (0.56 mL, 3.0 mmol) was added dropwise to
compound 8D (0.85 g, 2.57 mmol) in MeOH (12 mL) at 0.degree. C. The
resulting solution was stirred at 0.degree. C. for 30 min and then
at room temperature for 4 h. The mixture was concentrated under
vacuum. The residue was dissolved in DCM and washed with 1 N NaOH.
The organic layer was washed with brine, dried (MgSO.sub.4) and
concentrated in vacuo. The residue was purified over a 40 g silica
gel column, eluting with 5% EtOAc in hexanes, followed by 10% EtOAc
in hexanes to give 0.68 g desired product 8E as an off-white solid
(78%).
Step 5
[0478] LHMDS (0.4 mL, 1 M in THF, 0.40 mmol) was added to compound
8E; (35 mg, 0.16 mmol) in THF (2 mL) at 0.degree. C. The mixture
was stirred at room temperature overnight. The reaction was
monitored by TLC and LCMS. EtOAc and water were added to the
mixture. The aqueous layer was separated and extracted with EtOAc.
The organic extracts were combined, washed with brine, dried
(MgSO.sub.4), filtered and concentrated. The residue was purified
by silica gel thin-layer-chromatography, eluting with 1:5
EtOAc-hexanes, to give 20 mg of desired product 8F.
Step 6
[0479] Triflic acid (20 .mu.L, 0.23 mmol) was added to a solution
of compound 8F (20 mg, 0.11 mmol) in DCE (1 mL) at 0.degree. C. The
reaction was followed by LCMS until done. The reaction mixture was
diluted with EtOAc and washed with 1 N NaOH. The aqueous layer was
separated and extracted with EtOAc. The combined organic extracts
was washed with brine, dried (MgSO.sub.4), filtered and
concentrated in vacuo. The residue was purified by
thin-layer-chromatography, eluting with EtOAc-hexanes, to give 15
mg desired compound 8 (75%). The enantiomeric purity of compound 8,
predominantly in (3aS, 9aR) configuration, was determined by HPLC
analysis to be 92%.
Example 9
Preparation of Compounds 9, 9A, and 9B
[0480] The compounds in the following table were prepared from
corresponding unsubstituted tricyclic ketone or N-Cbz substituted
tricyclic ketone in a similar manner to the process shown in
Example 1, step 5, and Example 7, steps 1 and 2. The corresponding
unsubstituted ketone or N-Cbz substituted ketones were resolved
with chiral HPLC to provide enantiomerically pure ketone
intermediates which were converted to final products.
TABLE-US-00001 Stereo # Structure designation Name [M + H].sup.+ 9
##STR00056## cis, cis, single enantiomer 3-(phenylmethyl) cis,
cis-8-[(3- carboxy-1-oxopropyl)cyclopropyl-
amino]-5-fluoro-2,2a,8,8a- tetrahydrocyclobuta[b]
quinoline-3(1H)-carboxylate 489 [M + Na].sup.+ 9A ##STR00057## cis,
cis, single enantiomer 4-(phenylmethyl) cis, cis-[(3-
carboxy-1-oxopropyl)cyclopropyl- amino]-6-chloro-1,2,3,3a,9,9a-
hexahydro-4H-cyclopenta[b] quinoline-4-carboxylate 519.0 [M +
Na].sup.+ 9B ##STR00058## 3aS,9R,9aR, single enantiomer
4-(((3aS,9R,9aR)-4- ((benzyloxy)carbonyl)-7-
fluoro-2,3,3a,4,9,9a-hexahydro- 1H-cyclopenta[b]quinolin-9-
yl)(cyclopropyl)amino)-4- oxobutanoic acid 481.2
Example 10
Preparation of Racemic
4-[{cis,cis-4-[(Benzyloxy)carbonyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta-
[b]quinolin-9-yl}(cyclopropyl)amino]-2-m ethyl-4-oxobutanoic acid
(10)
##STR00059##
[0482] A solution of racemic benzyl
cis,cis-9-(cyclopropylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quin-
oline-4-carboxylate (1E) (25 mg, 0.069 mmol, 1 equiv) and
3-methyldihydrofuran-2,5-dione (0.15 mL, 1.6 mmol, 23 equiv) in
dioxane (0.35 mL) was heated to 110.degree. C. in a sealed tube.
After heating for 1 h, the oil bath temperature was increased to
130.degree. C. for 1 h. The reaction mixture was then cooled to
23.degree. C. and partitioned between ethyl acetate and aqueous
hydrochloric acid solution. The organic layer was washed with
saturated aqueous sodium chloride solution, and the washed solution
was dried over sodium sulfate. The dried solution was filtered, and
the filtrate was concentrated. The residue was purified by
flash-column chromatography (dichloromethane, grading to 10%
methanol-dichloromethane). The residue was then dissolved in DMSO
(1 mL), and purified by reverse-phase HPLC (40% acetonitrile-water,
grading to 80% acetonitrile-water, with 0.1% trifluoroacetic acid
in both the acetonitrile and water) to afford 10. [M+H].sup.+:
477.2.
Example 11
Preparation of
N1-cyclopropyl-N1-((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)--
2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-N4-(methylsulfonyl)-
succinamide
##STR00060##
[0484] Carbonyldiimidazole (13.65 mg, 0.084 mmol) was added to a
stirred mixture of compound 17 (30 mg, 0.056 mmol) (see Example 17
below) in tetrahydrofuran (2 mL) at room temperature. The mixture
was stirred at 70.degree. C. for 2 h before it was cooled to room
temperature and DBU (0.017 mL, 0.112 mmol) and methanesulfonamide
(8.01 mg, 0.084 mmol) were added. The reaction mixture was stirred
at room temperature for overnight before it was concentrated under
reduced pressure. The residue was purified via preparative TLC,
eluting with CH.sub.2Cl.sub.2/MeOH=10:1 to give enantiopure 11
(26.3 mg, 0.043 mmol, 77% yield) as a white solid. [M+H].sup.+:
611.8.
[0485] Compound 11A, 11B, and 11C were prepared using a similar
procedure as is described above. Compound 11A was prepared from
compound 17. Compounds 11B and 11C were prepared from compound 83
(see below).
TABLE-US-00002 Stereo # Structure designation Name [M + H].sup.+
11A ##STR00061## 3aS,9R,9aR, single enantiomer N1-cyclopropyl-N4-
(cyclopropylsulfonyl)-N1- ((3aS,9R,9aR)-7-fluoro-4-(4-
(trifluoromethoxy)benzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl)succinamide 637.7 11B ##STR00062## cis,
cis, single enantiomer N1-(cyclopropylsulfonyl)-N4- ethyl-N4-(cis,
cis-3-(4- (trifluoromethylthio)benzoyl)- 1,2,2a,3,8,8a-hexahydro-
cyclobuta[b]quinolin-8- yl)succinamide 610.1 11C ##STR00063## cis,
cis, single enantiomer N1-ethyl-N4-(methylsulfonyl)- N1-(cis,
cis-3-(4- (trifluoromethylthio)benzoyl)- 1,2,2a,3,8,8a-hexahydro-
cyclobuta[b]quinolin-8- yl)succinamide 584.1
Example 12
Preparation of Racemic Benzyl
cis,cis-9-[(4-methoxy-4-oxobutanoyl)(phenyl)amino]-1,2,3,3a,9,9a-hexahydr-
o-4H-cyclopenta[b]quinoline-4-carboxylate (12)
Step 1: Racemic Benzyl
cis,cis-9-anilino-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-car-
boxylate (12A)
##STR00064##
[0487] Tris(dibenzylideneacetone)dipalladium (89 mg, 0.098 mmol,
0.15 equiv), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl
(115 mg, 0.293 mmol, 0.45 equiv), and benzyl
cis,cis-9-amino-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carbo-
xylate 2 (210 mg, 0.651 mmol, 1 equiv) were charged in a reaction
vial and tetrahydrofuran (6.5 mL) was added. Nitrogen gas was
bubbled through the solution for 5 min to remove excess oxygen, and
then iodobenzene (0.145 mL, 1.30 mmol, 2.0 equiv) and lithium
bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 0.977 mL, 0.977
mmol, 1.50 equiv) were added sequentially. The reaction vial was
sealed and heated to 55.degree. C. for 16 h. After cooling to
23.degree. C., the reaction mixture was partitioned between ethyl
acetate and water, and the organic layer was washed with saturated
aqueous sodium chloride solution. The washed solution was dried
over sodium sulfate, and the dried solution was filtered. The
filtrate was purified by flash-column chromatography (hexanes,
grading to 30% ethyl acetate-hexanes) to afford 12A. [M+Na].sup.+:
421.2.
Step 2: Racemic Benzyl
cis,cis-9-[(4-methoxy-4-oxobutanoyl)(phenyl)amino]-1,2,3,3a,9,9a-hexahydr-
o-4H-cyclopenta[b]quinoline-4-carboxylate (12)
##STR00065##
[0489] Sodium hydride (60% dispersion in oil, 58.2 mg, 1.46 mmol,
4.0 equiv) was added to a solution of methyl
4-chloro-4-oxobutanoate (0.183 mL, 1.46 mmol, 4.0 equiv) and 12A
(145 mg, 0.364 mmol, 1 equiv) in dioxane (2.4 mL) at 23.degree. C.
The reaction vessel was sealed, and the reaction mixture was heated
to 75.degree. C. After stirring for 2.5 h, the temperature was
increased to 85.degree. C. After stirring at 85.degree. C. for 2.5
h, the reaction mixture was cooled to 23.degree. C., and saturated
aqueous ammonium chloride solution was added slowly (vigorous gas
evolution). The quenched reaction mixture was partitioned between
ethyl acetate and water, and the organic layer was washed with
saturated aqueous sodium chloride solution. The washed solution was
dried over sodium sulfate, and the dried solution was filtered. The
filtrate was purified by flash-column chromatography (hexanes,
grading to 60% ethyl acetate-hexanes) to afford compound 17.
[M+H].sup.+: 513.3.
[0490] The following compounds were prepared from racemic benzyl
cis,cis-9-[(4-methoxy-4-oxobutanoyl)(phenyl)amino]-1,2,3,3a,9,9a-hexahydr-
o-4H-cyclopenta[b]quinoline-4-carboxylate 12A, using procedures
similar to those described in Example 14 below.
TABLE-US-00003 Stereo # Structure designation Name [M + H].sup.+
12B ##STR00066## racemic, cis, cis methyl 4-oxo-4-{phenyl[cis,
cis-4-(pyridin-3-ylcarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}butanoate 484.2 12C ##STR00067##
racemic, cis, cis 4-[{cis, cis-4- [(benzyloxy)carbonyl]-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl}(phenyl)amino]-4- oxobutanoic acid 499.2 12D ##STR00068##
racemic, cis, cis 4-oxo-4-{phenyl[cis, cis-4-
(pyridin-3-ylcarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}butanoic acid 470.2 12E
##STR00069## racemic, cis, cis 4-oxo-4-{phenyl[cis, cis-4-
(phenylcarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}butanoic acid 469.2
Example 13
Preparation of Racemic
4-[{cis,cis-4-[(Benzyloxy)carbonyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta-
[b]quinolin-9-yl}(ethyl)amino]-4-oxobutanoic acid (13)
Step 1: Racemic benzyl
cis,cis-9-(ethylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline--
4-carboxylate (13)
##STR00070##
[0492] 13A was prepared from benzyl
cis-9-oxo-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate
1D using a procedure similar to that used in Example 1, Step 5.
[M+H].sup.+: 351.2.
Step 2: Racemic
4-[{cis,cis-4-[(Benzyloxy)carbonyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta-
[b]quinolin-9-yl}(ethyl)amino]-4-oxobutanoic acid (13)
##STR00071##
[0494] 4-[{C is,
cis-4-[(Benzyloxy)carbonyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quino-
lin-9-yl}(ethyl)amino]-4-oxobutanoic acid ([M+H].sup.+: 451.2) was
prepared from 13B using a sequence similar to that used for Example
7, step 2. Compound 13B was prepared from 13A following a similar
procedure as Example 7, step 1.
[0495] The following examples were prepared from racemic benzyl
cis,cis-9-[ethyl(4-methoxy-4-oxobutanoyl)amino]-1,2,3,3a,9,9a-hexahydro-4-
H-cyclopenta[b]quinoline-4-carboxylate (13B) using procedures
similar to those used in Example 14.
TABLE-US-00004 Stereo # Structure designation Name [M + H].sup.+
13C ##STR00072## racemic, cis, cis 4-{ethyl[cis, cis-4-{[4-
(trifluoromethoxy)phenyl] carbonyl}-2,3,3a,4,9,9a- hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}-4-oxobutanoic acid 505.1 13D
##STR00073## racemic, cis, cis 4-{ethyl[cis, cis-4-
(phenylcarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}-4-oxobutanoic acid 421.2 13E
##STR00074## racemic, cis, cis 4-{ethyl[cis, cis-4-(pyridin-3-
ylcarbonyl)-2,3,3a,4,9,9a- hexahydro-1H- cyclopenta[b]quinolin-9-
yl]amino}-4-oxobutanoic acid 422.2
Example 14
Preparation of Racemic
4-{Cyclopropyl[cis,cis-4-(phenylcarbonyl)-2,3,3a,4,9,9a-hexahydro-1H-cycl-
openta[b]quinolin-9-yl]amino}-4-oxobutanoic acid (14)
Step 1: Methyl
4-{cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-
-yl]amino}-4-oxobutanoate (14A)
##STR00075##
[0497] Palladium (10% on carbon, 103 mg, 0.050 equiv) was added to
a solution of benzyl
cis,cis-9-[cyclopropyl(4-methoxy-4-oxobutanoyl)amino]-1,2,3,3a,9,9a-hexah-
ydro-4H-cyclopenta[b]quinoline-4-carboxylate 7A (922 mg, 1.93 mmol,
1 equiv) in ethanol (14.5 mL) and ethyl acetate (4.84 mL). A
three-way stopcock connected to a hydrogen balloon and a vacuum
line was fitted to the top of the flask, and the flask was
subjected to alternating vacuum purging and hydrogen filling cycles
(4.times.). The reaction mixture was then stirred under hydrogen
for 90 min at 23.degree. C., and then was filtered through cotton.
The filtrate was concentrated to afford 14A, which was used without
further purification. [M+H].sup.+: 343.2.
Step 2: Methyl
4-[[cis,cis-4-benzoyl-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9--
yl](cyclopropyl)amino]-4-oxobutanoate (14B)
##STR00076##
[0499] Benzoyl chloride (0.028 mL, 0.24 mmol, 1.5 equiv) was added
to a solution of methyl
4-{cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-
-yl]amino}-4-oxobutanoate 14A (55 mg, 0.16 mmol, 1 equiv) and
N,N-diisopropylethylamine (0.084 mL, 0.48 mmol, 3.0 equiv) in
dichloromethane (1.60 mL) at 23.degree. C. The reaction mixture was
stirred at 23.degree. C. for 30 min, and then was partitioned
between ethyl acetate and aqueous hydrochloric acid solution (1 N).
The organic layer was washed with saturated aqueous sodium chloride
solution, and the washed solution was dried over sodium sulfate.
The dried solution was filtered, and the filtrate was concentrated.
The residue was purified by flash-column chromatography (40% ethyl
acetate-hexanes, grading to ethyl acetate) to afford 14B.
[M+H].sup.+: 447.2.
Step 3:
4-[[cis,cis-4-Benzoyl-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quin-
olin-9-yl](cyclopropyl)amino]-4-oxobutanoic acid (14)
##STR00077##
[0501] Compound 14 was prepared from methyl
4-[[cis,cis-4-benzoyl-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9--
yl](cyclopropyl)amino]-4-oxobutanoate 14B using a procedure similar
to that used in Example 2, Step 2. [M+H].sup.+: 433.2
[0502] The following compounds were made from racemic methyl
4-{cyclopropyl[cis,
cis-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobut-
anoate (14A) using procedures similar to those used in Example 14,
Steps 2 and 3:
TABLE-US-00005 Stereo # Structure designation Name [M + H].sup.+
14C ##STR00078## racemic, cis, cis 4-{cyclopropyl[cis, cis-4-{[4-
(trifluoromethoxy)phenyl] carbonyl}-2,3,3a,4,9,9a- hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}-4-oxobutanoic acid 517.2 14D
##STR00079## racemic, cis, cis 4-(cyclopropyl{cis, cis-4-[(1-
methyl-1H-indol-2-yl)carbonyl]- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl}amino)-4-oxobutanoic acid 486.2 14E
##STR00080## racemic, cis, cis 4-{cyclopropyl[cis, cis-4-
(thiophen-3-ylcarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}-4-oxobutanoic acid 439.0 14F
##STR00081## racemic, cis, cis 4-[{cis, cis-4-[(4-
bromophenyl)carbonyl]- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl}(cyclopropyl)amino]-4- oxobutanoic acid
511.1 14G ##STR00082## racemic, cis, cis 4-{cyclopropyl[cis, cis-4-
(cyclopropylcarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}-4-oxobutanoic acid 397.0 14H
##STR00083## racemic, cis, cis 4-(cyclopropyl{cis, cis-4-[(3-
morpholin-4-ylphenyl)carbonyl]- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl}amino)-4-oxobutanoic acid 518.2 14i
##STR00084## racemic, cis, cis 4-{cyclopropyl[cis, cis-4-
(pyridin-3-ylcarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}-4-oxobutanoic acid 434.2 14K
##STR00085## racemic, cis, cis 4-[{cis, cis-4-[(4-
chlorophenyl)carbonyl]- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl}(cyclopropyl)amino]-4- oxobutanoic acid
467.1 14L ##STR00086## racemic, cis, cis 4-(cyclopropyl{cis,
cis-4-[(4- methoxyphenyl)carbonyl]- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl}amino)-4-oxobutanoic acid 463.2 14N
##STR00087## racemic, cis, cis methyl 4-(cyclopropyl{cis, cis-
4-[(1-methyl-1H-indol-2- yl)carbonyl]-2,3,3a,4,9,9a- hexahydro-1H-
cyclopenta[b]quinolin-9- yl}amino)-4-oxobutanoate 500.2 14o
##STR00088## racemic, cis, cis methyl 4-{cyclopropyl[cis, cis-
4-(thiophen-3-ylcarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}-4-oxobutanoate 453.2 14P
##STR00089## racemic, cis, cis methyl 4-[{cis, cis-4-[(4-
chlorophenyl)carbonyl]- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl}(cyclopropyl)amino]-4- oxobutanoate
481.2
Example 15
Preparation of Racemic Benzyl
cis,cis-9-[cyclopropyl(4-methoxy-4-oxobutanoyl)amino]-6-fluoro-1,2,3,3a,9-
,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate (15)
##STR00090##
[0504] 15 was prepared from benzyl
cis,cis-9-(cyclopropylamino)-6-fluoro-1,2,3,3a,9,9a-hexahydro-4H-cyclopen-
ta[b]quinoline-4-carboxylate (6D) using a procedure similar to that
used for Example 7, Step 1. [M+H].sup.+: 495.2.
Example 16
4-[{cis,cis-4-[(Benzyloxy)carbonyl]-6-fluoro-2,3,3a,4,9,9a-hexahydro-1H-cy-
clopenta[b]quinolin-9-yl}(cyclopropyl)amino]-4-oxobutanoic acid
(16)
##STR00091##
[0506] 16 was prepared from benzyl
cis,cis-9-[cyclopropyl(4-methoxy-4-oxobutanoyl)amino]-6-fluoro-1,2,3,3a,9-
,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate (15) using a
procedure similar to that used in Example 7, Step 2. [M+H].sup.+:
481.2.
[0507] The following examples were prepared from racemic benzyl
cis,cis-9-[cyclopropyl(4-methoxy-4-oxobutanoyl)amino]-6-fluoro-1,2,3,3a,9-
,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate (15) using
procedures similar to that used in Example 14, Steps 1 and 2 (for
the esters in the table) and Example 14, Steps 1-3 (for the
carboxylic acids in the table).
TABLE-US-00006 Stereo # Structure Designation Name [M + H].sup.+
16A ##STR00092## racemic, cis, cis Methyl 4-{cyclopropyl[cis,
cis-6- fluoro-4-(pyridin-3-ylcarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9-yl]amino}- 4-oxobutanoate 466.2 16B
##STR00093## racemic, cis, cis Methyl 4-{cyclopropyl[cis, cis-6-
fluoro-4-[(4- phenoxyphenyl)carbonyl]- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9-yl}amino)- 4-oxobutanoate 557.2 16C
##STR00094## racemic, cis, cis Methyl 4-{cyclopropyl[cis, cis-6-
fluoro-4-(phenylcarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9-yl]amino}- 4-oxobutanoate 465.2 16D
##STR00095## racemic, cis, cis 4-{cyclopropyl[cis, cis-6-fluoro-4-
(phenylcarbonyl)-2,3,3a,4,9,9a- hexahydro-1H-
cyclopenta[b]quinolin-9-yl]amino}- 4-oxobutanoic acid 461.1 16E
##STR00096## racemic, cis, cis 4-{cyclopropyl[cis, cis-6-fluoro-4-
[(4-phenoxyphenyl)carbonyl]- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9-yl}amino)- 4-oxobutanoic acid 543.2
Example 17
Preparation of Enantiopure
4-(Cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,-
3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid (17)
Step 1
##STR00097##
[0509] In a 500 mL round bottom flask was added acetic acid (81
mL), water (8.05 mL, 447 mmol), 4-fluoroaniline (10 mL, 97 mmol),
ethyl 2-oxocyclopentanecarboxylate (13.13 mL, 97 mmol) followed by
zinc (25.4 g, 388 mmol). The reaction was warmed to 80.degree. C.,
during which time gas evolution was noted. After 2 h, the bubbling
had stopped and the reaction was cooled to rt. The slurry was then
diluted with MeOH and the zinc solids were removed by filtering
through a fitted funnel. The collected filtrate was then
concentrated on the rotovap and then diluted with DCM and wet ice.
The solution was neutralized with NH.sub.4OH to pH=10. The mixture
was then poured into a separation funnel containing DCM and water.
The mixture was extracted 3.times. with DCM. The combined fractions
were washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The resulting oil 17A was used without
further purification.
Step 2
##STR00098##
[0511] The above obtained ester 17A (24.0 g, 96 mmol) was dissolved
in Dioxane (95 mL) and treated with NaOH (96 mL, 478 mmol). The
reaction stirred at 100 C for one hour. The reaction was then
cooled to rt and acidified with 2 N HCl to pH=3. The reaction
mixture was then poured into a separation funnel containing EtOAc
and water. The mixture was extracted 3.times. with EtOAc. The
combined fractions were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The resulting oil was
used without further purification.
Step 3
##STR00099##
[0513] Acid 17B (21.3 g, 95 mmol) was treated with Eaton's reagent
(100 mL, 630 mmol) and warmed to 70.degree. C. The reaction stirred
for one hour. As the reaction stirred it turned deep red/brown.
LCMS shows that the SM has been consumed. The reaction is cooled to
rt and then quenched by the portionwise addition of wet ice. The
mixture was then treated with solid NaOH pellets until the pH was
10. The reaction mixture was then poured into a separation funnel
containing EtOAc and water. The mixture was extracted 3.times. with
EtOAc. The combined fractions were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was
purified by column chromatography (Biotage, 340 g, 0-50%
EtOAc/heptane) which afforded 17C (10 g).
Step 4
##STR00100##
[0515] Boc.sub.2O (9.50 g, 41.7 mmol) was added to the solution of
7-fluoro-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinolin-9(9aH)-one
17C (13.9 mmol), Et.sub.3N (5.80 mL, 41.7 mmol) and DMAP (1.70 g,
13.9 mmol) in 1,4-dioxane (100 mL), the resultant mixture was kept
stirring at rt overnight. The mixture was diluted with EtOAc (100
mL), washed with H.sub.2O (100 mL), and brine (100 mL), the organic
was dried over MgSO.sub.4 and concentrated. The residue was
purified via silica gel column chromatography (EtOAc/Hexane=1:10),
to obtain the racemic, Boc protected ketone amine 17D' as a light
yellow syrup, 4.0 g. The racemic ketone 17D' was resolved with
chiral HPLC to give enantiomerically pure 17D using an OJ-H,
4.6.times.250 mm column eluting with an isocratic system of 15%
w/IPA in supercritical CO.sub.2 at a flow rate of 3 mL/min. The
configuration of 17D was determined to have the 3aS, 9aR
configuration by inference from the configuration of the
subsequently prepared product 17 below.
Step 5
##STR00101##
[0517] The ketone 17D was converted to the desired enantiopure
amide 17E following steps similar to those described in Example 1
and Example 7.
Step 6
##STR00102##
[0519] TFA (1 mL) was added to the solution of Boc amide 17E (0.723
mmol) in CH.sub.2Cl.sub.2 (2 mL), the resultant mixture was kept
stirring at rt for 2 hrs. The solution was concentrated to dryness,
the residue was taken up in CH.sub.2Cl.sub.2 (10 mL), washed with
NaHCO.sub.3 (1 N, 5 mL), the organic layer was dried over
MgSO.sub.4 and concentrated. The residue was purified via silica
gel column chromatography (EtOAc/Hexane=1:3), obtained enantiopure
free amine 17F as a light yellow solid 200 mg; [M+H].sup.+=357.
Step 7
##STR00103##
[0521] The amine 17F was converted the final enantiopure amide
product 17 by following steps similar to those described in Example
14, steps 2 and 3. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm:
7.29 (d, 2H); 7.08 (d, 2H); 6.60 (m, 2H); 6.38 (m, 1H); 5.168 (m,
1H); 3.09 (m, 3H); 2.82 (m, 3H); 2.42 (m, 1H); 2.03 (m, 1H); 1.57
(m, 2H); 1.40 (m, 2H); 1.22=1.00 (m, 5H). [M+H].sup.+=534.8.
[0522] The structure of product 17,
C.sub.27H.sub.26F.sub.4N.sub.2O.sub.5, C.sub.7H.sub.8, was
determined by single-crystal X-ray crystallography on a crystal
isolated from material crystallized from toluene (10 mg anhydrous
compound dissolved in 200 .mu.L toluene and evaporated overnight).
The crystal selected was representative of the bulk sample. Crystal
data at 100 K:
TABLE-US-00007 a = 11.1083(13) .ANG. .alpha. = 90.00.degree. V =
1528.4(3) .ANG..sup.3 b = 8.7372(10) .beta. = 100.730(6) Space
group = P2.sub.1, #4 c = 16.028(2) .gamma. = 90.00 Z = 2
[0523] Data were collected on a Bruker CCD diffractometer using
copper K.alpha. radiation and integrated to a resolution of 0.84
.ANG..sup.-1 which yielded 4840 unique reflections from 34030
measured reflections.
[0524] The structure was solved using direct methods. The refined
model has all non-H atoms refined anisotropically, and H atoms at
their calculated positions, with agreement statistics of:
R.sub.1=3.4%, for 407 variables and 4629 reflections and
wR.sub.2=9.4% using all 4840 reflections. The compound crystallized
as a monotoluene solvate. There were no unusual bond distances or
angles. The absolute stereochemistry was determined unambiguously
using resonant scattering effects as R, S, R at C1, C8 and C 12,
respectively. A perspective view of 17 calculated from the
crystallographic coordinates is presented in FIG. 1.
[0525] The compounds in the following table were prepared by a
similar synthetic process as illustrated in Examples 1, 14 and 17.
The enantiomerically pure final products are either obtained
through chiral resolution of final racemic compounds (17BN, 17BX,
17BY, 17BZ, 17CA, 17CJ) or prepared from enantiomerically pure
tetraquinoline amides (prepared from a Boc-protected,
CBz-protected, or unprotected chiral tetrahydroquinolin-9(9aH)-one)
(17AE, 17AF, 17AG, 17BM, 17BO, 17BP, 17BQ, 17BR, 17BS, 17BT, 17BU,
17BV, 17BW, 17CC, 17CD, 17CE, 17CF, 17CG, 17CH, 17CI, 17CK, and
17CL-17DL). Chiral HPLC separation of racemic
tetrahydroquinolin-9(9aH)-ones such as 17D' (Boc-protected), 1D
(CBz-protected), and 17C (unprotected) affords enantiomerically
pure chiral tetrahydroquinolin-9(9aH)-ones.
TABLE-US-00008 stereo # structure designation chemical name [M +
H].sup.+ 17G ##STR00104## racemic, cis, cis 4-[[cis, cis-4-benzoyl-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl](cyclopropylmethyl) amino]-4-oxobutanoic acid 447.2 17H
##STR00105## racemic, E, cis, cis (2E)-4-[[cis, cis-4-benzoyl-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl](cyclopropylmethyl) amino]-4-oxo-2-butenoic acid 445.2 17i
##STR00106## racemic, cis, cis 4-[[cis, cis-4-benzoyl-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-yl](1-
methylcyclopropyl)amino]- 4-oxobutanoic acid 447.2 17J ##STR00107##
racemic, cis, cis methyl 4- [(cyclopropylmethyl)[cis, cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoate 545.3 17K
##STR00108## racemic, cis, cis 4-(phenylmethyl) cis, cis-9-
[(3-carboxy-1- oxopropyl)(cyclopropyl- methyl)amino]-1,2,3,3a,9,9a-
hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate 477.3 17L
##STR00109## racemic, cis, cis 4-[(cyclopropylmethyl)[cis, cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 531.3 17M
##STR00110## racemic, cis, cis 4-[[cis, cis-4-benzoyl-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl](1-methylethyl)amino]-4- oxobutanoic acid 435.2 17N ##STR00111##
racemic, cis, cis 5-[[cis, cis-4-benzoyl-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl]methylamino]-5- oxopentanoic acid 421.2 17o ##STR00112##
racemic, cis, cis 5-[[cis, cis-2,3,3a,4,9,9a- hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-9-
yl]methylamino]-5- oxopentanoic acid 505.3 17P ##STR00113##
racemic, cis, cis (2E)-4-[[cis, cis-4-benzoyl-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl]methylamino]-4-oxo-2- butenoic acid 405.2 17Q ##STR00114##
racemic, cis, cis (2E)-4-[[cis, cis- 2,3,3a,4,9,9a-hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-9-
yl]methylamino]-4-oxo-2- butenoic acid 489.3 17R ##STR00115##
racemic, cis, cis methyl 4-[[cis, cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]methylamino]-4- oxobutanoate 505.3
17S ##STR00116## racemic, cis, cis 4-[[cis, cis-2,3,3a,4,9,9a-
hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]methylamino]-4- oxobutanoic acid
491.3 17T ##STR00117## racemic, cis, cis 4-[[cis,
cis-2,3,3a,4,9,9a- hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl](1-methylethyl)amino]-4- oxobutanoic
acid 519.3 17U ##STR00118## racemic, cis, cis 4-(phenylmethyl) cis,
cis-9- [(3-carboxy-1- oxopropyl)methylamino]-
1,2,3,3a,9,9a-hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate
437.2 17V ##STR00119## racemic, cis, cis 4-[[cis,
cis-2,3,3a,4,9,9a- hexahydro-4-(3- pyridinylcarbonyl)-1H-
cyclopenta[b]quinolin-9- yl]methylamino]-4- oxobutanoic acid 408.2
17W ##STR00120## racemic, cis, cis 4-[[cis, cis-4-([1,1'-
biphenyl]-4-ylcarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]methylamino]-4- oxobutanoic acid 483.3
17X ##STR00121## racemic, cis, cis 4-[[cis, cis-4-(4-
chlorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]methylamino]-4- oxobutanoic acid 441.2
17Y ##STR00122## racemic, cis, cis 4-[[cis, cis-4-(4-
ethylbenzoyl)-2,3,3a,4,9,9a- hexahydro-1H- cyclopenta[b]quinolin-9-
yl]methylamino]-4- oxobutanoic acid 435.2 17Z ##STR00123## racemic,
cis, cis 4-[[cis, cis-4-(3,4- dichlorobenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl]methylamino]-4- oxobutanoic acid 475.3 17AA ##STR00124##
racemic, cis, cis 4-[[cis, cis-4-(3- chlorobenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl]methylamino]-4- oxobutanoic acid 441.2 17AB ##STR00125##
racemic, cis, cis 4-[[cis, cis-2,3,3a,4,9,9a- hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-9- yl](3,3,3-
trifluoropropyl)amino]-4- oxobutanoic acid 573.3 17AC ##STR00126##
racemic, cis, cis 4-[[cis, cis-2,3,3a,4,9,9a- hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-9- yl](1-
methylcyclopropyl)amino]- 4-oxobutanoic acid 531.3 17AD
##STR00127## racemic, cis, cis 4-[(cyclobutylmethyl)[cis, cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 545.3 17AE
##STR00128## cis, cis single enantiomer 4-[ethyl[cis, cis-4-(4-
ethylbenzoyl)-2,3,3a,4,9,9a- hexahydro-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 449.2 17AF ##STR00129## (cis, cis);
Cyclopropyl ring trans (racemic). 4-[ethyl[cis, cis-2,3,3a,4,9,9a-
hexahydro-4-[(2-phenyl-1- cyclopropyl)carbonyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 461.3 17AG
##STR00130## cis, cis single enantiomer 4-[ethyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4- (3,4,5-trifluorobenzoyl)-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 475.3 17AH
##STR00131## racemic, cis, cis 4-[[cis, cis-4-(3- bromobenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl]cyclopropylamino]-4- oxobutanoic acid 511.3 17Ai ##STR00132##
racemic, cis, cis 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4-[3- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 517.3 17AJ
##STR00133## racemic, cis, cis 4-[[cis, cis-4-(2- bromobenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl]cyclopropylamino]-4- oxobutanoic acid 511.3 17AK ##STR00134##
racemic, cis, cis 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4- (3-phenoxybenzoyl)-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxo-butanoic acid 525.3 17AL
##STR00135## racemic, cis, cis 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4- (3-methoxybenzoyl)-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 463.3 17AM
##STR00136## racemic, cis, cis 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4- (2-methoxybenzoyl)-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 463.3 17AN
##STR00137## racemic, cis, cis 4-[cyclopropyl[cis. cis-
2,3,3a,4,9,9a-hexahydro-4- (2-quinolinylcarbonyl)-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 484.3 17Ao
##STR00138## racemic, cis, cis 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4-[2- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 517.3 17AP
##STR00139## racemic, cis, cis 4-[cyclopropyl[cis, cis-4-[4-
(difluoromethoxy)benzoyl]- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 499.3 17AQ
##STR00140## racemic, cis, cis 4-((cis, cis-4-
(cyclohexanecarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl)(cyclopropyl)amino)-4- oxobutanoic acid
439.2 17AR ##STR00141## racemic, cis, cis 4-(cyclopropyl(cis,
cis-4- (thiophene-2-carbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl)amino)-4-oxobutanoic acid 439.2 17AS
##STR00142## racemic, cis, cis 4-(cyclopropyl(cis, cis-4-(2-
phenylacetyl)-2,3,3a,4,9,9a- hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 447.2 17AT ##STR00143## racemic, cis,
cis 4-(cyclopropyl(cis, cis-4-(3- methylbenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 447.2 17AU ##STR00144## racemic, cis,
cis 4-(cyclopropyl(cis, cis-4-(4- methylbenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 447.2 17AV ##STR00145## racemic, cis,
cis 4-(cyclopropyl(cis, cis-4-(2- fluorobenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 451.2 17AW ##STR00146## racemic, cis,
cis 4-(cyclopropyl(cis, cis-4-(3- fluorobenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 451.2 17AX ##STR00147## racemic, cis,
cis 4-(cyclopropyl(cis, cis-4-(4- fluorobenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 451.2 17AY ##STR00148## racemic, cis,
cis 4-(cyclopropyl(cis, cis-4- (3,5-dimethylisoxazole-4-
carbonyl)-2,3,3a,4,9,9a- hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 452.2 17AZ ##STR00149## racemic, cis,
cis 4-(cyclopropyl(cis, cis-4-(2- (thiophen-2-yl)acetyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 453.2 17BA ##STR00150## racemic, cis,
cis 4-(cyclopropyl(cis, cis-4-(3- phenylpropanoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 461.3 17BB ##STR00151## racemic, cis,
cis 4-(cyclopropyl(cis, cis-4-(2- phenoxyacetyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 463.3 17BC ##STR00152## racemic, cis,
cis 4-(cyclopropyl(cis, cis-4- (2,4-difluorobenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 469.3 17BD ##STR00153## racemic, cis,
cis 4-(cyclopropyl((cis, cis-4- (3,5-difluorobenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 469.3 17BE ##STR00154## racemic, cis,
cis (cyclopropyl ring is trans substituted) 4-(cyclopropyl(cis,
cis-4- trans-2- phenylcyclopropanecarbonyl)-
2,3,3a,4,9,9a-hexahydro- 1H-cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 473.3 17BF ##STR00155## racemic, cis,
cis 4-(cyclopropyl(cis, cis-4-(2- (4-methoxyphenyl)acetyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 477.3 17BG ##STR00156## racemic, cis,
cis 4-((cis, cis-4-(1-naphthoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl)(cyclopropyl)amino)-4- oxobutanoic acid
483.3 17BH ##STR00157## racemic, cis, cis 4-(cyclopropyl(cis,
cis-4- (2,4-dichlorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl)amino)-4-oxobutanoic acid 501.3 17Bi
##STR00158## racemic, cis, cis 4-((cis, cis-4-(2-naphthoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl)(cyclopropyl)amino)-4- oxobutanoic acid 483.3 17BJ ##STR00159##
racemic, cis, cis 4-(cyclopropyl(cis, cis-4-(2-
(3,4-dimethoxyphenyl)acetyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl)amino)-4-oxobutanoic acid 507.3 17BK
##STR00160## racemic, cis, cis 4-(((cis, cis)-4-
(benzo[d][1,3]dioxole-5- carbonyl)-2,3,3a,4,9,9a- hexahydro-1H-
cyclopenta[b]quinolin-9- yl)(cyclopropyl)amino)-4- oxobutanoic acid
477.3 17BL ##STR00161## racemic, cis, cis 4-(cyclopropyl(cis,
cis-4- (furan-2-carbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl)amino)-4-oxobutanoic acid 423.2 17BM
##STR00162## cis, cis at fused ring enantiopure; (racemic
cyclopropyl ring is trans substituted) 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4- [(trans-2- phenylcyclopropyl)carbonyl]-
1H-cyclopenta[b]quinolin- 9-yl]amino]-4-oxobutanoic acid 473.3 17BN
##STR00163## cis, cis, single enantiomer 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4- (2-thienylcarbonyl)-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 439.2
17Bo ##STR00164## cis, cis, single enantiomer 4-[cyclopropyl[cis,
cis- 2,3,3a,4,9,9a-hexahydro-4- (1-naphthalenylcarbonyl)-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 483.3 17BP
##STR00165## cis, cis, single enantiomer 4-[cyclopropyl[cis,
cis-4-[4- (difluoromethoxy)benzoyl]- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 499.3 17BQ
##STR00166## cis, cis, single enantiomer 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4- (2-quinolinylcarbonyl)-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 484.3 17BR
##STR00167## cis, cis, single enantiomer 4-[cyclopropyl[cis,
cis-4-(2- fluorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 451.2 17BS
##STR00168## cis, cis at fused ring (enantiopure), trans-
substitution at cyclopropyl, single diastereomer 1
4-[cyclopropyl[cis, cis- 2,3,3a,4,9,9a-hexahydro-4- [(trans-2-
phenylcyclopropyl)carbonyl]- 1H-cyclopenta[b]quinolin-
9-yl]amino]-4-oxobutanoic acid 473.3 17BT ##STR00169## cis, cis at
fused ring (enantiopure), trans- substitution at cyclopropyl,,
single diastereomer 2 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4- [(trans-2- phenylcyclopropyl)carbonyl]-
1H-cyclopenta[b]quinolin- 9-yl]amino]-4-oxobutanoic acid 473.3 17BU
##STR00170## cis, cis,, single enantiomer 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4- (2-naphthalenylcarbonyl)-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 483.3 17BV
##STR00171## cis, cis, single enantiomer 4-[cyclopropyl[cis, cis-4-
(2,4-difluorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 469.3 17BW
##STR00172## cis, cis, single enantiomer 4-[cyclopropyl[cis,
cis-4-(3- fluorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 451.2 17BX
##STR00173## cis, cis, single enantiomer, peak 1 4-[[cis,
cis-6-chloro-7-fluoro- 2,3,3a,4,9,9a-hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-9-
yl]cyclopropylamino]-4- oxobutanoic acid 568.8 17BY ##STR00174##
cis, cis, single enantiomer, peak2 4-[[cis, cis-6-chloro-7-fluoro-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]cyclopropylamino]-4- oxobutanoic
acid 590.8 [M + Na].sup.+ 17BZ ##STR00175## cis, cis, single
enantiomer, peak 1 [[[[cis, cis-6-chloro-7-fluoro-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]cyclopropylamino]
carbonyl]oxy]acetic acid 571 17CA ##STR00176## cis, cis, single
enantiomer, peak 2 [[[[cis, cis-6-chloro-7-fluoro-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]cyclopropylamino]
carbonyl]oxy]acetic acid 571 17CB ##STR00177## racemic, cis, cis
4-[[cis, cis-2,3,3a,4,9,9a- hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-9-
yl](2-propenyl)amino]-4- oxobutanoic acid 517 17CC ##STR00178##
cis, cis, single enantiomer 4-[cyclopropyl[cis, cis-5-
fluoro-3-(4-fluorobenzoyl)- 1,2,2a,3,8,8a-hexahydro-
cyclobuta[b]quinolin-8- yl]amino]-4- oxobutanoic acid 455 17CD
##STR00179## cis, cis, single enantiomer 4-[cyclopropyl[cis,
cis-3-(4- ethylbenzoyl)-5-fluoro- 1,2,2a,3,8,8a-hexahydro-
cyclobuta[b]quinolin-8- yl]amino]-4- oxobutanoic acid 465 17CE
##STR00180## cis, cis, single enantiomer 4-[cyclopropyl[cis, cis-5-
fluoro-1,2,2a,3,8,8a- hexahydro-3-[4- (trifluoromethoxy)benzoyl]
cyclobuta[b]quinolin-8- yl]amino]-4-oxobutanoic acid 543 [M +
Na].sup.+ 17CF ##STR00181## cis, cis, single enantiomer
deuterated-4- [cyclopropyl[cis, cis- 2,3,3a,4,9,9a-hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-
9(R)-yl-(d)]amino]-4- oxobutanoic acid 518.2 17CG ##STR00182##
racemic, cis, cis 4-[[cis-6-chloro- 2,3,3a,4,9,9a-hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-9-
yl]cyclopropylamino]-4- oxobutanoic acid 550.5 17CH ##STR00183##
racemic, cis, cis 4-[[cis, cis-6-chloro-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]cyclobutylamino]-4- oxobutanoic acid
564.5 17Ci ##STR00184## racemic, cis, cis 2-[[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]carbonyl]benzoic acid 564.6
17CJ ##STR00185## cis, cis, single enantiomer 4-[cyclopropyl[cis,
cis- 2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 516.7 17CK
##STR00186## cis, cis, single enantiomer 4-[[cis, cis-6-chloro-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]cyclobutylamino]-4- oxobutanoic acid
565.3 17CL ##STR00187## cis, cis, single enantiomer 4-[[cis,
cis-6-chloro- 2,3,3a,4,9,9a-hexahydro-4-[3-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-9-
yl]cyclobutylamino]-4- oxobutanoic acid 565.3 17CM ##STR00188##
cis, cis, single enantiomer 4-[[cis, cis-6-chloro-4-(4-
fluorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]cyclobutylamino]-4- oxobutanoic acid
499.3 17CN ##STR00189## cis, cis, single enantiomer 4-[[cis,
cis-6-chloro-4-(3- fluorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]cyclobutylamino]-4- oxobutanoic acid
499.3 17Co ##STR00190## cis, cis, single enantiomer 4-[[cis,
cis-6-chloro-4-(3,4- difluorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]cyclobutylamino]-4- oxobutanoic acid
517.3 17CP ##STR00191## cis, cis, single enantiomer 4-[[cis,
cis-6-chloro-4-(3,5- difluorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]cyclobutylamino]-4- oxobutanoic acid
538.5 [M + Na].sup.+ 17CQ ##STR00192## cis, cis, single enantiomer
4-[[cis, cis-6-chloro-4-(4- ethylbenzoyl)-2,3,3a,4,9,9a-
hexahydro-1H- cyclopenta[b]quinolin-9- yl]cyclobutylamino]-4-
oxobutanoic acid 509.3 17CR ##STR00193## cis, cis, single
enantiomer 4-[[cis, cis-6-chloro- 2,3,3a,4,9,9a-hexahydro-4-
(2-naphthalenylcarbonyl)- 1H-cyclopenta[b]quinolin-9-
yl]cyclobutylamino]-4- oxobutanoic acid 531.3 17CS ##STR00194##
cis, cis, single enantiomer 4-[[cis, cis-6-chloro-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethyl)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]cyclobutylamino]-4- oxobutanoic acid
549.3 17CT ##STR00195## cis, cis, single enantiomer 4-[[cis,
cis-6-chloro- 2,3,3a,4,9,9a-hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-9-
yl]cyclopropylamino]-4- oxobutanoic acid 551 17CU ##STR00196## cis,
cis, single enantiomer 4-[[cis, cis-6-chloro-
2,3,3a,4,9,9a-hexahydro-4-[3- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]cyclopropylamino]-4- oxobutanoic
acid 551 17CV ##STR00197## cis, cis, single enantiomer 4-[[cis,
cis-6-chloro-4-(4- fluorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]cyclopropylamino]-4- oxobutanoic acid
485.6 17CW ##STR00198## cis, cis, single enantiomer 4-[[cis,
cis-6-chloro-4-(3,5- difluorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]cyclopropylamino]-4- oxobutanoic acid
503.6 17CX ##STR00199## cis, cis at fused ring (enantiopure) trans
substitution at cyclopropyl ring (enantiopure), single
diastereomer, (less polar one) 4-[[cis, cis-6-chloro-
2,3,3a,4,9,9a-hexahydro-4- [(trans-2- phenylcyclopropyl)carbonyl]-
1H-cyclopenta[b]quinolin- 9-yl]cyclopropylamino]-4- oxobutanoic
acid 506.7 17CY ##STR00200## cis, cis at fused ring (enantiopure),
trans substitution at the cyclopropyl ring (enantiopure) single
diastereomer, (more polar one) 4-[[cis, cis-6-chloro-
2,3,3a,4,9,9a-hexahydro-4- [(trans-2- phenylcyclopropyl)carbonyl]-
1H-cyclopenta[b]quinolin- 9-yl]cyclopropylamino]-4- oxobutanoic
acid 506.6 17CZ ##STR00201## cis, cis, single enantiomer
4-[cyclobutyl[cis, cis- 2,3,3a,4,9,9a-hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 552.5 [M + Na].sup.+ 17DA ##STR00202##
cis, cis, single enantiomer 4-[cyclobutyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4-[3- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 552.5 [M +
Na].sup.+ 17DB ##STR00203## cis, cis, single enantiomer
4-[cyclobutyl[cis, cis-4-(4- fluorobenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 486.7 [M + Na].sup.+ 17DC ##STR00204##
cis, cis, single enantiomer 4-[cyclobutyl[cis, cis-4-(3,5-
difluorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 504.6 [M +
Na].sup.+ 17DD ##STR00205## cis, cis at fused ring (enantiopure),
trans substitution at cyclopropyl ring (enantiopure), single
diastereomer, (less polar one) 4-[cyclobutyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4- [(trans-2- phenylcyclopropyl)carbonyl]-
1H-cyclopenta[b]quinolin- 9-yl]amino]-4-oxobutanoic acid 508.6 [M +
Na].sup.+ 17DE ##STR00206## cis, cis at fused ring (enantiopure),
trans substitution at cyclopropyl ring (enantiopure), single
diastereomer, (more polar one) 4-[cyclobutyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4- [(trans-2- phenylcyclopropyl)carbonyl]-
1H-cyclopenta[b]quinolin- 9-yl]amino]-4-oxobutanoic acid 486.7 17DF
##STR00207## 3aS,9R,9aR single enantiomer
4-[cyclopropyl[(3aS,9R,9aR)- 7-fluoro-2,3,3a,4,9,9a-
hexahydro-4-[3- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 534.6 17DG
##STR00208## 3aS,9R,9aR single enantiomer
4-[cyclopropyl[(3aS,9R,9aR)- 7-fluoro-4-(3- fluorobenzoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 468.7 17DH ##STR00209## cis, cis,
single enantiomer 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4-[[4- (trifluoromethoxy)phenyl]
acetyl]-1H- cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid
530.7 17Di ##STR00210## cis, cis, single enantiomer
4-[cyclopropyl[cis, cis- 2,3,3a,4,9,9a-hexahydro-4- [1-oxo-3-[4-
(trifluoromethoxy)phenyl] propyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 544.7 17DJ ##STR00211## Cis, cis at
fused ring (enantiopure); R and S diastereomers at 1 napthalenyl
atom 4-[[cis, cis-6-chloro- 2,3,3a,4,9,9a-hexahydro-4-
[(1,2,3,4-tetrahydro-1- naphthalenyl)carbonyl]-1H-
cyclopenta[b]quinolin-9- yl]cyclopropylamino]-4- oxobutanoic acid
520.6 17DK ##STR00212## cis, cis, single enantiomer 4-[[cis,
cis-6-chloro-4-[(2,3- dihydro-1H-inden-2-
yl)carbonyl]-2,3,3a,4,9,9a- hexahydro-1H- cyclopenta[b]quinolin-9-
yl]cyclopropylamino]-4- oxobutanoic acid 506.6 17DL ##STR00213##
cis, cis (enantiopure), R and S diastereomers at 1 napthalenyl atom
4-[[cis, cis-6-chloro- 2,3,3a,4,9,9a-hexahydro-4-
[(1,2,3,4-tetrahydro-2- naphthalenyl)carbonyl]-1H-
cyclopenta[b]quinolin-9- yl]cyclopropylamino]-4- oxobutanoic acid
521.2 17DN ##STR00214## racemic, cis, cis 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4- [(1-methyl-1H-benzimidazol-
2-yl)carbonyl]-1H- cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic
acid 487.3 17Do ##STR00215## racemic, cis, cis [[cyclopropyl[cis,
cis- 2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]sulfonyl]acetic acid 539
Alternative Preparation of the Intermediate (3aS,9aR)-tert-butyl
7-fluoro-9-oxo-3,3a,9,9a-tetrahydro-1H-cyclopenta[b]quinoline-4(2H)-carbo-
xylate (17D)
##STR00216##
[0526] Step 1
Cis-methyl 2-((4-fluorophenyl)amino)cyclopentanecarboxylate
(racemic cis-17A')
[0527] A 1-L, three-necked, round-bottomed flask was charged with
4-fluoroaniline (50 mL, 528 mmol), methyl
2-oxocyclopentane-1-carboxylate (78.0 g, 528 mmol), 600 mL of AcOH,
and 60 mL of water. Zn dust (<10 micron, 103.6 g, 1584 mmol) was
added portionwise over 10 minutes and then, the mixture was stirred
at 70.degree. C. for 3 h. The reaction mixture was cooled to room
temperature, filtered through Celite.RTM. with the aid of MeOH, and
concentrated. Dichloromethane (500 mL) was added in one portion and
the pH was carefully adjusted with ammonium hydroxide to 10. The
resulting organic layer was separated, washed with brine, and
concentrated to give 130 g of an orange solid. Recrystallization
from hexanes afforded 80 g (64%) of cis-methyl
2-((4-fluorophenyl)amino)cyclopentanecarboxylate (racemic cis-17A')
as off-white crystals.
Step 2
Cis-6-(4-fluorophenyl)-6-azabicyclo[3.2.0]heptan-7-one (racemic
17DP)
[0528] A 500-mL, three-necked, round-bottomed flask was charged
with cis-methyl 2-((4-fluorophenyl)amino)cyclopentanecarboxylate
(racemic cis-17A') (15.77 g, 66.5 mmol) and 75 mL of THF. The
reaction mixture was cooled at 5.degree. C. while a 1 M solution of
LiHMDS (73.1 mL, 73.1 mmol) was added dropwise via syringe over 10
min. The resulting reaction mixture was stirred at 5.degree. C. to
15.degree. C. for 1.5 h. The reaction mixture was then quenched
into 200 mL of aqueous ammonium chloride and 250 mL of ethyl
acetate. The organic layer was separated, washed with brine, dried
over magnesium sulfate, filtered, and concentrated to give 14 g of
cis-6-(4-fluorophenyl)-6-azabicyclo[3.2.0]heptan-7-one (racemic
17DP) as an orange oil.
Step 3
7-Fluoro-2,3,3a,4-tetrahydro-1H-cyclopenta[b]quinolin-9(9aH)-one
[0529] A 500-mL, three-necked, round-bottomed flask was charged
with cis-6-(4-fluorophenyl)-6-azabicyclo[3.2.0]heptan-7-one
(racemic 17DP) (26.5 g, 129 mmol) and 250 mL of dichloroethane. The
reaction mixture was cooled at 5.degree. C. while triflic acid was
added via syringe over 10 min. The reaction mixture was stirred at
50.degree. C. for 4 h. The reaction mixture was cooled to room
temperature with an ice-water bath and then quenched with saturated
sodium bicarbonate to adjust the pH to 10. The organic layer was
separated, washed with brine, dried over MgSO.sub.4, filtered, and
concentrated to give 26.5 g of a 90:10 mixture of the title
compound as a brown semi-solid.
Step 4
Cis-tert-butyl
7-fluoro-9-oxo-3,3a,9,9a-tetrahydro-1H-cyclopenta[b]quinoline-4(2H)-carbo-
xylate (racemic cis-17D')
[0530] A 500-mL, three-necked, round-bottomed flask was charged
with the tricyclic aniline (90:10) (26.5 g, 129 mmol),
triethylamine (45.0 mL, 323 mmol), DMAP (1.57 g, 12.9 mmol), and
200 mL of dioxane. Boc.sub.2O (59.2 g, 271 mmol) was added in one
portion and the reaction mixture was stirred at room temperature
for 17 h. The reaction mixture was then diluted with EtOAc and
water. The organic layer was separated, washed with a 0.5 M
solution of HCl, washed with saturated sodium bicarbonate, washed
with brine, dried over MgSO.sub.4, filtered, and concentrated to
give a brown oil. This material was diluted with 200 mL of MeOH and
charged with potassium carbonate. The reaction mixture was stirred
at room temperature for 2 h. Purification by column chromatography
afforded 30 g (76% 3-step yield from the starting tricyclic
aniline) of cis-tert-butyl
7-fluoro-9-oxo-3,3a,9,9a-tetrahydro-1H-cyclopenta[b]quinoline-4(2H)-carbo-
xylate (racemic cis-17D') as a thick, yellow oil.
Step 5
(3aS,9aR)-tert-butyl
7-fluoro-9-oxo-3,3a,9,9a-tetrahydro-1H-cyclopenta[b]quinoline-4(2H)-carbo-
xylate (17D)
[0531] Racemic cis-17D' (30 g) was separated by supercritical fluid
chromatography using the conditions described below to give 13.5 g
of (3aS,9aR)-tert-butyl
7-fluoro-9-oxo-3,3a,9,9a-tetrahydro-1H-cyclopenta[b]quinoline-4(2H)-carbo-
xylate (17D) (45% yield, >99% ee). 17D was the first eluting
enantiomer under these conditions.
[0532] SFC Separation Conditions:
[0533] Flow rate: 260 g/min
[0534] Modifier percentage: 5%
[0535] Back Pressure: 150 bar
[0536] Column: AD-H, 50.times.250 mm
[0537] Inj: 0.7 mL
[0538] Modifier: IPA
[0539] UV: 227 nm
[0540] Concentration: 50 mg/mL in MeOH
Example 18
Preparation of Racemic
4-[Cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(2-pyrimidinyl)benzoy-
l]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic acid
##STR00217##
[0542] Bromide (18A, 60 mg, 0.11 mmol.) which was prepared from 14A
following a similar procedure as described in Example 14, step 2
with 4-bromobenzoylchloride, 2-(tributylstannyl)pyrimidine (126 mg,
0.34 mmol) and tetrakis(triphenylphosphine)palladium(0) (26 mg,
0.023 mmol) were mixed in DMF (1 mL). The reaction mixture was
degassed and heated in a sealed vial at 80.degree. C. overnight.
The reaction mixture was cooled to room temperature, filtered
through Centel.RTM.. The filtrate was diluted with ethyl acetate
and washed with water. The organic extracts were combined, washed
with brine, dried (MgSO.sub.4), filtered and concentrated. The
residue was purified by preparative TLC (eluted with 50% ethyl
actetate-hexane) to afford the desired compound (20 mg, 0.038
mmol). Ester 18B was hydrolyzed to give compound 18 following the
same procedure as described in Example 14, step 3.
[M+H].sup.+=511.3.
[0543] The compounds in the following table were prepared in a
similar fashion to the process illustrated in Example 18, starting
from the appropriate bromides using coupling reactions.
TABLE-US-00009 Stereo # Structure Designation Name [M + H].sup.+
18C ##STR00218## racemic, cis, cis
4-[[cis,cis-4-([1,1'-biphenyl]-4- ylcarbonyl)-2,3,3a,4,9,9a-
hexahydro-1H- cyclopenta[b]quinolin-9- yl]cyclopropylamino]-4-
oxobutanoic acid 509.3 18D ##STR00219## racemic, cis, cis
4-[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[4-
(1H-pyrazol-1-yl)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 499.3 18E ##STR00220## racemic, cis,
cis 4-[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[3-
(2-pyrimidinyl)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 511.3 18F ##STR00221## racemic, cis,
cis 4-[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[3-
(5-pyrimidinyl)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 511.3 18G ##STR00222## racemic, cis,
cis 4-[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[3-
(5-thiazolyl)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 516.3 18H ##STR00223## racemic, cis,
cis 4-[cyclopropyl[cis,cis-4-[3-(2- ethoxy-5-pyrimidinyl)benzoyl]-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 555.3 18i ##STR00224## racemic, cis,
cis 4-[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[3-
(4-pyridazinyl)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 511.3 18J ##STR00225## racemic, cis,
cis 4-[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[3-
(2-methoxy-4- thiazolyl)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 546.3 18K ##STR00226## racemic, cis,
cis 4-[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[3-
(2-methoxy-5- thiazolyl)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 546.3 18L ##STR00227## cis, cis,
single enantiomer 4-[[cis, cis-4-([1,1'-biphenyl]-4-
ylcarbonyl)-2,3,3a,4,9,9a- hexahydro-1H- cyclopenta[b]quinolin-9-
yl]cyclopropylamino]-4- oxobutanoic acid 509.3 18M ##STR00228##
cis, cis, single enantiomer 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4-(3- phenoxybenzoyl)-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 525.3 18N
##STR00229## racemic, cis, cis 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (5-pyrimidinyl)benzoyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 511.3 18o
##STR00230## racemic, cis, cis 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (5-thiazolyl)benzoyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 516.3 18P
##STR00231## racemic, cis, cis 4-[cyclopropyl[cis,cis-4-[4-(5-
ethoxy-2-pyrimidinyl)benzoyl]- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 555.3 18Q
##STR00232## racemic, cis, cis 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (4-pyridazinyl)benzoyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 511.3 18R
##STR00233## racemic, cis, cis 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (2-methoxy-5- thiazolyl)benzoyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 546.3 18S
##STR00234## Cis, cis, single enantiomer 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4-[3- (5-thiazolyl)benzoyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 516.3 18T
##STR00235## cis, cis, single enantiomer 4-[cyclopropyl[cis, cis-
2,3,3a,4,9,9a-hexahydro-4-[3- (4-pyridazinyl)benzoyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 511.3
Example 19
Preparation of Racemic 4-(Phenylmethyl)
cis,cis-9-[(3-carboxy-1-oxopropyl)cyclopropylamino]-1,2,3,3a,9,9a-hexahyd-
ro-2,2-dimethyl-4H-cyclopenta[b]quinoline-4-carboxylate (19)
Step 1
##STR00236##
[0545] 4,4-Dimethylcyclohexanone (9.0 g, 71.31 mmol) and potassium
permanganate (22.53 g, 142.63 mmol) were taken up in 450 mL of
water. To this, an aqueous solution of NaOH (1.02 g, 25.67 mmol) in
9 mL water was added at room temperature. The mixture was stirred
for 48 hours. Aqueous sodium bisulfite was then added until the
purple color disappeared. A brown solid was filtered off, and the
clear filtrate was brought to pH 1 with concentrated HCl. The
solution was extracted with ether (100 mL) three times. The
combined ether layers were then dried over anhydrous sodium
sulfate. The filtrate was concentrated in vacuo to afford the
product diacid 19A (9.01 g) in 73% yield.
Step 2
##STR00237##
[0547] The diacid 19A (4.0 g, 22.96 mmol) was dissolved in 10 mL
methanol, and to this solution, concentrated sulfuric acid (0.7 mL)
was added dropwise. The solution was heated to 85.degree. C. for 2
hours. The methanol was removed by concentration. Water was added
and the pH of the mixture was adjusted to pH 7 by slow addition of
saturated sodium bicarbonate. The solution was extracted with ether
three times. The combined ether layers were then dried over
anhydrous sodium sulfate. The filtrate was concentrated in vacuo to
afford the product diester 19B (3.86 g) in 83% yield.
Step 3
##STR00238##
[0549] Potassium tert-butoxide (5.3 g, 47.31 mmol) was taken up in
45 mL THF and cooled to 0.degree. C. To this, the diester 19B (6.38
g, 31.54 mmol) was added, and the solution was stirred at room
temperature for 24 hours. Glacial acetic acid (2.5 mL) was added
resulting in an orange solution containing a white precipitate. A
solution of Na.sub.2HPO.sub.4 (7.2 g) in 50 mL water was added
causing the suspension to become homogeneous. The solution was
extracted with dichloromethane (25 mL) three times. The combined
organic layers were then washed with brine and dried over anhydrous
sodium sulfate. The filtrate was concentrated in vacuo and the
residue was purified by flash chromatography on silica gel eluting
with 0 to 20% ethyl acetate in hexane to afford the product
ketoester 19C (5.36 g) in 100% yield.
Step 4
##STR00239##
[0551] In a 1 L flask, was added glacial acetic acid (20 mL), water
(2.5 mL), aniline (2.15 mL, 23.62 mmol), keto-ester 19C (4.0 g,
23.62 mmol), and zinc (6.17 g, 94.48 mmol) and heated to 80.degree.
C. for 1 hour and 15 minutes. Zinc salts were filtered off, and the
solution was diluted with methanol. The filtrate was concentrated
followed by dilution with dichloromethane and ice water. The pH was
adjusted to pH 10 with ammonium hydroxide, and the mixture was
extracted with dichloromethane three times. The combined organic
layers were then washed with brine and dried over anhydrous sodium
sulfate. The filtrate was concentrated in vacuo to afford the
product aniline ester 19D (7.72 g) in >100% yield (crude).
Step 5
##STR00240##
[0553] Aniline ester 19D (5.84 g, 23.61 mmol) was dissolved in
dioxane (25 mL) and 5M NaOH (23.61 mL, 118.05 mmol) added and
heated to 100.degree. C. for 1 hour. The reaction mixture was
cooled to room temperature and brought to pH 3 with 2 N
concentrated HCl. The solution was extracted with dichloromethane
three times. The combined organic layers were then washed with
brine and dried over anhydrous sodium sulfate. The filtrate was
concentrated in vacuo to afford the product aniline acid 19E (6.3
g) in >100% yield (crude).
Step 6
##STR00241##
[0555] Aniline acid 19E (5.5 g, 23.57 mmol) was taken up in Eaton's
Reagent (24.69 mL, 155.58 mmol) and heated to 70.degree. C. for 3
hours. The mixture was cooled to 0.degree. C. and quenched
portion-wise with ice water. NaOH pellets were added until pH 10
was reached. The mixture extracted with ethyl acetate three times.
The combined organic layers were then washed with brine and dried
over anhydrous sodium sulfate. The filtrate was concentrated in
vacuo and the residue purified by flash chromatography on silica
gel eluting with 0 to 50% ethyl acetate in hexane to afford the
product cis-ketone amine 19F (0.550 g) in 11% yield.
Step 7
##STR00242##
[0557] Compound 19 (racemic, cis, cis) was obtained from the
cis-ketone amine 19F following steps similar to those described in
Examples 6, step 3 and 4, and Example 7, steps 1 and 2.
[M+H].sup.+=491.3.
Example 20
Preparation of
4-[Cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-2,2-dimethyl-4-[4-(trifluo-
romethoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic
acid (20)
##STR00243##
[0559] Compound 20 was prepared from the ketone amine 19F following
similar procedures as those described in Examples 14, step 2 (to
introduce 4-trifluoromethoxy benzoylamide), and Example 6, step 4,
and then Example 7, steps 1 and 2. [M+H].sup.+=545.3.
Example 21
Preparation of Racemic
4-(Cyclopropyl{cis,cis-4-[(1-methylethoxy)carbonyl]-2,3,3a,4,9,9a-hexahyd-
ro-1H-cyclopenta[b]quinolin-9-yl}amino)-4-oxobutanoic acid (21)
##STR00244##
[0561] A solution of methyl
4-[[cis,cis-4-(chlorocarbonyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]qu-
inolin-9-yl](cyclopropyl)amino]-4-oxobutanoate (prepared as in
Example 22, mixture A) (36 mg, 0.089 mmol) in tetrahydrofuran (356
.mu.l) was added to isopropanol (13.6 .mu.l, 0.178 mmol) in a
Bohdan tube. Sodium bis(trimethylsilyl)amide (133 .mu.l, 0.133
mmol) was added to the reaction mixture. The tube was capped and
left to shake at rt overnight. In the morning, the reaction mixture
was transferred to a microwave vial and lithium hydroxide (1.0 M in
water, 540 .mu.l, 0.54 mmol) was added. The vial was capped, and
the reaction mixture was heated thermally at 65.degree. C. for 1 h.
The reaction mixture was allowed to cool to rt, dried in vacuo, and
diluted with DMSO (1 mL). Analytically pure material was obtained
by purification by preparative HPLC reverse phase (C-18), eluting
with acetonitrile/water+0.05% formic acid. Lyophilizing afforded 21
as the formate salt. [M+H].sup.+: 415.1.
[0562] The following compounds were prepared from racemic methyl
4-[[cis,cis-4-(chlorocarbonyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]qu-
inolin-9-yl](cyclopropyl)amino]-4-oxobutanoate with a procedure
similar to that used for example 21, varying the alcohol used in
the first step:
TABLE-US-00010 Stereo # Structure designation Name [M + H].sup.+
21A ##STR00245## racemic, cis, cis 4-{[cis, cis-4-{[(4-
chlorobenzyl)oxy]carbonyl}- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl](cyclopropyl)amino}- 4-oxobutanoic
acid 497.2 21B ##STR00246## racemic, cis, cis 4-(cyclopropyl{cis,
cis-4-[(4- fluorophenoxy)carbonyl]- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl}amino)-4-oxobutanoic acid 467.1 21C
##STR00247## racemic, cis, cis 4-(cyclopropyl{cis, cis-4-
[(naphthalen-2- ylmethoxy)carbonyl]- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl}amino)-4-oxobutanoic acid 513.2 21D
##STR00248## racemic, cis, cis 4-{cyclopropyl[cis, cis-4-{[(2-
fluorobenzyl)oxy]carbonyl}- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl]amino}-4-oxobutanoic acid 481.1 21E
##STR00249## racemic, cis, cis 4-{cyclopropyl[cis, cis-4-{[(4-
methoxybenzyl)oxy]carbonyl}- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}-4-oxobutanoic acid 493.2 21F
##STR00250## racemic, cis, cis 4-(cyclopropyl{cis, cis-4-[(1-
phenylethoxy)carbonyl]- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl}amino)-4-oxobutanoic acid 477.1 21G
##STR00251## racemic, cis, cis 4-(cyclopropyl{cis, cis-4-
[(pyridin-2- ylmethoxy)carbonyl]- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl}amino)-4-oxobutanoic acid 464.1 21H
##STR00252## racemic, cis, cis 4-(cyclopropyl{cis, cis-4-[(2,2-
dimethylpropoxy)carbonyl]- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl}amino)-4-oxobutanoic acid 443.2 21i
##STR00253## racemic, cis, cis 4-(cyclopropyl{cis, cis-4-
[(cyclopropylmethoxy) carbonyl]-2,3,3a,4,9,9a- hexahydro-1H-
cyclopenta[b]quinolin-9- yl}amino)-4-oxobutanoic acid 427.1 21J
##STR00254## racemic, cis, cis 4-(cyclopropyl{cis, cis-4-
[(pyridin-4- ylmethoxy)carbonyl]- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl}amino)-4-oxobutanoic acid 464.2 21K
##STR00255## racemic, cis, cis 4-{cyclopropyl[cis, cis-4-
(phenoxycarbonyl)- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl]amino}-4-oxobutanoic acid 449.1 21L
##STR00256## racemic, cis, cis 4-{cyclopropyl[cis, cis-4-
{[(3,4-dichlorobenzyl)oxy] carbonyl}-2,3,3a,4,9,9a- hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}-4-oxobutanoic acid 531.1
Example 22
Preparation of Enantiopure
4-[(4-Fluorophenyl)methyl]cis,cis-[(3-carboxy-1-oxopropyl)cyclopropylamin-
o]-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate
(22)
##STR00257##
[0564] The solution of starting enantiopure ester 14A' (50 mg,
0.146 mmol, prepared from enantiomer of 1D after chiral HPLC
separation following similar sequences in Example 1, step 5;
Example 7, step 1 and Example 14, step 1.) and DIPEA (80 .mu.L,
0.438 mmol) in CH.sub.2Cl.sub.2 (1 mL) was cooled in an
ice-H.sub.2O bath, phosgene (20% solution in toluene) (170 .mu.L,
0.292 mmol) was added, the resultant mixture was kept stirring at
0.degree. C. for 2 hrs, then rt for 15 mins. The mixture was
concentrated to dryness; the residue was taken up in THF (1 mL) and
cooled in an ice-H.sub.2O bath as mixture A.
[0565] To the solution of the benzyl alcohol (0.876 mmol) in THF (1
mL) was added NaH (72 mg, 1.75 mmol). The resultant mixture was
kept stirring at rt for 30 min, and then cooled in an ice-H.sub.2O
bath as mixture B.
[0566] The mixture A was added to the mixture B in an ice-H.sub.2O
bath via a syringe, the resultant mixture was kept stirring at
0.degree. C. for 1 hrs, then rt for 16 h. The mass spectrum
indicated the disappearance of the starting material ester and
intermediate.
[0567] MeOH (2 mL) and H.sub.2O (2 mL) were added, the mixture was
kept stirring at rt for 1 h. The mass spectrum indicated completion
of the hydrolysis of the ester. Et.sub.2O (3 mL) and H.sub.2O (1
mL) were added, the aqueous layer was separated, acidified with 1 N
HCl to pH .about.2, extracted with Et.sub.2O (2.times.3 mL), the
combined organic layer was dried over MgSO.sub.4 and concentrated.
The residue was purified by reverse phase HPLC, to obtain a white
solid, 40 mg as the desired enantiopure product 22.
[M+H].sup.+=480.8. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm:
7.37 (m, 3H); 7.19 (t, 1H); 7.06 (m, 3H); 6.75 (m, 1H); 5.24 (d,
J=11 Hz, 1H); 5.13 (d, J=11 Hz, 1H); 4.86 (m, 1H); 3.09.about.2.75
(m, 6H); 2.15 (m, 1H); 1.91 (m, 1H); 1.53 (m, 2H); 1.40 (m, 1H);
1.20.about.0.9 (m, 6H).
[0568] The compounds in the following table were prepared in a
similar manner as described in Example 22 from the appropriate
starting material tetraquinoline amide esters. The enantiomerically
pure final products were either obtained through chiral resolution
of final racemic product (22J, 22K) or were prepared from
enantiomerically pure tetraquinoline amides (prepared from chiral
tetrahydroquinolin-9(9aH)-one) (22A, 22D-22I, 22L-22Y). Some final
acids were obtained from hydrolysis of esters with NaOH (1 N).
TABLE-US-00011 stereo # Structure designation Name [M + H].sup.+
22A ##STR00258## cis, cis,, single enantiomer
4-[(3,5-difluorophenyl)methyl] cis, cis-[(3-carboxy-1-
oxopropyl)ethylamino]- 1,2,3,3a,9,9a-hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 487.3 22D ##STR00259## cis,
cis, single enantiomer 4-[(2,4-difluorophenyl)methyl] cis, cis-
[[(carboxymethoxy)carbonyl] cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate
523 [M + Na].sup.+ 22E ##STR00260## cis, cis, single enantiomer
4-(2-thienylmethyl) cis, cis- [[(carboxymethoxy)carbonyl]
cyclopropylamino]- 1,2,3,3a,9,9a-hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 493 [M + Na].sup.+ 22F
##STR00261## cis, cis, single enantiomer
4-[(2,4-difluorophenyl)methyl] cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-chloro-7-fluoro-
1,2,3,3a,9,9a-hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate
551.3 22G ##STR00262## cis, cis, single enantiomer 4-[[3-
(trifluoromethoxy)phenyl] methyl] cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-chloro-7-fluoro-
1,2,3,3a,9,9a-hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate
599.3 22H ##STR00263## cis, cis, single enantiomer
4-(2-pyridinylmethyl) cis, cis- [(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-chloro-7-fluoro-
1,2,3,3a,9,9a-hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate
516.3 22i ##STR00264## cis, cis (enantiopure), (S configuration at
benzylic carbon atom) 4-[1(S)-(4-fluorophenyl)ethyl] cis,
cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]- 6-chloro-7-fluoro-
1,2,3,3a,9,9a-hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate
547.3 22J ##STR00265## Single enantiomer, derived from Peak I off
SFC separation 4-[[4- (trifluoromethoxy)phenyl] methyl] cis,
cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate
546.7 22K ##STR00266## Single enantiomer, derived from Peak II off
SFC searation 4-[[4- (trifluoromethoxy)phenyl] methyl] cis,
cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate
546.7 22L ##STR00267## cis, cis, single enantiomer
4-(2,3-dihydro-1H-inden-2-yl) cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 1,2,3,3a,9,9a-hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 510.8 [M + Na].sup.+ 22M
##STR00268## cis, cis, single enantiomer
4-[(3,4-difluorophenyl)methyl] cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 1,2,3,3a,9,9a-hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 498.7 22N ##STR00269## cis,
cis, single enantiomer 4-[(3,5-difluorophenyl)methyl] cis,
cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate
498.7 22o ##STR00270## cis, cis, single enantiomer 4-[[4-
(trifluoromethyl)phenyl] methyl] cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 1,2,3,3a,9,9a-hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 530.7 22P ##STR00271## cis,
cis, single enantiomer 4-[(4-cyanophenyl)methyl] cis,
cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate
487.7 22Q ##STR00272## cis, cis (enantiopure), (R-configuration at
fluorobenzylic carbon) single enantiomer
4-[1(R)-(4-fluorophenyl)ethyl] cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 1,2,3,3a,9,9a-hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 516.7 [M + Na].sup.+ 22R
##STR00273## cis, cis (enantiopure), (S-configuration at
fluorobenzylic carbon) single enantiomer
4-[1(S)-(4-fluorophenyl)ethyl] cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 1,2,3,3a,9,9a-hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 516.7 [M + Na].sup.+ 22S
##STR00274## 3aS,9R,9aR, (racemic at 2-tetralene carbon atom)
4-(1,2,3,4-tetrahydro-2(RS)- naphthalenyl) (3aS,9R,9aR)-
[(3-carboxy-1- oxopropyl)cyclopropylamino]- 7-fluoro-1,2,3,3a,9,9a-
hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate 520.8 22T
##STR00275## cis, cis, single enantiomer 4-[(4-fluorophenyl)methyl]
cis, cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
6-chloro-1,2,3,3a,9,9a- hexahydro-4H- cyclopenta[b]quinoline-4-
carboxylate 514.8 22U ##STR00276## cis, cis, single enantiomer
4-[1(S)-(4-fluorophenyl)ethyl] cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-chloro-1,2,3,3a,9,9a- hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 551.7 [M + Na].sup.+ 22V
##STR00277## cis, cis (enantiopure), S (S configuration at 1-indane
carbon atom) single enantiomer 4-(2,3-dihydro-1H-inden-1(S)- yl)
cis, cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
6-chloro-1,2,3,3a,9,9a- hexahydro-4H- cyclopenta[b]quinoline-4-
carboxylate 545.3 [M + Na].sup.+ 22W ##STR00278## cis, cis
(enantiopure), (R configuration at 1-indane carbon atom) single
enantiomer 4-(2,3-dihydro-1H-inden-1(R)- yl) cis,
cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
6-chloro-1,2,3,3a,9,9a- hexahydro-4H- cyclopenta[b]quinoline-4-
carboxylate 545.2 [M + Na].sup.+ 22X ##STR00279## cis, cis, single
enantiomer 4-(2,3-dihydro-1H-inden-2-yl) cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-chloro-1,2,3,3a,9,9a- hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 545.8 [M + Na].sup.+ 22Y
##STR00280## cis, cis, single enantiomer
4-[(2,4-difluorophenyl)methyl] cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-chloro-1,2,3,3a,9,9a- hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 555.8 [M + Na].sup.+
Example 23
Preparation of Racemic
4-{Cyclopropyl[cis,cis-4-(2,3-dihydro-1H-indol-1-ylcarbonyl)-2,3,3a,4,9,9-
a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobutanoic acid
(23)
Step 1: Methyl
4-{cyclopropyl[cis,cis-4-(2,3-dihydro-1H-indol-1-ylcarbonyl)-2,3,3a,4,9,9-
a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobutanoate
(23A)
##STR00281##
[0570] Indoline (36.8 mg, 0.309 mmol, 2.5 equiv) was added to a
solution of methyl 4-[[(cis,
cis,)-4-(chlorocarbonyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-
-9-yl](cyclopropyl)amino]-4-oxobutanoate (50 mg, 0.123 mmol, 1
equiv, prepared from Example 22 mixture A where the crude reaction
mixture was worked up by diluting with ethyl acetate and water, and
the organic phase was washed with brine and dried (MgSO.sub.4)
followed by removal of solvent) in dichloromethane at 23.degree. C.
The reaction mixture was heated at 60.degree. C. in a sealed tube
for 16 h, and then was cooled to 23.degree. C. The cooled reaction
mixture was partitioned between dichloromethane and aqueous
potassium bisulfate. The organic layer was washed with water, and
concentrated to afford 23A, which was used in the subsequent step
without further purification. [M+H].sup.+: 488.2.
Step 2:
4-{Cyclopropyl[cis,cis-4-(2,3-dihydro-1H-indol-1-ylcarbonyl)-2,3,3-
a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobutanoic
acid (23)
##STR00282##
[0572] 23 was prepared from methyl
4-{cyclopropyl[cis,cis-4-(2,3-dihydro-1H-indol-1-ylcarbonyl)-2,3,3a,4,9,9-
a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]amino}-4-oxobutanoate 23A
using a procedure similar to that used in Example 14, Step 3.
[M+H].sup.+: 474.2.
[0573] The following examples were prepared from racemic methyl
4-[[cis,cis-4-(chlorocarbonyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]qu-
inolin-9-yl](cyclopropyl)amino]-4-oxobutanoate using a procedure
similar to that used in Example 23, Steps 1 and 2.
TABLE-US-00012 Stereo # Structure designation Name [M + H].sup.+
23B ##STR00283## racemic, cis, cis 4-{cyclopropyl[cis,cis-4-(1H-
imidazol-1-ylcarbonyl)- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino}-4-oxobutanoic acid 423.2 23C
##STR00284## racemic, cis, cis 4-{[cis,cis-4- (benzylcarbamoyl)-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl](cyclopropyl)amino}-4- oxobutanoic acid 462.2 23D ##STR00285##
racemic, cis, cis 4-(cyclopropyl{cis,cis-4-
[methyl(phenyl)carbamoyl]- 2,3,3a,4,9,9a-hexahydro-1H-
cyclopenta[b]quinolin-9- yl}amino)-4-oxobutanoic acid 462.2 23E
##STR00286## racemic, cis, cis 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[[(3- methoxyphenyl)amino]carbonyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 478.3 23F
##STR00287## racemic, cis, cis 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[[(2- methoxyphenyl)amino]carbonyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 478.3 23G
##STR00288## racemic, cis, cis 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4- [(phenylamino)carbonyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 448.2 23H
##STR00289## racemic, cis, cis 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[[(4- methoxyphenyl)amino]carbonyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 478.3 23i
##STR00290## racemic, cis, cis 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[[[2- (trifluoromethoxy)phenyl]
amino]carbonyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 532.3
Example 24
Preparation of Racemic
4-[Cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-(phenylsulfonyl)-1H-cycl-
openta[b]quinolin-9-yl]amino]-4-oxobutanoic acid (24)
##STR00291##
[0575] Methyl
4-(cyclopropyl(2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amin-
o)-4-oxobutanoate 14A (30 mg, 0.088 mmol) and benzenesulfonyl
chloride (23 mg, 0.13 mmol) were mixed in pyridine (0.3 mL). The
reaction mixture was heated at 70.degree. C. overnight and cooled
to room temperature. 1 N HCl (aq.) was added. The aqueous layer was
separated and extracted with DCM. The organic extracts were
combined, washed with brine, dried (MgSO.sub.4), filtered and
concentrated. The residue was purified by preparative TLC (eluted
with 50% ethyl acetate-hexane) to afford sulfonamide methyl
4-(cyclopropyl(4-(phenylsulfonyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b-
]quinolin-9-yl)amino)-4-oxobutanoate 24A (20 mg, 0.042 mmol) which
was hydrolyzed to compound 24 with a similar procedure as Example
7, step 2. [M+H].sup.+=469.3.
[0576] The compounds in the following table were prepared in a
similar fashion to Example 24.
TABLE-US-00013 Stereo # Structure designation Name [M + H].sup.+
24B ##STR00292## racemic, cis, cis 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[(4- phenoxyphenyl)sulfonyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 561.3 24C
##STR00293## racemic, cis, cis 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[(4- methoxyphenyl)sulfonyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 499.3 24D
##STR00294## racemic, cis, cis 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[[4- (trifluoromethoxy)phenyl]
sulfonyl]-1H-cyclopenta[b] quinolin-9-yl]amino]- 4-oxobutanoic acid
553.3
Example 25
Preparation of Racemic
4-[{cis,cis-3-[(Benzyloxy)carbonyl]-1,2,2a,3,8,8a-hexahydrocyclobuta[b]qu-
inolin-8-yl}(cyclopropyl)amino]-4-oxobutanoic acid (25)
Step 1: Benzyl
4-oxo-2-(2-oxoethyl)-3,4-dihydroquinoline-1(2H)-carboxylate
(25A)
##STR00295##
[0578] Osmium tetroxide (5% in water, 2.0 mL, 0.33 mmol, 0.025
equiv) was added to a biphasic mixture of benzyl
2-allyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1A) (4.20 g,
13.1 mmol, 1 equiv), sodium periodate (11.2 g, 52.3 mmol, 4.00
equiv) and 2,6-lutidine (3.04 mL, 26.1 mmol, 2.0 equiv) in water
(33 mL) and dioxane (98 mL) at 23.degree. C. The reaction mixture
was stirred at 23.degree. C. for 3 h, and then it was partitioned
between water and dichloromethane. The aqueous layer was further
extracted with dichloromethane (1.times.), and the combined organic
layers were dried over sodium sulfate. The dried solution was
filtered, and the filtrate was concentrated. The residue was
purified by flash-column chromatography (15% ethyl acetate-hexanes,
grading to 70% ethyl acetate-hexanes) to afford 25A. [M+H].sup.+:
324.1
Step 2: Benzyl
2-(2-hydroxyethyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate
(25B)
##STR00296##
[0580] Sodium borohydride (1.27 g, 33.5 mmol, 3.0 equiv) was added
to a solution of 25A (3.61 g, 11.2 mmol, 1 equiv) in methanol (112
mL) at 0.degree. C. After stirring at 0.degree. C. for 25 min, the
reaction mixture was partitioned between ethyl acetate and water.
The organic layer was washed with saturated aqueous sodium chloride
solution, and the washed solution was dried over sodium sulfate.
The dried solution was filtered, and the filtrate was
concentrated.
[0581] The residue was dissolved in 1,2-dichloroethane (50 mL), and
manganese dioxide (4.41 g, 50.7 mmol, 5 equiv) was added. The
reaction mixture was heated to 65.degree. C. for 2.5 h, and then
the heating bath was removed. The cooled reaction mixture was
filtered through Celite.RTM., and the filtrate was concentrated to
afford 25B, which was used in subsequent steps without further
purification. [M+H].sup.+: 326.2.
Step 3: Benzyl
cis-8-oxo-2,2a,8,8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate
(25C)
##STR00297##
[0583] 25C was prepared from benzyl
2-(2-hydroxyethyl)-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate
(25B) using procedure similar to those used in Example 1, Steps 3
and 4. [M+H].sup.+: 308.2.
Step 4: Benzyl
cis,cis-8-[cyclopropyl(4-methoxy-4-oxobutanoyl)amino]-2,2a,8,8a-tetrahydr-
ocyclobuta[b]quinoline-3(1H)-carboxylate (25D)
##STR00298##
[0585] 25D was prepared from benzyl
cis-8-oxo-2,2a,8,8a-tetrahydrocyclobuta[b]quinoline-3(1H)-carboxylate
25C using a procedure similar to that used for Example 1, Step 5
and Example 7, Step 1. [M+H].sup.+: 463.2.
Step 5: Racemic
4-[{cis,cis-3-[(Benzyloxy)carbonyl]-1,2,2a,3,8,8a-hexahydrocyclobuta[b]qu-
inolin-8-yl}(cyclopropyl)amino]-4-oxobutanoic acid (25)
##STR00299##
[0587] Compound 25 was prepared from benzyl
cis,cis-8-[cyclopropyl(4-methoxy-4-oxobutanoyl)amino]-2,2a,8,8a-tetrahydr-
ocyclobuta[b]quinoline-3 (1H)-carboxylate 25D using a procedure
similar to that used for Example 7, Step 2. [M+H].sup.+: 449.2.
Example 26
Preparation of Racemic Methyl
4-{cyclopropyl[cis,cis-3-{[4-(trifluoromethoxy)phenyl]carbonyl}-1,2,2a,3,-
8,8a-hexahydrocyclobuta[b]quinolin-8-yl]amino}-4-oxobutanoate
(26)
##STR00300##
[0589] Compound 26 was prepared from benzyl
cis,cis-8-[cyclopropyl(4-methoxy-4-oxobutanoyl)amino]-2,2a,8,8a-tetrahydr-
ocyclobuta[b]quinoline-3(1H)-carboxylate (25D) using a procedure
similar to that used in Example 14, Steps 1 and 2. [M+H].sup.+:
517.2.
Example 27
Preparation of Racemic
4-{Cyclopropyl[cis,cis-3-{[4-(trifluoromethoxy)phenyl]carbonyl}-1,2,2a,3,-
8,8a-hexahydrocyclobuta[b]quinolin-8-yl]amino}-4-oxobutanoic acid
(27)
##STR00301##
[0591] Compound 27 was prepared from methyl
4-{cyclopropyl[cis,cis-3-{[4-(trifluoromethoxy)phenyl]carbonyl}-1,2,2a,3,-
8,8a-hexahydrocyclobuta[b]quinolin-8-yl]amino}-4-oxobutanoate 26
using a procedure similar to that used in Example 14, Step 3.
[M+H].sup.+: 503.2.
[0592] The compounds in the following table were prepared by a
similar synthetic process as illustrated in Examples 25-27, and 14.
The enantiomerically pure final products were prepared from
enantiomerically pure tetraquinoline amides (prepared from chiral
tetrahydroquinolin-9(9aH)-one).
TABLE-US-00014 Stereo # Structure designation Name [M + H].sup.+
27A ##STR00302## cis, cis, single enantiomer
3-(phenylmethyl)cis,cis-[(3- carboxy-1-
oxopropyl)cyclopropylamino]- 6-fluoro-2,2a,8,8a-
tetrahydrocyclobuta[b] quinoline-3(1H)-carboxylate 467 27B
##STR00303## cis, cis, single enantiomer 4-[cyclopropyl[cis,cis-6-
fluoro-1,2,2a,3,8,8a-hexahydro- 3-[4- (trifluoromethoxy)benzoyl]
cyclobuta[b]quinolin-8-yl] amino]-4-oxobutanoic acid 521 27C
##STR00304## cis, cis, single enantiomer
4-[cyclopropyl[cis,cis-3-(3,5- difluorobenzoyl)-6-fluoro-
1,2,2a,3,8,8a- hexahydrocyclobuta[b] quinolin-8-yl]amino]-
4-oxobutanoic acid 473 27D ##STR00305## cis, cis single enantiomer
3-(phenylmethyl)cis,cis-[(3- carboxy-1-
oxopropyl)cyclopropylamino]- 5-chloro-2,2a,8,8a-
tetrahydrocyclobuta[b] quinoline-3(1H)-carboxylate 483 27E
##STR00306## cis, cis single enantiomer
4-[cyclopropyl[cis,cis-3-(3,5- difluorobenzoyl)-6-fluoro-
1,2,2a,3,8,8a- hexahydrocyclobuta[b] quinolin-8-yl]amino]-4-
oxobutanoic acid 472 27F ##STR00307## cis, cis single enantiomer
4-[cyclopropyl[cis,cis-6- fluoro-1,2,2a,3,8,8a-hexahydro- 3-[3-
(trifluoromethoxy)benzoyl] cyclobuta[b]quinolin-8-
yl)amino]-4-oxobutanoic acid 520 27G ##STR00308## cis, cis, single
enantiomer 3-(phenylmethyl)cis,cis-[(3- carboxy-1-
oxopropyl)cyclopropylamino]- 5-chloro-2,2a,8,8a-
tetrahydrocyclobuta[b] quinoline-3(1H)-carboxylate 483 27H
##STR00309## cis, cis single enantiomer 4-[[cis,cis-5-chloro-
1,2,2a,3,8,8a-hexahydro-3-[4- (trifluoromethoxy)benzoyl]
cyclobuta[b)quinolin-8- yl]cyclopropylamino]-4- oxobutanoic acid
537 27i ##STR00310## cis, cis single enantiomer
4-[[cis,cis-5-chloro- 1,2,2a,3,8,8a-hexahydro-3-[3-
(trifluoromethoxy)benzoyl] cyclobuta[b]quinolin-8-
yl]cyclopropylamino]-4- oxobutanoic acid 537 27J ##STR00311## cis,
cis single enantiomer 4-[[cis,cis-5-chloro-3-(3,5-
difluorobenzoyl)-1,2,2a,3,8,8a- hexahydrocyclobuta[b]
quinolin-8-yl] cyclopropylamino]-4- oxobutanoic acid 489 27K
##STR00312## cis, cis, single enantiomer 4-[[cis,cis-5-chloro-
1,2,2a,3,8,8a-hexahydro-3-[4- (trifluoromethoxy)
benzoyl]cyclobuta[b]quinolin- 8-yl]cyclopropylamino]-4- oxobutanoic
acid 537 27L ##STR00313## cis, cis, single enantiomer
4-[[cis,cis-5-chloro- 1,2,2a,3,8,8a-hexahydro-3-[3-
(trifluoromethoxy)benzoyl] cyclobuta[b]quinolin-8-
yl]cyclopropylamino]-4- oxobutanoic acid 537 27M ##STR00314## cis,
cis, single enantiomer 4-[[cis,cis-5-chloro-3-(3,5-
difluorobenzoyl)-1,2,2a,3,8,8a- hexahydrocyclobuta[b]
quinolin-8-yl] cyclopropylamino]-4- oxobutanoic acid 489 27N
##STR00315## cis, cis, single enantiomer
3-(phenylmethyl)cis,cis-[(3- carboxy-1-
oxopropyl)cyclopropylamino]- 2,2a,8,8a- tetrahydrocyclobuta[b]
quinoline-3(1H)-carboxylate 449 27O ##STR00316## cis, cis, single
enantiomer 4-[cyclopropyl[cis,cis- 1,2,2a,3,8,8a-hexahydro-3-[4-
(trifluoromethoxy)benzoyl] cyclobuta[b]quinolin-8-
yl]amino]-4-oxobutanoic acid 503 27Q ##STR00317## cis, cis, single
enantiomer 4-[cyclopropyl[cis,cis-3-(4-
fluorobenzoyl)-1,2,2a,3,8,8a- hexahydrocyclobuta[b]
quinolin-8-yl]amino]- 4-oxobutanoic acid 437 27R ##STR00318## cis,
cis, single enantiomer 4-[cyclopropyl[cis,cis-3-(3-
fluorobenzoyl)-1,2,2a,3,8,8a- hexahydrocyclobuta[b]
quinolin-8-yl]amino]- 4-oxobutanoic acid 437 27S ##STR00319## cis,
cis, single enantiomer 4-[cyclopropyl[cis,cis-
1,2,2a,3,8,8a-hexahydro-3-[3- (trifluoromethoxy)benzoyl]
cyclobuta[b]quinolin-8- yl]amino]-4-oxobutanoic acid 503
Example 28
Racemic
4-[{cis,cis-10-[(Benzyloxy)carbonyl]-1,2,3,4,4a,9,9a,10-octahydroa-
cridin-9-yl}(cyclopropyl)amino]-4-oxobutanoic acid (28)
Step 1: Benzyl
2-but-3-en-1-yl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate
(28A)
##STR00320##
[0594] 3-Butenylmagnesium bromide (0.5 M in THF, 100 mL, 50.0 mmol,
1.7 equiv) was added was added to a solution of 4-methoxyquinoline
(4.65 g, 29.2 mmol, 1 equiv) in tetrahydrofuran (195 mL) at
-78.degree. C. The reaction mixture was stirred at -78.degree. C.
for 1 h, then benzyl chloroformate (8.34 mL, 58.4 mmol, 2.00 equiv)
was added via syringe over 5 min. Stirred for an additional 15
minutes at -78.degree. C., then the cooling bath was removed and
the reaction mixture was allowed to warm to 23.degree. C. After 1
h, methanol was added (20 mL). After stirring for 5 min, aqueous
hydrochloric acid solution (2 N, 20 mL) was added and the mixture
was stirred for 10 min. The mixture was then concentrated by rotary
evaporation to remove most of the tetrahydrofuran and methanol, and
the residue was partitioned between ethyl acetate and water. The
organic phase was washed with brine, and the washed solution was
dried over sodium sulfate. The dried solution was filtered, and the
filtrate was concentrated. The residue was purified by flash-column
chromatography (5% ethyl acetate-hexanes, grading to 20% ethyl
acetate-hexanes) to afford 28A as a colorless oil. [M+H].sup.+:
336.2.
Step 2:
4-[{cis,cis-10-[(Benzyloxy)carbonyl]-1,2,3,4,4a,9,9a,10-octahydroa-
cridin-9-yl}(cyclopropyl)amino]-4-oxobutanoic acid was prepared
from benzyl
2-but-3-en-1-yl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate
(28)
##STR00321##
[0596] 28 was prepared from benzyl
2-but-3-en-1-yl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (28A)
using a sequence with procedures similar to those used for Example
1, Steps 2-5, and Example 7. [M+H].sup.+: 477.2.
Example 29
Racemic 2-Hydroxyethyl
cyclopropyl[cis,cis-4-(phenylcarbonyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclope-
nta[b]quinolin-9-yl]carbamate (29)
Step 1: Benzyl
cis,cis-9-[{[2-(benzyloxy)ethoxy]carbonyl}(cyclopropyl)amino]-1,2,3,3a,9,-
9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate (29A)
##STR00322##
[0598] 2-(Benzyloxy)ethyl chloridocarbonate (0.080 mL, 0.44 mmol,
2.0 equiv) was added to a solution of benzyl
cis,cis-9-(cyclopropylamino)-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quin-
oline-4-carboxylate 1E (80 mg, 0.22 mmol, 1 equiv) and
N,N-diisopropylethylamine (0.154 mL, 0.883 mmol, 4.0 equiv) in
dioxane (1.5 mL). The reaction mixture was heated at 40.degree. C.
for 16 h, and then cooled to 23.degree. C. The cooled reaction
mixture was partitioned between ethyl acetate and water. The
organic layer was washed with saturated aqueous sodium chloride
solution, and the washed solution was dried over sodium sulfate.
The dried solution was filtered, and the filtrate was concentrated.
The residue was purified by flash-column chromatography (15% ethyl
acetate-hexanes, grading to 65% ethyl acetate-hexanes) to afford
29A. [M+H].sup.+: 541.2.
Step 2: 2-(Benzyloxy)ethyl
cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl-
]carbamate (29B)
##STR00323##
[0600] 29B was prepared from benzyl
cis,cis-[{[2-(benzyloxy)ethoxy]carbonyl}(cyclopropyl)amino]-1,2,3,3a,9,9a-
-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate using a
procedure similar to that used in Example 14, Step 1. [M+H].sup.+:
407.2.
Step 3:
2-(Benzyloxy)ethyl[cis,cis-4-benzoyl-2,3,3a,4,9,9a-hexahydro-1H-cy-
clopenta[b]quinolin-9-yl]cyclopropylcarbamate (29C)
##STR00324##
[0602] 29C was prepared from 2-(benzyloxy)ethyl
cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl-
]carbamate 29B using a procedure similar to that used for Example
14, Step 2. [M+H].sup.+: 511.2.
Step 4: 2-Hydroxyethyl
cyclopropyl[cis,cis-4-(phenylcarbonyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclope-
nta[b]quinolin-9-yl]carbamate (29)
##STR00325##
[0604] Palladium (10% on carbon, 12.3 mg, 0.012 mmol, 0.10 equiv)
was added to a solution of
2-(benzyloxy)ethyl[cis,cis-4-benzoyl-2,3,3a,4,9,9a-hexahydro-1H-cyclopent-
a[b]quinolin-9-yl]cyclopropylcarbamate 29C (62 mg, 0.12 mmol, 1
equiv) in tetrahydrofuran (2.4 mL). A three-way stopcock connected
to a hydrogen balloon and a vacuum line was fitted to the top of
the flask, and the flask was subjected to alternating vacuum
purging and hydrogen filling cycles (4.times.). The reaction
mixture was then stirred under hydrogen for 18 h at 23.degree. C.,
and then was filtered through cotton. The filtrate was
concentrated, and the residue was purified by flash-column
chromatography (50% ethyl acetate-hexanes, grading to ethyl
acetate) to afford 29. [M+H].sup.+: 421.2.
Example 30
Preparation of Racemic
({Cyclopropyl[cis,cis-4-(phenylcarbonyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclo-
penta[b]quinolin-9-yl]carbamoyl}oxy)acetic acid (30)
##STR00326##
[0606] Jones Reagent (0.200 mL) was added to a solution of
2-hydroxyethyl
cyclopropyl[cis,cis-4-(phenylcarbonyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclope-
nta[b]quinolin-9-yl]carbamate 29 (46 mg, 0.11 mmol) in acetone (2.2
mL) at 23.degree. C. After stirring for 30 min, an additional
portion of Jones Reagent (0.200 mL) was added, and the reaction
mixture was stirred at 23.degree. C. for a further 20 min. The
reaction mixture was then partitioned between ethyl acetate and
aqueous hydrogen chloride solution (1 N). The organic layer was
washed with saturated aqueous sodium chloride solution, and the
washed solution was dried over sodium sulfate. The dried solution
was filtered, and the filtrate was concentrated. The residue was
then dissolved in DMSO (2 mL), and purified by reverse-phase HPLC
(40% acetonitrile-water, grading to 80% acetonitrile-water, with
0.1% trifluoroacetic acid in both the acetonitrile and water) to
afford 30. [M+H].sup.+: 435.2.
Example 31
Preparation of
({Cyclopropyl[cis,cis-4-{[4-(trifluoromethoxy)phenyl]carbonyl}-2,3,3a,4,9-
,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]carbamoyl}oxy)acetic
acid (31)
##STR00327##
[0608] Compound 31 was prepared from 2-(benzyloxy)ethyl
cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl-
]carbamate 29B, using procedures similar to those used in Example
29, Steps 3-4, and Example 30. [M+H].sup.+: 519.1.
Example 32
Preparation of Enantiopure 4-(Phenylmethyl)
cis,cis-[[(1(S)-carboxyethoxy)carbonyl]cyclopropylamino]-1,2,3,3a,9,9a-he-
xahydro-4H-cyclopenta[b]quinoline-4-carboxylate (32)
Step 1: Enantiopure cis,cis-Benzyl
9-(chlorocarbonyl(cyclopropyl)amino)-3,3a,9,9a-tetrahydro-1H-cyclopenta[b-
]quinoline-4(2H)-carboxylate (32A)
##STR00328##
[0610] Triphosgene (1.2 g, 4.14 mmol) was added to a solution of
enantiopure cis,cis-benzyl
9-(cyclopropylamino)-3,3a,9,9a-tetrahydro-1H-cyclopenta[b]quinoline-4(2H)-
-carboxylate (1.0 g, 2.76 mmol) and DIPEA (720 .mu.L, 4.14 mmol) in
THF (20 mL). After stirring at rt for 2 h, EtOAc (20 mL) and
H.sub.2O (20 mL) were added. The aqueous layer was extracted once
more with EtOAc (15 mL). The combined organic was washed with brine
(10 mL), dried over MgSO.sub.4 and concentrated. The residue 32A
was used directly in the next step.
Step 2: Enantiopure(cis, cis,)-Benzyl
9-(cyclopropyl(((S)-1-methoxy-1-oxopropan-2-yloxy)carbonyl)amino)-3,3a,9,-
9a-tetrahydro-1H-cyclopenta[b]quinoline-4(2H)-carboxylate (32B)
##STR00329##
[0612] A solution of enantiopure cis,cis-benzyl
9-(chlorocarbonyl(cyclopropyl)amino)-3,3a,9,9a-tetrahydro-1H-cyclopenta[b-
]quinoline-4(2H)-carboxylate 32A (25 .mu.L, 0.240 mmol) in
1,4-dioxane (2 mL) was stirred at rt, and NaH (16 mg, 0.4 mmol) was
added. After stirring at rt for 30 mins, (S)-methyl
2-hydroxypropanoate (85 mg, 0.2 mmol) in 1,4-dioxane (1 mL) was
added, and the resultant mixture was kept stirring at rt for 2
hours. EtOAc (10 mL) was added, followed by the icy-H.sub.2O (5
mL), and the organic was dried over MgSO.sub.4 and concentrated.
The residue was purified via silica gel column chromatography
(EtOAc/Hexane=1:3), to obtain 32B as a yellow foam, 36 mg;
[M+H].sup.+=493.
Step 3: Enantiopure (cis, cis,)-Benzyl
9-(cyclopropyl(((S)-1-methoxy-1-oxopropan-2-yloxy)carbonyl)amino)-3,3a,9,-
9a-tetrahydro-1H-cyclopenta[b]quinoline-4(2H)-carboxylate (32)
##STR00330##
[0614] 32B was converted to the desired enantiopure acid 32 by
hydrolysis with NaOH (1 N), [M+Na].sup.+=500.7. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. ppm: 7.42 (m, 6H); 7.25 (m, 1H); 7.24 (m
1H); 7.17 (m, 1H); 7.04 (m, 1H); 5.32 (d, J=13 Hz, 1H); 5.22 (d,
J=13 Hz, 1H); 5.11 (q, J=7 Hz, 1H); 3.01 (m, 1H); 2.71 (m 1H); 2.15
(m, 1H); 1.94 (m, 1H); 1.59 (m, 3H); 1.45 (m, 2H); 1.32 (m, 1H);
1.22-1.14 (m, 2H); 1.11.about.0.80 (m, 4H).
[0615] The compounds in the following table were prepared by a
similar synthetic process as described above in Example 32. The
enantiomerically pure final products were prepared from
enantiomerically pure tetraquinoline amides (prepared from chiral
tetrahydroquinolin-9(9aH)-one).
TABLE-US-00015 Stereo # Structure designation Name [M + H].sup.+
32C ##STR00331## cis, cis (enantiopure), R single enantiomer
4-(phenylmethyl)cis,cis- [[(1R)- carboxyethoxy)carbonyl]
cyclopropylamino]- 1,2,3,3a,9,9a- hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 500.6 [M + Na].sup.+ 32D
##STR00332## cis, cis single enantiomer 4-(phenylmethyl)cis,cis-
[[(carboxymethoxy)carbonyl] cyclopropylamino]-1,2,3,3a,9,9a-
hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate 464.7 32E
##STR00333## cis, cis single enantiomer 4-(phenylmethyl)cis,cis-
[[(carboxymethoxy)carbonyl] cyclopropylamino]-1,2,3,3a,9,9a-
hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate 464.7 32F
##STR00334## 3aS,9R,9aR single enantiomer
4-(phenylmethyl)(3aS,9R,9aR)- [[(carboxymethoxy)carbonyl]
cyclopropylamino]-7-fluoro- 1,2,3,3a,9,9a-hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 505.0 [M + Na].sup.+ 32G
##STR00335## cis, cis, single enantiomer 3-(phenylmethyl)cis,cis-
[[(carboxymethoxy)carbonyl] cyclopropylamino]-2,2a,8,8a-
tetrahydrocyclobuta[b] quinoline-3(1H)-carboxylate 472.6 [M +
Na].sup.+
[0616] The compounds in the following table were prepared by
similar synthetic processes as those described in Examples 32 and
14. The enantiomerically pure final products were prepared from
enantiomerically pure tetraquinoline amides (prepared from chiral
tetrahydroquinolin-9(9aH)-one).
TABLE-US-00016 Stereo # Structure designation Name [M + H].sup.+
32H ##STR00336## cis, cis, single enantiomer
[[[cyclopropyl[cis,cis- 1,2,2a,3,8,8a-hexahydro-3-[4-
(trifluoromethoxy)benzoyl] cyclobuta[b]quinolin-8-
yl]amino]carbonyl]oxy]acetic acid 505.1 32i ##STR00337## cis, cis,
single enantiomer r [[[cyclopropyl[cis,cis-3-(4-
fluorobenzoyl)-1,2,2a,3,8,8a- hexahydrocyclobuta[b] quinolin-8-
yl]amino]carbonyl]oxy]acetic acid 439.2 32J ##STR00338## cis, cis
single enantiomer [[[cyclopropyl[cis,cis-3-(3-
fluorobenzoyl)-1,2,2a,3,8,8a- hexahydrocyclobuta[b] quinolin-8-
yl]amino]carbonyl]oxy]acetic acid 439.2 32K ##STR00339## cis, cis,
single enantiomer [[[cyclopropyl[cis,cis-3-(3,4-
difluorobenzoyl)-1,2,2a,3,8,8a- hexahydrocyclobuta[b] quinolin-8-
yl]amino]carbonyl]oxy]acetic acid 457.3 32L ##STR00340## racemic,
cis, cis [[[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[3-
(trifluoromethoxy)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]carbonyl]oxy]acetic acid 519.3 32M ##STR00341## cis, cis,
single enantiomer [[[cyclopropyl[cis,cis-4-(4-
fluorobenzoyl)-2,3,3a,4,9,9a- hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino]carbonyl]oxy]acetic acid 452.7
32N ##STR00342## cis, cis, single enantiomer
[[[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[4-
(trifluoromethyl)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]carbonyl]oxy]acetic acid 524.6 [M + Na].sup.+ 32o
##STR00343## cis, cis, single enantiomer
[[[cyclopropyl[cis,cis-4-(4- ethylbenzoyl)-2,3,3a,4,9,9a-
hexahydro-1H- cyc!openta[b]quinolin-9- yl]amino]carbonyl]oxy]acetic
acid 462.7 32P ##STR00344## cis, cis, single enantiomer
[[[cyclopropyl[cis,cis-4-(3,4- difluorobenzoyl)-2,3,3a,4,9,9a-
hexahydro-1H- cyclopenta[b]quinolin-9- yl]amino]carbonyl]oxy]acetic
acid 470.7 32Q ##STR00345## cis, cis, single enantiomer
[[[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-(2-
naphthalenylcarbonyl)-1H- cyclopenta[b]quinolin-9-
yl]amino]carbonyl]oxy]acetic acid 484.7 32R ##STR00346## cis, cis,
single enantiomer [[[cyclopropyl[cis,cis-4-(3,5-
difluorobenzoyl)-2,3,3a,4,9,9a- hexahydro-1H-
cyclopenta[b]quinolin-9- yl]amino]carbonyl]oxy]acetic acid 470.6
32S ##STR00347## cis, cis, single enantiomer
[[[cyclopropyl[cis,cis-4-(3- fluorobenzoyl)-2,3,3a,4,9,9a-
hexahydro-1H- cyclopenta[b]quinolin-9- yl]amino)carbonyl]oxy]acetic
acid 453.7 32T ##STR00348## 3aS,9R,9aR, single enantiomer
[[[cyclopropyl[(3aS,9R,9aR)-7- fluoro-2,3,3a,4,9,9a-hexahydro-
4-[4- (trifluoromethoxy)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]carbonyl]oxy]acetic acid 536.6 32U ##STR00349## cis, cis,
single enantiomer deuterated-[[[cyclopropyl[cis,
cis-2,3,3a,4,9,9a-hexahydro-4- [4-(trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9-yl- (d)]amino]carbonyl]oxy]acetic acid
520
Example 33
Preparation of Enantiopure 4-(Phenylmethyl)
cis,cis-[[(2(S)-carboxy-1-azetidinyl)carbonyl]cyclopropylamino]-1,2,3,3a,-
9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate (33)
##STR00350##
[0618] To a solution of the enantiopure amine 1E (0.05 g, 0.138
mmol) in anhydrous dichloromethane (5 mL) was added phosgene (0.1
mL, 1 M solution) and triethylamine (0.04 mL). The reaction mixture
was stirred for two hours and evaporated to dryness. The residue
was redissolved in dichloromethane (5 mL) and treated with the
amino acid (S)-azetidine-2-carboxylic acid (28 mg) and
triethylamine (0.074 mL) and stirred over night. The reaction
mixture was acidified with 1 N HCl, extracted with ethyl acetate,
and purified by reversed phase HPLC to give compound 33 (0.055 g,
82%). [M+H].sup.+=490.3.
Example 34
Preparation of Enantiopure 4-(phenylmethyl)
(3aS,9R,9aR)-[[(3-carboxy-1-azetidinyl)carbonyl]cyclopropylamino]-7-fluor-
o-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate
(34)
##STR00351##
[0620] The enantiopure amine 34A was prepared from compound 17C
(after chiral HPLC, the stereochemistry was confirmed by conversion
to 17D) using a similar procedure as Example 22 to introduce the
Cbz group and Example 1, step 5. The solution of amine 34A (38 mg,
0.1 mmol) and DIPEA (40 .mu.L, 0.2 mmol) in CH.sub.2Cl.sub.2 (1 mL)
was cooled in an ice-H.sub.2O bath, (COCl).sub.2 in toluene (20%
solution) (86 .mu.L, 0.15 mmol) was added. The mixture was kept
stirring at 0.degree. C. for 2 hrs, then rt for 15 mins, the
mixture was concentrated, the residue was taken up in THF (2 mL),
azetidine-3-carboxylic acid (30 mg, 0.3 mmol) and NaH (24 mg, 0.6
mmol) were added, respectively. The resultant mixture was kept
stirring at rt overnight. EtOAc (10 mL) was added to the mixture,
followed by the H.sub.2O (5 mL). The organic layer was washed with
H.sub.2O (2 mL), and the combined aqueous layer was acidified with
2 N HCl to pH .about.2-3, extracted with Et.sub.2O (2.times.5 mL).
The combined ether layer was dried over MgSO.sub.4 and
concentrated. The residue was purified via reverse phase HPLC, to
obtain 4-(phenylmethyl)
(3aS,9R,9aR)-[[(3-carboxy-1-azetidinyl)carbonyl]cyclopropylamino]-7-fluor-
o-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate
34 as a white solid, 25 mg; [M+H].sup.+508.1. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. ppm: 7.36 (m, 5H); 6.86 (m, 1H); 6.69 (m, 1H);
5.26 (d, J=13 Hz, 1H); 5.17 (d, J=13 Hz, 1H); 5.02 (m, 1H); 4.86
(m, 1H); 4.26 (m, 4H); 3.41 (m, 1H); 2.97 (m, 1H); 2.52 (m, 1H);
2.10 (m, 1H); 1.93 (m, 1H); 1.55 (m, 1H); 1.42 (m, 2H); 1.20-0.97
(m, 4H); 0.79 (m, 1H).
Example 35
Preparation of
N-[[Cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)be-
noyl]-1H-cyclopenta[b]quinolin-9-yl]amino]carbonyl]-N-methylglycine
(35)
Step 1
##STR00352##
[0622] Triphosgene (1.8 g, 6.1 mmol) was added to a mixture of
amine 1E (2.0 g, 5.5 mmol), and triethylamine (0.92 mL, 6.6 mmol)
in dry DCM (18 mL) at 0.degree. C. The reaction mixture was stirred
at room temperature under nitrogen for 15 minutes, and concentrated
to dryness. NaH (0.27 g, 10.6 mmol) was added to a mixture of
sarcosine methyl ester hydrochloride (1.54 g, 11.0 mmol) in THF (18
mL) at 0.degree. C. under nitrogen. The resulting mixture was
stirred at 0.degree. C. for 2 hours, and at room temperature
overnight. Water and EtOAc were added. The aqueous layer was
separated and extracted with EtOAc. The organic extracts were
combined, washed with brine, dried (MgSO.sub.4), filtered and
concentrated. The residue was purified by silica gel column
chromatography (eluted with 10% ethyl acetate-hexane, to 40% ethyl
acetate in hexane) to afford pure product urea ester 35A (2.57 g,
5.23 mmol).
Step 2
##STR00353##
[0624] 10% Pd on carbon (2.0 g) was added to the solution of urea
ester 35A (2.57 g, 5.22 mmol) in EtOH (17 mL). The reaction mixture
was stirred under a balloon of hydrogen at room temperature for 1
h. The reaction mixture was filtered though a pad of Celite.RTM.,
and the filtrate was concentrated. The residue was purified by
silica gel column chromatography (eluted with 10% ethyl acetate in
hexane) to afford pure urea amine 35B (0.43 g, 1.2 mmol).
Step 3
##STR00354##
[0626] 4-(Trifluoromethoxy)benzoyl chloride (50 mg, 0.22 mmol) was
added to a solution of urea amine 35B (40 mg, 0.11 mmol) and
triethylamine (34 mg, 0.34 mmol) in DCM (2 mL) The reaction mixture
was stirred at room temperature for 1 h. Water was added. The
aqueous layer was separated and extracted with DCM. The organic
extracts were combined, washed with brine, dried (MgSO.sub.4),
filtered and concentrated. The residue was purified by preparative
thin layer chromatography (eluted with 50% ethyl acetate-hexane) to
afford the urea amide 35C (30 mg, 0.055 mmol).
Step 4
N-[[Cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)ben-
zoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]carbonyl]-N-methylglycine
(35)
##STR00355##
[0628] Lithium hydroxide monohydrate (18.2 mg, 0.43 mmol) was added
to a solution of urea amide (30 mg, 0.055 mmol) in THF (0.5 mL) and
H.sub.2O (0.5 mL). The reaction mixture was stirred at room
temperature over night. 1 N HCl (aq.) was added to the reaction
mixture. The aqueous layer was separated and extracted with EtOAc.
The organic extracts were combined, washed with brine, dried
(MgSO.sub.4), filtered and concentrated to give acid 35 (20 mg,
0.038 mmol). [M+H].sup.+=532.3.
[0629] The compounds in the following table were prepared following
protocols similar to those described in Example 35.
TABLE-US-00017 Stereo # Structure designation Name [M + H].sup.+
35D ##STR00356## racemic, cis, cis N-[[[cis,cis-4-benzoyl-
2,3,3a,4,9,9a-hexahydro-1H- cyclopenta[b]quinolin-9-
yl]cyclopropylamino]carbonyl]- N-methylglycine 448.2 35E
##STR00357## racemic, cis, cis S at acid side chain
N-[[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[4-
(trifluoromethoxy)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]carbonyl]-1-alanine 532.3 35F ##STR00358## racemic, cis,
cis R at acid side chain N-[[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]carbonyl]-D-alanine 532.3 35G
##STR00359## racemic, cis, cis N-[[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]carbonyl]-beta- alanine 532.3 35H
##STR00360## cis, cis, single enantiomer HPLC peak 1
N-[[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[4-
(trifluoromethoxy)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]carbonyl]-N- methylglycine 532.3 35i ##STR00361## cis,
cis, single enantiomer HPLC peak 2 N-[[cyclopropyl[cis,cis-
23,3a,4,9,9a-hexahydro-4-[3- (trifluoromethoxy)benzoyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]carbonyl]-N- methylglycine 532.3
35J ##STR00362## cis, cis,, single enantiomer
N-[[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-(2-
thienylcarbonyl)-1H- cyclopenta[b]quinolin-9- yl]amino]carbonyl]-N-
methylglycine 454.2 35K ##STR00363## cis, cis racemic
N-[[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[4-
(trifluoromethoxy)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]carbonyl]glycine 518.3
Example 36
Preparation of Racemic
4-{[cis-4-(5-Benzyl-1,3,4-oxadiazol-2-yl)-2,3,3a,4,9,9a-hexahydro-1H-cycl-
openta[b]quinolin-9-yl](cyclopropyl)amino}-4-oxobutanoic acid
(36)
Step 1
##STR00364##
[0631] Triphosgene (589 mg, 1.99 mmo, 0.40 equiv) was added to a
solution of methyl
4-{cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]-
quinolin-9-yl]amino}-4-oxobutanoate 14A (1.7 g, 5.0 mmol, 1 equiv)
and N, N-diisopropylethylamine (1.04 mL, 5.96 mmol, 1.2 equiv) in
dichloromethane (25 mL) at 23.degree. C. The reaction mixture was
stirred at 23.degree. C. for 15 min, and then was partitioned
between ethyl acetate and saturated aqueous sodium bicarbonate
solution. The organic layer was washed with saturated aqueous
sodium chloride solution, and the washed solution was dried over
sodium sulfate. The dried solution was filtered, and the filtrate
was concentrated to afford methyl
4-[[cis,cis-4-(chlorocarbonyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]qu-
inolin-9-yl](cyclopropyl)amino]-4-oxobutanoate, which was used in
subsequent steps without further purification. [M+H].sup.+:
405.1.
Step 2
##STR00365##
[0633] 2-Phenylacetohydrazide (26.5 mg, 0.177 mmol, 1.1 equiv) was
added to a solution of methyl 4-[[cis,
cis-4-(chlorocarbonyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-
-yl](cyclopropyl)amino]-4-oxobutanoate 36D (65 mg, 0.16 mmol, 1
equiv) and N,N-diisopropylethylamine (0.033 mL, 0.19 mmol, 1.2
equiv) in tetrahydrofuran (0.80 mL), and the reaction mixture was
warmed to 60.degree. C. After stirring for 2 h at 60.degree. C.,
the reaction mixture was cooled to 23.degree. C., and
3,3,3-triethyl-1-(methoxycarbonyl)diazathian-3-ium-1-ide
2,2-dioxide (Burgess reagent, 77 mg, 0.32 mmol, 2.0 equiv) was
added. The reaction vessel was sealed, and heated in a microwave at
120.degree. C. for 15 min. The reaction mixture was then cooled to
23.degree. C., and aqueous sodium hydroxide solution (1 N, 8 equiv)
was added. The reaction mixture was then heated in a microwave at
110.degree. C. for 30 min. After cooling to 23.degree. C., dimethyl
sulfoxide (1 mL) was added, and the mixture was purified by
reverse-phase HPLC (10% acetonitrile-water, grading to 90%
acetonitrile-water, with 0.1% trifluoroacetic acid in both the
acetonitrile and water) to afford 36 as a white solid. [M+H].sup.+:
487.3.
[0634] The following examples were prepared from methyl
4-[[cis,cis-4-(chlorocarbonyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]qu-
inolin-9-yl](cyclopropyl)amino]-4-oxobutanoate using procedures
similar to Example 36, Step 2, and the appropriate hydrazides:
TABLE-US-00018 Stereo # Structure designation Name [M + H].sup.+
36A ##STR00366## racemic, cis, cis racemic 4-
{cyclopropyl[cis,cis-4- (5-phenyl-1,3,4- oxadiazol-2-yl)-
2,3,3a,4,9,9a- hexahydro-1H- cyclopenta[b]quinolin- 9-yl]amino}-4-
oxobutanoic acid 473.2 36B ##STR00367## racemic, cis, cis racemic
4- (cyclopropyl{cis,cis-4- [5-(4-fluorophenyl)-
1,3,4-oxadiazol-2-yl]- 2,3,3a,4,9,9a- hexahydro-1H-
cyclopenta[b]quinolin- 9-yl}amino)-4- oxobutanoic acid 491.2 36C
##STR00368## racemic, cis, cis racemic 4- {cyclopropyl[cis,cis-4-
{5-[4- (trifluoromethoxy) phenyl]-1,3,4- oxadiazol-2-
yl}-2,3,3a,4,9,9a- hexahydro-1H- cyclopenta[b]quinolin-
9-yl]amino}-4- oxobutanoic acid 557.2
Example 37
Preparation of Racemic
({Cyclopropyl[cis,cis-4-(5-phenyl-1,3,4-oxadiazol-2-yl)-2,3,3a,4,9,9a-hex-
ahydro-1H-cyclopenta[b]quinolin-9-yl]carbamoyl}oxy)acetic acid
(37)
##STR00369##
[0636] Compound 37 was prepared from 2-(benzyloxy)ethyl
cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl-
]carbamate 29B, using a sequence of procedures similar to Example
36, Step 1, Example 36, Step 2 (without the hydrolysis step),
Example 29, Step 4, and Example 30. [M+H].sup.+: 475.2.
Example 38
Preparation of Racemic
[[[Cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[5-[3-(trifluoromethoxy)-
phenyl]-1,3,4-oxadiazol-2-yl]-1H-cyclopenta[b]quinolin-9-yl]amino]carbonyl-
]oxy]acetic acid (38)
Step 1
##STR00370##
[0638] Triphosgene (41 mg, 0.32 mmol) was added to a mixture of
amine 38A (0.23 g, 0.67 mmol, prepared from 1E following a similar
procedure as in Example 32, steps 1 and 2, and Example 14, step 1)
and i-Pr.sub.2NEt (0.14 mL, 0.80 mmol) in DCM (4 mL). The resulting
mixture was stirred at room temperature for 1.5 h, and partitioned
in EtOAc and water. The organic layer was separated, washed with
brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The
residue was taken up with THF (2 mL), and treated with Hunigs base
(0.14 mL, 0.80 mmol) and anhydrous hydrazine (0.05 mL, 1.59 mmol).
The resulting mixture was stirred at room temperature overnight.
The volatiles were removed. The residue was taken up with DCM (4
mL), and treated with Et.sub.3N (0.14 mL, 1.0 mmol), DMAP (30 mg,
0.21 mmol), followed by 3-(trifluoromethoxy)benzoyl chloride (185
mg, 0.82 mmol). The resulting mixture was stirred at room
temperature overnight. DCM was added and washed with 1 N HCl. The
aqueous layer was separated and extracted with DCM. The organic
extracts were combined, washed with brine, dried (MgSO.sub.4), and
concentrated. The residue was purified by a silica gel
chromatography (eluted with EtOAc-hexanes, 1:1 to 2:1) to give the
desired product hydrazine amide 38B.
Step 2
##STR00371##
[0640] Starting material hydrazine amide 38B (50 mg) was treated
with POCl.sub.3 (1.5 mL) and heated at 120.degree. C. for 2 h. The
reaction mixture was cooled to room temperature and poured into DCM
and washed with 1 N NaOH. The aqueous layer was extracted with DCM.
The organic extracts were combined, washed with brine, and dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified by preparative thin-layer-chromatography (eluted with 1:30
7 N NH.sub.3/MeOH-DCM), to give desired product oxadiazole ester
38C (27 mg).
Step 3
[[[Cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[5-[3-(trifluoromethoxy)p-
henyl]-1,3,4-oxadiazol-2-yl]-1H-cyclopenta[b]quinolin-9-yl]amino]carbonyl]-
oxy]acetic acid (38)
##STR00372##
[0642] Starting material oxadiazole ester 38C (29 mg) in THF (0.5
mL) was treated with 2 N LiOH (0.5 mL). The resulting mixture was
stirred at room temperature for 3 h. The reaction mixture was
treated with 1 N HCl (aq.) until pH reached 6, and was extracted
with DCM. The organic extracts were combined, washed with brine,
dried (MgSO.sub.4), filtered and concentrated in vacuo to give
desired product 38, [M+H].sup.+=559.3.
[0643] The compounds in the following table were prepared following
a similar protocol as described in Example 38.
TABLE-US-00019 Stereo # Structure designation Name [M + H].sup.+
38D ##STR00373## racemic, cis, cis [[[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[5- [[4- (trifluoromethoxy)phenyl]
methyl]-1,3,4-oxadiazol-2-yl]-1H- cyclopenta[b]quinoline-9-
yl]amino]carbonyl]oxy]acetic acid 573.2 38E ##STR00374## racemic,
cis, cis [[[cyclopropyl[cis,cis-4-[5-[(4-
fluorophenyl)methyl]-1,3,4- oxadiazol-2-yl]-2,3,3a,4,9,9a-
hexahydro-1H- cyclopenta[b]quinoline-9-
yl]amino]carbonyl]oxy]acetic acid 507.2 38F ##STR00375## single
enantiomer, cis, cis peak 1 from chiral HPLC
[[[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[5- [[4-
(trifluoromethoxy)phenyl]methyl]- 1,3,4-oxadiazol-2-yl]-1H-
cyclopenta[b]quinoline-9- yl]amino]carbonyl]oxy]acetic acid 573 38G
##STR00376## single enantiomer, cis, cis peak 2 from chiral HPLC
[[[cyclopropyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-[5- [[4-
(trifluoromethoxy)phenyl] methyl]-1,3,4-oxadiazol-2-yl]-1H-
cyclopenta[b]quinoline-9- yl]amino]carbonyl]oxy]acetic acid 573
Example 39
Preparation of Racemic
2-[{cis,cis-4-[(Benzyloxy)carbonyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta-
[b]quinolin-9-yl}(ethyl)amino]-1,3-thiazole-4-carboxylic acid
(39)
Step 1
Benzyl
cis,cis-9-{[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]amino}-1,2,3,3a,9,9-
a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate (39A)
##STR00377##
[0645] Benzyl
cis,cis-9-amino-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carbo-
xylate (2, 104 mg, 0.323 mmol, 1 equiv),
Tris(dibenzylideneacetone)dipalladium (44 mg, 0.048 mmol, 0.15
equiv), dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (57
mg, 0.15 mmol, 0.45 equiv), and ethyl
2-bromo-1,3-thiazole-4-carboxylate (152 mg, 0.645 mg, 2.0 equiv)
were combined in a microwave tube. Dioxane (3.2 mL) was added to
the microwave tube, and nitrogen gas was bubbled through the
reaction mixture for 5 min. Lithium bis(trimethylsiyl)amide in
tetrahydrofuran (1.0 M, 0.484 mL, 0.484 mmol, 1.5 equiv) was then
added, and the reaction mixture was heated to 110.degree. C. After
stirring at 110.degree. C. for 25 min, the heating bath was removed
and the reaction mixture was partitioned between ethyl acetate and
water. The organic layer was washed with saturated aqueous sodium
chloride solution, and the washed solution was dried over sodium
sulfate. The dried solution was filtered, and the filtrate was
concentrated. The residue was purified by flash-column
chromatography (5% ethyl acetate-hexanes, grading to 65% ethyl
acetate-hexanes) to afford 39A [M+H].sup.+: 478.1.
Step 2
Benzyl
cis,cis-9-[[4-(ethoxycarbonyl)-1,3-thiazol-2-yl](ethyl)amino]-1,2,3-
,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate
(39B)
##STR00378##
[0647] Lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M,
0.095 mL, 0.095 mmol, 1.0 equiv) was added to a solution of 39A (38
mg, 0.080 mmol, 1 equiv) in tetrahydrofuran (0.80 mL) at 0.degree.
C. The reaction mixture was stirred at 0.degree. C. for 10 min, and
then iodoethane (0.026 mL, 0.32 mmol, 4.0 equiv) was added. The
cooling bath was removed, and the reaction mixture was stirred at
23.degree. C. After stirring at 23.degree. C. for 3 h, the
temperature was increased to 40.degree. C., and the reaction
mixture was stirred for 16 h. After cooling to 23.degree. C., the
reaction mixture was partitioned between ethyl acetate and water.
The organic layer was washed with saturated aqueous sodium chloride
solution, and the washed solution was dried over sodium sulfate.
The dried solution was filtered, and the filtrate was concentrated.
The residue was purified by flash-column chromatography (10% ethyl
acetate-hexanes, grading to 40% ethyl acetate-hexanes) to afford
39B. [M+H].sup.+: 506.2.
Step 3
2-[{cis,cis-4-[(benzyloxy)carbonyl]-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[-
b]quinolin-9-yl}(ethyl)amino]-1,3-thiazole-4-carboxylic acid
(39)
##STR00379##
[0649] Compound 39 was prepared from benzyl
cis,cis-9-[[4-(ethoxycarbonyl)-1,3-thiazol-2-yl](ethyl)amino]-1,2,3,3a,9,-
9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxylate 39B using a
procedure similar to that used in Example 14, Step 3. [M+H].sup.+:
478.1.
Example 40
Preparation of Racemic
2-[Ethyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]--
1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxazolecarboxylic acid
(40)
Step 1
##STR00380##
[0651] Amine 40A (100 mg, 0.26 mmol, prepared from 1D following a
similar procedure as in Example 14, step 1 and 2, and Example 2),
ethyl 2-chlorooxazole-4-carboxylate (120 mg, 0.68 mmol) and
iPr.sub.2NEt were dissolved in dioxane (8 mL) and heated in a
sealed tube at 130.degree. C. overnight. The resulting mixture was
cooled to room temperature, diluted with EtOAc and washed with 1 N
HCl. The aqueous layer was separated and extracted with EtOAc. The
organic extracts were combined and washed with brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified with preparative thin-layer-chromatography (eluted with
1:30 7 N NH.sub.3/MeOH:DCM), to give the desired product amino
oxazole 40B (71 mg).
Step 2
##STR00381##
[0653] Starting material amino oxazole 40B (40 mg, 0.078 mmol) was
dissolved in DMF (1 mL), treated with NaH (20 mg, 10 mmol). The
mixture was stirred at room temperature for 1 h, and EtI (0.06 mL,
0.75 mmol) was added. The resulting mixture was stirred at room
temperature overnight, and diluted with EtOAc and washed with
water. The aqueous layer was separated and extracted with EtOAc.
The organic extracts were combined and washed with brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo. The residue was
purified with preparative thin-layer-chromatography (eluted with
1:4 EtOAc-hexanes), to give the desired product ethyl amino oxazole
40C (28 mg).
Step 3:
2-[Ethyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)be-
nzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxazolecarboxylic
acid (40)
##STR00382##
[0655] Starting material ethyl amino oxazole 40C (28 mg) in THF
(0.5 mL) was treated with 2 N LiOH (0.5 mL). The resulting mixture
was stirred at room temperature for 3 h. The reaction mixture was
treated with 1 N HCl (aq.) until pH reached 6, and was extracted
with DCM. The organic extracts were combined, washed with brine,
dried (MgSO.sub.4), filtered and concentrated in vacuo to give the
desired product 40, [M+H].sup.+=516.
Example 41
Preparation of Racemic
5-[Cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)ben-
zoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-1,3,4-oxadiazole-2-acetic
acid (41)
Step 1
##STR00383##
[0657] Triphosgene (148 mg, 0.50 mmol) was added to a mixture of
starting amine 41A (200 mg, 0.48 mmol, prepared from 1D following a
similar procedure as in Example 14, step 1 and 2, and Example 6,
step 4) and iPr.sub.2NEt (0.1 mL, 0.57 mmol) in DCM (4 mL). The
resulting mixture was stirred at room temperature overnight.
iPr.sub.2NEt (0.1 mL, 0.57 mmol) was added followed by anhydrous
hydrazine (0.1 mL. 3.2 mmol). The resulting mixture was stirred at
room temperature for 2 h and concentrated in vacuo. The residue was
purified with silica gel chromatogaphy (eluted with 1:50 7 N
NH.sub.3/MeOH-DCM), to give
N-cyclopropyl-N-[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)b-
enzoyl]-1H-cyclopenta[b]quinolin-9-yl]hydrazine carboxamide
41B.
Step 2
##STR00384##
[0659] Starting material hydrazine 41B (170 mg, 0.36 mmol) and
iPr.sub.2NEt (0.1 mL, 0.57 mmol) were dissolved in DCM (4 mL) and
cooled to -4.degree. C. To the mixture, ethyl malonyl chloride (136
mg, 0.90 mmol) was added. The resulting mixture was stirred at room
temperature overnight. DCM and 0.1 N HCl were added. The aqueous
layer was separated and extracted with DCM. The organic extracts
were combined and washed with brine, dried (MgSO.sub.4), filtered
and concentrated in vacuo. The residue was purified with
preparative thin-layer-chromatography (eluted with 1:50 7 N
NH.sub.3/MeOH-DCM), to give desired product hydrazine amide 41C
(200 mg).
Step 3
5-[Cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benz-
oyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-1,3,4-oxadiazole-2-acetic
acid (41)
##STR00385##
[0661] The starting material hydrazine amide 41C (214 mg, 0.36
mmol) was treated with POCl.sub.3 (2 mL), and heated at 120.degree.
C. for 2 h. The reaction mixture was cooled to room temperature and
poured into 4 N NaOH. The aqueous layer was separated and extracted
with DCM. The organic extracts were combined and washed with brine,
dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue
was purified with preparative thin-layer-chromatography (eluted
with 1:50 7 N NH.sub.3/MeOH-DCM), to give desired product 41D (36
mg). The oxadiazole ester 41D (31 mg) in THF (0.5 mL) was treated
with 2 N LiOH (0.5 mL). The resulting mixture was stirred at room
temperature for 3 h and then treated with 1 N HCl (aq.) until the
pH turned 6. The aqueous layer separated and extrated with DCM. The
organic extracts were combined, washed with brine, dried
(MgSO.sub.4), filtered and concentrated in vacuo to give desired
product 41, [M+H].sup.+=543.3.
Example 42
Preparation of Racemic
N-Cyclopropyl-N-[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)b-
enzoyl]-1H-cyclopenta[b]quinolin-9-yl]-2H-tetrazole-5-propanamide
(42)
Step 1
##STR00386##
[0663] To a solution of the amine 41A (0.050 g, 0.119 mmol) in
anhydrous dioxane (5 mL) was added 3-bromopropionylchloride (0.81
mg, 0.48 mmol) and Hunigs base (0.084 mL, 0.48 mmol) at 0.degree.
C. The mixture was stirred at room temperature for two hours.
Removal of solvent and chromatographic purification using ethyl
acetate/hexane gave the bromoamide 42A as a white solid (0.04 g,
71%)
Step 2
3-Cyano-N-cyclopropyl-N-[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorome-
thoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]propanamide (42B)
##STR00387##
[0665] A mixture of bromo amide 42A and potassium cyanide in DMF
was stirred at room temperature and heated to 65.degree. C.
overnight. The reaction mixture was taken into a separation funnel,
washed with water, brine and dried over anhydrous sodium sulfate.
Filtration and removal of the solvent gave the crude cyanide (42B),
which was used in the next step without purification (0.032 mg,
76%).
Step 3:
N-Cyclopropyl-N-[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluorome-
thoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]-2H-tetrazole-5-propanamide
(42)
##STR00388##
[0667] To a solution of the nitrile (42B) (0.08 g, 0.16 mmol) and
trimethylsilylazide
[0668] (0.32 mmol) in toluene (5 mL) was added dibutyltin oxide
(0.016 mmol), and the mixture was heated for two days until the
nitrile was consumed. The reaction mixture was concentrated and the
residue was dissolved in methanol and concentrated. The residue was
partitioned between ethyl acetate and 10% sodium bicarbonate
solution. The organic phase was extracted with an additional 10%
sodium bicarbonate solution. The combined aqueous phase was
acidified to pH 2 with 10% HCl and then extracted with ethyl
acetate. The tetrazole product 42 was purified by reverse phase
HPLC. (0.040 g, 45%), [M+H].sup.+=541.3.
Example 43
Preparation of Enantiopure 4-(Phenylmethyl)
deuterated-cis,cis-9-[(3-carboxypropyl)cyclopropylamino]-1,2,3,3a,9,9a-he-
xahydro-4H-cyclopenta[b]quinoline-4-carboxylate-(9D) (43)
Step 1
##STR00389##
[0670] Titanium (IV) ethoxide (4.84 mL, 23.3 mmol, 2.50 equiv) was
added to a solution of enantiopure benzyl
cis,cis-9-oxo-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carboxy-
late 1D' (3.00 g, 9.34 mmol, 1 equiv, enantiomer of 1D after chiral
HPLC) and cyclopropylamine (1.83 mL, 23.3 mmol, 2.50 equiv) in
tetrahydrofuran. The reaction vessel was sealed and heated to
60.degree. C. After stirring for 16 h, the reaction mixture was
cooled to 23.degree. C. and poured over saturated aqueous sodium
chloride solution (50 mL). The biphasic mixture was stirred for 5
min, then filtered through Celite.RTM. with the aid of ethyl
acetate. The filtrate was partitioned between ethyl acetate and
brine, and the organic phase was then dried over sodium sulfate.
The dried solution was filtered, and the filtrate was concentrated.
The residue was dissolved in methanol (30 mL) and tetrahydrofuran
(60 mL), and the solution was cooled to 0.degree. C. Sodium
borodeuteride (855 mg, 22.6 mmol, 2.50 equiv) was added to the
cooled solution. After stirring for 15 min at 0.degree. C., the
cooling bath was removed, and the reaction mixture was partitioned
between ethyl acetate and saturated aqueous sodium bicarbonate
solution. The organic layer was washed with saturated aqueous
sodium chloride solution, and the washed solution was dried over
sodium sulfate. The dried solution was filtered, and the filtrate
was concentrated to afford the desired product 43A. [M+H].sup.+:
364.3.
Step 2: Enantiopure 4-(Phenylmethyl)
deuterated-cis,cis-9-[(3-carboxypropyl)cyclopropylamino]-1,2,3,3a,9,9a-he-
xahydro-4H-cyclopenta[b]quinoline-4-carboxylate-(9D) (43)
##STR00390##
[0672] Enantiopure amine 43A (100 mg) and aldehyde (200 mg) in DCE
were treated with NaBH(OAc).sub.3 (500 mg) at room temperature
overnight. The reaction mixture was then diluted with EtOAc (50
mL), washed with aq. NaHCO.sub.3 (30 mL) and brine (30 mL). The
organic layer was dried with Na.sub.2SO.sub.4, concentrated by
rotovap. The residue was dissolved in MeOH/THF (3/3 mL) and treated
with 1 N aq. NaOH (3 mL) and the reaction mixture was stirred at
room temperature for 3 hours. The crude product was directly
purified by reverse phase HPLC to give the product 43 (100 mg, 85%)
as white foam, [M+H].sup.+=450. .sup.1H NMR (500 MHz, CD.sub.3OD)
.delta. ppm: 7.52-7.30 (m, 9H), 5.28 (d, J=12.0 Hz, 1H), 5.23 (d,
J=12.5 Hz, 1H), 5.06 (m, 1H), 3.69-3.59 (m, 3H), 3.33 (m, 1H), 3.17
(m, 1H), 2.46 (dd, J=6.5, 7.0 Hz, 2H), 2.34 (m, 1H), 2.26 (m, 1H),
2.12 (m, 1H), 1.76 (m, 1H), 1.54-1.42 (m, 2H), 1.35 (m, 1H),
1.25-1.10 (m, 4H), 0.99 (m, 1H).
[0673] The compounds in following table were synthesized by as
similar route as that described in Example 43, wherein the reducing
agent in Step 1 was NaBH.sub.4, instead of NaBD.sub.4.
TABLE-US-00020 Stereo # Structure designation Name [M + H].sup.+
43B ##STR00391## cis, cis, single enantiomer 4-((cis,cis-3-
(benzyloxycarbonyl)-5-fluoro- 1,2,2a,3,8,8a- hexahydrocyclobuta[b]
quinolin-8- yl)(cyclopropyl)amino)butanoic acid 453 43C
##STR00392## cis, cis, single enantiomer 4-((cis,cis-3-
(benzyloxycarbonyl)-5-fluoro- 1,2,2a,3,8,8a- hexahydrocyclobuta[b]
quinolin-8-yl)(oxetan-3- yl)amino)butanoic acid 491 [M +
Na].sup.+
Example 44
Preparation of Racemic
4-[Cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)ben-
zoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]butanoic acid (44)
##STR00393##
[0675] Amine 41A (100 mg, racemic) and aldehyde (200 mg) in DCE
were treated with NaBH(OAc).sub.3 (500 mg) at room temperature
overnight. The reaction mixture was then diluted with EtOAc (50
mL), washed with aq. NaHCO.sub.3 (30 mL) and brine (30 mL). The
organic layer was dried with Na.sub.2SO.sub.4, and then
concentrated on a rotary evaporator. The residue was dissolved in
MeOH/THF (3/3 mL) and treated with 1 N aq. NaOH (3 mL) and the
reaction mixture was stirred at room temperature for 3 hours. The
crude was directly purified by reverse phase HPLC to give the
product 44 (100 mg, 85%) as a white foam, [M+H].sup.+=503. .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. ppm: 7.56 (d, J=8.5 Hz, 2H), 7.51
(d, J=8.0 Hz, 1H), 7.29 (dd, J=7.5, 7.5 Hz), 7.23 (d, J=7.5 Hz,
2H), 7.16 (d, J=7.5 Hz, 1H), 7.12 (dd, J=7.0, 7.5 Hz, 1H), 5.26
(br, 1H), 5.09 (s, 1H), 3.83-3.64 (m, 3H), 3.32 (m, 1H), 3.19 (m,
1H), 2.59 (ddd, J=5.5, 6.0, 18 Hz, 1H), 2.48-2.24 (m, 3H), 1.80 (m,
1H), 1.49-1.38 (m, 3H), 1.32-1.27 (m, 2H), 1.22-1.10 (m, 3H), 0.99
(m, 1H).
[0676] The compounds in following table were synthesized by a
similar route as described in Example 44.
TABLE-US-00021 Stereo # Structure designation Name [M + H].sup.+
44B ##STR00394## racemic, cis, cis 4-[[cis,cis-2,3,3a,4,9,9a-
hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]butanoic acid 463 44C
##STR00395## (racemic) cis, cis at 3a,9,9a, (racemic) trans at
cyclopropyl, trans-2-[[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]methyl] cyclopropanecarboxylic
acid 515 44D ##STR00396## cis, cis, single enantiomer
4-(cyclopropyl(cis,cis-5- fluoro-3-(4- (trifluoromethoxy)benzoyl)-
1,2,2a,3,8,8a- hexahydrocyclobuta[b] quinolin-8-yl)amino) butanoic
acid 507 44E ##STR00397## racemic, cis, cis
4-[[cis,cis-2,3,3a,4,9,9a- hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-9-
yl](phenylmethyl)amino] butanoic acid 553 44F ##STR00398## racemic,
cis, cis 4- [(cyclopropylmethyl)[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin-9- yl]amino]butanoic acid 517
Example 45
Preparation of Racemic
4-[[cis,cis-2,3,3a,4,9,9a-Hexahydro-4-[4-(trifluoromethoxy)benzoyl]-1H-cy-
clopenta[b]quinolin-9-yl]amino]-4-oxobutanoic acid (45)
##STR00399##
[0678] Methyl 4-chloro-4-oxobutanoate (0.2 mL, 2.2 equiv) was added
to a solution of amine 40A (200 mg, 1 equiv) and
N,N-diisopropylethylamine (0.2 mL, 3.00 equiv) in DCM (8 mL) at
23.degree. C. (used a 23.degree. C. water bath to control the
exotherm that was observed during the addition). The reaction
mixture was stirred for 1 h, and then it was partitioned between
ethyl acetate and aqueous hydrochloric acid solution (1 N). The
organic layer was washed sequentially with aqueous sodium hydroxide
solution (1 N) and saturated aqueous sodium chloride solution, and
the washed organic layer was dried over sodium sulfate. The dried
solution was filtered, and the filtrate was concentrated. The
residue was purified by flash-column chromatography (20% ethyl
acetate-hexanes, grading to ethyl acetate) to afford the methyl
ester of the desired product.
[0679] Aqueous sodium hydroxide solution (1 N, 3 mL) was added to a
solution of the ester (80 mg,) in THF/MeOH (3/3 mL). The reaction
was stirred at room temperature overnight. The mixture was purified
by reverse phase HPLC to give the desired acid 45,
[M+H].sup.+=477.
Example 46
Preparation of Enantiopure
4-[Cyclopropyl[cis,cis-4-[2-[(4-fluorophenyl)amino]-2-oxoethyl]-2,3,3a,4,-
9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic
acid (46)
Step 1
##STR00400##
[0681] Cs.sub.2CO.sub.3 (110 mg, 0.337 mmol) was added to a
solution of enantiopure amine 14A'' (60 mg, 0.168 mmol, prepared in
the same manner as compound 14A' with an ethyl ester.) in DMF (2
mL), and the mixture was stirred at rt for 30 mins. Benzyl
2-bromoacetate (170 .mu.L, 0.84 mmol) was added. The resultant
mixture was placed in a Biotage microwave reactor: T=120.degree. C.
t=1 h, Absorption=High. EtOAc (10 mL) was added to the cooled
mixture, followed by H.sub.2O (10 mL). The organic layer was washed
with brine (10 mL), dried over MgSO.sub.4 and concentrated. The
residue was purified via silica gel column chromatography
(EtOAc/Hexane=1:2), to obtain enantiopure benzyl ester 46A as a
brown syrup, 32 mg; [M+H].sup.+=505.
Step 2
##STR00401##
[0683] 10% Pd on C (6 mg) was added to a solution of benzyl ester
(26 mg, 0.05 mmol) in a mixed solvent of EtOH (3 mL)--EtOAc (1 mL).
The resultant mixture was degassed and filled with H.sub.2
(balloon, 3 times), the mixture was kept under H.sub.2, stirring at
rt for 2 h. The catalyst was filtered off and washed with EtOH. The
filtrate was concentrated to obtain a clear syrup as the acid, 17
mg; [M+H].sup.+=415.
Step 3
##STR00402##
[0685] The above obtained enantiopure acid 46B (17 mg, 0.041 mmol),
4-fluoroaniline (7 .mu.L, 0.082 mmol), HOBt (11 mg, 0.082 mmol),
EDC (16 mg, 0.082 mmol) and DIPEA (22 .mu.L, 0.123 mmol) were mixed
in CH.sub.2Cl.sub.2 (1 mL), and the resultant mixture was kept
stirring at rt overnight. The mixture was concentrated, and the
residue was purified via silica gel column chromatography
(EtOAc/Hexane=1:1) to obtain amide 46C as a clear syrup, 17 mg;
[M+H].sup.+=508.
Step 4
##STR00403##
[0687] The above obtained amide was converted to the desired
enantiopure acid 46 using a similar procedure to that described in
Example 14, [M+H].sup.+=479.7. .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. ppm: 7.54 (m, 2H); 7.10 (m, 1H); 7.01 (m, 2H); 6.75 (m,
1H); 6.52 (m, 1H); 3.93 (s, 2H); 3.76 (m, 2H); 3.05 (m 1H);
2.75.about.2.63 (m, 5H); 1.86 (m, 6H); 1.12.about.0.90 (m, 4H).
Example 47
Preparation of Racemic
4-[Acetyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]-
-1H-cyclopenta[b]quinolin-9-yl]amino]butanoic acid (47)
Step 1:
Cis,cis-2,3,3a,4,9,9a-hexahydro-n-(4-hydroxybutyl)-4-[4-(trifluoro-
methoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-amine (47A)
##STR00404##
[0689]
Cis,cis-2,3,3a,4,9,9a-hexahydro-n-(4-hydroxybutyl)-4-[4-(trifluorom-
ethoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-amine 47A was obtained
from 1D following the similar procedure as Example 14, step 1, 2 to
obtain ketone amide 47A' which was reacted with 4-hydroxybutyl
amine following similar procedure as Example 6, step 4.
Step 2:
N-[4-(Acetyloxy)butyl]-N-[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(tr-
ifluoromethoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]acetamide
(47B)
##STR00405##
[0691] To a solution of the amino alcohol 47A (0.312 g, 0.696 mmol)
in anhydrous dichloromethane (10 mL) was added acetyl chloride
(0.19 mL, 2.78 mmol) and Hunigs base (0.61 mL, 3.48 mmol) at
0.degree. C. The mixture was stirred at room temperature for six
hours. Removal of solvent and chromatographic purification using
ethyl acetate/hexane gave the amide 47B as the major product as a
white solid (0.3 g, 81%) and small amount of 47C.
Step 3:
N-[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoyl]-
-1H-cyclopenta[b]quinolin-9-yl]-N-(4-hydroxybutyl)acetamide
(47D)
##STR00406##
[0693] A solution of the acetate 47B (0.102 g, 0.19 mmol) in
methanol (5 mL) and water (1 mL) was treated with potassium
hydroxide (0.76 mmol) and refluxed for one hour. The reaction
mixture was concentrated and extracted with ethyl acetate, washed
with water, brine and dried over anhydrous sodium sulfate.
Filtration and removal of the solvent gave the crude alcohol 47D
which was used for the next step without purification (0.070 g,
75%).
Step 4:
4-[Acetyl[cis,cis-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)b-
enzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]butanoic acid (47)
##STR00407##
[0695] To a solution of the alcohol 47C (0.051 mmol) in carbon
tetrachloride/acetonitrile/water (2 mL, 2 mL, 3 mL) was treated
with sodium periodate followed by catalytic amount of
rutheniumchloride.trihydrate. The reaction mixture was stirred at
room temperature for two hours, 1 mL of saturated ammonium chloride
solution was added and filtered. The filtrate diluted with ethyl
acetate and taken into a separatory funnel, was washed with water,
brine and dried over anhydrous sodium sulfate. Removal of the
solvent gave the crude acid 47 which was purified by using reverse
phase HPLC. (0.015 mg, 60%). [M+H].sup.+=505.3
[0696] The compounds in the following table were prepared in a
similar procedure as showed above in Example 47.
TABLE-US-00022 Stereo # Structure designation Name [M + H].sup.+
47D ##STR00408## racemic, cis, cis 4-[benzoyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4-[4- (trifluoromethoxy)benzoyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]butanoic acid 567.3 47E
##STR00409## racemic, cis, cis 4-[[cis,cis-2,3,3a,4,9,9a-
hexahydro-4-[4- (trifluoromethoxy)benzoyl]-1H-
cyclopenta[b]quinolin-9-yl][4- (trifluoromethoxy)benzoyl]
amino]butanoic acid 651.4 47F ##STR00410## racemic, cis, cis
4-[[cis,cis-2,3,3a,4,9,9a- hexahydro-4-[4-
(trifluoromethoxy)benzoyl]-1H- cyclopenta[b]quinolin-9-yl](4-
methylbenzoyl)amino]butanoic acid 581.3 47G ##STR00411## racemic,
cis, cis 4-[[cis,cis-2,3,3a,4,9,9a- hexahydro-4-[4-
(trifluoromethoxy)benzoyl]-1H- cyclopenta[b]quinolin-9-yl](2-
methyl-1- oxopropyl)amino]butanoic acid 533.3
Example 48
Preparation of Enantiopure Ketone Intermediate Containing a
Bridgehead Methyl Group for Compounds 48 and 48C
##STR00412##
[0698] The ketone 25C' (0.5 g, 1.62 mmol, single enantiomer after
resolution of the racemate 25C via chiral HPLC) was taken up in 5
mL of THF, and cooled to -78.degree. C. To this mixture, LiHMDS was
slowly added and the resulting solution stirred for one hour.
Excess methyl iodide was then slowly added at -78.degree. C., and
the ice bath was removed. The reaction mixture was stirred at room
temperature for an additional hour. The solution was quenched with
aqueous NH.sub.4Cl and extracted with ethyl acetate (20 mL) three
times. The combined organic layers were then dried over anhydrous
sodium sulfate. The filtrate was concentrated in vacuo to afford
the product 48A (0.480 g) in 92% yield.
[0699] The ketone 48A was converted to a mixture of the enantiopure
acids 48 and 48C using procedures similar to those used for Example
1, Step 5 and Example 43, Steps 2. The acids 48 and 48C were
separated at the last stage.
TABLE-US-00023 Stereo # Structure designation Name [M + H].sup.+ 48
##STR00413## cis, cis (cyclobutyl ring and cyclopropyl amine),
methyl trans to cyclopropyl amine, single enantiomer 4-((cis,cis-3-
(benzyloxycarbonyl)-8a- methyl-1,2,2a,3,8,8a- hexahydrocyclobuta[b]
quinolin-8- yl)(cyclopropyl)amino) butanoic acid 449 48C
##STR00414## Cyclobutyl ring cis fused which is trans to
cyclopropyl amine, methyl cis to cyclopropyl amine, single
enantiomer 4-((cis,trans-3- (benzyloxycarbonyl)-8a-
methyl-1,2,2a,3,8,8a- hexahydrocyclobuta[b] quinolin-8-
yl)(cyclopropyl)amino) butanoic acid 449
Example 49
Preparation of Ketone Intermediate for enantiopure
4-[(2,4-Difluorophenyl)methyl]cis,cis-7-bromo-9-[(3-carboxy-1-oxopropyl)c-
yclopropylamino]-1,2,3,3a,9,9a-hexahydro-4H-cyclopenta[b]quinoline-4-carbo-
xylate (49) and enantiopure
4-[[cis,cis-7-bromo-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoy-
l]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid (49B)
##STR00415##
[0701] To a stirring solution of enantiomerically pure compound
cis-49A' (800 mg, 4.27 mmol, prepared in a similar sequence in
Example 17, steps 1, 2, 3 where the racemic ketone was resolved by
chiral HPLC.) in DMF (40 mL) was added NBS (760 mg, 4.27 mmol). The
resulting solution was stirred at room temperature overnight. The
mixture was diluted with EtOAc. The organic layer was washed with
water, brine, dried (MgSO.sub.4), filtered and concentrated in
vacuo to give desired enantiomerically pure cis product 49A (1.14
g) as a yellow solid.
[0702] Following procedures similar to those described in Examples
22 without hydrolysis (for 49) or Example 14, step 2 (for 49B), and
Example 6, step 4, and Example 7, enantiopure cis ketone 49A was
converted into compounds 49 and 49B below.
TABLE-US-00024 Stereo # Structure designation Name [M + H].sup.+ 49
##STR00416## cis, cis, single enantiomer 4-[(2,4-
difluorophenyl)methyl]cis, cis-7-bromo-9-[(3-carboxy- 1-
oxopropyl)cyclopropylamino]- 1,2,3,3a,9,9a-hexahydro-
4H-cyclopenta[b]quinoline- 4-carboxylate 579.3 49B ##STR00417##
cis, cis,, single enantiomer 4-[[cis,cis-7-bromo-
2,3,3a,4,9,9a-hexahydro-4- [4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin- 9-yl]cyclopropylamino]-4- oxobutanoic
acid 597.3
Example 50
Preparation of Ketone Intermediate for enantiopure
4-[[cis,cis-7-cyano-2,3,3a,4,9,9a-hexahydro-4-[4-(trifluoromethoxy)benzoy-
l]-1H-cyclopenta[b]quinolin-9-yl]cyclopropylamino]-4-oxobutanoic
acid (50)
##STR00418##
[0704] Starting material enantiopure cis 49A (100 mg, 0.376 mmol),
Zn(CN).sub.2 (44 mg, 0.376 mmol), Pd(PPh.sub.3).sub.4 (43 mg,
0.0037 mmol) were mixed in DMF (1.3 mL) and heated in a microwave
oven at 110.degree. C. for 30 min. The reaction mixture was diluted
with EtOAc and washed with water. The organic layer was separated
and washed with brine, dried (MgSO.sub.4), filtered, and
concentrated. The residue was purified with preparative TLC,
eluting with EtOAc-hexanes, 1:1, to give desired product
enantiopure cis 50A (10 mg).
[0705] Following procedures similar to those described in Examples
14, step 2, Example 6, step 4, Example 7, ketone 50A was converted
into enantiopure compound 50. [M+H].sup.+: 542.3
TABLE-US-00025 Stereo # Structure designation Name [M + H].sup.+ 50
##STR00419## cis, cis,, single enantiomer
4-[[cis,cis-7-cyano-2,3,3a,4,9,9a- hexahydro-4-[4-
(trifluoromethoxy)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]cyclopropylamino]-4-oxobutanoic acid 542.3
Example 51
Preparation of enantiopure cis Ketone Intermediate for enantiopure
Compound
4-[Cyclopropyl[cis,cis-2,3,3a,4,9,9a-hexahydro-7-methyl-4-[4-(tr-
ifluoromethoxy)benzoyl]-1H-cyclopenta[b]quinolin-9-yl]amino]-4-oxobutanoic
acid (51)
##STR00420##
[0707] Starting material enantiopure cis 49A (100 mg, 0.376 mmol),
methylboronic acid (45 mg, 0.752 mmol), CsF (171 mg, 1.13 mmol),
Pd(dppf).sub.2Cl.sub.2(31 mg, 0.0038 mmol) were mixed in DMF (1.3
mL), and heated in a microwave oven at 110.degree. C. for 80 min.
The reaction mixture was diluted with DCM and filtered through a
pad of Celite.RTM.. The filtrate concentrated under reduced
pressure. The residue was purified with preparative TLC, eluting
with EtOAc-hexanes, 1:3, to give desired enantiopure cis product
51A (30 mg).
[0708] Following procedures similar to those described in Examples
14, step 2, Example 6, step 4, Example 7, ketone 51A was converted
into enantiopure compound 51 below.
TABLE-US-00026 Stereo # Structure designation Name [M + H].sup.+ 51
##STR00421## cis, cis, single enantiomer 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-7- methyl-4-[4-
(trifluoromethoxy)benzoyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 531.3
Example 52
Preparation of Intermediate (52B) for enantiopure
4-(Cyclopropyl(cis,cis-5,6-difluoro-3-(4-(trifluoromethoxy)benzoyl)-1,2,2-
a,3,8,8a-hexahydrocyclobuta[b]quinolin-8-yl)amino)-4-oxobutanoic
acid (52)
##STR00422##
[0710] To a stirring mixture of compound 52A (10 g, 55.2 mmol, Beta
Pharma, Inc., Branford, Conn.) in 200 mL toluene in a sealed
reaction vessel Ag.sub.2CO.sub.3 (75 g, 273 mmol) and MeI (3.75 mL,
59.9 mmol) was added. The resulting mixture was heated at
120.degree. C. overnight. The mixture was cooled to room
temperature and filtered through a pad of Celite.RTM.. The filtrate
was concentrated, and the residue was loaded on a pad of silica
gel, eluting with EtOAc, to give 7.9 g (73%) desired product 52B as
a white solid.
[0711] Following procedures similar to those described in Example
1, Step 1, Example 25, Steps 1-3 (where chiral ketone was obtained
via chiral HPLC resolution of the racemic ketone), Example 25, Step
4, Example 26, and Example 2527, compound 52B was converted into
enantiopure compound 52 below.
TABLE-US-00027 Stereo # Structure designation Name [M + H].sup.+ 52
##STR00423## cis, cis, single enantiomer
4-(cyclopropyl(cis,cis-5,6- difluoro-3-(4-
(trifluoromethoxy)benzoyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quinolin- 8-yl)amino)-4-oxobutanoic acid
539.8
Example 53
Preparation of Enantiopure 4-(Cyclopropyl((cis,
cis,)-4-(4-(trifluoromethoxy)benzoyl)-7-vinyl-2,3,3a,4,9,9a-hexahydro-1H--
cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (53)
Step 1
##STR00424##
[0713] Enantiopure 53A (180 mg, 0.289 mmol),
2,6-di-tert-butyl-4-methylphenol (6.36 mg, 0.029 mmol) and
Palladium Tetrakis (16.7 mg, 0.014 mmol), tributyl(vinyl)stannane
(110 mg, 0.346 mmol) and lithium chloride (36.7 mg, 0.866 mmol)
were mixed in a microwave vial, degassed and refilled with nitrogen
(3 times). The vial was placed in an oil bath at 100.degree. C.
overnight. The mixture was diluted with ethyl acetate (15 mL) and
water (6 mL) The mixture was filtered through Celite.RTM., and the
filtrate was separated. The organic layer was washed with brine
(1.times.5 mL), dried (MgSO.sub.4), filtered and the solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel silica gel (Si; 40 g
prepacked), eluting with EtOAc/isohexane=1:3 to give 53B (120 mg,
72% yield, [M+H].sup.+: 571) as a white foam.
Step 2
##STR00425##
[0715] NaOH (1 M aq) (0.5 mL, 0.500 mmol) was added to a stirred
mixture of enantiopure 53B (30 mg, 0.053 mmol) in MeOH (0.5 mL) and
THF (0.500 mL), and the mixture was stirred at room temperature for
2 h. The reaction mixture was diluted with diethyl ether (3 mL),
and water (2 mL) was added. The aqueous layer was separated,
acidified with to pH 2-3, extracted with diethyl ether (3.times.2
mL), the combined organic was dried MgSO.sub.4, filtered and
concentrated. The residue was purified by preparative HPLC (reverse
phase C-18), eluting with acetonitrile/water+0.1% TFA, to give 53
(15 mg, 0.028 mmol, 52.6% yield, [M+H].sup.+: 543.1) as a white
foam. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm: 7.31 (d, J=8.5
Hz, 2H); 7.06 (d, J=8.5 Hz, 2H); 6.94 (d, 1H); 6.85 (s, 1H); 6.61
(dd, J1=11 Hz, J2=17 Hz, 1H); 6.38 (d, J=8.5 Hz, 1H); 5.62 (d, J=17
Hz, 1H); 5.22 (d, J=11 Hz 1H); 5.14 (m, 1H); 3.15 (m, 2H); 3.06 (m,
1H); 2.84 (m, 3H); 2.44 (m, 1H); 2.04 (m, 1H); 1.59 (m, 1H); 1.41
(m, 2H); 1.23 (m, 3H); 1.06 (m, 1H); 0.97 (m, 1H).
Example 54
Preparation of enantiopure 4-(Cyclopropyl((cis,
cis,)-7-ethyl-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H--
cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid (54)
Step 1
##STR00426##
[0717] Palladium on carbon 10% (5.0 mg, 4.70 .mu.mol) was added to
a stirred, room temperature mixture of enantiopure 53B (25 mg,
0.044 mmol) in EtOH (1.500 mL) and EtOAc (0.5 mL). The mixture was
stirred under hydrogen (using a balloon filled with hydrogen) at
room temperature for overnight. The mixture was filtered, washing
with ethanol. The filtrate was concentrated to obtain a white foam
54A (16 mg, 64% yield, [M+Na].sup.+=595), which was used in the
next step directly.
Step 2
##STR00427##
[0719] NaOH (1 M aq) (0.028 mL, 0.028 mmol) was added to a stirred
mixture of enantiopure 54A (16 mg, 0.028 mmol) in MeOH (0.3 mL) and
THF (0.3 mL) and the mixture was stirred at room temperature for 2
h. The mixture was concentrated, and the residue was purified by
preparative HPLC (C-18 reverse phase solid phase), eluting with
acetonitrile/water+0.1% TFA, to give 54 (10 mg, 0.018 mmol, 65.7%
yield, [M+H].sup.+=544.8) as a white solid. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. ppm: 7.28 (d, J=8 Hz, 2H); 7.04 (d, J=8 Hz,
2H); 6.71 (d, J=8 Hz, 1H); 6.61 (s, 1H); 6.33 (d J=8 Hz, 1H); 5.16
(m, 1H); 3.13 (m, 2H); 3.05 (m, 1H); 2.83 (m, 3H); 2.55 (q, J=8 Hz,
2H); 2.434 (m, 1H); 2.03 (m, 1H); 2.60 (m, 1H); 1.40 (m, 2H); 1.22
(m, 2H); 1.17 (t, J=8 Hz, 3H); 1.19.about.0.93 (m, 3H).
Example 55
Preparation of Enantiopure
4-(Cyclopropyl((cis,cis,)-7-(hydroxymethyl)-4-(4-(trifluoromethoxy)benzoy-
l)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutan-
oic acid (55)
Step 1
##STR00428##
[0721] Ozone was bubbled into a stirred, cooled -78.degree. C.
mixture of enantiopure 53B (235 mg, 0.412 mmol) in DCM (2 mL) and
MeOH (1.000 mL). The mixture was stirred at -78.degree. C. for 15
min. until the mixture turned blue. Oxygen was bubbled in to remove
the excess ozone, until the blue color disappeared. Dimethyl
sulfide (0.2 mL, 2.70 mmol) was added, and the mixture was kept
stirring at room temperature for 1 h. The mixture was diluted with
DCM (10 mL), washed with water (5 mL), dried MgSO.sub.4, filtered
and the solvent was evaporated under reduced pressure to obtain a
white foam. The residue was purified by column chromatography on
silica gel (Si; 40 g prepacked), eluting with EtOAc/isohexane=1:1
to give 55A (184 mg, 0.321 mmol, 78% yield, [M+H].sup.+=573) as a
white foam.
Step 2
##STR00429##
[0723] Sodium borohydride (10.57 mg, 0.279 mmol) was added to a
stirred, room temperature mixture of enantiopure 55A (80 mg, 0.140
mmol) in DCM (1 mL) and MeOH (1 mL), and the mixture was stirred at
room temperature overnight.
[0724] An LCMS analysis revealed that starting material along with
product was present in the mixture. In addition, the ethyl ester
was partially replaced by methyl ester. The mixture was cooled,
diluted with dichloromethane (5 mL), washed with aqueous sodium
hydrogen carbonate (saturated, 2.times.3 mL), dried (MgSO.sub.4),
filtered and the solvent was evaporated under reduced pressure. The
residue was purified by column chromatography on silica gel (Si; 24
g prepacked), eluting with EtOAc/isohexane=1:1 to 3:1 to give 55B
(34 mg, 0.059 mmol, 42.4% yield [M+Na].sup.+=597) as a white
solid.
Step 3
##STR00430##
[0726] NaOH (1 M aq) (0.5 mL, 0.500 mmol) was added to a stirred
mixture of enantiopure 55B (10 mg, 0.017 mmol) in tetrahydrofuran
(0.500 mL) and MeOH (0.5 mL), and the mixture was stirred at room
temperature for 2 h. The reaction mixture was diluted with water (1
mL), diethyl ether (1 mL) was added, the aqueous layer was
separated, acidified with 2 M hydrochloric acid to pH 2.about.3,
extracted with diethyl ether (2.times.2 mL), the combined organic
was dried Na.sub.2SO.sub.4, filtered and concentrated to give 55
(8.3 mg, 0.015 mmol, 87% yield [M+Na].sup.+=568.8) as a white
solid. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm: 7.32 (d, J=8
Hz, 2H); 7.06 (d, J=8 Hz, 2H); 6.76 (d, J=8 Hz, 1H); 6.63 (d, J=8
Hz, 1H); 5.16 (m, 1H); 4.60 (d, J=12.5 Hz, 1H); 4.51 (d, J=12.5 Hz,
1H); 3.12.about.2.70 (m, 5H); 2.37 (m, 1H); 1.95 (m, 1H); 1.46 (m,
2H); 1.24.about.1.07 (m, 5H).
Example 56
Preparation of enantiopure 4-(Cyclopropyl((cis,
cis,)-7-(fluoromethyl)-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-hexa-
hydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid
(56)
Step 1
##STR00431##
[0728] DEOXO-FLUOR (bis(2-methoxyethyl)aminosulfur trifluoride)
(0.2 mL, 1.085 mmol) was added to a stirred, room temperature
mixture of enantiopure 55B (24 mg, 0.042 mmol) in tetrahydrofuran
(1 mL) and the mixture was stirred at 80.degree. C. for 6 h. The
mixture was cooled, poured into icy water (1 mL), diluted with
ethyl acetate (5 mL), and basified with NaHCO.sub.3 (saturated 3
mL). The organic layer was separated, washed with brine (saturated,
1.times.3 mL), dried (MgSO.sub.4), filtered and the solvent was
evaporated under reduced pressure obtained a light brown foam, 56A
(27 mg, 0.047 mmol, [M+Na].sup.+=599), which was used directly in
the hydrolysis step.
Step 2
##STR00432##
[0730] NaOH (1 M aq) (1 mL, 1.000 mmol) was added to a stirred
mixture of enantiopure 56A (27 mg, 0.047 mmol) in MeOH (1.000 mL)
and tetrahydrofuran (1 mL), and the mixture was stirred at room
temperature for 2 h. The reaction mixture was diluted with water (1
mL), and diethyl ether (2 mL) was added. The aqueous layer was
separated, acidified to pH 2-3, extracted with diethyl ether
(3.times.2 mL). The combined organic were dried over MgSO.sub.4,
filtered and concentrated. The reaction mixture was concentrated
and the residue was purified by preparative TLC with
CH.sub.2Cl.sub.2/isohexane/MeOH/AcOH (1%), to give 56 (15 mg, 0.027
mmol, 58.4% yield, [M+H].sup.+=549.1) as a white solid. .sup.1H NMR
(500 MHz, CDCl.sub.3) .delta. ppm: 7.30 (d, J=8 Hz, 2H); 7.06 (d,
J=8 Hz, 2H); 6.87 (m, 2H); 6.45 (d, J=8 Hz, 1H); 5.33 (dd, J1=6 Hz,
J2=17 Hz, 1H); 5.23 (dd, J1=6 Hz, J2=17 Hz, 1H); 5.14 (m, 1H); 3.10
(m, 3H); 2.85 (m, 1H); 2.81 (m, 2H); 2.44 (m, 1H); 2.02 (m, 1H);
1.56 (m, 1H); 1.41 (m, 2H); 1.21.about.1.07 (m, 7H).
Example 57
Preparation of enantiopure 4-(cyclopropyl((cis,
cis,)-7-(difluoromethyl)-4-(4-(trifluoromethoxy)benzoyl)-2,3,3a,4,9,9a-he-
xahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic acid
(57)
Step 1
##STR00433##
[0732] DEOXO-FLUOR (bis(2-methoxyethyl)aminosulfur trifluoride)
(0.077 mL, 0.419 mmol) was added to a stirred, room temperature
mixture of enantiopure 55A (60 mg, 0.105 mmol) in THF (1 mL) and
the mixture was stirred at 80.degree. C. overnight. LCMS check
revealed that both starting material and product were present in
the mixture. More DEOXO-FLUOR (0.077 mL, 0.419 mmol) was added. The
reaction mixture was heated at 80.degree. C. overnight. The mixture
was cooled, poured into icy water (3 mL), diluted with ethyl
acetate (10 mL), basified with saturated NaHCO.sub.3 (5 mL), the
organic was separated, washed with brine (1.times.5 mL), dried
(MgSO.sub.4), filtered and the solvent was evaporated under reduced
pressure to obtain a light brown foam. The residue was purified by
preparative HPLC (Reverse phase C-18), eluting with
acetonitrile/water+0.1% TFA, to give 57A (25 mg, 0.032 mmol, 30.1%
yield, [M+H].sup.+=595) as a yellow gum.
Step 2
##STR00434##
[0734] NaOH (1 M aq) (0.042 mL, 0.042 mmol) was added to a stirred
mixture of enantiopure 57A (25 mg, 0.042 mmol) in MeOH (1 mL) and
tetrahydrofuran (1.000 mL). The mixture was stirred at room
temperature for 2 h. The reaction mixture was diluted with water (1
mL), and diethyl ether (2 mL) was added. The aqeuous layer was
separated, acidified with hydrochloric acid 2 M to pH 2.about.3,
and extracted with diethyl ether (3.times.2 mL). The combined
organic layer was dried (MgSO.sub.4), filtered and concentrated.
The residue was purified by preparative TLC,
CH.sub.2Cl.sub.2/isohexane/MeOH/AcOH (1%)=2:1:0.4. The residue was
further purified by preparative HPLC (reverse phase C-18), eluting
with acetonitrile/water+0.1% TFA, to give 57 (8.3 mg, 0.015 mmol,
34.8% yield, [M+H].sup.+=567) as a white foam. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. ppm: 7.29 (d, J=8 Hz, 2H); 7.07 (d, J=8
Hz, 2H); 7.04 (d, J=8 Hz, 1H); 6.98 (m, 1H); 6.57 (t, J=11.5 Hz,
1H); 6.51 (d, J=8 Hz, 1H); 5.13 (m, 1H); 3.11 (m, 3H); 2.87 (m,
1H); 2.81 (m, 2H); 2.44 (m, 1H); 2.02 (m, 1H); 1.55 (m, 1H); 1.41
(m, 2H); 1.23 (m, 1H); 1.12.about.0.98 (m, 4H).
[0735] The following compounds were prepared following procedures
similar to those described in the examples above.
TABLE-US-00028 Stereo # Structure designation Name [M + H].sup.+ 58
##STR00435## cis, cis (enentiopure), R- configuration at azetidine,
single enantiomer 4-(phenylmethyl)cis,cis- [[(2(R)-carboxy-1-
azetidinyl)carbonyl]cyclo- propylamino]-1,2,3,3a,9,9a-
hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate 490.3 59
##STR00436## cis, cis (enantiopure), S- configuration at azetidine,
single enantiomer 4-(phenylmethyl)cis,cis- [[(2(S)-carboxy-1-
azetidinyl)carbonyl]cyclo- propylamino]-1,2,3,3a,9,9a-
hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate 490.3 60
##STR00437## cis, cis, single enantiomer 4-(phenylmethyl)cis,cis-
[(3- carboxypropyl)cyclopropyl- amino]-1,2,3,3a,9,9a- hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 449.2 61 ##STR00438## cis,
cis, single enantiomer 4-[ethyl[cis,cis-4-(4- fluorobenzoyl)-
2,3,3a,4,9,9a-hexahydro- 1H-cyclopenta[b]quinolin-
9-yl]amino]-4-oxobutanoic acid 439.2 62 ##STR00439## cis, cis,
single enantiomer 4-[[cis,cis-4-(3,4- difluorobenzoyl)-
2,3,3a,4,9,9a-hexahydro- 1H-cyclopenta[b]quinolin-
9-yl]ethylamino]-4- oxobutanoic acid 457.3 63 ##STR00440## cis,
cis, single enantiomer 4-[cyclopropyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4- [4- [(trifluoromethyl)thio] benzoyl]-1H-
cyclopenta[b]quinolin-9- yl]amino]-4-oxobutanoic acid 533.3 64
##STR00441## cis, cis, single enantiomer 4-[[cis,cis-4-(3,5-
difluorobenzoyl)- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl]ethylamino]-4- oxobutanoic acid
457.3 65 ##STR00442## cis, cis, single enantiomer
4-[ethyl[cis,cis-4-(4- ethylbenzoyl)- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl]amino]-4-oxobutanoic acid 449.2 66
##STR00443## cis, cis, single enantiomer 4-[ethyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4- (3,4,5-trifluorobenzoyl)-
1H-cyclopenta[b]quinolin- 9-yl]amino]-4-oxobutanoic acid 475.3 67
##STR00444## cis, cis, single enantiomer 4-[ethyl[cis,cis-4-[4-
fluoro-3- (trifluoromethyl)benzoyl]- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl]amino]-4-oxobutanoic acid 507.3 68
##STR00445## cis, cis, single enantiomer 4-[ethyl[cis,cis-
2,3,3a,4,9,9a-hexahydro-4- [4- (trifluoromethyl)benzoyl]-
1H-cyclopenta[b]quinolin- 9-yl]amino]-4-oxobutanoic acid 489.3 69
##STR00446## (cis, cis,); trans at cyclopropyl (enantiopure);
single enantiomer 4-[ethyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4-
[(2-phenyl-1- cyclopropyl)carbonyl]-1H- cyclopenta[b]quinolin-9-
yl]amino]-4-oxobutanoic acid 461.3 70 ##STR00447## cis, cis, single
enantiomer 4-[cyclobutyl[cis,cis- 2,3,3a,4,9,9a-hexahydro-4- [4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-
9-yl]amino]butanoic acid 517.3 71 ##STR00448## cis, cis, single
enantiomer 4-[(4-fluorophenyl)methyl] cis,cis-[(3-carboxy-1-
oxopropyl)ethylamino]- 1,2,3,3a,9,9a-hexahydro-
4H-cyclopenta[b]quinoline- 4-carboxylate 469.3 72 ##STR00449## cis,
cis, single enantiomer 4-[(3,4- difluorophenyl)methyl]cis,
cis-[(3-carboxy-1- oxopropyl)ethylamino]- 1,2,3,3a,9,9a-hexahydro-
4H-cyclopenta[b]quinoline- 4-carboxylate 487.3 73 ##STR00450## cis,
cis, single enantiomer 4-[(3,5- difluorophenyl)methyl]cis,
cis-[(3-carboxy-1- oxopropyl)ethylamino]- 1,2,3,3a,9,9a-hexahydro-
4H-cyclopenta[b]quinoline- 4-carboxylate 487.3 74 ##STR00451## cis,
cis (enantiopure), racemic at benzylic methyl.
4-(1-phenylethyl)cis,cis- [(3-carboxy-1- oxopropyl)ethylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
465.3 75 ##STR00452## cis, cis, single enantiomer 4-[[4-
(trifluoromethyl)phenyl] methyl]cis,cis-[(3-carboxy-1-
oxopropyl)ethylamino]- 1,2,3,3a,9,9a-hexahydro-
4H-cyclopenta[b]quinoline- 4-carboxylate 519.3 76 ##STR00453## cis,
cis, single enantiomer 4-[(3-fluorophenyl)methyl]
cis,cis-[(3-carboxy-1- oxopropyl)ethylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
469.3 77 ##STR00454## (cis, cis), S configuration at benzylic
carbon atom, single enantiomer 4-(2,2,2-trifluoro-1(S)-
phenylethyl)cis,cis-[(3- carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
531.3 78 ##STR00455## (cis, cis), R configuration at benzylic
carbon atom, single enantiomer 4-(2,2,2-trifluoro-1(R)-
phenylethyl)cis,cis-[(3- carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
531.3 79 ##STR00456## cis, cis, single enantiomer (cis,cis)-4H-
cyclopenta[b]quinoline-4- carboxylic acid, 9-[(3- carboxy-1-
oxopropyl)cyclopropylamino]- 1,2,3,3a,9,9a-hexahydro-
,4-(8-quinolinylmethyl) ester 514.3 80 ##STR00457## cis, cis,
single enantiomer 4-((cis,cis-3- (biphenylcarbonyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)(ethyl)amino)-4- oxobutanoic
acid 483.2 81 ##STR00458## cis, cis, single enantiomer
4-(ethyl(cis,cis-3- (thiophene-2-carbonyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4- oxobutanoic acid
413.2 82 ##STR00459## cis, cis, single enantiomer
4-(ethyl(cis,cis-3-(4- fluorobenzoyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4- oxobutanoic acid
425.2 83 ##STR00460## cis, cis, single enantiomer
4-(ethyl(cis,cis-3-(4- (trifluoromethylthio)benzoyl)-
1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4-
oxobutanoic acid 507.2 84 ##STR00461## cis, cis, single enantiomer
4-(ethyl(cis,cis-3-(4- ethylbenzoyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4- oxobutanoic acid
435.2 85 ##STR00462## cis, cis, single enantiomer
4-((cis,cis-3-(3,5- difluorobenzoyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)(ethyl)amino)-4- oxobutanoic
acid 443.2 86 ##STR00463## cis, cis, single enantiomer
4-(ethyl(cis,cis-3-(3,4,5- trifluorobenzoyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4- oxobutanoic acid
461.2 87 ##STR00464## cis, cis, single enantiomer
4-(ethyl(cis,cis-3-(4- fluoro-3- (trifluoromethyl)benzoyl)-
1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4-
oxobutanoic acid 493.2 88 ##STR00465## cis, cis, single enantiomer
4-(ethyl(cis,cis-3-(4- (trifluoromethyl)benzoyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4- oxobutanoic acid
475.2 89 ##STR00466## cis, cis, single enantiomer
4-(ethyl(cis,cis-3-((4- fluorobenzyloxy)carbonyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4- oxobutanoic acid
455.1 90 ##STR00467## cis, cis, single enantiomer
4-((cis,cis-3-((3,4- difluorobenzyloxy)carbonyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)(ethyl)amino)-4- oxobutanoic
acid 473.1 91 ##STR00468## cis, cis, single enantiomer
4-(ethyl(cis,cis-3-((4- (trifluoromethyl)benzyloxy)
carbonyl)-1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin-
olin-8-yl)amino)-4- oxobutanoic acid 505.1 92 ##STR00469## cis,
cis, single enantiomer 4-(ethyl(cis,cis-3-((3-
fluorobenzyloxy)carbonyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4- oxobutanoic acid
455.1 93 ##STR00470## cis, cis, single enantiomer
4-(ethyl(cis,cis-3-((4- (methylthio)benzyloxy)
carbonyl)-1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin-
olin-8-yl)amino)-4- oxobutanoic acid 483.1 94 ##STR00471## cis,
cis, single enantiomer 4-((cis,cis-3-((benzofuran-
5-ylmethoxy)carbonyl)- 1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin-
olin-8-yl)(ethyl)amino)-4- oxobutanoic acid 477.2 95 ##STR00472##
cis, cis, single enantiomer 4-((cis,cis-3- (benzo[d][1,3]dioxole-5-
carbonyl)-1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin-
olin-8-yl)(ethyl)amino)-4- oxobutanoic acid 451.2 96 ##STR00473##
cis, cis, single enantiomer 4-((cis,cis-3-(1-naphthoyl)-
1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin-
olin-8-yl)(ethyl)amino)-4- oxobutanoic acid 457.2 97 ##STR00474##
cis, cis, single enantiomer 4-((cis,cis-3-(2,4- difluorobenzoyl)-
1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin-
olin-8-yl)(ethyl)amino)-4- oxobutanoic acid 443.2 98 ##STR00475##
cis, cis (enantiopure), trans at cyclopropyl ring racemic
4-(ethyl(cis,cis-3-(2- phenylcyclopropanecarbon- yl)-1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4- oxobutanoic acid
447.2 99 ##STR00476## cis, cis, single enantiomer 4-((cis,cis-3-
(benzyloxycarbonyl)-6- phenyl-1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8- yl)(cyclopropyl)amino)-4-
oxobutanoic acid 525.2 100 ##STR00477## cis, cis, single enantiomer
3-[[4- (trifluoromethyl)phenyl] methyl]cis,cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-fluoro-2,2a,8,8a-
tetrahydrocyclobuta[b]quin- oline-3(1H)-carboxylate 535 101
##STR00478## cis, cis (enantiopure), single enantiomer
3-(1(S)-phenylethyl)cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-fluoro-2,2a,8,8a-
tetrahydrocyclobuta[b]quin- oline-3(1H)-carboxylate 481 102
##STR00479## cis, cis, single enantiomer 3-[(3-fluorophenyl)methyl]
cis,cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
6-fluoro-2,2a,8,8a- tetrahydrocyclobuta[b]quin-
oline-3(1H)-carboxylate 485 103 ##STR00480## cis, cis (racemic),
racemic at alpha carbon of acid chain 4-(phenylmethyl)cis,cis-
[(2(RS)- carboxypropyl)amino]- 1,2,3,3a,9,9a-hexahydro-
4H-cyclopenta[b]quinoline- 4-carboxylate 409 104 ##STR00481## cis,
cis, racemic; R configuration at beta carbon of acid chain
4-(phenylmethyl)cis,cis-9- [(3-carboxy-2(R)-methyl-1-
oxopropyl)ethylamino]- 1,2,3,3a,9,9a-hexahydro-
4H-cyclopenta[b]quinoline- 4-carboxylate 465 105 ##STR00482## all
cis, racemic; R configuration at alpha carbon of acid chain
4-(phenylmethyl)cis,cis-9- [(3(R)-carboxy-1- oxobutyl)ethylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
465 106 ##STR00483## cis, cis (enantiopure), single enantiomer, R
configuration at alpha carbon of acid chain (R)-4-(((cis,cis)-4-
(benzyloxycarbonyl)- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl)(cyclopropyl)amino)-
2-methyl-4-oxobutanoic acid 477 107 ##STR00484## cis, cis, single
enantiomer 4-((cis,cis-3- (benzyloxycarbonyl)-6-
chloro-1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin- olin-8-
yl)(cyclopropyl)amino)-4- oxobutanoic acid 484 108 ##STR00485##
cis, cis, single enantiomer 4-((cis,cis-3- (benzyloxycarbonyl)-6-
chloro-1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin- olin-8-
yl)(cyclopropyl)amino) butanoic acid 470 109 ##STR00486## cis, cis
(enantiopure), single enantiomer (R)-4-((cis,cis-3-
(benzyloxycarbonyl)- 1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin-
olin-8-yl)(ethyl)amino)-3- methyl-4-oxobutanoic acid 451 110
##STR00487## cis, cis, single enantiomer 3-(phenylmethyl)cis,cis-
[(3-carboxy-1- oxopropyl)(2- hydroxyethyl)amino]- 2,2a,8,8a-
tetrahydrocyclobuta[b]quin- oline-3(1H)-carboxylate 474.9 [M +
Na].sup.+ 111 ##STR00488## cis, cis, single enantiomer
3-(phenylmethyl) deuterated-cis,cis-[(3- carboxy-1-
oxopropyl)cyclopropylamino]- 2,2a,8,8a- tetrahydrocyclobuta[b]quin-
oline-3(1H)-carboxylate- (8D) 449.9 112 ##STR00489## cis, cis,
single enantiomer 4-[[3-fluoro-4- (trifluoromethoxy)phenyl]
methyl]cis,cis-[(3- carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
565.3 113 ##STR00490## cis, cis, single enantiomer
4-(2-pyridinylmethyl)cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 1,2,3,3a,9,9a-hexahydro-
4H-cyclopenta[b]quinoline- 4-carboxylate 464.3 114 ##STR00491##
cis, cis, single enantiomer 4-(2-thienylmethyl)cis,cis-
[(3-carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
469
115 ##STR00492## cis, cis, single enantiomer 1 3-(phenylmethyl)
8-[(3- carboxy-1- oxopropyl)cyclopropylamino]-
5,6-difluoro-2,2a,8,8a- tetrahydro- cyclobuta[b]quinoline-
3(1H)-carboxylate 485.2 116 ##STR00493## cis, cis, single
enantiomer 2 3-(phenylmethyl) 8-[(3- carboxy-1-
oxopropyl)cyclopropylamino]- 5,6-difluoro-2,2a,8,8a- tetrahydro-
cyclobuta[b]quinoline- 3(1H)-carboxylate 485.2 117 ##STR00494##
cis, cis, single enantiomer 4-((cis,cis-3- (benzyloxycarbonyl)-5,6-
difluoro-1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin- olin-8-
yl)(cyclopropyl)amino) butanoic acid 470.8 118 ##STR00495## cis,
cis, single enantiomer 4-(phenylmethyl)cis,cis- [(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-chloro-7-fluoro-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
515.3 119 ##STR00496## cis, cis, single enantiomer
3-(phenylmethyl)cis,cis-8- [(3-carboxy-1-
oxopropyl)cyclopropylamino]- 5,6-dichloro-2,2a,8,8a-
tetrahydrocyclobuta[b]quin- oline-3(1H)-carboxylate 519.3 120
##STR00497## cis, cis, single enantiomer 3-(phenylmethyl)cis,cis-8-
[(3-carboxy-1- oxopropyl)cyclopropylamino]- 5,6-dichloro-2,2a,8,8a-
tetrahydrocyclobuta[b]quin- oline-3(1H)-carboxylate 519.3 121
##STR00498## cis, cis, single enantiomer
4-[cyclopropyl[cis,cis-5,6- dichloro-1,2,2a,3,8,8a- hexahydro-3-[4-
(trifluoromethoxy)benzoyl] cyclobuta[b]quinolin-8-
yl]amino]-4-oxobutanoic acid 573.3 122 ##STR00499## racemic, cis,
cis 4- [(cyclobutylmethyl)[cis,cis- 2,3,3a,4,9,9a-hexahydro-4- [4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-
9-yl]amino]butanoic acid 531 123 ##STR00500## racemic, cis, cis
4-[(cyclopentylmethyl)[cis- 2,3,3a,4,9,9a-hexahydro-4- [4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-
9-yl]amino]butanoic acid 545 124 ##STR00501## cis, cis, single
enantiomer 3-(phenylmethyl) deuterated-cis,cis-8-[(3-
carboxypropyl)cyclopropyl- amino]-2,2a,8,8a-
tetrahydrocyclobuta[b]quin- oline-3(1H)-carboxylate- (8D) 436 125
##STR00502## 3aS,9R,9aR, single enantiomer 4-(phenylmethyl)
(3aS,9R,9aR)-9-[(3- carboxypropyl)cyclopropyl- amino]-7-fluoro-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
467 126 ##STR00503## racemic, cis, cis 4-[[cis,cis-2,3,3a,4,9,9a-
hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin- 9-yl](2- phenylethyl)amino]butanoic acid
567 127 ##STR00504## racemic, cis, cis 4-[[cis,cis-2,3,3a,4,9,9a-
hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin- 9-yl](2- oxazolylmethyl)amino] butanoic
acid 544 128 ##STR00505## racemic, cis, cis
4,4'-[[cis,cis-2,3,3a,4,9,9a- hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-
9-yl]imino]bisbutanoic acid 549 129 ##STR00506## racemic, cis, cis
4-[[cis,cis-2,3,3a,4,9,9a- hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-
9-yl]phenylamino]butanoic acid 561 130 ##STR00507## cis, cis,
single enantiomer 4-[cyclopropyl[cis,cis-4-(4- fluorobenzoyl)-
2,3,3a,4,9,9a-hexahydro- 1H-cyclopenta[b]quinolin-
9-yl]amino]butanoic acid 437 131 ##STR00508## cis, cis, single
enantiomer 4-(phenylmethyl)cis,cis- [(3-carboxy-1-
oxopropyl)cyclopropylamino]- 1,2,3,3a,9,9a-hexahydro-
4H-cyclopenta[b]quinoline- 4-carboxylate 462.9 132 ##STR00509##
cis, cis, single enantiomer 4-(phenylmethyl)
deuterated-cis,cis-[(3- carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline-
4-carboxylate-(9D) 463.9 133 ##STR00510## 3aS,9R,9aR, single
enantiomer, R configuration at azetidine carbon atom
4-(phenylmethyl) (3aS,9R,9aR)-[[[2(R)- carboxy-1-
azetidinyl]carbonyl]cyclo- propylamino]-7-fluoro-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
507.9 134 ##STR00511## cis, cis, single enantiomer
4-[cyclopropyl[cis,cis-7- fluoro-2,3,3a,4,9,9a- hexahydro-4-[4-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-
9-yl]amino]-4-oxobutanoic acid 534.8 135 ##STR00512## cis, cis,
single enantiomer 4-[cyclopropyl[cis,cis-6- fluoro-2,3,3a,4,9,9a-
hexahydro-4-[4- (trifluoromethoxy)benzoyl]-
1H-cyclopenta[b]quinolin- 9-yl]amino]-4-oxobutanoic acid 534.8 136
##STR00513## 3aS,9R,9aR, single enantiomer 4-
[cyclopropyl[(3aS,9R,9aR)- 7-fluoro-2,3,3a,4,9,9a- hexahydro-4-[3-
(trifluoromethoxy)benzoyl]- 1H-cyclopenta[b]quinolin-
9-yl]amino]-4-oxobutanoic acid 534.8 137 ##STR00514## cis, cis,
single enantiomer, R configuration at benzylic carbamate
4-(1(R)-phenylbutyl)cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 1,2,3,3a,9,9a-hexahydro-
4H-cyclopenta[b]quinoline- 4-carboxylate 526.8 [M + Na].sup.+ 138
##STR00515## cis, cis, single enantiomer, S configuration at
benzylic carbon carbamate 4-(1(S)-phenylbutyl)cis,
cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
526.8 [M + Na].sup.+ 139 ##STR00516## cis, cis, single enantiomer,
S configuration at benzylic carbamate 4-(1(S)-phenylpropyl)cis,
cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
512.8 [M + Na].sup.+ 140 ##STR00517## cis, cis (enantiopure),
racemic at benzylic carbamate 4-[1-[4- (trifluoromethoxy)phenyl]
ethyl]cis,cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
582.7 [M + Na].sup.+ 141 ##STR00518## cis, cis, single enantiomer,
R at benzylic carbamate 4-(1(R)-phenylpropyl)cis,
cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
512.8 [M + Na].sup.+ 142 ##STR00519## cis, cis, single enantiomer,
racemic at benzylic carbamate 4- (cyclopropylphenylmethyl)
cis,cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
1,2,3,3a,9,9a-hexahydro- 4H-cyclopenta[b]quinoline- 4-carboxylate
502.8 143 ##STR00520## cis, cis (enantiopure), racemic at benzylic
carbamate 4-[1-(4- methoxyphenyl)ethyl]cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 1,2,3,3a,9,9a-hexahydro-
4H-cyclopenta[b]quinoline- 4-carboxylate 529.2 [M + Na].sup.+ 144
##STR00521## cis, cis, single enantiomer, S configuration at
benzylic carbamate 4-(1(S)-phenylethyl)cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-fluoro-1,2,3,3a,9,9a- hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 516.8 [M + Na].sup.+ 145
##STR00522## cis, cis, single enantiomer, R configuration at
benzylic carbamate 4-(1(R)-phenylethyl)cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-fluoro-1,2,3,3a,9,9a- hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 516.8 [M + Na].sup.+ 146
##STR00523## cis, cis, single enantiomer, S configuration at
benzylic carbamate 4-[1(S)-(4- fluorophenyl)ethyl]cis,cis-
[(3-carboxy-1- oxopropyl)cyclopropylamino]- 6-fluoro-1,2,3,3a,9,9a-
hexahydro-4H- cyclopenta[b]quinoline-4- carboxylate 534.8 [M +
Na].sup.+ 147 ##STR00524## cis, cis, single enantiomer, R
configuration at benzylic carbamate 4-[1(R)-(4-
fluorophenyl)ethyl]cis, cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-fluoro-1,2,3,3a,9,9a- hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 534.7 [M + Na].sup.+ 148
##STR00525## cis, cis, single enantiomer 4-(2-pyridinylmethyl)cis,
cis-[(3-carboxy-1- oxopropyl)cyclopropylamino]-
6-fluoro-1,2,3,3a,9,9a- hexahydro-4H- cyclopenta[b]quinoline-4-
carboxylate 481.8 149 ##STR00526## cis, cis, single enantiomer
4-(2,3-dihydro-1H-inden-2- yl)cis,cis-[(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-fluoro-1,2,3,3a,9,9a- hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 506.8 150 ##STR00527## cis,
cis, single enantiomer 4-(phenylmethyl)cis,cis- [(3-carboxy-1-
oxopropyl)cyclopropylamino]- 6-fluoro-1,2,3,3a,9,9a- hexahydro-4H-
cyclopenta[b]quinoline-4- carboxylate 480.8 151 ##STR00528## cis,
cis, single enantiomer; R at acid side chain (R)-1-((cis,cis-3-
(benzyloxycarbonyl)-5,6- difluoro-1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8- yl)(cyclopropyl)carbamoyl)
azetidine-2-carboxylic acid 533.7 [M + Na].sup.+ 152 ##STR00529##
3aS,9R,9aR single enantiomer 4-(((3aS,9R,9aR)-4-
(benzo[d]thiazole-2- carbonyl)-7-fluoro- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl)(cyclopropyl)amino)- 4-oxobutanoic
acid 507.8 153 ##STR00530## cis, cis, single enantiomer
4-(cyclopropyl((cis,cis)-7- (4-fluorophenyl)-4-(4-
(trifluoromethoxy)benzoyl)- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl)(cyclopropyl)amino)- acid 610.6 154
##STR00531## cis, cis, single enantiomer 4-(((cis,cis)-4-
((benzo[d]thiazol-2- ylmethoxy)carbonyl)-6- fluoro-2,3,3a,4,9,9a-
hexahydro-1H- cyclopenta[b]quinolin-9- yl)(cyclopropyl)amino)-4-
oxobutanoic acid 537.8 155 ##STR00532## cis, cis, single
enantiomer, racemic at benzylic carbon of the alcohol
4-((cis,cis-3- ((benzyloxy)carbonyl)-6- (1-hydroxyethyl)-
1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin- olin-8-
yl)(cyclopropyl)amino)-4- oxobutanoic acid 515 [M + Na] 156
##STR00533## cis, cis, single enantiomer 4-((cis,cis-3-
((benzyloxy)carbonyl)-6- (difluoromethyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8- yl)(cyclopropyl)amino)-4-
oxobutanoic acid 499 157 ##STR00534## single enantiomer,
cyclopropyl- amine trans to cyclobutyl ring, cyclobutyl ring cis
fused 4-(cyclopropyl(cis,trans- 8a-methyl-3-(4-
(trifluoromethoxy)benzoyl)- 1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4- oxobutanoic acid 517
158 ##STR00535## single enantiomer, cyclobutyl ring cis fused,
cyclopropyl- amine cis to cyclobutyl ring
4-(cyclopropyl(cis,cis-8a- methyl-3-(4- (trifluoromethoxy)benzoyl)-
1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4-
oxobutanoic acid 517 159 ##STR00536## cis, cis, single enantiomer
4-(cyclopropyl(cis,cis-3- (4- ((trifluoromethyl)thio)benz-
oyl)-1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4-
oxobutanoic acid 519 160 ##STR00537## single enantiomer,
cyclopentyl ring cis fused, cyclopropyl- amine cis to cyclopentyl
ring 4-((cis,cis-4- ((benzyloxy)carbonyl)-9a- methyl-2,3,3a,4,9,9a-
hexahydro-1H- cyclopenta[b]quinolin-9- yl)(cyclopropyl)amino)-4-
oxobutanoic acid 477 161 ##STR00538## single enantiomer,
cyclopentyl ring cis fused, cyclopropyl- amine cis to cyclopentyl
ring 4-((cis,cis-4- ((benzyloxy)carbonyl)-9a- methyl-2,3,3a,4,9,9a-
hexahydro-1H- cyclopenta[b]quinolin-9- yl)(cyclopropyl)amino)
butanoic acid 463 162 ##STR00539## cis, cis, single enantiomer
4-(cyclopropyl(cis,cis-4- (4-cyclopropylbenzoyl)-
2,3,3a,4,9,9a-hexahydro- 1H-cyclopenta[b]quinolin-
9-yl)amino)-4-oxobutanoic acid 473 163 ##STR00540## cis, cis,
single enantiomer 4-(cyclopropyl(cis,cis-4- (6-
(trifluoromethyl)nicotinoyl)- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl)amino)-4-oxobutanoic acid 502 164
##STR00541## cis, cis, single enantiomer
4-(ethyl(cis,cis-6-fluoro-3- (4- ((trifluoromethyl)thio)benz-
oyl)-1,2,2a,3,8,8a- hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4-
oxobutanoic acid 525 165 ##STR00542## 3aS,9R,9aR, single enantiomer
4-(ethyl((3aS,9R,9aR)-7- fluoro-4-(4- ((trifluoromethyl)thio)benz-
oyl)-1,2,2a,3,8,8a- hexahydro-1H- cyclopenta[b]quinolin-9-
yl)amino)-4-oxobutanoic acid 539 166 ##STR00543## 3aS,9R,9aR,
single enantiomer 4- (cyclopropyl((3aS,9R,9aR)- 7-fluoro-4-(4-
((trifluoromethyl)thio)benz- oyl)-1,2,2a,3,8,8a- hexahydro-1H-
cyclopenta[b]quinolin-9- yl)amino)-4-oxobutanoic acid 551 167
##STR00544## cis, cis, single enantiomer 4-(cyclopropyl(cis,cis-6-
fluoro-3-(4- ((trifluoromethyl)thio)benz- oyl)-1,2,2a,3,8,8a-
hexahydrocyclobuta[b]quin- olin-8-yl)amino)-4- oxobutanoic acid 537
168 ##STR00545## cis, cis, single enantiomer
4-(cyclopropyl(cis,cis-7- cyclopropyl-4-(4-
(trifluoromethoxy)benzoyl)- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl)amino)-4-oxobutanoic acid 557 169
##STR00546## cis, cis, single enantiomer 4-(cyclopropyl(cis,cis-7-
(pyrimidin-5-yl)-4-(4- (trifluoromethoxy)benzoyl)-
2,3,3a,4,9,9a-hexahydro- 1H-cyclopenta[b]quinolin-
9-yl)amino)-4-oxobutanoic acid 595
170 ##STR00547## 3aS,9R,9aR, Single enantiomer 4-
(cyclopropyl((3aS,9R,9aR)- 7-fluoro-4-(4-
(trifluoromethoxy)benzoyl)- 2,3,3a,4,9,9a-hexahydro-
1H-cyclopenta[b]quinolin- 9-yl)amino)butanoic acid 521
Example 171
Preparation of
4-(Cyclopropyl-(3aS,9R,9aR)-7-fluoro-4-(2-hydroxy-4-(trifluoromethoxy)ben-
zoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobu-
tanoic acid (171)
Step 1
##STR00548##
[0737] A mixture of 2-methoxy-4-(trifluoromethoxy)benzoic acid
(70.9 mg, 0.300 mmol) in thionyl chloride (2 mL, 27.4 mmol) was
heated up 40.degree. C. for 2 h before the mixture was cooled and
then concentrated under reduced pressure to remove the excess
thionyl chloride. The residue was taken up in dichloromethane (2
mL), the solution was added to a stirred, room temperature mixture
of ethyl
4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-2,3,3a,4,9,9a-hexahydro-1H-cyclopent-
a[b]quinolin-9-yl)amino)-4-oxobutanoate (75 mg, 0.200 mmol), DMAP
(4.89 mg, 0.040 mmol) and Hunig's Base (0.105 mL, 0.601 mmol) in
dichloromethane (2 mL) and the mixture was stirred at room
temperature for overnight before it was diluted with
dichloromethane (10 mL), washed with aqueous sodium hydroxide (0.5
M, 2.times.6 mL), dried (MgSO.sub.4), filtered and the solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography on silica gel 40 g prepacked column, eluting
with EtOAc/isohexane=50% to give ethyl
4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(2-methoxy-4-(trifluoromethoxy)ben-
zoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobu-
tanoate 171A (73 mg, 0.123 mmol, 61.5% yield) as a white foam.
Step 2
##STR00549##
[0739] 1 M BBr.sub.3 (0.089 mL, 0.089 mmol) in dichloromethane was
added to a stirred mixture of ethyl
4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(2-methoxy-4-(trifluoromethoxy)ben-
zoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobu-
tanoate (42 mg, 0.071 mmol) in dichloromethane (5 mL) at
-78.degree. C. and the mixture was stirred at -78.degree. C. for 30
min. then room temperature for 1 h. LCMS showed the reaction was
complete. The mixture was concentrated, the residue was taken up in
MeOH (1.0 mL) and tetrahydrofuran (1.0 mL), NaOH (1 M aq) (0.284
mL, 0.284 mmol) was added, the mixture was kept stirring at room
temperature for 2 h. The reaction mixture was diluted with water (5
mL), diethyl ether (20 mL) was added. The aqeuous layer was
separated, acidified with 2 M hydrochloric acid to pH .about.3,
extracted with dichloromethane (2.times.10 mL), the combined
organic was dried MgSO.sub.4, filtered and concentrated. The
residue was purified by column chromatography on silica gel; 24 g
prepacked column, eluting with CH.sub.2Cl.sub.2/MeOH=6% to
4-(Cyclopropyl-(3aS,9R,9aR)-7-fluoro-4-(2-hydroxy-4-(trifluoromethoxy)ben-
zoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobu-
tanoic acid 171 (35 mg, 0.064 mmol, 90% yield) as a white solid;
[M+H.sup.+]=551.2.
Example 172
Preparation of
4-(Cyclopropyl-(3aS,9R,9aR)-7-fluoro-4-(2-methoxy-4-(trifluoromethoxy)ben-
zoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobu-
tanoic acid (172)
##STR00550##
[0741] NaOH (1 M aq) (0.017 mL, 0.017 mmol) was added to a stirred,
room temperature mixture of ethyl
4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(2-methoxy-4-(trifluoromethoxy)ben-
zoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobu-
tanoate (10 mg, 0.017 mmol) in MeOH (1 mL) and tetrahydrofuran (1.0
mL), and the mixture was stirred at room temperature for 2 h. The
reaction mixture was diluted with water (2 mL), diethyl ether (2
mL) was added. The aqeuous layer was separated, acidified with
hydrochloric acid (1 M) to pH .about.3, extracted with
dichloromethane (2.times.3 mL), the combined organic was dried
(MgSO.sub.4), filtered and concentrated to give
4-(cyclopropyl(3aS,9R,9aR)-7-fluoro-4-(2-methoxy-4-(trifluoromethoxy-
)benzoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-o-
xobutanoic acid 172 (4.5 mg, 7.97 .mu.mol, 47.2% yield) as a white
foam; [M+H.sup.+]=565.2
Example 173
Preparation of
4-(Cyclopropyl-(3aS,9R,9aR)-7-fluoro-4-(3-hydroxy-4-(trifluoromethoxy)ben-
zoyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobu-
tanoic acid (173)
Step 1
##STR00551##
[0743] NaH (1.647 g, 41.2 mmol) was added to a stirred, 0.degree.
C. mixture of methyl vanillate (5 g, 27.4 mmol) in DMF (30 mL) and
the mixture was stirred at 0.degree. C. for 30 min.
Dibromofluoromethane (14.96 mL, 165 mmol) in DMF (30 mL) was then
added via an additional funnel, the resultant mixture was allowed
to warm up to 50.degree. C. and kept stirring at 50.degree. C. for
16 h. The mixture was cooled, diluted with ethyl acetate (150 mL),
washed with water (100 mL), the organic was washed with brine (100
mL), dried (MgSO.sub.4), filtered and the solvent was evaporated
under reduced pressure. The residue was purified by column
chromatography on; 120 g prepacked column, eluting with 10%
EtOAc/isohexane to give methyl
4-(bromodifluoromethoxy)-3-methoxybenzoate 173A (1.5 g, 4.82 mmol,
17.57% yield) as a colorless liquid.
Step 2
##STR00552##
[0745] Antimony (V) Chloride (26.4 mg, 0.088 mmol) was added to a
stirred, room temperature mixture of 173A (550 mg, 1.768 mmol) and
antimony trifluoride (221 mg, 1.238 mmol) in a sealed tube, and the
mixture was stirred at 170.degree. C. for 4 h. The mixture was
cooled, diluted with diethyl ether (50 mL), washed with water (50
mL), dried (MgSO.sub.4), filtered and the solvent was evaporated
under reduced pressure. The residue was purified by column
chromatography on silica gel; 24 g prepacked column, eluting with
EtOAc/isohexane=10% to give methyl
3-methoxy-4-(trifluoromethoxy)benzoate 173B (240 mg, 0.959 mmol,
54.3% yield) as a white solid.
Step 3
##STR00553##
[0747] NaOH (1 M aq) (1 mL, 1.000 mmol) was added to a stirred,
room temperature mixture of 179B (120 mg, 0.480 mmol) in
tetrahydrofuran (2 mL) MeOH (2.000 mL), and the mixture was stirred
at room temperature for 1 h. The reaction mixture was diluted with
diethyl ether (10 mL), water (2 mL) was added, the aqueous layer
was separated, acidified with hydrochloric acid (2 M) to pH 2-3,
extracted with dichloromethane (3.times.6 mL). The combined organic
layers were dried (MgSO.sub.4), filtered and concentrated to give
3-methoxy-4-(trifluoromethoxy)benzoic acid 173C (110 mg, 0.466
mmol, 97% yield) as a white solid.
Steps 4 and 5
##STR00554##
[0749] 3-methoxy-4-(trifluoromethoxy)benzoic acid was converted to
4-(cyclopropyl-(3aS,9R,9aR-7-fluoro-4-(3-hydroxy-4-(trifluoromethoxy)benz-
oyl)-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobut-
anoic acid 173 as a white solid ([M+H].sup.+=551.2) by following
similar procedure as described in Steps 1 and 2 of Example 171.
Example 172
Preparation of
6-((4-(Cyclopropyl-(3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)--
2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoyl-
)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid
(174)
Step 1
##STR00555##
[0751] N-methylmorpholine (0.077 mL, 0.702 mmol) was added to a
stirred mixture of
4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,3,-
3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoic
acid (150 mg, 0.281 mmol), HATU (133 mg, 0.351 mmol) and benzyl
3,4,5,6-tetrahydroxytetrahydro-2H-pyran-2-carboxylate (100 mg,
0.351 mmol) in acetonitrile (3 mL) and the mixture was stirred at
room temperature for 3 h. TLC showed clean reaction (MeOH in DCM
10%). Solvent was removed and the residue was purified by column
chromatography on silica gel (24 g prepacked column) eluting with
DCM/MeOH gradient up to 20% MeOH to give benzyl
644-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)-2,-
3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoyl)o-
xy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate 174A (0.23
g).
Step 2
##STR00556##
[0753] Palladium on carbon (80 mg, 0.752 mmol) was added to a
stirred mixture of benzyl
6-((4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)--
2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoyl-
)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylate (0.23 g,
0.29 mmol) and cyclohexadiene (1.5 mL, 0.293 mmol) in isopropanol
(7.5 mL) and cyclopentylmethyl ether (7.50 mL) and the mixture was
stirred at 60.degree. C. for 1 h. The mixture was filtered through
a Celite.RTM. pad and washed with ether/isopropanol (1/1). Solvent
was removed to give crude product which was purified using reverse
phase HPLC to give
6-((4-(cyclopropyl((3aS,9R,9aR)-7-fluoro-4-(4-(trifluoromethoxy)benzoyl)--
2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]quinolin-9-yl)amino)-4-oxobutanoyl-
)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid 174
(140 mg), [M+H].sup.+=710.1.
Biological Assays
Radioligand Binding Assays
[0754] Certain representative compounds of the invention were
tested in Radioligand Binding Assay A and others were tested in
Radioligand Binding Assay B.
[0755] Radioligand Binding Assay A.
[0756] Radioligand Binding Assay A was performed at room
temperature in 50 mM Tris-HCl pH 7.4, 1 mM EDTA containing 2 mM
MnCl.sub.2 and 3.0 nM [.sup.3H]PGD.sub.2 (New England Nuclear,
Boston, Mass.) (171 Ci mmol.sup.-1), in a final volume of 0.2 mL.
Competing ligands were diluted in dimethylsulfoxide (Me.sub.2SO)
that was kept constant at 1% (v/v) of the final incubation volume.
The reaction was initiated by the addition of 8-20 .mu.g of
membrane protein prepared from a human embryonic kidney
(HEK)-hCRTH.sub.2 cell line. Total and non-specific binding were
determined in the absence and the presence of 10 .mu.M PGD.sub.2,
respectively. Under these conditions, specific binding (total minus
non-specific) of the radioligand to the receptor reached
equilibrium within 50 min and was stable up to 180 min. The
reaction was routinely conducted for 60 min at room temperature and
terminated by rapid filtration through prewetted (0.3%
polyethyleneimine) 96-well printed Filtermate.TM. (Wallac) using a
Tomtec.RTM. harvester (Hamden, Conn.). After washing with cold
buffer, the filter was dried for 2 minutes in microwave, and
Meltilex Scintillator sheet (Wallac) was melted on for 2 min. The
radioactivity was measured with Betaplate model 1205 (Wallac).
Table A below lists representative compounds of the invention with
binding data which were tested in Radioligand Binding Assay A
whereby the Ki values are rated "A", "B," "C," or "D." The Ki
values are rated "A" for Ki values in the range of 1.0 to 5.0 nM,
"B" for Ki values in the range from 5.1-20.0 nM, "C" for Ki values
in the range from 20.1-200 nM, and "D" for Ki values in the range
from 201-7500 nM. The designation "N.A." indicates that data is
unavailable for that entry.
TABLE-US-00029 TABLE A No. Ki (nM) No. Ki (nM) 9 B 27K A 9A A 27L A
9B B 27M B 11 D 27N B 11A C 27o A 11B C 27Q B 11C B 27R B 17 B 27S
A 17G B 32 C 17i C 32C C 17J D 32D C 17K B 32E A 17L B 32F A 17M C
32G A 17R D 32H A 17S B 32i A 17T C 32J A 17U D 32K A 17V C 32L A
17W B 32M A 17X C 32N A 17Y C 32O A 17Z C 32P B 17AA C 32Q A 17AB C
32R B 17AC B 32S A 17AD B 32T A 17AE D 32U A 17AF D 33 D 17AG C 34
D 17AH B 35 B 17Ai B 35D B 17AJ C 35E C 17AK A 35F D 17AL B 35G D
17AM C 35H B 17AN C 35i B 17Ao C 35J B 17AP B 35K B 17AQ C 38 C
17AR B 38D B 17AS C 38E C 17AT B 38F B 17AU B 38G D 17AV B 40 C
17AW B 41 D 17AX B 42 C 17AY C 43 B 17AZ C 43B A 17BA C 43C C 17BB
C 44 A 17BC C 44B D 17BD C 44C C 17BE B 44D A 17BF C 44E B 17BG B
44F C 17BH B 45 C 17Bi B 46 D 17BJ C 47 D 17BK B 47D B 17BL C 47E
N.A. 17BM A 47F D 17BN B 47G D 17Bo A 48 B 17BP B 48C D 17BQ B 49 C
17BR B 49B B 17BS B 50 C 17BT A 51 B 17BU A 52 A 17BV B 53 B 17BW B
54 C 17BX D 55 C 17BY A 56 B 17BZ D 57 B 17CA A 58 C 17CB B 59 D
17CC A 60 C 17CD A 61 B 17CE A 62 B 17CF B 63 B 17CG B 64 B 17CH B
65 B 17Ci D 66 B 17CJ D 67 B 17CK A 68 B 17CL B 69 A 17CM B 70 C
17CN B 71 A 17Co B 72 B 17CP B 73 C 18CQ A 74 C 17CR A 75 B 17CS B
76 B 17CT A 77 C 17CU A 78 B 17CV A 79 C 17CW B 80 B 17CX A 81 A
17CY A 82 B 17CZ B 83 A 17DA C 84 B 17DB C 85 C 17DC C 86 C 17DD C
87 B 17DE B 88 B 17DF D 89 C 17DG D 90 C 17DH B 91 C 17Di C 92 C
17DJ B 93 C 17DK B 94 C 17DL A 95 C 17DN B 96 B 17Do D 97 C 18 C 98
B 18C A 99 D 18D B 100 A 18E B 101 D 18F C 102 D 18G B 103 D 18H C
104 D 18i # C 105 D 18J B 106 D 18K B 107 B 18L A 108 B 18M A 109 C
18N C 110 D 18o B 111 B 18P C 112 C 18Q C 113 C 18R B 114 C 18S B
115 D 18T C 116 A 19 D 117 A 20 C 118 B 22 B 119 A 22A D 120 D 22D
A 121 A 22E B 122 C 22F B 123 C 22G B 124 B 22H B 125 B 22i A 126 B
22J D 127 C 22K B 128 D 22L B 129 C 22M B 130 B 22N C 131 C 22O C
132 B 22P C 133 B 22Q B 134 D 22R B 135 A 22S B 136 B 22T B 137 C
22U A 138 B 22V A 139 B 22W B 140 C 22X B 141 C 22Y B 142 C 23E C
143 C 23F C 144 A 23G C 145 B 23H C 146 A 23i D 147 B 24B C 148 B
24C C 149 A 27A B 150 A 27B A 151 B 27C B 152 B 27D D 153 C 27E D
154 B 27F D 155 D 27G B 156 C 27H D 157 C 27i D 158 C 27J D 159 A
160 D 161 C 162 B 163 C 164 B 165 A 166 B 167 B 168 C 169 D 170 A
171 B 172 B 173 B 174 D
[0757] Representative compounds of the invention had the Ki values
specified in parentheses immediately following the compound number
in Radioligand Binding Assay A: 9A (4.7 nM), 17 (5.1 nM), 17U
(604.9 nM), 17BL (36.0 nM), 17Co (10.9 nM), 17Ci (838.0), 18CQ (2.4
nM), 17DA (34.2 nM), 18o (9.8 nM), 18 P (28.5 nM), 22A (1083.5 nM),
27K (1.5 nM), 38G (637.5 nM), 44 (2.541 nM), 51 (6.9 nM), 55 (37.7
nM), 60 (21.2 nM), 69 (4.972), 72 (15.7 nM), and 134 (236.4
nM).
[0758] Radioligand Binding Assay B.
[0759] Radioligand Binding Assay B was performed at room
temperature in 10 mM HEPES/KOH pH 7.4, 1 mM EDTA containing 10 mM
MnCl.sub.2 and 0.7 nM [.sup.3H]PGD.sub.2 (NEN, 171 Ci mmol.sup.-1),
in a final volume of 0.2 mL. Competing ligands were diluted in
dimethylsulfoxide (Me.sub.2SO) that was kept constant at 1% (v/v)
of the final incubation volume. The reaction was initiated by the
addition of 8-20 .mu.g of membrane protein prepared from a
HEK-hCRTH2 cell line. Total and non-specific binding were
determined in the absence and the presence of 10 .mu.M PGD.sub.2,
respectively. Under these conditions, specific binding (total minus
non-specific) of the radioligand to the receptor reached
equilibrium within 50 min and was stable up to 180 min. The
reaction was routinely conducted for 60 min at room temperature and
terminated by rapid filtration through prewetted Unifilters GF/C
(Packard), using a Tomtec MachIII semi-automated harvester (for
HEK-hCRTH.sub.2). The filters were then washed with 4 mL of the
same buffer and residual radioligand bound to the filter was
determined by liquid scintillation counting following equilibration
in 25 .mu.l Ultima Gold F.TM. (Unifilter) (Packard). Table B below
lists representative compounds of the invention with binding data
which were tested in Radioligand Binding Assay B whereby the Ki
values are rated "A", "B," "C," or "D." The Ki values are rated "A"
for Ki values in the range of 1.0 to 5.0 nM, "B" for Ki values in
the range from 5.1-20.0 nM, "C" for Ki values in the range from
20.1-200 nM, and "D" for Ki values in the range from 201-7500
nM.
TABLE-US-00030 TABLE B No. Ki (nM) 7 A 10 D 12 D 12B C 12C B 12D B
12E B 13 B 13C B 13D B 13E C 14 B 14C B 14D B 14E B 14F B 14G C 14H
C 14i C 14K B 14L C 14N D 14o D 14P D 15 C 16 A 16A D 16B B 16C C
16D C 16E A 17H D 17N D 17o D 17P D 17Q D 21 C 21A C 21B D 21C C
21D C 21E C 21F C 21G C 21H D 21i C 21J D 21K D 21L C 23 C 23B C
23C C 23D C 24 C 24D C 25 C 26 C 27 B 28 C 29 D 30 B 31 B 36 C 36A
C 36B C 36C D 37 B 39 C
[0760] Representative compounds of the invention had the Ki values
specified in parentheses immediately following the compound number
in Radioligand Binding Assay B: 7 (3.1 nM), 10 (514.5 nM), 13E
(122.6 nM), 14E (9.9 nM), 14K (18.4 nM), 14P (413.6 nM), 16 (2.7
nM), 16C (140.3 nM), 21A (45.7 nM), 21K (905.4 nM), and 27 (7.7
nM).
i[cAMP] Measurements.
[0761] The ability of the compounds to antagonize the formation of
cAMP can be assayed using the ELISA-based assay described in this
example. HEK-hCRTH.sub.2 cells are grown to 80-90% confluency. On
the day of the assay, the cells are washed with phosphate buffered
saline (PBS), incubated for 2 min in cell dissociation buffer,
harvested by centrifugation at 300 g for 7 min at room temperature
and resuspended at 1.25e10.sup.6 cells mL.sup.-1 in Hanks' balanced
salt solution containing 20 mM HEPES pH 7.4 and 0.75 mM IBMX
(HBSS/HEPES/IBMX). The assay is performed in 384-plate format with
0.01 mL HBSS/HEPES/IBMX per well containing 12 500 cells and 70 to
75 nl of the test compound and DK-PGD.sub.2 at various
concentrations. Following a 0 to 10 to min pre-incubation of the
cells with the test compound at 37.degree. C., 0.005 mL of 30 .mu.M
Forskolin dilute in HBSS 20 mM HEPES, is added at a final
concentration of 10 uM to initiate the reaction. After 10 to 60 min
incubation at room temperature or 37.degree. C., the cAMP content
was quantified using the cAMP XS+HitHunter chemiluminescence assay
(GE Healthcare 90-0075). Percent inhibition is calculated using the
Forskolin and EC85 DK-PGD.sub.2 controls.
.beta.-Arrestin Assay:
[0762] CHO-K1 cells obtained from DiscoverX are stably transfected
with human CRTH.sub.2 (propagation medium: F-12, 10% FBS, 300 ug/mL
hygB and 800 ug/mL G418). Cells are grown in T175 cm.sup.2 flask.
While in log phase, cells are collected via 0.05% trypsin
treatment. Triturated cells are filtered and 40 uL (10K cells) are
plated per well in a 384-well white clear bottom plate and
incubated 0/N. Cell plate is emptied via inversion and blotted dry.
Each well is filled with 35 uL of HBSS (with Ca.sup.++ and
Mg.sup.++) and incubated for 5 min. Compounds are added in volumes
of 1 .mu.L and the plate is gently shaken for 2 min., followed by
incubation at 37.degree. C. for 20 min. All compounds and controls
are diluted in HBSS assay buffer (with Ca.sup.++ and Mg.sup.++)
with a final concentration range of 10.sup.-5M to
3.times.10.sup.-11 M, 11 point Dose response curves at appropriate
half-log increments. Final DMSO % is .ltoreq.0.3%. Agonist Assay: 1
.mu.l/well of compound is added into cell plate and left to
incubate at 37.degree. C. for 90 min. Antagonist Assay: 1
.mu.l/well of compounds are added into a cell plate. Incubate 30
minutes at 37.degree. C. Stimulate cells with 1 ul/well of
PGD.sub.2 [100 nM] final. Incubate plate for 60 minutes at
37.degree. C. Resulting luminescent signal is detected via
Discoverx PathHunter Detection Kit per manufacturer's instructions.
A total of 12 .mu.l/well is added to each well. The plate is
covered and incubated for 60 min. with gentle shaking.
Chemiluminescent detection is done by a SpectraMax plate
reader.
Eosinophil Shape Change Assay in Human Whole Blood:
[0763] Blood is collected in vacutainers containing EDTA. The
antagonist is added to blood and incubated for 10 min at room
temperature. DK-PGD.sub.2 (13,14-dihydro-15-keto prostaglandin
D.sub.2) are then added to blood for 4 mM at 37.degree. C. in a
running water bath. Blood cells are then fixed in presence of cold
0.25% (v/v) paraformaldehyde prepared in 75% (v/v) DPBS without
Ca.sup.++ and Mg.sup.++ for 1 min on ice. 175 .mu.L of fixed blood
is transferred into 870 .mu.L of cold 155 mM NH.sub.4Cl lysis
solution and incubated at 4.degree. C. for at least 40 min. The
solution is then centrifuged at 430 g for 5 min and the supernatant
is discarded. Centrifuged cells are resuspended in residual
supernatant and sodium azide is added (1% final concentration).
Samples are analyzed with a FACs Calibur flow cytometer (Becton
Dickinson). Flow cytometry raw data is analyzed with Diva software
by isolating the eosinophils from the neutrophils based on their
high autofluorescence and determining the percent of total
eosinophils with increased forward light scatter. Maximum (100%)
and minimum (0%) shape change is determined in the presence of 10
.mu.M DK-PGD.sub.2 and DPBS, respectively. A dose response curve
with DK-PGD.sub.2 is performed with every assay to determine the
EC.sub.50 for each blood donor. Compounds are tested in 11-dose
titration curves in the presence of 50 nM DK-PGD.sub.2 to determine
an antagonist IC.sub.50.
[0764] Compounds of the present invention are selective for the
CRTH.sub.2 receptor over the DP receptor. Assays on the DP, as well
as other prostanoid, receptors are described in WO2003/06220.
[0765] While the present invention has been described in
conjunction with the specific embodiments set forth above, many
alternatives, modifications and other variations thereof will be
apparent to those of ordinary skill in the art. All such
alternatives, modifications and variations are intended to fall
within the spirit and scope of the present invention.
* * * * *