U.S. patent application number 09/918039 was filed with the patent office on 2002-01-31 for sulfonic acid or sulfonylamino n-(heteroaralkyl)-azaheterocyclylamide compounds.
Invention is credited to Barton, Jeffrey N., Becker, Michael R., Choi-Sledeski, Yong Mi, Ewing, William R., Gong, Yong, Green, Daniel M., Levell, Julian, Pauls, Heinz W..
Application Number | 20020013310 09/918039 |
Document ID | / |
Family ID | 23800027 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013310 |
Kind Code |
A1 |
Choi-Sledeski, Yong Mi ; et
al. |
January 31, 2002 |
Sulfonic acid or sulfonylamino
N-(heteroaralkyl)-azaheterocyclylamide compounds
Abstract
The compounds of formula I herein exhibit useful pharmacological
activity and accordingly are incorporated into pharmaceutical
compositions and used in the treatment of patients suffering from
certain medical disorders. More specifically, they are inhibitors
of the activity of Factor Xa. The present invention is directed to
compounds of formula I, compositions containing compounds of
formula I, and their use, for treating a patient suffering from, or
subject to, a physiological condition which can be ameliorated by
the administration of an inhibitor of the activity of Factor
Xa.
Inventors: |
Choi-Sledeski, Yong Mi;
(Collegeville, PA) ; Pauls, Heinz W.;
(Collegeville, PA) ; Barton, Jeffrey N.;
(Philadelphia, PA) ; Ewing, William R.;
(Downingtown, PA) ; Green, Daniel M.; (Ambler,
PA) ; Becker, Michael R.; (Norristown, PA) ;
Gong, Yong; (Norristown, PA) ; Levell, Julian;
(Royersford, PA) |
Correspondence
Address: |
Synnestvedt & Lechner LLP
2600 Aramark Tower
1101 Market Street
Philadelphia
PA
19107-2950
US
|
Family ID: |
23800027 |
Appl. No.: |
09/918039 |
Filed: |
July 30, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09918039 |
Jul 30, 2001 |
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09453307 |
Dec 2, 1999 |
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6281227 |
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09453307 |
Dec 2, 1999 |
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PCT/US99/12312 |
Jun 3, 1999 |
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PCT/US99/12312 |
Jun 3, 1999 |
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09090492 |
Jun 3, 1998 |
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09090492 |
Jun 3, 1998 |
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PCT/US97/22406 |
Dec 3, 1997 |
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60033159 |
Dec 13, 1996 |
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Current U.S.
Class: |
514/217.11 ;
514/329; 514/426; 540/605; 546/223; 548/557 |
Current CPC
Class: |
A61K 31/4365 20130101;
A61K 31/4184 20130101; C07D 491/04 20130101; A61K 31/437 20130101;
C07D 401/14 20130101; A61K 31/519 20130101; C07D 403/14 20130101;
A61K 45/06 20130101; A61K 31/00 20130101; A61P 9/00 20180101; C07D
401/12 20130101; A61K 31/517 20130101; A61K 31/4709 20130101; C07D
403/06 20130101; C07D 401/06 20130101; C07D 409/14 20130101; C07D
471/04 20130101; C07D 495/04 20130101; A61K 31/4725 20130101 |
Class at
Publication: |
514/217.11 ;
514/426; 514/329; 540/605; 546/223; 548/557 |
International
Class: |
A61K 031/55; A61K
031/445; A61K 031/40; C07D 223/12 |
Claims
What is claimed is:
1. 79wherein 80 is a monocyclic heteroaryl group containing at
least one nitrogen atom, or a bicyclic heteroaryl group which
includes a first proximal ring that is attached to Z and a ring
distal to said first ring, said distal ring including at least one
nitrogen atom; Z is alkylenyl,
--(CH.sub.2).sub.rC(O)NR"(CH.sub.2).sub.s--,
--(CH.sub.2).sub.sR"NC(O)(CH- .sub.2).sub.r--,
--(CH.sub.2).sub.rNR"(CH.sub.2).sub.s-- or
--(CH.sub.2).sub.s,NR"(CH.sub.2).sub.r--; R.sub.1 is hydrogen,
optionally substituted alkyl, optionally substituted alkenyl,
optionally substituted aralkyl, optionally substituted
heteroaralkyl, R'O(CH.sub.2).sub.x--, R'O.sub.2C(CH.sub.2).sub.x--,
R'C(O)(CH.sub.2).sub.x--, Y.sup.1Y.sup.2NC(O)CH.sub.2).sub.x--, or
Y.sup.1Y.sup.2(CH.sub.2).sub.x--- ; R' and R" are independently
hydrogen, optionally substituted alkyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
aralkenyl, optionally substituted heteroaralkenyl, optionally
substituted aralkyl or optionally substituted heteroaralkyl;
R.sub.2 is hydrogen, optionally substituted aralkyl, optionally
substituted heteroaralkyl, optionally substituted aralkenyl,
optionally substituted heteroaralkenyl,
R.sub.3R.sub.4NC(O)(CH.sub.2).sub.x--, R.sub.3S(O).sub.p-- or
R.sub.3R.sub.4NS(O).sub.p--; R.sub.3 is hydrogen, optionally
substituted alkyl, optionally substituted cycloalkyl, optionally
substituted heterocyclyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted aralkyl, optionally
substituted heteroaralkyl, optionally substituted aralkenyl or
optionally substituted heteroaralkenyl, or R.sub.1 and R.sub.3
taken together with the --N--S(O).sub.p--NR.sub.4-- moiety or the
-N-S(O)p-NR.sub.4- moiety through which R.sub.1 and R.sub.3 are
linked form a 5 to 7 membered optionally substituted heterocyclyl;
and R.sub.4 is hydrogen, optionally substituted alkyl, optionally
substituted cycloalkyl or optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted aralkyl or
optionally substituted heteroaralkyl, or R.sub.3 and R.sub.4 taken
together with the nitrogen to which R.sub.3 and R.sub.4 are
attached form an optionally substituted 4 to 7 membered
heterocyclyl; X.sub.1 and X.sub.1a are independently selected from
H, optionally substituted alkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted heteroaryl,
optionally substituted heteroaralkyl, or X.sub.1 and X.sub.1a taken
together form oxo; X.sub.2 and X.sub.2a are H, or taken together
form oxo; X.sub.3 is H, hydroxy, optionally substituted alkyl,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted aralkyl or optionally substituted
heteroaralkyl, or X.sub.3 and one of X.sub.1 and X.sub.1a taken
together form a 4 to 7 membered cycloalkyl; X.sub.4 is H,
optionally substituted alkyl, optionally substituted aralkyl, or
hydroxyalkyl; X.sub.5, X.sub.5a and X.sub.5b are independently
selected from H, R.sub.5R.sub.6N--, (hydroxy)HN--, (alkoxy)HN--, or
(amino)HN--, R.sub.7O--, R.sub.5R.sub.6NCO--,
R.sub.5R.sub.6NSO.sub.2--, R.sub.7CO--, halo, cyano, nitro and
R.sub.8(O)C(CH.sub.2).sub.q--, and when 81 is a bicyclic heteroaryl
group, one of X.sub.5, X.sub.5a and X.sub.5b is a substituent that
is alpha to a nitrogen of said distal ring of 82 and is selected
from the group consisting of H, hydroxy and H.sub.2N--, (optionally
substituted lower alkyl)HN (hydroxy)HN--, (alkoxy)HN--, or
(amino)HN--; Y.sup.1 and Y.sub.2 are independently hydrogen,
optionally substituted alkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted aralkyl
or optionally substituted heteroaralkyl, or Y.sup.1 and Y.sub.2
taken together with the N through which Y.sup.1 and Y.sup.2 are
linked form a 4 to 7 membered heterocyclyl; R.sub.5 and R.sub.6 are
independently H or optionally substituted lower alkyl, or one of
R.sub.5 and R.sub.6 is H and the other of R.sub.5 and R.sub.6 is
R.sub.8(O)CCH.sub.2-- or lower acyl; R.sub.7 is H, optionally
substituted lower alkyl, lower acyl or R.sub.8(O)CCH.sub.2--;
R.sub.8 is H, optionally substituted lower alkyl, alkoxy or
hydroxy; m is 0, 1, 2or 3; p and r are independently 1 or 2; q is 0
or 1, s is 0, 1 or 2; and x is 1, 2, 3, 4, or 5, or a
pharmaceutically acceptable salt thereof, an N-oxide thereof, a
hydrate thereof or a solvate thereof.
2. 83wherein 84 is a bicyclic heteroaryl which includes a first
proximal ring that is attached to Z and a ring distal to said first
ring, said distal ring including at least one nitrogen atom; Z is
alkylenyl; R.sub.1 is hydrogen, optionally substituted alkyl,
optionally substituted aralkyl, optionally substituted
heteroaralkyl, R'O(CH.sub.2).sub.x--, R'O.sub.2C(CH.sub.2).sub.x--,
Y.sup.1Y.sub.2NC(O)(CH.sub.2).sub.x--, or
Y.sup.1Y.sup.2N(CH.sub.2).sub.x--; R' is hydrogen, optionally
substituted alkyl, optionally substituted aralkyl or optionally
substituted heteroaralkyl; R.sub.2 is R.sub.3S(O).sub.p-- or
R.sub.3R.sub.4NS(O).sub.- p--; R.sub.3 is optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted aralkyl, optionally substituted
heteroaralkyl, optionally substituted aralkenyl or optionally
substituted heteroaralkenyl, or R.sub.1 and R.sub.3 taken together
with the --N--S(O).sub.p-- moiety or the --N--S(O).sub.p--NR.sub-
.4-- moiety through which R.sub.1 and R.sub.3 are linked form a 5
to 7 membered optionally substituted heterocyclyl; and R.sub.4 is
optionally substituted alkyl, optionally substituted cycloalkyl or
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted aralkyl or optionally substituted
heteroaralkyl, or R.sub.3 and R.sub.4 taken together with the
nitrogen to which R.sub.3 and R.sub.4 are attached form an
optionally substituted 4 to 7 membered heterocyclyl; X.sub.1 and
X.sub.1a are independently selected from H, optionally substituted
alkyl, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted heteroaryl or optionally substituted
heteroaralkyl, or X.sub.1 and X.sub.1a taken together form oxo;
X.sub.2 and X.sub.2a are H, or taken together form oxo; X.sub.3 is
H, hydroxy, optionally substituted alkyl, optionally substituted
aryl, optionally substituted heteroaryl, optionally substituted
aralkyl or optionally substituted heteroaralkyl, or X.sub.3 and one
of X.sub.1 and X.sub.1a taken together form a 4 to 7 membered
cycloalkyl; X.sub.4 is H, optionally substituted alkyl, optionally
substituted aralkyl, or hydroxyalkyl; X.sub.5, X.sub.5a and X5b are
independently selected from H, R.sub.5R.sub.6N--, (hydroxy, alkoxy
or amino)HN--, R.sub.7O--, R.sub.5R.sub.6NCO--,
R.sub.5R.sub.6NSO.sub.2--, R.sub.7CO--, halo, cyano, nitro or
R.sub.8(O)C(CH.sub.2).sub.q--, and one of X.sub.5, X.sub.5a, and
X.sub.5b is a substituent that is alpha to a nitrogen of said
distal ring of 85 and is selected from the group consisting of H,
hydroxy or H.sub.2N--, (optionally substituted lower alkyl)HN
(hydroxy)HN--, (alkoxy)HN--, or (amino)HN--; Y.sup.1 and Y.sup.2
are independently hydrogen, optionally substituted alkyl,
optionally substituted aryl, optionally substituted aralkyl or
optionally substituted heteroaralkyl, or Y.sub.1 and Y.sup.2 taken
together with the N through which Y.sup.1 and Y.sup.2 are linked
form a 4 to 7 membered heterocyclyl; R.sub.5 and R.sub.6 are
independently H or optionally substituted lower alkyl, or one of
R.sub.5 and R.sub.6 is H and the other of R.sub.5 and R.sub.6 is
R.sub.8(O)CCH.sub.2-- or lower acyl; R.sub.7 is H, optionally
substituted lower alkyl, lower acyl or R.sub.8(O)CCH.sub.2--;
R.sub.8 is H, optionally substituted lower alkyl, alkoxy or
hydroxy; m is 0, 1, 2or 3; p is 1 or 2; q is 0 or 1, and x is 1, 2,
3, 4, or 5, or a pharmaceutically acceptable salt thereof, an
N-oxide thereof, a hydrate thereof or a solvate thereof.
3. The compound of claim 1 wherein 86is a monocyclic heteroaryl
group containing at least one nitrogen atom.
4. The compound of claim 1 wherein Z is alkylenyl,
--(CH.sub.2).sub.rC(O)N- R"(CH.sub.2).sub.s--,
--(CH.sub.2).sub.sR"NC(O)(CH.sub.2).sub.r--,
--(CH.sub.2).sub.rNR"(CH.sub.2).sub.s-- or
--(CH.sub.2).sub.sNR"(CH.sub.2- ).sub.r--.
5. The compound of claim 1 wherein R.sub.1 is hydrogen, optionally
substituted alkyl, optionally substituted alkenyl, optionally
substituted aralkyl, optionally substituted heteroaralkyl,
R'O(CH.sub.2).sub.x--, R'O.sub.2C(CH.sub.2).sub.x--,
R'(O)(CH.sub.2).sub.x--, Y.sup.1Y.sup.2NC(O)(CH.sub.2).sub.x--, or
Y.sup.1Y.sup.2N(CH.sub.2).sub.x- --.
6. The compound of claim 1 wherein R.sub.2 is selected from the
group consisting of 87
7. The compound of claim 1 wherein 88is selected from the group
consisting of 89
8. The compound of claim 1 wherein R.sub.1 is H, optionally
substituted heteroaralkyl, optionally substituted aralkyl or
optionally substituted alkyl.
9. The compound of claim 1 wherein R.sub.2 is
R.sub.3S(O).sub.p--.
10. The compound of claim 9 wherein p is 2.
11. The compound of claim 9 wherein R.sub.3 is optionally
substituted phenyl, optionally substituted naphthyl, optionally
substituted thienyl, optionally substituted benzothienyl,
optionally substituted thienyopyridyl, optionally substituted
quinolinyl, or optionally substituted isoquinolinyl.
12. The compound of claim 1 wherein Z is methylenyl and m is 1.
13. The compound of claim 1 wherein X.sub.2 and X.sub.2a taken
together are oxo.
14. The compound of claim 1 wherein each of X.sub.1, X.sub.1a,
X.sub.3 and X.sub.4 is H.
15. The compound of claim 1 wherein 90is optionally substituted
isoquinolinyl.
16. The compound of claim 15 wherein Z is attached to isoquinolinyl
at the 7-position thereof.
17. The compound of claim 1 wherein 91is optionally substituted
quinolinyl.
18. The compound of claim 17 wherein Z is attached to quinolinyl at
the 7-position thereof.
19. The compound of claim 1 wherein 92is an optionally substituted
quinazolinyl.
20. The compound of claim 19 wherein Z is attached to quinazolinyl
at the 7-position thereof.
21. The compound of claim 1 wherein 93is an optionally substituted
moiety of formula 94and W is S, O or NR.sub.11, wherein R.sub.11 is
H, alkyl, aralkyl, heteroaralkyl, R.sub.8(O)C(CH.sub.2).sub.q--,
and A is CH or N.
22. The compound of claim 21 wherein Z is bonded to said moiety
through the 5 membered ring.
23. The compound of claim 1 wherein one of X.sub.5, X.sub.5a and
X.sub.5b is a substituent that is on the proximal ring of bicyclic
95at a position that is alpha to where Z is attached to 96and is
selected from the group consisting of H, hydroxy and amino.
24. The compound of claim 23 wherein one of X.sub.5, X.sub.5a, and
X.sub.5b is hydroxy or amino.
25. The compound of claim 1 wherein one of X.sub.5, X.sub.5a and
X.sub.5b that substitutes the distal ring of 97at the position
alpha to a nitrogen thereof is H or (H, optionally substituted
loweralkyl, hydroxy or amino)HN--.
26. A compound according to claim 1 which is selected from
3-[[1-(4-Aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-(5-chloro-1H-
-indol-2-ylmethyl)amino]propionic acid methyl ester;
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)-(3-e-
thylbutyl)amino]pyrrolidin-2-one;
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[be-
nzyl-(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)thiaz-
ol-5-ylmethylamino]pyrrolidin-2-one;
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)--
[(5-chloro-1H-indol-2-ylmethyl-(2H-pyrazol-3-ylmethyl))amino]pyrrolidin-2--
one;
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(6-chlorobenzo[b]thiophen-2-y-
lmethyl)amino]pyrrolidin-2-one;
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(6-
-chlorothieno[2,3-b]pyridin-2-ylmethyl)amino]pyrrolidin-2-one;
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(1H-pyrrolo[2,3-c]pyridin-2-ylmet-
hyl)amino]pyrrolidin-2-one;
3-{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrr-
olidin-3-(S)-ylamino]methyl}-1H-quinolin-2-one;
1-(7-Aminothieno[3,2-b]pyr-
idin-2-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-o-
ne; 2-(5-Chlorothiophen-2-yl)ethenesulfonic
acid[2-oxo1-(1H-pyrrolo[3,2-c]-
pyridin-2-ylmethyl)-pyrrolidin3-(R)-yl]amide;
{[2-(5-Chlorothiophen-2-yl)e-
thenesulfonyl]-[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-
-(R)-yl]amino}acetic acid isopropyl ester;
1-(4-Aminoquinolin-7-ylmethyl)--
3-(R)-[(5-chloro-1H-indol-2-ylmethyl)amino]pyrrolidin-2-one;
5-Chloro-1H-benzoimidazole-2-sulfonic
acid[1-(4-aminoquinolin-7-ylmethyl)-
-2-oxopyrrolidin-3-(R)-yl]amide7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amide
trifluoroacetate; 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquino-
lin-7-yl-methyl)-2-oxopyrrolidin-3-yl]amide hydrochloride;
7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-yl-methyl)-2-
-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sul- fonic
acid[1-(1-aminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(R)-yl]ami-
de trifluoroacetate; 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-hydroxyisoquinolin-7ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]amide;
7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-ylmethyl)-2--
oxopyrrolidin-3-(R,S)-yl]methylamide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-ylmethyl)-2--
oxopyrrolidin-3-(S)-yl]methyl amide trifluoroacetate;
Benzo[b]thiophene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxo-
pyrrolidin-3-(S)-yl]amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-s- ulfonic
acid[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]am-
ide trifluoroacetate; 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-amino-6-methoxyisoquinolin-7-ylmethyl2-oxopyrrolidin-3-(S)-yl]a-
mide hydrochloride; 7-Methoxynaphthalene-2-sulfonic
acid[1-(6-methoxyisoquinolin-7-ylmethyl)-2-oxo
pyrrolidin-3-(S)-yl]amide trifluoroacetate;
4-(2-Chloro-6-nitophenoxy)benzene sulfonic
acid[1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl-
]amide trifluoroacetate; 7-Methoxynaphthalene-2-sulfonic
acid[1-(1,6-diaminoisoquinolin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amid-
e trifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1,6-diaminoisoquinolin-7-yl-methyl)-2-oxo
pyrrolidin-3-(S)-yl]ami- de trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1(2-aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate; Benzo[b]thiophene-2-sulfonic
acid[1-(2-aminoquinolin-7--
ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-7-ylmethyl)-2-oxo-
pyrrolidin-3-(S)-yl]methyl amide trifluoroacetate;
7-Methoxynaphthalene-2-- sulfonic
acid[1-(2-hydroxyquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)yl]met-
hyl amide; 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-5-ylmet-
hyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-5-ylmethyl)-2-oxo-
pyrrolidin-3-(S)-yl]methyl amide trifluoroacetate;
7-Methoxynaphthalene-2-- sulfonic
acid[1-(2-hydroxyquinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]me-
thylamide; 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-6-ylmet-
hyl)-2-oxopyrrolidin-3-(S)-yl]amide;
7-Methoxynaphthalene-2-sulfonic
acid[1-(2-hydroxyquinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide;
7-Methoxynaphthalene-2-sulfonic
acid[1-(1H-benzimidazol-5-ylmethyl)-2-oxo-
pyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfoni- c
acid[2-(1H-benzimidazol-5-ylethyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate; 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-aminoquinazol-
in-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]methylamide
trifluoroacetate; 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-aminothieno[2,3-d]pyrimidin-6-y-
l-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic
acid[2-(6-aminothieno[2,3-d]pyrimidin-6-y-
l-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic
acid[1-(7-aminothieno[2,3-c]pyridin-3-yl--
methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic
acid[1-(7-hydroxythieno[2,3-c]pyridin-3-y-
l-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic
acid[1-(4-aminothieno[3,2-c]pyridin-3-yl--
methyl)-2-oxopyrrolidin-3-(R,S)-yl]amide trifluoroacetate;
7-Methoxynaphthalene-2-sulfonic
acid[1-(4-hydroxythieno[3,2-c]pyridin-3-y-
l-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amide trifluoroacetate;
Benzo[b]thiophene-2-sulfonic
acid[1-(4-aminothieno[3,2-c]pyridin-3-yl-met-
hyl)-2-oxopyrrolidin-3-(R,S)-yl]amide trifluoroacetate;
Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-amino-isoquinolin-7-ylmethyl)--
2-oxo-pyrrolidin-3-(S)-yl]-amide; Thieno[2,3-b]pyridine-2-sulfonic
acid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
4-Pyridin-3-yl-thiophene-2-sulfonic
acid[1-(1-amino-isoquinolin-7-ylmethy-
l)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
5'Chloro-[2,2']bithiophenyl-5-sulfoni- c
acid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3(S)-yl]-a-
mide; 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[2-oxo-1-(1H-pyrrolo[3-
,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;
5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(1-amino-isoquinolin-7-ylm-
ethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
2-(5-Chloro-thiophen-2-yl)-ethene- sulfonic
acid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl-
]-amide; 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinazolin--
6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-thieno[2,3-d]pyrimi-
din-6yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-thieno[3,2-d]pyrimi-
din-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
5'-Chloro-[2,2']bithiophenyl-5-2-sulfonic
acid[1-(4-amino-thieno[3,2-d]py-
rimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1,6-diamino-isoquinolin-7-ylmeth-
yl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
2-(5-Chloro-thiophen-2-yl)-ethenesul- fonic
acid[1-(1-amino-isoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-a-
mide; 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(1-amino-isoquinolin--
7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
2-(5-Chloro-thiophen-2-yl)-e- thenesulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidi-
n-3-(S)-yl]-amide; 3-(R)-5 Chlorothiophen-2-yl)-ethenesulphonic
acid[1-(4-aminoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate; 2-(S)-[[1-(4
Amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidi-
n-3-yl]-(6-chloro-benzo[b]thiophene-2-sulfonyl)-amino]-acetic acid
methyl ester, trifluoroacetate;
2-(S)-6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide,
trifluoroacetate; 2-(s)-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide,
trifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(4-amino-quinolin-6-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide,
ditrifluoroacetate:
N-(3-Amino-pyridin-4-yl)-2-[3-(7-methoxy-naphthalene--
2-sulfonylamino)-2-oxo-pyrrolidin-1-yl]-acetamide;
2-[3-(7-Methoxy-naphtha-
lene-2-sulfonylamino)-2-oxo-pyrrolidin-1-yl]-N-pyridin-4-yl-acetamide;
6-Chlorobenzo[b]thiophene-2-sulfonic
acid{2-oxo-1-[2-(pyridin-4-yl-amino)-
ethyl]-pyrrolidin-3-(S)-yl}-amide trifluoroacetate;
5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid{2-oxo-1-[2-(pyridin-4-ylamin-
o)-ethyl]-pyrrolidin-3-yl}-amide;
6-Chloro-thieno[2,3-b]pyridine-2-sulfoni- c
acid{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide
trifluoacetate; Thieno[3,2-b]pyridine-2-sulfonic
acid{2-oxo-1-[2-(pyridin- -4ylamino)-ethyl]-pyrrolidin-3-yl}-amide
ditrifluoroacetate; 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid{2-oxo-1-[2-(pyridin-4-ylam-
ino)-ethyl]-pyrrolidin-3-yl}-amide;
(S)-5'-Chloro-[2,2']bithiophenyl-5-sul- fonic
acid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolid-
in-3-yl}-amide ditrifluoroacetate;
(S)-6Chloro-benzo[b]thiophene-2-sulfoni- c
acid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-
-yl}-amide ditrifluoroacetate;
((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-
-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3(-yl}-amino)-acetic
acid methyl ester;
((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyrid-
in-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid
trifluoroacetate; 6-Chloro-benzo[b]thiophene-2-sulfonic acid
allyl-{2-oxo-1-[2-(pyridin-4-y-
lamino)-ethyl]-pyrrolidin-3-yl}-amide;
6-Chloro-benzo[b]thiophene-2-sulfon- ic acid
methyl-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-ami-
de; (S)-2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid{1-[2-(2-amino-3-chl-
oro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amide
trifluoroacetate; (S)-Thieno[3,2-b]pyridine-2-sulfonic
acid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3--
yl}-amide ditrifluoroacetate;
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-
-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic
acid methyl ester;
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1--
[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid
isopropyl ester;
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-
-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid
trifluoroacetate. 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid
(2-methoxy-ethyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-
-amide trifluoroacetate;
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-o-
xo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic
acid ethyl ester trifluoroacetate;
3-(5-Chloro-thiophen-2-yl)-N-{2-oxo-1-[2-(p-
yridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-acrylamide
trifluoroacetate;
1-[1-(4-Aminoquinazolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(4-chlorop-
henyl)urea trifluoroacetate;
N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrr-
olidin-3-(S)-yl]-2-(5-chlorothiophen-2-yloxy)acetamide
trifluoroacetate;
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmethyl)ami-
no]pyrrolidin-2-one trifluoroacetate;
1-[(4-Aminoquinazolin-7-ylmethyl)-2--
oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl) urea
trifluoroacetate and 5-Chlorothiophene-2-carboxylic
acid[1-(4-aminoquinazolin-7-ylmethyl)--
2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
{[1-(4-Aminoquinazolin-7--
ylmethyl2-oxo-pyrrolidin-3-(S)-yl]-[3-(5-chlorothiophen-2-yl)acryloyl]amin-
o}acetic acid methyl ester trifluoroacetate;
6-Chlorobenzo[b]thiophene-2-s- ulfonic
acid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]ami-
de trifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-aminoisoquinolin
-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indo-
l-2-ylmethyl)amino]pyrrolidin-2-one trifluoroacetate;
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[3-(5-chlorothiophen-2-yl)allylami-
no]pyrrolidin-2-one trifluoroacetate;
N-[1-(4-Aminoquinazolin-7-ylmethyl)--
2-oxopyrrolidin-3-(S)-yl]-3-(5-chlorothiophen-2-yl)acrylamide
trifluoroacetate; 1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro
1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-one trifluoroacetafe;
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][2-(5-chlorot-
hiophen-2-yl)ethenesulfonyl]amino}acetic acid methyl ester
trifluoroacetate;
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S-
)-yl](5-chloro-1H-indol-2-ylmethyl)amino]acetic acid methyl ester
trifluoroacetate;
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S-
)-yl][(5-chlorothiophen-2-yl)allyl]amino}acetic acid methyl ester
trifluoroacetate;
{1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3--
(S)-yl]-3-(5-chlorothiophen-2-yl)ureido}acetic acid methyl ester
trifluoroacetate;
N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(-
R)-yl]-3-(5-chlorothiophen-2-yl)acrylamide trifluoroacetate;
1-(4-Aminoquinazolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)ami-
no]pyrrolidin-2-one trifluoroacetate;
1-[1-(4-Aminoquinazolin-7-ylmethyl)--
2-oxopyrrolidin-3-(R)-yl]-3-(5-chlorothiophen-2-yl) urea
trifluoroacetate and 5-Chlorothiophene-2-carboxylic
acid[1-(4-aminoquinazolin-7-ylmethyl)--
2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
{[1-(4-Aminoquinazolin-7--
ylmethyl)-2-oxopyrrolidin-3-(R)-yl](5-chloro-1H-indol-2-ylmethyl)amino]ace-
tic acid methyl ester trifluoroacetate;
1-(4-Aminoquinolin-7-ylmethyl)-3-(-
S)-[(5-chloro-1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-one
trifluoroacetate; 5-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate; 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3(S)--
yl]-amide; 7-Methoxy-naphthalene-2-sulfonic
acid[1-(4-amino-quinazolin-7-y-
lmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(4-amino-quinazolin-7-yl-
methyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid[1-
(4-amino-quinazolin-7-ylmet- hyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate; 5-Chloro-benzo[b]thiophene-2-sulfonic acid
(S)-[1-(4-amino-thieno[3,2-d]p-
yrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide trifluoroacetate;
Thieno[3,2-b]pyridine-2-sulfonic acid
(S)-[1-(4-amino-thieno[3,2-d]pyrimi-
din-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic acid
(S)-[1-(4-amino-thieno[3,2-d]p-
yrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide trifluoroacetate.
5'-Chloro-[2,2']bithiophenyl-5-sulfonic acid
(S)-[1-(4-amino-thieno[3,2-d-
]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate; 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid
(S)-[1-(4-amino-thieno[3,2-
-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate; 5-Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)-1-(4-amino-thieno[3,2-d]py-
rimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide trifluoroacetate;
5-Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)-1-(4-amino-thieno[2,3-d]py-
rimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide trifluoroacetate;
5'-Chloro[2,2']bithiophenyl-5-sulfonic
acid[(S)-1-(4-amino-thieno[2,3-d]p-
yrimidin-6ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide trifluoroacetate;
Thieno[3,2-b]pyridine-2-sulfonic
acid[(S)-1-(4-amino-thieno[2,3-d]pyrimid-
in-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)1-(4-amino-thieno[2,3-d]pyr-
imidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide trifluoroacetate;
5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(4-amino-thieno[3,2-d]pyri-
midin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(4-amino-thieno[3,2-d]pyrimidin-7-
-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)-1-(4-amino-thieno[3,2-d]pyri-
midin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide;
6-Chloro-benzo[b]thiophene- -2-sulfonic acid[1-
(4-aminoquinolin-7-yl methyl)-2-oxo-3(R)-pyrrolidin-3-- yl]amide
trifluoroacetate; and 2-(5-Chlorothiophen-2-yl)-ethenesulfonic
acid[1-(4-aminoquinazolin-7-yl
methyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate.
27. A compound according to claim 1 which is selected from
7-Methoxynaphthalene-2-sulfonic
acid[1-(6methoxyisoquinolin-7-ylmethyl)-2-
-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate;
1-(4-Aminoquinolin-7-ylme-
thyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-ylmethyl)amino]pyrrolidin-2-one
trifluoroacetate: 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-a-
mide; 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(4-amino-quinazolin-
-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid
(S)-[1-(4-amino-thieno[3,2-
-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonic acid[1-
(1-aminoisoquinolin-7-ylmethyl)-- 2-oxopyrrolidin-3-(R)-yl]amide
trifluoroacetate: 6-Chlorobenzo[b]thiophene- -2-sulfonic
acid{2-oxo-1-[2-(pyridin-4-yl-amino)ethyl]-pyrrolidin-3-(S)-yl-
}-amide trifluoroacetate;
((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo--
1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3(-yl}-amino)-acetic
acid methyl ester; Thieno[3,2-b]pyridine-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[2-
,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
ditrifluoroacetate; Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-amino-isoquinolin-7-ylmethyl)--
2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
2(S)-(5Chloro-thiophen2- -yl)-ethenesulfonic
acid[1-(4amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-
-(S)-yl]-amide trifluoroacetate;
6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1,6diamino-isoquinolin-7yl
methyl)-2-oxo-pyrrolidin-3-(S)-yl]-ami- de bistrifluoroacetate;
6-Chlorobenzo[b]thiophene-2-sulfonic acid[1-(4-aminoquinolin-7-yl
methyl)-2-oxo-3(R)-pyrrolidin-3-yl]amide trifluoroacetate; and
2-(5-Chlorothiophen-2-yl)-ethenesulfonic
acid[1-(4-aminoquinazolin-7-yl
methyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate.
28. A compound according to claim 1 of the formula 98wherein 99 is
a radical selected from the group consisting of 100W is S, O or
NR.sub.11, wherein R.sub.11 is H, alkyl, aralkyl, heteroaralkyl or
R.sub.8(O)C(CH.sub.2).sub.q--; A is CH or N; and R.sub.2 is a
radical selected from the group consisting of 101
29. A compound according to claim 1 of the formula 102wherein
103R.sub.1 is H; and R.sub.2 is a radical selected from the group
consisting of: 104R.sub.1 is H; and R.sub.2 is a radical selected
from the group consisting of: 105R.sub.1 is H; and R.sub.2 a
radical selected from the group consisting of: 106R.sub.1 is H; and
R.sub.2 is a radical selected from the group consisting of: 107
30. A pharmaceutical composition comprising a pharmaceutically
acceptable amount of a compound according to claim 1 and a
pharmaceutically acceptable carrier.
31. A method for treating a patient suffering from a physiological
disorder capable of being modulated by inhibiting an activity of
Factor Xa comprising administering to the patient a therapeutically
effective amount of a compound according to claim 1.
32. The method according to claim 31 wherein the physiological
disorder is abnormal thrombus formation, acute myocardial
infarction, unstable angina, thromboembolism, acute vessel closure
associated with thrombolytic therapy or percutaneous transluminal
coronary angioplasty, transient ischemic attacks, stroke,
pathologic thrombus formation occurring in the veins of the lower
extremities following abdominal, knee and hip surgery, a risk of
pulmonary thromboembolism, or disseminated systemic intravascular
coagulopathy occurring in vascular systems during septic shock,
certain viral infections or cancer.
33. The method according to claim 31 wherein the physiological
disorder is abnormal thrombus formation, acute myocardial
infarction, unstable angina, thromboembolism, acute vessel closure
associated with thrombolytic therapy, transient ischemic attacks,
restenosis post coronary or venous angioplasty, pathologic thrombus
formation occurring in the veins of the lower extremities following
abdominal, knee and hip surgery or a risk of pulmonary
thromboembolism.
34. The method according to claim 31 wherein the physiological
disorder is stroke, vessel luminal narrowing, or disseminated
systemic intravascular coagulopathy occurring in vascular systems
during septic shock, certain viral infections or cancer.
35. The method of claim 31 wherein said compound according to claim
1 is administered in combination with at least one other agent
selected from diagnostic agents, cardioprotective agents, direct
thrombin inhibiting agents, anticoagulant agents, antiplatelet
agents and fibrinoloytic agents.
36. The method of claim 35 wherein said other agent is selected
from standard heparin, low molecular weight heparin, direct
thrombin inhibitors, aspirin, fibrinogen receptor antagonists,
streptokinase, urokinase and tissue plasminogen activator.
37. The method of claim 36 wherein said other agent is selected
from direct thrombin inhibitors and fibrinogen receptor
antagonists.
38. The method of claim 37 wherein said thrombin inhibitor is
selected from boroarginine derivatives, boropeptides, hirudin,
argatroban and the pharmaceutically acceptable salts, prodrugs,
derivatives and analogs thereof.
39. The pharmaceutical composition of claim 30 further comprising
at least one other agent selected from diagnostic agents,
cardioprotective agents, direct thrombin inhibiting agents,
anticoagulant agents, antiplatelet agents and fibrinoloytic
agents.
40. The pharmaceutical composition of claim 39 wherein said other
agent is selected from standard heparin, low molecular weight
heparin, direct thrombin inhibitors, aspirin, fibrinogen receptor
antagonists, streptokinase, urokinase and tissue plasminogen
activator.
41. The pharmaceutical composition of claim 40 wherein said other
agent is selected from direct thrombin inhibitors and fibrinogen
receptor antagonists.
42. A kit for treating a patient suffering from a physiological
disorder capable of being modulated by inhibiting an activity of
Factor Xa, said kit comprising a plurality of separate containers,
wherein at least one of said containers contains a compound
according to claim 1 and at least one other of said containers
contains at least one other agent selected from diagnostic agents,
cardioprotective agents, direct thrombin inhibiting agents,
anticoagulant agents, antiplatelet agents and fibrinoloytic agents,
each of said containers optionally further containing a
pharmaceutically acceptable carrier.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of International
Application No. PCT/US99/12312, filed Jun. 3, 1999, which is, in
turn, a continuation-in-part of U.S. application Ser. No.
09/090,492, filed Jun. 3, 1998, which is, in turn, a
continuation-in-part of International Application No.
PCT/US97/22406, filed Dec. 3, 1997, which is, in turn, a
continuation-in-part of U.S. Provisional Application No.
60/033,159, filed Dec. 13, 1996, now abandoned.
FIELD OF THE INVENTION
[0002] The compounds of formula I exhibit useful pharmacological
activity and accordingly are incorporated into pharmaceutical
compositions and used in the treatment of patients suffering from
certain medical disorders. More specifically, they are Factor Xa
inhibitors. The present invention is directed to compounds of
formula I, compositions containing compounds of formula I and their
use for treating a patient suffering from, or subject to,
conditions which can be ameliorated by the administration of an
inhibitor of Factor Xa.
[0003] Factor Xa is the penultimate enzyme in the coagulation
cascade. Both free factor Xa and factor Xa assembled in the
prothrombinase complex (Factor Xa, Factor Va, calcium and
phospholipid) are inhibited by compounds of formula I. Factor Xa
inhibition is obtained by direct complex formation between the
inhibitor and the enzyme, and is therefore independent of the
plasma co-factor antithrombin III. Effective factor Xa inhibition
is achieved by administering the compounds either by oral
administration, continuous intravenous infusion, bolus intravenous
administration or any other parenteral route such that it achieves
the desired effect of preventing the factor Xa induced formation of
thrombin from prothrombin.
[0004] Anticoagulant therapy is indicated for the treatment and
prophylaxis of a variety of thrombotic conditions of both the
venous and arterial vasculature. In the arterial system, abnormal
thrombus formation is primarily associated with arteries of the
coronary, cerebral and peripheral vasculature. The diseases
associated with thrombotic occlusion of these vessels principally
include acute myocardial infarction (AMI), unstable angina,
thromboembolism, acute vessel closure associated with thrombolytic
therapy and percutaneous transluminal coronary angioplasty (PTCA),
transient ischemic attacks, stroke, and intermittent claudication
and bypass grafting (CABG) of the coronary or peripheral arteries.
Chronic anticoagulant therapy may also be beneficial in preventing
the vessel luminal narrowing (restenosis) that often occurs
following PTCA and CABG, and in the maintenance of vascular access
patency in long-term hemodialysis patients. With respect to the
venous vasculature, pathologic thrombus formation frequently occurs
in the veins of the lower extremities following abdominal, knee and
hip surgery (deep vein thrombosis, DVT). DVT further predisposes
the patient to a higher risk of pulmonary thromboembolism. A
systemic, disseminated intravascular coagulopathy (DIC) commonly
occurs in both vascular systems during septic shock, certain viral
infections and cancer. This condition is characterized by a rapid
consumption of coagulation factors and their plasma inhibitors
resulting in the formation of life-threatening clots throughout the
microvasculature of several organ systems. The indications
discussed above include some, but not all, of the possible clinical
situations where anticoagulant therapy is warranted. Those
experienced in this field are well aware of the circumstances
requiring either acute or chronic prophylactic anticoagulant
therapy.
SUMMARY OF THE INVENTION
[0005] This invention is directed to compounds of formula I below
as well as to their pharmaceutical use for treating a patient
suffering from a physiological disorder capable of being modulated
by inhibiting the activity of Factor Xa: 1
[0006] wherein 2
[0007] is a monocyclic heteroaryl group containing at least one
nitrogen atom, or a bicyclic heteroaryl group which includes a
first proximal ring that is attached to Z and a ring distal to said
first ring, said distal ring including at least one nitrogen
atom;
[0008] Z is alkylenyl, --(CH.sub.2).sub.rC(O)NR"(CH.sub.2).sub.s--,
--(CH.sub.2).sub.sR"NC(O)(CH.sub.2).sub.r--,
--(CH.sub.2).sub.rNR"(CH.sub- .2).sub.s-- or
--(CH.sub.2).sub.sNR"(CH.sub.2).sub.r--;
[0009] R.sub.1 is hydrogen, optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted aralkyl,
optionally substituted heteroaralkyl, R'O(CH.sub.2).sub.x--,
R'O.sub.2C(CH.sub.2).su- b.x--, R'C(O)(CH.sub.2).sub.x--,
Y.sup.1Y.sup.2NC(O)(CH.sub.2).sub.x--, or
Y.sup.1Y.sup.2N(CH.sub.2).sub.x--;
[0010] R' and R" are independently hydrogen, optionally substituted
alkyl, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted aralkenyl, optionally
substituted heteroaralkenyl, optionally substituted aralkyl or
optionally substituted heteroaralkyl;
[0011] R.sub.2 is hydrogen, optionally substituted aralkyl,
optionally substituted heteroaralkyl, optionally substituted
aralkenyl, optionally substituted heteroaralkenyl,
R.sub.3R.sub.4NC(O)(CH.sub.2)x--, R.sub.3S(O).sub.p-- or
R.sub.3R.sub.4NS(O).sub.p--;
[0012] R.sub.3 is hydrogen, optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted
heterocyclyl, optionally substituted aryl, optionally substituted
heteroaryl, optionally substituted aralkyl, optionally substituted
heteroaralkyl, optionally substituted aralkenyl or optionally
substituted heteroaralkenyl, or R.sub.1 and R.sub.3 taken together
with the --N--S(O).sub.p-- moiety or the
--N--S(O).sub.p--NR.sub.4-- moiety through which R.sub.1 and
R.sub.3 are linked form a 5 to 7 membered optionally substituted
heterocyclyl; and
[0013] R.sub.4 is hydrogen, optionally substituted alkyl,
optionally substituted cycloalkyl or optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted aralkyl
or optionally substituted heteroaralkyl, or R.sub.3 and R.sub.4
taken together with the nitrogen to which R.sub.3 and R.sub.4 are
attached form an optionally substituted 4 to 7 membered
heterocyclyl;
[0014] X.sub.1 and X.sub.1a are independently selected from H,
optionally substituted alkyl, optionally substituted aryl,
optionally substituted aralkyl, optionally substituted heteroaryl,
optionally substituted heteroaralkyl, or X.sub.1 and X.sub.1a taken
together form oxo;
[0015] X.sub.2 and X.sub.2a are independently H, or taken together
form oxo;
[0016] X.sub.3 is H, hydroxy, optionally substituted alkyl,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted aralkyl or optionally substituted
heteroaralkyl, or X.sub.3 and one of X.sub.1 and X.sub.1a taken
together form a 4 to 7 membered cycloalkyl;
[0017] X.sub.4 is H, optionally substituted alkyl, optionally
substituted aralkyl, or hydroxyalkyl;
[0018] X.sub.5, X.sub.5a and X.sub.5b are independently selected
from H R.sub.5R.sub.6N--, (hydroxy)HN--, (alkoxy)HN--,-or
(amino)HN--, R.sub.7O--, R.sub.5R.sub.6NCO--,
R.sub.5R.sub.6NSO.sub.2--, R.sub.7CO--, halo, cyano, nitro and
R.sub.8(O)C(CH.sub.2).sub.q--, and, when 3
[0019] is a bicyclic heteroaryl group, one of X.sub.5, X.sub.5a and
X.sub.5b is a substituent that is alpha to a nitrogen of said
distal ring of 4
[0020] and is selected from the group consisting of H, hydroxy and
H.sub.2N--, (optionally substituted lower alkyl)HN (hydroxy)HN--,
(alkoxy)HN--, and (amino)HN--;
[0021] Y.sup.1 and Y.sup.2 are independently hydrogen, optionally
substituted alkyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted aralkyl or
optionally substituted heteroaralkyl, or Y.sup.1 and Y.sup.2 taken
together with the N through which Y.sup.1 and Y.sup.2 are linked
form a 4 to 7 membered heterocyclyl;
[0022] R.sub.5 and R.sub.6 are independently H or optionally
substituted lower alkyl, or one of R.sub.5 and R.sub.6 is H and the
other of R.sub.5 and R.sub.6 is R.sub.8(O)CCH.sub.2-- or lower
acyl;
[0023] R.sub.7 is H, optionally substituted lower alkyl, lower acyl
or R.sub.8(O)CCH.sub.2--;
[0024] R.sub.8 is H, optionally substituted lower alkyl, alkoxy or
hydroxy;
[0025] m is 0, 1, 2 or3;
[0026] p and r are independently 1 or 2;
[0027] q is 0 or 1,
[0028] s is 0, 1 or 2; and
[0029] x is 1, 2, 3, 4, or 5, or a pharmaceutically acceptable salt
thereof, an N-oxide thereof, a hydrate thereof or a solvate
thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0030] As used above, and throughout the description of the
invention, the following terms, unless otherwise indicated, shall
be understood to have the following meanings:
[0031] Definitions
[0032] "Patient" includes both humans and other mammals.
[0033] "Alkyl" means an aliphatic hydrocarbon group which may be
straight- or branched-chain having about 1 to about 20 carbon atoms
in the chain. Preferred alkyl groups have 1 to about 12 carbon
atoms in the chain. Branched means that one or more lower alkyl
groups such as methyl, ethyl or propyl are attached to a linear
alkyl chain. "Lower alkyl" means an alkyl group having about 1 to
about 4 carbon atoms in the chain which may be straight or
branched. The alkyl group may be substituted with one or more
"alkyl group substituents" which may be the same or different, and
include halo, cycloalkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy,
amino, acylamino, aroylamino, carboxy, alkoxycarbonyl,
aralkyloxycarbonyl, heteroaralkyloxycarbonyl or
R.sub.9R.sub.10NCO--, wherein R.sub.9 and R.sub.10 are
independently hydrogen, optionally substituted alkyl, optionally
substituted aryl, optionally substituted aralkyl or optionally
substituted heteroaralkyl, or R.sub.9 and R.sub.10 taken together
with the N through which R.sub.9 and R.sub.10 are linked form a 4
to 7 membered heterocyclyl. Exemplary alkyl groups include methyl,
trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl,
n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl,
methoxyethyl, carboxymethyl, methoxycarbonylethyl,
benzyloxycarbonylmethyl, pyridylmethyloxycarbonylmethyl.
[0034] "Alkenyl" means an aliphatic hydrocarbon group containing a
carbon-carbon double bond and which may be straight or branched
having about 2 to about 15 carbon atoms in the chain. Preferred
alkenyl groups have about 2 to about 12 carbon atoms in the chain,
more preferably about 2 to about 4 carbon atoms in the chain.
Branched means that one or more lower allyl groups such as methyl,
ethyl or propyl are attached to a linear alkenyl chain. "Lower
alkenyl" means about 2 to about 4 carbon atoms in the chain, which
may be straight or branched. The alkenyl group may be substituted
by one or more halo or cycloalkyl groups. Exemplary alkenyl groups
include ethenyl, propenyl, n-butenyl, i-butenyl,
3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl,
cyclohexylbutenyl and decenyl.
[0035] "Cycloalkyl" means a non-aromatic mono- or multicyclic ring
system of about 3 to about 10 carbon atoms. Exemplary monocyclic
cycloalkyl rings include cyclopentyl, fluorocyclopentyl, cyclohexyl
and cycloheptyl. The cycloalkyl group is optionally partially
unsaturated or optionally substituted by one or more halo,
methylene (H.sub.2C.dbd.), alkyl, fused aryl or fused heteroaryl.
Exemplary multicyclic cycloalkyl rings include 1-decalin,
adamant-(1- or 2-)yl and norbornyl.
[0036] "Heterocyclyl" means a non-aromatic monocyclic or
multicyclic hydrocarbon ring system of about 3 to about 10 ring
atoms in which one or more of the carbon atoms of the ring systems
is replaced by an element other than carbon. Preferred rings
include about 5 to about 6 ring atoms wherein one of the ring atoms
is oxygen, nitrogen or sulfur. The heterocyclyl is optionally
partially unsaturated or optionally substituted by one or more
alkyl, halo, aryl, heteroaryl, fused aryl or fused heteroaryl.
Exemplary monocyclic heterocyclyl ring systems include pyrrolidyl,
piperidyl, tetrahydrofuranyl, tetrahydrothienyl and
tetrahydrothiopyranyl. The thio or nitrogen moiety of the
heterocyclyl may also be optionally oxidized to the corresponding
N-oxide, S-oxide or S,S-dioxide. Exemplary multicyclic heterocyclyl
ring systems include 1,4 diazabicyclo-[2.2.2]octane and
1,2-cyclohexanedicarboxylic acid anhydride.
[0037] "Aryl" means a 6 to 10 membered aromatic monocyclic or
multicyclic hydrocarbon ring system. Exemplary aryl include phenyl
or naphthyl, either of which may be substituted with one or more
ring system substituents which may be the same or different, where
"ring system substituents" are as defined herein.
[0038] "Ring system substituents" means substituents attached to an
aromatic or non-aromatic ring system, inclusive of hydrogen, alkyl,
aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl,
alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano,
carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,
acylamino, aroylamino, alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,
heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio,
aralkylthio, heteroaralkykthio, fused cycloalkyl, fused
heterocyclyl, arylazo, heteroarylazo, R.sub.9R.sub.10N--,
R.sub.9R.sub.10NCO-- or R.sub.9R.sub.10NSO.sub.2--, wherein R.sub.9
and R.sub.10 are independently hydrogen, optionally substituted
alkyl, optionally substituted aryl, optionally substituted aralkyl
or optionally substituted heteroaralkyl, or R.sub.9 and R.sub.10
taken together with the N through which R.sub.9 and R.sub.10 are
linked form a 4 to 7 membered heterocyclyl. When a ring system is
saturated or partially saturated the "ring system substituents"
further include methylene (CH.sub.2.dbd.), oxo (O.dbd.) or thio
(S.dbd.). Preferred ring system substituents include hydrogen,
alkyl, hydroxy, acyl, aryl aroyl, aryloxy, halo, nitro, alkoxy,
cyano, alkoxycarbonyl, acylamino, alkylthio, R.sub.9R.sub.10N--,
R.sub.9R.sub.10NCO-- and R.sub.9R.sub.10NSO.sub.2--, where R.sub.9
and R.sub.10 are independently optionally substituted alkyl, aryl,
aralkyl or heteroaralkyl. Particularly, preferred phenyl group
substituents are hydroxy, halogen, alkyl and amino.
[0039] "Heteroaryl" means about a 5- to about a 10-membered
aromatic monocyclic or multicyclic hydrocarbon ring system in which
one or more of the carbon atoms in the ring system is replaced by
an element other than carbon, for example nitrogen, oxygen or
sulfur. A nitrogen atom in the ring system may be optionally
oxidized to the N-oxide. Where the heteroaryl is a multicyclic
hydrocarbon ring system then one of said ring systems is optionally
partially or fully saturated. The "heteroaryl" may also be
substituted by one or more of the above-mentioned "ring system
substituents". Exemplary heteroaryl groups include pyrazinyl,
furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl,
oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl,
imidazo[2,1-b]thiazolyl, thiono[3,2-b]pyridyl,
thieno[2,3-b]pyridyl, benzofurazanyl, indolyl, azaindolyl,
benzimidazolyl, benzothienyl, quinolinyl, imidazolyl,
thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl,
imidazopyridyl, isoquinolinyl and 1,2,3,4tetrahydroisoquinolinyl.
Where the heteroaryl is a multicyclic hydrocarbon ring system then
it may be bonded to the rest of the molecule through any atom of
the ring system thereof capable of such. Preferred heteroaryl
groups in the R.sub.1 substituent include benzothienyl, thienyl,
thienopyridyl, isoquinolinyl and quinolinyl all of which may be
optionally substituted. Preferred 5
[0040] bicyclic heteroaryl groups include isoquinolinyl,
quinolinyl, benzothienyl, isoquinolinyl, isoquinazolinyl,
thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, (1,2-
or 2,3-) benzodiazinyl and imidazopyridyl. Preferred 6
[0041] monocyclic heteroaryl groups include pyridyl. Preferred
heteroaryl groups in the R.sub.3 substituent of formula I include
benzothienyl, thieno[3,2-b]pyridyl, naphthyl, and
thieno[2,3-b]pyridyl.
[0042] "Aralkyl" means an aryl-alkyl-group in which the aryl and
alkyl are as previously described. Preferred aralkyls contain a
lower alkyl moiety. Exemplary aralkyl groups include benzyl,
2-phenethyl and naphthalenemethyl.
[0043] "Heteroaralkyl" means a heteroaryl-alkyl-group in which the
heteroaryl and alkyl are as previously described. Preferred
heteroaralkyls contain a lower alkyl moiety. Exemplary
heteroaralkyl groups include thienylalkyl, pyridylalkyl,
imidazolylalkyl, pyrazinylalkyl, benzimidazolylmethyl,
indolylmethyl, pyrazolylmethyl, and thiazolylmethyl.
[0044] "Aralkenyl" means an aryl-alkenyl-group in which the aryl
and alkenyl are as previously described. Preferred aralkenyls
contain a lower alkenyl moiety. An exemplary aralkenyl group is
2-phenethenyl.
[0045] "Heteroaralkenyl" means a heteroaryl-alkenyl-group in which
the heteroaryl and alkenyl are as previously described. Preferred
heteroaralkenyls contain a lower alkenyl moiety. Exemplary
heteroaralkenyl groups include thienylallyl, thienyl-2-ethenyl,
pyridyl-2-ethenyl, imidazolyl-2-ethenyl and pyrazinyl-2-ethenyl,
thienylpropenyl, pyridylpropenyl, imidazolylpropenyl and
pyrazinyl-propenyl.
[0046] "Hydroxyalkyl" means an HO-alkyl-group in which alkyl is as
previously defined. Preferred hydroxyalkyls contain lower alkyl.
Exemplary hydroxyalkyl groups include hydroxymethyl and
1-hydroxyethyl.
[0047] "Acyl" means an H--CO-- or alkyl-CO-group in which the alkyl
group is as previously described. Preferred acyls contain a lower
alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl,
2-methylpropanoyl, butanoyl and palmitoyl.
[0048] "Aroyl" means an aryl-CO-group in which the aryl group is as
previously described. Exemplary aroyl groups include benzoyl and 1-
and 2-naphthoyl.
[0049] "Alkoxy" means an alkyl-O-group in which the alkyl group is
as previously described. Exemplary alkoxy groups include methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, heptoxy and t-butoxy.
[0050] "Aryloxy" means an aryl-O-group in which the aryl group is
as previously described. Exemplary aryloxy groups include phenoxy
and naphthoxy.
[0051] "Heteroaryloxy" means an heteroaryl-O-group in which the
heteroaryl group is as previously described. Exemplary
heteroaryloxy groups include thienyloxy.
[0052] "Aralkyloxy" means an aralkyl-O-group in which the aralkyl
groups is as previously described. Exemplary aralkyloxy groups
include benzyloxy and 1- or 2-naphthylmethoxy.
[0053] "Alkylthio" means an alkyl-S-group in which the alkyl group
is as previously described. Exemplary alkylthio groups include
methylthio, ethylthio, i-propylthio and heptylthio.
[0054] "Arylthio" means an aryl-S-group in which the aryl group is
as previously described. Exemplary arylthio groups include
phenylthio and naphthylthio.
[0055] "Aralkylthio" means an aralkyl-S-group in which the aralkyl
group is as previously described. An exemplary aralkylthio group is
benzylthio.
[0056] "R.sub.9R.sub.10N--" means a substituted or unsubstituted
amino group, wherein R.sub.9 and R.sub.10 are as previously
described. Exemplary amino groups include amino (H.sub.2N--),
methylamino, ethylmethylamino, dimethylamino, diethylamino,
pyrrolidino and piperidino.
[0057] "Alkoxycarbonyl" means an alkyl-O--CO-group wherein alkyl is
as defined herein. Exemplary alkoxycarbonyl groups include
(methoxy-, ethoxy- and t-butoxy)carbonyl.
[0058] "Aryloxycarbonyl" means an aryl-O--CO-group wherein aryl is
as defined herein. Exemplary aryloxycarbonyl groups include
phenoxy- and naphthoxycarbonyl.
[0059] "Aralkoxycarbonyl" means an aralkyl-O--CO-group wherein
aralkyl is as defined herein. An exemplary aralkoxycarbonyl group
is benzyloxycarbonyl.
[0060] "R.sub.9R.sub.10NCO--" means a substituted or unsubstituted
carbamoyl group, wherein R.sub.9 and R.sub.10 are as previously
described. Exemplary carbamoyl groups are carbamoyl (H.sub.2NCO--)
and dimethylcarbamoyl (Me.sub.2NCO--).
[0061] "R.sub.9R.sub.10NSO.sub.2--" means a substituted or
unsubstituted sulfamoyl group, wherein R.sub.9 and R.sub.10 are as
previously described. Exemplary sulfamoyl groups are sulfamoyl
(H.sub.2NSO.sub.2--) and dimethylsulfamoyl
(Me.sub.2NSO.sub.2--).
[0062] "Acylamino" is an acyl-NH-group wherein acyl is as defined
herein.
[0063] "Aroylamino" is an aroyl-NH-group wherein aroyl is as
defined herein.
[0064] "Alkylsulfonyl" means an alkyl-SO.sub.2-group wherein alkyl
is as defined herein. Preferred groups are those in which the alkyl
group is lower alkyl.
[0065] "Arylsulfonyl" means an aryl-SO.sub.2-group wherein aryl is
as defined herein.
[0066] "Alkylenyl" means, for example, a methylenyl, ethylenyl or
propylenyl group.
[0067] "Halo" means fluoro, chloro, bromo, or iodo. Preferred are
fluoro, chloro or bromo, and more preferred are fluoro or
chloro.
[0068] Preferred Embodiments
[0069] A preferred embodiment of the invention is a method for
treating a patient suffering from a physiological disorder capable
of being modulated by inhibiting an activity of Factor Xa by
administering a therapeutically effective amount of a compound of
formula I.
[0070] A preferred compound aspect of the invention is the compound
of formula I wherein R.sub.1 is H, optionally substituted
heteroaralkyl, optionally substituted alkenyl, optionally
substituted aralkyl or optionally substituted alkyl.
[0071] Another preferred compound aspect of the invention is the
compound of formula I wherein R.sub.2 is R.sub.3S(O).sub.p--, and
more preferable is R.sub.3S(O).sub.p-- wherein p is 2.
[0072] Another preferred compound aspect of the invention is the
compound of formula I wherein R.sub.2 is hydrogen, optionally
substituted aralkyl, optionally substituted heteroaralkyl,
optionally substituted aralkenyl, optionally substituted
heteroaralkenyl, or R.sub.3R.sub.4NC(O)(CH.sub.2)x- --. Another
preferred compound aspect of the invention is the compound of
formula I wherein R.sub.3 is hydrogen, optionally substituted
phenyl, optionally substituted naphthyl, optionally substituted
thienyl, optionally substituted benzothienyl, optionally
substituted thienopyridyl, optionally substituted quinolinyl, or
optionally substituted isoquinolinyl; more preferred R.sub.3 is
optionally selected from substituted naphthyl, optionally
substituted thienyl, optionally substituted benzothienyl and
optionally substituted thienopyridyl.
[0073] Another preferred compound aspect of the invention is the
compound of formula I wherein R.sub.2 is selected from the group
consisting of 7
[0074] Another preferred compound aspect of the invention is the
compound of formula I wherein R.sub.2 is selected from the group
consisting of 8
[0075] Another preferred compound aspect of the invention is the
compound of formula I wherein R.sub.2 is 9
[0076] R.sub.a is hydrogen, alkyl, hydroxy, alkoxy,
Y.sup.1Y.sup.2N--, halogen, --CO.sub.2R.sub.d,
--C(O)NY.sup.1Y.sup.2, --(CH.sub.2).sub.xOR.sub.d,
--(CH.sub.2).sub.xNY.sup.1Y.sup.2, or --CN;
[0077] R.sub.b and R.sub.c are independently selected from
hydrogen, hydroxy, alkoxy, Y.sup.1Y.sup.2N--, halogen,
--CO.sub.2R.sub.d, --C(O)NY.sup.1Y.sup.2,
--(CH.sub.2).sub.xOR.sub.d, --(CH.sub.2).sub.xNY.sup.1Y.sup.2,
--CN, optionally substituted alkyl, optionally substituted
cycloalkyl, optionally substituted heterocyclyl, optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted aralkyl, optionally substituted heteroaralkyl,
optionally substituted aralkenyl or optionally substituted
heteroaralkenyl, or R.sub.b and R.sub.c taken together with the
carbon atoms through which they are linked form an optionally
substituted 5 to 7 membered fused cycloalkyl, or an optionally
substituted 5 to 7 membered fused heterocyclyl ring or an
optionally substituted 6 membered fused aryl, or an optionally
substituted 5 to 6 membered fused heteroaryl ring;
[0078] R.sub.d is hydrogen, optionally substituted alkyl,
optionally substituted aralkyl or optionally substituted
heteroaralkyl;
[0079] Y.sup.1 and Y.sup.2 are independently hydrogen, optionally
substituted alkyl, optionally substituted aryl, optionally
substituted aralkyl or optionally substituted heteroaralkyl, or
Y.sup.1 and Y.sup.2 taken together with the N through which Y.sup.1
and Y.sup.2 are linked form a 4 to 7 membered heterocyclyl;
[0080] Z.sub.1 is S or --CH.dbd.CH--; and
[0081] x is 1, 2, 3, 4, or 5.
[0082] Another preferred compound aspect of the invention is the
compound of formula I wherein R.sub.3 is optionally substituted
aralkenyl or optionally substituted heteroaralkenyl, more
preferably optionally substituted heteroaralkenyl.
[0083] Another preferred compound aspect of the invention is the
compound of formula I wherein when R.sub.3 is optionally
substituted arkey or optionally substituted heteroaralkenyl, then
the alkenyl moiety thereof is of the formula 10
[0084] Another preferred compound aspect of the invention is the
compound of formula I wherein when R.sub.3 is optionally
substituted aralkenyl or optionally substituted heteroaralkenyl,
then the alkenyl moiety thereof is of the formula 11
[0085] wherein one of Q.sub.1 and Q.sub.2 is hydrogen, lower alkyl
(more preferably methyl), or halo (more preferably fluoro or
chloro) and the other of Q.sub.1 and Q.sub.2 is lower alkyl (more
preferably methyl), or halo (more preferably fluoro or chloro).
[0086] Another preferred compound aspect of the invention is the
compound of formula I wherein when R.sub.3 is optionally
substituted aralkenyl then the aryl moiety thereof is halo
substituted phenyl; more preferably chloro substituted phenyl.
[0087] Another preferred compound aspect of the invention is the
compound of formula I wherein when R.sub.3 is optionally
substituted heteroaralkenyl then the heteroaryl moiety thereof is
halo substituted thienyl, more preferably 2-chlorothien-5-yl.
[0088] Another preferred compound aspect of the invention is the
compound of formula I wherein Z is methylenyl.
[0089] Another preferred compound aspect of the invention is the
compound of formula I wherein 12
[0090] is selected from the group consisting of 13
[0091] Another preferred compound aspect of the invention is the
compound of formula I wherein 14
[0092] is selected from the group consisting of 15
[0093] Another preferred compound aspect of the invention is the
compound of formula I wherein Z.sub.1 is --CH.dbd.CH--; and R.sub.b
and R.sub.c taken together with the carbon atoms through which
R.sub.b and R.sub.c are linked form an optionally substituted 5 or
6 membered heteroaryl ring, preferably containing at least one
hetero atom which is preferably N, or an optionally substituted 6
membered aryl ring, and wherein said optional substituents are
preferably selected from chloro, hydroxy and amino.
[0094] Another preferred compound aspect of the invention is the
compound of formula I wherein Z.sub.1 is --CH.dbd.CH--; R.sub.b is
hydrogen; and R.sub.c is an optionally substituted heteroaryl ring,
preferably 5 or 6 membered heteroaryl ring, more preferably
containing at least one hetero atom which is preferably N or S, or
an optionally substituted 6 membered aryl ring, and wherein said
optional substituents are preferably chloro, hydroxy or amino.
[0095] Another preferred compound aspect of the invention is the
compound of formula I wherein Z.sub.1 is S (sulfur).
[0096] Another preferred compound aspect of the invention is the
compound of formula I wherein Z.sub.1 is S (sulfur); and R.sub.b
and R.sub.c taken together with the carbon atoms through which
R.sub.b and R.sub.c are linked form an optionally substituted 5 or
6 membered heteroaryl ring, preferably containing at least one
hetero atom which is preferably N, or an optionally substituted 6
membered aryl ring, and wherein said optional substituents are
preferably chloro, hydroxy or amino.
[0097] Another preferred compound aspect of the invention is the
compound of formula I wherein Z.sub.1 is S (sulfur); R.sub.b is
hydrogen; and R.sub.c is an optionally substituted heteroaryl ring,
preferably a 5 or 6 membered heteroaryl ring, preferably containing
at least one hetero atom which is preferably N or S, or an
optionally substituted 6 membered aryl ring, and wherein said
optional substituents are preferably chloro, hydroxy or amino.
[0098] Another preferred compound aspect of the invention is the
compound of formula I wherein Z is methylenyl, and m is 1.
[0099] Another preferred compound aspect of the invention is the
compound of formula I wherein X.sub.2 and X.sub.2a taken together
are oxo.
[0100] Another preferred compound aspect of the invention is the
compound of formula I wherein each of X.sub.1, X.sub.1a, X.sub.3
and X.sub.4 is H.
[0101] Another preferred compound aspect of the invention is the
compound of formula I wherein 16
[0102] is an optionally substituted isoquinolinyl; more preferred
the isoquinolinyl is attached to Z at the 7-position thereof.
[0103] Another preferred compound aspect of the invention is the
compound of formula I wherein 17
[0104] is an optionally substituted quinolinyl; more preferred the
quinolinyl is attached to Z at the 7-position thereof.
[0105] Another preferred compound aspect of the invention is the
compound of formula I wherein 18
[0106] is an optionally substituted quinazolinyl; more preferred
the quinazolinyl is attached to Z at the 7-position thereof.
[0107] Another preferred compound aspect of the invention is the
compound of formula I wherein 19
[0108] is an optionally substituted moiety of formula 20
[0109] and W is S, O or NR.sub.11, wherein R.sub.11 is H, alkyl,
aralkyl, heteroaralkyl, or R.sub.8(O)C(CH.sub.2).sub.q--, and A is
independently CH or N; more preferably the moiety is bonded to Z
through the ring containing W, and yet more preferably the moiety
is bonded to Z through the ring containing W at the 2-position
thereof.
[0110] Another preferred compound aspect of the invention is the
compound of formula I wherein one of X.sub.5, X.sub.5a and X.sub.5b
is H, hydroxy or amino, more preferably hydroxy or amino
substituted on the proximal ring of 21
[0111] at a position that is adjacent to the position of the
proximal ring to which Z is attached.
[0112] Another preferred compound aspect of the invention is the
compound of formula I wherein one of X.sub.5, X.sub.5a and X.sub.5b
is a substituent on the distal ring of 22
[0113] at the position alpha to a nitrogen thereof selected from H,
H.sub.2N--, (optionally substituted loweralkyl)HN--, (hydroxy)HN--,
and (amino)HN--.
[0114] Preferred species according to the invention are selected
from the group consisting of:
[0115]
3-[[1-(4-Aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-(5-chl-
oro-1H-indol-2-ylmethyl)amino]propionic acid methyl ester;
[0116]
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl-
)-(3-ethylbutyl)amino]pyrrolidin-2-one;
[0117]
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[benzyl-(5-chloro-1H-indol-2-y-
lmethyl)amino]pyrrolidin-2-one;
[0118]
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl-
)thiazol-5-ylmethylamino]pyrrolidin-2-one;
[0119]
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl-
)-(2H-pyrazol-3-ylmethyl))amino]pyrrolidin-2-one;
[0120]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(6-chlorobenzo[b]thiophen-2-
-ylmethyl)amino]pyrrolidin-2-one;
[0121]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(6-chlorothieno[2,3-b]pyrid-
in-2-ylmethyl)amino]pyrrolidin-2-one;
[0122]
1-(4-Aminoquinazolin-7-ylmethyl)3-(S)-[(1H-pyrrolo[2,3-c]pyridin-2--
ylmethyl)amino]pyrrolidin-2-one;
[0123]
3-{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-ylamino]-
methyl}-1H-quinolin-2-one;
[0124]
1-(7-Aminothieno[3,2-b]pyridin-2-ylmethyl)-3-(R)-[(5-chloro-1H-indo-
l-2-ylmethyl)amino]pyrrolidin-2-one;
[0125] 2-(5-Chlorothiophen-2-yl)-ethenesulfonic acid
[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)pyrrolidin-3-(R)yl]amide;
[0126]
{[2-(5-Chlorothiophen-2-yl)ethenesulfonyl]-[2-oxo-1-(1H-pyrrolo[3,2-
-c]pyridin-2-ylmethyl)pyrrolidin-3-(R)-yl]amino}acetic acid
isopropyl ester;
[0127]
1-(4-Aminoquinolin-7-ylmethyl)3-(R)-[(5-chloro-1H-indol-2-ylmethyl)-
amino]pyrrolidin-2-one;
[0128] 5-Chloro-1H-benzoimidazole-2-sulfonic
acid[1-(4-aminoquinolin-7-ylm-
ethyl)-2-oxopyrrolidin-3-(R)-yl]amide;
[0129] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-yl-met-
hyl)-2-oxopyrrolidin-3-(R,S)-yl]amide trifluoroacetate;
[0130] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-yl-met-
hyl)-2-oxopyrrolidin-3-(S)-yl]amide hydrochloride;
[0131] 7-Methoxynaphthalene-2-sulfonic acid
[1-(1-aminoisoquinolin-7-yl-me-
thyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0132] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-yl-met-
hyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
[0133] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-hydroxyisoquinolin-7ylmet-
hyl)-2-oxopyrrolidin-3-(R,S)-yl]amide;
[0134] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-ylmeth-
yl)-2-oxopyrrolidin-3-(R,S)-yl]methylamide trifluoroacetate;
[0135] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-ylmeth-
yl)-2-oxopyrrolidin-3-(S)-yl]methyl amide trifluoroacetate;
[0136] Benzo[b]thiophene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-ylmethyl)-
-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0137] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1-aminoisoquinolin-7--
ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0138] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-amino-6-methoxyisoquinoli-
n-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide hydrochloride;
[0139] 7-Methoxynaphthalene-2-sulfonic
acid[1-(6-methoxyisoquinolin-7-ylme- thyl)-2-oxo
pyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0140] 4-(2-Chloro-6-nitophenoxy)benzene sulfonic
acid[1-(1-amino-6-methox-
yisoquinolin-7-ylmethyl)2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate;
[0141] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1,6-diaminoisoquinolin-7-yl-
-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0142] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1,6-diaminoisoquinoli- n-7-yl-methyl)-2-oxo
pyrrolidin-3-(S)-yl ]amide trifluoroacetate;
[0143] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-7-ylmethyl)-
-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0144] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(2-aminoquinolin-7-ylm-
ethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0145] Benzo[b]thiophene-2-sulfonic
acid[1-(2-aminoquinolin-7-ylmethyl)-2--
oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0146] 7 Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-7-ylmethyl)-
-2-oxopyrrolidin-3-(S)-yl]methyl amide trifluoroacetate;
[0147] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-hydroxyquinolin-7-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]methyl amide;
[0148] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-5ylmethyl)-- 2-oxopyolidin-3-(S)-yl]amide
trifluoroacetate;
[0149] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-5-ylmethyl)-
-2-oxopyrrolidin-3-(S)-yl]methyl amide trifluoroacetate;
[0150] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-hydroxyquinolin-5-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]methylamide;
[0151] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-6-ylmethyl)-
2-oxopyrrolidin-3-(S)-yl]amide;
[0152] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-hydroxyquinolin-6-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]amide;
[0153] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1H-benzimidazol-5-ylmethyl)-
-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0154] 7-Methoxynaphthalene-2-sulfonic
acid[2-(1H-benzimidazol-5-ylethyl)-- 2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate;
[0155] 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-aminoquinazolin-6-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]methylamide trifluoroacetate,
[0156] 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-aminothieno[2,3-d]pyrimid-
in-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate;
[0157] 7-Methoxynaphthalene-2-sulfonic
acid[2-(6-aminothieno[2,3-d]pyrimid-
in-6yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0158] 7-Methoxynaphthalene-2-sulfonic
acid[1-(7-aminothieno[2,3-c]pyridin-
-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate,
[0159] 7-Methoxynaphthalene-2-sulfonic
acid[1-(7-hydroxythieno[2,3-c]pyrid-
in-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate;
[0160] 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-aminothieno[3,2-c]pyridin-
-3-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amide
trifluoroacetate;
[0161] 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-hydroxythieno[3,2-c]pyrid-
in-3-yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amide
trifluoroacetate;
[0162] Benzo[b]thiophene-2-sulfonic
acid[1-(4-aminothieno[3,2-c]pyridin-3--
yl-methyl)-2-oxopyrrolidin-3-(R,S)-yl]amide trifluoroacetate;
[0163] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-amino-isoquinolin-7-ylme-
thyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
[0164] Thieno[2,3-b]pyridine-2-sulfonic
acid[1-(1-amino-isoquinolin-7-ylme-
thyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
[0165] 4-Pyridin-3-yl-thiophene-2-sulfonic
acid[1-(1-amino-isoquinolin-7-y-
lmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;
[0166] 5'Chloro-[2,2']bithiophenyl-5-sulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2-
-c]pyridin-2-ylmethyl)-pyrrolidin-3(S)-yl]-amide;
[0167] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[2-oxo-1-(1H-pyrrolo[-
3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;
[0168] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(1-amino-isoquinolin-
-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
[0169] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(1-amino-isoquinol-
in-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;
[0170] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinazolin-6--
yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0171] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-thieno[2,3-d]-
pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate;
[0172] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-thieno[3,2-d]-
pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate;
[0173] 5'-Chloro-[2,2']bithiophenyl-5-2-sulfonic
acid[1-(4-amino-thieno[3,-
2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate;
[0174] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1,6-diamino-isoquinolin-7--
ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
[0175] 2(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(1-amino-isoquinoli-
n-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;
[0176] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(1-amino-isoquinolin-
-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
[0177] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[2oxo-1-(1H-pyrrolo[3-
,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;
[0178] 3(R)-5 Chlorothiophen-2-yl)-ethenesulphonic
acid[1-(4-aminoquinolin- -7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0179]
2-(S)-[[1-(4-Amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-(6-c-
hloro-benzo[b]thiophene-2-sulfonyl)-amino]-acetic acid methyl
ester, trifluoroacetate;
[0180] 2-(S)-6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinoli-
n-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide, trifluoroacetate;
[0181] 2-(s)-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide,
trifluoroacetate;
[0182] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(4-amino-quinolin-6-ylmethy-
l)-2-oxo-pyrrolidin-3-(S)-yl]-amide, ditrifluoroacetate:
[0183]
N-(3-Amino-pyridin-4-yl)2-[3-(7-methoxy-naphthalene-2-sulfonylamino-
)-2-oxo-pyrrolidin-1-yl]-acetamide;
[0184]
2-[3-(7-Methoxy-naphthalene-2-sulfonylamino)2-oxo-pyrrolidin-1-yl]--
N-pyridin-4-yl-acetamide;
[0185] 6-Chlorobenzo[b]thiophene-2-sulfonic
acid{2-oxo-1-[2-(pyridin-4-yl--
amino)ethyl]-pyrrolidin-3-(S)-yl}-amide trifluoroacetate;
[0186] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid{2-oxo-1-[2-(pyridin-4--
ylamino)-ethyl]-pyrrolidin-3-yl}-amide;
[0187] 6-Chloro-thieno[2,3-b]pyridine-2-sulfonic
acid{2-oxo1-[2-(pyridin-4- -ylamino)-ethyl]-pyrrolidin-3-yl}-amide
trifluoacetate;
[0188] Thieno[3,2-b]pyridine-2-sulfonic
acid{2-oxo-1-[2-(pyridin-4-ylamino- )ethyl]-pyrrolidin-3-yl}-amide
ditrifluoroacetate;
[0189] 2(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid{2-oxo-1-[2-(pyridin-4-
-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;
[0190] (S)-5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid{1-[2-(2-amino-3-ch-
loro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amide
ditrifluoroacetate;
[0191] (S)-6-Chloro-benzo[b]thiophene-2-sulfonic
acid{1-[2-(2-amino-3-chlo-
ro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amide
ditrifluoroacetate;
[0192]
((6-Chloro-benzo[b]thiophene-2-sulfonyl){-2-oxo-1-[2-(pyridin-4-yla-
mino)-ethyl]-pyrrolidin-3(-yl}-amino)-acetic acid methyl ester,
[0193]
((6-Chloro-benzo[b]thiophene-2-sulfonyl){-2-oxo-1-[2-(pyridin-4-yla-
mino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid
trifluoroacetate;
[0194] 6-Chloro-benzo[b]thiophene-2-sulfonic acid
allyl-{2-oxo-1-[2-(pyrid-
in-4ylamino)ethyl]-pyrrolidin-3-yl}-amide;
[0195] 6-Chloro-benzo[b]thiophene-2-sulfonic acid
methyl-{2-oxo-1-[2pyridi-
n-4-ylamino)ethyl]-pyrrolidin-3-yl}-amide;
[0196] (S)-2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid{1-[2-(-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-y-
l}-amide trifluoroacetate;
[0197] (S)- Thieno[3,2-b]pyridine-2-sulfonic
acid{1-[2-(2-amino-3-chloro-p-
yridin-4-ylamino)-ethyl-2-oxo-pyrrolidin-3-yl}-amide
ditrifluoroacetate;
[0198]
([5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-yl-
amino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid methyl ester;
[0199]
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-
-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid isopropyl
ester;
[0200]
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-
-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid
trifluoroacetate;
[0201] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid
(2-methoxy-ethyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-
-amide trifluoroacetate;
[0202]
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-
-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid ethyl ester
trifluoroacetate;
[0203]
3-(5-Chloro-thiophen-2-yl)-N-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-
-pyrrolidin-3-yl}-acrylamide trifluoroacetate;
[0204]
1-[1-(4-Aminoquinazolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(4-c-
hlorophenyl)urea trifluoroacetate;
[0205]
N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-2-(5--
chlorothiophen-2-yloxy)acetamide trifluoroacetate;
[0206]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmeth-
yl)amino]pyrrolidin-2-one trifluoroacetate;
[0207]
1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]3-(5-c-
hlorothiophen-2-yl)urea trifluoroacetate;
[0208] 5-Chlorothiophene-2-carboxylic
acid[1-(4-aminoquinazolin-7-ylmethyl-
)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0209]
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-[3-(5-
-chlorothiophen-2-yl)acryloyl]amino}acetic acid methyl ester
trifluoroacetate;
[0210] 6-Chlorobenzo[b]thiophene-2-sulfonic
acid[1-(4-aminoquinazolin-7-yl-
methyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
[0211] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-aminoisoquinolin-7-ylmet-
hyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
[0212]
1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmethyl-
)amino]pyrrolidin-2-one trifluoroacetate;
[0213] 1-(4-Aminoquinazolin-7-ylmethyl)-3-(S
)-[3-(5-chlorothiophen-2-yl)a- llylamino]pyrrolidin-2-one
trifluoroacetate;
[0214]
N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5--
chlorothiophen-2-yl)acrylamide trifluoroacetate;
[0215]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-
-ylmethyl)amino]pyrrolidin-2-one trifluoroacetate;
[0216]
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][2-(5-c-
hlorothiophen-2-yl)ethenesulfonyl]amino}acetic acid methyl ester
trifluoroacetate;
[0217]
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl](5-chlo-
ro-1H-indol-2-ylmethyl)amino]acetic acid methyl ester
trifluoroacetate;
[0218]
{[1-(Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][3-(5-chl-
orothiophen-2-yl)allyl]amino}acetic acid methyl ester
trifluoroacetate;
[0219]
{1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-
-chlorothiophen-2-yl)ureido}acetic acid methyl ester
trifluoroacetate;
[0220]
N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5--
chlorothiophen-2-yl)acrylamide trifluoroacetate;
[0221]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmeth-
yl)amino]pyrrolidin-2-one trifluoroacetate;
[0222]
1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5--
chlorothiophen-2-yl)urea trifluoroacetate and
5-Chlorothiophene-2-carboxyl- ic
acid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide
trifluoroacetate;
[0223]
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl](5-chlo-
ro-1H-indol-2-ylmethyl)amino]acetic acid methyl ester
trifluoroacetate;
[0224]
1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-y-
lmethyl)amino]pyrrolidin-2-one trifluoroacetate;
[0225] 5-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinazolin-7--
ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0226] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(4amino-thieno[3,2-
-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3(S)-yl]-amide;
[0227] 7-Methoxy-naphthalene-2-sulfonic
acid[1-(4-amino-quinazolin-7-ylmet-
hyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0228] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(4-amino-quinazoli-
n-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0229] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinazolin-7--
ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0230] 5-Chloro-benzo[b]thiophene-2-sulfonic acid
(S)-[1-(4-amino-thieno[3-
,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0231] Thieno[3,2-b]pyridine-2-sulfonic acid
(S)-[1-(4-amino-thieno[3,2-d]-
pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0232] 6-Chloro-benzo[b]thiophene-2-sulfonic acid
(S)-[1-(4-amino-thieno[3-
,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0233] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic acid
(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-
-amide trifluoroacetate;
[0234] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid
(S)[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]--
amide trifluoroacetate;
[0235] 5-Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)1-(4-amino-thieno[3,2-
-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0236] 5-Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)-1-(4-amino-thieno[2,-
3-d]pyrimidin-6-ylmethyl)2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0237] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[(S)1-(4-amino-thieno[2-
,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0238] Thieno[3,2-b]pyridine-2-sulfonic
acid[(S)1-(4-amino-thieno[2,3-d]py-
rimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0239] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)-1-(4-amino-thieno[2,-
3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0240] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(4-amino-thieno[3,2--
d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate;
[0241] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(4-amino-thieno[3,2-d]pyrim-
idin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S))-yl]-amide
trifluoroacetate; and
[0242] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)1-(4-amino-thieno[3,2-
-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide.
[0243] More preferred species according to the invention are
selected from the group consisting of
[0244]
3-[[1-(4-Aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-(5-chl-
oro-1H-indol-2-ylmethyl)amino]propionic acid methyl ester,
[0245]
1-(4Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)-
(3-ethylbutyl)amino]pyrrolidin-2-one;
[0246]
1(4-Aminoquinolin-7-ylmethyl)-3-(R)-[benzyI-(5-chloro1H-indol-2-ylm-
ethyl)amino]pyrrolidin-2-one;
[0247]
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl-
)thiazol-5-ylmethylamino]pyrrolidin-2-one;
[0248]
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl-
)-(2H-pyrazol-3-ylmethyl))amino]pyrrolidin-2-one;
[0249]
1-(4-Aminoquinazolin-7-ylmethyl)3-(S)-[(6-chlorobenzo[b]thiophen-2--
ylmethyl)amino]pyrrolidin-2-one;
[0250]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(6-chlorothieno[2,3-b]pyrid-
in-2-ylmethyl)amino]pyrrolidin-2-one;
[0251]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(1H-pyrrolo[2,3-c]pyridin-2-
-ylmethyl)amino]pyrrolidin-2-one;
[0252]
3-{[1-(4-Aminoquinazolin-7-ylmethyl;2-oxopyrrolidin-3-(S)-ylamino]m-
ethyl}-1H-quinolin-2-one;
[0253]
1-(7-Aminothieno[3,2-b]pyridin-2-ylmethyl)-3-(R)-[(5-chloro-1H-indo-
l-2-ylmethyl)amino]pyrrolidin-2-one;
[0254] 2-(5-Chlorothiophen-2-yl)ethenesulfonic
acid[2-oxo-1-(1H-pyrrolo[3,-
2-c]pyridin-2-ylmethyl)pyrrolidin-3-(R)-yl]amide;
[0255]
{[2-(5-Chlorothiophen-2-yl)ethenesulfonyl]-[2-oxo-1-(1H-pyrrolo[3,2-
-c]pyridin-2-ylmethyl)pyrrolidin-3-(R)-yl]amino}acetic acid
isopropyl ester;
[0256]
1-(4Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl)-
amino]pyrrolidin-2-one;
[0257] 5-Chloro-1H-benzoimidazole-2-sulfonic
acid[1-(4-aminoquinolin-7-ylm-
ethyl)-2-oxopyrrolidin-3-(R)-yl]amide;
[0258] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-ylmeth-
yl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0259] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-ylmeth-
yl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
[0260] 7-Methoxynaphthalene-2-sulfonic
acid-[1-(1-aminoisoquinolin-7-ylmet-
hyl)-2-oxopyrrolidin-3-(S)-yl]methylamide trifluoroacetate;
[0261] Benzo[b]thiophene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-ylmethyl)-
-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0262] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1-aminoisoquinolin-7--
ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0263] 7-Methoxynaphthalene-2-sulfonic
acid-[1-(1,6-diaminoisoquinolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0264] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1,6-diaminoisoquinoli-
n-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0265] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-7-ylmethyl)-
-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0266] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(2-aminoquinolin7-ylme-
thyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0267] Benzo[b]thiophene-2-sulfonic
acid[1-(2-aminoquinolin-7-ylmethyl)-2--
oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0268] 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-aminothieno[3,2-c]pyridin- -2-ylmethyl)-2-oxo-3-yl]amide
trifluoroacetate;
[0269] Benzo[b]thiophene-2-sulfonic
acid[1-(4-aminothieno[3,2-c]pyridin-2-- ylmethyl)-2-oxo-3-yl]-amide
trifluoroacetate;
[0270] 5-Pyridin4-yl-thiophene-2-sulfonic
acid-[1-(1-aminoisoquinolin-7-yl-
methyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0271] 5-Pyridin-3-yl-thiophene-2-sulfonic
acid-[1-(1-aminoisoquinolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0272] Benzothiophene-2-sulfonic
acid[1-(4-aminoquinolin-6-ylmethyl)-2-oxo-
pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0273] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2--
c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;
[0274] 7Methoxynaphthalene-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2-b]pyrid-
in-2-ylmethyl)pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0275] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2--
b]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate;
[0276] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[2-oxo-1(1H-pyrrolo[2,3-c-
]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl ]-amide
trifluoroacetate;
[0277] Thieno[3,2-b]pyridine-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[2,3-c
pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
ditrifluoroacetate;
[0278] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-amino-isoquinolin-7-ylme-
thyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide;
[0279] 5'Chloro-[2,2']bithiophenyl-5-sulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2-
-c]pyridin-2-ylmethyl)-pyrrolidin-3(S)-yl]-amide;
[0280] 6-Chlor-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-thieno[2,3-d]p-
yrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate;
[0281] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-thieno[3,2-d]-
pyrimidin-7-yl-methyl2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate;
[0282] 5'-Chloro-[2,2']bithiophenyl-5-2-sulfonic
acid[1-(4-amino-thieno[3,-
2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate;
[0283] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1,6-diamino-isoquinolin-7--
ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;
[0284] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(1-amino-isoquinol-
in-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;
[0285] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(1-amino-isoquinolin-
-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]amide;
[0286] 2(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[2-oxo-1(1H-pyrrolo[3,-
2-c]pyridin-2-ylmethyl)pyrrolidin-3-(S)-yl]-amide;
[0287] 3-(R)-5 Chlorothiophen-2-yl)-ethenesulphonic acid 8
1-(4-aminoquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0288]
2-(S)-[[1-(4-Amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-(6-c-
hloro-benzo[b]thiophene-2-sulfonyl)-amino]-acetic acid methyl
ester, trifluoroacetate;
[0289] 2-(S)-6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinoli-
n-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide, trifluoroacetate;
[0290] 2-(s)-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl amide,
trifluoroacetate;
[0291] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(4-amino-quinolin-6-ylmethy-
l)-2-oxo-pyrrolidin-3-(S)-yl]-amide, ditrifluoroacetate;
[0292]
N-(3-Amino-pyridin-4-yl)-2-[3-(7-methoxy-naphthalene-2-sulfonylamin-
o)-2-oxo-pyrrolidin-1-yl]-acetamide;
[0293]
2-[3-(7-Methoxy-naphthalene-2-sulfonylamino)-2-oxo-pyrrolidin-1-yl]-
-N-pyridin4-yl-acetamide;
[0294] 6-Chlorobenzo[b]thiophene-2-sulfonic
acid{2-oxo-1-[2-(pyridin4-yl-a-
mino)ethyl]-pyrrolidin-3-(S)-yl}-amide trifluoroacetate;
[0295] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid{2-oxo-1-[2-(pyridin-4--
ylamino)-ethyl]-pyrrolidin-3-yl}amide;
[0296] 6-Chloro-thieno[2,3-b]pyridine-2-sulfonic
acid{2-oxo-1-[2-(pyridin4- -ylamino)-ethyl]-pyrrolidin-3-yl}-amide
trifluoacetate;
[0297] Thieno[3,2-b]pyridine-2-sulfonic
acid{2-oxo-1-[2-(pyridin4-ylamino)- -ethyl]-pyrrolidin-3-yl}-amide
ditrifluoroacetate;
[0298] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid{2-oxo-1-[2-(pyridin--
4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;
[0299] (S)-5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid{-1-[2-(2-amino-3-c-
hloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amide
ditrifluoroacetate;
[0300] (S)-6-Chloro-benzo[b]thiophene-2-sulfonic
acid{1-[2-(2-amino-3-chlo-
ro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amide
ditrifluoroacetate;
[0301]
((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin-4-yla-
mino)-ethyl]-pyrrolidin-3(-yl}-amino)-acetic acid methyl ester;
[0302]
((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin-4-yla-
mino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid
trifluoroacetate;
[0303] 6-Chloro-benzo[b]thiophene-2-sulfonic acid
allyl-{2-oxo-1-[2-(pyrid-
in-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;
[0304] 6-Chloro-benzo[b]thiophene-2-sulfonic acid
methyl-{2-oxo-1-[2-(pyri-
din-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide;
[0305] (S)-2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3--
yl}-amide trifluoroacetate;
[0306] (S)-Thieno[3,2-b]pyridine-2-sulfonic
acid{1-[2-(2-amino-3-chloro-py-
ridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amide
ditrifluoroacetate;
[0307]
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-
-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid methyl
ester;
[0308]
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-
-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid isopropyl
ester;
[0309] ([2
(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-
-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid
trifluoroacetate;
[0310] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid
(2-methoxy-ethyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-
-amide trifluoroacetate;
[0311]
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin4y-
lamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid ethyl ester
trifluoroacetate;
[0312]
3-(5-Chloro-thiophen-2-yl)-N-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-
-pyrrolidin-3-yl}-acrylamide trifluoroacetate;
[0313]
1-[1-(4-Aminoquinazolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(4ch-
lorophenyl)urea trifluoroacetate;
[0314]
N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-2-(5--
chlorothiophen-2-yloxy)acetamide trifluoroacetate;
[0315]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmeth-
yl)amino]pyrrolidin-2-one trifluoroacetate;
[0316]
1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5--
chlorothiophen-2-yl)urea trifluoroacetate;
[0317] 5-Chlorothiophene-2-carboxylic
acid[1-(4-aminoquinazolin-7-ylmethyl-
)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate;
[0318]
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-[3-(5-
-chlorothiophen-2-yl)acryloyl]amino}acetic acid methyl ester
trifluoroacetate;
[0319] 6 -Chlorobenzo[b]thiophene-2-sulfonic
acid[1-(4-aminoquinazolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
[0320] Thieno[3,2-b]pyridine-2-sulfonic
acid[l-(1-aminoisoquinolin-7-ylmet-
hyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
[0321]
1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmethyl-
)amino]pyrrolidin-2-one trifluoroacetate;
[0322]
1-(4Aminoquinazolin-7-ylmethyl)-3-(S)-[3-(5-chlorothiophen-2-yl)all-
ylamino]pyrrolidin-2-one trifluoroacetate;
[0323] N
-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-
-chlorothiophen-2-yl)acrylamide trifluoroacetate;
[0324]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-
-ylmethyl)amino]pyrrolidin-2-one trifluoroacetate;
[0325] {[1-(4-Aminoquinazolin-7-
ylmethyl)2-oxopyrrolidin-3-(S)-yl][2-(5-c-
hlorothiophen-2-yl)ethenesulfonyl]amino}acetic acid methyl ester
trifluoroacetate;
[0326]
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl](5-chlo-
ro-1H-indol-2-ylmethyl)amino]acetic acid methyl ester
trifluoroacetate;
[0327]
{[1-(Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][3-(5-chl-
orothiophen-2-yl)allyl]amino}acetic acid methyl ester
trifluoroacetate;
[0328]
{1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-
-chlorothiophen-2-yl)ureido}acetic acid methyl ester
trifluoroacetate;
[0329]
N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5--
chlorothiophen-2-yl)acrylamide trifluoroacetate;
[0330]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmeth-
yl)amino]pyrrolidin-2-one trifluoroacetate;
[0331]
1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5--
chlorothiophen-2-yl)urea trifluoroacetate;
[0332] 5-Chlorothiophene-2-carboxylic
acid[1-(4-aminoquinazolin-7-ylmethyl-
)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
[0333]
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl](5-chlo-
ro-1H-indol-2-ylmethyl)amino]acetic acid methyl ester
trifluoroacetate;
[0334]
1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-y-
lmethyl)amino]pyrrolidin-2-one trifluoroacetate;
[0335] 5-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinazolin-7--
ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0336] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid
[1-(4-amino-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3(S)-yl]--
amide;
[0337] 7-Methoxy-naphthalene-2-sulfonic
acid[1-(4-amino-quinazolin-7-ylmet-
hyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0338] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(4-amino-quinazoli-
n-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate;
[0339] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinazolin-7--
ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0340] 5-Chloro-benzo[b]thiophene-2-sulfonic acid
(S)-[1-(4-amino-thieno[3-
,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0341] Thieno[3,2-b]pyridine-2-sulfonic acid
(S)-[1-(4-amino-thieno[3,2-d]-
pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0342] Chloro-benzo[b]thiophene-2-sulfonic acid
(S)-[1-(4amino-thieno[3,2--
d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0343] 5'-Chloro [2,2']bithiophenyl-5-sulfonic acid
(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-
-amide trifluoroacetate;
[0344] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid
(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-
-amide trifluoroacetate;
[0345] Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)-1-(4-amino-thieno[3,2--
d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0346] 5-Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)-1-(4-amino-thieno[2,-
3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0347] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[(S)-1-(4-amino-thieno[-
2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0348] Thieno[3,2-b]pyridine-2-sulfonic
acid[(S)-1-(4-amino-thieno[2,3-d]p-
yrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0349] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)-1-(4-amino-thieno[2,-
3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate;
[0350] 5'Chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(4-amino-thieno[3,2-d-
]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate;
[0351] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(4-amino-thieno[3,2-d]pyrim-
idin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
and
[0352] 6Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)-1-(4-amino-thieno[3,2-
-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide.
[0353] Still more preferred species according to the invention are
selected from the group consisting of:
[0354] 7-Methoxynaphthalene-2-sulfonic
acid[1-(6-methoxyisoquinolin-7-ylme-
thyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0355]
1(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-yl-
methyl)amino]pyrrolidin-2-one trifluoroacetate;
[0356] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[2-oxo-1-(1H-pyrrolo[-
3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide;
[0357] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid
[1-(4-amino-quinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate;
[0358] 2-(5Chloro-thiophen-2-yl)-ethenesulfonic acid
(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-
-amide trifluoroacetate;
[0359] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-aminoisoquinolin-7-ylmet-
hyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
[0360] 6-Chlorobenzo[b]thiophene-2-sulfonic acid
(2-oxo-1-[2-(pyridin4yl-a- mino)ethyl]-pyrrolidin-3-(S)-y}-amide
trifluoroacetate;
[0361]
((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin-4-yla-
mino)-ethyl]-pyrrolidin-3(-yl}-amino)-acetic acid methyl ester;
[0362] Thieno[3,2-b]pyridine-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[2,3-c]pyr-
idin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide ditrifluoroacetate;
[0363] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-amino-isoquinolin-7-ylme-
thyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0364] 2(S)-(5Chloro-thiophen2-yl)-ethenesulfonic
acid[1-(4amino-quinolin--
7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate;
[0365] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1,6-diamino-isoquinol- in-7yl
methyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide bistrifluoroacetate;
[0366] 6-Chlorobenzo[b]thiophene-2-sulfonic
acid[1-(4-aminoquinolin-7-yl
methyl)-2-oxo-3(R)-pyrrolidin-3-yl]amide trifluoroacetate; and
[0367] 2-(5-Chlorothiophen-2-yl)-ethenesulfonic
acid[1-(4-aminoquinazolin-- 7-yl
methyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate.
[0368] This invention also encompasses all combinations of
preferred aspects of the invention noted herein.
[0369] A compound of formula I may be prepared by the application
or adaptation of known methods, by which is meant methods used
heretofore or described in the literature.
[0370] A preparative embodiment according to the invention for
preparing a compound of formula I wherein Ar.sub.1, R.sub.1,
R.sub.2, X.sub.3, X.sub.4, X.sub.5, X.sub.5a, X.sub.5b, Z and m are
as defined above, X.sub.1 and X.sub.1a are H and X.sub.2 and
X.sub.2a, taken together, form oxo, may be prepared by coupling a
compound of formula II 23
[0371] wherein X.sub.3, X.sub.4 and m are as defined above, X.sub.1
and X.sub.1a are H, X.sub.2 and X.sub.2a taken together form oxo,
and P.sub.1 is an (alkyl, aralkyl or aryl) carbamate with a
compound of formula III 24
[0372] wherein Ar.sub.1 is bicyclic heteroaryl, X.sub.5, X.sub.5a,
X.sub.5b and Z are as defined above, and one of X.sub.5, X.sub.5a,
X.sub.5b is H, chloro, bromo or aryloxy at the position alpha to
the nitrogen of the distal ring of Ar.sub.1, and L is a leaving
group such as chloro, bromo, iodo, or optionally substituted lower
alkylsulfonyloxy or arylsulfonyloxy, to give a compound of formula
IV 25
[0373] A compound of formula IV is converted to a compound of
formula I by the methods herein described.
[0374] A compound of formula III may be prepared by reacting a
compound of formula V, 26
[0375] wherein X.sub.5c is H, R.sub.5R.sub.6N--, R.sub.7O--,
R.sub.5R.sub.6NCO--, R.sub.5R.sub.6NSO.sub.2--, R.sub.7CO--, halo,
cyano, nitro or R.sub.8(O)C(CH.sub.2).sub.q--, and wherein an amino
or hydroxy group thereof is suitably protected by an amino or
hydroxy protecting group, n is 0 to 2, and Ar.sub.2 is a monocyclic
aryl or heteroaryl ring, with an appropriate malonic acid in a
polar solvent such as pyridine or ethanol and a base such as
piperidine or pyridine at reflux to give a compound of formula VI
27
[0376] wherein R.sub.12 is H, X.sub.5c attached to the
carboxymethylidene moiety is H, X.sub.5c attached to 28
[0377] n and 29
[0378] are as described above. Alternatively, a compound of formula
V may be reacted with a suitable Wittig reagent in an inert solvent
such as THF to give a compound of formula VI wherein R.sub.12 is
lower alkyl, 30
[0379] X.sub.5c attached to the carboxymethylidene moiety or 31
[0380] are as described above. When R.sub.12 is lower alkyl, the
ester is hydrolyzed to the corresponding carboxylic acid, wherein
R.sub.12 is H, by an appropriate strong acid or alkali base. The
corresponding acid is converted to the acid chloride using standard
methods such as thionyl chloride or is converted to the mixed
anhydride in a polar solvent such as acetone or THF to form an
activated acyl compound. The activated acyl compound is then
treated with a solution of NaN.sub.3 in water at about -10.degree.
C. to about 25.degree. C. to yield the corresponding acyl azide.
The acyl azide compound is then heated slowly in an inert solvent
such as benzene or toluene at about 60.degree. C. to about
110.degree. C. then concentrated in vacuo and heated in a higher
boiling inert solvent such as 1,2-dichlorobenzene or phenyl ether
at about 180.degree. C. to about 240.degree. C. with a catalyst
such as iodine or tributylamine to obtain a compound of formula
VII, 32
[0381] wherein X.sub.5c is H, R.sub.5R.sub.6N--, R.sub.7O--,
R.sub.5R.sub.6NCO--, R.sub.5R.sub.6NSO.sub.2--, R.sub.7CO--, halo,
cyano, nitro or R.sub.8(O)C(CH.sub.2).sub.q--, and wherein an amino
or hydroxy group thereof are suitably protected by an amino or
hydroxy protecting group, n is 0, 1 or 2, and Ar.sub.2 is a
monocyclic aryl or heteroaryl ring. Alternatively the acyl azide
compound can be added directly to a high boiling inert solvent such
as phenyl ether at about 190.degree. C. to about 240.degree. C.
with a catalyst such as iodine or tributylamine to obtain the
compound of formula VII.
[0382] A compound of formula VIII, 33
[0383] prepared as described in Syn., 739 (1975) which is
incorporated herein by reference, wherein X.sub.5c is H,
R.sub.5R.sub.6N--, R.sub.7O--, R.sub.5R.sub.6NCO--,
R.sub.5R.sub.6NSO.sub.2--, R.sub.7CO--, halo, cyano, nitro or
R.sub.8(O)C(CH.sub.2).sub.q--, and wherein an amino or hydroxy
group thereof are suitably protected by an amino or hydroxy
protecting group, n is 0, 1, or 2, and Ar.sub.2 is a monocyclic
aryl or heteroaryl ring, or formula VII above, or those compounds
wherein the amino or hydroxy moieties thereof are suitably
protected by an amino or hydroxy protecting group, may be
chlorinated using standard methods such as POCl.sub.3 or
POCl.sub.3/PCl.sub.5 to obtain the following corresponding
chlorinated intermediates such as compounds of formula (IX) and
(X), wherein X.sub.5c, n and Ar.sub.2 are as defined above. 34
[0384] Furthermore, a compound of formula IX and formula X wherein
X.sub.5c is a protected amino moiety wherein the protection is
effected with an acid labile group such as acyl or dibenzylidene
can be deprotected using standard methods such as a strong acid in
an alcoholic solvent such as ethanol or a polar solvent such as
ethyl acetate to yield the free amine which can then be chlorinated
as above. Alternatively the free amine may be liberated by the
action of the POCl.sub.3, but in either case the free amine may be
reprotected with a suitable protecting group such as
dibenzylidene.
[0385] A compound of formula XI, 35
[0386] such as compounds of formulae IX and X, wherein Ar.sub.1,
X.sub.5, X.sub.5a and X.sub.5b are as defined above, and one of
X.sub.5, X.sub.5a and X.sub.5b is chloro at the position alpha to
the nitrogen of the distal ring of Ar.sub.1 when AR.sub.1 is
bicyclic, and the methyl moiety is attached to the proximal ring of
Ar.sub.1, may be treated with NaBr or an arylhydroxy compound such
as phenol and potassium hydroxide to afford a compound of formula
XI wherein the chloro at the position alpha to the nitrogen of the
distal ring of Ar.sub.1 is replaced by bromo or aryloxy at that
position.
[0387] The methyl moiety of a compound of formula XI, wherein
Ar.sub.1, X.sub.5, X.sub.5a and X.sub.5b are as defined above,
provided that wherein X.sub.5, X.sub.5a and X.sub.5b is hydroxy or
amino bearing a hydrogen then the hydroxy and amino are protected
by appropriate hydroxy and/or amino protecting groups, may be
halogenated using standard conditions such as N-halosuccinimide and
benzoyl peroxide in an inert solvent such as carbon tetrachloride
to give the corresponding halomethyl compound of formula III
wherein L is bromo, chloro, or iodo, and one of X.sub.5, X.sub.5a
and X.sub.5b is chloro, bromo or aryloxy at the position alpha to
the nitrogen of the distal ring of Ar.sub.1.
[0388] Alternatively, a compound of formula III wherein 36
[0389] is 37
[0390] A is CH, W is NH and Z is methylenyl, L is halo, one of
X.sub.5, X.sub.5a and X.sub.5b is on the 5-membered ring of 38
[0391] and is a substituent as defined above or one wherein amino
or hydroxy moieties thereof are suitably protected, another of
X.sub.5, X.sub.5a and X.sub.5b is on the 6-membered ring of 39
[0392] and is a substituent as defined above or one wherein amino
or hydroxy moieties thereof are suitably protected, and the other
of X.sub.5, X.sub.5a and X.sub.5b is hydrogen, chloro, bromo or
aryloxy and is substituted alpha to the nitrogen in the 6-membered
ring of 40
[0393] may be prepared by reacting a compound of formula XII,
formula XIII or formula XIIIa 41
[0394] (prepared as described in J. Het. Chem., 29, 359 (1992);
Bull. Soc. Chim. Belg. 301 (1970); and J. Med. Chem. 33, 2087
(1990), the contents of all of which are hereby incorporated herein
by reference) wherein W is NH and X.sub.6 is H, with POCl.sub.3 or
POCl.sub.3/PCl.sub.5 as described above to obtain the corresponding
chloro compound. A compound of formula XII or formula XIII wherein
W is NH and X.sub.7 is H can be protected using standard methods
such as with benzenesulfonyl chloride using a strong base such as
sodium hydroxide in an halogenated solvent such as dichloromethane
in the presence of a phase transfer catalyst such as
tetrabutylammonium chloride to yield a compound of formula XII or
formula XIII wherein W is N--SO.sub.2Ph and X.sub.7 is H. These are
treated with a strong base such as sodium hydride, lithium
hexamethyldisilylazide, or lithium diisopropyl amine in an inert
organic solvent such as tetrahydrofuran or dimethylformamide at
about -78.degree. C. to about 25.degree. C., followed by the
addition of ethyl chloroformate to yield a compound of formula XII
or formula XIII wherein W is N--SO.sub.2Ph and X.sub.7 is
--CO.sub.2 lower alkyl, which in turn can be converted to a
compound of formula XII or formula XIII wherein W is N--SO.sub.2Ph
and X.sub.7 is --CH.sub.2OH using standard hydride reducing agents
such as lithium aluminum hydride in an appropriate organic solvent
such as diethyl ether at about -10.degree. C. to about 25.degree.
C. Then a compound of formula XII or formula XIII wherein W is
N--SO.sub.2Ph and X.sub.7, is --CH.sub.2OH may be halogenated using
standard conditions such as PBr.sub.3 in an organic solvent such as
diethyl ether to give a compound of formula III as defined
above.
[0395] Alternatively, a compound of formula III may be prepared by
condensing an appropriate beta-aryl or beta-heteroaryl amino acid
of formulae XIV or XV, 42
[0396] wherein W and X.sub.7 are as defined herein, with Gold's
reagent under basic conditions using sodium hydride or another
equally strong base followed by an acidic work-up. The resulting
compound is then processed as described above to yield a compound
of formula III.
[0397] A compound of formula II as defined above is treated with a
strong base such as sodium hydride, lithium hexamethyldisilylazide,
or lithium diisopropyl amine in an inert organic solvent such as
tetrahydrofuran or dimethylformamide at about -78.degree. C. to
about 25.degree. C. followed by the addition of a compound of
formula III above wherein one X.sub.5, X.sub.5a and X.sub.5b is
substituted alpha to a nitrogen of the distal ring of 43
[0398] and is hydrogen, chloro, bromo or aryloxy, and L is a good
leaving group such as chloro, bromo, or iodo, to give a compound of
formula IV above.
[0399] Alternatively a compound of formula IV wherein 44
[0400] is 45
[0401] A is CH, W is NH and Z is methylenyl, L is halo, one of
X.sub.5, X.sub.5a and X.sub.5b is on the 5-membered ring of 46
[0402] and is a substituent as defined above or one wherein amino
or hydroxy moieties thereof are suitably protected, another of
X.sub.5, X.sub.5a and X.sub.5b is on the 6-membered ring of 47
[0403] and is a substituent as defined above or one wherein amino
or hydroxy moieties thereof are suitably protected, and the other
of X.sub.5, X.sub.5a and X.sub.5b is hydrogen, chloro, bromo or
aryloxy and is substituted alpha to the nitrogen in the 6membered
ring of 48
[0404] may be prepared by alkylation of a
(2-oxopyrrolidin-3-(S)-yl)-carba- mic acid alkyl or aralkyl ester
with propargyl bromide in the presence of a base such as sodium
hydride. The alkyne that is obtained is heated (100-120.degree. C.)
with a halopyridine optionally substituted with hydroxy,
alkoxycarbonylamino, or sulfhydryl, a catalyst such as
Pd(PPh.sub.3).sub.2Cl.sub.2, copper iodide and triethylamine in a
suitable solvent such as acetonitrile in a sealed vessel or in DMF,
for 2-20 hours. When the pyridine is substituted with a hydroxyl
moiety, furopyridines are isolated directly if the pyridine is
substituted with an alkoxycarbonylamino moiety. Additional
treatment with DBU at about 60.degree. C. in DMF yields
pyrrolopyridines. Subsequent deprotection yields the desired
2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-furopyridin- es or
pyrrolopyridine-1-carboxylic acid alkyl esters. These compounds are
sulfonylated in the normal manner (using arene sulfonyl chlorides
and base such as triethylamine) and in the case of furopyridines
purified (HPLC) to obtain arenesulfonic acid
[2-oxo-1-(furopyridinyl-methyl)pyrrol- idine-3-(S)-yl]-amides
generally as the TFA salts. In the case of pyrrolopyridines an
additional deprotection step (such as acid for BOC protecting
groups) yields corresponding arenesulfonic acid
[2-oxo-1-(pyrrolopyridinyl-methyl)-pyrrolidin-3-(S)-yl]-amides.
[0405] The P.sub.1 moiety of the compound of formula IV is then
removed by the appropriate deprotecting procedures known for
carbamates such as strong acid, strong base or catalytic
hydrogenation to give a compound of formula XVI, wherein Ar.sub.1,
X.sub.5, X.sub.5a, X.sub.5b, Z and m are as defined above. 49
[0406] The amine of the compound of formula XVI liberated by the
removal of P.sub.1 is then coupled to a compound of formulae XVII
or XVIII
R.sub.3S(O).sub.pHalo (XVII)
[0407] or
R.sub.3R.sub.4NS(O).sub.pHalo (XVIII)
[0408] where R.sub.3, R.sub.4, and p are as defined above, and Halo
is a halogen atom such as chloro, using a base such as a
trialkylamine in an inert solvent such as dichloromethane,
tetrahydrofuran, ether or acetonitrile at about 0.degree. C. to
about 100.degree. C. in the presence or absence of an activating
agent such as dimethyl aminopyridine (DMAP) to give a compound of
formula XIX 50
[0409] wherein Ar.sub.1, R.sub.1, R.sub.3, R.sub.4, X.sub.1,
X.sub.1a, X.sub.2, X.sub.2a, X.sub.3, X.sub.4, X.sub.5, X.sub.5a,
X.sub.5b, Z and m are as defined above.
[0410] Compounds represented by formula XIX wherein one X.sub.5,
X.sub.5a and X.sub.5b is substituted alpha to a nitrogen of the
distal ring of 51
[0411] and is bromo or chloro may be converted to the corresponding
aryloxide by reaction with an arylhydroxy compound such as phenol,
and a strong alkali base such as potassium hydroxide at 70.degree.
C. to about 120.degree. C. The aryloxide intermediate (Y.dbd.ArO--)
is then treated with an ammonium salt such as ammonium acetate at
about 90.degree. C. to 180.degree. C. to give a compound of formula
I wherein Ar.sub.1, R.sub.1, R.sub.3, R.sub.4, X.sub.1, X.sub.1a,
X.sub.2, X.sub.2a, X.sub.3, X.sub.4, X.sub.5, X.sub.5a, X.sub.5b, Z
and m are as defined above, and wherein one X.sub.5, X.sub.5a and
X.sub.5b is substituted alpha to a nitrogen of the distal ring of
52
[0412] and is NH.sub.2.
[0413] Alternatively, a compound of formula XIX wherein one
X.sub.5, X.sub.5a, and X.sub.5b is substituted alpha to a nitrogen
of the distal ring of 53
[0414] and is bromo or chloro may be treated with an arylhydroxy
such as phenol and an ammonium salt such as ammonium acetate at
about 90.degree. C. to 180.degree. C. to give compounds represented
by formula I wherein Ar.sub.1, R.sub.1, R.sub.3, R.sub.4, X.sub.1,
X.sub.1a, X.sub.2, X.sub.2a, X.sub.3, X.sub.4, X.sub.5, X.sub.5a,
X.sub.5b, Z and m are as defined above, and wherein one X.sub.5,
X.sub.5a and X.sub.5b is substituted alpha to a nitrogen of the
distal ring of 54
[0415] and is NH.sub.2.
[0416] Alternatively, a compound of formula I may be prepared
starting with a compound of formula XX. 55
[0417] wherein X.sub.3, X.sub.4, P.sub.1 and m are as defined
above, and P.sub.2 is alkyl, aralkyl or aryl, by reductive
amination using a (heteroaryl)alkylamine of formula XXI 56
[0418] wherein Ar.sub.1, X.sub.5, X.sub.5a, X.sub.5b and Z are as
defined above, in an alcoholic solvent such as methanol and an
imine reducing reagent such as sodium cyanoborohydride or sodium
triacetoxyborohydride at about 0.degree. C. to about 100.degree. C.
to give the cyclic structure represented by formula IV which is
then converted to a compound of formula I as described above.
[0419] A compound of formula XXI used in the reductive amination
described above may be prepared by treatment of a compound of
formula III wherein one of X.sub.5, X.sub.5a, X.sub.5b is H or
aryloxy at the position alpha to the nitrogen of the distal ring of
Ar.sub.1, and L is a leaving group such as chloro, bromo, iodo or
the like, with sodium azide followed by reduction using standard
reducing methods such as triphenylphosphine in solvents such as
water/tetrahydrofuran or catalytic reduction.
[0420] A compound of formula I in which R.sub.1 is other than H may
be prepared starting with a compound of formula I wherein R.sub.1
is H by dissolving it in an inert organic solvent such as
tetrahydrofuran, dioxane, or dimethyl formamide at about 0.degree.
C. to about 100.degree. C. To the resulting solution is added a
base such as sodium hydride or potassium carbonate and a compound
of formula XXII.
R.sub.1-Halo XXII
[0421] wherein R.sub.1 is as defined above except that R.sub.1 is
not H, and Halo is a halogen such as bromo or chloro.
[0422] A compound of formula I including an heteroaryl group
containing one or more nitrogen ring atoms, preferably imine
(.dbd.N--), may be converted to the corresponding compound wherein
one or more nitrogen ring atom of the heteroaryl moiety is oxidized
to an N-oxide, preferably by reacting with a peracid, for example
peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an
inert solvent such as dichloromethane, at a temperature from about
room temperature to reflux, preferably at an elevated
temperature.
[0423] The compounds of the present invention are useful in the
form of the free base or acid or in the form of a pharmaceutically
acceptable salt thereof. All forms are within the scope of the
invention.
[0424] Where a compound of the present invention is substituted
with a basic moiety, acid addition salts are formed and are simply
a more convenient form for use; and in practice, use of the salt
form inherently amounts to use of the free base form. The acids
which can be used to prepare the acid addition salts include
preferably those which produce, when combined with the free base,
pharmaceutically acceptable salts, that is, salts whose anions are
non-toxic to the patient in pharmaceutical doses of the salts, so
that the beneficial inhibitory effects on the activity of Factor Xa
inherent in the free base are not vitiated by side effects
ascribable to the anions. Although pharmaceutically acceptable
salts of said basic compounds are preferred, all acid addition
salts are useful as sources of the free base form even if the
particular salt, per se, is desired only as an intermediate product
as, for example, when the salt is formed only for purposes of
purification, and identification, or when it is used as
intermediate in preparing a pharmaceutically acceptable salt by ion
exchange procedures. Pharmaceutically acceptable salts within the
scope of the invention are those derived from the following acids:
mineral acids such as hydrochloric acid, sulfuric acid, phosphoric
acid and sulfamic acid; and organic acids such as acetic acid,
citric acid, lactic acid, tartaric acid, malonic acid,
methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and
the like. The corresponding acid addition salts include the
following: hydrohalides, e.g. hydrochloride and hydrobromide,
sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate,
tartarate, malonate, oxalate, salicylate, propionate, succinate,
fumarate, maleate, methylene-bis-B-hydroxynaphthoa- tes,
gentisates, mesylates, isothionates and di-p-toluoyltartrates,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate, cyclohexylsulfamate and quinate,
respectively.
[0425] According to a further feature of the invention, acid
addition salts of the compounds of this invention are prepared by
reaction of the free base with the appropriate acid, by the
application or adaptation of known methods. For example, the acid
addition salts of the compounds of this invention are prepared
either by dissolving the free base in aqueous or aqueous-alcohol
solution or other suitable solvents containing the appropriate acid
and isolating the salt by evaporating the solution, or by reacting
the free base and acid in an organic solvent, in which case the
salt separates directly or can be obtained by concentration of the
solution.
[0426] The compounds of this invention may be regenerated from the
acid addition salts by the application or adaptation of known
methods. For example, parent compounds of the invention can be
regenerated from their acid addition salts by treatment with an
alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia
solution.
[0427] Where a compound of the invention is substituted with an
acidic moiety, base addition salts may be formed and are simply a
more convenient form for use; and in practice, use of the salt form
inherently amounts to use of the free acid form. The bases which
can be used to prepare the base addition salts include preferably
those which produce, when combined with the free acid,
pharmaceutically acceptable salts, that is, salts whose cations are
non-toxic to the animal organism in pharmaceutical doses of the
salts, so that the beneficial inhibitory effects on the activity of
Factor Xa inherent in the free acid are not vitiated by side
effects ascribable to the cations. Pharmaceutically acceptable
salts, including for example alkali and alkaline earth metal salts,
within the scope of the invention are those derived from the
following bases: sodium hydride, sodium hydroxide, potassium
hydroxide, calcium hydroxide, aluminum hydroxide, lithium
hydroxide, magnesium hydroxide, zinc hydroxide, ammonia,
ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine,
choline, N,N'-dibenzylethylenediamine, chloroprocaine,
diethanolamine, procaine, N-benzylphenethylamine, diethylamine,
piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium
hydroxide, and the like.
[0428] Metal salts of compounds of the present invention may be
obtained by contacting a hydride, hydroxide, carbonate or similar
reactive compound of the chosen metal, in an aqueous or organic
solvent, with the free acid form of the compound. The aqueous
solvent employed may be water or it may be a mixture of water with
an organic solvent, preferably an alcohol such as methanol or
ethanol, a ketone such as acetone, an aliphatic ether such as
tetrahydrofuran, or an ester such as ethyl acetate. Such reactions
are normally conducted at ambient temperature but they may, if
desired, be conducted with heating.
[0429] Amine salts of compounds of the present invention may be
obtained by contacting an amine in an aqueous or organic solvent
with the free acid form of the compound. Suitable aqueous solvents
include water and mixtures of water with alcohols such as methanol
or ethanol, ethers such as tetrahydrofuran, nitriles such as
acetonitrile, or ketones such as acetone. Amino acid salts may be
similarly prepared.
[0430] The base addition salts of the compounds of this invention
can be regenerated from the salts by the application or adaptation
of known methods. For example, parent compounds of the invention
can be regenerated from their base addition salts by treatment with
an acid, e.g. hydrochloric acid.
[0431] Salt forms according to invention also include compounds
having a quarternarized nitrogen. The quarternarized salts are
formed by methods such as by alkylation of a sp.sup.3 or sp.sup.2
hybridized nitrogen in the compounds.
[0432] As will be self-evident to those skilled in the art, some of
the compounds of this invention do not form stable salts. However,
acid addition salts are most likely to be formed by compounds of
this invention having a nitrogen-containing heteroaryl group and/or
possessing an amino group as a substituent. Preferable acid
addition salts of the compounds of the invention are those wherein
there is not an acid labile group.
[0433] As well as being useful in themselves as active compounds,
salts of compounds of the invention are useful for the purposes of
purification of the compounds, for example by exploitation of the
solubility differences between the salts and the parent compounds,
side products and/or starting materials by techniques well known to
those skilled in the art.
[0434] Compounds of the present invention may contain asymmetric
centers. These asymmetric centers may independently be in either
the (R) or (S) configuration. It will also be apparent to those
skilled in the art that certain compounds of formula I may exhibit
geometrical isomerism. Geometrical isomers include the cis and
trans forms of compounds of the invention having an alkenyl moiety.
The present invention comprises the individual geometrical isomers
and stereoisomers and mixtures thereof.
[0435] Such isomers can be separated from their mixtures by the
application or adaptation of known methods, for example,
chromatographic techniques and recrystallization techniques, or
they are separately prepared from the appropriate isomers of their
intermediates, for example by the application or adaptation of
methods described herein.
[0436] The starting materials and intermediates are prepared by the
application or adaptation of known methods, for example methods as
described in the Reference Examples or their obvious chemical
equivalents.
[0437] The present invention is further exemplified but not limited
by the following examples, which illustrate the preparation of the
compounds according to the invention.
[0438] In the nuclear magnetic resonance spectra (NMR) the chemical
shifts are expressed in ppm relative to tetramethylsilane.
Abbreviations have the following significance: s=singlet;
d=doublet; t=triplet; m=multiplet; dd=doublet of doublets;
ddd=doublet of doublets of doublets; dt=doublet of triplets,
b=broad, bs=broad singlet, q=quartet, AB=AB pattern.
EXAMPLE 1
[0439] 7-Methoxynaphthalene-2-sulfonic
acid-[1-(1-aminoisoquinolin-7-yl-me-
thyl)-2-oxopyrrolidin-3(R,S)-yl]-amide trifluoroacetate
[0440] A. 3-p-Tolyl-acryloyl chloride
[0441] Thionyl chloride (9.44 mL, 129.5 mmol) is added dropwise to
a solution of 3-p-tolyl-acrylic acid (20 g, 123.3 mmol) in benzene
(50 mL) at 0.degree. C. The resulting solution is allowed to warn
to room temperature then heated to reflux for 2 hours. The mixture
is concentrated to dryness on the rotovap to give the crude product
(22.3 g, 123.3 mmol) which is taken onto the next step.
[0442] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.80 (d, 1H), 7.50
(d, 2H), 7.26 (d, 2H), 6.58 (d, 1H), 2.40 (s, 3H).
[0443] B. 3-p-Tolyl-acryloyl azide
[0444] 3-p-Tolyl-acryloyl chloride (22.3 g, 123.3 mmol) in dioxane
(50 mL) is slowly added to an ice cooled solution of sodium azide
(16 g, 246.6 mmol) in water/dioxane (50 mL, 1/1, v/v) so as to
maintain the temperature between 5-10.degree. C. The mixture is
stirred for 1.5 hours then poured over 300 g of ice. The resulting
white solid is filtered and washed with additional water. The solid
(20.72 g, 110.7 mmol) was dried over P.sub.2O.sub.5 under vacuum
overnight and used in the next step without further
purification.
[0445] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.73 (d, 1H), 7.45
(d, 2H), 7.21 (d, 2H), 6.38 (d, 1H), 2.38 (s, 3H). EI MS,
[M.].sup.+=187.
[0446] C. 1-(2-Isocyanato-vinyl)-4-methyl-benzene
[0447] 3-p-Tolyl-acryloyl azide (20.72 g, 110.7 mmol) in benzene
(100 mL) is heated slowly to 75.degree. C. for 3.5 hours then
concentrated to give a brown oil (ca. 20 g). This material was
taken onto the next step without further purification.
[0448] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.18 (d, 2H), 7.12
(d, 2H), 6.53 (d, 1H), 6.40 (d, 1H), 2.32 (s, 3H). EI MS,
[M.].sup.+=159.
[0449] D. 7-Methyl-2H-isoquinolin-1-one
[0450] Iodine (0.63 g, 2.51 mmol) is added to a solution of
1-(2-isocyanato-vinyl)4-methyl-benzene (ca. 20 g, 125.6 mmol) in
o-dicblorobenzene (125 mL), then is heated io reflux (180.degree.
C.) overnight. The mixture is cooled to room temperature then
concentrated to dryness. The residue is purified by column
chromatography eluting with 40% EtOAc/hexanes. The product (6.23 g,
39.1 mmol) is obtained as a tan solid.
[0451] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.12.25 (bs, 1H),
8.21 (s, 1H), 7.42 (bs, 2H), 7.14 (d, 1H), 6.50 (d, 1H), 2.46 (s,
3H). EI MS, [M.].sup.+159.
[0452] E. 1-Chloro-7-methylisoquinoline
[0453] 7-Methyl-2H-isoquinolin-1-one (2.1 g, 13.2 mmol) in
phosphorus oxychloride (30 mL) is heated to reflux for 13 hours.
The mixture is cooled to room temperature, then concentrated to a
smaller volume. The residue is diluted with ice water and the pH is
adjusted to ca. 8 by slow addition of 10 N NaOH. The aqueous
solution is extracted with methylene chloride (4.times.20 mL) and
the combined organic layers are washed with brine, dried over
MgSO.sub.4, filtered and concentrated. The resulting dark oil is
purified by column chromatography eluting with 25% EtOAc/hexanes to
give the product (1.6 g, 9 mmol) as a light yellow solid.
[0454] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.18 (d, 1H), 8.05
(d, 1H), 7.71 (d, 1H), 7.55 (m, 2H), 7.55 (s, 3H). EI MS,
[M.].sup.+177, 179, Cl pattern.
[0455] F. 7-Bromomethyl-1-chloro-isoquinoline
[0456] N-Bromosuccinimide (1.10 g, 6.19 mmol) and benzoyl peroxide
( 0.39 g, 1.13 mmol) are added to a solution of
1-chloro-7-methylisoquinoline (1 g, 5.63 mmol) in carbon
tetrachloride (70 mL). The resulting mixture is heated to reflux
for 6 hours then cooled to room temperature and diluted with
methylene chloride. The organic layer is washed with IN NaOH and
brine, then dried over MgSO.sub.4, filtered and concentrated. The
residue is purified by column chromatography eluting with a
gradient of 10% EtOAc/hexanes to 25% EtOAc/hexanes to give the
product (1.4 g, 5.46 mmol) as a white solid.
[0457] .sup.1H NMR(CDCl.sub.3, 300 MHz) .delta.8.31 (s, 1H), 8.28
(d, 1H), 7.86 (d, 1H), 7.77 (dd, 1H), 7.58 (d, 1H), 4.69 (s, 2H).
EI MS, [M.].sup.+=255, 257, Cl, Br pattern.
[0458] G.(2-Oxopyrrolidin-3-(S)-yl carbamic acid tert-butyl
ester
[0459] (S)Boc-Diaminobutyric acid (25 g, 115 mmol), triethylamine
(35 g, 344 mmol), and hydroxybenzotriazole (19.3 g, 143 mmol) are
dissolved in THF (300 mL).
1-(3-Dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (27.4 g,
143 mmol) is added to the solution. The solution is heated to
60.degree. C. over 15 minutes. A white precipitate forms and the
solution is kept at 60.degree. C. for 4 hours. After this time, the
solution is filtered and the collected liquid is concentrated. The
crude product is purified by column chromatography in a gradient of
1% MeOH/CH.sub.2Cl.sub.2 to 3% MeOH/CH.sub.2Cl.sub.2 to afford the
title compound (19.6 g, 98 mmol) as a white solid.
[0460] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.6.17 (bs, 1H), 5.08
(bs, 1H), 4.12 (m, 1H), 3.33 (m, 2H), 2.65 (m, 1H), 2.00 (m, 1H),
1.42 (s, 9H).
[0461] H.
[1-(1-Chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3(S)-yl]-ca-
rbamic acid tert-butyl ester
[0462] Sodium hydride (0.24 g, 6.05 mmol, 60% mineral oil
dispersion) is added to a solution of
[2-oxopyrrolidin-3(S)-yl]-carbamic acid tert-butyl ester (1.18 g,
5.89 mmol) in THF/DMF (62 mL, 9/1, v/v) at 0.degree. C. The mixture
is stirred for 2 minutes, then a solution of
7-bromomethyl-1-chloro-isoquinoline (1.4 g, 5.46 mmol) in THF (10
mL) is added dropwise via a cannula. The resulting yellow solution
is stirred for 1 hour at 0.degree. C. then at room temperature for
3 hours. The reaction mixture is quenched with saturated ammonium
chloride solution, then diluted with EtOAc. The organic layer is
washed with water and brine, then dried over MgSO.sub.4, filtered
and concentrated. The residue is purified by column chromatography
eluting with a gradient of 50% EtOAc/hexanes to 70% EtOAc/hexanes
to give the product (1.67 g, 4.44 mmol) as a foamy white solid.
[0463] .sup.1H NMR (CDCl.sub.3, 300 MHz) 67 8.25 (d, 1H), 8.12 (s,
1H), 7.83 (d, 1H), 7.68 (dd, 1H), 7.58 (d, 1H), 5.55 (bs, 1H), 4.71
(AB, 2H), 4.30 (m, 1H), 3.26 (m, 2H), 2.60 (m, 1H), 1.98 (m, 1H),
1.46 (s, 9H). EI MS, [M+H].sup.+=376, 378, Cl pattern.
[0464] I.
3-(S)-Amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride
[0465] To a solution of
[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolid-
in-3(S)-yl]-carbamic acid tert-butyl ester (2.1 g, 5.6 mmol) in
EtOAc (170 mL) at 0.degree. C. is bubbled HCl gas for 5 minutes.
The solution is stirred at 0.degree. C. for 15 minutes, then the
ice bath is removed and the solution allowed to warm to room
temperature. After 4 hours at room temperature, the solution is
concentrated and the remaining solid is washed with ether to give
the title compound (1.74 g, 5.6 mmol) as a pale yellow solid.
[0466] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.64 (d, 3H),
8.31 (d, 1H), 8.18 (s, 1H), 8.10 (d, 1H), 7.90 (d, 1H), 7.80 (d,
1H), 4.71 (AB, 2H), 4.10 (m, 1H), 3.30 (m, 2H), 2.41 (m, 1H), 1.98
(m, 1H). FAB MS, [M+H].sup.+=276.
[0467] J. 7-Methoxynaphthalene-2-sulfonyl chloride
[0468] To a suspension of 7-hydroxynaphthalene-2-sulfonic acid,
sodium salt (15 g, 60.9 mmol) in H.sub.2O/ethanol (150 mL, 2:1) is
added solid NaOH (2.68 g, 67 mmol) at room temperature. The mixture
is stirred until a homogenous solution forms and dimethyl sulfate
(6.34 mL, 67 mmol) is then added. A precipitate slowly forms and
the mixture is stirred over a period of 16 hours. The crude mixture
is concentrated in vacuo and the residue is stirred in absolute
EtOH (100 mL) as a slurry for 2 hours. The precipitate is filtered
and dried. The solid is heated at reflux in 95% EtOH (100 mL) for 2
h, allowed to cool to room temperature, filtered and dried to give
12.6 g of crude 7-methoxynaphthalene-2-sulfonic acid, sodium salt.
A mixture of the sulfonic acid, sodium salt (12.6 g, 48.6 mmol) in
phosphorous oxychloride (20 mL) and phosphorous pentachloride (13.2
g, 63.2 mmol) is heated slowly to 60.degree. C. until a homogenous
solution forms and then is heated at 120.degree. C. for 4 hours.
The resulting mixture is cooled in an ice bath and a mixture of
ice/ice water is added slowly with stirring. The mixture is diluted
with water and extracted with CHCl.sub.3 (2.times.100 mL). The
combined organic layers are washed successively with water,
saturated NaHCO.sub.3 solution and saturated NaCl. The organic
phase is dried over anhydrous MgSO.sub.4, filtered and concentrated
to give 10 g of a crude oil. The crude product is purified by
column chromatography in a gradient of 5% EtOAc/hexanes to 30%
EtOAc/hexanes to afford the title compound (3.8 g, 14.8 mmol) as a
white crystalline solid.
[0469] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.49 (d, 1H), 7.96
(d, 1H), 7.85 (d, 2H), 7.39 (dd, 1H), 7.29 (d, 1H), 3.99 (s, 3H).
EI MS, [M].sup.+256.
[0470] K. 7-Methoxynaphthalene-2-sulfonic acid[1-(
1-chloro-isoquinolin-7--
ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0471]
3-(S)-Amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride (1.74 g, 5.6 mmol) is suspended in CH.sub.3CN (120
mL). To this solution is added triethylamine (2.35 mL, 16.9 mmol)
followed by 7-methoxynaphthalene-2-sulfonyl chloride (1.52 g, 5.93
mmol). The mixture is stirred overnight, then concentrated to
dryness. The crude product is purified by column chromatography
eluting with a gradient of 2% MeOH/CH.sub.2Cl.sub.2 to 5%
MeOH/CH.sub.2Cl.sub.2 to give the title compound (2.7 g, 5.4 mmol)
as a light yellow solid.
[0472] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.35 (d, 1H), 8.27
(d, 1H), 8.08 (s, 1H), 7.91 (d, 1H), 7.80 (d, 1H), 7.78 (s, 1H),
7.74 (dd, 1H), 7.56 (s, 1H), 7.51 (d, 1H), 7.30 (dd, 1H), 7.24 (d,
1H), 5.42 (d, 1H), 4.63 (AB, 2H), 3.95 (s, 3H), 3.78 (m, 1H), 3.25
(m, 2H), 2.60 (m, 1H), 2.08 (m, 1H). FAB MS, [M+H].sup.+=496, 498,
Cl pattern.
[0473] L. 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-phenoxy-isoquinolin-7--
ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]-amide
[0474] Phenol (6.81 g, 72.4 mmol) and potassium hydroxide ( 0.41 g,
7.31 mmol) are added to 7-methoxynaphthalene-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
(1.8 g, 3.6 mmol) and heated to 90.degree. C. until a homogeneous
mixture is obtained. The mixture is stirred overnight at 90.degree.
C., then cooled to room temperature and diluted with methylene
chloride (100 mL) and water. The aqueous layer is neutralized to pH
7 using 1 N HCl, then the two layers are separated and the aqueous
layer is extracted with additional methylene chloride. The combined
organic layers are washed with brine, dried over MgSO.sub.4,
filtered and concentrated. The residue is purified by column
chromatography eluting with a gradient of 30% EtOAc/hexanes to 60%
EtOAc/hexanes to give the product (1.66 g, 3 mmol) as a white
solid.
[0475] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.40 (s, 1H), 8.20
(s, 1H), 7.94 (d, 1H), 7.82 (d, 1H), 7.74 (d, 1H), 7.70 (d, 1H),
7.51 (dd, 1H), 7.40 (m, 2H), 7.15-7.30 (m, 7H), 5.80 (bs, 1H), 4.60
(AB, 2H), 3.98 (s, 3H), 3.82 (m, 1H), 3.20 (m, 2H), 2.52 (m, 1H),
2.04 (m, 1H). FAB MS, [M+H].sup.+=554.
[0476] M. 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-yl--
methyl)-2-oxopyrrolidin-3-(RS)-yl]-amide trifluoroacetate
[0477] In around-bottomed flask fitted with a water condenser,
7-methoxynaphthalene-2-sulfonic
acid[1-(1-phenoxy-isoquinolin-7-ylmethyl)-
-2-oxopyrtolidin-3-(S)yl]-amide (0.318 g, 0.574 mmol) and ammonium
acetate (5 g, 65 mmol) are heated to 160.degree. C. After ca. 6
hours, the homogeneous mixture is cooled to room temperature and
the mixture is purified by RP-HPLC eluting with a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 100% CH.sub.3CN. The appropriate
fractions are lyophilized to give the title racemic compound (0.157
g, 0.266 mmol) as a white solid.
[0478] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.95 (bs, 2H),
8.39 (s, 1H), 8.23-8.29 (m, 2H), 8.02 (d, 1H), 7.95 (d, 1H), 7.93
(d, 1H), 7.77 (d, 1H), 7.74 (dd, 1H), 7.65 (d, 1H), 7.58 (d, 1H),
7.35 (dd, 1H), 7.24 (d, 1H), 4.56 (AB, 2H), 4.20 (m, 1H), 3.89 (s,
3H), 3.15 (m, 2H), 2.05 (m, 1H), 1.60 (m, 1H). FAB MS,
[M+H].sup.+=477.
EXAMPLE 2
[0479] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-yl-met-
hyl)-2-oxopyrrolidin-3-(S)-yl]-amide hydrochloride
[0480] In a round-bottomed flask fitted with a cold finger
condenser, phenol (0.569 g, 6 mmol) and
7-methoxy-naphthalene-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
(0.2 g, 0.4 mmol) is melted at 70.degree. C. The mixture is stirred
for 5 minutes, then ammonium acetate (0.462 g, 6 mmol) is added and
heated at 115.degree. C. for 2 hours. After this time, additional
ammonium acetate (0.462 g, 6 mmol) is added. After 2 hours the
reaction mixture is cooled to room temperature then partitioned
between EtOAc and 0.5N NaOH. The organic layer is separated and
washed with water and brine, then dried over Na.sub.2SO.sub.4,
filtered and concentrated. The resulting residue is partially
purified by RP-HPLC eluting with a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 100% CH.sub.3CN. The appropriate
fractions are concentrated in vacuo. The solid which precipitates
out from the solution is then filtered, dried and purified again by
column chromatography eluting with 5% MeOH/CH.sub.2Cl.sub.2. This
product is then triturated with cold MeOH and the collected solid
is suspended in MeOH and cooled to 0.degree. C. HCl(g) is bubbled
through the slurry for a few minutes during which time all the
solid dissolves into the solution. The solvent is removed in vacuo
and the title product (0.11 g, 0.214 mmol) is washed with ether and
dried.
[0481] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.13.30 (bs, 1H),
9.18 (bs, 2H), 8.32 (s, 1H), 8.25 (d, 1H), 7.99 (d, 1H), 7.85-7.91
(m, 2H), 7.60-7.80 (m, 3H), 7.50 (s, 1H), 7.25 (dd, 1H), 7.18 (d,
1H), 4.51 (AB, 2H), 4.23 (m, 1H), 3.85 (s, 3H), 3.12 (m, 2H), 1.95
(m, 1H), 1.65 (m, 1H). FAB MS, [M+H].sup.+=477. Melting point:
187-192.degree. C. The enantiomeric purity is 88% ee as determined
by analytical Chiralpak AD reverse phase HPLC.
EXAMPLE 3
[0482] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-yl-met-
hyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0483] The title compound is prepared by resolution of the racemic
compound described in EXAMPLE 1, Part M using a Chiralpak AD HPLC
column (55% EtOH/Heptane(0.1% TFA)).
[0484] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.95 (bs, 2H),
8.39 (d, 1H), 8.30 (s, 1H), 8.23 (d, 1H), 8.04 (d, 1H), 7.95 (d,
1H), 7.93 (d, 1H), 7.77 (d, 1H), 7.74 (dd, 1H), 7.65 (d, 1H), 7.58
(d, 1H), 7.35 (dd, 1H), 7.24 (d, 1H), 4.56 (AB, 2H), 4.20 (m, 1H),
3.89 (s, 3H), 3.15 (m, 2H), 2.05 (m, 1H), 1.60 (m, 1H). FAB MS,
[M+H].sup.+=477. The enantiomeric purity is 96.3% ee as determined
by analytical Chiralpak AD reverse phase HPLC.
[a].sub.D+3.16.degree. (MeOH). cl EXAMPLE 4
[0485] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-yl-met-
hyl)-2-oxopyrrolidin-3-(R)-yl]-amide trifluoroacetate
[0486] The title compound is prepared by resolution of the racemic
compound described in EXAMPLE 1, Part M using a Chiralpak AD HPLC
column (55% EtOH/Heptane (0.1% TFA)).
[0487] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.95 (bs, 2H),
8.39 (d, 1H), 8.30 (s, 1H), 8.23 (d, 1H), 8.04 (d, 1H), 7.95 (d,
1H), 7.93 (d, 1H), 7.77 (d, 1H), 7.74 (dd, 1H), 7.65 (d, 1H), 7.58
(d, 1H), 7.35 (dd, 1H), 7.24 (d, 1H), 4.56 (AB, 2H), 4.20 (m, 1H),
3.89 (s, 3H), 3.15 (m, 2H), 2.05 (m, 1H), 1.60 (m, 1H). FAB MS,
[M+H].sup.+477. The enantiomeric purity is 90.7% ee as determined
by analytical Chiralpak AD reverse phase HPLC.
[a].sub.D-3.89.degree. (MeOH).
EXAMPLE 5
[0488] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-hydroxyisoquinolin-7ylmet-
hyl)-2-oxopyrrolidin-3(R,S)-yl]amide
[0489] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-ylme-
thyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.07 g, 0.14 mmol), prepared
as described in EXAMPLE 1, Part K , is treated with dioxane (1 mL)
and 10% aq. NaOH (3 mL) and heated to reflux for 48 hours. The
reaction was cooled, acidified with 1 N HCl and extracted with
CH.sub.2Cl.sub.2. The organic layer is separated, dried and
concentrated. The residue is purified by column chromatography
eluting with 2.5% MeOH/CH.sub.2Cl.sub.2. The product fractions are
collected, concentrated and precipitated with dilute HCl/ether to
yield the title compound (0.041 g, 0.086 mmol).
[0490] .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta.8.41 (s, 1H), 8.25
(d, 1H), 8.06 (bs, 1H), 7.93 (d, 1H), 7.85 (d, 1H), 7.76 (d, 1H),
7.58 (AB, 2H), 7.39 (s, 1H), 7.24 (dd, 1H), 7.17 (d, 1H), 6.66 (bs,
1H), ), 4.55 (AB, 2H), 4.20 (m, 1H), 3.92 (s, 3H), 3.19 (m, 2H),
2.20 (m, 1H), 1.59 (m, 1H), 1.70 (m, 1H). FAB MS, [M+H].sup.+=478.
Elemental analysis calculated with 1.6 mole of H.sub.2O: C=58.42%,
H=4.71%, N=8.18%; found C=59.30%, H=5.04%, N=7.96%.
EXAMPLE 6
[0491] 7-Methoxynaphthalene-2-sulfonic
acid-[1-(1-amino-isoquinolin-7-ylme-
thyl)-2-oxopyrrolidin-3-(R,S)-yl]-methylamide trifluoroacetate
[0492] A. 7-Methoxynaphthalehe-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide To a solution of
7-methoxynaphthalene-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-ylmethyl)--
2-oxopyrrolidin-3-(S)-yl]-amide (0.1 51 g, 0.304 mmol) in acetone
(20 mL) is added potassium carbonate (0.084 g, 0.608 mmol) followed
by methyl iodide (0.12 mL, 1.93 mmol). The resulting mixture is
heated to reflux overnight, then cooled to room temperature and
diluted with methylene chloride. The solution is washed with
saturated NaHCO.sub.3 solution, water and brine. The organic layer
is dried over MgSO.sub.4, filtered and concentrated. The residue is
purified by column chromatography eluting with 5%
MeOH/CH.sub.2Cl.sub.2 to give the product (0.093 mg, 0.18 mmol) as
an oil.
[0493] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.41 (s, 1H), 8.04
(s, 1H), 8.23-8.26 (m, 2H), 8.07 (s, 1H), 7.90 (d, 1H), 7.90 (d,
1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.58 (dd, 1H), 7.28 (m, 1H), 5.02
(m, 1H), 4.63 (AB, 2H), 3.92 (s, 3H), 3.24 (m, 2H), 2.82 (s, 3H),
2.32 (m, 1H), 2.05 (m, 1H).
[0494] B. 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-phenoxy-isoquinolin-7--
ylmethyl)-2-oxopyrrolidin-3-(R,S)-yl]-methylamide
[0495] The title compound is prepared as described in EXAMPLE 1,
Part L using 7-methoxynaphthalene-2-sulfonic acid
[1-(1-chloro-isoquinolin-7-ylm-
ethyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide in place of
7-methoxynaphthalene-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-ylmethyl)--
2-oxopyrrolidin-3-(S)-yl]-amide.
[0496] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.45 (s, 1H), 8.20
(s, 1H), 7.90 (d, 1H), 7.81 (d, 1H), 7.74 (d, 1H), 7.70 (d, 1H),
7.54 (dd, 1H), 7.38-7.45 (m, 3H), 7.14-7.30 (m, 6H), 5.00 (m, 1H),
4.62 (AB, 2H), 3.88 (s, 3H), 3.25 (m, 2H), 2.81 (s, 3H), 2.30 (m,
1H), 2.01 (m, 1H).
[0497] C. 7-Methoxynaphthalene-2-sulfonic
acid-[1-(1-amino-isoquinolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(R,S)-yl]-methylamide
trifluoroacetate
[0498] The title compound is prepared as described in EXAMPLE 1,
Part M using 7-methoxynaphthalene-2-sulfonic acid
[1-(1-phenoxy-isoquinolin-7-yl-
methyl)-2-oxopyrrolidin-3-(R,S)yl]-methyl-amide in place of
7-methoxynaphthalene-2-sulfonic
acid[1-(1-phenoxy-isoquinolin-7-ylmethyl)-
-2-oxopyrrolidin-3-(R,S)-yl]-amide.
[0499] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.00 (bs, 2H),
8.40 (s, 1H), 8.26 (s, 1H), 8.04 (d, 1H), 7.90-7.95 (m, 2H), 7.79
(d, 1H), 7.71 (dd, 1H), 7.65 (d, 1H), 7.56 (d, 1H), 7.32 (d, 1H),
7.21 (d, 1H), 4.95 (m, 1H), 4.54 (AB, 2H), 3.86 (s, 3H), 3.20 (m,
2H), 2.65 (s, 3H), 2.00 (m, 1H), 1.75 (m, 1H). FAB MS,
[M+H].sup.+=491. Elemental analysis calculated with 1.5 mole of
H.sub.2O: C=53.25%, H=4.79%, N=8.87%, found C=53.43%, H=4.50%,
N=8.58%.
EXAMPLE 7
[0500] 7-Methoxynaphthalene-2-sulfonic
acid-[1-(1-amino-isoquinolin-7-ylme-
thyl)-2-oxopyrrolidin-3-(S)-yl]-methylamide trifluoroacetate
[0501] The title compound is prepared by resolution of the racemic
compound described in EXAMPLE 6, Part C using a Chiralpak AD
reverse phase HPLC column (55% EtOH/Heptane(0. 1% TFA)).
[0502] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.13.5 (bs, 1H),
9.20 (bs, 2H), 8.40 (s, 1H), 8.26 (s, 1H), 8.04 (d, 1H), 7.90-8.00
(m, 2H), 7.79 (d, 1H), 7.71 (dd, 1H), 7.65 (d, 1H), 7.58 (d, 1H),
7.34 (dd, 1H), 7.23 (d, 1H), 4.98 (m, 1H), 4.54 (AB, 2H), 3.86 (s,
3H), 3.20 (m, 2H), 2.68 (s, 3H), 2.05 (m, 1H), 1.80 (m, 1H). FAB
MS, [M+H].sup.+=491. The enantiomeric purity is 92.6% ee as
determined by analytical Chiralpak AD reverse phase HPLC.
EXAMPLE 8
[0503] Benzo[b]thiophene-2-sulfonic
acid[1-(1-amino-isoquinolin-7-ylmethyl-
)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0504] A. Benzo[bthiophene-2-sulfonyl chloride
[0505] To a solution of thianaphthalene (11.8 g, 88.1 mmol), in THF
(400 mL) at -78.degree. C. is added n-BuLi (55 mL of a 1.6 M
solution in hexanes, 88.1 mmol). After 15 minutes, the solution is
added by cannula to a precooled (-78.degree. C.) solution of
SO.sub.2 (200 g) in THF (100 mL). After addition, the solution is
allowed to warm to ambient temperatures. After 0.5 h, the solution
is concentrated. The residue is suspended in hexanes (400 mL) and
is cooled to 0.degree. C. To the solution is added SO.sub.2Cl.sub.2
(12.5 g, 92.5 mmol). After stirring for 15 minutes, the solution is
concentrated. The residue is dissolved in EtOAc. The organic
solution is washed with satuated NH.sub.4Cl (aq.), H.sub.2O and
saturated NaCl (aq.). The organic layer is dried over MgSO.sub.4,
filtered and concentrated. The crude product is dissolved in
CH.sub.2Cl.sub.2 and filtered through a plug of silica gel. The
organic solution is then concentrated. The resulting solid is
triturated with hexane to give the title compound (12.1 g, 38
mmol).
[0506] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.16 (s, 1H), 7.97
(m, 2H), 7.57 (m, 2H).
[0507] B. Benzo[b]thiophene-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-ylme-
thyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0508] The title compound is prepared as described in EXAMPLE 1,
Part K using benzo[b]thiophene-2-sulfonyl chloride in place of
7-methoxynaphthalene-2-sulfonyl chloride.
[0509] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.29 (d, 1H), 8.12
(s, 1H), 7.93 (s, 1H), 7.84-7.92 (m, 2H), 7.82 (d, 1H), 7.54-7.62
(m, 2H), 7.46-7.52 (m, 2H), 5.50 (d, 1H), 4.66 (AB, 2H), 3.95 (m,
1H), 3.25 (m, 2H), 2.65 (m, 1H), 2.15 (m, 1H).
[0510] FAB MS, [M+H].sup.+472, 474, Cl pattern.
[0511] C. Benzo[b]thiophene-2-sulfonic
acid[1-(1-amino-isoquinolin-7-ylmet-
hyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0512] The Title compound was prepared as described in EXAMPLE 2
using benzo[b]thiophene-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-ylmethyl)-2-o-
xopyrrolidin-3-(S)-yl]-amide as the starting material. No
extractive work up is performed. The crude product is purified by
RP-HPLC eluting with a gradient of 10% CH.sub.3CN/H.sub.2O (0.1%
TFA) to 100% CH.sub.3CN. The appropriate fractions are lyophilized
to provide the title compound as a white solid.
[0513] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.00 (bs, 2H),
8.65 (d, 1H), 8.30 (s, 1H), 8.07-8.15 (m, 3H), 8.05 (d, 1H), 7.94
(d, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.45-7.58 (m, 2H), 7.22 (d,
1H), 4.55 (AB, 2H), 4.31 (m, 1H), 3.25 (m, 2H), 2.20 (m, 1H), 1.73
(m, 1H). FAB MS, [M+H].sup.+=453.
EXAMPLE 9
[0514] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1-amino-isoquinolin-7-
-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0515] A. 1-Chloro-3-(2,2-dimethoxy-ethyl-sulfanyl)-benzene
[0516] To a solution of 3-chlorothiophenol (2.4 g, 16.6 mmol) in
THF (200 mL) at 0.degree. C. is added bromoacetaldehyde dimethyl
acetal (2.8 g, 16.6 mmol). To the solution is added sodium hydride
(0.70 g, 17.4 mmol, 60% mineral oil dispersion). The reaction is
stirred for 16 hours, then quenched by the addition of saturated
NH.sub.4Cl (aq.). The solution is diluted with EtOAc. The organic
layer is washed with saturated NaCl (aq.). The organic layer is
dried over MgSO.sub.4, filtered and concentrated. The crude product
is purified by column chromatography eluting with hexanes. The
title compound (3.7 g, 15.9 mmol) is obtained as an oil.
[0517] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.32 (m, 1H), 7.25
(m, 1H), 7.12 (m, 1H), 4.47 (m, 1H), 3.07 (s, 3H), 3.02 (s,
3H).
[0518] B. 4Chloro-benzo[b]-thiophene and
6-chloro-benzo[b]-thiophene
[0519] A solution containing polyphosphoric acid (8 g) and
chlorobenzene (50 mL) is heated to reflux. A solution containing
1-chloro-3-(2,2-dimethoxy-ethyl-sulfanyl)-benzene (2.7 g, 11.6
mmol) in chlorobenzene (5 mL) is added dropwise to the refluxing
polyphosphoric acid solution. After 6 hours, the solution is cooled
to ambient temperatures. The solution is diluted with
CH.sub.2Cl.sub.2 and washed with water and saturated NaCl (aq.).
The organic layer is dried over MgSO.sub.4, filtered and
concentrated. The crude product is purified by column
chromatography eluting with hexanes to yield the title compounds
(2.4 g, 9 mmol) as a 1:1 isomeric mixture.
[0520] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.88 (m, 1H), 7.75
(m, 2H), 7.42 (m, 2H). EI MS, [M].sup.+=168, 170, Cl pattern.
[0521] C. 6-Chloro-benzo[b]thiophene-2-sulfonyl chloride
[0522] The title compound is prepared as described in EXAMPLE 8,
Part A substituting the 4-chloro-benzo[b]-thiophene and
6Chloro-benzo[b]-thiophe- ne mixture for thianaphthalene. The crude
product is purified by column chromatography eluting with hexanes
to yield the title compound as well as
4-chlorobenzo[b]thiophene-2-sulfonyl chloride as white solids.
[0523] 6-Chloro-benzo[b]thiophene-2-sulfonyl chloride
[0524] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.11 (s, 1H), 7.88
(m, 2H), 7.50 (m, 1H).
[0525] 4-Chloro-benzo[b]thiophene-2-sulfonyl chloride
[0526] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.32 (m, 1H), 7.81
(m, 1H), 7.53 (m, 2H).
[0527] D. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1-chloro-isoquinol-
in-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0528] The title compound is prepared as in EXAMPLE 1, Part K using
6-chloro-benzo[b]thiophene-2-sulfonyl chloride in place of
7-methoxynaphthalene-2-sulfonyl chloride.
[0529] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.29 (d, 1H), 8.12
(s, 1H), 7.91 (s, 1H), 7.87 (m, 1H), 7.83 (d, 1H), 7.80 (d, 1H),
7.60 (d, 1H), 7.58 (dd, 1H), 7.42 (dd, 1H), 5.50 (d, 1H), 4.65 (AB,
2H), 3.95 (m, 1H), 3.25 (m, 2H), 2.65 (m, 1H), 2.15 (m, 1H).
[0530] FAB MS, [M+H].sup.+506, 508, Cl pattern.
[0531] E. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1-amino-isoquinoli-
n-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0532] The title compound is prepared as described in EXAMPLE 2
using 6-Chloro-benzo[b]thiophene-2-sulfonic acid
[1-(1-chloro-isoquinolin-7-ylm-
ethyl)-2-oxopyrrolidin-3-(S)-yl]-amide as the starting material. No
extractive work up is performed. The crude product is purified by
RP-HPLC eluting with a gradient of 10% CH.sub.3CN/H.sub.2O (0.1%
TFA) to 100% CH.sub.3CN. The appropriate fractions are lyophilized
to provide the title compound as a solid.
[0533] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.00 (bs, 2H),
8.71 (d, 1H), 8.29 (bs, 2H), 8.05 (s, 1H), 8.01 (d, 1H), 7.94 (d,
1H), 7.80 (d, 1H), 7.65 (d, 1H), 7.55 (dd, 1H), 7.21 (d, 1H), 4.58
(AB, 2H), 4.30 (m, 1H), 3.20 (m, 2H), 2.20 (m, 1H), 1.75 (m,
1H).
[0534] FAB MS, [M+H].sup.+=487, 489, Cl pattern.
EXAMPLE 10
[0535] 7-Methoxynaphthalene-2-sulfonic acid
1-(1-amino-6-methoxyisoquinoli-
n-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide hydrochloride
[0536] A. 6Methoxy-7-methyl-2H-isoquinolin-1-one
[0537] 3-(3-Methoxy-4-methylphenyl)propenoic acid (5.33 g, 27.7
mmol) (prepared according to the procedure described in J. Med.
Chem. 1991, 34, 1662-1668) is suspended in benzene (30 mL) and
treated dropwise with thionyl chloride (2.22 mL, 30.5 mmol) at
0.degree. C. The reaction is heated to reflux and it is maintained
for 1 hour. The volatiles are removed in vacuo and the resulting
solid is dissolved in dioxane and added dropwise to a mixture of
sodium azide (3.6 g, 55.4 mmol) in water/dioxane (30 mL, 1:5) at
0.degree. C. After stirring 1 hours, the solution is poured over
ice-water, the precipitate is collected and washed with water. The
solid is dried under vacuum over P.sub.2O.sub.5 (24 hours),
dissolved in benzene (30 mL) and heated to reflux slowly over about
4 hours. The benzene is removed to give
2-(3-methoxy-4-methyl-pheny- l)vinylisocyanate as a brown oil. The
oil is taken up in o-dichlorobenzene, treated with iodine and
heated to reflux for 3.5 hours. The volatiles are removed and the
residue is mixed with 2.5% MeOH/CH.sub.2Cl.sub.2 (10 mL), then
allowed to stand overnight at room temperature. The resulting solid
is collected washed with hexane and ether, and dried to give the
title compound (2.67 g, 14.1 mmol).
[0538] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.11.80 (bs, 1H),
8.18 (s, 1H), 7.16 (d, 1H), 6.86 (s, 1H), 6.51 (d, 1H),3.94 (s,
3H), 2.35 (s, 3H). EI MS, [M.].sup.+=189.
[0539] B. 7-bromomethyl-1-chloro-6-methoxy-isoquinoline
[0540] 6-Methoxy-7-methyl-2H-isoquinolin-1-one (2.6 g, 13.7 mmol)
is converted to 6methoxy-7-methyl-2-chloroisoquinoline (2.45 g,
11.8) by the method described in EXAMPLE 1, Part E. A portion of
this material (1.20 g, 5.8 mmol) is converted to
7-bromomethyl-1-chloro-6-methoxy-isoquinolin- e (0.8 g, 2.8 mmol)
by the method described in EXAMPLE 1, Part F.
[0541] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.30 (s, 1H), 8.22
(d, 1H), 7.49 (d, 1H), 7.10 (s, 1H), 4.70 (s, 2H), 4.06 (s, 3H). EI
MS, [M.].sup.+=285, 287, Cl pattern.
[0542] C. [1-(1-Chloro
6-methoxyisoquinolin-7ylmethyl)2-oxopyrrolidin-3-(S- )-yl]-carbamic
acid tert-butyl ester
[0543] Sodium hydride (0.057 g, 1.4 mmol, 60% mineral oil
dispersion) is suspended in anhydrous THF (5 mL) and treated with a
solution of (2-oxopyrrolidin-3-(S)-yl)carbanic acid tert-butyl
ester (0.223 g, 1.1 mmol) and
7-bromomethyl-1-chloro-6-methoxy-isoquinoline (0.32 g, 1.1 mmol in
THF/DMF (10 mL, 6:1) at 0.degree. C. The reaction mixture is warmed
to ambient temperature, stirred for3 hours, quenched by the
addition of saturated NH.sub.4Cl and diluted with EtOAc. The layers
are separated. The organic layer is washed with saturated NaCl,
dried over Na.sub.2SO.sub.4, filtered, and concentrated to give a
white solid. The solid is collected, washed with a small amount of
EtOAc and copious amounts of Et.sub.2O to yield the title compound
(0.18 g, 0.47 mmol).
[0544] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.22 (d, 1H), 8.06
(s, 1H), 7.51 (d, 1H), 7.11 (s, 1H), 5.20 (bs, 1Il), 4.68 (AB, 2H),
4.23 (m, 1H), 3.98 (s, 3H), 3.21 (m, 2H), 2.65 (m, 1H), 1.90 (m,
1H), 1.46 (s, 9H). FAB MS, [M+H].sup.+=387.
[0545] D. 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-chloro-6-methoxyisoqui-
nolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0546]
[1-(1-Chloro-6-methoxyisoquinolin-7ylmethyl)-2-oxopyrrolidin-3-(S)--
yl]-carbamic acid tert-butyl ester (0.15 g, 0.37 mmol) is converted
to 7-methoxynaphthalene-2-sulfonic
acid[1-(1-chloro-6-methoxyisoquinolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.08 g, 0.15 mmol) by the
method described in EXAMPLE 1, Parts I and K.
[0547] .sup.1H NMR (CDCl.sub.3/CD.sub.3OD, 300 MHz) .delta.8.40 (s,
1H), 8.14 (d, 1H), 7.99 (s, 1H), 7.95 (d, 1H), 7.83 (d, 1H), 7.78
(d, 1H), 7.55 (d, 1H), 7.28 (s, 1H), 7.13 (s, 1H), 4.62 (s, 2H),
4.0 (s, 3H), 3.97 (s, 3H), 3.89 (dd, 1H), 3.2-3.4 (m, 2H), 2.52 (m,
1H), 2.07 (m, 1H). FAB MS, [M+H].sup.+=526.
[0548] E. 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-amino-6-methoxyisoquin-
olin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide hydrochloride
[0549] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-chloro-6-methoxyisoquinol-
in-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.080 g, 0.15 mmol)
and phenol (0.430 g, 4.6 mmol) are melted together with stirring at
70.degree. C. for 5 minutes. Ammonium acetate (0.354 g, 4.6 mmol)
is added and the reaction mixture is heated to 115.degree. C. for
about 5 hours. Additional ammonium acetate (0.177 g, 2.3 mmol) is
added and the reaction is heated for a further 3 hours. The
reaction is cooled and partitioned between 0.5 N NaOH and
CH.sub.2Cl.sub.2. The organic layer is dried over Na.sub.2SO.sub.4
and concentrated. The residue is purified by column chromatography
eluting with 5% MeOH/CH.sub.2Cl.sub.2. The product fractions are
collected and concentrated to a small volume, then the residue is
acidified with 1N HCl/ether to give a beige solid (0.046 g, 0.095
mmol).
[0550] .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta.8.38 (s, 1H), 8.05
(s, 1H), 7.88 (d, 1H), 7.80 (d, 1H), 7.73 (dd, 1H), 7.44 (d, 1H),
7.32 (d, 1H), 7.30 (s, 1H), 7.23 (dd, 1H), 7.07 (d, 1H), 4.53 (AB,
2H), 4.23 (t, 1H), 3.98 (s, 3H), 3.89 (s, 3H), 3.30 (m, 2H), 2.22
(m, 1H), 1.89 (m, 1H). FAB MS, [M+H].sup.+=478. Elemental analysis
calculated with 1.4 mole of H.sub.2O: C=54.96%, H=5.29%, N=9.86%;
found C=54.81%, H=5.12%, N=9.71%.
EXAMPLE 11
[0551] 7-Methoxynaphthalene-2-sulfonic acid
[1-(6-methoxyisoquinolin-7-ylm-
ethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0552] A suspension of 7-methoxynaphthalene-2-sulfonic
acid[1-(1-chloro-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-y-
l]-amide in methanol/CH.sub.2Cl.sub.2 (35 mL, 6:1) is treated with
THF (5 mL), AcOH (5 mL) and 10% Pd on carbon (0.04 g). The
suspension is stirred under an atmosphere of hydrogen for 7 hours.
The suspension is filtered, then the filtrate is concentrated and
the residue is purified by RP-HPLC eluting in a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 90% CH.sub.3CN/H.sub.2O (0.1%
TFA). The appropriate product fractions are lyophilized to provide
the title compound as a white solid (0.325g; 0.66 mmol)
[0553] .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta.9.37 (s, 1H), 8.40
(d, 1H), 8.38 (d, 1H), 8.23 (d, 1H), 8.15 (s; 11), 7.93 (d, 1H),
7.85 (d, 1H), 7.77 (dd, 1H), 7.66 (s, 1H), 7.35 (s, 1H), 7.27 (dd,
1H), 4.66 (AB, 2H), 4.28 (t, 1H), 4.12 (s, 3H), 3.92 (s, 3H), 3.40
(m, 2H), 2.35 (m, 1H), 1.92 (m, 1H). FAB MS, [M+H].sup.+492.
Elemental analysis calculated with 1.2 mole of H.sub.2O: C=53.66%,
H=4.57%, N=6.70%; found C=53.62%, H=4.38%, N=6.67%.
EXAMPLE 12
[0554] 4-(2-Chloro-6-nitophenoxy)benzene sulfonic acid
[1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-am-
ide trifluoroacetate
[0555]
[1-(1-Chloro-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-
-yl]-carbamic acid tert-butyl ester (0.845 g, 2 mmol) is converted
to
[1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-ca-
rbamic acid tert-butyl ester (0.314 g, 0.081 mmol) by the method
described in EXAMPLE 10, Part E. A portion of this material (0.285
g, 0.7 mmol) is deprotected as described in EXAMPLE 1, Part I to
yield
[1-(1-amino-6-methoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-am-
ine dihydrochloride (0.28 g, 0.78 mmol) and coupled with
4-(2-chloro-6-nitophenoxy)benzene sulfonyl chloride (0.35 g, 1
mmol) as described in EXAMPLE 1, Part K. The material obtained upon
extractive workup and column chromatography is further purified by
RP HPLC to give the title compound (0.04 g, 0.067 mmol).
[0556] .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta.8.14 (s, 1H), 8.07
(d, 1H), 7.92-7.98 (m, 3H), 7.53-7.60 (m, 2H), 7.40 (s, 1H), 7.18
(d, 1H), 7.05 (d, 2H), 4.63 (AB, 2H), 4.18 (t, 11H), 4.06 (s, 3H),
3.36 (m, 2H), 2.32 (m, 1H), 1.87 (m, 1H). FAB MS, [M+H].sup.+=598,
600, Cl pattern. Elemental analysis calculated with 1.5 mole of
H.sub.2O: C=47.13%, H=3.82%, N=9.48%; found C=47.07%, H=3.66%,
N=9.24%.
EXAMPLE 13
[0557] 7-Methoxynaphthalene-2-sulfonic
acid-[1-(1,6-diamino-isoquinolin-7--
yl-methyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0558] A. 3-(3-Acetamido-4-methylphenyl)propenoic acid
[0559] To a solution of 3-acetamido-4-methylbenzaldehyde (14 g, 79
mmol) in pyridine (210 mL) is added piperidine (3.9 mL, 39.4 mmol)
and malonic acid (15.26 g, 146.6 mmol). The mixture is heated to
100.degree. C. for 4 hours, then stirred at room temperature
overnight. The solution is concentrated in vacuo, then diluted with
water. Cold 1 N HCl is added to the slurry until pH is ca. 4. The
solid product (16.178 g, 73.8 mmol) is collected and washed
generously with water. The title compound (16.178 g, 73.8 mmol) is
then dried over P.sub.2O.sub.5 under vacuum overnight to yield a
white solid.
[0560] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.12.30 (bs, 1H),
9.30 (bs, 1H), 7.65 (s, 1H), 7.51 (d, 1H), 7.42 (d, 1H), 7.25 (d,
1H), 6.42 (d, 1H), 2.25 (s, 3H), 2.09 (s, 3H). El MS
[M+H].sup.+=220.
[0561] B. 3-(3-Acetylamino-4-methyl-phenyl)acryloyl azide
[0562] To a slurry of3-(3-acetamido4-methylphenyl)propenoic acid
(20.11 g, 91.7 mmol) in acetone (450 mL) at 0.degree. C. is added
triethylamine (12.8 mL, 91.8 mmol) followed by dropwise addition of
ethyl chloroformate (11.8 mL, 123 mmol) over a 10 minutes period.
The resulting yellow slurry is stirred using a mechanical stirrer
for 1.5 hours, then a solution of sodium azide (8.94 g, 138 mmol)
in water (25 mL) is added slowly so as to maintain the temperature
below 5.degree. C. The thick mixture is stirred at 0OC for I hours,
then the ice bath is removed and the reaction mixture allowed to
warm to room temperature. The suspension is poured over water (800
mL) then filtered. The remaining swlid is washed generously with
water and dried under vacumn over P.sub.2O.sub.5 overnight to give
the product as a pale yellow solid (21.40 g, 87.6 mmol).
[0563] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.10 (s, 1H), 6.71
(d, 1H), 7.22 (m, 2H), 6.95 (bs, 1H), 6.38 (d, 1H), 2.29 (s, 3H),
2.21 (s, 3H). El MS [M.].sup.+=244.
[0564] C.
N-(7-Methyl-1-oxo-1,2-dihydro-isoquinolin-6-yl)acetamide
[0565] To a solution of diphenyl ether (250 mL) and tributylamine
(11.9 mL, 49.9 mmol) at 220-240.degree. C. is added a slurry of
3-(3-acetylamino-4-methyl-phenyl)acryloyl azide (12.2 g, 49.9 mmol)
in diphenyl ether. After 2 hours, the yellow solution is cooled to
room temperature and poured over hexane (800 mL). A brown solid
precipitates out and the title product (3.56 g, 16.5 mmol) is
obtained as a light yellow solid by recrystallization from
DMF/MeOH.
[0566] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.11.0 (bs, 1H),
9.35 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.05 (m, 1H), 6.45 (d,
1H), 2.32 (s, 3H), 2.12 (s, 3H). El MS [M.].sup.+=216.
[0567] D. 6-Amino-7-methyl-2H-isoquinolin-1-one
[0568] N-(7-Methyl-1-oxo-1,2-dihydro-isoquinolin-6-yl)acetamide
(0.366 g, 1.69 mmol) and conc. HCl (0.5 mL) is heated to reflux in
EtOH (0.84 mL). After 6 hours, the mixture is concentrated to
dryness, then diluted with water and basified using 1 N NaOH until
pH is ca. 10. The aqueous solution is extracted with methylene
chloride (4.times.50 mL) and the organic layers are combined and
washed with brine, dried over MgSO.sub.4, filtered and
concentrated. The crude product is purified by column
chromatography eluting with a gradient of 3% MeOH/CH.sub.2Cl.sub.2
to 5% MeOH/CH.sub.2Cl.sub.2 to give the title product (0.200 g,
1.15 mmol) as a white solid.
[0569] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.90 (bs, 1H), 8.06
(s, 1H), 6.90 (m, 1H), 6.65 (s, 1H), 6.28 (d, 1H), 4.05 (bs, 2H),
2.20 (s, 3H). EI MS [M.].sup.+=174.
[0570] E. 1-Chloro-7-methyl-isoquinolin-6-ylamine
[0571] The title compound is prepared as described in EXAMPLE 1,
Part E using 6-amino-7-methyl-2H-isoquinolin-1-one as the starting
material. The crude product is purified by column chromatography
eluting with a gradient of 5% MeOH/CH.sub.2Cl.sub.2 to 10%
MeOH/CH.sub.2Cl.sub.2 to afford the title compound as a yellow
solid.
[0572] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.05 (d, 1H), 8.00
(s, 1H), 7.30 (d, 1H), 6.90 (s, 1H), 4.25 (bs, 2H), 2.40 (s, 3H).
EI MS [M.].sup.+192, 194, Cl pattern.
[0573] F.
Benzhydrylidene-(1-chloro7-methyl-isoquinolin-6-yl)-amine
[0574] To a solution of 1-chloro-7-methyl-isoquinolin-6-ylamine
(0.1 g, 0.52 mmol) in MeOH (5 mL) at 0.degree. C. is bubbled HCl
gas for 1 minute, then the solvent is removed in vacuo. The
remaining white solid is diluted with 1,2dichloroethane and
benzophenone imine (0.15 mL, 0.89 mmol) is added. The resulting
suspension is heated to reflux for 48 hours, then cooled to room
temperature and concentrated to dryness. The crude material is
diluted with CH.sub.2Cl.sub.2 and washed with saturated NaHCO.sub.3
solution and brine. The organic layer is dried over MgSO.sub.4,
filtered and concentrated. The crude product is purified by column
chromatography using 10% EtOAc/hexanes as the eluent to afford the
title compound (0.159 g, 0.45 mmol) as a yellow oil.
[0575] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.05 (m, 2H), 7.80
(m, 2H), 7.45-7.55 (m, 4H), 7.20-7.30(m, 3H), 7.10 (m, 2H), 6.75
(s, 1H), 2.50 (s, 3H). FAB MS, [M+H].sup.+357, 359, Cl pattern.
[0576] G.
Benzhydrylidene-(7-bromomethyl1-chloro-isoquinolin-6-yl)amine
[0577] The title compound is prepared as decribed in EXAMPLE 1,
Part F using benzhydrylidene-(
1-chloro-7-methyl-isoquinolin-6-yl)-amine as the starting material.
The title compound is obtained as an oil.
[0578] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.33 (s, 1H), 8.06
(d, 1H), 7.84 (m, 2H), 7.41 (m, 4H), 7.32 (m, 41), 7.20 (d, 1H),
6.66 (s, 1H), 4.79 (s, 2H). FAB MS, [M+H].sup.+=435, 437, Cl Br
pattern.
[0579] H.
{1-[6-(Benzhydrylidene-amino)1-chloro-isoquinolin-7-ylmethyl]-2--
oxopyrrolidin-3-(S)-yl}-carbamic acid tert-butyl ester
[0580] The title compound is prepared as described in EXAMPLE 1,
Part H using
benzhydrylidene-(7-bromomethyl-1-chloro-isoquinolin-6-yl)-amine in
place of 7-bromomethyl-1-chloroisoquinoline. The crude product is
purified by column chromatography eluting with a gradient of 10%
EtOAc/hexanes to 30% EtOAc/hexanes to give the product as a foamy
yellow solid.
[0581] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.09 (d, 1H), 8.01
(s, 1H), 7.80 (m, 2H), 7.20-7.45 (m, 9H), 6.70 (s, 1H), 5.30 (d,
1H), 4.65 (AB, 2H), 4.21 (m, 1H), 3.32 (m, 2H), 2.70 (m, 1H), 1.95
(m, 1H), 1.46 (s, 9H). FAB MS, [M+H].sup.+=555, 557, Cl
pattern.
[0582] I. 7-Methoxynaphthalene-2-sulfonic
acid[1-(6-amino1-chloro-isoquino-
lin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0583]
{1-[6-(Benzhydrylidene-amino)-1-chloro-isoquinolin-7-ylmethyl]-2-ox-
opyrrolidin-3-(S)-yl}-carbamic acid tert-butyl ester is deprotected
as described in EXAMPLE 1, Part I to yield
3-(S)-amino-1-(6-amino-1-chloro-i-
soquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride and coupled
with 7-methoxynaphthalene-2-sulfonyl chloride as described in
EXAMPLE 1, Part K. The material obtained upon extractive workup is
purified by column chromatography eluting with a gradient of 30%
EtOAc/hexanes to 60% EtOAc/hexanes to give the product.
[0584] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.34 (s, 1H), 8.02
(d, 1H), 7.93 (s, 1H), 7.87 (d, 1H), 7.79 (d, 1H), 7.72 (dd, 1H),
7.29 (dd, 1H), 7.26 (d, 1H), 7.25 (s, 1H), 6.77 (s, 1H), 5.61 (bs,
1H), 4.93 (bs, 2H), 4.49 (AB, 2H), 3.92 (s, 3H), 3.85 (m, 1H), 3.20
(m, 2H), 2.52 (m, 1H), 2.05 (m, 1H). Ion spray MS, [M+H].sup.+=511,
513, Cl pattern.
[0585] J. 7-Methoxynaphthalene-2-sulfonic
acid[1-(1,6-diamino-isoquinolin--
7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0586] The title compound is prepared as described in EXAMPLE 2
using 7-methoxynaphthalene-2-sulfonic
acid[1-(6-amino-1-chloro-isoquinolin-7-yl-
methyl)-2-oxopyrrolidin-3-(S)-yl]-amide as the starting material.
No extractive work up is performed. The crude product is purified
by RP-HPLC eluting with a gradient of 10% CH.sub.3CN/H.sub.2O (0.1%
TFA) to 100% CH.sub.3CN. The appropriate fractions are lyophilized
to provide the title compound as a white solid.
[0587] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.12.25 (bs, 1H),
8.34-8.38 (d, 2H), 8.24 (d, 1H), 7.95 (d, 1H) 7.90-7.93 (d, 2H),
7.68 (dd, 1H), 7.53 (d, 1H), 7.38 (d, 1H), 7.30 (dd, 1H), 6.83 (d,
1H), 6.78 (s, 1H), 6.49 (bs, 2H), 4.26 (AB, 2H), 4.20 (m, 1H), 3.90
(s, 3H), 3.06 (m, 2H), 2.00 (m, 1H), 1.60 (m, 1H). FAB MS,
[M+H].sup.+=492.
EXAMPLE 14
[0588] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1,6-diamino-isoquinol-
in-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[0589] A. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(6-amino1-chloro-is-
oquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0590]
{1-[6-(Benzhydrylidene-amino)-1-chloro-isoquinolin-7-ylmethyl]-2-ox-
opyrrolidin-3-(S)-yl}carbamic acid tert-butyl ester is deprotected
as described in EXAMPLE 1, Part I to yield
3-(S)-amino-1-(6-amino1-chloro-is-
oquinolin-7-ylmethyl)-pyrrolidin-2-one hydrochloride and coupled
with 6-chloro-benzo[b]thiophene2-sulfonyl chloride as described in
EXAMPLE 1, Part K. The material obtained upon extractive workup is
purified by column chromatography eluting with a gradient of 20%
EtOAc/hexanes to 60% EtOAc/hexanes to give the product.
[0591] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.05 (d, 1H), 8.02
(s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.86 (d, 1H), 7.81(d, 1H),
7.44 (dd, 1H), 6.82 (s, 1H), 5.40 (d, 1H), 4.90 (bs, 2H), 5.42 (AB,
2H), 3.95 (m, 1H), 330 (m, 2H), 2.65 (m, 1H), 2.05 (m, 1H).
[0592] Ion spray MS, [M+H].sup.+=521, 523, Cl pattern.
[0593] B. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1,6-diamino-isoqui-
nolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[0594] The title compound is prepared as described in EXAMPLE 2
using 6-chloro-benzo[b]thiophene-2-sulfonic
acid[1-(6-amino-1-chloro-isoquinoli-
n-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide as the starting
material. No extractive work up is performed. The crude product is
purified by RP-HPLC eluting with a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 100% CH.sub.3CN/H.sub.2O. The
appropriate fractions are lyophilized to provide the title compound
as a tan solid.
[0595] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.12.05 (bs, 1H),
8.70 (d, 1H), 8.35 (bs, 2H), 8.20 (s, 1H), 8.00-8.05 (m, 2H), 7.94
(s, 1H), 7.51 (d, 1H), 7.38 (m, 1H), 6.71-6.80 (m, 2H), 6.51 (bs,
2H), 4.30 (m, 3H), 3.20 (m, 2H), 2.15 (m, 1H), 1.71 (m, 1H).
[0596] Ion spray MS, [M+H].sup.+=502, 504, Cl pattern.
EXAMPLE 15
[0597] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin7-ylmethyl)2- -oxopyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[0598] A. 7-Methyl-1H-quinolin-2-one and
5-methyl-1H-quinolin-2-one
[0599] The title compounds are prepared from m-toluidine and
cinnamoyl chloride according to the procedure described in
Synthesis 1975, 739. The crude solid residue obtained is triturated
in Et.sub.2O/hexanes and filtered to give a mixture of product
isomers in a ratio of 1.5:1 of 7-methyl-1H-quinolin-2-one to
5-methyl-1H-quinolin-2-one as a beige solid. Several attempts at
purification through fractional crystallization in methanol gave
only an enriched 2:1 mixture of isomers which is used in the
subsequent step.
[0600] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.7.85 (d, 1H),
7.53 (d, 1H), 7.09 (s, 1H), 7.01 (d, 1H), 6.42 (d, 1H), 2.38 (s,
3H) for major isomer (7-methyl); and 67 8.03 (d, 1H), 7.38 (dd,
1H), 7.17 (s, 1H), 7.01 (d, 1H), 6.51 (d, 1H), 2.50 (s, 3H) for
minor isomer (5-methyl).
[0601] B. 2-Chloro-7-methyl-quinoline and
2-chloro-5-methyl-quinoline
[0602] The title compounds are prepared as described in EXAMPLE 1,
Part E using a 2:1 mixture of 7-methyl-1H-quinolin-2-one and
5-methyl-1H-quinolin-2-one in place of
7-methyl-2H-isoquinolin-1-one. The crude product is purified by
column chromatography eluting with a gradient of 5%
EtOAc/CH.sub.2Cl.sub.2 to 10% EtOAc/CH.sub.2Cl.sub.2 to afford a
2:1 mixture of 2-chloro-7-methyl-quinoline to
2-chloro-5-methyl-quinoline as a beige solid.
[0603] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.02 (d, 1H), 7.78
(s, 1H), 7.68 (d, 1H), 7.39 (m, 1H), 7.30 (d, 1H), 2.56(s, 3H) for
major isomer (7-methyl); and .delta.8.25 (d, 1H), 7.86 (d, 1H),
7.60 (dd, 1H), 7.39 (m, 2H), 2.65 (s, 3H) for minor isomer
(5-methyl).
[0604] C. 7-Bromomethyl-2-chloro-quinoline and
5-bromomethyl-2-chloro-quin- oline
[0605] The title compounds are prepared as described in EXAMPLE 1,
Part F using a 2:1 mixture of 2-chloro-7-methyl-quinoline and
2-chloro-5-methyl-quinoline in place of
1-chloro-7-methyl-isoquinoline. The crude mixture of isomers
obtained is partially purified by trituration in EtOAc/hexanes to
yield the 7-bromomethyl-2-chloro-quinolin- e as a beige solid (7.4
g, 38%).
[0606] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.10 (d, 1H), 8.00
(s, 1H), 7.82 (d, 1H), 7.60 (d, 1H), 4.67 (s, 2H).
[0607] An enriched 2:1 mixture of 5-bromomethyl-2-chloro-quinoline
to 7-bromomethyl-2-chloro-quinoline is isolated as a beige solid
(6.8 g) from the concentrated filtrate by fractional
recrystallization in Et.sub.2O/hexanes/EtOAc.
[0608] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.43 (d, 1H), 8.09
(dd, 1H), 8.03 (m, 1H), 7.68 (m, 1H), 7.50 (d, 1H), 4.88 (s, 2H)
for major isomer (5-bromomethyl).
[0609] D.
[1-(2-Chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carb-
amic acid tert-butyl ester
[0610] The title compound is prepared from
(2-oxopyrrolidin-3-(S)-yl)-carb- amic acid tert-butyl ester as
described in EXAMPLE 1, Part H using
7-bromomethyl-2-chloro-quinoline in place of
7-bromomethyl-1-chloro-isoqu- inoline. The crude product is
triturated in 20% EtOAc/hexanes and filtered to afford the title
compound as a beige solid.
[0611] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.10 (d, 1H), 7.83
(s, 1H), 7.80 (d, 1H), 7.46 (d, 1H), 7.40 (d, 1H), 5.17 (bs, 1H),
4.68 (AB, 2H), 4.25 (m, 1H), 3.26 (m, 2H), 2.64 (m, 1H), 1.88 (m,
1H), 1.46 (s, 9H).
[0612] E.
7-(3-(S)-Amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline
hydrochloride
[0613] The title compound is prepared as described in EXAMPLE 1,
Part I using
[1-(2-chloro-quinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbami-
c acid tert-butyl ester as the starting material. The title
compound is obtained as a white solid.
[0614] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.75 (bs, 2H),
8.47 (d, 1H), 8.06 (d, 1H), 7.86 (s, 1H), 7.61 (d, 1H), 7.58 (d,
1H), 4.69 (AB, 2H), 4.15 (m, 1H), 3.35 (m, 2H), 2.43 (m, 1H), 2.04
(m, 1H).
[0615] F. 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-chloro-quinolin-7-ylme-
thyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0616] The title compound is prepared in CH.sub.2Cl.sub.2 instead
of CH.sub.3CN as described in EXAMPLE 1, Part K using
7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline
hydrochloride in place of
7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)1-chl- oro-isoquinoline
hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as
prepared in EXAMPLE 1, Part J. The crude product is triturated in
20% EtOAc/hexanes and filtered to afford the title compound as a
white solid.
[0617] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.38 (s, 1H), 8.08
(d, 1H), 7.92 (d, 1H), 7.81 (d, 1H), 7.76 (m, 3H), 7.38 (d, 1H),
7.36 (dd, 1H), 7.30 (dd, 1H), 7.25 (m, 1H), 5.44 (s, 1H), 4.61 (s,
2H), 3.96 (s, 3H), 3.78 (m, 1H), 3.23 (m, 2H), 2.60 (m, 1H), 2.10
(m, 1H). FAB MS, [M+H].sup.+=496, 498, Cl pattern. Elemental
analysis calculated C=60.54%, H=4.47%, N=8.47%, Cl=7.15%, found
C=60.44%, H=4.18%, N=8.45, Cl=7.19%.
[0618] G. 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin7-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0619] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-chloro-quinolin-7-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]-amide is converted to the title
compound when heated at 125.degree. C. as described in EXAMPLE 2.
The crude product is partially purified by RP-HPLC eluting in a
gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 60%
CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate product
fractions are concentrated in vacuo, filtered and triturated with
MeOH as previously described to provide the title compound as a
white solid.
[0620] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.62 (bs, 2H),
8.38 (s,1H), 8.31 (d, 1H), 8.25 (d, 1H), 8.03 (d, 1H), 7.94 (d,
1H), 7.86 (d, 1H), 7.72 (d, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.32
(dd, 1H), 7.27 (d, 1H), 7.01 (d, 1H), 4.50 (AB, 2H), 4.11 (m, 1H),
3.88 (s, 3H), 3.09 (m, 2H), 2.00 (m, 1H), 1.58 (m, 1H). Ion spray
MS, [M+H].sup.+=477. Elemental analysis calculated C=54.93%,
H=4.27%, N=9.49%, found C=54.69%, H=4.24%, N=9.30%. The
enantiomeric purity is 81.9% ee as determined by analytical
Chiralpak AS RP-HPLC.
EXAMPLE 16
[0621] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(2-aminoquinolin7-ylme-
thyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0622] A. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(2-chloro-quinolin--
7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0623] The title compound is prepared in CH.sub.2Cl.sub.2 instead
of CH.sub.3CN from
7-(3-(S)amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinol- ine
hydrochloride as described in EXAMPLE 1, Part K using
6-chloro-benzo[b]thiophene-2-sulfonyl chloride as prepared in
EXAMPLE 9, Parts A, B and C in place of
7-methoxynaphthalene-2-sulfonyl chloride. The crude product is
triturated from EtOAc/hexanes to afford the title compound as a
beige solid.
[0624] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.77 (d, 1H),
8.42 (d, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 8.04 (d, 1H), 8.02 (d,
1H), 7.75 (s, 1H), 7.58 (d, 1H), 7.52 (dd, 1H), 7.48 (d, 1H), 4.55
(AB, 2H), 4.28 (m, 1H), 3.18 (m, 2H), 2.18 (m, 1H), 1.71 (m, 1H).
Ion spray MS, [M+H].sup.+=506, 508, Cl pattern.
[0625] B. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(2-aminoquinolin7-y-
lmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0626] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(2-chloro-quinolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide is converted to the title
compound when heated at 120.degree. C. as described in EXAMPLE 2.
The crude product is purified by RP-HPLC eluting in a gradient of
10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 80% CH.sub.3CN/H.sub.2O (0.1%
TFA) and the appropriate product fractions are lyophilized to
provide the title compound as a tan solid.
[0627] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta.8.73 (d, 1H),
8.34 (d, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 8.03 (d, 1H), 7.89 (d,
1H), 7.54 (dd, 1H), 7.52 (d, 1H), 7.47 (s, 1H), 7.31 (d, 1H), 7.04
(d, 1H), 6.94 (d, 1H), 6.42 (d, 1H), 4.53 (AB, 2H), 4.22 (m, 1H),
3.18 (m, 2H), 2.18 (m, 1H), 1.72 (m, 1H). FAB MS, [M+H]+=487.
EXAMPLE 17
[0628] Benzo[b]thiophene-2-sulfonic
acid[1-(2-aminoquinolin7-ylmethyl)-2-o-
xopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0629] A. Benzo[b]thiophene-2-sulfonic
acid[1-(2-chloro-quinolin-7-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]-amide
[0630] The title compound is prepared in CHCl.sub.3 instead of
CH.sub.3CN from
7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline
hydrochloride as described in EXAMPLE 1, Part K using
benzo[b]thiophene-2-sulfonyl chloride as prepared in EXAMPLE 8,
Part A in place of 7-methoxynaphthalene-2-sulfonyl chloride. The
crude product is triturated from CH.sub.2Cl.sub.2 to afford the
title compound as a beige solid.
[0631] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.08 (d, 1H), 7.95
(d, 1H), 7.88 (m, 2H), 7.99 (d, 1H), 7.76 (s, 1H), 7.49 (m, 2H),
7.39 (m, 2H), 5.62 (s, 1H), 4.64 (s, 2H), 3.95 (m, 1H), 3.27 (m,
2H), 2.65 (m, 1H), 2.16 (m, 1H).
[0632] B. Benzo[b]thiophene-2-sulfonic
acid[1-(2-aminoquinolin7-ylmethyl)--
2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0633] Benzo[b]thiophene-2-sulfonic
acid[1-(2-chloro-quinolin-7-ylmethyl)--
2-oxopyrrolidin-3-(S)-yl]-amide is converted to the title compound
when heated at 130.degree. C. as described in EXAMPLE 2. The crude
product is purified by RP-HPLC eluting in a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 60% CH.sub.3CN/H.sub.2O (0.1%
TFA) and the appropriate product fractions are lyophilized to
provide the title compound as a tan solid.
[0634] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta.8.68 (d, 1H),
8.35 (d, 1H), 8.09 (dd, 1H), 8.06 (s, 1H), 8.02 (dd, 1H), 7.90 (d,
1H), 7.52 (m, 2H), 7.45 (s, 1H), 7.32 (d, 1H), 7.04 (d, 1H), 4.53
(AB, 2H), 4.22 (m, 1H), 3.17 (m, 2H), 2.18 (m, 1H), 1.72 (m, 1H).
Ion spray MS, [M+H].sup.+=453.
EXAMPLES 18 AND 19
[0635] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin7-ylmethyl)--
2-oxopyrrolidin-3-(S)-yl]-methyl amide trifluoroacetate and
7-methoxynaphthalene-2-sulfonic acid
methyl-[2-oxo-1-(2-oxo-1,2-dihydro-q-
uinolin-7-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
[0636] A. 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-chloro-quinolin-7-ylme-
thyl)-2-oxopyrrolidin-3-(S)-yl]-methyl amide
[0637] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-chloro-quinolin-7-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]-amide (0.4 g, 0.81 mmol), prepared as
in EXAMPLE 15, Part F, is dissolved in DMF (20 mL) and cooled to
0.degree. C. To the solution is added methyl iodide (0.28 g, 2.01
mmol) and sodium hydride (34 mg, 0.85 mmol, 60% mineral oil
dispersion). The ice water bath is removed and the mixture is
stirred at room temperature for 3 hours. The resulting solution is
poured into a separatory funnel and diluted with EtOAc (100 mL).
The organic layer is washed with 1N HCl, H.sub.2O and saturated
NaCl. The organic phase is then dried over MgSO.sub.4, filtered and
concentrated. The crude residue is purified by column
chromatography eluting with 10% EtOAc/CH.sub.2Cl.sub.2 to give the
title compound (0.36 g, 0.71 mmol) as a solid.
[0638] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.44 (s, 1H), 8.09
(d, 1H), 7.92 (d, 1H), 7.82 (dd, 1H), 7.78 (m, 3H), 7.42 (dd, 1H),
7.40 (d, 1H), 7.28 (dd, 1H), 7.26 (s, 1H), 5.00 (m, 1H), 4.62 (AB,
2H), 3.94 (s, 3H), 3.23 (m, 2H), 2.84 (s, 3H), 2.33 (m, 1H), 2.03
(m, 1H).
[0639] B. 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin7-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]-methyl amide trifluoroacetate and
7-methoxynaphthalene-2-sulfonic acid
methyl-[2-oxo-1-(2-oxo-1,2-dihydro-q-
uinolin-7-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
[0640] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-chloro-quinolin-7-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]-methyl amide is converted to the title
compounds when heated at 125.degree. C. as described in EXAMPLE 2.
The crude mixture of products is purified by RP-HPLC eluting in a
gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 80%
CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate product
fractions are lyophilized to provide
7-methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin7-ylmethyl)-2-oxop-
yrrolidin-3-(S)-yl]-methyl amide trifluoroacetate as a white
solid.
[0641] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.42 (s, 1H),
8.33 (d, 1H), 8.04 (d, 1H), 7.96 (d, 1H), 7.87 (d, 1H), 7.70 (dd,
1H), 7.58 (s, 1H), 7.42 (s, 1H), 7.35 (dd, 1H), 7.31 (d, 1H), 7.02
(d, 1H), 4.93 (m, 1H), 4.51 (AB, 2H), 3.89 (s, 3H), 3.18 (m, 2H),
2.70 (s, 3H), 2.02 (m, 1H), 1.78 (m, 1H). Ion spray MS,
[N+H].sup.+=491. Elemental analysis calculated with 1.8 mol of
H.sub.2O cal. C=52.79%, H=4.84%, N=8.80%, found C=52.80%, H=4.35%,
N=8.55%.
[0642] 7-Methoxynaphthalene-2-sulfonic acid
methyl-[2-oxo-1-(2-oxo-1,2-dih-
ydro-quinolin-7-ylmethyl)-pyrrolidin-3-(S)-yl]-amide is also
isolated from the reaction mixture as a by-product.
[0643] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.42 (s, 1H),
8.04 (d, 1H), 7.97 (d, 1H), 7.85 (d, 1H), 7.70 (d, 1H), 7.60 (d,
1H), 7.58 (s, 1H), 7.35 (dd, 1H), 7.04 (s, 1H), 6.98 (d, 1H), 6.45
(d, 1H), 4.90 (m, 1H), 4.40 (AB, 2H), 3.89 (s, 3H), 3.15 (m, 2H),
2.71 (s, 3H), 2.01 (m, 1H), 1.76 (m, 1H). Ion spray MS,
[M+H].sup.+=492.
EXAMPLE 20
[0644] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin5-ylmethyl)--
2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0645] A.
[1-(2-Chloro-quinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carb-
amic acid tert-butyl ester
[0646] The title compound is prepared from
(2-oxopyrrolidin-3-(S)-yl)-carb- amic acid tert-butyl ester as
described in EXAMPLE 1, Part H using a 2:1 mixture of
5-bromomethyl-2-chloro-quinoline to 7-bromomethyl-2-chloro-qui-
noline, as prepared in EXAMPLE 15, Part C, in place of
7-bromomethyl-1-chloro-isoquinoline. The crude product mixture is
purified by column chromatography eluting with 1% MeOH in 25%
EtOAc/CH.sub.2Cl.sub.2 to afford as the major product the title
compound as a beige solid.
[0647] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.53 (d, 1H), 7.98
(d, 1H), 7.69 (dd, 1H), 7.50 (d, 1H), 7.41 (d, 1H), 5.59 (d, 1H),
4.89 (AB, 2H), 4.22 (m, 1H), 3.19 (m, 1H), 3.12 (m, 1H), 2.51 (m,
1H), 1.86 (m, 1H), 1.45 (s, 9H).
[0648] B.
5-(3-(S)-Amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline
hydrochloride
[0649] The title compound is prepared as described in EXAMPLE 1,
Part I using
[1-(2-chloro-quinolin-5-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbami-
c acid tert-butyl ester as the starting material. The title
compound is obtained as a white solid.
[0650] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.63 (d, 1H),
8.59 (bs, 3H), 7.94 (d, 1H), 7.81 (m, 1H), 7.65 (m, 2H), 4.89 (s,
2H), 4.08 (m, 1H), 3.24 (m, 2H), 2.34 (m, 1H), 1.94 (m, 1H).
[0651] C. 7-Methoxynaphthalene-2-sulfonic acid[1-
(2-chloro-quinolin-5-ylm- ethyl)-2-oxopyrrolidin-3-(S)-yl]-amide ps
The title compound is prepared in CH.sub.2Cl.sub.2 instead of
CH.sub.3CN as described in EXAMPLE 1, Part K using
5-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline
hydrochloride in place of
7-(3-(S)amino-2-oxopyrrolidin-1-ylmethyl)-1-chl- oro-isoquinoline
hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as
prepared in EXAMPLE 1, Part J. The crude product is purified by
column chromatography eluting with 25% EtOAc/CH.sub.2Cl.sub.2 to
provide the title compound as a light yellow solid.
[0652] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.36 (d, 1H), 8.33
(s, 1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.82 (d, 1H), 7.73 (d, 1H),
7.66 (m, 1H), 7.42 (d, 1H), 7.35 (d, 1H), 7.30 (dd, 1H), 7.25 (dd,
1H), 5.40 (s, 1H), 4.82 (AB, 2H), 3.94 (s, 3H), 3.71 (m, 1H), 3.12
(m, 1H), 3.02 (m, 1H), 2.50 (m, 1H), 1.98 (m, 1H). EI MS,
[m].sup.+=495, 497, Cl pattern. Elemental analysis calculated
C=60.54%, H=4.47%, N=8.47%, Cl=7.15%, found C=59.79%, H H=4.70%,
N=7.88, Cl=7.21%.
[0653] D. 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-5-ylmeth-
yl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0654] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-chloro-quinolin-5-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]-amide is converted to the title
compound when heated at 125.degree. C. as described in EXAMPLE 2.
The crude product is partially purified by RP-HPLC eluting in a
gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 80%
CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate product
fractions are concentrated in vacuo, filtered, triturated with MeOH
and then purified further by column chromatography eluting with a
gradient of 1% MeOH/CH.sub.2Cl.sub.2 to 3% MeOH/CH.sub.2Cl.sub.2 to
yield the title compound as a pale yellow solid.
[0655] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.48 (d, 1H),
8.37 (s,lH), 8.23 (d, 1H), 8.03 (d, 1H), 7.93 (d, 1H), 7.72 (m,
1H), 7.69 (d, 1H), 7.60 (d, 1H), 7.55 (s, 1H), 7.33 (m, 2H), 7.07
(d, 1H), 4.71 (AB, 2H), 4.11 (m, 1H), 3.88 (s, 3H), 3.00 (m, 2H),
1.94 (m, 1H), 1.48 (m, 1H). FAB MS, [M+H].sup.+=477. Elemental
analysis calculated with 2.5 mol of H.sub.2O cal. C=50.98%,
H=4.14%, N=8.38%, found C=50.96%, H=4.14%, N=8.38%. The
enantiomeric purity is 84.5% ee as determined by analytical
Chiralpak AS RP-HPLC.
EXAMPLES 21 AND 22
[0656] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-5-ylmethyl)-
2-oxopyrrolidin-3-(S)-yl]-methyl amide trifluoroacetate and
7-methoxynaphthalene-2-sulfonic acid
methyl-[2-oxo-1-(2-oxo-1,2-dihydro-q-
uinolin-5-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
[0657] A. 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-chloro-quinolin-5-ylme-
thyl)2-oxopyrrolidin-3-(S)-yl]-methyl amide
[0658] The title compound is prepared as in EXAMPLES 18 AND 19,
Part A using 7-methoxynaphthalene-2--sulfonic
acid[1-(2-chloro-quinolin-5-ylmeth-
yl)-2-oxopyrrolidin-3-(S)-yl]-amide as the starting material. The
crude product is purified by column chromatography eluting with 50%
EtOAc/hexanes to afford the title compound as a white solid.
[0659] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.42 (s, 1H), 8.38
(s, 1H), 7.97 (d, 1H), 7.91 (d, 1H), 7.78 (m, 2H), 7.66 (dd, 1H),
7.43 (d, 1H), 7.30 (d, 1H), 7.25 (m, 2H), 4.92 (m, 1H), 4.80 (AB,
2H), 3.92 (s, 3H), 3.08 (m, 2H), 2.74 (s, 3H), 2.22 (m, 1H), 1.80
(m, 1H).
[0660] B. 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin-5-ylmeth-
yl)-2-oxopyrrolidin-3-(S)-yl]-methyl amide trifluoroacetate and
7-methoxynaphthalene-2-sulfonic acid
methyl-[2-oxo-1-(2-oxo-1,2-dihydro-q-
uinolin-5-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
[0661] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-chloro-quinolin-5-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]-methyl amide is converted to the title
compounds when heated at 120.degree. C. as described in EXAMPLE 2.
The crude product is purified by RP-HPLC eluting in a gradient of
10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 80% CH.sub.3CN/H.sub.2O (0.1%
TFA) and the appropriate product fractions are lyophilized to
provide 7-methoxynaphthalene-2-sulfonic acid
[1-(2-aminoquinolin5-ylmethyl)-2-oxo- pyrrolidin-3-(S)-yl]-methyl
amide trifluoroacetate as a white solid.
[0662] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.46 (d, 1H),
8.39 (s, 1H), 8.03 (d, 1H), 7.96 (d, 1H), 7.70 (m, 2H), 7.60 (d,
1H), 7.58 (s, 1H), 7.36 (dd, 1H), 7.34 (d, 1H), 7.06 (d, 1H), 4.90
(m, 1H), 4.71 (AB, 2H), 3.89 (s, 3H), 3.11 (m, 1H), 3.00 (m, 1H),
2.63 (s, 3H), 1.95 (m, 1H), 1.68 (m, 1H). FAB MS, [M+H].sup.+=491.
7-Methoxynaphthalene-2-sulfon- ic acid
methyl-[2-oxo-1-(2-oxo-1,2-dihydro-quinolin-5-ylmethyl)-pyrrolidin-
-3-(S)-yl]-amide is also isolated from the reaction mixture as a
by-product.
[0663] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.39 (s, 1H),
8.04 (d, 1H), 7.98 (d,1H), 7.94 (d, 1H), 7.68 (d, 1H), 7.57 (s,
1H), 7.42 (m, 1H), 7.34 (dd, 1H), 7.25 (d, 1H), 7.05 (d, 1H), 6.46
(d, 1H), 4.88 (m, 1H), 4.60 (AB, 2H), 3.89 (s, 3H), 3.08 (m, 1H),
2.97 (m, 1H), 2.63 (s, 3H), 1.96 (m, 11i), 1.65 (m, 1H). FAB MS,
[M+H].sup.+=492.
EXAMPLES 23 AND 24
[0664] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin6-ylmethyl)--
2-oxopyrrolidin-3-(S)-yl]-amide and 7-methoxynaphthalene-2-sulfonic
acid[2-oxo-1-(2-oxo-1,2-dihydro-quinolin-6-ylmethyl)-pyrrolidin-3-(S)-yl]-
-amide
[0665] A. 6-Methyl-1H-quinolin-2-one
[0666] The title compound is prepared from p-toluidine and
cinnamoyl chloride according to the procedure described in
Synthesis 1975, 739. The crude product obtained is triturated in
Et.sub.2O/hexanes and filtered to give the title compound as a
beige solid which is used in the subsequent step.
[0667] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.11.60 (bs, 1H),
7.82 (d, 1H), 7.41 (s, 111), 7.30 (d, 1H), 7.18 (d, 1H), 6.45 (d,
1H), 2.30 (s, 3H).
[0668] B. 2-Chloro-6-methyl-quinoline
[0669] The title compound is prepared as described in EXAMPLE 1,
Part E using 6-methyl-1H-quinolin-2-one in place of
7-methyl-2H-isoquinolin-1-on- e. The crude product precipitated out
during neutralization of the aqueous workup and the solid is
filtered and dried. The crude product is recrystallized in MeOH to
afford the title compound as a beige solid.
[0670] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.02 (d, 1H), 7.92
(d, 1H), 7.60 (s, 1H), 7.58 (d, 1H), 7.33 (d, 1H), 2.53 (s,
3H).
[0671] C. 6-Bromomethyl-2-chloro-quinoline
[0672] The title compound is prepared as described in EXAMPLE 1,
Part F using 2-chloro-6methyl-quinoline in place of
1-chloro-7-methyl-isoquinoli- ne. The crude residue obtained is
recrystallized from 50% EtOAc/hexanes to yield 7.4 g (38%) of the
6-bromomethyl-2-chloro-quinoline as a beige solid.
[0673] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.08 (d, 1H), 8.02
(d, 1H), 7.83 (s, 1H), 7.77 (dd, 1H), 7.40 (d, 1H), 4.65 (s, 2H).
EI MS, [M].sup.+=256, 258, Cl pattern.
[0674] D.
[1-(2-Chloro-quinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carb-
amic acid tert-butyl ester
[0675] The title compound is prepared from
(2-oxopyrrolidin-3-(S)-yl)-carb- amic acid tert-butyl ester as
described in EXAMPLE 1, Part H using
6-bromomethyl-2-chloro-quinoline in place of
7-bromomethyl-1-chloro-isoqu- inoline. The crude product is
purified by column chromatography eluting with a gradient of 2%
MeOH/CH.sub.2Cl.sub.2 to 4% MeOH/CH.sub.2Cl.sub.2 to afford the
title compound as a beige solid.
[0676] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.08 (d, 1H), 8.00
(d, 1H), 7.69 (s, 1H), 7.61 (dd, 1H), 7.40 (d, 1H), 5.23 (bs, 1H),
4.67 (AB, 2H), 4.25 (m, 1H), 3.26 (m, 2H), 2.63 (m, 1H), 1.90 (m,
1H), 1.46 (s, 9H).
[0677] E.
6-(3-(S)-Amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline
hydrochloride
[0678] The title compound is prepared as described in EXAMPLE 1,
Part I using
[1-(2-chloro-quinolin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbami-
c acid tert-butyl ester as the starting material. The title
compound is obtained as a white solid.
[0679] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.74 (bs, 3H),
8.48 (d, 1H), 8.00 (s, 1H), 7.95 (d, 1H), 7.71 (d, 1H), 7.60 (d,
1H), 4.64 (AB, 2H), 4.11 (m, 1H), 3.35 (m, 2H), 2.42 (m, 1H), 2.09
(m, 1H).
[0680] F. 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-chloro-quinolin-6-ylme-
thyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0681] The title compound is prepared in CH.sub.2Cl.sub.2 instead
of CH.sub.3CN as described in EXAMPLE 1, Part K using
6-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-2-chloro-quinoline
hydrochloride as the starting material and
7-methoxynaphthalene-2-sulfony- l chloride. The crude product is
triturated in CH.sub.2Cl.sub.2 and filtered to provide the title
compound as a white solid.
[0682] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.36 (s, 1H), 8.03
(d, 1H), 7.97 (d, 1H), 7.91 (d, 1H), 7.80 (d, 1H), 7.75 (dd, 1H),
7.60 (s, 1H), 7.51 (dd, 1H), 7.37 (d, 1H), 7.29 (dd, 1H), 7.25 (dd,
1H), 5.43 (s, 1H), 4.58 (AB, 2H), 3.94 (s, 3H), 3.76 (m, 1H), 3.22
(m, 2H), 2.59 (m, 1H), 2.09 (m, 1H). FAB MS, [M+H].sup.+=496, 498,
Cl pattern. Elemental analysis calculated C=60.54%, H=4.47%,
N=8.47%, Cl=7.15%, found C=60.43%, H=4.17%, N=8.37, Cl=7.06%.
[0683] G. 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin6-ylmethy- l)-2-oxopyrrolidin-3S)-yl]-amide
and 7-methoxynaphthalene-2-sulfonic
acid[2-oxo-1-(2-oxo-1,2-dihydro-quinolin-6-ylmethyl)-pyrrolidin-3-(S)-yl]-
-amide
[0684] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-chloro-quinolin-6-ylmethy-
l)-2-oxopyrrolidin-3-(S)-yl]-methyl amide is converted to the title
compounds when heated at 130.degree. C. as described in EXAMPLE 2.
The crude mixture of products is purified by RP-HPLC eluting in a
gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 60%
CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate product
fractions are concentrated in vacuo and then purified further by
column chromatography eluting with 5% MeOH/CH.sub.2Cl.sub.2 to
yield 7-methoxynaphthalene-2-sulfonic
acid[1-(2-aminoquinolin6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
as a tan solid.
[0685] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.38 (s, 1H),
8.23 (d, 1H), 8.03 (d, 1H), 7.93 (d, 1H), 7.80 (d, 1H), 7.72 (d,
1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.38 (d, 1H), 7.32 (dd, 1H), 7.25
(d, 1H), 6.73 (d, 1H), 6.43 (bs, 2H), 4.37 (AB, 2H), 4.10 (m, 1H),
3.88 (s, 3H), 3.04 (m, 2H), 1.96 (m, 1H), 1.51 (m, 1H). FAB MS,
[M+H].sup.+=477. Elemental analysis calculated with 0.6 mol of
H.sub.2O cal. C=61.58%, H=5.22%, N=11.49%, found C=61.59%, H=5.08%,
N=11.14%. The enantiomeric purity is 87.0% ee as determined by
analytical Chiralpak AS RP-HPLC.
[0686] 7-Methoxynaphthalene-2-sulfonic
acid[2-oxo-1-(2-oxo-1,2-dihydro-qui-
nolin-6-ylmethyl)-pyrrolidin-3-(S)-yl]-amide is also isolated from
the reaction mixture as a minor by-product.
[0687] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.11.70 (bs, 1H),
8.37 (s, 1H), 8.21 (d, 1H), 8.01 (d, 1H), 7.93 (d, 1H), 7.82 (d,
1H), 7.69 (d, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 7.32 (m, 2H), 7.25
(m, 1H), 6.47 (d, 1H), 4.35 (s, 2H), 4.12 (m, 1H), 3.89 (s, 3H),
3.06 (m, 2H), 1.97 (m, 1H), 1.53 (m, 1H). FAB MS,
[M+H].sup.+=478.
EXAMPLE 25
[0688] 7-Methoxynaphthalene-2-sulfonic acid[1-(
1H-benzoimidazol-5-ylmethy- l)-2-oxopyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[0689] A. [1-(4-Nitrobenzyl)2-oxopyrrolidin-3-(S)-yl]-carbamic acid
tert-butyl ester
[0690] The title compound is prepared from
(2-oxopyrrolidin-3-(S)-yl)-carb- amic acid tert-butyl ester as
described in EXAMPLE 1, Part H using 4-nitrobenzyl bromide in place
of 7-bromomethyl-1-chloro-isoquinoline. The crude product is
purified by column chromatography eluting with a gradient of 10%
EtOAc/CH.sub.2Cl.sub.2 to 25% EtOAc/CH.sub.2Cl.sub.2 to afford the
title compound as a yellow solid.
[0691] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.20 (d, 2H), 7.43
(d, 2H), 5.18 (bs, 1H), 4.58 (AB, 2H), 4.22 (m, 1H), 3.26 (m, 2H),
2.65 (m, 1H), 1.93 (m, 1H), 1.46 (s, 9H).
[0692] B. 3-(S)-Amino-1-(4-nitrobenzyl)pyrrolidin-2-one
hydrochloride
[0693] The title compound is prepared as described in EXAMPLE 1,
Part I using [1-(4-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-carbamic
acid tert-butyl ester as the starting material. The title compound
is obtained as a white solid.
[0694] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.65 (bs, 3H),
8.22 (d, 2H), 7.57 (d, 2H), 4.59 (AB,2H), 4.10 (m, 1H), 3.32 (m,
2H), 2.40 (m, 1H), 2.03 (m, 1H).
[0695] C.
2,2,2-Trifluoro-N-[1-(4-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-a-
cetamide
[0696] The title compound is prepared in CH.sub.2Cl.sub.2 instead
of CH.sub.3CN as described in EXAMPLE 1, Part K using
3-(S)-amino-1-(4-nitrobenzyl)-pyrrolidin-2-one hydrochloride as the
starting material and trifluoroacetic anhydride in place of
7-methoxynaphthalene-2-sulfonyl chloride. The crude product is
concentrated in vacuo and used as is in the subsequent step.
[0697] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.24 (d, 2H), 7.43
(d, 2H), 7.25 (bs, 1H), 4.60 (AB, 2H), 4.44 (m, 1H), 3.35 (m, 2H),
2.80 (m, 1H), 2.01 (m, 1H).
[0698] D.
N-[1-(4-Acetylamino-3-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2-
,2-trifluoroacetamide
[0699] To a solution of
2,2,2-trifluoro-N-[1-(4-nitrobenzyl)-2-oxopyrrolid-
in-3-(S)-yl]-acetamide (0.75 g, 2.27 mmol) in AcOH (12 mL) is added
acetic anhydride (1 mL) and a catalytic amount of 10% palladium on
activated carbon. The heterogenous mixture is hydrogenated at room
temperature on a Parr apparatus under 70 p.s.i. of H.sub.2. After
4.5 h, the reaction mixture is filtered through a pad of Celite,
washed with CH.sub.2Cl.sub.2 and then MeOH. The crude product is
concentrated in vacuo to yield 1.2 g of crude
N-[1-(4-acetylamino-benzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trif-
luoroacetamide as a residue (wet with HOAc). A solution of the
crude
N-[1-(4-acetylamino-benzyl)-2-oxopyrrolidin-3-(S)-yl]-2,2,2-trifluoroacet-
amide (1.2 g, wet with AcOH) in AcOH (12 mL) is cooled at 0.degree.
C. and acetic anhydride (1 mL) is added. The resulting mixture is
treated with a catalytic amount of NaNO.sub.2, followed by the
dropwise addition of fuming HNO.sub.3 (3.8 mL). The reaction
mixture is stirred at 0.degree. C. for 1.5 hours, then at room
temperature for 1.5 hours. Upon re-cooling to 0.degree. C., a
mixture of ice/ice water is added slowly with stirring. The mixture
is diluted further with water and extracted with EtOAc (3.times.50
mL). The combined organic layers are washed twice with water. The
organic phase is dried over anhydrous MgSO.sub.4, filtered and
concentrated. The crude product is purified by column
chromatography eluting with a gradient of 25%
EtOAc/CH.sub.2Cl.sub.2 to 50% EtOAc/CH.sub.2Cl.sub.2 to provide the
title compound (0.65 g, 1.67 mmol) as a beige solid.
[0700] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.10.27 (s, 1H), 8.77
(d, 1H), 8.08 (s, 1H), 7.54 (m, 1H), 7.40 (bs, 1H), 4.51 (AB, 2H),
4.46 (m, 1H), 3.34 (m, 2H), 2.78 (m, 1H), 2.31 (s, 3H), 1.98 (m,
1H) for the major component of a mixture of rotamers.
[0701] E.
3-(S)-Amino-1-(4-amino-3-nitrobenzyl)-pyrrolidin-2-one
[0702] To a solution of
N-[1-(4-acetylamino-3-nitrobenzyl)2-oxopyrrolidin--
3-(S)-yl]-2,2,2-trifluoroacetamide (0.65 g, 1.67 mmol) in EtOH (4
mL) is added 1 N NaOH (6 mL) solution. The yellow mixture is heated
at 50.degree. C. for 3 hours as a brown solution resulted. The
reaction mixture is allowed to cool and then concentrated in vacuo.
The crude residue is diluted with water and 1 N NaOH 10 mL) and the
aqueous phase is extracted with CHCl.sub.3 (4.times.50 mL). The
combined organic layers are dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to give the title compound (0.22 g, 0.88
mmol) as a yellow solid which is used as is in the subsequent
step.
[0703] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.98 (s, 1H), 7.30
(dd, 1H), 6.79 (d, 1H), 6.12 (bs, 2H), 4.36 (AB, 2H), 3.67 (m, 1H),
3.19 (m, 2H), 2.43 (m, 1H), 1.71 (m, 1H).
[0704] F. 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-amino-3-nitrobenzyl)-2-
-oxopyrrolidin-3-(S)-yl]-amide
[0705] The title compound is prepared in CH.sub.2Cl.sub.2 instead
of CH.sub.3CN as described in EXAMPLE 1, Part K using
3-(S)-amino-1-(4-amino-3-nitrobenzyl)-pyrrolidin-2-one in place of
7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline
hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as
prepared in EXAMPLE 1, Part J. The crude product is purified by
column chromatography eluting with a gradient of 20%
EtOAc/CH.sub.2Cl.sub.2 to 50% EtOAc/CH.sub.2Cl.sub.2 to afford the
title compound as a pale yellow solid.
[0706] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.37 (s, 1H), 7.94
(s, 1H), 7.92 (d, 1H), 7.82 (d, 1H), 7.75 (dd, 1H), 7.30 (dd, 1H),
7.25 (dd, 1H), 7.19 (dd, 1H), 6.77 (d, 1H), 6.12 (bs, 2H), 5.38
(bs, 1H), 4.30 (AB, 2H), 3.94 (s, 3H), 3.73 (m, 1H), 3.18 (m, 2H),
2.58 (m, 1H), 2.05 (m, 1H).
[0707] G. 7-Methoxynaphthalene-2-sulfonic
acid[1-(1H-benzoimidazol-5-ylmet-
hyl)-2-oxopyrrolidin-3-(S)-y1-amide trifluoroacetate
[0708] To a solution of 7-methoxynaphthalene-2-sulfonic
acid[1-(4-amino-3-nitrobenzyl)-2-oxopyrrolidin-3-(S)-yl]-amide
(0.38 g, 0.82 mmol) in 88% HCO.sub.2H (15 mL) is added a catalytic
amount of 10% palladium on activated carbon. The heterogenous
mixture is hydrogenated at room temperature on a Parr apparatus
under 70 p.s.i. of H.sub.2 for 1 hour. The reaction mixture is
filtered through a pad of Celite, washed with EtOAc and MeOH, and
the filtrate is concentrated in vacuo. The crude product is
purified by RP-HPLC eluting in a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 80% CH.sub.3CN/H.sub.2O (0.1%
TFA) and the appropriate product fractions are lyophilized to
provide the title compound (0.17 g, 0.30 mmol) as a white
solid.
[0709] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.38 (bs, 1H),
8.38 (s, 1H), 8.25 (d, 1H), 8.03 (d, 1H), 7.95 (d, 1H), 7.78 (d,
1H), 7.72 (dd, 1H), 7.66 (bs, 1H), 7.56 (s, 1H), 7.35 (d, 1H), 7.32
(dd, 1H), 4.48 (AB, 2H), 4.09 (m, 1H), 3.88 (s, 3H), 3.06 (m, 2H),
1.96 (m, 1H), 1.53 (m, 1H). FAB MS, [M+H].sup.+=451. Elemental
analysis calculated with 1.2 mol H.sub.2O cal. C=51.19%, H=4.37%,
N=9.55%, found C=51.19%, H=3.95%, N=9.36%.
EXAMPLE 26
[0710] 7-Methoxynaphthalene-2-sulfonic
acid[2-(1H-benzoimidazol-5-ylethyl)-
-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0711] A. Boc-L-Asp(H)--OBn.
[0712] Boc-L-Asp-OBn (15 g, 46.4 mmol) is dissolved in THF (50 mL)
and cooled to -10.degree. C. The solution is treated with
N-methylmorpholine (4.9 g, 48.7 mmol) and stirred for 5 minutes. To
the solution is added dropwise isobutyl chloroformate (6.3 g, 46.4
mmol). After the addition is completed, the mixture is stirred for
1 minute and then filtered through a pad of Celite. The filtrate is
cooled to -10.degree. C. To the solution is added sodium
borohydride (2.63 g, 70 mmol) which is predissolved in water (50
mL). The resulting solution is stirred for 2 minutes. The solution
is poured into a separatory funnel and diluted with EtOAc (800 mL).
The organic layer is washed with water and saturated NaCl. The
organic layer is dried over MgSO.sub.4, filtered and concentrated
in vacuo. The residue is added to a solution of oxalyl chloride (30
mL, 60 mmol, 2M solution in CH.sub.2Cl.sub.2), and methyl sulfoxide
(7.25 g, 92.8 mmol) in CH.sub.2Cl.sub.2(250 mL) at -78.degree. C.
The mixture is stirred at -78.degree. C. for 40 minutes, then
triethylamine (14 g, 140 mmol) is added. The reaction mixture is
stirred at -78.degree. C. for 1 hour and then is stirred at room
temperature for 30 minutes. The solution is poured into a 20%
citric acid/water (200 mL) solution. The resulting mixture is
poured into a separatory funnel and the layers are separated. The
organic layer is washed with water and saturated NaCl. The organic
phase is dried over MgSO.sub.4, filtered and concentrated. The
crude residue is purified by column chromatography eluting with a
gradient of 10% EtOAc/hexanes to 30% EtOAc/hexanes to give the
title compound (12.0 g, 39 mmol) as an oil.
[0713] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.9.68 (s, 1H), 7.32
(m, 4H), 5.42 (bs, 1H), 5.16 (s, 2H), 4.62 (m, 2H), 3.05 (ddd, 2H),
1.40 (s, 9H).
[0714] B.
{1-[2-(4-Nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl}-carbamic
acid tert-butyl ester
[0715] To a solution of Boc-L-Asp(H)--OBn (3.3 g, 10.7 mmol)
dissolved in methanol (50 mL) is added 4 .ANG. molecular sieves,
4-nitrophemethylamine hydrochloride (4.35 g, 21.5 mmol) and
triethylamine (2.25 g, 22.2 mmol). The solution is stirred at room
temperature for 45 minutes and then the mixture is treated with
sodium cyanoborohydride (0.72 g, 11.5 mmol). The reaction mixture
is stirred at room temperature for 16 hours. After this time, 1 N
NaOH (10 mL) followed by water (25 mL) is added. The resulting
mixture is stirred for 30 minutes and then concentrated in vacuo to
a smaller volume. The solution is diluted with EtOAc (250 mL),
filtered through a pad of Celite and washed with water and EtOAc.
The solution is poured into a separatory funnel and the layers are
separated. The aqueous layer is extracted with EtOAc. The combined
organic layers are washed with 1N HCl, H.sub.2, saturated
NaHCO.sub.3 solution and saturated NaCl. The organic phase is dried
over MgSO.sub.4, filtered and concentrated. The crude residue is
purified by column chromatography eluting with 50%
EtOAc/CH.sub.2Cl.sub.2 to afford the title compound (1.46 g, 4.18
mmol) as a pale yellow solid.
[0716] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.17 (d, 2H), 7.39
(d, 2H), 5.12 (bs, 1H), 4.09 (m, 1H), 3.63 (m, 2H), 3.25 (m, 2H),
2.99 (t, 2H), 2.62 (m, 1H), 1.83 (m, 1H), 1.44 (s, 9H).
[0717] C. 3-(S)-Amino-1-[2-(4-nitrophenyl)-ethyl]-pyrrolidin-2-one
hydrochloride
[0718] The title compound is prepared as described in EXAMPLE 1,
Part I using
{1-[2-(4-nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S)-yl}-carbamic
acid tert-butyl ester as the starting material. The title compound
is obtained as a beige solid.
[0719] .sup.1H NMR (CDCl.sub.3/CD.sub.3OD, 300 MHz) .delta.8.77
(bs, 1H), 8.72 (bs, 1H), 8.16 (d, 2H), 7.45 (d, 2H), 4.15 (m, 1H),
3.59 (t, 2H), 3.38 (m, 2H), 2.98 (t, 2H), 2.58 (m, 1H), 2.37 (m,
1H).
[0720] D.
2,2,2-Trifluoro-N-{1-[2-(4-nitrophenyl)-ethyl]-2-oxopyrrolidin-3-
-(S)-yl}-acetamide
[0721] The title compound is prepared in CH.sub.2Cl.sub.2 instead
of CH.sub.3CN as described in EXAMPLE 1, Part K using
3-(S)-amino-1-[2-(4-nitrophenyl)-ethyl]-pyrrolidin-2-one
hydrochloride as the starting material and trifluoroacetic
anhydride in place of 7-methoxynaphthalene-2-sulfonyl chloride. The
crude product is concentrated in vacuo and used as is in the
subsequent step.
[0722] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.17 (d, 2H), 8.15
(bs, 1H), 7.39 (d, 2H), 4.40 (m, 1H), 3.70 (m, 1H), 3.55 (m, 1H),
3.34 (m, 2H), 2.99 (t, 2H), 2.68 (m, 1H), 1.96 (m, 1H).
[0723] E.
N-{-[2-(4-Acetylamino-3-nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S-
)-yl]-2,2,2-trifluoroacetamide
[0724] The title compound is prepared as described in EXAMPLE 25,
Part D using
2,2,2-trifluoro-N-{1-[2-(4-nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S-
)-yl}-acetamide as the starting material. The crude intermediate is
concentrated in vacuo to yield
N-{1-[2-(4-acetylamino-phenyl)-ethyl]-2-ox-
opyrrolidin-3-(S)-yl]-2,2,2-trifluoroacetamide as a residue (wet
with HOAc) which is also used directly in the nitration step. The
nitric acid reaction mixture is allowed to warm to room temperature
and stirred for 18 hours. The crude product is purified by column
chromatography eluting with a gradient of 25%
EtOAc/CH.sub.2Cl.sub.2 to 50% EtOAc/CH.sub.2Cl.sub.2 to provide the
title compound as a solid.
[0725] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.10.24 (s, 1H), 8.70
(d, 1H), 7.98 (bs, 1H), 7.40 (d, 1H), 7.26 (bs, 1H), 4.43 (m, 1H),
3.58 (m, 2H), 3.38 (m, 2H), 2.94 (m, 2H), 2.66 (m, 1H), 2.06 (s,
3H), 1.98 (m, 1H) for the major component of a mixture of
rotamers.
[0726]
F.3-(S)-Amino-1-[2-(4-amino-3-nitrophenyl)ethyl]-pyrrolidin-2-one
[0727] The title compound is prepared as described in EXAMPLE 25,
Part F using
N-{1-[2-(4-acetylamino-3-nitrophenyl)-ethyl]-2-oxopyrrolidin-3-(S)--
yl]-2,2,2-trifluoroacetamide as the starting material. The reaction
mixture is stirred at room temperature for 18 hours. After similar
workup, the organic phase is concentrated in vacuo to give the
title compound as a yellow solid which is used as is in the
subsequent step.
[0728] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.90 (s, 1H), 7.25
(d, 1H), 6.80 (d, 1H), 6.24 (bs, 1H), 3.48 (m, 3H), 3.26 (m, 2H),
2.77 (t, 2H), 2.40 (m, 1H), 2.25 (bs, 3H), 1.69 (m, 1H).
[0729] G. 7-Methoxynaphthalene-2-sulfonic
acid{1-[2-(4-amino-3-nitrophenyl-
)-ethyl]-2-oxopyrrolidin-3-(S)-yl}-amide
[0730] The title compound is prepared in CH.sub.2Cl.sub.2 instead
of CH.sub.3CN as described in EXAMPLE 1, Part K using
3-(S)-amino-1-[2-(4-amino-3-nitrophenyl)-ethyl]-pyrrolidin-2-one in
place of
7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline
hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as
prepared in EXAMPLE 1, Part J. After similar workup, the organic
phase is concentrated in vacuo to afford the title compound as a
pale yellow solid which is used as is in the subsequent step.
[0731] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.36 (s, 1H), 7.87
(d, 1H), 7.83 (s, 1H), 7.77 (d, 1H), 7.72 (dd, 1H), 7.27 (dd, 1H),
7.22 (s, 1H), 7.13 (dd, 1H), 6.68 (d, 1H), 6.04 (bs, 2H), 5.33 (bs,
1H), 3.93 (s, 3H), 3.68 (m, 1H), 3.44 (m, 2H), 3.20 (m, 2H), 2.68
(t, 2H), 2.49 (m, 1H), 1.98 (m, 1H).
[0732] H. 7-Methoxynaphthalene-2-sulfonic
acid{1-[2-(1H-benzoimidazol-5-yl-
)-ethyl]-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0733] 7-Methoxynaphthalene-2-sulfonic
acid{1-[2-(4-amino-3-nitrophenyl)-e-
thyl]-2-oxopyrrolidin-3-(S)-yl}-amide is converted to the title
compound as described in EXAMPLE 25, Part H. The crude product is
purified by RP-HPLC eluting in a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 60% CH.sub.3CN/H.sub.2O (0.1%
TFA) and the appropriate product fractions are lyophilized to
provide the title compound as a white solid.
[0734] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.38 (bs, 1H),
8.35 (s, 1H), 8.13 (d, 1H), 8.02 (d, 1H), 7.93 (d, 1H), 7.73 (d,
1H), 7.69 (s, 1H), 7.65 (d, 1H), 7.55 (s, 1H), 7.38 (d, 1H), 7.32
(dd, 1H), 3.90 (m, 1H), 3.88 (s, 3H), 3.39 (m, 2H), 3.11 (m, 2H),
2.88 (t, 2H), 1.94 (m, 1H), 1.47 (m, 1H). FAB MS, [M+H] 465.
Elemental analysis calculated with 1.4 mol H.sub.2O cal. C=51.68%,
H=4.65%, N=9.27%, found C=51.68%, H=4.25%, N=8.93%.
EXAMPLE 27
[0735] 7-Methoxynaphthalene-2-sulfonic acid
acetyl-[2-oxo-1-(2-pyrrolo[3,2-
-b]pyridin-1-ylethyl)-pyrrolidin-3-(S)-yl ]-amide
trifluoroacetate
[0736] A. 1H-Pyrrolo[3,2-c]pyridine
[0737] The title compound is prepared from 3-picoline-N-oxide
according to the procedure described in Tetrahedron 1993, 2885. The
crude product obtained is dissolved in EtOH and decolorizing carbon
is added. The mixture is filtered through a large column of
SiO.sub.2 gel eluting with EtOH to provide the title compound as a
beige solid.
[0738] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.10.92 (bs, 1H),
8.98 (s, 1H), 8.31 (d, 1H), 7.36 (d, 1H), 7.32 (d, 1H), 6.66 (d,
1H).
[0739] B. Pyrrolo[3,2-c]pyridin1-yl-acetic acid tert-butyl
ester
[0740] The title compound is prepared from
1H-pyrrolo[3,2-c]pyridine as described in EXAMPLES 18 and 19, Part
A using tert-butyl bromoacetate in place of methyl iodide. The
crude product is purified by column chromatography eluting with a
gradient of 3% MeOH/CH.sub.2Cl.sub.2 to 6% MeOH/CH.sub.2Cl.sub.2 to
give the title compound as an oil.
[0741] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.93 (s, 1H), 8.34
(d, 1H), 7.18 (d, 1H), 7.12 (d, 1H), 6.65 (d, 1H), 4.75 (s, 2H),
1.45 (s, 9H).
[0742] C. Pyrrolo[3,2-c]pyridin-1-yl-acetic acid
[0743] To a solution of pyrrolo[3,2-c]pyridin-1-yl-acetic acid
tert-butyl ester (0.44 g, 1.89 mmol) in CH.sub.2Cl.sub.2 (10 mL) at
0.degree. C. is added trifluoroacetic acid (1 mL). After 15
minutes, the solution is allowed to warm to room temperature and
stirred for 18 hours. The reaction mixture is concentrated in vacuo
and then azeotroped with toluene to give 0.5 g of the title
compound as a residue (wet with excess TFA) which is used as is in
the subsequent step
[0744] .sup.1H NMR (CDCl.sub.3+CD.sub.3OC, 300 MHz) .delta.9.09 (s,
1H), 8.34 (d, 1H), 7.91 (d, 1H), 7.71 (d, 1H), 7.08 (d, 1H), 5.18
(s, 2H).
[0745] D.
2-(S)-Benzyloxycarbonylamino4-(2-pyrrolo[3,2-c]pyridin-1-yl-acet-
ylamino)-butyric acid methyl ester
[0746] Pyrrolo[3,2-c]pyridin-1-yl-acetic acid (0.50 g, 1.89 mmol),
2-(S)-benzyloxycarbonylamino-4-amino-butyric acid methyl ester
trifluoroacetate (0.93 g, 2.45 mmol), 4-methylmorpholine (0.75 g,
7.41 mmol), and 1-hydroxybenzotriazole hydrate (0.36 g, 2.65 mmol)
are dissolved in DMF (11 mL) and the resulting mixture is cooled to
0.degree. C. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiiimide
hydrochloride (0.80 g, 4.17 mmol) is added to the solution. The ice
bath is removed and the reaction mixture is stirred at room
temperature. After 18 hours, the solution is diluted with a
saturated solution of NH.sub.4Cl and extracted twice with EtOAc.
The combined organic layers are washed with H.sub.2, saturated
NaHCO.sub.3 and saturated NaCl. The organic phase is dried over
MgSO.sub.4, filtered and concentrated in vacuo. The crude product
is purified by column chromatography in a gradient of 3%
MeOH/CH.sub.2Cl.sub.2 to 10% MeOH/CH.sub.2Cl.sub.2 to afford the
title compound (0.33 g, 0.78 mmol) as a solid.
[0747] .sup.1NMR (CDCl.sub.3, 300 MHz) .delta.8.95 (s, 1H), 8.35
(d, 1H), 7.34 (m, 3H), 7.27 (m, 3H), 7.17 (d, 1H), 6.73 (d, 1H),
6.44 (bs, 1H), 5.45 (d, 1H), 4.93 (s, 2H), 4.78 (s, 2H), 4.08 (m,
1H), 3.69 (s, 3H), 3.67 m, 1H), 2.90 (m, 1H), 2.03 (m, 1H), 1.58
(m, 1H).
[0748] E. 7-Methoxynaphthalene-2-sulfonic acid
acetyl-[2-oxo-1-(2-pyrrolo[-
3,2-b]pyridin-1-ylethyl)-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[0749] To a solution of
2-(S)-benzyloxycarbonylamino-4-(2-pyrrolo[3,2-c]py-
ridin-1-yl-acetylamino)-butyric acid methyl ester (0.51 g, 1.20
mmol) in THF (5 mL) is added diborane (5 mL, 0.500 mmol, 1 M
solution in THF). The resulting mixture is stirred at room
temperature for 4 hours and then concentrated in vacuo. The residue
is suspended in EtOAc (10 mL), treated with 10 drops of H.sub.2O, 5
drops of 1 N NaOH and further quenched with saturated NH.sub.4Cl
solution. The mixture is concentrated in vacuo to about 1/2 volume,
partitioned between EtOAc and 10% Na.sub.2CO.sub.3 solution and the
layers are separated. The aqueous layer is extracted with EtOAc.
The combined organic phases are washed with saturated NaCl, dried
over MgSO.sub.4, filtered and concentrated in vacuo. The crude
product obtained is partially purified by column chromatography in
a gradient of 2% MeOH/CH.sub.2Cl.sub.2 to 10% MeOH/CH.sub.2Cl.sub.2
to afford
[2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-
-carbamic acid benzyl ester. FAB MS, [M+H].sup.+=379. To a solution
of this crude
[2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-
-yl]-carbamic acid benzyl ester in MeOH (10 mL) and AcOH (3 mL) is
added a catalytic amount of 10% palladium on activated carbon. The
heterogenous mixture is stirred at room temperature under a balloon
of H.sub.2 for 18 hours. The reaction mixture is filtered through a
pad of Celite and washed with MeOH (3.times.). The crude product is
concentrated in vacuo and then azeotroped with toluene to give
3-(S)-amino-1-(2-pyrrolo[3,2-c]p-
yridin-1-yl-ethyl)pyrrolidin-2-one acetate as a residue (wet with
excess HOAc). FAB MS, [M+H].sup.+=245. The title compound is
prepared in CH.sub.2Cl.sub.2 instead of CH.sub.3CN as described in
EXAMPLE 1, Part K using the above
3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrol-
idin-2-one acetate in place of
7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-- 1-chloro-isoquinoline
hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as
prepared in EXAMPLE 1, Part J. The crude product is partially
purified by column chromatography eluting in a gradient of 3%
MeOH/CH.sub.2Cl.sub.2 to 5% MeOH/CH.sub.2Cl.sub.2. The residue
obtained is further purified by RP-HPLC eluting in a gradient of
10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 80% CH.sub.3CN/H.sub.2O (0.1%
TFA) and the appropriate product fractions are lyophilized to
provide the title compound as a white solid.
[0750] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.24 (s, 1H),
8.58 (s, 1H), 8.48 (d, 1H), 8.20 (d, 1H), 8.08 (d, 1H), 8.00 (d,
1H), 7.98 (s, 1H), 7.75 (dd, 1H), 7.61 (s, 1H), 7.42 (dd, 1H), 7.03
(d, 1H), 4.87 (m, 1I, 4.56 (m, 2H), 3.90 (s, 3H), 3.63 (m, 2H),
3.30 (m, 2H), 2.27 (m, 1H), 2.15 (s, 3H), 2.04 (m, 1H). FAB MS,
[M+H].sup.+=507.
EXAMPLE 28
[0751] 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-amino-quinazolin-6-yl-met-
hyl)-2-oxopyrrolidin-3-(S)yl]-methylamide trifluoroacetate
[0752] A. 6Methyl-3H-quinazolin-4-one
[0753] Sodium hydride (2.6 g, 65 mmol, 60% mineral oil dispersion)
is added to dioxane (100 mL) at 0.degree. C. To the solution is
added 2-amino-5-methyl benzoic acid (7.6 g, 50 mmol) followed by
[3-(dimethylamino)-2-azoprop2-en-1-ylidene]dimethyl ammonium
chloride (9.9 g, 60 mmol). After addition, the solution is heated
to reflux. Refluxing is continued for 16 hours. The reaction
mixture is cooled to ambient temperature and methanol (3 mL) is
added followed by AcOH (10 mL). The solution is then refluxed for 3
hours. The solution is cooled to ambient temperatures. The solution
is concentrated. The resulting solid is diluted with water (60 mL).
The pH of the resulting solution is adjusted to 7. The solution is
filtered. The resulting solid is dried under vacuum to give the
title compound (6.0 g, 38 mmol).
[0754] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.03 (s, 1H), 7.89
(s, 1H), 7.57 (m, 2H), 2.41 (s, 3H). EI MS, [M+H].sup.+=507.
[0755] B. 4-Chloro-6-methyl-quinazoline
[0756] 6-Methyl-3H-quinazolin-4-one (1.1 g, 6.9 mmol) is dissolved
in toluene (70 mL). To the solution is added triethyl amine (1.82
g, 18 mmol) and P(O)Cl.sub.3 (1.06 g, 6.9 mmol). The solution is
heated to reflux. After 3 h, the solution is poured into water (100
mL). The solution is diluted with EtOAc (200 mL). The layers are
separated. The organic layer is washed with water, saturated
NaHCO.sub.3 (aq.) and saturated NaCl (aq.). The organic layer is
dried over MgSO.sub.4, filtered and concentrated. The title
compound is obtained as an oil (0.75 g, 4.2 mmol).
[0757] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.98 (s, 1H), 8.04
(s, 1H), 7.98 (d, 1H), 7.82 (d, 1H), 2.62 (s, 3H).
[0758] C. 6-Bromomethyl-4-chloro-quinazoline
[0759] The title compound is prepared as described in EXAMPLE 1,
Part F substituting 4-chloro-6-methyl-quinazoline for
1-chloro-7-methylisoquinol- ine. The crude product is purified by
column chromatography eluting with a gradient of 5% EtOAc/hexanes
to 10% EtOAc/hexanes to give the title compound as a white
solid.
[0760] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.9.08 (s, 1H), 8.23
(s, 1H), 8.00 (dd, 2H), 4.68 (s, 2H).
[0761] D. 7-Methoxynaphthalene-2-sulfonic acid
(2-oxopyrrolidin-3-(S)-yl)-- amide
[0762] To a solution of trifluoroacetic acid/CH.sub.2Cl.sub.2 (20
mL) at 0.degree. C. is added (2-oxopyrrolidin-3-(S)-yl)-carbamic
acid tert-butyl ester (04 g, 2 mmol), prepared as described in
EXAMPLE 1, Part G. The resulting solution is allowed to warm to
ambient temperatures and is stirred for 12 hours. The solution is
then concentrated. The resulting oil is reconcentrated from
toluene. The oil is then dissolved in CH.sub.3CN (6 mL). To the
solution is added CH.sub.2Cl.sub.2 (6 mL). The resulting solution
is cooled to 0.degree. C. and triethyl amine (0.67 g, 6.6 mmol)
followed by 7-methoxynaphthalene sulfonyl chloride (0.64 g, 2.5
mmol), prepared as described in EXAMPLE 1, Part J, are added. The
solution is stirred for 6 hours. After this time, the solution is
concentrated. The resulting crude solid is triturated with EtOAc.
The crude solid is then further purified by column chromatography
eluting with a gradient of 2.5% MeOH/CH.sub.2Cl.sub.2 to 5%
MeOH/CH.sub.2Cl.sub.2 to give the title compound (0.40 g, 1.25
mmol) as a white foam.
[0763] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.35 (s, 1H), 7.88
(d, 1H), 7.78 (d, 1H), 7.28 (m, 2H), 5.65 (bs, 1H), 5.34 (bs, 1H),
3.94 (s, 3H), 3.67 (m, 1H), 3.32 (m, 2H), 2.62 (m, 1H), 2.21 (m,
1H).
[0764] E. 7-Methoxynaphthalene-2-sulfonic acid
methyl-(2-oxopyrrolidin-3-(- S)-yl)-amide
[0765] The title compound is prepared as described in EXAMPLE 6,
Part A substituting 7-methoxynaphthalene-2-sulfonic acid
(2-oxopyrrolidin-3-(S)-- yl)-amide for
7-methoxynaphthalene-2-sulfonic acid[1-(1-chloro-isoquinolin-
-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide. The crude product is
purified by column chromatography eluting with a gradient of 40%
EtOAc/CH.sub.2Cl.sub.2 to 60% EtOAc/CH.sub.2Cl.sub.2 to give the
title compound as a white solid.
[0766] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.39 (s, 1H), 7.90
(d, 1H), 7.76 (m, 2H), 7.28 (m, 2H), 6.42 (bs, 1H), 4.82 (m, 1H),
3.92 (s, 3H), 3.32 (m, 2H), 2.80 (s, 3H), 2.31 (m, 1H), 2.05 (m,
1H).
[0767] F. 7 Methoxynaphthalene-2-sulfonic
acid[1-(4-chloro-quinazolin-6-yl-
methyl)-2-oxopyrrolidin-3-(S)-yl]-methyl amide
[0768] To a solution of 7-methoxynaphthalene-2-sulfonic acid
methyl-(2-oxopyrrolidin-3-(S)-yl)amide (0.35 g, 1.04 mmol) in THF
(7 mL) at 0.degree. C. is added LiN(SiMe.sub.3).sub.2 (1 mL, 1
mmol, 1 M solution in THF). The solution is stirred at 0.degree. C.
for 40 minutes. After this time, 6-bromomethyl-4-chloro-quinazoline
(0.24 g, 0.94 mmol) is added. The resulting solution is stirred for
4 hours. The reacton is quenched by the addition of a saturated
NH.sub.4Cl solution. The solution is diluted with EtOAc and water.
The layers are separated. The organic layer is washed with water
and brine. The organic layer is dried over MgSO.sub.4, filtered and
concentrated. The crude product is purified by column
chromatography eluting with a gradient of 20%
EtOAc/CH.sub.2Cl.sub.2 to 40% EtAc/CH.sub.2Cl.sub.2 to give the
title compound (0.25 g, 0.49 mmol) as a white solid.
[0769] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.9.03 (s, 1H), 8.40
(s, 1H), 8.03 (m, 2H), 7.89 (d, 1H), 7.81 (m, 3H), 7.28 (m, 2H)
5.00 (m, 1H), 4.75 (AB, 1H), 4.50 (AB, 1H), 3.92 (s, 3H), 3.22 (m,
2H), 2.87 (s, 3H), 2.38 (m, 1H), 2.03(m, 1H). FAB MS,
[M+H].sup.+=511.
[0770] G. 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-amino-quinazolin-6-yl--
methyl)-2-oxopyrrolidin-3S)-yl]-methylamide trifluoroacetate
[0771] To 7-methoxynaphthalene-2-sulfonic
acid[1-(4-chloro-quinazolin-6ylm-
ethyl)2-oxopyrrolidin-3-(S)-yl]-methyl amide (0.05 g, 0.1 mmol)
suspended in EtOH (10 mL) is added triethylamine (0.02 g, 0.2 mmol)
and ammonium acetate (0.08 g, 1 mmol). The reaction is heated to
80.degree. C. The solution is concentrated. The residue is purified
by RP-HPLC eluting in a gradient of 10% CH.sub.3CN/H.sub.2O (0.1%
TFA) to 80% CH.sub.3CN/H.sub.2O (0. 1% TFA) and the appropriate
product fractions are lyophilized to provide the title compound
(0.03 g, 0.05 mmol) as a white solid.
[0772] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.78 (bs, 2H),
8.78 (s, 1H), 8.36 (s, 1H), 8.11 (s, 1H), 8.02 (d, 1H), 7.92 (d,
1H), 7.83 (d, 1H), 7.68 (m, 2H), 7.56 (s, 1H), 7.49 (s, 1H), 7.32
(dd, 1H), 4.93 (m, 1H), 4.50 (AB, 2H), 3.82 (s, 3H), 3.15 (m, 2H),
2.62 (s, 3H), 2.02 (m, 1H), 1.78 (m, 1H). FAB MS,
[M+H].sup.+=492.
EXAMPLE 29
[0773] 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-amino-thieno[2,3-d]pyrimi-
din-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[0774] A. 2-Amino-5-methylthiophene-3-carboxylic acid methyl
ester
[0775] To a solution of methyl cyanoacetate (19.8 g, 200 mmol) in
DMF (25 mL) is added triethyl amine (10.9 g, 108 mmol). To the
solution is added sulfur (6.4 g, 200 mmol). The solution is heated
to 60.degree. C. Over a 20 minutes period, propionaldehyde (11.6 g,
200 mmol) is added dropwise. After addition, the solution is
allowed to cool to ambient temperatures over 1 hour. The solution
is stirred for 16 hours. The reaction is poured into water (300
mL). The resulting solution is extracted with Et.sub.2O (
2.times.200 mL). The combined Et.sub.2O extracts are washed with
water and saturated NaCl (aq.). The organic layer is dried over
MgSO.sub.4, filtered and concentrated. The resulting crude product
is recrystallized from MeOH/CH.sub.2Cl.sub.2 to give the title
compound (13.7 g, 80 mmol) as a yellow solid.
[0776] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.6.58 (s, 1H), 5.78
(bs, 2H), 3.78 (s, 3H), 2.28 (s, 3H).
[0777] B. 2-Amino-5-methylthiophene-3-carboxylic acid
[0778] To a solution of 2-amino-5-methylthiophene-3-carboxylic acid
methyl ester (13.7 g, 80 mmol) in MeOH/H.sub.2O/THF (400 mL, 1:1:1)
is added LiOH.H.sub.2O (16 g, 400 mmol). The solution is heated to
50.degree. C. After 4 hours, the solution is concentrated. The
resulting residue is dissolved in water. The pH of the solution is
adjusted to between 5-6 using 1 N HCl. The precipitate is collected
by filtration, washed with a small amount of water and is dried
under vacuum. The title compound (12 g, 76 mmol) is obtained as a
yelow solid.
[0779] EI MS, [M].sup.+=157.
[0780] C. 6-Methyl-thieno[2,3-d]pyrimidin-4-ol
[0781] The title compound is prepared as described in EXAMPLE 28,
Part A substituting 2-amino-5-methylthiophene-3-carboxylic acid for
2-amino-5-methyl benzoic acid. The crude product is purified by
column chromatography eluting with a gradient of 2%
MeOH/CH.sub.2Cl.sub.2 to 6% MeOH/CH.sub.2Cl.sub.2 to give the title
compound as a solid.
[0782] EI MS, [M].sup.+=165.
[0783] D. 4-Chloro-6-methyl -thieno[2,3-d]pyrimidine
[0784] The title compound is prepared as described in EXAMPLE 28,
Part B substituting 6-methyl-thieno[2,3-d]pyrimidin-4-ol for
6-methyl-3H-quinazolin-4-one. The crude product is purified by
column chromatography eluting with a gradient of CH.sub.2Cl.sub.2
to 5% EtOAc/CH.sub.2Cl.sub.2 to give the title compound as a
solid.
[0785] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.84 (s, 1H), 7.42
(s, 1H), 2.68 (s, 3H).
[0786] E. 6-Bromomethyl-4-chloro-thieno[2,3-d]pyrimidine
[0787] The title compound is prepared as described in EXAMPLE 1,
Part F substituting 4-chloro-6-methyl-thieno[2,3-d]pyrimidine for
1-chloro-7-methylisoquinoline. The crude product is purified by
column chromatography eluting with a gradient of 70%
CH.sub.2Cl.sub.2/hexanes to 100% CH.sub.2Cl.sub.2to give the title
compound as a white solid.
[0788] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.84 (s, 1H), 7.42
(s, 1H), 4.72 (s, 2H).
[0789] F.
[1-(4-Chloro-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxopyrrolidin--
3-(S)-yl]-carbamic acid tert-butyl ester
[0790] The title compound is prepared as described in EXAMPLE 1,
Part H substituting 6-bromomethyl-4-chloro-thieno[2,3-d]pyrimidine
for 7-bromomethyl-1-chloroisoquinoline. The crude product is
purified by column chromatography eluting with a gradient of 20%
EtOAc/CH.sub.2Cl.sub.2 to 30% EtOAc/CH.sub.2Cl.sub.2 to give the
title compound as a white foam.
[0791] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.80 (s, 1H), 7.31
(s, 1H), 5.15 (bs, 1H), 4.75 (AB, 2H), 4.18 (m, 1H), 3.36 (m, 2H),
2.62 (m, 1H), 1.96 (m, 1H), 1.42 (s, 9H).
[0792] G. 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-chloro-thieno[2,3-d]py-
rimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide _ps The title
compound is prepared as described in EXAMPLE 1, Part I substituting
[1-(4-chloro-thieno[2,3-d]pyrimidin-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-
-carbamic acid tert-butyl ester for
[1-(1-chloro-isoquinolin-7-ylmethyl)-2-
-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester. The
resulting product is then taken directly on as described in EXAMPLE
1, Part K. The crude product is purified by column chromatography
eluting with a gradient of 30% EtOAc/CH.sub.2Cl.sub.2 to 40%
EtOAc/CH.sub.2Cl.sub.2 to give the title compound as a white
solid.
[0793] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.80 (s, 1H), 8.32
(s, 1H), 7.92 (d, 1H), 7.76 (m, 2H), 7.24 (m, 3H), 5.51 (bs, 1H),
4.68 (s, 2H), 3.93 (s, 3H), 3.78 (m, 1H), 3.32 (m, 2H), 2.62 (m,
1H), 2.12 (m, 1H).
[0794] H. 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-amino-thieno[2,3-d]pyr-
imidin-6-yl-methyl)2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[0795] The title compound is prepared as dscribed in EXAMPLE 28,
Part G substituting 7-methoxynaphthalene-2-sulfonic
acid[1-(4-chloro-thieno[2,3--
d]pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide for
7-methoxynaphthalene-2-sulfonic
acid[1-(4-chloro-quinazolin-6-ylmethyl)-2-
-oxopyrrolidin-3-(S)-yl]-methyl amide. The residue is purified by
RP-HPLC eluting in a gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA)
to 80% CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate product
fractions are lyophilized to provide the title compound as a white
solid.
[0796] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.33 (m, 2H),
8.21 (d, 1H), 8.02 (m, 2H), 7.91 (d, 1H), 7.70 (dd, 1H), 7.52 (s,
1H), 7.43 (s, 1H), 7.30 (dd, 1H), 4.58 (AB, 2H), 4.05 (m, 2H), 3.93
(s, 3H), 3.17 (m, 2H), 1.98 (m, 1H), 1.55 (m, 1H). FAB MS,
[M+H].sup.+=484.
EXAMPLE 30
[0797] 7-Methoxynaphthalene-2-sulfonic
acid[2-(6-amino-thieno[2,3-d]pyrimi-
din-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[0798] A. 4-Chloro-7-methyl-thieno[3,2-d]pyrimidine
[0799] The title compound is prepared as described in EXAMPLE 28,
Part B substituting 7-methyl-thieno[2,3-d]pyrimidin4-ol for
6-methyl-3H-quinazolin-4-one. The crude product is purified by
column chromatography eluting with a gradient of CH.sub.2Cl.sub.2
to 10% EtOAc/CH.sub.2Cl.sub.2 to give the title compound as a
solid.
[0800] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.9.02 (s, 1H), 7.68
(s, 1H), 2.51 (s, 3H).
[0801] B. 7-Bromomethyl1chloro-thieno[3,2-d]pyrimidine
[0802] The title compound is prepared as described in EXAMPLE 1,
Part F substituting 4-chloro-7-methyl-thieno[3,2-d]pyrimidine for
1-chloro-7-methylisoquinoline. The crude product is purified by
column chromatography eluting with a gradient of 5% EtOAc/hexanes
to 10% EtOAc/hexanes to give the title compound as a white
solid.
[0803] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.9.04 (s, 1H), 8.08
(s, 1H), 4.77 (s, 2H).
[0804] C.
[1-(4-Chloro1thieno[3,2-d]pyrimidin-7-ylmethyl1)2-oxopyrrolidin--
3-(S)-yl- carbamic acid tert-butyl ester
[0805] The title compound is prepared as described in EXAMPLE 1,
Part H substituting 7-bromomethyl4-chloro-thieno[3,2-d]pyrimidine
for 7-bromomethyl-1-chloroisoquinoline. The crude product is
purified by column chromatography eluting with a gradient of 20%
EtOAc/CH.sub.2Cl.sub.2 to 30% EtOAc/CH.sub.2Cl.sub.2 to give the
title compound as a white foam.
[0806] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.95 (s, 1H), 8.06
(s, 1H), 5.18 (bs, 1H), 4.76 (AB, 2H), 4.13 (m, 1H), 3.44 (m, 1H),
3.37 (m, 1H), 2.64 (m, 1H), 1.92 (m, 1H), 1.42 (s, 9H).
[0807] D. 7-Methoxylnaphthalene-2-sulfonic
acid[1-(4-chloro-thieno[3,2-d]p-
yrimidin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide
[0808] The title compound is prepared as described in EXAMPLE 1,
Part I substituting
[1-(4-chloro-thieno[3,2-d]pyrimidin-7-ylmethyl)-2-oxopyrroli-
din-3-(S)-yl]-carbamic acid tert-butyl ester for
[1-(1-chloro-isoquinolin--
7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl
ester. The resulting product is then taken directly on as described
in EXAMPLE 1, Part K. The crude product is purified by column
chromatography eluting with a gradient of 30%
EtOAc/CH.sub.2Cl.sub.2 to 40% EtOAc/CH.sub.2Cl.sub.2 to give the
title compound as a white solid.
[0809] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.92 (s, 1H), 8.32
(s, 1H),7.96 (s, 1H), 7.86 (d, 1H), 7.74 (m, 2H), 7.28 (d, 1H),
7.19 (d, 1H), 5.64 (bs, 1H), 4.71 (AB, 2H), 3.93 (s, 3H), 3.72 (m,
1H), 3.44 (m, 1H), 3.32 (m, 1H), 2.52 (m, 1H), 2.05 (m, 1H).
[0810] E. 7-Methoxynaphthalene-2-sulfonic
acid[2-(4-amino-thieno[3,2-d]pyr-
imidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[0811] The title compound is prepared as described in EXAMPLE 28,
Part G substituting 7-methoxynaphthalene-2-sulfonic
acid[1-(4-chloro-thieno[3,2--
d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide for
7-methoxynaphthalene-2-sulfonic
acid[1-(4-chloro-quinazolin-6-ylmethyl)-2-
-oxopyrrolidin-3-(S)-yl]-methyl amide. The residue is purified by
RP-HPLC eluting in a gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA)
to 80% CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate product
fractions are lyophilized to provide the title compound as a white
solid.
[0812] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.55 (s, 1H),
8.35 (bs, 3H), 8.14 (d, 1H), 8.00 (m, 2H), 7.93 (d, 1H), 7.68 (d,
1H), 7.52 (s, 1H), 7.32 (dd, 1H), 4.49 (AB, 2H), 4.09 (m, 1H), 3.90
(s, 3H), 3.18 (m,.2H), 1.96 (m, 1H), 1.54 (m, 1H). FAB MS,
[M+H].sup.+=483. Elemental analysis calculated with 1.5 mol
H.sub.2O and 1.5 mol trifluoroacetate cal. C=44.75%, H=3.83%,
N=10.44%, found C=44.75%, H=3.77%, N=11.12%.
EXAMPLE 31
[0813] 7-Methoxynaphthalene-2-sulfonic
acid[1-(7-amino-thieno[2,3-c]pyridi-
n-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate
[0814] A. 3-Bromomethyl-7-chlorothieno[2,3-c]pyridine
[0815] The title compound is prepared as described in EXAMPLE 1,
Part F substituting 7-chloro-3-methyl-thieno[2,3-c]pyrimidine for
1-chloro-7-methylisoquinoline. The crude product is purified by
column chromatography eluting with a gradient of 5% EtOAc/hexanes
to 10% EtOAc/hexanes to give the title compound as a white
solid.
[0816] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.38 (d, 1H), 7.73
(s, 1H), 7.71 (d, 1H), 4.72 (s, 2H).
[0817] B.
[1-(7-Chloro-thieno[2,3-c]pyridin-3-ylmethyl)-2-oxopyrrolidin-3--
(S)-yl]-carbamic acid tert-butyl ester
[0818] The title compound is prepared as described in EXAMPLE 1,
Part H substituting 3-bromomethyl-7-chloro-thieno[2,3-c]pyridine
for 7-bromomethyl1-chloroisoquinoline. The crude product is
purified by column chromatography eluting with a gradient of 20%
EtOAc/CH.sub.2Cl.sub.2 to 40% EtOAc/CH.sub.2Cl.sub.2 to give the
title compound as a white foam.
[0819] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.28 (d, 1H), 7.74
(d, 1H), 7.64 (s, 1H), 5.18 (bs, 1H), 4.68 (AB, 2H), 4.17 (m, 1H),
3.18 (m, 2H), 2.54 (m, 1H), 1.86 (m, 1H), 1.42 (s, 9H).
[0820] C. 7-Methoxynaphthalene-2-sulfonic
acid[1-(7-chloro-thieno[2,3-c]py-
ridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
[0821] The title compound is prepared as described in EXAMPLE 1,
Part I substituting
[1-(7-chloro-thieno[2,3-c]pyridin-3-ylmethyl)-2-oxopyrrolidi-
n-3-(S)-yl]-carbamic acid tert-butyl ester for
[1-(1-chloro-isoquinolin-7--
ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester.
The resulting product is then taken directly on as described in
EXAMPLE 1, Part K. The crude product is purified by column
chromatography eluting with a gradient of 30%
EtOAc/CH.sub.2Cl.sub.2 to 40% EtOAc/CH.sub.2Cl.sub.2 to give the
title compound as a white solid.
[0822] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.833 (s, 1H), 8.30
(d, 1H), 8.16 (d, 1H), 8.07 (s, 1H), 7.99 (d, 1H), 7.92 (d, 1H),
7.78 (d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.28 (dd, 1H), 4.58 (AB,
2H), 4.08 (m, 1H), 3.88 (s, 2H), 1.89 (m, 1H), 1.48 (m, 1H).
[0823] D. 7-Methoxynaphthalene-2-sulfonic acid[1-
(7-amino-thieno[2,3-c]py-
ridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[0824] The title compound is prepared as described in EXAMPLE 28,
Part G substituting 7-methoxynaphthalene-2-sulfonic
acid[1-(7-chloro-thieno[2,3--
c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide for
7-methoxynaphthalene-2-sulfonic
acid[1-(4-chloro-quinazolin-6-ylmethyl)-2-
-oxopyrrolidin-3-(S)-yl]-methyl amide. The residue is purified by
RP-HPLC eluting in a gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA)
to 80% CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate product
fractions are lyophilized to provide the title compound as a white
solid.
[0825] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.90 (bs, 3H),
8.34 (s, 1H), 8.16 (d, 1H), 7.90 (d, 1H), 7.82 (d, 1H), 7.68 (d,
1H), 7.62 (d, 1H), 7.34 (m, 3H), 7.23 (dd, 1H), 4.64 (AB, 2H), 4.08
(m, 1H), 3.88 (s, 3H), 3.09 (M, 2H), 2.11 (m, 1H), 1.60 (m, 1H).
FAB MS, [M+H].sup.+=483.
EXAMPLE 32
[0826] 7-Methoxynaphthalene-2-sulfonic
acid[1-(7-hydroxy-thieno[2,3-c]pyri-
din-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[0827] A. 7-Methoxynaphthalene-2-sulfonic
acid[1-(7-hydroxy-thieno[2,3-c]p-
yridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[0828] The title compound is prepared as described in EXAMPLE 28,
Part G substituting 7-methoxynaphthalene-2-sulfonic
acid[1-(7-chloro-thieno[2,3--
c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide for
7-methoxynaphthalene-2-sulfonic
acid[1-(4-chloro-quinazolin-6-ylmethyl)-2-
-oxopyrrolidin-3-(S)-yl]-methyl amide. The residue is purified by
RP-HPLC eluting in a gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA)
to 80% CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate product
fractions are lyophilized to provide the title compound as a white
solid.
[0829] .sup.1HNMR (DMSO-d.sub.6, 300 MHz) .delta.8.36 (s, 1H), 8.18
(d, 1H), 8.01 (d, 1H), 7.92 (d, 1H), 7.86 (s, 1H), 7.68 (d, 1H),
7.52 (s, 1H), 7.28 (m, 3H), 6.62 (d, 1H), 4.42 (AB, 2H), 4.00 (m,
1H), 3.88 (s, 3H), 3.04 (m, 2H), 1.89 (m, 1H), 1.44 (m, 1H). FAB
MS, [M+H].sup.+=484.
EXAMPLE 33
[0830] 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-amino-thieno[3,2-c]pyridi-
n-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate
[0831] A. 3-(5-Methyl-thiophen-2-yl)-acrylic acid methyl ester
[0832] To 5-methyl-thiophene-2-carboxaldehyde (5 g, 40 mmol) in
CH.sub.2Cl.sub.2 (100 mL) is added methyl
(triphenylphosphoranylidene) acetate (13.3 g, 40 mmol). The
solution is stirred for 72 hours. After this time, the solution is
concentrated. The residue is slurried in Et.sub.2O. The solution is
filtered through a bed of Celite. The collected liquid is
concentrated. The residue is purified by column chromatography
eluting with a gradient of 50% EtOAc/hexanes to 60% EtOAc/hexanes
to give the title compound (4.5 g,. 25 mmol) as an oil.
[0833] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.69 (d, 1H), 7.04
(d, 1H), 6.71 (d, 1H), 6.11 (d, 1H), 3.79 (s, 3H), 2.49 (S,
3H).
[0834] B. 3-(5-Methyl-thiophen-2-yl)-acrylic acid
[0835] The title compound is prepared as described in EXAMPLE 29,
Part B substituting 3-(5-methyl-thiophen-2-yl)-acrylic acid methyl
ester for 2-amino-5-methylthiophene-3-carboxylic acid methyl ester.
The title compound is obtained by filtration as a white solid.
[0836] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.58 (d, 1H), 7.24
(d, 1H), 7.82 (d, 1H), 5.98 (d, 1H), 2.46 (s, 3H).
[0837] C. 2-Methyl-5H-thieno[3,2-c]pyridin-4-one
[0838] The title compound is prepared as described in EXAMPLE 1,
Part A, substituting 3-(5-methyl-thiophen-2-yl)-acrylic acid for
3-p-tolyl-acrylic acid. The product is then treated as described in
EXAMPLE 1, Part B, C, and D. The crude product is purified by
column chromatography eluting with 1% MeOH/CH.sub.2Cl.sub.2 to 5%
MeOH/CH.sub.2Cl.sub.2 to give the title compound as a white
solid.
[0839] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.11.72 (bs, 1H),
7.31 (s, 1H), 7.18 (d, 1H), 6.68 (d, 1H), 2.58 (s, 3H). EI MS,
[M].sup.+=165.
[0840] D. 4-Chloro-2-methyl-thieno[3,2-c]pyridine
[0841] The title compound is prepared as described in EXAMPLE 1,
Part E, substituting 2-methyl-5H-thieno[3,2-c]pyridin-4-one for
7-methyl-2H-isoquinolin-1-one. The crude product is purified by
column chromatography eluting with a gradient of 70%
CH.sub.2Cl.sub.2/hexanes to 100% CH.sub.2Cl.sub.2to give the title
compound as a white solid.
[0842] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.13 (d, 1H), 7.58
(d, 1H), 7.16 (d, 1H), 2.61 (s, 3H).
[0843] E. 2-Bromomethyl-4-chloro-thieno[3,2-c]pyridine
[0844] The title compound is prepared as described in EXAMPLE 1,
Part F substituting 4-chloro-2-methyl-thieno[3,2-c]pyridine for
1-chloro-7-methylisoquinoline. The crude product is purified by
column chromatography eluting with a gradient of 5% EtOAc/hexanes
to 10% EtOAc/hexanes to give the title compound as a white
solid.
[0845] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.21 (d, 1H), 7.63
(d, 1H), 7.49 (s, 1H), 4.80 (s, 2H).
[0846] F.
I-(4-Chloro-thieno[3,2-c]pyridin-2-ylmethyl2-oxopyrrolidin-3-(S)-
-yl]carbamic acid tert-butyl ester
[0847] The title compound is prepared as described in EXAMPLE 1,
Part H substituting 2-bromomethyl-4-chloro-thieno[3,2-c]pyridine
for 7-bromomethyl1-chloroisoquinoline. The crude product is
purified by column chromatography eluting with a gradient of 20%
EtOAc/CH.sub.2Cl.sub.2 to 30% EtOAc/CH.sub.2Cl.sub.2 to give the
title compound as a white foam.
[0848] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.22 (d, 1H), 7.63
(d, If), 7.39 (s, 1H), 5.13 (bs, 1H), 4.78 (AB, 2H), 4.21 (m, 1H),
3.33 (m, 2H), 2.62 (M, 1H), 1.90 (m, 1H), 1.42 (s, 9H).
[0849] G.
3-(S)-Amino-1(4-chloro-thieno[3,2-c]pyridin-2-ylmethyl)-pyrrolid-
in-2-one hydrochloride
[0850] The title compound is prepared as described in EXAMPLE 1,
Part I substituting
1-(4chloro-thieno[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin--
3-(S)-yl]carbamic acid tert-butyl ester for
[1-(1-chloro-isoquinolin-7-ylm-
ethyl)2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester. The
title compound is obtained as a white solid.
[0851] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.50 (bs, 3H),
8.22 (d, 1H), 8.06 (d, 1H), 7.51 (s, 1H), 4.81 (AB, 2H), 4.04 (m,
2H), 3.32 (m, 2H), 2.31 (m, 1H), 1.96 (m, 1H).
[0852] H. 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-chloro-thieno[3,2-c]py-
ridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
[0853] The title compound is prepared as described in EXAMPLE 1,
Part K substituting
3-amino-1-(4-chloro-thieno[3,2-c]pyridin-2-ylmethyl)-pyrroli-
din-2-one for
3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2- -one
hydrochloride. The title compound is obtained as a white solid.
[0854] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.36 (s, 1H),
8.28 (d, 1H), 8.18 (d, 1H), 8.02 (m, 2H), 7.91 (d, 1H), 7.69 (d,
1H), 7.56 (d, 1H), 7.42 (s, 1H), 7.29 (dd, 1H),4.66 (AB,2H),4.10
(m, 1H), 3.88 (s, 3H),3.14 (m,2H), 1.97 (m, 1H), 1.58 (m, 1H).
[0855] I. 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-amino-thieno[3,2-c]pyr-
idin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[0856] The title compound is prepared as described in EXAMPLE 1,
Part L substituting 7-methoxynaphthalene-2-sulfonic
acid[1-(4-chloro-thieno[3,2--
c]pyridin-3-yl-methyl2-oxopyrrolidin-3-(S)-yl]amide for
7-methoxynaphthalene-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-ylmethyl)--
2-oxopyrrolidin-3-(S)-yl]-amide. The resulting product is then
treated as described in EXAMPLE 1, Part M. The residue is purified
by RP-HPLC eluting with a gradient of 10% CH.sub.3CN/H.sub.2O (0.1%
TFA) to 80% CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate
product fractions are lyophilized to provide the title compound as
a white solid.
[0857] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.58 (bs, 3H),
8.32 (s, 1H), 8.26 (d, 1H), 8.02 (d, 1H), 7.92 (d, 1H), 7.78 (s,
1H), 7.69 (m, 2H), 7.49 (dd, 1H), 7.28 (dd, 1H), 4.62 (AB, 2H),
4.02 (m, 1H)H), 3.88 (s, 3H), 3.13 (m, 2H), 1.96 (m, 1H), 1.58 (m,
1H). FAB MS, [M+H].sup.+=483.
EXAMPLE 34
[0858] 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-hydroxy-thieno[3,2-c]pyri-
din-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[0859] A. 7-Methoxynaphthalene-2-sulfonic
acid[1-(4-hydroxy-thieno[3,2-c]p-
yridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[0860] The title compound is prepared as described in EXAMPLE 1,
Part L substituting 7-methoxynaphthalene-2-sulfonic
acid[1-(4-chloro-thieno[3,2--
c]pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide for
7-methoxynaphthalene-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-ylmethyl)--
2-oxopyrrolidin-3-(S)-yl]-amide. The resulting product is then
treated as described in EXAMPLE 1, Part M. The residue is purified
by RP-HPLC eluting with a gradient of 10% CH.sub.3CN/H.sub.2O (0.1%
TFA) to 80% CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate
product fractions are lyophilized to provide the title compound as
a white solid.
[0861] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.11.32 (bs, 1H),
8.33 (s, 1H), 8.20 (d, 1H), 8.02 (d, 1H), 7.92 (d, 1H), 7.69 (d,
1H), 7.52 (d, 1H), 7.46 (s, 1H), 7.30 (m, 2H), 7.19 (m, 1H), 6.71
(d, 1H), 4.52 (AB, 2H), 4.06 (m, 1H), 3.88 (s, 3H), 3.10 (m, 2H),
1.90 (m, 1H), 1.50 (m, 1H). FAB MS, [M+H].sup.+=484.
EXAMPLE 35
[0862] Benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-thieno[3,2-c]pyridin-3-
-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate.
[0863] A. Benzo[b]thiophene-2-sulfonic
acid[1-(4-chloro-thieno[3,2-c]pyrid-
in-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
[0864] The title compound is prepared as described in EXAMPLE 1,
Part K substituting
3-amino-1-(4-chloro-thieno[3,2-c]pyridin-2-ylmethyl)-pyrroli-
din-2-one for
3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2- -one
hydrochloride and benzo[b]thiophene-2-sulfonyl chloride for
7-methoxynaphthalene-2-sulfonyl chloride. The title compound is
obtained as a white solid.
[0865] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.21 (d, 1H), 7.96
(s, 1H), 7.90 (m, 2H), 7.64 (d, 1H), 7.49 (m, 2H), 7.39 (s, 1H),
5.58 (bs, 1H), 4.76 (s, 2H), 3.97 (m, 1H), 3.38 (m, 2H), 2.68 (m,
1H), 2.18 (m, 1H).
[0866] C. Benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-thieno[3,2-c]pyridi-
n-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate
[0867] The title compound is prepared as described in EXAMPLE 1,
Part L substituting benzo[b]thiophene-2-sulfonic
acid[1-(4-chloro-thieno[3,2-c
pyridin-3-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide for
7-methoxynaphthalene-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-ylmethyl)--
2-oxopyrrolidin-3-(S)-yl]-amide. The resulting product is then
treated as described in EXAMPLE 1, Part M. The residue is purified
by RP-HPLC eluting with a gradient of 10% CH.sub.3CN/H.sub.2O (0.1%
TFA) to 80% CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate
product fractions are lyophilized to provide the title compound as
a white solid.
[0868] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.70 (d, 1H),
8.55 (bs, 2H), 8.07 (m, 3H), 7.78 (s, 1H), 7.70 (d, 1H), 7.49 (m,
3H), 4.66 (AB, 2H), 4.16 (m, 1H), 3.24 (m, 2H), 2.12 (m, 1H), 1.72
(m, 1H). FAB MS, [M+H].sup.+=459.
EXAMPLE 36
[0869] 5-Pyridin-4-Yl-thiophene-2-sulfonic
acid-[1-(1-aminoisoquinolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0870] A. 4-Thiophen-2-yl-pyridine
[0871] 2-Bromothiophene (7.6 mL, 78.5 mmol) is added dropwise to a
flame and vacuum dried three-necked round-bottomed flask fitted
with a condenser, stopper and magnesium (2 g, 82.3 mmol) in diethyl
ether (70 mL). The resulting grey solution is stirred at reflux for
1.5 hours. Meanwhile 4-bromopyridine hydrochloride is converted to
the free base in the following manner: 4-Bromopyridine
hydrochloride (15.3 g, 78.7 mmol) is dissolved in water (100 mL),
and cooled in an ice bath. One equivalent of 1 N NaOH (ca. 100 mL)
is added dropwise until pH is .about.5.6. The ice-cooled aqueous
solution is extracted with hexane (3.times.150 mL) and the combined
organic layers are dried over MgSO.sub.4 and filtered. Hexane is
removed under vacuum (11 mm Hg) while cooling in an ice-bath to a
volume of ca. 30 mL. The resulting colorless clear solution is
diluted with THF (150 mL) under N.sub.2. The Grignard reagent is
then cooled to room temperature and added via cannula to the
solution of NiCl.sub.2dppp (0.54 g, 1 mmol) and 4-bromopyridine in
THF. The resulting dark solution is refluxed overnight. The
reaction mixture is then poured over saturated NH.sub.4Cl solution
and extracted with diethyl ether (3.times.200 mL). The combined
ethereal layers are acidified with 2 N HCl (300 mL) and the aqueous
layer is washed with diethyl ether. The aqueous layer is then
cooled in an ice-bath and neutralized with sodium bicarbonate. The
aqueous layer is extracted with ethyl acetate (3.times.200 mL) and
the combined organic layers are dried over MgSO.sub.4, filtered and
concentrated to give a brown solid. The crude solid is taken up in
hot hexanes and the yellow solution is separated from the insoluble
black solid. The hexane solution is concentrated and the above
procedure is repeated. Upon cooling the hexane solution, yellow
solid precipitates form. The yellow solid is collected to give the
title compound (8.99 g, 55.8 mmol).
[0872] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.60 (d, 2H), 7.51
(m, 1H), 7.49 (d, 2H), 7.42 (dd, 1H), 7.14 (dd, 1H). EI MS,
[M.].sup.+=161.
[0873] B. 5-Pyridin-4-yl-thiophene-2-sulfonyl chloride
[0874] To a solution of 4-thiophen-2-yl-pyridine (3.33 g, 20.7
mmol) in THF (137 mL) at -78.degree. C. is added n-BuLi (8.7 mL of
a 2.5 M solution in hexanes, 21.7 mmol). After stirring for 15
minutes, SO.sub.2 gas is bubbled through the solution for 30
minutes. The solution is then allowed to warm to room temperature
and stirred overnight. The solution is concentrated to dryness and
the resulting solid is suspended in hexane (100 mL). To the
ice-cooled solution is added sulfuryl chloride (1.7 mL. 21.7 mmol).
The ice bath is removed and the suspension is stirred for 2 hours.
The mixture is then concentrated to dryness and diluted with ethyl
acetate and washed with saturated NaHCO.sub.3 (aq), water and
brine. The organic layer is dried over MgSO.sub.4, filtered and
concentrated to give a yellow solid as the title product (3.39 g,
13.1 mmol) which is used in the subsequent step without further
purification.
[0875] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.75(d, 2H), 8.60
(d, 1H), 7.90 (d, 1H), 7.51 (d, 2H), EI, [M].sup.+=259, 261, Cl
pattern.
[0876] C. 5-Pyridin-4-yl-thiophene-2-sulfonic
acid-[1-(1-chloro-isoquinoli-
n-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0877] 5-Pyridin-4-yl-thiophene-2-sulfonyl chloride is added to a
solution of
3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride (0.12 g, 0.38 mmol) in pyridine (2 mL). The resulting
mixture is stirred overnight then concentrated to dryness. The
residue is diluted with methylene chloride and washed with
saturated NaHCO.sub.3 solution and brine. The organic layer is
dried over MgSO.sub.4, filtered and concentrated to give 105 mg of
a crude solid. The crude product is purified by column
chromatography eluting with 5% MeOH/CH.sub.2Cl.sub.2 to afford the
title product (0.026 g, 0.052 mmol) as a white solid.
[0878] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.67 (d, 2H), 8.30
(d, 1H), 8.14 (s, 1H), 7.83 (d, 1H), 7.70 (d, 1H), 7.57-7.61 (m,
2H), 7.48-7.46 (m, 3H), 5.60 (bs, 1H), 4.67 (AB, 2H), 3.98 (m, 1H),
3.29 (m, 2H), 2.68 (m, 1H), 2.15 (m, 1H). APCI MS, [M+H].sup.+=499,
501, Cl pattern.
[0879] D. 5-Pyridin-4-yl-thiophene-2-sulfonic
acid-[1-(1-aminoisoquinolin--
7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0880] Ammonium acetate (0.12 g, 1.56 mmol), phenol (0.049 g, 0.52
mmol), and 5-pyridin-4-yl-thiophene-2-sulfonic
acid-[1-(1-chloro-isoquinolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (0.026 g, 0.052 mmol) is
heated to 90.degree. C. for 6 hours then cooled to room
temperature. The product is purified by RP-HPLC eluting with a
gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 80%
CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate product
fractions are lyophilized to give the title compound (0.005 g,
0.007 mmol) as a white solid.
[0881] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.13.0 (bs, 1H),
9.0 (bs, 1H), 8.60-8.70 (m, 3H), 8.29 (s, 1H), 7.91 (d, 1H), 7.89
(d, 1H), 7.71-7.80 (m, 4H), 7.66 (d, 1H), 7.23 (d, 1H). FAB MS,
[M+H].sup.+=480.
EXAMPLE 37
[0882] 5-Pyridin-3-yl-thiophene-2-sulfonic
acid-[1-(1-aminoisoquinolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0883] A. 3-Thiophen-2-yl-pyridine
[0884] The title compound is prepared as described in EXAMPLE 36,
Part A using 3-bromopyridine in place of 4-bromopyridine
hydrochloride.
[0885] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.89 (dd, 1H), 8.52
(dd, 1H), 7.87 (ddd, 1H), 7.38 (s, 1H), 7.36 (d, 1H), 7.31 ((m,
1H), 7.12 (dd, 1H). EI, [M].sup.+=161.
[0886] B. 5-Pyridin-3-yl-thiophene-2-sulfonyl chloride
[0887] The title compound is prepared as described in EXAMPLE 36,
Part B using 3-thiophen-2-yl-pyridine in place of
4-thiophen-2-yl-pyridine.
[0888] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.95 (bs, 1H), 8.70
(bs, 1H), 7.95 (d, 1H), 7.90 (d, 1H), 7.45 (bs, 1H), 7.44 (d, 1H).
EI, [M].sup.+=259, 261, Cl pattern.
[0889] C. 5-Pyridin-3-yl-thiophene-2-sulfonic
acid-[1-(1-chloro-isoquinoli-
n-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0890] Triethylamine (0.35 mL, 2.5 mmol) is added dropwise to a
solution of 5-pyridin-3-yl-thiophene-2-sulfonyl chloride (0.22 g,
0.85 mmol) and
3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride (0.22 g, 0.71 mmol) in CH.sub.3CN (5 mL). The
suspension is stirred at room temperature overnight then
concentrated to dryness. The residue is diluted with methylene
chloride and washed with saturated NaHCO.sub.3 solution and brine.
The organic layer is dried over MgSO.sub.4, filtered, concentrated,
and then purified by column chromatography eluting with a gradient
of 1% MeOH/CH.sub.2Cl.sub.2 to 5% MeOH/CH.sub.2Cl.sub.2 to give the
product (0.23 g, 0.45 mmol) as a white solid.
[0891] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.89 (d, 1H), 8.63
(dd, 1H), 8.30 (d, 1H), 8.13 (d, 1H), 7.82-7.89 (m, 2H), 7.70 (d,
1H), 7.57-7.68 (m, 2H), 7.33-7.40 (m, 2H), 5.45 (d, 1H), 4.67 (AB,
2H), 3.95 (m 1H), 3.28 (m, 2H), 2.75 (m, 1H), 2.10 (m, 1H). Ion
spray MS, [M+H].sup.+=499, 501, Cl pattern.
[0892] D. 5-Pyridin-3-yl-thiophene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-
-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0893] The title compound is prepared as described in EXAMPLE 36,
Part D using 5-pyridin-3-yl-thiophene-2-sulfonic
acid-[1-(1-chloro-isoquinolin-7-
-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide in place of
5-pyridin-4-yl-thiophene-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-ylmeth-
yl)-2-oxopyrrolidin-3-(S)-yl]-amide and heating at 100.degree. C.
overnight. The crude product is purified by RP-HPLC eluting with a
gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 100% CH.sub.3CN.
The appropriate product fractions are lyophilized to give the title
compound as a white solid.
[0894] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.12.95 (bs, 1H),
8.90-9.05 (m, 2H), 8.55-8.65 (m, 2H), 8.31 (s, 1H), 8.17 (m, 1H),
8.96 (d, 1H), 8.82 (d, 1H), 7.70-7.72 (m, 2H), 7.65 (d, 1H), 7.53
(dd, 1H), 7.21 (d, 1H), 4.60 (AB, 2H), 4.30 (m, 1H), 3.25 (m, 2H),
2.29 (m, 1H), 1.78 (m, 1H). FAB MS, [M+H].sup.+=480.
EXAMPLE 38
[0895] Benzothiophene-2-sulfonic
acid[1-(4-aminoquinolin-6-ylmethyl)2-oxop-
yrrolidin-3-(S)-yl]-amide trifluoroacetate
[0896] A. 4-Chloro-6-methylquinoline
[0897] 6-Methyl-(1H)-quinolin-4-one (1.57 g, 9.7 mmol) in 20 mL
phosphorus oxychloride is heated to 110.degree. C. for 4 hours. The
mixture is cooled to room temperature then diluted with ice water
(.about.200 mL) and the pH is adjusted to ca. 10 by the slow
addition of 10 N NaOH. The aqueous solution is extracted with
methylene chloride (4.times.250 mL) and the combined organic layers
washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The crude residue is filtered through silica gel with
33% EtOAc/hexanes to give the product (1.05 g, 5.9 mmol) as a
yellow solid.
[0898] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.69 (d, 1H), 8.0
(m, 2H), 7.58 (dd, 1H), 7.44 (d, 1H), 2.58 (s, 3H1). EI MS,
[M.].sup.+=177, 179, Cl pattern.
[0899] B. 6Bromomethyl-4-chloro-quinoline
[0900] N-Bromosuccinimide (1.1 g, 6.19 mmol) and 70% benzoyl
peroxide (0.215 g, 0.62 mmol) are added to a solution of
4-chloro-6-methylquinolin- e (1.05 g, 5.93 mmol) in 35 mL carbon
tetrachloride. The resulting mixture is heated to reflux overnight
then cooled to room temperature and diluted with methylene
chloride. The organic layer is washed with 1 N NaOH, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue is
purified by column chromatography eluting with 33% EtOAc/hexanes to
give the product (0.915 g, 3.57 mmol) as a white solid.
[0901] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.73 (d, 1H), 8.13
(d, 1H), 8.07 (d, 1H), 7.74 (dd, 1H), 7.42 (d, 1H), 4.67 (s, 2H).
Ion Spray, [M+H].sup.+=256, 258, 260 Cl, Br pattern.
[0902] C.
3-(S)-Amino-1-(4-Chloroquinolin-6-ylmethyl)-pyrrolidin-2-one
hydrochloride
[0903] Sodium hydride (0.096 g, 2.4 mmol, 60% by weight) is added
to a solution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid
tert-butyl ester (0.4 g, 2 mmol) in 15 mL of THF at 0.degree. C.
The mixture is stirred for 30 minutes then a solution of
6-bromomethyl-4chloroquinoline (0.513 g, 2 mmol) in 15 mL THF is
added slowly. The resulting solution is warmed to room temperature
over 4 hours. The reaction mixture is quenched with saturated
ammonium chloride solution then diluted with EtOAc. The organic
layer is separated, washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated. The residue is dissolved in ethyl
acetate (50 mL), and saturated with HCl gas at 0.degree. C. The
solution is stirred at 0.degree. C. for 15 minutes, then the
solution is warmed to room temperature. After four hours at room
temperature, the solid that precipitates is collected, and washed
with ether to give the title compound (0.445 g, 1.43 mmol) as a
pale yellow solid.
[0904] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.05 (d, 1H),
8.78 (bs, 3H), 8.27 (d, 1H), 8.23 (s, 1H), 8.02 (d, 1H), 7.96 (d,
1H), 4.67 (AB, 2H), 4.12 (m, 1H), 3.35 (m, 2H), 2.43 (m, 1H), 2.09
(m, 1H). Ion Spray MS, [M+H].sup.+=276, 278.
[0905] D. Benzothiophene-2-sulfonic
acid[1-(4-chloroquinolin-6-ylmethyl)-2-
-oxopyrrolidin-3-(S)-yl]-amide
[0906] 3-(S)-Amino-1-(4-chloroquinolin-6-ylmethyl)-pyrrolidin-2-one
hydrochloride (0.12 g, 0.38 mmol) is suspended in 15 mL CH.sub.3CN.
To this solution is added triethylarpine (110 mL, 0.79 mmol)
followed by benzothiophene-2-sulfonyl chloride (0.094 g, 0.40
mmol). The mixture is stirred overnight at room temperature,
subjected to aqueous work up then concentrated to dryness. The
crude product is purified by column chromatography eluting with
2-10% MeOH/CH.sub.2Cl.sub.2 to give the title compound (0.11 g,
0.23 mmol) as an off-white solid.
[0907] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.77 (d, 1H), 8.08
(d, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.88 (m, 2H), 7.58 (dd, 1H),
7.49 (m, 3H), 6.01 (bs, 1H), 4.67 (AB, 2H), 4.03 (t, 11H), 3.27 (m,
2H), 2.65 (m, 1H), 2.16 (m, 1H). FAB MS, [M+H].sup.+=472, 474, Cl
pattern.
[0908] E. Benzothiophene-2-sulfonic acid
1-(4-aminoquinolin-6-ylmethyl)-2-- oxopyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[0909] Benzothiophene-2-sulfonic
acid[1-(4-chloroquinolin-6ylmethyl)-2-oxo- pyrrolidin-3-(Syl]-amide
(0.11 g, 0.23 mmol) is treated with phenol (1 g) and ammonium
acetate (0.22 g, 2.8 mmol) at 110.degree. C. as previously
described. After five hours the mixture is cooled to room
temperature and diluted with 100 mL methylene chloride. The organic
solution is washed with 1 N NaOH (2.times.) and saline, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The residue is
purified by HPLC eluting with a gradient of 10 to 100%
CH.sub.3CN/0.1% TFA in water over 30 minutes. Fractions containing
pure product are lyophilized to give the title compound as a white
solid (0.02 g, 0.044 mmol).
[0910] .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta.8.25 (d, 1H), 8.13
(s, 1H), 7.97 (s, 1H), 7.85 (m, 2H), 7.80 (AB, 2H), 7.48 (m, 2H),
6.80 (d, 1H), 4.64 (s, 2H), 4.35 (t, 1H), 3.31 (m, 2H), 2.48 (m,
1H), 1.89 (m, 1H). Ion Spray MS, [M+H].sup.+=453.
EXAMPLE 39
[0911] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1-amino-isoquinolin-6-
-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0912] A. 1-Phenoxy-6-bromomethyl-isoquinoline
[0913] To 1-chloro-6-methyl-isoquinoline (2.28 g, 13.3 mmol), which
is prepared as described in EXAMPLE 1, Part E, substituting
6-methyl-2H-isoquinolin-1-one for 7-methyl-2H-isoquinolin-1-one, is
added 20 g of phenol. The solution is heated to 80.degree. C. and
KOH (3.73 g, 66.4 mmol) is added. After the addition, the solution
is stirred and heated to 140.degree. C. After 24 hours, the
solution is cooled to ambient temperatures, and dissolved in
CH.sub.2Cl.sub.2. The organic solution is washed with H.sub.2O. The
organic layer is washed with 1 N NaOH and saturated NaCl. the
organic layer is dried over MgSO.sub.4, filtered and concentrated.
The resulting residue is dissolved in 50 mL of CCL.sub.4. to the
resulting solution is added NBS (2.01 g, 11.27 mmol) and benzoyl
peroxide (0.6 g, 1.73 mmol). The solution is heated to reflux.
After 16 hours, the solution is diluted with CH.sub.2Cl.sub.2. The
organic layer is washed with 10% Na.sub.2CO.sub.3 and saturated
NaCl. The organic layer is dried over MgSO.sub.4, filtered and
concentrated. The residue is purified by column chromatography
eluting with 5% EtOAc/hexanes and 10% EtOAc/hexanes. MS,
[M].sup.+=313, 315, Br pattern.
[0914] B.
[1-(1-Chloro-isoquinolin-6-ylmethyl)-2-oxopyrrolidin-3(S)-yl]-ca-
rbamic acid benzyl ester
[0915] To a solution of (2-oxopyrrolidin-3-(S)-yl) -carbamic acid
benzyl ester (0.15 g, 0.64 mmol) in 6 mL of 10:1 THF:DMF at
0.degree. C. is added a 60% NaH dispersion (0.03 g, 0.71 mmol)
followed by 1-phenoxy-6-bromomethyl-isoquinoline (0.2 g, 0.64
mmol). After 16 hours, the solution is treated with 10 mL of
saturated NH.sub.4Cl. The solution is diluted with
CH.sub.2Cl.sub.2. The organic layer is washed with H.sub.2O and
saturated NaCl. The resulting product is suspended in 5 g of
NH.sub.4OAc and heated to 120.degree. C. After 36 hours, the
solution is cooled to ambient temperatures. The solution is diluted
with H.sub.2O and CH.sub.2Cl.sub.2. The organic layer is washed
with H.sub.2O and saturated NaCl. The organic layer is dried over
MgSO.sub.4, filtered and concentrated. The residue is purified by
column chromatography eluting with 5% MeOH/CH.sub.2Cl.sub.2 to 10%
MeOH/CH.sub.2Cl.sub.2 to give the product as a white solid (0.043
g, 0.11 mmol).
[0916] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.41 (d, 1H), 7.98
(d, 1H), 7.63 (s, 1H), 7.42 (m, 3H), 7.32 (m, 4H), 7.22 (m, 5H),
5.40 (bs, 1H), 5.14 (s, 2H), 4.64 (AB, 2H), 4.30 (m, 1H), 3.24 (m,
2H), 2.66 (m, 1H), 1.92 (m, 1H). FAB MS, [M+H].sup.+=391.
[0917] C. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[-1-(1-amino-isoquinol-
in-6-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0918] To a solution of
[1-(1-chloro-isoquinolin-6-ylmethyl)-2-oxopyrrolid-
in-3(S)-yl]-carbamic acid benzyl ester (0.043 g, 0.11 mmol) in 4 mL
of MeOH, is added 10% by weight Pd/C (0.02 g). The atmosphere above
the reaction is replaced by hydrogen. After 16 hours, the solution
is filtered through Celite and the Celite is washed with MeOH. The
collected solution is concentrated. The resulting residue is
dissolved in 3 mL of CH.sub.2Cl.sub.2:EtOH (2:1). To the solution
is added Et.sub.3N (0.01 g, 0.11 mmol) and
6-Chloro-benzo[b]thiophene sulfonyl chloride (0.03 g, 0.11 mmol).
After 4 hours, the solution is concentrated. The residue is
purified by RP-HPLC eluting with a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 80% CH.sub.3CN/H.sub.2O (0.1%
TFA). The appropriate fractions are lyophilized to provide the
title compound as a white solid.
[0919] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.95 (bs, 3H),
8.71 (d, 1H), 8.46 (d, 1H), 8.24 (s, 1H), 8.04 (m, 2H), 7.71 (s,
1H), 7.63 (d, 1H), 7.52 (m, 2H), 7.12 (d, 1H), 4.52 (AB, 2H), 4.28
(m, 1H), 3.17 (m, 2H), 2.12 (m, 1H), 1.67(m, 1H). FAB MS,
[M+H].sup.+=487, 489, Cl pattern.
EXAMPLE 40
[0920] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[2-oxo-1-(1,2,3,4-tetrahy-
dro-isoquinolin-7-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[0921] A.
[1-(1-(1,2,3,4-Tetrahydro-isoquinolin-7-ylmethyl)-2-oxopyrrolidi-
n-3(S)-yl]carbamic acid tert-butyl ester
[0922] To a solution of
[1-(1-chloro-isoquinoline-7-ylmethyl)-2-oxopyrroli-
din-3(S)-yl]carbamic acid tert-butyl ester (0.48 g, 1.28 mmol) in
50 mL of AcOH:MeOH (1:1) is added 5% by weight PtO.sub.2/C (0.1 g).
The atmosphere over the reaction is replaced by hydrogen. After 16
hours, the solution is filtered through Celite and the Celite is
washed with MeOH. The organic solution is concentrated to give the
product as a white foam.
[0923] MS, [M+H].sup.+=346.
[0924] B.
7-(3-tert-Butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl)-3,4-di-
hydro-1H-isoquinoline-2-carboxylic acid benzyl ester
[0925] To a solution of
[1-(1-(1,2,3,4-tetrahydro-isoquinolin-7-ylmethyl)--
2-oxopyrrolidin-3(S)-yl]carbamic acid tert-butyl ester (0.54g, 1.58
mmol) in 50 mL of CH.sub.2Cl.sub.2 is added triethyl amine (0.66
mL, 4.73 mmol) and benzyl chloroformate (0.39 mL, 1.89 mmol). The
solution is stirred for 16 hours. After this time, the solution is
diluted with CH.sub.2Cl.sub.2. The organic solution is washed with
H.sub.2O and saturated NaCl. The residue is purified by column
chromatography eluting with 20% EtOAc/CH.sub.2Cl.sub.2.
[0926] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.35 (m, 5H), 7.08
(d, 1H), 7.02 (d, 1H), 6.95 (s, 1H), 5.14 (s, 2H), 5.10 (m, 1H),
4.58 (s, 2H), 4.38 (m, 2H), 4.16 (m, 1H), 3.68 (m, 2H), 3.18 (dd,
2H), 2.78 (m, 2H), 2.59 (m, 1H), 1.81 (m, 1H), 1.42 (s, 9H).
[0927] FAB MS, [M+H].sup.+=480.
[0928] C.
7-[3-(6-Chloro-benzo[b]thiophene-2-sulfonylamino)2-oxopyrrolidin-
-1-ylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl
ester
[0929] To a solution of
7-(3-tert-butoxycarbonylamino-2-oxopyrrolidin-1-yl-
methyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester
(0.347 g, 0.72 mmol) in 8 mL of CH.sub.2Cl.sub.2 is added 2 mL of
TFA. After 4 hours, the solution is concentrated. The residue is
dissolve in CH.sub.2Cl.sub.2 and Et.sub.3N (0.30 mL, 2.17 mmol) and
6-chloro benzo[b]thiophene sulfonyl chloride (0.23 g, 0.87 mmol)
are added. After 16 hours, the solution is concentrated. The
residue is purified by column chromatography eluting with 10%
EtOAc/CH.sub.2Cl.sub.2. The product (0.25 g, 0.51 mmol) was
obtained as a white solid.
[0930] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.91 (s, 1H), 7.80
(m, 2H), 7.42 (d, 1H), 7.34 (m, 5H), 7.08 (d, 1H), 6.96 (d, 1H),
6.88 (s, 1H), 5.10 (s, 2H), 4.58 (s, 2H), 4.34 (s, 2H), 3.88 (m,
1H), 3.68 (m, 2H), 3.18 (m, 2H), 2.77 (m, 2H), 2.59 (m, 1H), 2.08
(m, 1H).
[0931] D. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[2-oxo-1(1,2,3,4-tetra-
hydro-isoquinolin-7-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[0932]
7-[3-(6-Chloro-benzo[b]thiophene-2-sulfonylamino)-2-oxopyrrolidin-1-
-ylmethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl
ester (0.25 g, 0.51 mmol) is added to 5 mL of 30% HBr/AcOH at
0.degree. C. The solution is stirred for 30 minutes. After this
time, 30 mL of Et.sub.2O is added. The resulting solid is collected
by filtration. The crude solid is purified by RP-HPLC eluting with
a gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 80%
CH.sub.3CN/H.sub.2O (0.1% TFA). The appropriate fractions are
lyophilized to provide the title compound as a white solid.
[0933] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.95 (bs, 2H),
868 (d, 1H), 8.24 (s, 1H), 8.00 (m, 2H), 7.51 (dd, 1H), 7.16 (d,
1H), 7.06 (m, 1H), 6.96 (s, 1H) 4.27 (s, 2H), 4.16 (m, 3H), 3.30
(m, 2H), 3.05 (m, 2H), 2.92 (m, 2H), 2.08 (m, 1H), 1.60 (m, 1H).
FAB MS, [M+H].sup.+=476, 478, chlorine pattern.
EXAMPLE 41
[0934] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-chloro-1H-pyrrolo[3-
,2-c]pyridin-2-ylmethyl)2-oxopyrrolidin-3-(S)-yl]-amide
[0935] A. 1-Benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridine
[0936] Benzenesulfonyl chloride (3 mL, 23.5 mmol) is added dropwise
to a solution of tetrabutylammonium hydrogen sulfate (.0.53 g, 1.56
mmol), sodium hydroxide (1.56 g, 38.9 mmol) and
4-chloro-1H-pyrrolo[3,2-c]pyridi- ne (2.38 g, 15.6 mmol) (prepared
according to Rasmussen, M. J. Het. Chem, 1992, 29, 359) in
CH.sub.2Cl.sub.2. The mixture is stirred at room temperature for 4
hours the diluted with CH.sub.2Cl.sub.2 and washed with saturated
NH.sub.4Cl solution and brine. The organic layer is dried over
MgSO.sub.4, filtered and concentrated. The crude product is
purified by column chromatography eluting with 1%
MeOH/CH.sub.2Cl.sub.2 to 2% MeOH/CH.sub.2Cl.sub.2 to afford the
title product (3.21 g, 11 mmol) as a white solid.
[0937] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.25 (d, 1H),
7.92(m, 1H), 7.90 (d, 1H), 7.83 (dd, 1H), 7.60-7.66 (m, 2H), 7.51
(m, 2H), 6.80 (dd, 1H). EI MS, [M].sup.+=292, 294, Cl pattern.
[0938] B.
1-Benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxyli- c
acid ethyl ester
[0939] Lithium diisopropylamide (3.2 mL of a 1.5 M solution in THF,
4.80 mmol) is added to a solution of tetramethylethylenediamine
(0.71 mL, 4.75 mmol) and
1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridine (1 g, 3.42
mmol) in THF (13 mL). The resulting yellow solution is stirred at
-78.degree. C. for 1 hour, and then ethyl chloroformate (0.78 mL,
8.16 mmol) is added dropwise. The mixture is slowly brought to room
temperature over a 3.5 hour period. The reaction is quenched with
saturated NH.sub.4Cl solution and then diluted with ethyl acetate.
The organic layer is washed with brine, dried over MgSO.sub.4,
filtered and concentrated to give a light brown solid (1.46 g) as
the product which is used in the subsequent step without further
purification.
[0940] .sup.1H NMR(CDCl.sub.3, 300 MHz) .delta.8.30 (d, 1H), 8.12
(d,2H), 8.03 (d, 1H), 7.70(m, 1H), 7.55 (m,22H), 7.30(s, 1H). 4.45
(q, 2H), 1.46 (t, 3H). FAB MS, [M+H].sup.+=365, 367, Cl
pattern.
[0941] C.
1-Benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-yl)-methan-
ol
[0942] Lithium aluminum hydride (3.4 mL of a 1 M solution in THF)
is added dropwise to a solution of the
1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c- ]pyridine-2-carboxylic
acid ethyl ester (1.46 g, 3.42 mmol) in THF (27 mL) at 0.degree. C.
After stirring for 1.5 hours at 0.degree. C., the reaction is
quenched with H.sub.2O then diluted with ethyl acetate. The organic
layer is washed with saturated NH.sub.4Cl solution and brine then
dried over MgSO.sub.4, filtered and concentrated. The crude product
is purified by column chromatography eluting with a gradient of 1%
MeOH/CH.sub.2Cl.sub.2 to 3% MeOH/CH.sub.2Cl.sub.2 to afford the
title product ( 0.78 g, 2.42 mmol) as a white solid.
[0943] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.25 (d, 1H),
8.85-8.95 (m, 3H), 7.64 (m, 1H), 7.51 (m, 2H), 6.80 (s, 1H), 4.97
(d, 2H), 2.85 (t, 1H). EI MS, [M].sup.+=322, 324, Cl pattern.
[0944] D.
1-Benzenesulfonyl-2-bromomethyl-4-chloro-1H-pyrrolo[3,2-c]pyridi-
ne
[0945] Carbon tetrabromide (0.939 g, 2.83 mmol) is added to a
solution of triphenylphosphine (1.485 g, 5.66 mmol) and
1-benzenesulfonyl-4-chloro-1H-
-pyrrolo[3,2-c]pyridin-2-yl)-methanol (0.914 g, 2.83 mmol) in
CH.sub.2Cl.sub.2 (12 mL) at 0.degree. C. The resulting yellow
solution is stirred for 1 hour at 0.degree. C. then warmed to room
temperature over a 1 hour period. The reaction mixture is
concentrated then purified by column chromatography eluting with 1%
MeOH/CH.sub.2Cl.sub.2 to afford the title product (0.760 g, 1.97
mmol) as a white solid.
[0946] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.27 (d, 1H),
7.91-8.00 (m, 3H), 7.67 (m, 1H), 7.51 (m, 2H), 6.95 (s, 1H), 4.94
(s, 2H). FAB MS, [M+H].sup.+=385, 387, 389, Br, Cl pattern.
[0947] E.
[1-(1-Benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmeth-
yl)-2-oxopyrrolid-3-(S)-yl]-carbamic acid tert-butyl ester
[0948] Sodium hydride (0.081 g, 2.02 mmol, 60% mineral oil
dispersion) is added to a solution of
[2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester (0.404 g,
2.02 mmol) in DMF (5 mL) at 0.degree. C. The mixture is stirred for
10 minutes, then cannulated dropwise to a solution of
1-benzenesulfonyl-2-bromomethyl-4-chloro-1H-pyrrolo[3,2-c]pyridine
(0.74 g, 1.92 mmol) in DMF (10 mL) at 0.degree. C. The resulting
yellow solution is stirred for 1 hour at 0.degree. C. then quenched
with saturated ammonium chloride solution and diluted with EtOAc.
The organic layer is washed with water and brine, then dried over
MgSO.sub.4, filtered and concentrated. The solid product (0.94 g,
1.86 mmol) is used in the subsequent step without further
purification.
[0949] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.25 (d, 1H), 7.98
(m, 2H), 7.83 (d, 1H), 7.68 (m, 1H), 7.50 (m, 2H), 6.70 (s, 1H),
4.95 (AB, 2H), 4.20 (m, 1H), 3.55 (m, 2H), 2.65 (m, 1H), 2.03 (m,
1H), 1.45 (s, 9H). FAB MS, [M+H].sup.+=505, 507, Cl pattern.
[0950] F.
3-(S)-Amino-1-(1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyrid-
in-2-ylmethyl)-pyrrolidin-2-one hydrochloride
[0951] The title compound is prepared as described in EXAMPLE 1,
Part I using
[1-(1-benzenesulfonyl-4chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)--
2-oxopyrrolid-3-(S)-yl]-carbamic acid tert-butyl ester in place of
[1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3(S)yl]-carbamic
acid tert-butyl ester and stirring for 2 hours at 0.degree. C.
without warming to room temperature.
[0952] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.50 (d, 1H), 8.28
(d, 1H), 8.04 (m, 2H), 7.82 (m, 1H), 7.65 (m, 2H), 6.83 (s, 1H),
4.93 (s, 2H), 4.20 (m, 1H), 3.51 (m, 2H), 2.41 (m, 1H), 2.01 (m,
1H). FAB MS, [M+H].sup.+=405, 407, Cl pattern.
[0953] G. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(1-benzenesulfonyl4-
-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-ami-
de
[0954] The title compound is prepared as described in EXAMPLE 1,
Part K using 6-chlorobenzo[b]thiophene-2-sulfonyl chloride and
3-amino-1-(1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl-
)-pyrrolidin-2-one hydrochloride as the starting material. The
crude product is purified by column chromatography eluting with a
gradient of 1% MeOH/CH.sub.2Cl.sub.2 to 3% MeOH/CH.sub.2Cl.sub.2 to
give the product as a while solid.
[0955] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.23 (d, 1H), 7.96
(d, 1H), 7.90 (s, 1H), 7.70-7.7.88 (m, 3 H), 7.55-7.61 (m, 2H),
7.40-7.50 (m, 3H), 6.51 (s, 1H), 5.45 (bs, 1H), 4.86 (s, 2H), 3.98
(m, 1H), 3.41 (m, 2H), 2.70 (m, 1H), 2.18 (m, 1H).
[0956] FAB MS, [M+H].sup.+=635, 637, Cl pattern.
[0957] H. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-chloro-1H-pyrrol-
o[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0958] Ammonia gas is bubbled for 5 minutes into a solution of
6-chlorobenzo[b]thiophene-2-sulfonic
acid[1-(1-benzenesulfonyl-4-chloro-1-
H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
(0.14 g, 0.22 mmol) in MeOH (10 mL). The solution is refluxed
overnight then concentrated to dryness. The crude product is
purified by column chromatography eluting with 5%
MeOH/CH.sub.2Cl.sub.2 to give the product (0.065 g, 0.13 mmol) as a
white solid.
[0959] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.11.95 (bs, 1H),
8.71 (d, 1H), 8.30 (s, 1H), 8.05 (m, 1H), 7.91 (d, 1H), 7.50 (d,
1H), 7.35 (d, 1H), 6.40 (s, 1H), 4.50 (AB, 2H), 4.23 (m, 1H),
3.23m, 2H), 2.41 (M, 11H), 1.78 (m, 1H). Ion spray MS,
[M+H].sup.+=495, 497, Cl pattern.
EXAMPLE 42
[0960] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2--
c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
[0961] Palladium on carbon (0.01 g) is added to a solution of
6-chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-chloro-1H-pyrrolo[3,2-c]p-
yridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide in 95% ethanol
(5 mL) and charged with H.sub.2 gas. The mixture is heated at
65.degree. C. overnight then cooled to room temperature and
filtered through Celite. The solvent is removed and the crude
product is purified by RP-HPLC eluting with a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 100% CH.sub.3CN. The appropriate
product fractions are lyophilized to give the title compound as a
white solid.
[0962] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.14.60 (bs, 1H),
12.70 (bs, 1H), 9.15 (s, 1H), 8.71 (d, 1H), 8.38 (d, 1H), 8.29 (s,
1H), 8.08 (s, 1H), 8.00 (d, 1H), 7.85 (d, 1H), 7.52 (dd, 1H), 6.88
(s, 1H), 4.63 (AB, 2H), 4.21 (m, 1H), 3.25 (m, 2H), 2.10 (m, 1H),
1.75 (m, 1H). Ion spray MS, [M+H].sup.+=461, 463, Cl pattern.
EXAMPLE 43
[0963] 7-Methoxynaphthalene-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2-b]pyri-
din-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0964] A. 5-Chloro-1H-pyrrolo[3,2-b]pyridine
[0965] A mixture of pyrrolo[3,2-b]pyrid-5-one (prepared according
to the procedure described in J. Med. Chem. 1990, 33, 2087) (1.33
g, 9.91 mmol) and 20 mL of phosphorous oxychloride is heated in a
sealed Parr high pressure stainless steel vessel at 180.degree. C.
for 2.5 hours. After cooling, excess phosphorous oxychloride is
removed in vacuo. The residue is cooled in an ice bath and quenched
with ice water. The resulting mixture is neutralized by addition of
saturated NaHCO.sub.3 solution and extracted with EtOAc (3.times.).
The combined organic layers are dried over MgSO.sub.4, filtered and
concentrated in vacuo. The crude product (1.07 g, 7.01 mmol) is
used in the subsequent step without further purification.
[0966] .sup.1H NMR (CDCl.sub.3+CD.sub.3OD, 300 MHz) .delta.7.71 (d,
1H), 7.49 (d, 1H), 7.10 (d, 1H), 6.59 (d, 1H). EI MS,
[M].sup.+=152, 154, Cl pattern.
[0967] B. 1-Benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridine
[0968] The title compound is prepared from
5-chloro-1H-pyrrolo[3,2-b]pyrid- ine as described in EXAMPLE 41,
Part A. The crude product is purified by column chromatography
eluting with a gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes
to give the title compound as a solid.
[0969] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.23 (d, 1H), 7.87
(d, 2H), 7.81 (d, 1H), 7.62 (m, 1H), 7.49 (m, 2H), 7.26 (d, 1H),
6.81 (d, 1H).
[0970] C.
1-Benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxyli- c
acid ethyl ester
[0971] The title compound is prepared from
1-benzenesulfonyl-5-chloro-1H-p- yrrolo[3,2-b]pyridine as described
in EXAMPLE 41, Part B. The crude product is purified by column
chromatography eluting with a gradient of 10% EtOAc/hexanes to 33%
EtOAc/hexanes to yield the title compound as a solid.
[0972] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.41 (d, 1H), 8.04
(d, 2H), 7.66 (m, 1H), 7.55 (m, 2H), 7.37 (d, 1H), 7.21 (s, 1H),
4.41 (q, 2H), 1.40 (t, 3H). EI MS, [M].sup.+=364, 366, Cl
pattern.
[0973] D.
(1-Benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-yl)-metha-
nol
[0974] The title compound is prepared from
1-benzenesulfonyl-5-chloro-1H-p- yrrolo[3,2-b]pyridine-2-carboxylic
acid ethyl ester as described in EXAMPLE 41, Part C. The crude
product is purified by column chromatography eluting with a
gradient of 20% EtOAc/hexanes to 50% EtOAc/hexanes to afford the
title compound as a solid.
[0975] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.30 (d, 1H), 7.81
(d, 2H), 7.63 (m, 1H), 7.50 (m, 2H), 7.25 (d, 1H), 6.80 (s, 1H),
4.97 (s, 2H), 2.99 (bs, 1H). EI MS, [M].sup.+=322, 324, Cl
pattern.
[0976] E.
1-Benzenesulfonyl-2-bromomethyl-5-chloro-1H-pyrrolo[3,2-b]pyridi-
ne
[0977] To a solution of
(1-benzenesulfonyl-5-chloro-1H-pyrrolop[3,2-b]pyri-
din-2-yl)-methanol (0.16 g, 0.50 mmol) in 4 mL
Et.sub.2O/CH.sub.2Cl.sub.2 (1:1) at 0.degree. C. is added
phosphorous tribromide (0.023 mL, 0.25 mmol) dropwise. The reaction
vessel is kept in the dark and stirred at 0.degree. C. for 1 hour,
then at room temperature for 2 hours. The mixture is diluted with
water and EtOAc and the layers are separated. The aqueous layer is
extracted with EtOAc. The combined organic layers are washed with
water, saturated NaHCO.sub.3 solution and saturated NaCl solution,
then dried over MgSO.sub.4, filtered and concentrated. The crude
product (0.16 g, 0.41 mmol) is used in the subsequent step without
further purification.
[0978] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.33 (d, 1H), 7.87
(d, 2H), 7.64 (m, 1H), 7.50 (m, 2H), 7.28 (d, 1H), 6.93 (s, 1H),
4.96 (s, 2H).
[0979] F. [1-(
1-Benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmet-
hyl)-2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester
[0980] The title compound is prepared from
(2-oxopyrrolidin-3-(S)-yl)-carb- amic acid tert-butyl ester as
described in EXAMPLE 1, Part H using
1-benzenesulfonyl-2-bromomethyl-5-chloro-1H-pyrrolo[3,2-b]pyridine
in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product
is purified by column chromatography eluting with a gradient of 15%
EtOAc/hexanes to 50% EtOAc/hexanes to give the title compound as a
beige solid.
[0981] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.36 (d, 1H), 7.80
(d, 2H), 7.64 (m, 1H), 7.50 (m, 2H), 7.25 (s, 1H), 6.58 (s, 1H),
5.13 (bs, 1H), 4.93 (AB, 2H), 4.22 (m, 1H), 3.39 (m, 2H), 2.66 (m,
1H), 1.95 (m, 1H), 1.46 (s, 9H).
[0982] G.
3-(S)-Amino-1-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyrid-
in-2-ylmethyl)-pyrrolidin-2-one hydrochloride
[0983] The title compound is prepared as described in EXAMPLE 1,
Part I using
[1-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-
-2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester as the
starting material. The title compound is obtained as a white
solid.
[0984] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.51 (bs, 2H),
8.42 (d, 1H), 8.00 (d, 2H), 7.78 (m, 1H), 7.64 (m, 2H), 7.41 (d,
1H), 6.96 (s, 1H), 4.90 (AB, 2H), 4.16 (m, 1H), 3.49 (m, 2H), 2.47
(m, 1H), 2.10 (m, 1H).
[0985] H. 7-Methoxynaphthalene-2-sulfonic
acid[1-(1-benzenesulfonyl-5-chlo-
ro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0986] The title compound is prepared as described in EXAMPLE 1,
Part K using 7-methoxynaphthalene-2-sulfonyl chloride and
3-(S)-amino-1-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylme-
thyl)-pyrrolidin-2one hydrochloride as starting material. The crude
product is used in the subsequent step without further
purification.
[0987] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.37 (s, 1H), 8.34
(d, 1H), 7.92 (d, 1H), 7.79 (m, 2H), 7.72 (m, 2H), 7.58 (m, 1H),
7.45 (m, 2H), 7.31 (dd, 1H), 7.24 (m, 2H), 6.48 (s, 1H), 5.42 (s,
1H), 4.85 (s, 2H), 3.96 (s, 3H), 3.76 (m, 1H), 3.34 (m, 2H), 2.63
(m, 1H), 2.10 (m, 1H).
[0988] I. 7-Methoxynaphthalene-2-sulfonic
acid[1-(5-chloro-1H-pyrrolo[3,2--
b]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[0989] The title compound is prepared from
7-methoxynaphthalene-2-sulfonic
acid[1-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-2-
-oxopyrrolidin-3-(S)-yl]-amide as described in EXAMPLE 41, Part H.
The crude product is purified by column chromatography eluting with
a gradient of 1% MeOH/CH.sub.2Cl.sub.2 to 6% MeOH/CH.sub.2Cl.sub.2
to yield the title compound as a solid.
[0990] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.9.73 (bs, 1H), 8.35
(s, 1H), 7.70 (m, 3H), 7.49 (d, 1H), 7.30 (dd, 1H), 7.20 (m, 1H),
6.99 (d, 1H), 6.75 (bs, 1H), 6.48 (s, 1H), 4.58 (m, 2H), 3.93 (m,
1H), 3.90 (s, 3H), 3.35 (m, 2H), 2.48 (m, 1H), 2.08 (m, 1H).
[0991] J. 7-Methoxynaphthalene-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2-b]p-
yridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide trifluoroacetate
[0992] The title compound is prepared from
7-methoxynaphthalene-2-sulfonic acid
[1-(5-chloro-1H-pyrrolo[3,2-b]pyridin-2-ylmethyl)-2-oxopyrrolidin-3--
(S)-yl]-amide as described in EXAMPLE 42 at room temperature using
a catalytic amount of KOH in MeOH/benzene (1:1) instead of EtOH
solvent. The crude product is purified by RP-HPLC eluting in a
gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 70%
CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate product
fractions are lyophilized to provide the title compound as a white
solid.
[0993] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.12.65 (bs, 1H),
8.60 (bs, 1H), 8.43 (d, 1H), 8.39 (s, 1H), 8.26 (d, 1H), 8.03. (d,
1H), 7.94 (d, 1H), 7.71 (dd, 1H), 7.56 (m, 2H), 7.32 (dd, 1H), 6.80
(s, 1H), 4.66 (AB, 2H), 4.17 (m, 1H), 3.88 (s, 3H), 3.20 (m, 2H),
2.00 (m, 1H), 1.60 (m, 1H). FAB MS, [M+H].sup.+=451.
EXAMPLE 44
[0994] 6-Chloro-benzo[b]thiophene-2-sulfonic acid
(1-furo[3,2-b]pyridin-2--
ylmethyl-2-oxopyrrolidin-3-(S)-yl-amide
[0995] A. (2-Oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acid
tert-butyl ester
[0996] The title compound is prepared from
(2-oxopyrrolidin-3-(S)-yl)-carb- amic acid tert-butyl ester as
described in EXAMPLE 1, Part H using propargyl bromide in place of
7-bromomethyl1-chloro-isoquinoline. The crude product is triturated
from Et.sub.2O/hexanes to give the title compound as a white
solid.
[0997] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.5.09 (bs, 1H), 4.19
(m, 1H), 4.15 (m, 2H), 3.45 (m, 2H), 2.69 (m, 1H), 2.29 (t, 1H),
1.91 (m, 1H), 1.48 (s, 9H).
[0998] B.
(1-Furo[3,2-b]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl)-carba-
mic acid tert-butyl ester
[0999] A mixture of 2-iodo-3-hydroxy-pyridine (0.44 g, 2 mmol),
(2-oxo-1-prop2-ynyl-pyrrolidin-3-(S)-yl-carbamic acid tert-butyl
ester (0.6 g, 2.5 mmol), bis(triphenylphosphine)-palladium(II)
chloride (Pd(PPh.sub.3).sub.2Cl.sub.2) (50 mg), copper iodide (25
mg) and triethylamine (3 mL) in 3 mL of acetonitrile is heated in a
sealed tube at 120.degree. C. for 2 hours. After cooling, the
reaction mixture is diluted with water and EtOAc and the layers are
separated. The aqueous layer is extracted with EtOAc. The combined
organic layers are washed with water and saturated NaCl solution,
then dried over MgSO.sub.4, filtered and concentrated. The crude
product is purified by column chromatography eluting with a
gradient of 25% EtOAc/CH.sub.2Cl.sub.2 to 90%
EtOAc/CH.sub.2Cl.sub.2 to yield the title compound as a white
solid.
[1000] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.53 (d, 1H), 7.72
(dd, 1H), 7.21 (dd, 1H), 6.86 (s, 1H), 5.15 (bs, 1H), 4.69 (AB,
2H), 4.23 (m, 1H), 3.38 (m, 2H), 2.66 (m, 1H), 1.91 (m, 1H), 1.45
(s, 9H).
[1001] C.
3-(S)-Amino-1-(furo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-2-one
hydrochloride
[1002] The title compound is prepared as described in EXAMPLE 1,
Part I using
(1-furo[3,2-b]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl)-carbamic
acid tert-butyl ester as the starting material. The title compound
is obtained as a tan solid.
[1003] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.70 (bs, 2H),
8.65 (d, 1H), 8.35 (d, 1H), 7.58 (dd, 1H), 7.28 (s, 1H), 4.77 (s,
2H), 4.10 (m, 1H), 3.47 (m, 2H), 2.41 (m, 1H), 2.09 (m, 1H).
[1004] D. 6-Chloro-benzo[b]thiophene-2-sulfonic acid
(1-furo[3,2-b]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl)-amide
[1005] The title compound is prepared as described in EXAMPLE 1,
Part K using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride and
3-(S)-amino-1-(furo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-2-one
hydrochloride as starting material. The crude product is purified
by column chromatography eluting with a gradient of 25%
EtOAc/CH.sub.2Cl.sub.2 to 90% EtOAc/CH.sub.2Cl.sub.2 to provide the
title compound as a white solid.
[1006] .sup.1H NMR (CDCl.sub.3+CD.sub.3OD, 300 MHz) .delta.8.49
(bs, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.81 (d, 1H), 7.77 (d, 1H),
7.41 (dd, 1H), 7.24 (m, 1H), 6.85 (s, 1H), 4.63 (AB, 2H), 4.03 (m,
1H), 3.41 (m, 2H), 2.63 (m, 1H), 2.16 (m, 1H). FAB MS,
[M+H].sup.+=462, 464, Cl pattern.
EXAMPLE 45
[1007] 6-Chloro-benzo[b]thiophene-2-sulfonic acid
(1-furo[3,2-b]pyridin-2--
ylmethyl-2-oxopyrrolidin-3-(S)-yl)-amide
[1008] A. 1-Fluoro-3-(2,2-dimethoxy-ethyl-sulfanyl)-benzene
[1009] The title compound is prepared as described in EXAMPLE 9,
Part A substituting 3-fluorothiophenol for 3-chlorothiophenol. The
crude product is purified by column chromatography eluting with a
gradient of hexanes to 10% EtOAc/hexanes to afford the title
compound as an oil.
[1010] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.21 (m, 1H), 7.09
(m, 2H), 6.82 (m, 2H), 4.51 (m, 1H), 3.09 (s, 31H), 3.07 (s,
3H).
[1011] B. 6-Fluoro-benzo[b]thiophene
[1012] The title compound is prepared as described in EXAMPLE 9,
Part B substituting
1-fluoro-3-(2,2-dimethoxy-ethyl-sulfanyl)-benzene for
1-chloro-3-(2,2-dimethoxy-ethyl-sulfanyl)benzene. The crude product
is purified by column chromatography eluting with hexanes to afford
the title compound as a white solid. EI MS, [M].sup.+=152.
[1013] C. 6-Fluoro-benzo[b]thiophene-2-sulfonyl chloride
[1014] The title compound is prepared as described in EXAMPLE 8,
Part A substituting 6-fluoro-benzo[b]thiophene for thianaphthalene.
The crude product is purified by column chromatography eluting with
hexanes to yield the title compound as a white solid.
[1015] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.08 (s, 1H), 7.94
(dd, 1H), 7.58 (dd, 1H), 7.23 (dt, 1H).
[1016] D. 6-Fluoro-benzo[b]thiophene-2-sulfonic acid
(1-furo[3,2-b]pyridin-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl-amide
[1017] The title compound is prepared as described in EXAMPLE 1,
Part K using 6-fluoro-benzo[b]thiophene-2-sulfonyl chloride and
3-(S)-amino-1-(furo[3,2-b]pyridin-2-ylmethyl)-pyrrolidin-2-one
hydrochloride as starting material. The crude product is purified
by column chromatography eluting with 66% EtOAc/CH.sub.2Cl.sub.2 to
provide the title compound as a white solid.
[1018] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.46 (m, 1H), 7.96
(s, 1H), 7.91 (m, 1H), 7.77 (d, 1H), 7.58 (d, 1H), 7.44 (s, 1H),
7.29 (m, 2H), 6.86 (s, 1H), 4.65 (s, 2H), 4.14 (m, 1H), 3.42 (m,
2H), 2.58 (m, 1H), 2.09 (m, 1H). FAB MS, [M+H].sup.+=446.
EXAMPLE 46
[1019] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2--
b]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[1020] A. 2-Iodo-3-nitro-pyridine
[1021] To a solution of 2-amino-3-nitro-pyridine (8 g, 57.5 mmol)
in 60 mL of 6 N HCl cooled to 0.degree. C. is added dropwise a
solution of sodium nitrite (6.35 g, 92 mmol) in 40 mL of water. The
mixture is stirred at 0.degree. C. for 1.5 hours. Then a solution
of potassium iodide (22.9 g, 138 mmol) in 40 mL of water is added
dropwise to the yellow solution. The resulting red mixture is
stirred at 0.degree. C. for 30 minutes and then heated at
60.degree. C. for 45 minutes. After cooling, the mixture is made
basic by the careful addition of 3 N NaOH. The aqueous layer is
extracted with CH.sub.2Cl.sub.2 (4.times.) and the combined organic
layers are washed with 1 N HCl, dilute Na.sub.2SO.sub.3 and water.
The organic layer is dried over MgSO.sub.4, filtered and
concentrated in vacuo. The crude product (2.72 g, 10.9 mmol) is
used in the subsequent step without further purification.
[1022] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.65 (d, 1H), 8.25
(dd, 1H), 7.48 (m, 1H). IS MS, [M+H].sup.+=251.
[1023] B. 3-Amino-2-iodo-pyridine
[1024] To a solution of 2-iodo-3-nitro-pyridine (2.72 g, 10.9 mmol)
in 10 mL of concentrated HCl is added dropwise a solution of
tin(II) chloride dihydrate (10.3 g, 45.7 mmol) in 12 mL of
concentrated HCl. The mixture is heated at 90.degree. C. for 15
minutes. The resulting red mixture is cooled to 0.degree. C. and
stirred for 2 hours as a precipitate forms. The solid is filtered,
dissolved in water and made basic by addition of 1 N NaOH. The
aqueous layer is extracted with CH.sub.2Cl.sub.2 (4.times.) and the
combined organic layers are dried over MgSO.sub.4, filtered and
concentrated in vacuo. The crude product (1.5 g, 6.82 mmol) is used
in the subsequent step without further purification.
[1025] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.81 (m, 1H), 7.07
(m, 2H), 4.05 (bs, 2H). IS MS, [M+H].sup.+=221.
[1026] C. (2-Iodo-pyridin-3-yl)-carbamic acid ethyl ester
[1027] Ethyl chloroformate (0.91 mL, 9.5 mmol) is added to a
solution of 3-amino-2-iodo-pyridine (1.4 g, 6.36 mmol) in 15 mL of
pyridine cooled at 0.degree. C. The mixture is stirred at 0.degree.
C. for 2 hours and allowed to warm slowly to room temperature. At
this time, excess pyridine is removed in vacuo. The residue is
diluted with EtOAc and washed with water, 1N HCl and saturated
NaHCO.sub.3. The organic layer is dried over MgSO.sub.4, filtered
and concentrated in vacuo. The crude product is purified by column
chromatography eluting with 30% EtOAc/hexanes to give the title
compound (1.2 g, 4.11 mmol) as a beige solid.
[1028] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.51 (d, 1H), 8.07
(dd, 1H), 7.25 (dd, 1H), 7.16 (bs, 1H), 4.28 (q, 2H), 1.38 (t,
3H).
[1029] D.
2-(3-(S)-tert-Butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl)-py-
rrolo[3,2-b]pyridine-1-carboxylic acid ethyl ester
[1030] A mixture of (2-iodo-pyridin-3-yl)-carbamic acid ethyl ester
(0.6 g, 2.05 mmol),
(2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acid tert-butyl
ester (0.49 g, 2.05 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (72 mg),
copper iodide (12 mg) and triethylamine (1.1 mL) in 4 mL of
acetonitrile is heated in a sealed tube at 100.degree. C. for 18
hours. After cooling, the reaction mixture is diluted with MeOH and
filtered through a Celite pad. The filtrate is concentrated in
vacuo. The residue is diluted with EtOAc and washed with water
(4.times.). The combined aqueous layers are extracted with EtOAc
(2.times.). The combined organic layers are washed with water, then
dried over MgSO.sub.4, filtered and concentrated to yield the crude
intermediate coupled acetylene. IS MS, [M+H].sup.+=403. The crude
acetylene intermediate is dissolved in 16 mL of DMF and treated
with 1,8-diaza-bicyclo[5.4.0]undec-7ene (DBU) (0.58 mL, 4.1 mmol).
The mixture is heated at 60.degree. C. for 2 hours. After cooling,
the resulting mixture is diluted with water and EtOAc and the
layers are separated. The organic layer is washed with water and
then dried over MgSO.sub.4, filtered and concentrated. The crude
product is purified by column chromatography eluting with 90%
EtOAc/CH.sub.2Cl.sub.2 to yield the title compound (0.07 g, 0.22
mmol) as a beige solid.
[1031] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.51 (d, 1H), 8.35
(d, 1H), 7.21 (dd, 1H), 6.60 (s, 1H), 5.34 (bs, 1H), 4.95 (AB, 2H),
4.55 (q, 2H), 4.30 (m, 1H), 3.48 (m, 2H), 2.70 (m, 1H), 2.05 (m,
1H), 1.50 (t, 3H), 1.46 (s, 9H). IS MS, [M+H].sup.+=403.
[1032] E.
2-(3-(S)-Amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridin-
e-1-carboxylic acid ethyl ester hydrochloride.
[1033] The title compound is prepared as described in EXAMPLE 1,
Part I using
2-(3-(S)tert-butoxycarbonylamino-2-oxopyrrolidin-1-ylmethyl)-pyrrol-
o[3,2-b]pyridine-1-carboxylic acid ethyl ester as the starting
material. The title compound is obtained as a beige solid.
[1034] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.70 (m, 1H),
8.58 (m, 4H), 7.50 (m, 1H), 6.91 (s, 1H), 4.91 (m, 2H), 4.51 (q,
2H), 4.01 (m, 1H), 3.50 (m, 2H), 2.48 (m, 1H), 2.10 (m, 1H), 1.43
(t, 3H).
[1035] F.
2-[3-(S)-(6-Chloro-benzo[b]thiophene-2-sulfonylamino)-2-oxopyrro-
lidin-1-ylmethyl]-pyrrolo[3,2-b]pyridine-1-carboxylic acid ethyl
ester
[1036] The title compound is prepared as described in EXAMPLE 1,
Part K using 6chloro-benzo[b]thiophene-2-sulfonyl chloride and
2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carbo-
xylic acid ethyl ester hydrochloride as starting material. The
crude product is purified by column chromatography eluting with 60%
EtOAc/CH.sub.2Cl.sub.2 to provide the title compound as a
solid.
[1037] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.49 (d, 1H), 8.30
(d, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.75 (d, 1H), 7.48 (dd, 1H),
7.20 (dd, 1H), 6.88 (bs, 1H), 6.49 (s, 1H), 4.81 (AB, 2H), 4.49 (q,
2H), 4.13 (m, 1H), 3.39 (m, 2H), 2.61 (m, 1H), 2.13 (m, 1H), 1.45
(t, 3H).
[1038] G. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[3-
,2-b]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl-amide
trifluoroacetate
[1039] To a solution of
2-[3-(S)-(6-chloro-benzo[b]thiophene-2-sulfonylami-
no)2-oxopyrrolidin-1-ylmethyl]-pyrrolo[3,2-b]pyridine-1-carboxylic
acid ethyl ester (0.03 g, 0.06 mmol) in 3 mL of MeOH is added 4
drops of 10 N NaOH solution. The mixture is stirred at room
temperature for 1 hour. The crude mixture is purified by RP-HPLC
eluting in a gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 80%
CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate product
fractions are lyophilized to provide the title compound (0.015 g,
0.026 mmol) as a white solid.
[1040] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.72 (d, 1H),
8.58 (bs, 1H), 8.41 (d, 1H), 8.27 (d, 1H), 8.05 (s, 1H), 8.02 (d,
1H), 7.55 (m, 2H), 6.69 (bs, 1H), 4.68 (AB, 2H), 4.25 (m, 1H), 3.30
(m, 2H), 2.20 (m, 1H), 1.73 (m, 1H). IS MS, [M+H].sup.+=461, 463,
Cl pattern. Elemental analysis calculated with 1.6 mol H.sub.2O
cal. C=43.76%, H=3.54%, N=9.28%, found C=43.76%, H=2.98%,
N=8.95%.
EXAMPLE 47
[1041] 6-Chloro-benzo[b]thiophene-2-sulfonic acid[2-oxo-1-(
1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[1042] A. 3-(S)-Amino-1-prop-2-ynyl-pyrrolidin-2-one
hydrochloride
[1043] The title compound is prepared as described in EXAMPLE 1,
Part I using (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-carbamic
acid tert-butyl ester as the starting material. The title compound
is obtained as a beige solid.
[1044] .sup.1H NMR (CDCl.sub.3+DMSO-d.sub.6, 300 MHz) .delta.8.75
(bs, 3H), 4.15 (AB, 2H), 3.90 (m, 1H), 3.53 (m, 2H), 2.76 (t, 1H),
2.59 (m, 1H), 2.19 (m, 1H).
[1045] B. 6-Chloro-benzo[b]thiophene-2-sulfonic acid
(2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)amide
[1046] The title compound is prepared as described in EXAMPLE 1,
Part K using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride and
3-(S)-amino-1-prop-2-ynyl-pyrrolidin-2-one hydrochloride as
starting material. The crude product is isolated as a beige foam
and used in the subsequent step without further purification.
[1047] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.90 (s, 1H), 7.85
(s, 1H), 7.80 (d, 1H), 7.41 (dd, 1H), 5.53 (bs, 1H), 4.11 (AB, 2H),
3.91 (m, 1H), 3.42 (m, 2H), 2.70 (m, 1H), 2.27 (t, 1H), 2.15 (m,
1H).
[1048] C. (4-Iodo-pyridin-3-yl)-carbamic acid tert-butyl ester
[1049] To a solution of (pyridin-3-yl)-carbamic acid tert-butyl
ester (prepared according to the procedure described in Tetrahedron
Lett. 1994, 35, 9003) (2.2 g, 11.3 mmol) in 20 mL of THF at
-78.degree. C. is added dropwise t-BuLi (15.4 mL of a 1.7 M
solution in pentane, 26 mmol). After 15 minutes, the solution is
warmed to -10.degree. C. for 3 hours. The mixture is cooled to
-78.degree. C. and a solution of iodine (5.7 g, 22.4 mmol) in 20 mL
of THF is added via syringe. The resulting mixture is stirred at
-78.degree. C. for 1 hour, then allowed to warm to room temperature
and quenched with saturated NH.sub.4Cl solution. The aqueous layer
is extracted with EtOAc (2.times.). The combined organic layers are
washed with 1 N HCl, water, dilute Na.sub.2S.sub.20.sub.3,
saturated NaHCO.sub.3 and saturated NaCl. The organic layer is then
dried over MgSO.sub.4, filtered and concentrated. The crude product
is purified by column chromatography eluting with a gradient of 5%
EtOAc/CH.sub.2Cl.sub.2 to 20% EtOAc/CH.sub.2Cl.sub.2 to yield the
title compound (1.3 g, 4.06 mmol) as a brown solid.
[1050] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.9.17 (s, 1H), 7.92
(d, 1H), 7.70 (d, 1H), 6.69 (bs, 1H), 1.58 (s, 9H). EI MS,
[M].sup.+=320.
[1051] D.
2-[3-(S)-(6-Chloro-benzo[b]thiophene-2-sulfonylamino)-2-oxopyrro-
lidin-1-ylmethyl]-pyrrolo[2,3-c]pyridine-1-carboxylic acid
tert-butyl ester
[1052] A mixture of (4-iodo-pyridin-3-yl)-carbamic acid tert-butyl
ester (0.85 g, 2.65 mmol), 6-chloro-benzo[b]thiophene-2-sulfonic
acid (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-amide (0.98 g, 2.65
mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (95 mg), copper iodide (18 mg)
and triethylamine (1.45 mL) in 8 mL of DMF is heated at 100.degree.
C. for 1.5 hours. The reaction mixture is cooled to 50.degree. C.
and DBU is added. The resulting mixture is heated at 50.degree. C.
for 1.5 hours. After cooling, the crude mixture is diluted with
EtOAc and washed with saturated NH.sub.4Cl solution, water and
saturated NaCl. The organic layer is dried over MgSO.sub.4,
filtered and concentrated. The crude product is purified by column
chromatography eluting with a gradient of 1% MeOH/CH.sub.2Cl.sub.2
to 4% MeOH/CH.sub.2Cl.sub.2 to afford the title compound (0.73 g,
1.3 mmol) as a tan solid.
[1053] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.9.28 (s, 1H), 8.38
(d, 1H), 7.88 (m, 2H), 7.68 (d, 1H), 7.46 (m, 3H), 6.31 (s, 1H),
4.93 (AB, 2H), 4.00 (m, 1H), 3.49 (m, 2H), 2.76 (m, 1H), 2.26 (m,
1H), 1.60 (s, 9H). IS MS, [M].sup.+=561, 563, Cl pattern.
[1054] E. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[2-
,3-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[1055] The title compound is prepared from
2-[3-(S)-(6-chloro-benzo[b]thio-
phene-2-sulfonylamino)-2-oxopyrrolidin-1-ylmethyl]-pyrrolo[2,3-c]pyridine--
1-carboxylic acid tert-butyl ester as described in EXAMPLE 27, Part
C. The crude product is purified by RP-HPLC eluting in a gradient
of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 80% CH.sub.3CN/H.sub.2O
(0.1% TFA) and the appropriate product fractions are lyophilized to
provide the title compound as a white solid.
[1056] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.13.07 (bs, 1H),
9.07 (s, 1H), 8.74 (d, 1H), 8.29 (s, 1H), 8.27 (d, 1H), 8.03 (m,
311), 7.52 (dd, 1H), 6.79 (s, 1H), 4.71 (AB, 2H), 4.27 (m, 1H),
3.29 (m, 2H), 2.20 (m, 1H), 1.77 (m, 1H). FAB MS, [M+H].sup.+=461,
463, Cl pattern. Elemental analysis calculated with 0.7 mol
H.sub.2O cal. C=44.94%, H=3.33%, N=9.53%, found C=44.92%, H=2.91%,
N=8.91%.
EXAMPLE 48
[1057] Thieno[3,2-b]pyridine-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[2,3-c]pyr-
idin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide ditrifluoroacetate
[1058] A. Thieno[3,2-b]pyridine-2-sulfonyl chloride
[1059] The title compound is prepared as described in EXAMPLE 8,
Part A using thieno[3,2-b]pyridine (prepared according to the
procedure described in J. Heterocyclic Chem. 1984, 21, 785) in
place of thianaphthalene. The crude product is used in the
subsequent step without further purification.
[1060] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.93 (dd, 1H), 8.39
(s, 1H), 8.38 (d, 1H), 7.59 (m, 1H). EI MS, [M].sup.+=233, 235, Cl
pattern.
[1061] B. Thieno[3,2-b]pyridine-2-sulfonic acid
(2-oxo-1-prop-2-ynyl-pyrro- lidin-3-(S)-yl)-amide
[1062] The title compound is prepared as described in EXAMPLE 1,
Part K using thieno[3,2-b]pyridine-2-sulfonyl chloride and
3-(S)-amino-1-prop-2-ynyl-pyrrolidin-2-one hydrochloride as
starting material. The crude product is isolated as a white solid
and used in the subsequent step without further purification.
[1063] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.81 (d, 1H), 8.22
(d, 1H), 8.13 (s, 1H), 7.41 (m, 1H), 6.05 (bs, 1H), 4.10 (AB, 2H),
3.98 (m, 1H), 3.48 (m, 2H), 2.70 (m, 1H), 2.27 (t, 1H), 2.17 (m,
1H).
[1064] C. Thieno[3,2-b]pyridine-2-sulfonic
acid[2-oxo-1-(1H-pyrrolo[2,3-c]-
pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
ditrifluoroacetate
[1065] The title compound is prepared from
thieno[3,2-b]pyridine-2-sulfoni- c acid (2-oxo-I
-prop-2-ynyl-pyrrolidin-3-(S)-yl)-amide as described in EXAMPLE 47,
Part D. The crude mixture is diluted with EtOAc and washed with
saturated NH.sub.4Cl solution, water and saturated NaCl. The
aqueous layer is concentrated in vacuo to a residue. The mixture of
salts is triturated with MeOH and CH.sub.2Cl.sub.2, filtered,
washed with CH.sub.2Cl.sub.2/MeOH and the yellow filtrate is
concentrated. The crude product is purified by RP-HPLC eluting in a
gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 50%
CH.sub.3CN/H.sub.2O (0.1% TFA) and the appropriate product
fractions are lyophilized to provide the title compound as a beige
solid.
[1066] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.13.00 (bs, 1H),
9.06 (s, 1H), 8.88 (d, 1H), 8.77 (m, 1H), 8.60 (d, 1H), 8.26 (d,
1H), 8.12 (s, 1H), 8.01 (d, 1H), 7.52 (m, 1H), 6.80 (s, 1H), 4.71
(AB, 2H), 4.35 (m, 1H), 3.30 (m, 2H), 2.22 (m, 1H), 1.78 (m, 1H).
IS MS, [M+H].sup.+=428. Elemental analysis calculated with 1.9 mol
H.sub.2O cal. C=40.05%, H=3.33%, N=10.15%, found C=40.06%, H=2.82%,
N=9.87%.
EXAMPLE 49
[1067] Benzo[b]thiophene-2-sulfonic acid
(2-oxo-1-thieno[3,2-c]pyridin-2-y-
lmethyl-pyrrolidin-3-(S)-yl)-amide trifluoroacetate
[1068] A.
1-(Thieno[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]car-
bamic acid tert-butyl ester
[1069] To a solution of
1-(4-chlorothieno[3,2-c]pyridin-2-ylmethyl)-2-oxop-
yrrolidin-3-(S)-yl]carbamic acid tert-butyl ester (0.46 g, 1.2
mmol), prepared as described in EXAMPLE 33, Part F, in 20 mL of
MeOH is added 10% by weight Pd/C (0.1 g) and KOH (0.13 g, 2.4
mmol). The atmosphere above the reaction is replaced by hydrogen
and the solution is heated to 50.degree. C. After 16 hours, the
solution is filtered through Celite and the Celite is washed with
MeOH. The crude material is purified by column chromatography
eluting with a gradient of 30% EtOAc/CH.sub.2Cl.sub.2 to 40%
EtOAc/CH.sub.2Cl.sub.2 to give the product as a white solid (0.2 g,
0.7 mmol).
[1070] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.9.00 (s, 1H), 8.44
(d, 1H), 7.70 (s, 1H), 7.31 (s, 1H), 5.12 (bs, 1H), 4.72 (AB, 2H),
4.18 (m, 1H), 3.32 (m, 2H), 2.62 (m, 1H), 1.88 (m, 1H), 1.42 (s,
9H). FAB MS, [M+H].sup.+=348.
[1071] B. Benzo[b]thiophene-2-sulfonic acid
(2-oxo-1-thieno[3,2-c]pyridin--
2-ylmethyl-pyrrolidin-3-(S)-yl)-amide trifluoroacetate
[1072] To a solution of
1-(thieno[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidi-
n-3-(S)-yl]carbamic acid tert-butyl ester (0.1 g, 0.35 mmol) in 4
mL of CH.sub.2Cl.sub.2 is added Et.sub.3N (0.08 g, 0.78 mmol) and
benzo[b]thiophene sulfonyl chloride (0.08g, 0.35 mmol). After 6
hours, the solution is diluted with CH.sub.2Cl.sub.2 and washed
with 10% Na.sub.2CO.sub.3 and saturated NaCl. The residue is
purified by RP-HPLC eluting with a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 80% CH.sub.3CN/H.sub.2O (0.1%
TFA). The appropriate fractions are lyophilized to provide the
title compound as a white solid.
[1073] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.25 (bs, 1H),
8.63 (d, 1H), 8.50 (m, 1H), 8.39 (m, 1H), 7.99 (m, 4H), 7.61 (s,
1H), 7.46 (m, 2H), 4.70 (s, 2H), 4.14 (m, 1H), 3.11 (m, 2H), 2.08
(m, 1H), 1.62(m, 1H). FAB MS, [M+H].sup.+=444.
EXAMPLE 50
[1074] 7-Methoxynaphthalene-2-sulfonic
acid[1-(1H-imidazo[4,5-c]pyridin-2--
ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate
[1075] A. [3-(S)-Amino-2-oxo-cyclopentyl]-acetic acid benzyl ester
hydrochloride
[1076] Sodium hydride (0.13 g, 3.3 mmol, 60% by weight) is added to
a solution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl
ester (0.6 g, 3 mmol) in THF (30 mL) at 0.degree. C. The mixture is
stirred for 30 minutes then benzyl 2-bromo-acetate (0.76 g, 3.3
mmol) is added. The resulting solution is warmed to room
temperature and stirred for 1.5 hours. The reaction mixture is
quenched with saturated ammonium chloride solution then diluted
with methylene chloride. The organic layer is separated, washed
with brine, dried over MgSO.sub.4, filtered and concentrated. The
residue is purified by flash chromatography (0-3%
MeOH/CH.sub.2Cl.sub.2) and the material isolated is treated in
ethyl acetate with HCl gas (as described in EXAMPLE 1, Part I) to
give the title compound (0.55 g, 1.9 mmol) as a pale yellow
solid.
[1077] .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta.7.32 (m, 5H), 5.17
(s, 2H), 4.15 (d, 2H), 4.08 (m, 1H), 3.54 (m, 2H), 2.54 (m, 1H),
2.03 (m, 1H). EI MS, [M].sup.+=248.
[1078] B.
3-(S)-(7-Methoxy-naphthalene-2-sulfonylamino)2-oxopyrrolidin-1-y-
l]-acetic acid
[1079] [3-(S)-Amino-2-oxo-cyclopentyl]-acetic acid benzyl ester
hydrochloride (0.34 g, 1.2 mmol) is suspended in CH.sub.3CN (20
mL). To this mixture is added triethylamine (0.36 g, 3.6 mmol)
followed by 7-methoxy-naphthalene-2-sulfonyl chloride (0.31 g, 1.2
mmol). The mixture is stirred overnight at room temperature,
subjected to aqueous work up then concentrated to dryness. The
crude material is purified by flash chromatography (0-5%
MeOH/CH.sub.2Cl.sub.2). Subsequent hydrogenolysis in
MeOH/CH.sub.2Cl.sub.2 with 5% Pd/C at 25 psi for 1.5 hours gave the
title compound (0.40 g, 1 mmol) as a white solid.
[1080] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.33 (S, 1H), 7.80
(m, 3H), 7.23 (m, 2H), 5.90 (br, 1H), 3.95 (m, 6H), 3.38 (m, 2H),
2.40 (m, 1H), 2.07 (m, 1H). Ion Spray MS, [M+H].sup.+=379.
[1081] C.
N-(3-Amino-pyridin-4-yl)-2-[3-(S)-(7-methoxy-naphthalene-2-sulfo-
nylamino)-2-oxopyrrolidin-1-yl]-acetamide
[1082] Triethylamine (0.13 g, 1.3 mmol) and isobutyl chloroformate
(0.18 g, 1.3 mmol) are added to a solution of
[3-(S)-(7-methoxy-naphthalene-2-s-
ulfonylamino)-2-oxopyrrolidin-1-yl]-acetic acid (0.5 g, 1.3 mmol)
in THF (15 mL) at -10.degree. C. The mixture is stirred for 20
minutes then treated with a solution of 3,4-diamino-pyridine (0.16
g, 1.5 mmol) in DMF (5 mL). The resulting mixture is warmed to room
temperature and stirred for 3 hours. T he reaction mixture is
concentrated in vacuo, then diluted with methylene chloride. The
organic layer is washed with brine, dried over MgSO.sub.4, filtered
and concentrated. The residue is purified by flash chromatography
(5-8% MeOH/CH.sub.2Cl.sub.2). to give the title compound (0.27 g,
0.58 mmol) as a solid.
[1083] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.88 (br, 1H), 8.30
(s, 1H), 8.00 (s, 1H), 7.85 (d, 1H), 7.70 (m, 3H), 7.40 (d, 1H),
7.20 (d, 1H), 7.12 (s, 1H), 5.28 (s, 2H), 4.07 (m, 4H), 3.88 (3,
3H), 3.34 (m, 2H), 2.22 (m, 1H), 1.90 (m, 1H). Ion Spray MS,
[M+H].sup.+=470.
[1084] D. 7-Methoxy-naphthalene-2-sulfonic
acid[1-(1H-imidazor[4,5-c]pyrid-
in-2-ylmethyl-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[1085]
N-(3-Amino-pyridin-4-yl)-2-[3-(7-methoxy-naphthalene-2-sulfonylamin-
o)-2-oxopyrrolidin-1-yl]-acetamide (0.22 g, 0.47 mmol) in acetic
acid (15 mL) is heated at 110.degree. C. overnight. The resulting
solution is concentrated to dryness. The residue is purified by
HPLC eluting with a gradient of 10 to 100% CH.sub.3CN/0.1% TFA in
water over 30 minutes. Fractions containing pure product are
lyophilized to give the title compound as a white solid (0.24 g,
0.42 mmol).
[1086] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.9.30 (s, 1H), 8.40
(d, 1H), 8.28 (s, 1H), 7.95 (d, 1H), 7.70 (m, 3H), 7.40 (m, 1H),
7.20 (m, 2H), 7.14 (s, 1H), 4.92 (m, 2H), 4.46 (m, 1H), 3.82 (s,
3H), 3.38 (m, 2H), 2.20 (m, 1H), 2.03 (m, 1H). Ion Spray MS,
[M+H].sup.+=452.
EXAMPLE 51
[1087] 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-amino-3H-benzoimidazol-5--
methyl)2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[1088] A. 7-Methoxynaphthalene-2-sulfonic
acid[1-(3,4-diaminobenzyl)-2-oxo- pyrrolidin-3-(S)-yl]-amide
[1089] 10% Palladium on carbon (0.08 g) is added to a solution of
7-methoxy-naphthalene-2-sulfonic
acid[1-(4-amino-3-nitrobenzyl)-2-oxopyrr- olidin-3-(S)-yl]-amide
(0.22 g, 0.5 mmol) (prepared as described in EXAMPLE 25, Part F) in
MeOH (40 mL) and CHCl.sub.3 (3 mL) under nitrogen atmosphere. The
heterogeneous mixture is hydrogenated at room temperature on a Parr
apparatus under 47 p.s.i. of hydrogen for 5 hours. The catalyst is
filtered and the filtrate checked by tlc shows no starting
material. The filtrate is concentrated in vacuo and used in the
subsequent step without further purification.
[1090] .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta.8.41 (s, 1H), 7.93
(d, 1H), 7.85 (d, 1H), 7.73 (d, 1H), 7.39 (d, 1H), 7.25 (dd, 1H),
7.02 (d, 1H), 6.89 (s, 1H), 6.79 (dd, 1H), 4.30 (s, 2H), 4.13 (t,
1H), 3.95 (s, 3H), 3.13 (m, 2H), 2.14 (m, 1H), 1.70 (m, 1H). Ion
Spray MS, [M+H].sup.+=441.
[1091] B. 7-Methoxynaphthalene-2-sulfonic
acid[1-(2-amino-3H-benzoimidazol-
-5-methyl)-2-oxopyrrolidin-3-(S)-yl]-amide trifluoroacetate
[1092] Triethylamine (0.063 mL, 0.45 mmol) is added to a solution
of 7-methoxynaphthalene-2-sulfonic
acid[1-(3,4-diaminobenzyl)2-oxopyrrolidin- -3-(S)-yl]-amide (0.205
g, 0.47 mmol) in MeOH (8 mL) under nitrogen. Cyanogen bromide (0.19
mL of a 3 M solution, 0.56 mmol) is added dropwise to the reaction
mixture at 0.degree. C. After stirring for 5 minutes at 0.degree.
C., the reaction is brought to room temperature and stirred
overnight. The clear solution is then concentrated in vacuo and the
crude residue purified using column chromatography eluting with a
gradient of 9% MeOH/CH.sub.2Cl.sub.2 to 50% MeOH/CH.sub.2Cl.sub.2
to provide the product in 56% yield. The product is lyophilized in
acetonitrile/TFA-water to give the title compound as an off-white
solid.
[1093] .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta.8.40 (d, 1H), 7.90
(d, 1H), 7.81 (d, 1H), 7.75 (d, 1H), 7.36 (d, 1H), 7.25 (dd, 1H),
7.15 (d, 1H), 7.11 (d, 1H), 6.92 (dd, 1H), 4.41 (AB, 2H), 4.15 (t,
1H), 3.91 (s, 3H), 3.10 (m, 2H), 2.10 (m, 1H), 1.64 (m, 1H). Ion
Spray MS, [M+H].sup.+=466.
EXAMPLE 52
[1094]
3-(S)-Amino-1-(1-aminoisoquinolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride
[1095] A. 7-Methyl-1-phenoxyisoquinoline
[1096] The title compound is prepared as described in Example I,
Part L using 1-chloro-7-methylisoquinoline as the starting
material. The crude material is purified by column chromatography
eluting with 20% EtOAc/hexanes to afford the title product as a
pale yellow oil.
[1097] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.22 (s,1H), 7.90
(d,1H), 7.68-7.60 (m, 1H), 7.60-7.52 (m, 1H), 7.50-7.40 (m, 2H),
7.30-7.20 (m, 4H), 2.57 (s, 3H).
[1098] B. 7-Bromomethyl-1-phenoxyisoquinoline
[1099] The title compound is prepared as described in Example 1,
Part F using 7-methyl-1-phenoxyisoquinoline as the starting
material. The crude product is purified by column chromatography
eluting with 10% EtOAc/hexanes to afford the title product as a
clear oil.
[1100] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.40 (s, 1H), 7.95
(d, 1H), 7.80-7.65 (m, 2H), 7.50-7.40 (m, 2H), 7.30-7.20 (m, 4H),
4.65 (s, 2H).
[1101] C.
[1-(1-Phenoxyisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-c-
arbamic acid benzyl ester
[1102] The title compound is prepared as described in Example 1,
Part H using 7-bromomethyl-1-phenoxyisoquinoline and
[2-oxopyrrolidin-3-(S)-yl]c- arbamic acid benzyl ester as the
starting materials. The crude product is purified by column
chromatography eluting with 70% EtOAc/hexanes to afford the title
product as a clear oil.
[1103] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.25 (s, 1H), 7.97
(d, 1H), 7.79 (d, 1H), 7.60(d, 1H), 7.48-7.40 ( m, 2H), 7.38-7.20
(m, 9H), 5.40 (bs, 1H), 5.15 (s, 2H), 4.75 (AB, 2H), 4.30 (m, 1H),
3.30 (m, 2H), 2.67 (m, 1H), 1.90 (m, 1H).
[1104] D.
[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-car-
bamic acid benzyl ester
[1105] The title compound is prepared as described in Example 1,
Part M using
[1-(1-phenoxyisoquinolin-7-ylmethyl)2-oxopyrrolidin-3-(S)-yl]-carba-
mic acid benzyl ester as the starting material. The reaction
mixture is diluted with methylene chloride and washed with 3 N NaOH
and brine. The organic layer is dried over MgSO.sub.r, filtered and
concentrated in vacuo. The crude product is purified by column
chromatography eluting with 10% MeOH/CH.sub.2Cl.sub.2 to afford the
title product as a foamy yellow solid.
[1106] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.95-7.87 (m, 2H),
7.70 (d, 1H), 7.45 (d, 1H), 7.40-7.30 (m, SH), 7.00 (d, 1H),
5.75-5.55 (m, 3H), 5.20-5.15 (m, 4H), 4.3-4.1 (m, 1H), 3.25 (m,
2H), 2.55 (m, 1H), 2.27 (m, 1H).
[1107] E.
3-(S)-Amino-1-(1-aminoisoquinolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride
[1108] 10% Palladium on carbon (0.089 g) is added to a solution of
[1-(1-aminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-carbamic
acid benzyl ester (0.33 g, 0.84 mmol) in ethanol. The heterogeneous
mixture is hydrogenated at room temperature on a Parr apparatus
under 45 p.s.i. of hydrogen for 3 hours. The reaction mixture is
filtered through a pad of Celite, washed with ethanol and the
filtrate is concentrated in vacuo to give the product (0.2 g, 0.78
mmol) as a foamy solid. The product is dissolved in diethyl ether
and cooled to 0.degree. C. Hydrogen chloride gas is bubbled through
the solution to yield the product as a hydrochloride salt.
[1109] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.95-8.50 (b,
2H), 8.05 (s, 1H), 7.75-7.70 (m, 2H), 7.53 (d, 1H), 7.30-7.10 (b,
2H), 6.93 (d, 1H), 4.57 (AB, 2H), 3.40 (m, 1H), 3.15 (m, 1H), 2.37
(m, 1H), 2.02 (m, 1H). FAB MS: [M+H].sup.+=257.
[1110] F. 7-Methoxynapthalene-2-sulfonic
acid[1-(1-aminoisoquinolin-7-yl-m-
ethyl)-2-oxo-pyolidin-3-(S)-yl]-amide trifluoroacetate
[1111] The title compound can be prepared by an alternative route
using 3-(S)-amino-1-(1-aminoisoquinolin
-7-ylmethyl)-pyrrolidin-2-one hydrochloride and
7-methoxynaphthalene-2-sulfonyl chloride as the starting material
and proceeding as described in Example 1, Part K.
EXAMPLE 53
[1112] 6-Chlorothieno[2,3-b]pyridine-2-sulfonyl chloride
[1113] A. 2-Bromo-6-chlorothieno[2,3-b]pyridine
[1114] The title compound is prepared from 2-bromo-5-acetyl
thiophene according to the procedure described in J. Chem. Soc.,
Perkin Trans. I, 1981, 1531. The crude product is purified by
column chromatography eluting with 2% EtOAc/hexanes to afford a
white solid.
[1115] .sup.1HNMR (CDCl3, 300 MHz) .delta.7.89 (d, 1H), 7.28 (d,
1H), 7.27 (d, 1H).
[1116] B. 6-Chlorothieno[2,3-b]pyridine-2-sulfonyl chloride
[1117] The title compound is prepared as described in EXAMPLE 1,
Part D using 2-bromo-6-chlorothieno[2,3-b]pyridine in place of
thianaphthalene. The crude product is obtained as a white solid and
is of sufficient purity to be used in the subsequent step.
[1118] .sup.1H NMR (CDCl3, 300 MHz) .delta.8.22 (d, 1H), 8.09 (s,
1H), 7.52 (d, 1H). EI MS, [M]+=267, 269, Cl pattern.
EXAMPLE 54
[1119] 6-Fluorobenzo[b]thiophene-2-sulfonyl chloride
[1120] The title compound is prepared as described in EXAMPLE 9,
Parts A-C using 3-fluorothiophenol in place of
3-chlorothiophenol.
EXAMPLE 55
[1121] 6-Chlorothieno[3,2-b]pyridine-2-sulfonyl chloride
[1122] The title compound is prepared as described in EXAMPLE 48,
Part A using 6-chlorothieno[3,2-b]pyridine (prepared according to
the procedure described in J. Heterocyclic Chem. 1984, 21, 785) in
place of thianaphthalene. The crude product is used in the
subsequent step without further purification.
[1123] Other compounds prepared according to the procedures above
include those encompassed by the following formula: 57
[1124] wherein 58
[1125] is selected from the group of formulae consisting of 59
[1126] R.sub.1, X.sub.5, W and A are as defined herein; and R.sub.2
is selected from the group of formulae consisting of 60
EXAMPLE 56
[1127] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-amino-isoquinolin-7-ylme-
thyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1128] A. Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-chloro-isoquinolin-7--
ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[1129] To a solution of
3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-py- rrolidin-2-one
hydrochloride (0.15 g, 0.48 mmol) suspended in CH.sub.3CN (2.5 mL)
is added triethylamine (0.23 mL, 1.6 mmol) followed by
thieno[3,2-b]pyridine-2-sulfonyl chloride (0.14 g, 0.55 mmol). The
mixture is stirred overnight, then concentrated. The residue is
diluted with CH.sub.2Cl.sub.2 and washed with saturated NaHCO.sub.3
and brine. The organic layer is dried over MgSO.sub.4, filtered and
concentrated to dryness. The crude product is purified by column
chromatography eluting with 5% MeOH/CH.sub.2Cl.sub.2to give the
title compound (0.076 g, 0.16 mmol) as a light yellow solid.
[1130] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.85 (d, 1H), 8.32
(d, 1H), 8.27 (d, 1H), 8.15 (s, 2H), 7.85 (d, 1H), 7.58-7.65 (m,
2H), 7.45 (dd, 1H), 5.60 (bs, 1H), 4.68 (AB, 2H), 4.00 (m, 1H),
3.31 (m, 2H), 2.72 (m, 1H), 2.20 (m, 1H). EI MS,
[M.].sup.+=472.
[1131] B. Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-amino-isoquinolin-7-y-
lmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1132] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-chloro-isoquinolin-7-ylm-
ethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (1.36 g, 2.88 mmol) and
phenol (2.22 g, 23.6 mmol) are melted together with stirring at
70.degree. C. for 5 minutes. Ammonium acetate (2.71 g, 28.8 mmol)
is added and the reaction mixture is heated to 90.degree. C. and
stirred overnight. Additional ammonium acetate (0.50 g, 5.31 mmol)
is added and the reaction is heated for 20 more hours. The reaction
is cooled and the residue is purified by RP-HPLC eluting in a
gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 100% CH.sub.3CN.
The appropriate product fractions are lyophilized to provide the
title compound as a white solid. The enantiomeric purity is 90.5%
ee as determined by analytical Chiralpak AS RP-HPLC.
[1133] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.12.90 (bs, 1H),
9.00 (bs, 1H), 8.88 (d, 1H), 8.79 (dd, 1H), 8.60 (dd, 1H), 8.30 (s,
1H), 8.13 (s, 1H), 7.95 (d, 1H), 7.79 (dd, 1H), 7.65 (d, 1H), 7.53
(dd, 1H), 7.23 (d, 1H), 4.50 (AB, 2H), 4.38 (m, 1H), 3.21 (m, 2H),
2.20 (m, 1H), 1.81 (m, 1H). Ion Spray, [M+H].sup.+=454.
EXAMPLE 57
[1134] Thieno[2,3-b]pyridine-2-sulfonic
acid[1-(1-amino-isoquinolin-7-ylme-
thyl1)2-oxo-pyrrolidin-3-(S)-yl]-amide
[1135] A. Thieno[2,3-b]pyridine-2-sulfonyl chloride
[1136] n-Butyl lithium (6.0 mL of a 1.6 M solution in hexanes, 9.6
mmol) is added to a solution of thieno[2,3-b]pyridine (1.18 g, 8.7
mmol) (J. Org. Chem. 1969, 34(2), 347) in THF (30 mL) at
-78.degree. C. After 40 min., the solution is added to a precooled
(-78.degree. C.) solution of SO.sub.2 (ca. 6 mL) in Et.sub.2O (30
mL) via cannula. After addition, the solution is stirred for 30
min. then allowed to warm to ambient temperatures. After 2 h, the
solution is concentrated to give a brown solid. The residue is
suspended in hexanes (30 mL) and SO.sub.2Cl.sub.2 (0.6 mL, 7.5
mmol) is added dropwise at room temperature. After stirring for I
h, the solution is concentrated then diluted with methylene
chloride and saturated NaHCO.sub.3 solution. The organic layer is
separated and dried over MgSO.sub.4, filtered and concentrated. The
crude product is purified by column chromatography eluting with 20%
EtOAc/hexanes to give a white solid as the title product.
[1137] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.81 (dd, 1H), 8.30
(dd, 1H), 8.12 (s, 1H), 7.50 (dd, 1H). EI MS, [M.].sup.+=233, 235,
Cl pattern.
[1138] B. Thieno[2,3-b]pyridine-2-sulfonic
acid[1-(1-chloro-isoquinolin-7--
ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1139] The title compound is prepared as described in EXAMPLE 56,
Part A using thieno[2,3-b]pyridine-2-sulfonyl chloride and
3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride as starting material. The crude product is purified
by column chromatography eluting with 5% MeOH/CH.sub.2Cl.sub.2to
give the title compound as a white solid.
[1140] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.72 (dd, 1H), 8.31
(d, 1H), 8.22 (dd, 1H), 8.13 (d, 1H), 7.92 (s, 1H), 7.81 (d, 1H),
7.60 (d, 1H), 7.58 (d, 1H), 7.43 (dd, 1H), 5.89 (d, If), 4.70 (AB,
2H), 4.05 (m, 1H), 3.31 (m, 2H), 2.68 (m, 1H), 2.13 (m, 1H). Ion
Spray, [M+H].sup.+=473, 475, Cl pattern.
[1141] C. Thieno[2,3-b]pyridine-2-sulfonic
acid[1-(1-amino-isoquinolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide
[1142] The title compound is prepared as described in EXAMPLE 56,
Part B using thieno[2,3-b]pyridine-2-sulfonic
acid[-(1-chloro-isoquinolin-7-ylme-
thyl)-2-oxo-pyrrolidin-3-S-)yl]-amide as starting material. The
crude product is purified by RP-HPLC eluting with a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 100% CH.sub.3CN. The appropriate
fractions are lyophilized to provide the title compound as a white
solid.
[1143] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.12.90 (bs, 1H),
9.00 (bs, 1H), 8.80 (d, 1H), 8.72 (dd, 1H), 8.42 (dd, 1H), 8.27 (s,
1H), 8.08 (s, 1H), 7.95 (d, 1H), 7.79 (d, 1H), 7.65 (d, 1H), 7.58
(dd, 1H), 7.21 (d, 1H), 4.50 (AB, 2H), 4.35 (m, 1H), 3.25 (m, 2H),
2.21 (m, 1H), 1.80 (m, I11). Ion Spray, [M+H].sup.+=454.
EXAMPLE 58
[1144] 4-Pyridin-3-yl-thiophene-2-sulfonic
acid[1-(1-amino-isoquinolin-7-y-
lmethyl)-2-oxo-pyrrolidin-3)-yl]-amide
[1145] A. 4-Pyridin-3-yl-thiophene-2-sulfonyl chloride
[1146] The title compound is prepared as described in EXAMPLE 57,
Part A using 2-bromo-4-pyridin-3-yl-thiophene (J. Het. Chem. 1995,
32, 435) in place of thieno[2,3-b]pyridine and performing the
reaction at -100.degree. C. rather than at -78.degree. C. The crude
product is purified by column chromatography eluting with a
gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to give a pale
yellow solid.
[1147] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.87 (dd, 1H), 8.65
(dd, 1H), 8.3 (d, 1H), 7.98 (d, 1H), 7.90 (m, 1H), 7.42 (m, 1H). EI
MS, [M.].sup.+=259, 261, Cl pattern.
[1148] B. 4-Pyridin-3-yl-thiophene-2-sulfonic
acid[1-(1-chloro-isoquinolin-
-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1149] The title compound is prepared as described in EXAMPLE 56,
Part A using 4-pyridin-3-yl-thiophene-2-sulfonyl chloride and
3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride as starting material. The crude product is purified
by column chromatography eluting with a gradient of 2%
MeOH/CH.sub.2Cl.sub.2to 4% MeOH/CH.sub.2Cl.sub.2 to give the title
compound as a white solid.
[1150] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.88 (d, 1H), 8.60
(dd, 1H), 8.31 (d, 1H), 8.14 (s, 1H), 7.95 (d, 1H), 7.88 (m, 1H),
7.82 (d, 1H), 7.79 (d, 1H), 7.55-7.60 (m, 2H), 7.38 (m, 1H), 5.45
(d, 1H), 4.63 (AB, 2H), 3.95 (m, 1H), 3.29 (m, 2H), 2.68 (m, 1H),
2.14 (m, 1H), 1.6 (s, 9H). Ion Spray, [M+H.].sup.+=499, 501.
[1151] C. 4-Pyridin-3-yl-thiophene-2-sulfonic
acid[-1-(1-amino-isoquinolin-
-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1152] The title compound is prepared as described in EXAMPLE 56,
Part B using 4-pyridin-3-yl-thiophene-sulfonic
acid[1-(1-chloro-isoquinolin-7-yl-
methyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide as starting material. The
crude product is purified by RP-HPLC eluting with a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 100% CH.sub.3CN. The appropriate
fractions are lyophilized to provide the title compound as a white
solid.
[1153] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.12.98 (bs, 1H),
9.00 (bs, 2H), 8.48-8.57 (m, 2H), 8.39 (s, 1H), 8.27 (s, 1H),
8.15-8.21 (m, 2H), 7.92 (d, 1H), 7.78 (d, 1H), 7.61 (d, 1H), 7.48
(m, 1H), 7.21 (d, 1H), 4.56 (AB, 2H), 4.39 (m, 1H), 3.20 (m, 2H),
2.20 (m, 1H), 1.73 (m, 1H). Ion Spray, [M+H.].sup.+=480.
EXAMPLE 59
[1154] 5'Chloro-[2,2']bithiophenyl-5-sulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2-
-c]pyridin-2-ylmethyl)-pyrrolidin-3(S)-yl]-amide
[1155] A. 4-Amino-3-iodo-pyridine
[1156] A solution of potassium iodide (19.48 g, 117.4 mmol) and
iodine (18.37 g, 72.3 mmol) in water (77 mL) is added dropwise via
an addition funnel to a refluxing solution of 4-aminopyridine (9.21
g, 97.8 mmol) and sodium carbonate (6.12 g, 57.7 mmol) in water (35
mL). Upon complete addition the mixture is stirred for 2 h at
reflux then cooled to room temperature and extracted with ethyl
acetate. The combined organic layers are washed with saturated
sodium thiosulfate solution (.times.3) and brine then dried over
MgSO.sub.4, filtered and concentrated to give the title product
(8.37 g, 38.0 mmol) and a trace of the di-iodo compound as an
yellow/orange solid. This material was used in the subsequent step
without further purification.
[1157] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.70 (s, 1H), 8.10
(d, 1H), 6.55 (d, 1H), 4.60 (bs, 2H).
[1158] B. (3-lodo-pyridin-4-yl)-carbamic acid tert-butyl ester
[1159] Di-tert-butyl dicarbonate (20.7 g, 94.8 mmol) is added to a
solution of 4amino-3-iodo-pyridine (19.0 g, 86.4 mmol) in THF (86
mL). The resulting solution is stirred for 2 h at room temperature
then concentrated to dryness. The residue is diluted with ethyl
acetate and washed with saturated sodium bicarbonate solution and
brine. The organic layer is dried over MgSO.sub.4, filtered and
concentrated to dryness. The residue is purified by column
chromatography eluting with 1% EtOAc/CH.sub.2Cl.sub.2 to give the
title product and a small amount of the BOC-protected di-iodo
compound. Trituration of the mixture with ether/hexane removes the
undesired compound leaving the title product in the solution.
Filtration of the solid and concentration of the filtrate yields
the title product (18.95 g, 59.2 mmol).
[1160] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.75(s, 1H),
8.35(d, 1H), 8.1(d, 1H), 7.0(bs, 1H), 1.55(s, 9H).
[1161] C. (2-Oxo-1-prop2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acid
benzyl ester
[1162] Sodium hydride (1.11 g, 27.7 mmol, 60% mineral oil
dispersion) is added to a solution of
[2-oxopyrrolidin-3-(S)-yl]-carbamic acid benzyl ester (6.20 g, 26.4
mmol) in THF/DMF (88 mL, 3/1 v/v) at 0.degree. C. The mixture is
stirred for 5 min. then propargyl bromide (4.4 mL, 49.4 mmol) is
added dropwise. The resulting solution is stirred for 1 h then
brought to room temperature and stirred for 2 h. The reaction is
quenched with saturated ammonium chloride solution then diluted
with ethyl acetate and washed with water (.times.4) and brine. The
organic layer is dried over MgSO.sub.4, filtered and concentrated
to dryness. The residue is purified by column chromatography
eluting with 5% MeOH/CH.sub.2Cl.sub.2 to give the product (7.20 g,
26.4 mmol) as a white solid.
[1163] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.35 (m, 5H), 5.30
(bs, 1H), 5.12(s, 2H), 4.21(m,1H), 4.13 (s, 2H), 3.43(m, 2H), 2.73
(m, H), 2.25 (s, 1H), 1.95 (m, 1H).
[1164] D.
2-[3-(S)-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-ylmethyl)-pyr-
rolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester
[1165] Pd(PPh.sub.3).sub.2Cl.sub.2 (0.49 g, 0.70 mmol), Cul (0.08
g, 0.42 mmol) followed by triethylamine (7.8 mL, 56.0 mmol) is
added to a solution of
(2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acid benzyl
ester (3.81 g, 13.9 mmol) and (3-iodo-pyridin-4-yl)-carbamic acid
tert-butyl ester (4.48 g, 14.0 mmol) in DMF (50 mL) at room
temperature. The mixture is heated to 100.degree. C. and stirred
for 1.5 h. The reaction mixture is then cooled to 50.degree. C. and
DBU (4.2 mL, 28.1 mmol) is added. After 30 min the solution is
cooled to room temperature, diluted with ethyl acetate and washed
with saturated ammonium chloride, water and brine. The organic
layer is dried over MgSO.sub.4, filtered and concentrated to
dryness in vacuo. The resulting solid is purified by column
chromatography eluting with a gradient of 2% MeOH/CH.sub.2Cl.sub.2
to 5% MeOH/CH.sub.2Cl.sub.2 to give the product (4.79 g, 10.3 mmol)
as a white solid.
[1166] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.80 (s, 1H), 8.48
(d, 1H), 7.90 (d, 1H), 6.51 (s, 1H), 7.39 (m, 5H), 5.45 (d, 1H),
5.19 (s, 2H), 4.90 (AB, 2H), 4.30 (m, 1H), 3.49 (m, 2H), 2.75 (m,
1H), 2.10 (m, 1H), 1.78 (s, 9H). Ion spray MS, [M+H].sup.+=465.
[1167] E.
2-[3-(S)-Amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridi-
ne-1-carboxylic acid tert-butyl ester
[1168]
2-[3-(S)-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrol-
o[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (2.8 g, 6.0
mmol) in HCO.sub.2H/MeOH (30 mL, 4.4% solution) is quickly added
via cannula to a solution of palladium black (2.0 g, 18.8 mmol) in
water (1 mL). After ca. 40 min the catalyst is filtered through
Celite and basified with saturated sodium bicarbonate solution. The
filtrate is concentrated in vacuo to remove methanol then the
resulting solution is extracted with methylene chloride. The
organic layer is washed with brine, dried over MgSO.sub.4, filtered
and concentrated to dryness. The resulting white solid can be used
in the subsequent step without further purification. The title
compound was purified in the following manner to prepare a focused
sulfonamide library. The crude solid was purified by RP-HPLC
eluting with a gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to
100% CH.sub.3CN. The appropriate fractions are combined and
neutralized with saturated sodium bicarbonate solution then
concentrated to remove CH.sub.3CN. The aqueous layer is extracted
with methylene chloride (.times.4) and the organic layers are
washed with brine, dried over MgSO.sub.4, filtered and concentrated
to give the title compound as a white solid.
[1169] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.80 (s, 1H), 8.43
(d, 1H), 7.90 (d, 1H), 6.41 (s, 1H), 4.88 (AB, 2H), 3.65 (m, 1H),
3.45 (m, 2H), 2.55 (m, 1H), 1.90 (m, 1H), 1.75 (s, 9H). Ion spray
MS, [M+H].sup.+=331.
[1170] F. 5-Chloro-[2,2']bithiophenyl
[1171] The title compound is prepared from 2-chloro-thiophene
according to the procedure described in Bull Chem. Soc. Japan,
1979, 1126. The crude product is purified by column chromatography
eluting with a gradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes to
afford a white solid.
[1172] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.24 (m, 1H), 7.11
(d, 1H), 7.03 (dd, 1H), 6.94 (d, 1H), 6.83 (d, 1H). EI MS,
[M].sup.+=200, 202, Cl pattern.
[1173] G. 5'-Chloro-[2,2']bithiophenyl-5-sulfonyl chloride
[1174] The title compound is prepared as described in EXAMPLE 57,
Part A using 5-chloro[2,2']bithiophenyl in place of
thieno[2,3-b]pyridine. The crude product is purified by column
chromatography eluting with a gradient of 5% EtOAc/hexanes to 10%
EtOAc/hexanes to give a white solid.
[1175] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.76 (d, 1H), 7.14
(d, 1H), 7.09 (d, 1H), 6.92 (d, 1H). EI MS, [M].sup.+=298, 300, Cl
pattern.
[1176] H.
2-[3-(S)-(5'-Chloro-[2,2']bithiophenyl-5-sulfonylamino)2-oxo-pyr-
rolidin-1-ylmethyl]pyrrolo[3,2-c]pyridine-1-carboxylic acid
tert-butyl ester
[1177] The title compound is prepared as described in EXAMPLE 56,
Part A using 5'-chloro-[2,2']bithiophenyl-5-sulfonyl chloride and
2-[3-(S)amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carbo-
xylic acid tert-butyl ester as starting material. The crude product
can be purified by column chromatography eluting with 5%
MeOH/CH.sub.2Cl.sub.2 to give the title compound as a white solid
or used in the subsequent step after an aqueous work-up without
further purification. Ion spray MS, [M+H].sup.+=593, 595, Cl
pattern.
[1178] 1. 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[2-oxo-1-(1H-pyrrolo-
[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3(S)-yl]-amide
[1179] Trifluoroacetic acid (1.0 mL, 13.0 mmol) is added dropwise
to a slurry of
2-[3-(S)-(5'-chloro-[2,2']bithiophenyl-5-sulfonylamino)-2-oxo-p-
yrrolidin-1-ylmethyl]pyrrolo[3,2-c]pyridine-1-carboxylic acid
tert-butyl ester (0.13 g, 0.22 mmol) in CH.sub.2Cl.sub.2 (2 mL) at
0.degree. C. After 30 min, the ice bath is removed and the solution
is stirred at room temperature for 4 h. The reaction mixture is
concentrated to dryness and the crude product is purified by
RP-HPLC eluting in a gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA)
to 100% CH.sub.3CN. The appropriate product fractions are
lyophilized to provide the title compound as a white solid.
[1180] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.14.60 (bs, 1H),
12.78 (s, 1H), 9.18 (s, 1H), 8.55 (d, 1H), 8.40 (d, 1H), 7.88 (d,
1H), 7.61 (d, 1H), 7.38 (d, 1H), 7.36 (d, 1H), 7.21 (d, 1H), 6.91
(s, 1H), 4.70 (AB, 2H), 4.21 (m, 1H), 3.30 (m, 2H), 2.25 (m, 1H),
1.75 (m, 1H). Ion spray MS, [M+H].sup.+=493, 495, Cl pattern.
EXAMPLE 60
[1181] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[2-oxo-1-(1H-pyrrolo[-
3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
[1182] A. 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid ethyl
ester
[1183] n-Butyl lithium (1.6 mL of a 2.5 M solution in hexanes, 4.0
mmol) is added dropwise to a solution of ethyl
diethylphosphorylmethanesulfonat- e (1.0 g, 3.8 mmol), prepared as
described in Tetrahedron, 1987, 43(21), 5125, at -78.degree. C. in
THF (15 mL). The mixture is stirred for 20 min. then
5-chloro-2-thiophenecarboxaldehyde (0.45 mL, 4.2 mmol) is slowly
added. The yellow mixture is stirred at -78.degree. C. for 1 h then
allowed to warm to room temperature overnight. The bulk of the
solvents are evaporated and the residue is treated with water (2
mL) and extracted with CH.sub.2Cl.sub.2. The organic layer is
washed with brine, dried over MgSO.sub.4, filtered and
concentrated. The crude product is purified by column
chromatography eluting with CH.sub.2Cl.sub.2to give the title
compound as a yellow solid.
[1184] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.55 (d, 1H), 7.11
(d, 1H), 6.90 (d, 1H), 6.41 (d, 1H), 4.20 (q, 2H), 1.39 (t, 3H).
Ion spray MS, [M+H].sup.+=253.
[1185] B. 2-(5-Chloro-thiophen-2-yl)-ethene tetra-n-butylammonium
sulfonate
[1186] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid ethyl ester
(0.92 g, 3.2 mmol) in acetone (16 mL) is treated with
tetrabutylammonium iodide (1.3 g, 3.5 mmol) and heated to reflux
for 19 h. The mixture is concentrated to dryness then diluted with
CH.sub.2Cl.sub.2 and washed with water and brine. The organic layer
is dried over MgSO.sub.4, filtered and concentrated to give an
oil/solid which is taken on to the next step without further
purification.
[1187] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.28 (d, 1H), 6.81
(d, 1H), 6.77 (d, 1H), 6.73 (d, 1H), 3.29 (t, 8H), 1.65 (m, 8),
1.45 (m, 8H), 1.00 (t, 12H).
[1188] C. 2-(5-Chlorothiophen-2-yl)-ethenesulfonyl chloride
[1189] Sulfuryl chloride (0.61 mL, 7.6 mmol) is added to a solution
of triphenylphosphine (1.8 g, 6.9 mmol) in CH.sub.2Cl.sub.2 (8.6
mL) at 0.degree. C. The ice bath is removed and
2-(5-chloro-thiophen-2-yl)-ethen- e tetra-n-butylammonium sulfonate
(1.6 g, 3.4 mmol) in CH.sub.2Cl.sub.2(17 mL) is added to the
reaction mixture via cannula. The resulting yellow solution is
stirred for 1.5 h then hexane/ether (1:1 v/v, 200 mL) is added
until the solution is no longer cloudy and two layers form. The
solution is decanted and the lower oily layer is discarded. The
solution is concentrated to dryness and the product is purified by
column chromatography eluting with CH.sub.2Cl.sub.2to give the
title compound as a pale yellow solid.
[1190] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.71 (d, 1H), 7.25
(d, 1H), 7.00 (d, 1H), 6.91 (d, 1H). EI MS, [M.].sup.+=242, 244,
246, Cl pattern.
[1191] D.
2-{3-(S)-[2-(5-Chloro-thiophene-2-yl)-ethenesulfonylamino]2-oxo--
pyrrolidin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylic acid
tert-butyl ester
[1192] The title compound is prepared as described in EXAMPLE 56,
Part A using 2-(5-chlorothiophen-2-yl)-ethenesulfonyl chloride and
2-[3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carb-
oxylic acid tert-butyl ester as starting material. The crude
product can be purified by column chromatography eluting with 5%
MeOH/CH.sub.2Cl.sub.2to give the title compound as a white solid or
used in the subsequent step after an aqueous work-up without
further purification.
[1193] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.75 (s, 1H), 8.46
(d, 1H), 7.85 (d, 1H), 7.48 (d, 1H), 7.05 (d, 1H), 6.85 (d, 1H),
6.67 (d, 1H), 6.40 (s, 1H), 4.90 (AB, 2H), 4.15 (m, 1H), 3.49 (m,
2H), 2.71 (m, 1H), 2.21 (m, 1H), 1.7 (s, 9H). Ion spray MS,
[M+H].sup.+=537, 539, Cl pattern.
[1194] E. 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[2-oxo-1-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-a-
mide
[1195] The title compound is prepared as described in EXAMPLE 59,
Part I using
2-{3-(S)-[2-(5-chloro-thiophene-2-yl)-ethenesulfonylamino]-2-oxo-py-
rrolidin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylic acid
tert-butyl ester as starting material. The crude product is
purified by RP-HPLC eluting with a gradient of 10%
CH.sub.3CN/H.sub.2O (0.1% TFA) to 100% CH.sub.3CN. The appropriate
fractions are lyophilized to provide the title compound as a white
solid.
[1196] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.19 (s, 1H),
8.48 (d, 1H), 7.91 (d, 1H), 7.88 (d, 1H), 7.50 (d, 1H), 7.43 (d,
1H), 7.20 (d, 1H), 7.02 (d, 1H), 6.90 (s, 1H), 4.71 (AB, 2H), 4.12
(m, 1H), 3.21 (m, 2H), 2.42 (m, 1H), 1.85 (m, 1H). EI MS,
[M.].sup.+=436, 438, Cl pattern.
EXAMPLE 61
[1197] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(1-amino-isoquinolin-
-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1198] A. 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(1-chloro-isoquin-
olin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1199] The title compound is prepared as described in EXAMPLE 56,
Part A using 5'-chloro-[2,2']bithiophenyl-5-sulfonyl chloride and
3-(S)-amino-1-(1-chloro-isoquinolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride as starting material. The crude product is purified
by column chromatography eluting with 5% MeOH/CH.sub.2Cl.sub.2 to
give the title compound as a white solid.
[1200] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.30 (d, 1H), 8.15
(s, l1H), 7.82 (d, 1H), 7.52-7.60 (m, 3H), 7.01-7.09 (m, 2H), 6.88
(d, 1H), 5.41 (s, 1H), 4.68 (AB, 2H), 3.90 (m, 1H), 3.29 (m, 2H),
2.61 (m, 1H), 2.11 (m, 1H). Ion spray MS, [M+H].sup.+=538, 540, Cl
pattern.
[1201] B. 5'-Chloro-[2,2'[bithiophenyl-5-sulfonic
acid[1-(1-amino-isoquino-
lin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1202] The title compound is prepared as described in EXAMPLE 56,
Part B using 5'-chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(1-chloro-isoquinoli-
n-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide as starting
material. The crude product is purified by RP-HPLC eluting with a
gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 100% CH.sub.3CN.
The appropriate fractions are lyophilized to provide the title
compound as a white solid.
[1203] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.03 (bs, 2H),
8.58 (d, 1H), 8.31 (s, 1H), 7.95 (d, 1H), 7.81 (d, 1H), 7.69 (d,
1H), 7.61 (d, 1H), 7.30-7.41 (m, 2H), 7.29-7.25 (m, 2H), 4.60 (AB,
2H), 4.25 (m, 1H), 3.23 (m, 2H), 2.20 (m, 1H), 1.75 (m, 1H). Ion
spray MS, [M+H].sup.+=519, 521, Cl pattern.
EXAMPLE 62
[1204] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(1-amino-isoquinol-
in-7-ylmethyl1)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1205] The title compound is prepared as described in EXAMPLE 56,
Part B using 2-(5-chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(1-chloro-isoquino-
lin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide as starting
material. The crude product product is purified by RP-HPLC eluting
with a gradient of 10% CH.sub.3CN/H.sub.2O (0.1% TFA) to 100%
CH.sub.3CN. The appropriate fractions are lyophilized to provide
the title compound as a pale pink solid.
[1206] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.00 (bs, 2H),
8.32 (s, 1H), 7.90-7.98 (m, 2H), 7.80 (d, 1H), 7.63 (d, 1H), 7.50
(d, 1H), 7.48 (d, 1H), 7.25 (d, 1H), 7.18 (d, 1H), 7.00 (d, 1H),
6.73 (d, 1H), 4.52 (AB, 2H), 4.20 (m, 1H), 3.23 (m, 2H), 2.48 (m,
1H), 1.88 (m, 1H). Ion spray MS, [M+H].sup.+=463, 465, Cl
pattern.
EXAMPLE 63
[1207] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinazolin-6y-
l-methyl)-2-oxopyrrolidin-3-(S)-yl]amide trifluoroacetate
[1208] The title compound is prepared as described in example 28
Parts E, F, G using 6-chloro-benzo[b]thiophene-2-sulfonyl
chloride
[1209] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.83 (bs, 2H),
8.86 (m, 2H), 8.25 (s, 1H), 8.11 (s, 1H), 8.00 (m, 3H), 7.85 (m,
2H), 7.55 (m, 1H), 4.50 (AB, 2H), 4.15 (m, 1H), 3.14 (m, 2H), 2.17
(m, 1H), 1.72 (m, 1H). FAB MS, [M+H].sup.+488, 490; Cl pattern.
EXAMPLE 64
[1210] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-thieno[2,3-d]-
pyrimidin-6-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[1211] The title compound is prepared as described in example 29
Parts F, G and H using 6-chloro-benzo[b]thiophene-2-sulfonyl
chloride.
[1212] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.78 (m, 2H),
8.28 (m, 2H), 8.04 (m, 2H), 7.82 (m, 2H), 7.51 (d, 1H), 7.40 (s,
1H), 4.58 (AB, 2H), 4.13 (m, 1H), 3.19 (m, 2H), 2.17 (m, 1H), 1.68
(m, 1H). FAB MS, [M+H].sup.+=494, 496; Cl pattern.
EXAMPLE 65
[1213] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-thieno[3,2-d]-
pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[1214] The title compound is prepared as described in example 30
Parts D, E using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride
[1215] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.8.52 (m, 2H),
8.20 (m, 1H), 8.11 (s, 1H), 7.91 (m, 2H), 7.71 (s, 1H), 7.42 (m,
1H), 7.30 (m, 2H), 4.58 (AB, 2H), 4.15 (m, 1H), 3.21 (m, 2H), 2.20
(m, 1H), 1.72 (m, 1H). FAB MS, [M+H].sup.+=494, 496; Cl
pattern.
EXAMPLE 66
[1216] 5'-Chloro-[2,2']bithiophenyl-5-2-sulfonic
acid[1-(4-amino-thieno[3,-
2-d]pyrimidin-7-yl-methyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[1217] The title compound is prepared as described in example 30
Parts D, E using 5'-chloro-[2,2']bithiophenyl-5-sulfonyl
chloride.
[1218] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.9.30 (m, 2H),
8.70 (m, 1H), 8.44 (m, 1H), 8.20 (m, 1H), 7.55 (m, 1H), 7.21 (m,
2H), 7.00 (m, 1H), 4.57 (AB, 2H), 4.15 (m, 1H), 3.20 (m, 2H), 2.19
(m, 1H), 1.70 (m, 1H). FAB MS, [M+H].sup.+=526, 528; Cl
pattern.
EXAMPLE 67
[1219]
2-(3-(S)-Amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine--
1-carboxylic acid tert-butyl ester.
[1220] A. (2-Bromo-pyridin-3-yl)-carbamic acid tert-butyl ester
[1221] To a solution of 3-amino-2-bromopyridine (1.5 g, 8.7 mmol)
and di-tert-butyl dicarbonate (2.0 g, 9.2 mmol) in THF (15 ml) is
added 1.0 M sodium bis(trimethylsilyl)amide in THF (18 ml, 18 mmol)
at 0.degree. C. The mixture is stirred at r.t. for 4 h, and then
concentrated, quenched with saturated NH.sub.4Cl, diluted with
EtOAc, and washed with water. The organic layer is dried over
MgSO.sub.4, treated with charcoal, filtered and concentrated to
dryness. Title compound is obtained as a light yellow solid (2.1g,
7.7 mmol).
[1222] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.44 (d, 1H), 8.03
(d, 1H), 7.20 (m, 111), 7.02 (bs, 1H), 1.50 (s, 9H). EI MS
[M+H].sup.+=273, 275.
[1223] B.
2-(3-(S)-Amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridi-
ne-1-carboxylic acid tert-butyl ester
[1224] The title compound is prepared from
(2-bromo-pyridin-3-yl)-carbamic acid tert-butyl ester (1.6 g, 5.9
mmol) and (2-oxo-1-prop-2-ynyl-pyrrolid- in-3-(S)-yl carbamic acid
benzyl ester (1.6 g, 5.9 mmol) according to the methods described
in EXAMPLE 59, Parts C,D and E. The title compound was obtained as
a white solid (0.29 g, 0.88 mmol).
[1225] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.45 (d, 1H), 8.27
(d, 1H), 7.18 (dd, 1H), 6.50 (s, 1H), 4.90 (AB, 2H), 3.64 (m, 1H),
3.45 (m, 2H), 2.52 (m, 1H), 1.85 (m, 1H), 1.70 (s, 9H). EI MS
[M+H].sup.+=331.
EXAMPLE 68
[1226] 6-Chloro-1H-benzimidazole-2-sulfonyl chloride
[1227] A mixture of 4-chloro-1,2-phenylenediamine (4.3 g, 30 mmol),
potassium hydroxide (1.9 g, 34 mmol), carbon disulfide (2.1 ml, 34
mmol), ethanol (30 ml) and water (4.5 ml) is heated under reflux
for 3 h. Norit is added, the mixture is refluxed 10 min, then
filtered. The warm filtrate is diluted with water (30 ml,
50-75.degree. C.) followed by aqueous acetic acid (7.5 ml, 33%)
with stirring. Brown solid forms, and the mixture is cooled with an
ice bath. 6-Chloro-1H-benzimidazole-2-thiol (4.2 g, 2.3 mmol) is
collected, washed with water and vacuum dried.:
[1228] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta.12.6 (d, 2H), 7.1
(s, 3H). EI MS M.sup.+=184, 186. A suspension of
6-chloro-1H-benzimidazole-2-- thiol (1.0 g, 5.4 mmol) in 20% AcOH
(30 ml) is cooled in an ice bath; Cl.sub.2 gas is bubbled through
the mixture for 40 min. The resulting solid is collected by
filtration, washed with H.sub.2O and air dried to give the title
compound as a light brown solid.
[1229] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.7.75 (m, 2H), 7.50
(d, 1H).
EXAMPLE 69
[1230] Thieno[2,3-b]pyridine-2-sulfonyl chloride
[1231] Thieno[2,3-b]pyridine (1.18 g, 8.7 mmol) is to subjected to
the three step sequence described in EXAMPLE 8, Part A. Flash
chromatography (20% EtOAc/Hexane) of the crude product gives the
title compound (0.59 g, 2.5 mmol):
[1232] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.78 (dd, 1H), 8.26
(dd, 1H), 8.10 (s, 1H), 7.47 (dd, 1H). EI MS M.sup.+=233, 235.
EXAMPLE 70
[1233] 6-Chloro-thieno[2,3-b]pyridine-2-sulfonyl chloride
[1234] 6-Chloro-thieno[2,3-b]pyridine (0.73 g, 4.3 mmol) is to
subjected to the three step sequence sequence described in EXAMPLE
8, Part A. Flash chromatography (15% EtOAc/Hexane) of the crude
product gives the title compound (0.75 g, 2.8 mmol):
[1235] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.19 (d, 1H), 8.07
(s, 1H), 7.47 (d, 1H). EI MS M.sup.+=267, 269, 271.
[1236] The compounds of Examples 71-74 are synthesized using
methods and reagents analogous to those described herein.
EXAMPLE 71
[1237] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1,6-diamino-isoquinolin-7--
ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1238] EI MS, [M].sup.+469.
EXAMPLE 72
[1239] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(1-amino-isoquinol-
in-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1240] ESI MS, [M+H].sup.+=463, 465 (Cl pattern).
EXAMPLE 73
[1241] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(1-amino-isoquinolin-
-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1242] EI MS, [M+H].sup.+=519, 521 (Cl pattern).
EXAMPLE 74
[1243] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[2-oxo-1-(1H-pyrrolo[-
3,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(S)-yl]-amide
[1244] EI MS, [M+H].sup.+=436, 438 (Cl pattern).
EXAMPLE 75
[1245] 3-(R)-5 Chlorothiophen-2-yl)ethenesulphonic
acid[1-(4-aminoquinolin- -7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate
[1246] Part A 7-Methyloxycarbonyl-4-chloro-quinoline
[1247] 4-Chloro-7-trifluoromethylquinoline (5.0 g, 21.6 mmol) in
100 mL 80% H.sub.2SO.sub.4 is heated to 200.degree. C. for 24 hours
in a sealed tube. The solution is cooled, poured into water and
neutralized with sodium hydroxide to pH .about.3-4. The
precipitated solid is collected, washed with water and dissolved in
2 N sodium hydroxide. The aqueous solution is washed with ethyl
acetate then acidified to pH.about.3-4. The precipitate is
collected, washed with water and dried in a vacuum oven overnight
to yield 7-carboxy-4-chloroquinoline as a solid (5.1 g, 24.6 mmol).
A portion of this material (2.0 g, 9.6 mmol) is treated with
anhydrous THF (200 mL) and DMF (2 mL) and 2 M oxalyl chloride in
methylene chloride (14.5 mL, 29 mmol). The resulting suspension is
stirred at room temperature for 2 h then treated with methanol (10
mL). After stirring 30 min. the solution is concentrated and the
residue is taken up in methylene chloride. The solution is washed
with saturated sodium bicarbonate and dried (sodium sulfate) and
concentrated to yield the title compound as a solid (2.1 g, 9.5
mmol). MS m/z: M.sup.+=221;
[1248] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.6 (s, 1H), 8.2
(s, 1H), 7.9 (d, 1H), 7.65 (d, 1H), 7.45 (s, 1H), 3.95 (s, 3H).
[1249] Part B 7-Hydroxymethyl-4-chloroquinoline
[1250] 7-Methyloxycarbonyl-4-chloroquinoline (2.1 g, 9.5 mmol) is
dissolved in anhydrous THF (25 mL) and anhydrous ether (200 mL).
The solution is cooled in a dry ice/acetone bath and treated 1 M
lithium aluminum hydride in THF (11.0 mL, 11 mmol). The solution is
warmed (approximately -45.degree. C.) for 20 min. and quenched with
ethyl acetate. The solution is diluted with ether (100 mL) and
treated with water (36 mL), 15% NaOH (36 mL) and water (3.times.36
mL) in succession. The mixture is filtered and evaporated to yield
the title compound as a residue (2.0 g, 9.7 mmol) which is dried
under vacuum and used without further purification. MS m/z:
M.sup.+=193;
[1251] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.0.00, 8.65 (d, 1H),
8.15 (d, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 7.45 (d, 1H), 4.8 (s,
2H).
[1252] Part C 7-Bromomethyl-4-chloroquinoline
[1253] 7-Hydroxymethyl4-chloroquinoline (0.2 g, 0.97 mmol) is
treated with 48% HBr and heated to 120.degree. C. for 1 h. The
resulting solution is cooled with ice, diluted with water and
treated with ethyl acetate and sodium bicarbonate until basic to pH
paper. The layers are separated and the organic layer is washed
with water, dried (Na.sub.2SO.sub.4) and concentrated to give
7-Bromomethyl-4-chloroquinoline (0.23 g, 0.9 mmol). MS m/z:
M.sup.+=255;
[1254] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.75 (d, 1H), 8.25
(d, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.5 (d, I1), 4.7 (s. 2H).
[1255] Part D
3-amino-1-(4-Chloro-quinolin-7-ylmethyl)-2-oxo-pyrrolidinone
Hydrochloride
[1256] 3-(R)-(t-butylcarbamyl)2-oxo-pyrrolidinone (1.0 g, 5.0 mmol)
is dissolved in THF (70 mL), cooled in an ice bath and treated with
tretrabutylammonium iodide (0.18 g) and 60% sodium hydride (0.24 g,
6.0 mmol). The reaction mixture is stirred at 0.degree. C. for 30
min. then treated dropwise with a solution of
7-bromomethyl-4-chloroquinoline (1.3 g, 5.1 mmol) in THF (50 mL).
The resulting solution is stirred at 0.degree. C. for 2 h then
quenched with ammonium chloride solution and concentrated. Dilution
with ethyl acetate is followed by a water wash; the organic layer
is dried (sodium sulfate) and concentrated. The residue is
chromatographed (3% methanol/methylene chloride) to yield solid
3-(R)-(t-butylcarbamyl)-1-(4-Chloro-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-
one (1.3 g, 3.3 mmol). This material is treated with a saturated
solution of Hydrogen chloride in ethyl acetate is stirred for 2 h
at room temp. The solid is filtered, washed with ethyl ether and
air dried to give the title compound (0.95 g, 3.0 mmol) MS m/z:
M.sup.+=;
[1257] .sup.1H NMR (CD.sub.3OD, 300 MHz) 9.0 (d, 1H), 8.5 (d, 1H),
8.15 (s, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 4.9 (q, 2H), 4.2 (t, 1H)
3.4 (m, 2H), 2.65 (m, 1H), 2,1 (m, 1H)
[1258] Part E 3-(R)-5 Chloro-thiophen-2-yl)-ethenesulphonic
acid[1-(4-Chloroquinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
[1259] 3-amino-1-(4-Chloro-quinolin-7-ylmethyl)-2-oxo-pyrrolidinone
Hydrochloride (40,0 mg, 0.12 mol) is treated with DMF (2 ml),
acetonitrile (8 mL), triethyl amine (1.2 ml, 8.4 mmol) and a
solution of 5-Chloro-thiophen-2-yl)-ethenesulphonyl chloride (30.0
mg, 0.12 mmol) in acetonitrile (2.0 mL) at 0.degree. C. After 2 h
the solution is poured into water and extracted with ethyl acetate.
The organic layer is washed with water, dried over sodium sulfate
and concentrated to yielded the title compound (28 mg, 0.5 mmol).
MS m/z: 481 [M+1].sup.+;
[1260] .sup.1H NMR (CDCl3, 300 MHz) .delta.8.8 (d, 1H), 8.15 (d,
1H), 7.9 (d, 2H), 7.85 (s, 1H), 7.4-7.5 (m, 2H) 6.7 (d, 1H), 6.6
(d, 1H), 6.5 (d, 1H), 5.8-5.9 (m, 1H), 4.75 (q, 2H), 4.2 (t, 11H),
3.3-3.4 (m, 2H), 2.6 (m, 1H), 2.0 (m, 1H).
[1261] Part F 3-(R)-5-Chloro-thiophen-2-yl)ethenesulphonic
acid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate
[1262] 3-(R)-5 Chloro-thiophen-2-yl)-ethenesulphonic
acid[1-(4-Chloro-quinolin-7-ylmethyl)2-oxo-pyrrolidin-3-yl]-amide
(20 mg), ammonium acetate (0.5 g), and phenol (1.0 g) are heated in
a sealed tube at 120.degree. C. for 1.5 hours. The vessel contents
are diluted with ethyl acetate and washed with 1 N NaOH
(4.times.100 ml), water, concentrated, and purified by HPLC (20%
acetonitrile in 0.1% aqueous TFA to 100% acetonitrile) and
lyophylized to give 2.0 mg of the title compound: MS m/z: 463
[M+H]
[1263] .sup.1H NMR (CD3OD, 300 MHz) 8.3 (m, 1H), 7.7 (s, 1H), 7,6
(d, 1H), 7.5 (d, 1H), 7.2 (d, 1H), 7.0 (s, 1H), 6.9 (d, 1H), 6,8 (
d, 1H), 4.9 (q, 2H), 4.25 (t, 1H), 3,5 (m, 2H), 2.6 (m, 1H), 2.05
(m, 1H).
[1264] The compounds of Examples 76-81 are synthesized using
methods and reagents analogous to those described herein.
EXAMPLE 76
[1265]
3-(S)-[[1-(4-Amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-(6-c-
hloro-benzo[b]thiophene-2-sulfonyl)-amino]-acetic acid methyl
ester, trifluoroacetate
[1266] ESI MS, [M+H].sup.+=559, 561.
EXAMPLE 77
[1267] 3-(S)-6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinoli-
n-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide, trifluoroacetate
[1268] ESI MS, [M+H].sup.+=487, 489.
EXAMPLE 78
[1269] 3-(S)-5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(4-amino-quinolin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide,
trifluoroacetate
[1270] ESI MS, [M+H].sup.+=463, 465.
EXAMPLE 79
[1271] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(4-amino-quinolin-6-ylmethy-
l)-2-oxo-pyrrolidin-3-(S)-yl]-amide, ditrifluoroacetate
[1272] ESI MS, [M+H].sup.+=454.
EXAMPLE 80
[1273]
N-(3-Amino-pyridin-4-yl)2-[3-(7-methoxy-naphthalene-2-sulfonylamino-
)-2-oxo-pyrrolidin-1-yl]-acetamide
[1274] MS, [M+H].sup.+=470.
EXAMPLE 81
[1275]
2-[3-(7-Methoxy-naphthalene-2-sulfonylamino-2-oxo-pyrrolidin-1-yl]--
N-pyridin-4-yl-acetamide
[1276] MS, [M+H].sup.+=455.
EXAMPLE 82
[1277] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid{2-oxo-1-[2-(pyridin-4-yl-
-amino)ethyl]-pyrrolidin-3-(S)yl}-amide trifluoroacetate
[1278] Part A [1-(2-Amino-ethyl)-2-oxo-pyrrolidin-3(S)-
yl]-carbamic acid tert-butyl ester
[2-Oxo-pyrrolidin-3(S)-yl]-carbamic acid tert-butyl ester (4.0 g,
20 mmol) is dissolved in THF (150 mL), cooled in an ice bath and
treated with 60% sodium hydride (0.95 g, 24 mmol). The reaction
mixture is stirred for 30 min., then treated with
tetra-butylammonium iodide (0.16 g, 0.44 mmol) and
bromoacetonitrile (1.7 mL, 24 mmol). After 3 h the reaction is
quenched with water, concentrated to a small volume and extracted
with methylene chloride (4.times.). The combined organic extracts
are concentrated and the residue is chromatographed (2%
MeOH/CH.sub.2Cl.sub.2) to give
[1-cyanomethyl-2-oxo-pyrrolidin-3(S)-yl]-c- arbamic acid tert-butyl
ester (3.4 g, 14 mmol). ). EI MS m/z: 240, [M+1].sup.+;
[1279] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.5.08 (br, 1H), 4.27
(m, 2H), 4.15 (m, 1H), 3.47 (m, 2H), 2.68 (m, 1H), 2.00 (m, 1H),
1.45 (s, 9H). This material (3.0 g, 12.6 mmol) is dissolved in
ethanol (80 mL) and treated with platinum oxide (0.8 g) at 50 PSI
of hydrogen gas for 24 h. The catalyst is removed by filtration and
the solution is concentrated to yield the title compound (2.9 g, 12
mmol). EI MS m/z: 244, [M+1].sup.+;
[1280] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.5.13 (br, 1H), 4.13
(m, 1H), 3.34 (m, 5H), 2.85 (t, 1H), 2.60 (m, 1H), 1.90 (m, 1H),
1.40 (s, 9H).
[1281] Part B
{2-Oxo-1-[2-(2,3,5,6-tetrachloro-pyridin-4-ylamino)-ethyl]-p-
yrrolidin-3(S)-yl}-carbamic acid tert-butyl ester
[1282] [1-(2-Amino-ethyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid
tert-butyl ester (2.7 g, 11 mmol) is dissolved in methylene
chloride (100 mL) and treated with
4-nitro-2,3,5,6-tetrachloro-pyridine (3.2 g, 12 mmol) and
N-methylmorpholine (2.6 mL, 24 mmol). The reaction mixture is
stirred for 5 h, concentrated and the residue is purified by
chromatography (50-60% ethyl acetate/hexane) to give the title
compound (3.2 g, 7.0 mmol). EI MS m/z: 456, 458, 460, 462
[M].sup.+;
[1283] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.5.6 (br, 1H), 5.07
(br, 1H), 4.15 (m, 1H), 3.94 (m, 2H), 3.60 (m, 2H), 3.36 (m, 2H),
2.65 (m, 1H), 1.98 (m, 1H), 1.44 (s, 9H).
[1284] Part C
3-(S)-Amino-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-2-one
{2-Oxo-1-[2-(2,3,5,6-tetrachloro-pyridin-4-ylamino)-ethyl]-pyrrolidin-3(S-
)-yl}-carbamic acid tert-butyl ester (0.42 g, 0.92 mmol) is
dissolved in methanol (16 mL) and treated with 0.5 M sodium
methoxide in methanol (18 mL, 8 mmol). The solution is treated with
10% Pd/C and agitated under 60 PSI of hydrogen gas for 16 h. The
solvent is removed and the residue is treated with saturated
NH.sub.4Cl and then saturated NaHCO.sub.3. The aqueous solution is
extracted with methylene chloride (8.times.). The methylene
chloride layer is dried (MgSO.sub.4) and concentrated to a white
foam (0.19 g, 5.9 mmol). EI MS m/z: 321, [M+1].sup.+;
[1285] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.20 (d, 2H), 6.45
(d, 2H), 5.1 (br, 1H), 4.9 (br, 1H), 4.1 (m, 1H), 3.7 (m, 1H), 3,4
(m, SH), 2.57 (m, 1H), 1.96 (m, 1H), 1.46 (s, 9H). This material
(0.14 g, 0A4 mmol) is treated with 20% trifluoroacetic acid in
methylene chloride (10 mL) at ambient temperature for 2 h.
Concentration of the solution gives clean product in the form of
TFA salt. The free base (0.072 g, 0.33 mmol) is obtained by
applying the TFA salt to a silica gel column and eluting with
NH.sub.4OH/MeOH/CH.sub.2Cl.sub.2 (1:10:70). APCI MS m/z: 221,
[M+1].sup.+;
[1286] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.17 (d, 2H), 6.40
(d, 2H), 4.90 (br, 1H), 3.55 (m, 3H), 3,34 (m, 4H), 2.42 (m, 1H),
1.80 (m, 1H).
[1287] Part D 6-Chloro-benzo[b]thiophene-2-sulfonic
acid{2-oxo-1-[2-(pyridin-4-yl-amino)-ethyl]-pyrrolidin-3(S)-yl}-amide
trifluoroacetate
[1288] 3-(S)-Amino-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-2-one
(0.12 mmol) is dissolved in MeCN (5 mL) and treated with
4-methylmorphorline (0.035 mL, 0.32 mmol);
6-chlorobenzo[b]thio-phene-2-sulfonyl chloride (0.033 g, 0.12 mmol)
in MeCN (1 mL) is added dropwise. The reaction mixture is stirred
at r.t. for 2 h, then subjected to HPLC purification, to give the
title compound as white solid (0.060 g, 0.11 mmol). MS m/z 451, 453
[M+1].sup.+;
[1289] .sup.1H NMR (CD.sub.3OD, 300 MHz) .delta.8.15 (d, 1H), 8.05
(s, 1H), 8.0 (m, 2H), 7.03 (d, 1H), 6.96 (dd, 1H), 6.82 (dd, 1H),
4.05 (t, 1H), 3.60-3.35 (m, 6H), 2.37 (m, 1H), 1.83 (m, 1H).
[1290] The compounds of Examples 83-88 are synthesized using
methods and reagents analogous to those described herein.
EXAMPLE 83
[1291] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid{2-oxo-1-[2-(pyridin-4--
ylamino)-etlyl]-pyrrolidin-3-yl}-amide
[1292] MS, [M+H].sup.+=483, 485.
EXAMPLE 84
[1293] 6-Chloro-thieno[2,3-b]pyridine-2-sulfonic acid
{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide
trifluoacetate
[1294] MS, [M+H].sup.+=452, 454.
EXAMPLE 85
[1295] Thieno[3,2-b]pyridine-2-sulfonic
acid{2-oxo-1-[2-(pyridin-4-ylamino- )-ethyl]-pyrrolidin-3-yl}-amide
ditrifluoroacetate
[1296] MS, [M+H].sup.+=418.
EXAMPLE 86
[1297] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid{2-oxo-1-[2-(pyridin-- 4-ylamino)-ethyl]-pyrrolidin-3-yl
}-amide
[1298] MS, [M+H].sup.+=427, 429.
EXAMPLE 87
[1299] (S)-5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid{1-[2-(2-amino-3-ch-
loro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amide
ditrifluoroacetate
[1300] MS, [M+H].sup.+=532, 534, 536.
EXAMPLE 88
[1301] (S)-6-Chloro-benzo[b]thiophene-2-sulfonic
acid{1-[2-(2-amino-3-chlo-
ro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amide
ditrifluoroacetate
[1302] MS, [M+H].sup.+=500, 502, 504.
EXAMPLE 89
[1303]
((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin-4-yla-
mino)-ethyl]-pyrrolidin-3(-yl}-amino)-acetic acid methyl ester
[1304] To a DMF (2 ml) solution of
6-chloro-benzo[b]thiophene-2-sulfonic acid is added
{2-oxo-1-[2-(pyridin4-yl-amino)-ethyl]-pyrrolidin-(S)-yl}-a- mide
(0,030 g 0.066 mmol) and K.sub.2CO.sub.3 (0.027 g, 0.2 mmol). After
stirring at r.t. for 10 min., methyl bromoacetate ( 0.01 ml, 0.1
mmol) is added and the mixture is stirred for 3 h. The solvent is
removed, and the residue is purified by chromatography using
NH.sub.4OH/MeOH/CH.sub.2Cl.su- b.2 (1:5:95) as eluant. The title
compound is obtained as a white solid (0.011 g, 0.021 mmol). MS m/z
523, 525 [M+1].sup.+;
[1305] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.8.15 (d, 2H), 7.98
(s, 1H), 7.84 (s, 1H), 7.80 (d, 1H), 7.41 (d, 1H), 6.35 (d, 2H),
4.72 (br, 1H), 4.55 (t, 1H), 4.18 (d, 1H), 3.85 (d, 1H), 3.70 (s,
3H), 2.55 (m, 1H), 3.4 (m, 5H), 2.60 (m, 1H), 2.35 (m, 1H).
[1306] The compounds of Examples 90-100 are synthesized using
methods and reagents analogous to those described herein.
EXAMPLE 90
[1307]
((6-Chloro-benzo[b]thiophene-2-sulfonyl)-{2-oxo-1-[2-(pyridin4-ylam-
ino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid
trifluoroacetate
[1308] MS. [M+H].sup.+=509, 511.
EXAMPLE 91
[1309] 6-Chloro-benzo[b]thiophene-2-sulfonic acid
allyl-{2-oxo-1-[2-(pyrid-
in-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide
[1310] MS, [M+H].sup.+491, 493.
EXAMPLE 92
[1311] 6-Chloro-benzo[b]thiophene-2-sulfonic acid
methyl-{2-oxo-1-[2-(pyri-
din-4-ylamino)-ethyl]-pyrrolidin-3-yl}-amide
[1312] MS, [M+H].sup.+=465, 467.
EXAMPLE 93
[1313] (S)-2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid{1-[2-(2-amino-3-chloro-pyridin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3--
yl}-amide trifluoroacetate
[1314] MS, [M+H].sup.+=476, 478, 480.
EXAMPLE 94
[1315] (S)-Thieno[3,2-b]pyridine-2-sulfonic
acid{-[2-(2-amino-3-chloro-pyr-
idin-4-ylamino)-ethyl]-2-oxo-pyrrolidin-3-yl}-amide
ditrifluoroacetate
[1316] MS, [M+H].sup.+=467, 469.
EXAMPLE 95
[1317]
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-
-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid methyl
ester
[1318] MS, [M+H].sup.+=499, 501.
EXAMPLE 96
[1319]
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-
-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid isopropyl
ester
[1320] MS, [M+H].sup.+=527, 529.
EXAMPLE 97
[1321]
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-
-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid
trifluoroacetate
[1322] MS, [M+H].sup.+=485, 487.
EXAMPLE 98
[1323] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid
(2-methoxy-ethyl)-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-pyrrolidin-3-yl}-
-amide trifluoroacetate
[1324] MS, [M+H].sup.+=485, 487.
EXAMPLE 99
[1325]
([2-(5-Chloro-thiophen-2-yl)-ethenesulfonyl]-{2-oxo-1-[2-(pyridin-4-
-ylamino)-ethyl]-pyrrolidin-3-yl}-amino)-acetic acid ethyl ester
trifluoroacetate
[1326] MS, [M+H].sup.+=513, 515.
EXAMPLE 100
[1327]
3-(5-Chloro-thiophen-2-yl)-N-{2-oxo-1-[2-(pyridin-4-ylamino)-ethyl]-
-pyrrolidin-3-yl}-acrylamide trifluoroacetate
[1328] MS, [M+H].sup.+=390, 392.
EXAMPLE 101
[1329]
1-1-(4Aminoquinazolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(4-chl-
orophenyl)urea trifluoroacetate
[1330] A. (2-Oxopyrrolidin-3-(S)-yl) carbamic acid tert-butyl
ester
[1331] N-a-(S)-tert-Butoxycarbonyl-.alpha., .gamma.-diaminobutyric
acid (20 g, 92 mmol) is suspended/dissolved in THF (360 mL), and
1-hydroxybenzotriazole hydrate (1 5.5 g, 100 mmol) added, followed
by the addition of triethylamine (28 g, 280 mmol). The suspension
is stirred at room temperature for 15 minutes under nitrogen,
before adding 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride (22 g, 115 mmol). The reaction mixture is heated at
60.degree. C. for 22 hours, cooled, and the solids filtered off
through a plug of silica. The solids and silica are washed with THF
until no more product is observed in the filtrate by TLC. The
combined filtrate is concentrated, and the residual yellow tacky
solid is left under high vacuum overnight. The residual material is
triturated with ethyl acetate (100 mL), filtered off and washed
with ethyl acetate and ethyl ether, then dried under high vacuum.
The product is isolated as fine colorless needles (12.2 g, 61
mmol).
[1332] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta.6.18 (m, 1H); 5.11
(m, 1H); 4.15 (m, 1H); 3.35 (m, 2H); 2.70 (m, 1H); 1.96 (m, 1H);
1.45 (s, 9H). ESI MS, [M+H].sup.+=201.
[1333] B. 2-Benzylideneamino-4-methylbenzonitrile
[1334] Benzaldehyde(8.9 g, 84 mmol) is added to a suspension of
2-amino-4-methylbenzonitrile (10.0 g, 76 mmol) in heptane (250 mL),
and the mixture refluxed under nitrogen overnight. The hot solution
is decanted into a pre-warmed flask to leave the insoluble brown
oil material behind, and the solution cooled to room temperature
after adding ethyl acetate (2mL). The resulting solid is filtered
off and washed with heptane:ethyl acetate=100:1 (2.times.25 mL),
and dried under high vacuum to give a beige powder (12.54 g, 57
mmol).
[1335] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta.8.46 (H, s); 7.95
(dd, 2H); 7.50 (m, 4H); 7.07 (dd, 1H); 6.97 (s, 1H); 2.43 (s,
3H).
[1336] C. 2-Amino-4-(bromomethyl)benzonitrile
[1337] 2,2'-Azobisisobutyronitrile (AIBN) (1.31 g, 8 mmol) is added
to a solution of N-bromosuccinimide (6.87 g, 38 mmol) and
2-benzylideneamino-4-methylbenzonitrile (7 g, 31.8 mmol) in carbon
tetrachloride (250 mL), and the reaction mixture refluxed under
nitrogen overnight. The reaction mixture is cooled and filtered
through a plug of celite, and the celite washed with carbon
tetrachloride (100 mL). The combined filtrate is washed with 1N
HCl, saturated aqueous NaHCO.sub.3, dried over MgSO.sub.4 and
concentrated in vacuo. The crude product is purified by column
chromatography on silica with 10-20% ethyl acetate/hexanes. The
combined product fractions are concentrated, and the resulting
sticky solid is washed with ethyl ether/hexanes to give the product
as a pale yellow solid (3.26 g, 15 mmol).
[1338] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta.7.36 (d, 1H); 6.75
(m, 2H); 4.45 (br s, 2H); 4.35 (s, 2H). EI MS, [M+H].sup.+=212.
[1339] D.
[1-(3-Amino-4-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acid
tert-butyl ester
[1340] (2-Oxopyrrolidin-3-(S)-yl) carbamic acid tert-butyl ester (1
g, 5 mmol) is dissolved in THF (100 mL) under nitrogen, and cooled
to 0.degree. C. Potassium-tert-butoxide (0.62 g, 5.5 mmol) is added
in one portion to the vigorously stirring solution, followed by
18-crown-6 (10 mg, 0.038 mmol), and the reaction mixture allowed to
warm to room temperature and stirred for 1 hour. The solution is
cooled to 0.degree. C. and 2-amino-4-(bromomethyl)benzonitrile
(1.16 g, 5.5 mmol) added dropwise as a solution in THF (10 mL),
before leaving the reaction mixture to warm to room temperature and
stir overnight. The reaction is quenched with 0.25M HCl (20 mL),
then neutralized with saturated aqueous NaHCO.sub.3, and brine
added. The solution is extracted with ethyl acetate, and the
organic phase dried over MgSO.sub.4, concentrated, and purified by
column chromatography on silica with 0.5-5%
methanol/dichloromethane. The product fractions are combined,
concentrated, and the semi-solid oily residue triturated with
hexanes/dichloromethane=100/1 (25 mL). The product is isolated as a
pale yellow powder (1.24 g, 3.75 mmol).
[1341] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta.7.35 (d, 1H); 6.64
(d, 1H); 6.58 (dd, 1H); 5.15 (br s, 1H); 4.40 (m, 4H); 4.19 (m,
1H); 3.24 (m, 2H); 2.60 (m, 1H); 1.90 (m, 1H); 1.45 (s, 9H). ESI
MS, [M+H].sup.+331.
[1342] E.
[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carba-
mic acid tert-butyl ester
[1343] [1-(3-Amino-4-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]carbamic
acid tert-butyl ester (890 mg, 2.69 mmol) and 1,3,5-triazine (650
mmo, 8 mmol) are combined in ethanol (40 mL), and acetic acid (480
mg, 8 mmol) added. The reaction mixture is refluxed under nitrogen
overnight, cooled and presorbed directly onto silica. The product
is purified by column chromatography on silica with 5-20%
methanol/dichloromethane (containing 0.5% of 28% aqueous ammonium
hydroxide). The product fractions are combined and concentrated,
and the residue left under high vacuum overnight. The product is
isolated as a pale yellow powder(0.50 g, 1.4 mmol).
[1344] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.9.90 (br s, 2H);
8.35 (s, 1H); 8.16 (d, 1H); 7.49 (d, 1H); 7.31 (dd, 1H); 7.22 (br
d, 1H); 4.57 (d, 1H); 4.44 (d, 1H); 4.20 (m, 1H); 3.18 (m, 2H);
2.23 (m, 1H); 1.80 (m, 1H); 1.39 (s, 9H). ESI MS,
[M+H].sup.+=358.
[1345] F.
3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride
[1346]
[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamic
acid tert-butyl ester (1.70 g, 5.15 mmol) is dissolved in methanol
(100 mL) and stirred at 0.degree. C. while bubbling HCl.sub.(g)
through the solution until saturated (became cloudy). The reaction
mixture is left at room temperature for 10 minutes, then
concentrated in vacuo. The residue is washed with ethyl acetate and
ether, and dried under high vacuum to give the product as a pale
yellow powder (1.33 g, 4 mmol).
[1347] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.8.81 (s, 1H);
8.73 (br s, 2H); 8.57 (d, 1H); 7.87 (d, 1H); 7.65 (dd, 1H); 6.68
(br s, 2H); 4.73 (d, 1H); 4.60 (d, 1H); 4.13 (m, 1H); 3.35 (m, 2H);
2.43 (m, 1H); 2.10 (m? 1H). ESI MS, [M+H].sup.+=258.
[1348] G.
1-[1-(4-Aminoquinazolin-7ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(-
4-chlorophenyl) urea trifluoroacetate
[1349]
3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride (50mg, 0.15 mmol) and triethylamine (40mg, 0.40 mmol)
in dimethylformamide (3 mL) stirred at room temperature for 30
minutes, and 4-chlorophenylisocyanate (25 mg, 0.16 mmol) added as a
solution in DMF (2 mL). Left at room temperature for 1 hour, then
removed dimethylformamide at 45.degree. C./25 psi on air vortex
blower. The residue is dissolved in 30% acetonitrile/water (2%
trifluoroacetic acid) and purified by preparative reverse phase
HPLC with gradient elution 15-45% acetonitrile/water (0.1%
trifluoroacetic acid). The product fractions are combined, the
acetonitrile removed in vacuo, and the aqueous solution lyophilized
to give the product as an off-white powder, which is washed with
acetonitrile (2 mL) to give pure product as a white powder (45 mg,
0.086 mmol).
[1350] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.9.60 (br s, 2H);
8.87 (s, 1H); 8.80 (s, 1H); 8.37 (d, 1H); 7.62 (dd, 1H); 7.58 (d,
1H); 7.43 (d, 2H), 7.25 (d, 2H); 6.65 (d, 1H); 4.64 (m, 2H); 4.36
(m, 1H); 3.28 (m, 2H); 2.40 (m, 1H); 1.91 (m, 1H). ESI MS,
[M+H].sup.+=411.
EXAMPLE 102
[1351]
N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-2-(5--
clorothiophen-2-yloxy)acetamide trifluoroacetate
[1352]
3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride (40 mg, 0.12 mmol) and diisopropylethylamine (130 mg,
1 mmol) in dimethylformamide (1 mL) is stirred for 15 minutes at
room temperature. The aforementioned solution is added to a
solution of 2-(5-chlorothiophen-2-yloxy)acetic acid (23 mg, 0.12
mmol), diisopropylethylamine (20 mg, 0.16 mmol) and
2-(1H-benzotriazol-1-yl)-1,1- ,3,3-tetramethyluronium
tetrafluoroborate (TBTU) (39 mg, 0.12 mmol) in dimethylformamide (1
mL), which had been stirring at room temperature for 5 minutes
prior to addition. The reaction mixture is left stirring at room
temperature over the weekend. The dimethylformamide is removed at
45.degree. C./25 psi on a vortex air blower, and the residue
dissolved in 20% acetonitrile/water (2% trifluoroacetic acid) and
purified by preparative reverse phase HPLC with gradient elution
15-45% acetonitrile/water (0.1% trifluoroacetic acid). The product
fractions are combined, the acetonitrile removed in vacuo, and the
aqueous solution lyophilized to give the product as an off-white
powder (34 mg, 0.062 mmol).
[1353] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.9.62 (br s, 2H);
8.80 (s, 1H); 8.64 (d, 1H); 8.34 (d, 1H); 7.62 (dd, 111); 7.60 (d,
1H); 6.78 (d, 1H); 6.28 (d, 1H); 4.59 (m, 5 H); 3.27 (m, 2H); 2.32
(m, 1H); 1.97 (m, 1H). ESI MS, [M+H].sup.+=432.
EXAMPLE 103
[1354]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmeth-
yl)amino]pyrrolidin-2-one trifluoroacetate
[1355]
3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride (40 mg, 0.12 mmol) and powdered potassium carbonate
(80 mg, 0.58 mmol) are dissolved/suspended in DMF (1 mL), and to
this solution is added
2-bromomethyl-1-tert-butoxycarbonyl-5-chloroindole (41 mg, 0. 12
mmol) as a solution in DMF (1 mL). The reaction mixture is
sonicated for 10 minutes, then stirred at room temperature
overnight The dimethylformamide is removed at 45.degree. C./25 psi
on a vortex air blower, and extracted the residue into methanol
(2.times.10 mL). Diluted the filtrate with methanol (30 mL), and
cooled at 0.degree. C. whilst bubbling dry HCl.sub.(g) through the
solution until saturated. The reaction mixture is left overnight at
room temperature. The resulting red solution is concentrated in
vacuo and extracted into acetonitrile (2 mL), diluted with water
(1% trifluoroacetic acid) and the insoluble solids filtered off
prior to purification of the crude material by reverse phase
preparative HPLC with gradient elution 20-60% acetonitrile/water
(0.1% trifluoroacetic acid). The product fractions are combined,
the acetonitrile removed in vacuo, and the aqueous solution
lyophilized to give the product as an off-white powder (12 mg,
0.022 mmol).
[1356] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.11.43 (s, 1H);
9.61 (brs, 3H); 8.78 (s, 1H); 8.36 (d, 1H); 7.67 (s, 1H); 7.63 (d,
1H); 7.59 (dd, 1H); 7.46 (d, 1H); 7.13 (dd, 1H); 6.64 (d, 1H); 4.70
(d, 1H); 4.63 (d, 1H); 4.51 (m, 2H); 4.19 (m, 1H); 3.34 (m, 2H);
2.45 (m, 1H); 2.07 (m, 1H). ESI MS, [M+H].sup.+=421.
EXAMPLE 104
[1357]
1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5--
chlorothiophen-2-yl) urea trifluoroacetate and
5-Chlorothiophene-2-carboxy- lic
acid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide
trifluoroacetate
[1358] 3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one
hydrochloride (40 mg, 0.12 mmol) and diisopropylethylamine are
dissolved in DMF (1 mL) and added to 5-chlorothiophene-2-carboxylic
acid azide (23 mg, 0.12 mmol). The reaction mixture is heated at
100.degree. C. for 20 minutes, cooled to room temperature, and the
dimethylformamide removed at 45.degree. C./25 psi on a vortex air
blower. The residue is dissolved in 30% acetonitrile/water (2%
trifluoroacetic acid) and purified by preparative reverse phase
HPLC with gradient elution 15-30% acetonitrile/water (0.1%
trifluoroacetic acid). The fractions of the two different products
are separately combined, the acetonitrile removed in vacuo, and the
aqueous solutions lyophilized to give the products as white
powders: urea (9 mg, 0.017 mmol), amide (22 mg, 0.043 mmol).
[1359] Urea: .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.9.98 (s,
1H); 9.59 (br s, 2H); 8.80 (s, 1H); 8.38 (d, 1H); 7.59 (m, 2H);
6.88 (d, 1H); 6.75 (d, 1H); 6.24 (d, 1H); 4.67 (d, 1H); 4.59 (d,
1H); 4.39 (m, 1H); 3.27 (m, 2H); 2.40 (m, 1H); 1.94 (m, 1H). ESI
MS, [M+H].sup.+=421.
[1360] Amide: .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.9.73 (br
s, 2H); 9.02 (d, 1H); 8.82 (s, 1H); 8.40 (d, 1H); 7.65 (m, 3H);
7.21 (d, 1H); 4.68 (m, 3H); 3.31 (m, 2H); 2.37 (m, 1H); 2.06 (m,
1H). ESI MS, [M+H].sup.+=421.
EXAMPLE 105
[1361]
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-[3-(5-
-chlorothiophen-2-yl)acryloyl]amino}acetic acid methyl ester
trifluoroacetate
[1362] A. 3-(S)-Amino
1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one
[1363]
3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride (600 mg, 1.82 mmol) is chromatographed on silica with
12% methanol/2% ammonium hydroxide (28% aqueous)/86%
dichloromethane, and the product fractions combined and
concentrated to give the free base as a pale yellow powder (360 mg,
1.4 mmol).
[1364] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.8.35 (s, 1H);
8.16 (d. 1H); 7.74 (br s, 2H); 7.47 (d, 1H); 7.29 (dd, 1H); 4.55
(d, 1H); 4.49 (d, 1H); 3.95 (br d, 2H); 3.55 (t, 1H); 3.J 8 (m,
2H); 2.27 (m, 1H); 1.69 (m, 1H). ESI MS, [M+H].sup.+=258.
[1365] B.
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amin-
o}acetic acid tert-butyl ester trifluoroacetate
[1366] tert-Butyl bromoacetate (247 mg, 1.267 mmol) in
dimethylformamide (5 mL) is added dropwise to a solution of
3-(S)-Amino-1-(4-aminoquinazoli- n-7-ylmethyl)pyrrolidin-2-one (326
mg, 1.267 mmol) and pyridine (100 mg, 1.267 mmol) in
dimethylformamide, stirring at room temperature. After 90 minutes
an additional equivalent of pyridine (100 mg, 1.267 mmol) in
dimethylformamide (2 mL) is added, followed by the dropwise
addition of a second equivalent of tert-butyl bromoacetate (247 mg,
1.267 mmol) in dimethylformamide (5 mL). The reaction mixture is
left at room temperature for 180 minutes, diluted with
dichloromethane (150 mL) and flash chromatographed on silica with
neat dichloromethane, then 20% methanol/5% ammonium hydroxide (28%
aqueous)/75% dichloromethane. The crude product fractions are
combined and concentrated to give an impure yellow solid, which is
dissolved in 15% acetonitrile/water (2% trifluoroacetic acid) and
purified by preparative reverse phase HPLC with gradient elution
10-50% acetonitrile/water (0.1% trifluoroacetic acid). The product
fractions are combined and solvents removed in vacuo, and the
residue left under high vacuum overnight. The product is isolated
as a pale pink powder (300 mg, 0.808 mmol).
[1367] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.9.76 (br s, 3H);
8.82 (s, 1H); 8.39 (d, 1H); 7.68 (d, 1H); 7.61 (dd, 1H); 4.64 (m,
2H); 4.11 (m, 3H); 3.33 (m, 2H); 2.40 (m, 1H); 2.04 (m, 1H); 1.47
(s, 9H). ESI MS, [M+H].sup.+=372.
[1368] C.
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-[3-
-(5-chlorothiophen-2-yl)acryloyl]amino}acetic acid methyl ester
trifluoroacetate
[1369] Same coupling procedure as in EXAMPLE 102, except that the
coupling species are
{[1-(4-aminoquinazolin-7-ylmethyl)-2oxopyrrolidin-3-(S)-yl]am-
ino}acetic acid tert-butyl ester trifluoroacetate and
3-(5-chlorothiophen-2-yl)acrylic acid. The residue from
concentrating the reaction mixture is dissolved in 40%
acetonitrile/water (2% trifluoroacetic acid) and purified by
preparative reverse phase HPLC with gradient elution 30-100%
acetonitrile/water (0.1% trifluoroacetic acid). The product
fractions are combined and the solvents removed in vacuo to give
the tert-butyl ester intermediate as a white powder. This
intermediate is dissolved in methanol, and cooled to 0.degree. C.
whilst bubbling dry HCl.sub.(g) through the solution until
saturated. The reaction mixture is left at room temperature
overnight, then concentrated in vacuo, and the residue dissolved in
20% acetonitrile/water (2% trifluoroacetic acid) and purified by
preparative reverse phase HPLC with gradient elution 10-100%
acetonitrile/water (0.1% trifluoroacetic acid). The product
fractions are combined, the acetonitrile removed in vacuo, and the
aqueous solution lyophilized to give the product as a white powder
(9 mg, 0.015 mmol).
[1370] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) rotamers observed:
.delta.9.78 (br s, 2H); 8.82, 8.83 (2s, 1H); 7.62 (m, 3H); 7.36 (m,
1H); 7.15 (m, 1H); 6.88,6.73 (2d, 1H); 5.28, 4.17 (2t, 1H); 4.40
(m, 3H); 3.64, 3.59 (2s, 3H); 3.28 (m, 2H); 2.37 (m, 1H); 2.10 (m,
1H). ESI MS, [M+H].sup.+=500.
EXAMPLE 106
[1371] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-aminoquinazolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate
[1372] A. (2-Oxopyrrolidin-3-(R)-yl) carbamic acid tert-butyl
ester
[1373] Same procedure as EXAMPLE 101A, but using the (R) enantiomer
starting material, instead of the (S).
[1374] .sup.1H-NMR (CDCl.sub.3, 300MHz) .delta.6.18 (m, 1H); 5.11
(m, 1H); 4.15 (m, 1H); 3.35 (m, 2H); 2.70 (m, 1H); 1.96 (m, 1H);
1.45 (s, 9H). ESI MS, [M+H].sup.+=201.
[1375] B.
[1-(3-Amino-4-cyanobenzyl)-2-oxopyrrolidin-3-(R)-yl]carbamic acid
tert-butyl ester
[1376] Same procedure as EXAMPLE 101 D, but using the (R)
enantiomer as starting material, instead of the (S).
[1377] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta.7.35 (d, 1H); 6.64
(d, 1H); 6.58 (dd, 1H); 5.15 (br s, 1H); 4.40 (m, 4H); 4.19 (m,
1H); 3.24 (m, 2H); 2.60 (m, 1H); 1.90 (m, 1H); 1.45 (s, 9H). ESI
MS, [M+H].sup.+=331.
[1378] C.
[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]carba-
mic acid tert-butyl ester
[1379] Same procedure as EXAMPLE 101 E, but using the (R)
enantiomer as starting material, instead of the (S).
[1380] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.9.90 (br s, 2H);
8.35 (s, 1H); 8.16 (d, 1H); 7.49 (d, 1H); 7.31 (dd, 1H); 7.22 (br
d, 1H); 4.57 (d, 1H); 4.44 (d, 1H); 4.20 (m, 1H); 3.18 (m, 2H);
2.23 (m, 1H); 1.80 (m, 1H); 1.39 (s, 9H). ESI MS,
[M+H].sup.+=358.
[1381] D.
3-(R)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one
[1382] Same procedure as EXAMPLE 101 F, followed by procedure in
EXAMPLE 105A, but in each case using the (R) enantiomer as starting
material instead of the (S).
[1383] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.8.81 (s, 1H);
8.73 (br s, 2H); 8.57 (d, 1H); 7.87 (d, 1H); 7.65 (dd, if); 6.68
(br s, 2H); 4.73 (d, 1H); 4.60 (d, 1H); 4.13 (m, 1H); 3.35 (m, 2H);
2.43 (m, 1H); 2.10 (m, 1H). ESI MS, [M+H].sup.+=258.
[1384] E. 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-aminoquinazolin--
7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate
[1385] 3-(R)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one
(36 mg, 0.14 mmol) and 6-chlorothiophene-2-sulfonyl chloride (40
mg, 0.15 mmol) are dissolved in dichloromethane (2 mL) and DMF (1
mL), and triethylamine (36 mg, 0.35 mg) added. Left the reaction
mixture stirring overnight at room temperature, before
concentrating at 45.degree. C./25 psi on air vortex blower. The
residue is dissolved in 30% acetonitrile/water (2% trifluoroacetic
acid) and purified by preparative reverse phase HPLC with gradient
elution 20-60% acetonitrile/water (0.1% trifluoroacetic acid). The
product fractions are combined, the acetonitrile removed in vacuo,
and the aqueous solutions lyophilized to give the product as a
white powder (9 mg, 0.015 mmol).
[1386] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.9.61 (br s, 2H);
8.75 (m, 2H); 8.34 (d, 1H); 8.27 (s, 1H); 8.05 (s, 1H); 8.02 (d,
1H); 7.55 (m, 3H); 4.55 (m, 2H); 4.25 (m, 1H); 2.99 (m, 2H); 2.18
(m, 1H); 1.73 (m, 1H). ESI MS, [M+H]=488.
EXAMPLE 107
[1387] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-aminoisoquinolin-7-ylmet-
hyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate
[1388] A.
[1-(1-Chloroisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]car-
bamic acid tert-butyl ester
[1389] Same procedure as EXAMPLE 101D, but using
(2-oxopyrrolidin-3-(R)-yl- ) carbamic acid tert-butyl ester (312
mg, 1.56 mmol) and 7-bromomethyl-1-chloroisoquinoline (440 mg, 1.72
mmol) as the starting materials. The crude product is purified by
column chromatography on silica with 50-100% ethyl acetate/hexanes.
The product fractions are combined and concentrated to give the
product as a pale yellow powder (471 mg, 1.25 mmol).
[1390] .sup.1H-NMR (CDCl.sub.3, 300 MHz) .delta.8.28 (d, 1H); 8.14
(s, 1H); 7.83 (d, 1H); 7.67 (dd, I1H); 7.55 (d, 1H); 5.50 (br s,
1H); 4.77 (d, 1H); 4.65 (d, 1H); 4.31 (m, 1H); 3.27 (m, 2H); 2.60
(m, 1H); 1.96 (m, 1H); 1.47 (s, 9H). ESI MS, [M+H].sup.+=376.
[1391] B.
3-(R)-Amino-1-(1-aminoisoquinolin-7-ylmethyl)pyrrolidin-2-one
trifluoroacetate
[1392]
[1-(1-chloroisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]carbam-
ic acid tert-butyl ester (384 mg, 1.02 mmol), phenol (962 mg, 10.2
mmol), and anhydrous ammonium acetate (1.576 g, 20.4 mmol) are
combined in a sealed tube, and heated at 100.degree. C. overnight.
Then the mixture is cooled, acetonitrile (20 mL) and water (20 mL)
are added, and the phases are separated. The aqueous phase is
washed with ethyl acetate, and concentrated to dryness. The residue
from concentration is extracted into methanol, filtered off solids,
and the filtrate concentrated. The residue is dissolved in 10%
acetonitrile/water (2% trifluoroacetic acid) and purified by
preparative reverse phase HPLC with gradient elution 10-30%
acetonitrile/water (0.1% trifluoroacetic acid). The product
fractions are combined, the solvents removed in vacuo, and the
product dried under high vacuum. Isolated as a white powder (88 mg,
0.238 mmol).
[1393] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.9.11 (br s, 2H);
8.43 (br s, 2H); 8.37 (s, 1H); 7.98 (d, 1H); 7.83 (dd, 1H); 7.69
(d, 1H); 7.24 (d, 1H); 4.66 (d, 1H); 4.59 (d, 1H); 4.09 (m, 1H);
3.34 (m, 2H); 2.38 (m, 1H); 1.96 (m, 1H). ESI MS,
[M+H].sup.+=257.
[1394] C. Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(1-aminoisoquinolin-7-yl-
methyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate
[1395]
3-(R)-Amino-1-(1-aminoisoquinolin-7-ylmethyl)pyrrolidin-2-one
trifluoroacetate (80 mg, 0.216 mmol) and diisopropylethylamine (140
mg, 1.08 mmol) are dissolved in acetonitrile (12mL), and stirred at
room temperature for 15 minutes before adding
thieno[3,2-b]pyridine-2-sulfonyl chloride dropwise as a solution in
acetonitrile (8 mL). The reaction mixture is left at room
temperature overnight, water (4 mL) added, and the solution
concentrated in vacuo to remove the acetonitrile (ca. 4 mL of
solution). 75% Acetonitrile/water (4 mL) is added, and the product
purified by reverse phase preparative HPLC with gradient elution
10-40% acetonitrile/water (0.1% trifluoroacetic acid). The product
fractions are combined, the acetonitrile removed in vacuo, and the
aqueous solution lyophilized to give the product as a white powder
(52 mg, 0.092 mmol).
[1396] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.9.12 (br s, 2H);
8.86 (d, 1H); 8.77 (br d, 1H); 8.59 (d, 1H); 8.27 (s, 1H); 8.12 (s,
1H); 7.92 (d, 1H); 7.77 (dd, 1H); 7.65 (d, 1H); 7.51 (dd, 1H); 7.21
(d, 1H); 4.61 (d, 1H); 4.47 (d, 1H); 4.36 (m, 1H); 3.19 (m, 2H);
2.21 (m, 1H); 1.74 (m, 1H). ESI MS, [M+H].sup.+=454.
EXAMPLE 108
[1397]
1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-(5-chloro-1H-indol-2-ylmethyl)-
amino]pyrrolidin-2-one trifluoroacetate
[1398] A.
[1-(4-chloroquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbam-
ic acid tert-butyl ester
[1399] Same procedure as EXAMPLE 101D, but using
7-bromomethyl4-chloroquin- oline as the electrophile. The crude
product is purified by column chromatography on silica with 1-20%
methanol/ethyl acetate. The product fractions are combined and
concentrated to give a semi-solid/oil which is triturated with
ether to give the product as a white powder.
[1400] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.8.83 (d, 1H);
8.17 (d, 1H); 7.95 (s, 1H); 7.74 (d, 1H); 7.62 (dd, 1H); 7.22 (d,
1H); 4.66 (d, 1H); 4.57 (d, 1H); 3.20 (m, 2H); 2.23 (m, 1H); 1.83
(m, 1H); 1.39 (s, 9H). ESI MS, [M+H].sup.+=376.
[1401] B.
3-(S)-Amino-1-(4-aminoquinolin-7-ylmethyl)pyrrolidin-2-one
hydrochloride
[1402]
[1-(4-chloroquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamic
acid tert-butyl ester (250 mg, 0.665 mmol), phenol (626 mg, 6.65
mmol), and anhydrous ammonium acetate (513 mg, 6.65 mmol) are
combined and heated at 100.degree. C., with reflux apparatus, under
nitrogen overnight. Then the mixture is cooled to room temperature,
and acetonitrile (2 mL) and water (2 mL) are added. The solution
separates into 2 phases (both containing product), which are
concentrated to dryness, and separately purified by reverse phase
preparative HPLC with gradient elution 20-40% acetonitrile/water
(0.1% trifluoroacetic acid). The product fractions from each run
are combined, the solvents are removed in vacuo, and the residue
dried under high vacuum overnight. The
[1-(4-Aminoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]carbamic
acid tert-butyl ester intermediate is dissolved in methanol, and
cooled to 0.degree. C., whilst bubbling dry HCl.sub.(g) through the
solution until saturated. The reaction mixture is left at room
temperature for 2 hours, and concentrated in vacuo. The residue is
washed with ether to give the pure product as a colorless powder
(170 mg, 0.516 mmol).
[1403] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.9.15 (br s, 2H);
8.75 (br s, 2H); 8.50 (d, 1H); 8.35 (d, 1H); 7.96 (s, 1H); 7.53 (d,
1H); 6.79 (d, 1H); 4.71 (d, 1H); 4.58 (d, 1H); 4.11 (m, 1H); 3.11
(m, 2H); 2.45 (m, 1H); 2.13 (m, 1H). ESI MS, [M+H].sup.+=257.
[1404] C.
1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-indol-2-ylmet-
hyl)amino]pyrrolidin-2-one trifluoroacetate
[1405] Same procedure as EXAMPLE 103, except with
3-(S)-Amino-1-(4-aminoqu- inolin-7-ylmethyl)pyrrolidin-2-one
hydrochloride as starting material instead of
3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride.
[1406] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.11.39 (s, 1H);
9.73 (br s, 1H); 8.97 (br s, 2H); 8.38 (m, 1H); 7.73 (s, 1H); 7.62
(d, 1H); 7.52 (d, 1H); 7.45 (d, 1H); 7.13 (dd, 1H); 6.75 (d, 1H);
6.64 (s, 1H); 4.65 (m, 2H); 4.54 (d, 1H); 4.46 (d, 1H); 4.15 (m,
1H); 3.32 (m, 2H); 2.46 (m, 1H); 2.05 (m, 1H). ESI MS,
[M+H].sup.+=420.
EXAMPLE 109
[1407]
1(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[3-(5-chlorothiophen-2-yl)all-
ylamino]pyrrolidin-2-one trifluoroacetate
[1408] 3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one
hydrochloride (40 mg, 0.12 mmol) and powdered potassium carbonate
(80 mg, 0.58 mmol) are dissolved/suspended in DMF (1 mL), and to
this solution is added 3-(5-chlorothiophen-2-yl)allyl bromide (30
mg, 0.126 mmol) as a solution in DMF (1 mL). The reaction mixture
is sonicated for 10 minutes, then stirred at room temperature
overnight. The dimethylformamide is removed at 45.degree. C./25 psi
on a vortex air blower, the residue extracted into methanol
(2.times.10 mL), and filtered off the solids. The filtrate is
concentrated, and the crude material is purified by reverse phase
preparative HPLC with gradient elution 20-60% acetonitrilevater
(0.1% trifluoroacetic acid). The product fractions are combined,
the acetonitrile removed in vacuo, and the aqueous solution
lyophilized to give the product as an off-white powder (15 mg,
0.028 mmol).
[1409] .sup.1H-NMR (DMSO-d.sub.6, 300 MHz) .delta.9.64 (br s, 3H);
8.79 (s, H); 7.68 (d, H); 7.59 (dd, H); 7.08 (d, H); 6.95 (d, H);
5.96 (m, H); 4.71 (d, J); 4.64 (d, H); 4.25 (t, H); 3.87 (d, H);
3.37 (m, 2H); 2.47 (m, H); 2.05 (m, H). ESI MS,
[M+H].sup.+=414.
EXAMPLE 110
[1410]
N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5--
chlorothiophen-2-yl)acrylamide trifluoroacetate
[1411] Same procedure as EXAMPLE 102, but using
3-(5-chlorothiophen-2-yl)a- crylic acid instead of
2-(5-chlorothiophen-2-yloxy)acetic acid.
[1412] ESI MS, [M+H].sup.+=428.
EXAMPLE 111
[1413]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-
-ylmethyl)amino]pyrrolidin-2-one trifluoroacetate
[1414] Same procedure as EXAMPLE 103, but using a mixture of
2-chloromethyl-1-tert-butoxycarbonyl-5-chlorobenzimidazole and
2-chloromethyl-l-tert-butoxycarbonyl-6-chlorobenzimidazole instead
of 2-bromomethyl-1-tert-butoxycarbonyl-5-chloroindole.
[1415] ESI MS, [M+H].sup.+=422.
EXAMPLE 112
[1416]
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][2-(5-c-
hlorothiophen-2-yl)ethenesulfonyl]amino}acetic acid methyl ester
trifluoroacetate
[1417] Same initial procedure as EXAMPLE 106E, but using
{[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amino}acetic
acid tert-butyl ester trifluoroacetate instead of
3-(R)-amino-1-(4-aminoq- uinazolin-7-ylmethyl)pyrrolidin-2-one, and
2-(5-chlorothiophen-2-yl)ethene- sulfonyl chloride instead of
6-chlorothiophene-2-sulfonyl chloride. The intermediate tert-butyl
ester is isolated by reverse phase preparative HPLC with gradient
elution 10-100% acetonitrile/water (0.1% trifluoroacetic acid). The
product fractions are combined, the solvents removed in vacuo, and
the intermediate dried overnight under high vacuum. The dried
material is dissolved in methanol, and cooled at 0.degree. C.
whilst bubbling HCl.sub.(g) through the solution until saturated.
Left stirring at room temperature overnight. The reaction mixture
is concentrated to dryness in vacuo, and the residue dissolved in
20% acetonitrile/water (2% trifluoroacetic acid) and purified by
preparative reverse phase HPLC with gradient elution 20-100%
acetonitrile/water (0.1% trifluoroacetic acid). The product
fractions are combined, the acetonitrile removed in vacuo, and the
aqueous solution lyophilized to give the product as a white
powder.
[1418] ESI MS, [M+H].sup.+=536.
EXAMPLE 113
[1419]
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl](5-chlo-
ro-1H-indol-2-ylmethyl)amino]acetic acid methyl ester
trifluoroacetate
[1420] Same procedure as EXAMPLE 103, but using
{[1-(4-aminoquinazolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(S)-yl]amino}acetic acid tert-butyl
ester trifluoroacetate instead of
3-(S)-amino-1-(4-aminoquinazolin-7-ylmethyl)p- yrrolidin-2-one
hydrochloride.
[1421] ESI MS, [M+H].sup.+=493.
EXAMPLE 114
[1422]
{[1-(Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl][3-(5-chl-
orothiophen-2-yl)allyl]amino}acetic acid methyl ester
trifluoroacetate
[1423] Same procedure as EXAMPLE 103, but using
{[1-(4-aminoquinazolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(S)-yl]amino}acetic acid tert-butyl
ester trifluoroacetate instead of
3-(S)-amino-1-(4-aminoquinazolin-7-ylmethyl)p- yrrolidin-2-one
hydrochloride, and 3-(5-chlorothiophen-2-yl)allyl bromide instead
of added 2-bromomethyl-1-tert-butoxycarbonyl-5-chloroindole.
[1424] ESI MS, [M+H].sup.+=486.
EXAMPLE 115
[1425]
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-3-(5-c-
hlorothiophen-2-yl)ureido}acetic acid methyl ester
trifluoroacetate
[1426] Same initial procedure as EXAMPLE 104, but using
{[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amino}acetic
acid tert-butyl ester trifluoroacetate instead of
3-(R)-amino-1-(4-aminoq- uinazolin-7-ylmethyl)pyrrolidin-2-one.
Only the urea is observed--no amide. The intermediate tert-butyl
ester is isolated by reverse phase preparative HPLC with gradient
elution 10-100% acetonitrile/water (0.1% trifluoroacetic acid). The
product fractions are combined. the solvents removed in vacuo, and
the intermediate dried overnight under high vacuum. The dried
material is dissolved in methanol, and cooled at 0.degree. C.
whilst bubbling HCl.sub.(g) through the solution until saturated.
Left stirring at room temperature overnight. The reaction mixture
is concentrated to dryness in vacuo, and the residue dissolved in
20% acetonitrile/water (2% trifluoroacetic acid) and purified by
preparative reverse phase HPLC with gradient elution 20-60%
acetonitrile/water (0.1% trifluoroacetic acid). The product
fractions are combined, the acetonitrile removed in vacuo, and the
aqueous solution lyophilized to give the product as a white
powder.
[1427] ESI MS, [M+H].sup.+=489.
EXAMPLE 116
[1428]
N-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5--
chlorothiophen-2-yl)acrylamide trifluoroacetate
[1429] Same procedure as EXAMPLE 110, but using the (R) enantiomer
as starting material, instead of the (S).
[1430] ESI MS, [M+H].sup.+=428.
EXAMPLE 117
[1431]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(R)[(5-chloro-1H-indol-2-ylmethy-
l)amino]pyrrolidin-2-one trifluoroacetate
[1432] Same procedure as EXAMPLE 103, but using the (R) enantiomer
as starting material, instead of the (S).
[1433] ESI MS, [M+H].sup.+=421.
EXAMPLE 118
[1434]
1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5--
chlorothiophen-2-yl) urea trifluoroacetate and
5-Chlorothiophene-2-carboxy- lic
acid[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide
trifluoroacetate
[1435] Same procedure as EXAMPLE 104, but using the (R) enantiomer
as starting material, instead of the (S).
[1436] Urea: ESI MS, [M+H].sup.+=417. Amide: ESI MS,
[M+H].sup.+=402.
EXAMPLE 119
[1437]
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl](5-chlo-
ro-1H-indol-2-ylmethyl)amino]acetic acid methyl ester
trifluoroacetate
[1438] A.
{[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amin-
o}acetic acid tert-butyl ester
[1439] Same initial procedure as EXAMPLE 105B, but using the (R)
enantiomer as starting material, instead of the (S). No need to
carry out the HPLC purification, because pure material is obtained
by the column chromatography. Product isolated as the free
base.
[1440] ESI MS, [M+H].sup.+=372.
[1441] B.
{[1-(4-Aminoquinazolin-7-ylmethl)-2-oxopyrrolidin-3-(R)-yl](5-ch-
loro-1H-indol-2-ylmethyl)amino]acetic acid methyl ester
trifluoroacetate
[1442] Same procedure as EXAMPLE 113, but using
{[1-(4-aminoquinazolin-7-y-
lmethyl)-2-oxopyrrolidin-3-(R)-yl]amino}acetic acid tert-butyl
ester instead of
{[1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]am-
ino}acetic acid tert-butyl ester trifluoroacetate as the starting
material.
[1443] ESI MS, [M+H].sup.+=493.
EXAMPLE 120
[1444]
1-(4-Aminoquinolin-7-ylmethyl)-3-(S)-[(5-chloro-1H-benzimidazol-2-y-
lmethyl)amino]pyrrolidin-2-one trifluoroacetate
[1445] Same procedure as EXAMPLE 103, but using
3-(S)-Amino-1-(4-aminoquin- olin-7-ylmethyl)-pyrrolidin-2-one
hydrochloride as starting material instead of
3-(S)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one
hydrochloride; and a mixture of
2-chloromethyl-1-tert-butoxycarbonyl-5-ch- lorobenzimidazole and
2-chloromethyl-1-tert-butoxycarbonyl-6-chlorobenzimi- dazole
instead of 2-bromomethyl-1-tert-butoxycarbonyl-5-chloroindole.
[1446] ESI MS, [M+H].sup.+=421.
[1447] The compounds of Examples 121-138 are synthesized using
methods and reagents analogous to those described herein.
EXAMPLE 121
[1448] 5-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinazolin-7--
ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate
[1449] ESI MS, [M+H].sup.+=487, 489, Cl pattern.
EXAMPLE 122
[1450] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(4-amino-thieno[3,-
2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
[1451] ESI MS, [M+H].sup.+=470, 472, Cl pattern.
EXAMPLE 123
[1452] 7-Methoxy-naphthalene-2-sulfonic
acid[1-(4-amino-quinazolin-7-ylmet-
hyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate
[1453] ESI MS, [M+H].sup.+=477.
EXAMPLE 124
[1454] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic
acid[1-(4-amino-quinazoli-
n-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate
[1455] ESI MS, [M+H].sup.+=464, 466, Cl pattern.
EXAMPLE 125
[1456] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-amino-quinazolin-7--
ylmethyl)2-oxo-pyrrolidin-3-(S)-yl]-amide trifluoroacetate
[1457] ESI MS, [M+H].sup.+=488, 490, Cl pattern.
EXAMPLE 126
[1458] 5-Chloro-benzo[b]thiophene-2-sulfonic acid
(S)-[1-(4-amino-thieno[3-
,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate
[1459] ESI; MS, [M+H].sup.+=493, 395, Cl pattern.
EXAMPLE 127
[1460] Thieno[3,2-b]pyridine-2-sulfonic acid
(S)-[1-(4-amino-thieno[3,2-d]-
pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate
[1461] ESI MS, [M+H].sup.+=460.
EXAMPLE 128
[1462] 6-Chloro-benzo[b]thiophene-2-sulfonic acid
(S)-[1-(4-amino-thieno[3-
,2-d]pyrimidin-6ylmethyl)2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate
[1463] ESI MS, [M+H].sup.+=493, 495, Cl pattern.
EXAMPLE 129
[1464] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic acid
(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-
-amide trifluoroacetate
[1465] ESI MS, [M+H].sup.+=525, 527, Cl pattern.
EXAMPLE 130
[1466] 2-(5-Chloro-thiophen-2-yl)-ethenesulfonic acid
(S)-[1-(4-amino-thieno[3,2-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-
-amide trifluoroacetate
[1467] ESI MS, [M+H].sup.+=469, 471, Cl pattern.
EXAMPLE 131
[1468] 5-Chloro-benzo[b]thiophene-2-sulfonic acid
[(S)1-(4-amino-thieno[3,-
2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate
[1469] ESI MS, [M+H].sup.+32 493, 495, Cl pattern.
EXAMPLE 132
[1470] 5-Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)-1-(4-amino-thieno[2,-
3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate
[1471] ESI MS, [M+H].sup.+=493, 495, Cl pattern.
EXAMPLE 133
[1472] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[(S)-1-(4-amino-thieno[-
2,3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate
[1473] ESI MS, [M+H].sup.+=525, 527, Cl pattern.
EXAMPLE 134
[1474] Thieno[3,2-b]pyridine-2-sulfonic
acid[(S)1-(4-amino-thieno[2,3-d]py-
rimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate
[1475] ESI MS, [M+H].sup.+=460.
EXAMPLE 135
[1476] 6-Chloro-benzo[b]thiophene-2-sulfonic
acid[(S)-1-(4-amino-thieno[2.-
3-d]pyrimidin-6-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate
[1477] ESI MS, [M+H].sup.+=493, 495, Cl pattern.
EXAMPLE 136
[1478] 5'-Chloro-[2,2']bithiophenyl-5-sulfonic
acid[1-(4-amino-thieno[3,2--
d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[1479] ESI MS, [M+H].sup.+=525, 527, Cl pattern.
EXAMPLE 137
[1480] Thieno[3,2-b]pyridine-2-sulfonic
acid[1-(4-amino-thieno[3,2-d]pyrim-
idin-7-ylmethyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide
trifluoroacetate
[1481] ESI MS, [M+H].sup.+=460.
EXAMPLE 138
[1482] 6-Chloro-benzo[b]thiophene-2-sulfonic acid
[(S)-1-(4-amino-thieno[3-
,2-d]pyrimidin-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
[1483] ESI MS, [M+H].sup.+=493, 495, Cl pattern.
EXAMPLE 139
[1484] 3-(R)-6-Chloro-benzo[b]thiophene-2-sulfonic
acid[1-(4-aminoquinolin- e-7-ylmethyl)-2-oxo-pyrrolidin-3-yl]-amide
trifluoroacetate
[1485] 3-(R)-Amino-1-(4-aminoquinolin-7-ylmethyl)pyrrolidin-2-one
bis-hydrochloride (160 mg, 0.48 mmol) and diisopropylethylamine
(620 mg, 4.8 mmol) are dissolved in actonitrile (2 mL); and
6-chlorobenzo[b]thiophene-2-sulfonyl chloride (115 mg, 0.43 mmol)
is then added. The reaction mixture is stirred overnight at room
temperature and then concentrated in vacuo. The residue is
dissolved in 30% acetonitrile/water (2% trifluoroacetic acid) and
purified by preparative reverse phase HPLC with gradient elution
20-60% acetonitrile/water (0.1% trifluoroacetic acid). The product
fractions are combined, the acetonitrile removed in vacuo, and the
aqueous solutions lyophilized to give the product as a white powder
(46 mg, 0.076 mmol).
[1486] ESI MS, [M+H+=487, 489, Cl pattern.
EXAMPLE 140
[1487] 2-(5-Chlorothiophen-2-yl)-ethenesulfonic
acid[1-(4-aminoquinazolin--
7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate
[1488] 3-(R)-Amino-1-(4-aminoquinazolin-7-ylmethyl)pyrrolidin-2-one
bis-trifluoroacetate (97 mg, 0.2 mmol) and diisopropylethylamine
(260 mg, 2 mmol) are dissolved in acetonitrile (8 mL), and
2-(5-chlorothiophen-2-y- l)ethenesulfonyl chloride (54 mg, 0.22
mmol) is then added. The reaction mixture is stirred overnight at
room temperature and then concentrated in vacuo. The residue is
dissolved in 30% acetonitrile/water (2% trifluoroacetic acid) and
purified by preparative reverse phase HPLC with gradient elution
10-100% acetonitrile/water (0.1% trifluoroacetic acid). The product
fractions are combined, the acetonitrile removed in vacuo, and the
aqueous solutions lyophilized to give the product as a white powder
(32 mg, 0.057 mmol). ESI MS, [M+H].sup.+=464, 466, Cl pattern.
[1489] Similarly, the following compounds are synthesized using
methods and reagents analogous to those described above:
[1490] 3-[[1-(4-Aminoquinolin-7-ylmethyl)-
2-oxopyrrolidin-3-(R)-yl]-(5-ch-
loro-1H-indol-2-ylmethyl)amino]propionic acid methyl ester;
[1491]
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl-
)-(3-ethylbutyl)amino]pyrrolidin-2-one;
[1492]
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-benzyl-(5-chloro-1H-indol-2-yl-
methyl)amino]pyrrolidin-2-one;
[1493]
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl-
)thiazol-5-ylmethylamino]pyrrolidin-2-one;
[1494]
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl-
)-(2H-pyrazol-3-ylmethyl))amino]pyrrolidin-2-one;
[1495]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(6-chlorobenzo[b]thiophen-2-
-ylmethyl)amino]pyrrolidin-2-one;
[1496] 1(4
-Aminoquinazolin-7-ylmethyl)-3-(S)-(6-chlorothieno[2,3-b]pyridi-
n-2-ylmethyl)amino]pyrrolidin-2-one;
[1497]
1-(4-Aminoquinazolin-7-ylmethyl)-3-(S)-[(1H-pyrrolo[2,3-c]pyridin-2-
-ylmethyl)amino]pyrrolidin-2-one;
[1498]
3-{[1(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-ylamino]m-
ethyl}-1H-quinolin-2-one;
[1499]
1-(7-Aminothieno[3,2-b]pyridin-2-ylmethyl)-3(R)-[(5-chloro-1H-indol-
-2-ylmethyl)amino]pyrrolidin-2-one;
[1500] 2-(5-Chlorothiophen-2-yl)-ethenesulfonic
acid[2-oxo-1-(1H-pyrrolo[3-
,2-c]pyridin-2-ylmethyl)-pyrrolidin-3-(R)-yl]amide;
[1501]
{[2-(5-Chlorothiophen-2-yl)ethenesulfonyl]-[2-oxo-1-(1H-pyrrolo[3,2-
-c]pyridin-2-ylmethyl)-pyrrolidin-3-(R)-yl]amino}acetic acid
isopropyl ester,
[1502]
1-(4-Aminoquinolin-7-ylmethyl)-3-(R)-[(5-chloro-1H-indol-2-ylmethyl-
)amino]pyrrolidin-2-one; and
[1503] 5-Chloro-1H-benzoimidazole-2-sulfonic
acid[1-(4-aminoquinolin-7-ylm-
ethyl)-2-oxopyrrolidin-3-(R)-yl]amide. 61
[1504] Reaction vessels are charged with
4-hydroxy-2,3,5,6-tetraflurobenza-
midomethyl-copoly-(styrene-1%-divinylbenzene)-resin (0.20 g, 0.15
mmol). Each container is treated with methylene chloride (2 mL) for
10 minutes followed by an aromatic sulfonyl chloride (0.45 mmol)
and diisopropyethyl amine (0.104 ml, 0.60 mmol). The containers are
sealed and agitated for about 16 h. The reaction mixtures are
individually filtered and sequentially washed with 20% aqueous DMF
(10.times.), THF (5.times.) and dichloromethane (5.times.), then
dried in vacuo at ambient temperature overnight. By way of example
6-chlorobenzothiophene-2-sulfonyl)oxy-2,3,5,-
6-tetrafluro-benzamidomethyl-copoly-(styrene-1%-divinylbenzene)-resin
showed: .sup.19F-NMR d-144.572, -145.608; IR (cm-1) 1684 (C.dbd.O
stretch), 1391, (asymmetric SO.sub.2 stretch) 1195, 1177 (symmetric
SO.sub.2 stretch). 62
[1505] Reaction vessels are charged with
arylsulfonyloxy-2,3,5,6tetrafluro-
-benzamidomethyl-copoly-(styrene-1% divinylbenzene)-resins (0.024
g, 0.012 mmol), prepared as described above. The resins are swelled
with DMF, then treated with a 0.01 M solution of an amine (1 ml,
0.01 mmol) in DMF. The containers are covered with aluminum foil
and agitated for 72 h. The progress of the reaction is monitored by
TLC; for sluggish reactions 1,5,7-triazabicyclo[4.4.0]dec-5-ene
resin is added. The reaction mixtures are individually filtered and
the resins washed with methanol. The filtrates are concentrated
with a stream of nitrogen. The residues are redissolved in methanol
and reconcentrated twice more. The resulting residues are treated
with 20% trifluoroacetic acid in methylene chloride (1 ml) and
agitated overnight. The reaction mixture is concentrated by a steam
of nitrogen. Methylene choride (1 ml) is added; concentrate with a
steam of nitrogen. Methanol (1 ml) is added; concentrate with a
stream of nitrogen. The final residues are analyzed by LC/mass
spec; evidence of desired product was obtained in each case. By way
of example, the product from the reaction of
6-chlorobenzothiophene-2-sulfonyl)oxy-2,3,5,6-tetraf-
luro-benzamidomethyl-copoly-(styrene-1%-divinylbenzene)-resin with
2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carbo-
xylic acid tert-butyl ester and subsequent deprotection with 20%
TFA in methylene chloride showed: M+H=461 . This material had an
IC.sub.50 against Factor Xa of less than 500 nM.
[1506] By the methods described in this preparation
2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[3,2-b]pyridine-1-carbo-
xylic acid tert-butyl ester,
2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-py-
rrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester and
2-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-pyrrolo[2,3-c]pyridine-1-carbo-
xylic acid tert-butyl ester are reacted with fourteen
arylsulfonyloxy-2,3,5,6-tetrafluro-benzamidomethyl-copoly-(styrene-1%-div-
inylbenzene)-resins to obtain, after deprotection, compounds
encompassed by the following formula:
[1507] wherein 63
[1508] is selected from: 64
[1509] R.sub.1 is H; and R.sub.2 is selected from the group of
formulae consisting of: 65
[1510] or 66
[1511] is selected from: 67
[1512] R.sub.1 is H; and R.sub.2 is selected from the group of
formulae consisting of: 68
[1513] or 69
[1514] is selected from: 70
[1515] R.sub.1 is H; and R.sub.2 is selected from the group of
formulae consisting of: 71
[1516] By the methods described herein compounds encompassed by the
following formula: 72
[1517] wherein 73
[1518] is selected from: 74
[1519] R.sub.1 is H; and R.sub.2 is selected from the group of
formulae consisting of: 75
[1520] are also prepared.
[1521] By the methods described herein compounds encompassed by the
following formula: 76
[1522] wherein 77
[1523] R.sub.1 is H; and R.sub.2 is selected from the group of
formulae consisting of: 78
[1524] are also prepared.
[1525] The molecules described herein inhibit blood coagulation by
virtue of their ability to inhibit the penultimate enzyme in the
coagulation cascade, controlling the activity of Factor Xa. Both
the activity of free Factor Xa and Factor Xa assembled in the
prothrombinase complex (Factor Xa, Factor Va, calcium and
phospholipid) are inhibited by compounds of formula I. The
inhibition of the Factor Xa activity is obtained by direct complex
formation between the inhibitor and the enzyme and is therefore
independent of the plasma co-factor antithrombin III. Effective
inhibition of the Factor Xa activity is achieved by administering
the compounds either by oral administration, continuous intravenous
infusion, bolus intravenous administration or any other parenteral
route such that it achieves the desired effect of preventing Factor
Xa induced formation of thrombin from prothrombin.
[1526] Anticoagulant therapy is indicated for the treatment and
prophylaxis of a variety of thrombotic conditions of both the
venous and arterial vasculature. In the arterial system, abnormal
thrombus formation is primarily associated with arteries of the
coronary, cerebral and peripheral vasculature. The diseases
associated with thrombotic occlusion of these vessels principally
include acute myocardial infarction (AMI), unstable angina,
thromboembolism, acute vessel closure associated with thrombolytic
therapy and percutaneous transluminal coronary angioplasty (PTCA),
transient ischemic attacks, stroke, intermittent claudication and
bypass grafting (CABG) of the coronary or peripheral arteries.
Chronic anticoagulant therapy may also be beneficial in preventing
the vessel luminal narrowing (restenosis) that often occurs
following PTCA and CABG, and in the maintenance of vascular access
patency in long-term hemodialysis patients. With respect to the
venous vasculature, pathologic thrombus formation frequently occurs
in the veins of the lower extremities following abdominal, knee and
hip surgery (deep vein thrombosis, DVT). DVT further predisposes
the patient to a higher risk of pulmonary thromboembolism. A
systemic, disseminated intravascular coagulopathy (DIC) commonly
occurs in both vascular systems during septic shock, certain viral
infections and cancer. This condition is characterized by a rapid
consumption of coagulation factors and their plasma inhibitors
resulting in the formation of life-threatening thrombin throughout
the microvasculature of several organ systems. The indications
discussed above include some, but not all, of the possible clinical
situations where anticoagulant therapy is warranted. Those
experienced in this field are well aware of the circumstances
requiring either acute or chronic prophylactic anticoagulant
therapy.
[1527] The compounds of this invention may be used alone or in
combination with other diagnostic, cardioprotective, direct
thrombin inhibiting, anticoagulant, antiplatelet or fibrinolytic
agents. These agents may include anti-coagulants such as warfarin
or heparin; synthetic pentasaccharides; anti-platelet agents such
as aspirin, piroxicam or ticlopidine; direct thrombin inhibitors,
such as boroarginine derivatives, hirudin or argatroban
(Novastan.RTM.); fibrinogen receptor antagonists; statins/fibrates;
or fibrinolytic agents (thrombolytic agents) such as tissue
plasminogen activator, anistreplase (Eminase.RTM.), urokinase or
streptokinase; or combinations thereof.
[1528] For example, adjunctive administration of inhibitors of the
activity of Factor Xa with standard heparin, low molecular weight
heparin, direct thrombin inhibitors (i.e. hirudin), aspirin,
fibrinogen receptor antagonists, streptokinase, urokinase and/or
tissue plasminogen activator may result in greater antithrombotic
or thrombolytic efficacy or efficiency. The compounds described
herein may be administered to treat thrombotic complications in a
variety of animals such as primates, including humans. Inhibition
of factor Xa is useful not only in the anticoagulant therapy of
individuals having thrombotic conditions but is useful whenever
inhibition of blood coagulation is required such as to prevent
coagulation of stored whole blood and to prevent coagulation in
other biological samples for testing or storage. Thus, any
inhibitor of Factor Xa activity can be added to or contacted with
any medium containing or suspected of containing Factor Xa and in
which it is desired that blood coagulation be inhibited.
[1529] The term cardioprotective agents as used herein, denotes
agents that act to protect myocardium during ischemia. These
cardioprotective agents include, but are nor limited to, adenosine
agonists, .beta.-blockers and Na/H exchange inhibitors. Adendosine
agonists include those compounds disclosed in Spada et al., U.S.
Pat. No. 5,364,862 and Spada et al., U.S. Pat. No. 5,736,554, the
disclosures of which are hereby incorporated herein by reference.
An example of an adenosine agonists is AMP 579 (Rhone-Poulenc
Rorer). An example of a Na/H exchange inhibitor is Cariporide (HOE
642).
[1530] The term anti-coagulant agents as used herein, denotes
agents that inhibit blood coagulation. Such agents include warfarin
(Coumadin.RTM.) and heparin.
[1531] The term anti-platelet agents as used herein, denotes agents
that inhibit platelet function such as by inhibiting the
aggregation, adhesion or granular secretion of platelets. Such
agents include the various known non-steroidal anti-inflammatory
drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac,
indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and
piroxicam (Feldane.RTM.), including pharmaceutically acceptable
salts or prodrugs thereof. Other suitable anti-platelet agents
include ticlopidine (Ticlid), thromboxane-A2-receptor antagonists
and thromboxane-A2-synthetase inhibitors, as well as
pharmaceutically acceptable salts or prodrugs thereof.
[1532] The phrase direct thrombin inhibitors (i.e. Factor IIa
inhibitors), as used herein, denotes inhibitors of the serine
protease thrombin. By inhibiting thrombin directly, the inhibition
of the cleavage of fibrinogen to fibrin, activation of Factor
XIIIa, activation of platelets, and feedback of thrombin to the
coagulation cascade to generate more thrombin, occurs. Such direct
inhibitors include boroarginine derivatives and boropeptides,
hirudin and argatroban (Novastan.RTM.), including pharmaceutically
acceptable salts and prodrugs thereof. Boroarginine derivatives and
boropeptides include N-acetyl and peptide derivatives of boronic
acid, such as C-terminal .beta.-aminoboronic acid derivatives of
lysine, ornithine, arginine, homoarginine and corresponding
isothiouronium analogs thereof. The term hirudin, as used herein,
includes suitable derivatives or analogs of hirudin, referred to
herein as hirulogs, such as disulfatohirudin.
[1533] The phrase fibrinolytic agents (or thrombolytics or
fibrinolytics), as used herein, denotes agents that lyse blood
clots. Such agents include tissue plasminogen activator,
anistreplase (Eminase.RTM.), urokinase or streptokinase, including
pharmaceutically acceptable salts or prodrugs thereof Tissue
plasminogen activator (tPA) is commercially available from
Genentech Inc., South San Francisco, Calif. The term urokinase, as
used herein, is intended to denote both dual and single chain
urokinase, the latter also being referred to herein as
prourokinase.
[1534] In addition to their use in anticoagulant therapy,
inhibitors of Factor Xa activity may find utility in the treatment
or prevention of other physiological conditions in which the
generation of thrombin has been implicated as playing a pathologic
role. For example, thrombin has been proposed to contribute to the
morbidity and mortality of such chronic and degenerative diseases
as arthritis, cancer, atherosclerosis, restenosis post coronary
angioplasty and Alzheimer's disease by virtue of its ability to
regulate many different cell types through specific cleavage and
activation of a cell surface thrombin receptor. Inhibition of
factor Xa activity will effectively block thrombin generation and
therefore neutralize any pathologic effects of thrombin on various
cell types.
[1535] According to a further feature of the invention there is
provided a method for the treatment of a human or animal patient
suffering from, or subject to, a physiological condition which can
be ameliorated by the administration of an inhibitor of the Factor
Xa activity, for example conditions as hereinbefore described,
which comprises the administration to the patient of a
therapeutically effective amount of compound of formula I or a
composition containing a compound of formula I. "Effective amount"
is meant to describe an amount of compound of the present invention
effective in inhibiting the activity of Factor Xa and thus
producing the desired therapeutic effect.
[1536] The present invention also includes within its scope
pharmaceutical formulations which comprise at least one of the
compounds of formula I in association with a pharmaceutically
acceptable carrier or coating.
[1537] The compounds utilized in combination therapy may be
administered simultaneously, in either separate or combined
formulations, or at different times than the present compounds,
e.g., sequentially, such that a combined effect is achieved. The
amounts and regime of administration will be adjusted by the
practitioner, by preferably initially lowering their standard doses
and then titrating the results obtained.
[1538] In practice compounds of the present invention may generally
be administered parenterally, intravenously, subcutaneously
intramuscularly, colonically, nasally, intraperitoneally, rectally
or orally.
[1539] The products according to the invention may be presented in
forms permitting administration by the most suitable route and the
invention also relates to pharnmaceutical compositions containing
at least one product according to the invention which are suitable
for use in human or veterinary medicine. These compositions may be
prepared according to the customary methods, using one or more
pharmaceutically acceptable adjuvants or excipients. The adjuvants
comprise, inter alia, diluents, sterile aqueous media and the
various non-toxic organic solvents. The compositions may be
presented in the form of tablets, pills, granules, suppositories
powders, aqueous solutions or suspensions, injectable solutions,
elixirs or syrups, and can contain one or more agents chosen from
the group comprising sweeteners, flavorings, colorings, or
stabilizers in order to obtain pharmaceutically acceptable
preparations.
[1540] The choice of vehicle and the content of active substance in
the vehicle are generally determined in accordance with the
solubility and chemical properties of the product, the particular
mode of administration and the provisions to be observed in
pharmaceutical practice. For example, excipients such as lactose,
sodium citrate, calcium carbonate, dicalcium phosphate and
disintegrating agents such as starch, alginic acids and certain
complex silicates combined with lubricants such as magnesium
stearate, sodium lauryl sulfate and talc may be used for preparing
tablets. To prepare a capsule, it is advantageous to use lactose
and high molecular weight polyethylene glycols. When aqueous
suspensions are used they can contain emulsifying agents or agents
which facilitate suspension. Diluents such as sucrose, ethanol,
polyethylene glycol, propylene glycol, glycerol and chloroform or
mixtures thereof may also be used.
[1541] For parenteral administration, emulsions, suspensions or
solutions of the products according to the invention in vegetable
oil, for example sesame oil, groundnut oil or olive oil, or
aqueous-organic solutions such as water and propylene glycol,
injectable organic esters such as ethyl oleate, as well as sterile
aqueous solutions of the pharmaceutically acceptable salts, are
used. The solutions of the salts of the products according to the
invention are especially useful for administration by intramuscular
or subcutaneous injection. The aqueous solutions, also comprising
solutions of the salts in pure distilled water, may be used for
intravenous administration with the proviso that their pH is
suitably adjusted, that they are judiciously buffered and rendered
isotonic with a sufficient quantity of glucose or sodium chloride
and that they are sterilized by heating, irradiation or
microfiltration.
[1542] Suitable compositions containing the compounds of the
invention may be prepared by conventional means. For example,
compounds of the invention may be dissolved or suspended in a
suitable carrier for use in a nebulizer or a suspension or solution
aerosol, or may be absorbed or adsorbed onto a suitable solid
carrier for use in a dry powder inhaler.
[1543] Solid compositions for rectal administration include
suppositories formulated in accordance with known methods and
containing at least one compound of formula I.
[1544] The percentage of active ingredient in the compositions of
the invention may be varied, it being necessary that it should
constitute a proportion such that a suitable dosage shall be
obtained. Obviously, several unit dosage forms may be administered
at about the same time. The dose employed will be determined by the
physician, and depends upon the desired therapeutic effect, the
route of administration and the duration of the treatment, and the
condition of the patient. In the adult, the doses are generally
from about 0.01 to about 100, preferably about 0.01 to about 10,
mg/kg body weight per day by inhalation, from about 0.01 to about
100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body
weight per day by oral administration, and from about 0.01 to about
50, preferably 0.01 to 10, mg/kg body weight per day by intravenous
administration. In each particular case, the doses will be
determined in accordance with the factors distinctive to the
subject to be treated, such as age, weight, general state of health
and other characteristics which can influence the efficacy of the
medicinal product.
[1545] The products according to the invention may be administered
as frequently as necessary in order to obtain the desired
therapeutic effect. Some patients may respond rapidly to a higher
or lower dose and may find much weaker maintenance doses adequate.
For other patients, it may be necessary to have long-term
treatments at the rate of 1 to 4 doses per day, in accordance with
the physiological requirements of each particular patient.
Generally, the active product may be administered orally 1 to 4
times per day. It goes without saying that, for other patients, it
will be necessary to prescribe not more than one or two doses per
day.
[1546] Compounds within the scope of the present invention exhibit
marked pharmacological activities according to tests described in
the literature which tests results are believed to correlate to
pharmacological activity in humans and other mammals. The following
pharmacological test results are typical characteristics of
compounds of the present invention.
[1547] Enzyme Assays
[1548] The ability of the compounds in the present invention to act
as inhibitors of factor Xa, thrombin, trypsin, tissue-plasminogen
activator (t-PA), urokinase-plasminogen activator (u-PA), plasm in
and activated protein C is evaluated by determining the
concentration of inhibitor which resulted in a 50% loss in enzyme
activity (IC.sub.50) using purified enzymes.
[1549] All enzyme assays are carried out at room temperature in
96-well microtiter plates using a final enzyme concentration of 1
nM. The concentrations of factor Xa and thrombin are determined by
active site titration and the concentrations of all other enzymes
are based on the protein concentration supplied by the
manufacturer. Compounds according to the invention are dissolved in
DMSO, diluted with their respective buffers and assayed at a
maximal final DMSO concentration of 1.25%. Compound dilutions are
added to wells containing buffer and enzyme and pre-equilibrated
for between 5 and 30 minutes. The enzyme reactions are initiated by
the addition of substrate and the color developed from the
hydrolysis of the peptide-p-nitroanilide substrates is monitored
continuously for 5 minutes at 405 nm on a Vmax microplate reader
(Molecular Devices). Under these conditions, less than 10% of the
substrate is utilized in all assays. The initial velocities
measured are used to calculate the amount of inhibitor which
resulted in a 50% reduction of the control velocity (IC.sub.50).
The apparent Ki values are then determined according to the
Cheng-Prusoff equation (IC50 Ki[1+[S]/Km]) assuming competitive
inhibition kinetics.
[1550] By way of example, 7-methoxynaphthalene-2-sulfonic
acid[1-(1,6-diaminoisoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]
amide trifluoroacetate has a Ki value of 80 nM.
[1551] An additional in vitro assay may be used to evaluate the
potency of compounds according to the invention in normal human
plasma. The activated partial thromboplastin time is a plasma-based
clotting assay that relies on the in situ generation of factor Xa,
its assembly into the prothrombinase complex and the subsequent
generation of thrombin and fibrin which ultimately yields the
formation of a clot as the assay endpoint. This assay is currently
used clinically to monitor the ex vivo effects of the commonly used
anticoagulant drug heparin as well as direct acting antithrombin
agents undergoing clinical evaluation. Therefore, activity in this
in vitro assay is considered as a surrogate marker for in vivo
anticoagulant activity.
[1552] Human Plasma Based Clotting Assay
[1553] Activated partial thromboplastin clotting times are
determined in duplicate on a MLA Electra 800 instrument. A volume
of 100 ml of citrated normal human pooled plasma (George King
Biomedical) is added to a cuvette containing 100 ml of a compound
according to the invention in Tris/NaCl buffer (pH 7.5) and placed
in the instrument. Following a 3 minute warming period the
instrument automatically adds 100 ml of activated cephaloplastin
reagent (Actin, Dade) followed by 100 ml of 0.035 M CaCl.sub.2 to
initiate the clotting reaction. Clot formation is determined
spectrophotometrically and measured in seconds. Compound potency is
quantitated as the concentration required to double a control
clotting time measured with human plasma in the absence of the
compound according to the invention.
[1554] Compounds according to the invention may also be evaluated
for their in vivo antithrombotic efficacy in two well established
animal experimental models of acute vascular thrombosis. A rabbit
model of jugular vein thrombosis and a rat model of carotid artery
thrombosis are used to demonstrate the antithrombotic activity of
these compounds in distinct animal model paradigms of human venous
thrombosis and arterial thrombosis, respectively.
[1555] Experimental In Vivo Rabbit Venous Thrombosis Model
[1556] This is a well characterized model of fibrin rich venous
thrombosis that is validated in the literature and shown to be
sensitive to several anticoagulant drugs including heparin
(Antithrombotic Effect of Recombinant Truncated Tissue Factor
Pathway Inhibitor (TFPI 1-161) in Experimental Venous Thrombosis--a
Comparison with Low Molecular Weight Heparin, J. Holst, B.
Lindblad, D. Bergqvist, O. Nordfang, P. B. Ostergaard, J. G. L.
Petersen, G. Nielsen and U. Hedner. Thrombosis and Haemostasis, 71,
214-219 (1994). The purpose of utilizing this model is to evaluate
the ability of compounds to prevent the formation of venous thrombi
(clots) in vivo generated at a site of injury and partial stasis in
the jugular vein.
[1557] Male and female New Zealand white rabbits weighing 1.5-2 kg
are anesthetized with 35 mg/kg of ketamine and 5 mg/kg xylazine in
a volume of 1 ml/kg (i.m.). The right jugular vein is cannulated
for infusion of anesthetic (ketamine/xylazine 17/2.5 mg/kg/hr at a
rate of approximately 0.5 ml/hr) and administration of test
substances. The right carotid artery is cannulated for recording
arterial blood pressure and collecting blood samples. Body
temperature is maintained at 39 C with a GAYMAR T-PUMP. The left
external jugular vein is isolated and all side branches along an
exposed 2-3 cm of vessel are tied off. The internal jugular vein is
cannulated, just above the bifurcation of the common jugular, and
the tip of the cannula is advanced just proximal to the common
jugular vein. A 1 cm segment of the vein is isolated with
non-traumatic vascular clamps and a relative stenosis is formed by
tying a ligature around the vein with an 18G needle just below the
distal most clamp. This creates a region of reduced flow and
partial stasis at the injury site. The isolated segment is gently
rinsed with saline 2-3 times via the cannula in the internal
jugular. Thereafter the isolated segment is filled with 0.5 ml of
0.5% polyoxyethylene ether (W-1) for 5 minutes. W-1 is a detergent
which disrupts the endothelial cell lining of the segment, thus
providing a thrombogenic surface for initiating clot formation.
After 5 minutes the W-1 is withdrawn from the segment, and the
segment is again gently rinsed with saline 2-3 times. The vascular
clamps are then removed, restoring blood flow through this portion
of the vessel. Clot formation is allowed to form and grow for 30
minutes after which the vein is cut just below the stenotic
ligature and inspected for blood flow (the absence of blood flow is
recorded as complete occlusion). The entire isolated segment of
vein is then ligated and the formed clot is removed and weighed
(wet weight). The effect of test agents on final clot weights is
used as the primary end point. Animals are maintained for an
additional thirty minutes to obtain a final pharmacodynamic measure
of anticoagulation. Drug administration is initiated 15 minutes
prior to vascular injury with W-1 and continued through the period
of clot formation and maturation. Three blood samples (3 ml ea.)
are obtained for evaluation of hemostatic parameters: one just
prior to administration of W-1; a second 30 minutes after removal
of the vascular clamps and a third at the termination of the
experiment. Antithrombotic efficacy is expressed as a reduction in
the final clot weight in preparations treated with a compound
according to the invention relative to vehicle treated control
animals.
[1558] Experimental In Vivo Rat Arterial Thrombosis Model
[1559] The antithrombotic efficacy of factor Xa inhibitors against
platelet-rich arterial thrombosis may be evaluated using a well
characterized rat carotid artery FeCl.sub.2-induced thrombosis
model (Superior Activity of a Thromboxane Receptor Antagonist as
Compared with Aspirin in Rat Models of Arterial and Venous
Thrombosis, W. A. Schumacher, C. L. Heran, T. E. Steinbacher, S.
Youssef and M.L. Ogletree. Journal of Cardiovascular Pharmacology,
2, 526-533 (1993); Rat Model of Arterial Thrombosis Induced by
Ferric Chloride, K. D. Kurtz, B. W. Main, and G. E. Sandusky.
Thrombosis Research, 60 269-280 (1990); The Effect of Thrombin
Inhibition in a Rat Arterial Thrombosis Model, R. J. Broersma, L.
W. Kutcher and E. F. Heminger. Thrombosis Research 64 405-412
(1991). This model is widely used to evaluate the antithrombotic
potential of a variety of agents including heparin and the direct
acting thrombin inhibitors.
[1560] Sprague Dawley rats weighing 375-450 g are anesthetized with
sodium pentobarbital (50 mg/kg i.p.). Upon reaching an acceptable
level of anesthesia, the ventral surface of the neck is shaved and
prepared for aseptic surgery. Electrocardiogram electrodes are
connected and lead II is monitored throughout the experiment. The
right femoral vein and artery are cannulated with PE-50 tubing for
administration of a compound according to the invention and for
obtaining blood samples and monitoring blood pressure,
respectively. A midline incision is made in the-ventral surface of
the neck. The trachea is exposed and intubated with PE-240 tubing
to ensure airway patency. The right carotid artery is isolated and
two 4-0 silk sutures are placed around the vessel to facilitate
instrumentation. An electromagnetic flow probe (0.95-1 mm lumen) is
placed around the vessel to measure blood flow. Distal to the probe
a 4.times.4 mm strip of parafilm is placed under the vessel to
isolate it from the surrounding muscle bed. After baseline flow
measurements are made, a 2.times.5 mm strip of filter paper
previously saturated in 35% FeCl.sub.2 is placed on top of the
vessel downstream from the probe for ten minutes and then removed.
The FeCl.sub.2 is thought to diffuse into the underlying segment of
artery and cause deendothelialization resulting in acute thrombus
formation. Following application of the FeCl.sub.2-soaked filter
paper, blood pressure, carotid artery blood flow and heart rate are
monitored for an observation period of 60 minutes. Following
occlusion of the vessel (defined as the attainment of zero blood
flow), or 60 minutes after filter paper application if patency is
maintained, the artery is ligated proximal and distal to the area
of injury and the vessel is excised. The thrombus is removed and
weighed immediately and recorded as the primary end point of the
study.
[1561] Following surgical instrumentation a control blood sample
(B1) is drawn. All blood samples are collected from the arterial
catheter and mixed with sodium citrate to prevent clotting. After
each blood sample, the catheter is flushed with 0.5 ml of 0.9%
saline. A compound according to the invention is administered
intravenously (i.v.) starting 5 minutes prior to FeCl.sub.2
application. The time between FeCl.sub.2 application and the time
at which carotid blood flow reached zero is recorded as time to
occlusion (TTO). For vessels that did not occlude within 60
minutes, TTO is assigned a value of 60 minutes. Five minutes after
application of FeCl.sub.2, a second blood sample is drawn (B2).
After 10 minutes of FeCl.sub.2 exposure, the filter paper is
removed from the vessel and the animal is monitored for the
remainder of the experiment. Upon reaching zero blood flow blood a
third blood sample is drawn (B3) and the clot is removed and
weighed. Template bleeding time measurements are performed on the
forelimb toe pads at the same time that blood samples are obtained.
Coagulation profiles consisting of activated partial thromboplastin
time (APTT) and prothrombin time (PT) are performed on all blood
samples. In some instances a compound according to the invention
may be administered orally. Rats are restrained manually using
standard techniques and compounds are administered by intragastric
gavage using a 18 gauge curved dosing needle (volume of 5 ml/kg).
Fifteen minutes after intragastric dosing, the animal is
anesthetized and instrumented as described previously. Experiments
are then performed according to the protocol described above.
[1562] The present invention may be embodied in other specific
forms without departing from the spirit or essential attributes
thereof.
* * * * *