U.S. patent application number 11/864102 was filed with the patent office on 2008-03-27 for therapeutic heterocyclic compounds 507.
This patent application is currently assigned to AstraZeneca AB. Invention is credited to Marc Chapdelaine, Timothy Davenport, Markus Haeberlein, Carey Horchler, John P. McCauley, Edward Pierson, Daniel Sohn.
Application Number | 20080076759 11/864102 |
Document ID | / |
Family ID | 26655583 |
Filed Date | 2008-03-27 |
United States Patent
Application |
20080076759 |
Kind Code |
A1 |
Pierson; Edward ; et
al. |
March 27, 2008 |
Therapeutic Heterocyclic Compounds 507
Abstract
Provided herein is a compound having the formula (I): ##STR1##
Wherein said compounds are useful for the treatment of psychiatric
disorders including but not limited to depression, generalized
anxiety, eating disorders, dementia, panic disorder, and sleep
disorders. The compounds may also be useful in the treatment of
gastrointestinal disorders, cardiovascular regulation, motor
disorders, endocrine disorders, vasospasm and sexual dysfunction.
The compounds are 5HT.sub.1B and 5HT.sub.1D antagonists.
Inventors: |
Pierson; Edward;
(Wilmington, DE) ; Sohn; Daniel; (Sodertalje,
SE) ; Haeberlein; Markus; (Sodertalje, SE) ;
Davenport; Timothy; (Wilmington, DE) ; Chapdelaine;
Marc; (Wilmington, DE) ; Horchler; Carey;
(Wilmington, DE) ; McCauley; John P.; (Wilmington,
DE) |
Correspondence
Address: |
ASTRA ZENECA PHARMACEUTICALS LP;GLOBAL INTELLECTUAL PROPERTY
1800 CONCORD PIKE
WILMINGTON
DE
19850-5437
US
|
Assignee: |
AstraZeneca AB
Sodertalje
SE
|
Family ID: |
26655583 |
Appl. No.: |
11/864102 |
Filed: |
September 28, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11108587 |
Apr 18, 2005 |
7285662 |
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11864102 |
Sep 28, 2007 |
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10889350 |
Jul 12, 2004 |
7045514 |
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11108587 |
Apr 18, 2005 |
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10051776 |
Jan 16, 2002 |
6812225 |
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10889350 |
Jul 12, 2004 |
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60262107 |
Jan 16, 2001 |
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Current U.S.
Class: |
514/218 ;
514/228.2; 514/235.5; 514/235.8; 514/252.11; 514/254.01;
514/254.04; 514/254.05; 514/254.09; 514/254.11 |
Current CPC
Class: |
C07D 311/24 20130101;
A61P 5/00 20180101; A61P 25/24 20180101; A61P 43/00 20180101; C07D
413/06 20130101; C07D 215/50 20130101; A61P 25/28 20180101; C07D
405/14 20130101; C07D 311/58 20130101; C07D 405/12 20130101; A61P
25/00 20180101; A61P 1/00 20180101; C07D 401/04 20130101; A61P 9/00
20180101; A61K 31/497 20130101; A61P 25/18 20180101; A61K 31/551
20130101; A61K 31/541 20130101; C07D 401/12 20130101; C07D 417/12
20130101; A61P 25/02 20180101; A61P 25/20 20180101; C07D 231/12
20130101; A61P 21/00 20180101; A61P 15/00 20180101; A61K 31/5377
20130101; C07D 233/56 20130101; C07D 405/06 20130101; A61P 25/06
20180101; C07D 249/08 20130101; A61K 31/495 20130101; A61P 25/22
20180101 |
Class at
Publication: |
514/218 ;
514/228.2; 514/235.5; 514/235.8; 514/252.11; 514/254.01;
514/254.04; 514/254.05; 514/254.09; 514/254.11 |
International
Class: |
A61K 31/551 20060101
A61K031/551; A61K 31/495 20060101 A61K031/495; A61K 31/497 20060101
A61K031/497; A61P 1/00 20060101 A61P001/00; A61P 21/00 20060101
A61P021/00; A61P 5/00 20060101 A61P005/00; A61P 9/00 20060101
A61P009/00; A61P 25/06 20060101 A61P025/06; A61P 15/00 20060101
A61P015/00; A61K 31/5377 20060101 A61K031/5377; A61K 31/541
20060101 A61K031/541 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 2, 2001 |
SE |
0103650-8 |
Jan 15, 2002 |
SE |
PCT/SE02/00068 |
Claims
1-9. (canceled)
10. A method of treating migraine in a mammal or human in need of
such treatment comprising administering to the mammal or human an
effective amount of a compound of formula III: ##STR258## wherein:
R.sup.1 is halogen or methoxy when positioned at the 6.sup.th
position of the bicyclic ring, and is hydrogen, methyl, ethyl or
methoxy when positioned at the 5.sup.th position of the bicyclic
ring, and is hydrogen when positioned at the 7.sup.th position of
the bicyclic ring; R.sup.2 is methyl piperazine; R.sup.6 is
hydrogen; Y is --C(.dbd.O)NH--; R.sup.7 is phenyl substituted with
R.sup.8-R.sup.9; R.sup.8 is a single bond as tether; R.sup.9 is a
morpholinyl or piperazinyl attached to R.sup.8 by nitrogen and
optionally substituted on the other nitrogen (for piperazinyl) with
R.sup.11; R.sup.11 is AOH or --SO.sub.2A wherein A is represented
by methyl or ethyl, or a pharmaceutically acceptable salt
thereof.
11. A method of treating depression in a mammal or human in need of
such treatment comprising administering to the mammal or human an
effective amount of a compound of formula III: ##STR259## wherein:
R.sup.1 is halogen or methoxy when positioned at the 6.sup.th
position of the bicyclic ring, and is hydrogen, methyl, ethyl or
methoxy when positioned at the 5.sup.th position of the bicyclic
ring, and is hydrogen when positioned at the 7.sup.th position of
the bicyclic ring; R.sup.2 is methyl piperazine; R.sup.6 is
hydrogen; Y is --C(.dbd.O)NH--; R.sup.7 is phenyl substituted with
R.sup.8-R.sup.9; R.sup.8 is a single bond as tether; R.sup.9 is a
morpholinyl or piperazinyl attached to R.sup.8 by nitrogen and
optionally substituted on the other nitrogen (for piperazinyl) with
R.sup.11; R.sup.11 is AOH or --SO.sub.2A wherein A is represented
by methyl or ethyl, or a pharmaceutically acceptable salt
thereof.
12. A method of treating generalized anxiety in a mammal or human
in need of such treatment comprising administering to the mammal or
human an effective amount of a compound of formula III: ##STR260##
wherein: R.sup.1 is halogen or methoxy when positioned at the
6.sup.th position of the bicyclic ring, and is hydrogen, methyl,
ethyl or methoxy when positioned at the 5.sup.th position of the
bicyclic ring, and is hydrogen when positioned at the 7.sup.th
position of the bicyclic ring; R.sup.2 is methyl piperazine;
R.sup.6 is hydrogen; Y is --C(.dbd.O)NH--; R.sup.7 is phenyl
substituted with R.sup.8-R.sup.9; R.sup.8 is a single bond as
tether; R.sup.9 is a morpholinyl or piperazinyl attached to R.sup.8
by nitrogen and optionally substituted on the other nitrogen (for
piperazinyl) with R.sup.11; R.sup.11 is AOH or --SO.sub.2A wherein
A is represented by methyl or ethyl, or a pharmaceutically
acceptable salt thereof.
13. A method of treating panic disorder in a mammal or human in
need of such treatment comprising administering to the mammal or
human an effective amount of a compound of formula III: ##STR261##
wherein: R.sup.1 is halogen or methoxy when positioned at the
6.sup.th position of the bicyclic ring, and is hydrogen, methyl,
ethyl or methoxy when positioned at the 5.sup.th position of the
bicyclic ring, and is hydrogen when positioned at the 7.sup.th
position of the bicyclic ring; R.sup.2 is methyl piperazine;
R.sup.6 is hydrogen; Y is --C(.dbd.O)NH--; R.sup.7 is phenyl
substituted with R.sup.8-R.sup.9; R.sup.8 is a single bond as
tether; R.sup.9 is a morpholinyl or piperazinyl attached to R.sup.8
by nitrogen and optionally substituted on the other nitrogen (for
piperazinyl) with R.sup.11; R.sup.11 is AOH or --SO.sub.2A wherein
A is represented by methyl or ethyl, or a pharmaceutically
acceptable salt thereof.
14. A method of treating dementia, eating disorders, sleep
disorders, gastrointestinal disorders, motor disorders, endocrine
disorders, vasospasm and sexual dysfunction in a mammal or human in
need of such treatment comprising administering to the mammal or
human an effective amount of a compound of formula III: ##STR262##
wherein: R.sup.1 is halogen or methoxy at the 6.sup.th position of
the bicyclic ring, and is hydrogen, methyl, ethyl or methoxy at the
5.sup.th position of the bicyclic ring, and is hydrogen at the
7.sup.th position of the bicyclic ring; R.sup.2 is methyl
piperazine; R.sup.6 is hydrogen; Y is --C(.dbd.O)NH--; R.sup.7 is
phenyl substituted with R.sup.8-R.sup.9; R.sup.8 is a single bond
as tether; R.sup.9 is a morpholinyl or piperazinyl attached to
R.sup.8 by nitrogen and optionally substituted on the other
nitrogen (for piperazinyl) with R.sup.11; R.sup.11 is AOH or
--SO.sub.2A wherein A is represented by methyl or ethyl, or a
pharmaceutically acceptable salt thereof.
15. A method of treating a mammal or human in accordance with claim
14 wherein the disease is dementia.
16. A method of treating a mammal or human in accordance with claim
14 wherein the disease is eating disorder.
17. A method of treating a mammal or human in accordance with claim
14 wherein the disease is sleep disorder.
18. A method of treating a mammal or human in accordance with claim
14 wherein the disease is gastrointestinal disorders.
19. A method of treating a mammal or human in accordance with claim
14 wherein the disease is motor disorders.
20. A method of treating a mammal or human in accordance with claim
14 wherein the disease is endocrine disorders.
21. A method of treating a mammal or human in accordance with claim
14 wherein the disease is vasospasm.
22. A method of treating a mammal or human in accordance with claim
14 wherein the disease is sexual dysfunction.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/889,350, filed Jul. 12, 2004, now allowed, which is a
continuation of U.S. application Ser. No. 10/051,776, filed Jan.
16, 2002, now issued as U.S. Pat. No. 6,812,225, which claims
benefit of Swedish Application No. 0103650-8, filed Nov. 2, 2001,
and which also claims the benefit of U.S. Provisional Application
No. 60/262,107, filed Jan. 16, 2001; the contents of each is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to novel 8-amino derivatives, methods
for their preparation, pharmaceutical compositions containing them
and their use in therapy.
BACKGROUND OF THE INVENTION
[0003] Serotonin (5-HT) has been implicated in many psychiatric
disorders including but not limited to depression, generalized
anxiety, eating disorders, dementia, panic disorder, and sleep
disorders. Furthermore serotonin has been implicated in
gastrointestinal disorders, cardiovascular regulation, motor
disorders, endocrine disorders, vasospasm and sexual dysfunction.
Serotonin receptors have been subdivided into at least 14 subtypes,
see Barnes and Sharp, Neuropharmacology, 1999, 38, 1083-1152,
incorporated herein by reference. These various subtypes are
responsible for serotonin's action in many pathophysicogical
conditions. The 5-HT.sub.1 family of receptors has high affinity
for serotonin and consists of five related receptors. This family
includes the 5-HT.sub.1B and 5-HT.sub.1D receptor subtypes.
Compounds that interact with the 5-HT.sub.1 family are known to
have therapeutic potential in the above mentioned disorders and
diseases. In particular, compounds that are 5HT.sub.1B and
5HT.sub.1D antagonist have been known to be antidepressant and
anxiolytic agents. Compounds that are 5HT.sub.1B and 5HT.sub.1D
agonists have been used in the treatment of migraine.
SUMMARY OF THE INVENTION
[0004] Provided herein is a compound having the formula (I):
##STR2## wherein R.sup.1 is, at each position, independently
represented by hydrogen, optionally substituted alkyl, optionally
substituted cycloalkyl, thiomethoxy, --NHA, --NA.sub.2,
--NHC(.dbd.O)A, aminocarbonyl, --C(.dbd.O)NHA, --C(.dbd.O)NA.sub.2,
halogen, hydroxy, --OA, cyano or aryl; A is optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl or optionally substituted alkynyl; R.sup.2 is represented
by (i), (ii), (iii), or (iv) below: ##STR3## R.sup.3 is
independently at each position represented by --H, optionally
substituted C.sub.1-6alkyl, optionally substituted
C.sub.2-6alkenyl, optionally substituted C.sub.2-6alkynyl,
optionally substituted C.sub.3-6cycloalkyl or AOH; n is 2, 3 or 4;
P is a heterocyclic ring; R.sup.4 is --H or optionally substituted
C.sub.1-4alkyl; R.sup.5 is --H, .dbd.O, --OR.sup.4,
--NR.sup.4.sub.2.dbd.NR.sup.4, --SR.sup.4 or .dbd.S; R.sup.6 is --H
or methyl; X is O, N, NH or S; Y is --C(.dbd.O)NH--,
--C(.dbd.O)NA-, --C(.dbd.O)N(A)-, --NHC(.dbd.O)--, --C(.dbd.S)NH--,
--CH.sub.2NH--, --C(.dbd.O)CH.sub.2--, --CH.sub.2C(.dbd.O)--,
--C(.dbd.O)-piperazine-, --NAC(.dbd.O)--, --C(.dbd.S)N(A)-,
CH.sub.2NA, NACH.sub.2 or a 5-membered heterocyclic; R.sup.7 is a
monocyclic or bicyclic aromatic ring or a heterocycle optionally
substituted by one or more substituents selected from
R.sup.8-R.sup.9 and R.sup.10; wherein R.sup.7 is connected to Y
either by a single bond as tether, or by a ring fusion comprising a
bond and two ring atoms shared by both rings; R.sup.8 is
--CH.sub.2--, --C(.dbd.O)--, --SO.sub.2--, --SO.sub.2NH--,
--C(.dbd.O)NH--, --O--, --S--, --S(.dbd.O)-- a single bond as
tether from R.sup.7 to R.sup.9, or a five-membered heterocyclic
connected to R.sup.7 by either a single bond or by a ring fusion
comprising a bond and two ring atoms shared by both rings, R.sup.9
is optionally substituted heterocycle, optionally substituted aryl,
optionally substituted piperazinyl-R11, optionally substituted
morpholinyl-R.sup.11 or optionally substituted, C(.dbd.O)A;
R.sup.10 is optionally substituted alkyl, optionally substituted
cycloalkyl, hydroxy, aryl, cyano, halogen, --C(.dbd.O)NH.sub.2,
methylthio, --NHA, --NA.sub.2, --NHC(.dbd.O)A, --C(.dbd.O)NHA,
--C(.dbd.O)NA.sub.2, or --OA; R.sup.11 is --H, alkyl, AOH,
--SO.sub.2A, --SO.sub.2NH.sub.2, --SO.sub.2NHA, --SO.sub.2NA.sub.2,
--SO.sub.2NHAR.sup.9, --C(.dbd.O)R.sup.9, -alkylR.sup.9,
C(.dbd.O)A, C(.dbd.O)NH.sub.2, C(.dbd.O)NHA, C(.dbd.O)NA.sub.2 or
--C(.dbd.O)OA; or a pharmaceutically acceptable salt of said
compound. represents a bond which may be either a single bond or a
double bond, with the proviso that multiple double bonds are
separated from one another by at least one single bond.
[0005] In another aspect of the invention, R.sup.5 and X are both O
and thus provides a compound represented by the formula (II):
##STR4## wherein R.sup.1 is, at each position, independently
represented by hydrogen, optionally substituted alkyl, optionally
substituted cycloalkyl, thiomethoxy, --NHA, --NA.sub.2,
--NHC(.dbd.O)A, aminocarbonyl, --C(.dbd.O)NHA, --C(.dbd.O)NA.sub.2,
halogen, hydroxy, --OA, cyano or aryl; A is optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl or optionally substituted alkynyl; R.sup.2 is represented
by (i), (ii), (iii), or (iv) below: ##STR5## R.sup.3 is
independently at each position represented by --H, optionally
substituted C.sub.1-6alkyl, optionally substituted
C.sub.2-6alkenyl, optionally substituted C.sub.2-6alkynyl,
optionally substituted C.sub.3-6cycloalkyl or AOH; n is 2, 3 or 4;
P is a heterocyclic ring; R.sup.6 is --H or methyl; Y is
--C(.dbd.O)NH--, --C(.dbd.O)NA-, --C(.dbd.O)N(A)-, --NHC(.dbd.O)--,
--C(.dbd.S)NH--, --CH.sub.2NH--, --C(.dbd.O)--,
--C(.dbd.O)CH.sub.2--, --CH.sub.2C(.dbd.O)--,
--C(.dbd.O)-piperazine-, --[NAC(.dbd.O)--, --C(.dbd.S)N(A)-,
--CH.sub.2NA-, --NACH.sub.2-- or a 5-membered heterocyclic. R.sup.7
is a monocyclic or bicyclic aromatic ring or a heterocycle
optionally substituted by one or more substituents selected from
R.sup.8-R.sup.9 and R.sup.10; wherein R.sup.7 is connected to Y
either by a single bond or by a ring fusion; R.sup.8 is
--CH.sub.2--, --C(.dbd.O)--, --SO.sub.2--, --SO.sub.2NH--,
--C(.dbd.O)NH--, --O--, --S--, --S(.dbd.O)--, a single bond as
tether from R.sup.7 to R.sup.9, a five membered heterocyclic
connected to R.sup.7 by either a single bond or by a ring fusion;
R.sup.9 is optionally substituted heterocycle, optionally
substituted aryl, optionally substituted piperazinyl-R11,
optionally substituted morpholinyl-R.sup.11 or optionally
substituted thiomorpholinyl or --C(.dbd.O)A; R.sup.10 is optionally
substituted alkyl, optionally substituted cycloalkyl, hydroxy,
aryl, cyano, halogen, --C(.dbd.O)NH.sub.2--, methylthio, --NHA,
--NA.sub.2, --NHC(.dbd.O)A, --C(.dbd.O)NHA, --C(.dbd.O)NA.sub.2 or
OA; R.sup.11 is --H, alkyl, -AOH, --SO.sub.2A, --SO.sub.2NH.sub.2,
--SO.sub.2NHA, --SO.sub.2NA.sub.2, --SO.sub.2NHAR.sup.9,
--C(.dbd.O)R.sup.9, -alkylR.sup.9, C(.dbd.O)A, C(.dbd.O)NH.sub.2,
C(.dbd.O)NHA, C(.dbd.O)NA.sub.2 or --C(.dbd.O)OA; or a
pharmaceutically acceptable salt of said compound
[0006] In another aspect of the invention, R.sup.5 is H and X is O
and thus is provided a compound represented by the formula (III):
##STR6## wherein R.sup.1 is, at each position, independently
represented by hydrogen, optionally substituted alkyl, optionally
substituted cycloalkyl, thiomethoxy, --NHA, --NA.sub.2,
--NHC(.dbd.O)A, aminocarbonyl, --C(.dbd.O)NHA, --C(.dbd.O)NA.sub.2,
halogen, hydroxy, --OA, cyano or aryl; A is optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl or optionally substituted alkynyl; R.sup.2 is represented
by (i), (ii), (iii), or (iv) below: ##STR7## R.sup.3 is --H,
optionally substituted C.sub.1-6alkyl, optionally substituted
C.sub.2-6alkenyl, optionally substituted C.sub.2-6alkynyl,
optionally substituted C.sub.3-6cycloalkyl or AOH; n is 2, 3 or 4;
P is a heterocyclic ring; R.sup.6 is --H or methyl; Y is
--C(.dbd.O)NH--, --C(.dbd.O)NA-, --C(.dbd.O)N(A)-, --NHC(.dbd.O)--,
--C(.dbd.S)NH--, --CH.sub.2NH--, --C(.dbd.O)--,
--C(.dbd.O)CH.sub.2--, --CH.sub.2C(.dbd.O)--,
--C(.dbd.O)-piperazine-, --NAC(.dbd.O)--, --C(.dbd.S)N(A)-,
CH.sub.2NA, NACH.sub.2 or a 5-membered heterocyclic. R.sup.7 is a
monocyclic or bicyclic aromatic ring or a heterocycle optionally
substituted by one or more substituents selected from
R.sup.8-R.sup.9 and R.sup.10; wherein R.sup.7 is connected to Y
either by a single bond or by a ring fusion; R.sup.8 is
--CH.sub.2--, --C(.dbd.O)--, --SO.sub.2--, --SO.sub.2NH--,
--C(.dbd.O)NH--, --O--, --S--, --S(.dbd.O)--, a single bond as
tether from R.sup.7 to R.sup.9, 5-membered heterocycle connected to
R.sup.7 by either a single bond or by a ring fusion; R.sup.9 is
optionally substituted heterocycle, optionally substituted aryl,
optionally substituted piperazinyl-R11, optionally substituted
morpholinyl-R.sup.11 or optionally substituted or C(.dbd.O)A;
R.sup.10 is optionally substituted alkyl, optionally substituted
cycloalkyl, hydroxy, aryl, cyano, halogen, --C(.dbd.O)NH.sub.2--,
methylthio, --NHA, --NA.sub.2, --NHC(.dbd.O)A, C(.dbd.O)NHA,
C(.dbd.O)NA.sub.2 or OA; R.sup.11 is --H, alkyl, AOH, --SO.sub.2A,
--SO.sub.2NH.sub.2, --SO.sub.2NHA, --SO.sub.2NA.sub.2,
--SO.sub.2NHAR.sup.9, --C(.dbd.O)R.sup.9, -alkylR.sup.9,
C(.dbd.O)A, C(.dbd.O)NH.sub.2, C(.dbd.O)NHA, C(.dbd.O)NA.sub.2 or
--C(.dbd.O)OA; or a pharmaceutically acceptable salt of said
compound.
[0007] In another aspect of the invention, X is N and R.sup.5 is O
and thus provides a compound represented by the formula (IV):
##STR8## wherein R.sup.1 is, at each position, independently
represented by hydrogen, optionally substituted alkyl, optionally
substituted cycloalkyl, methoxy, thiomethoxy, --NHA, --NA.sub.2,
--NHC(.dbd.O)A, aminocarbonyl, --C(.dbd.O)NHA, --C(.dbd.O)NA.sub.2,
halogen, hydroxy, --OA, cyano or aryl; A is optionally substituted
alkyl, optionally substituted cycloalkyl, optionally substituted
alkenyl or optionally substituted alkynyl; R.sup.2 is represented
by (i), (ii), (iii), or (iv) below: ##STR9## R.sup.3 is --H,
optionally substituted C.sub.1-6alkyl, optionally substituted
C.sub.2-6alkenyl, optionally substituted C.sub.2-6alkynyl,
optionally substituted C.sub.3-6cycloalkyl or AOH; n is 2, 3 or 4;
P is a heterocyclic ring; R.sup.4 is --H or optionally substituted
C.sub.1-4alkyl; R.sup.5 is .dbd.O, .dbd.NR.sup.4 or .dbd.S; R.sup.6
is --H or methyl; Y is --C(.dbd.O)NH--, --C(.dbd.O)NA-,
--C(.dbd.O)N(A)-, --NHC(.dbd.O)--, --C(.dbd.S)NH--, --CH.sub.2NH--,
--C(.dbd.O)CH.sub.2--, --CH.sub.2C(.dbd.O)--,
--C(.dbd.O)-piperazine-, --C(.dbd.O)R.sup.8--, --NAC(.dbd.O)--,
--C(.dbd.S)N(A)-, --CH.sub.2N(A)-, --N(A)CH.sub.2-- or a 5-membered
heterocyclic. R.sup.7 is a monocyclic or bicyclic aromatic ring or
a heterocycle optionally substituted by one or more substituents
selected from R.sup.8-R.sup.9 and R.sup.10; wherein R.sup.7 is
connected to Y either by a single bond or by a ring fusion; R.sup.8
is --CH.sub.2--, --C(.dbd.O)--, --SO.sub.2--, --SO.sub.2NH--,
--C(.dbd.O)NH--, --O--, --S--, --S(.dbd.O)--, a single bond as
tether from R.sup.7 to R.sup.9, a five-membered heterocyclic
connected to R.sup.7 by either a single bond or by a ring fusion;
R.sup.9 is optionally substituted heterocycle, optionally
substituted aryl, optionally substituted piperazinyl-R11,
optionally substituted morpholinyl-R11 or optionally substituted
thiomorpholinyl or --C(.dbd.O)A; R.sup.10 is optionally substituted
alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano,
halogen, --C(.dbd.O)NH.sub.2--, methylthio, --NHA, --NA.sub.2,
--NHC(.dbd.O)A, --C(.dbd.O)NHA, --C(.dbd.O)NA.sub.2 or OA; R.sup.11
is --H, alkyl, AOH, --SO.sub.2A, --SO.sub.2NH.sub.2, --SO.sub.2NHA,
--SO.sub.2NA.sub.2, --SO.sub.2NHAR.sup.9, --C(.dbd.O)R.sup.9,
-alkylR.sup.9, C(.dbd.O)A, C(.dbd.O)NH.sub.2, C(.dbd.O)NHA,
C(.dbd.O)NA.sub.2 or --C(.dbd.O)OA; or a pharmaceutically
acceptable salt of said compound.
[0008] In another aspect of the invention, X is N and thus provides
a compound represented by the formula (V): ##STR10## wherein
R.sup.1 is, at each position, independently represented by
hydrogen, optionally substituted alkyl, optionally substituted
cycloalkyl, thiomethoxy, --NHA, --NA.sub.2, --NHC(.dbd.O)A,
aminocarbonyl, --C(.dbd.O)NHA, --C(.dbd.O)NA.sub.2, halogen,
hydroxy, --OA, cyano or aryl; A is optionally substituted alkyl,
optionally substituted cycloalkyl, optionally substituted alkenyl
or optionally substituted alkynyl; R.sup.2 is represented by (i),
(ii), (iii), or (iv) below: ##STR11## R.sup.3 is --H, optionally
substituted C.sub.1-6alkyl, optionally substituted
C.sub.2-6alkenyl, optionally substituted C.sub.2-6alkynyl,
optionally substituted C.sub.3-6cycloalkyl or AOH; n is 2, 3 or 4;
P is a heterocyclic ring; R.sup.4--H or optionally substituted
C.sub.1-4alkyl; R.sup.5 is --H, --OR.sup.4, --NR.sup.4.sub.2 or
--SR.sup.4; R.sup.6 is --H or methyl; Y is --C(.dbd.O)NH--,
--C(.dbd.O)NA-, --C(.dbd.O)N(A)-, --NHC(.dbd.O)--, --C(.dbd.S)NH--,
--CH.sub.2NH--, --C(.dbd.O)---C(.dbd.O)CH.sub.2--,
--CH.sub.2C(.dbd.O)--, --C(.dbd.O)-piperazine-, --N(A)C(.dbd.O)--,
--C(.dbd.S)N(A)-, --CH.sub.2N(A), --N(A)CH.sub.2-- or a 5-membered
heterocyclic. R.sup.7 is a monocyclic or bicyclic aromatic ring or
a heterocycle optionally substituted by one or more substituents
selected from R.sup.8-R.sup.9 and R.sup.10; wherein R.sup.7 is
connected to Y either by a single bond or by a ring fusion; R.sup.8
is --CH.sub.2--, --C(.dbd.O)--, --SO.sub.2--, --SO.sub.2NH--,
--C(.dbd.O)NH--, --O--, --S--, --S(.dbd.O)--, a single bond as
tether from R.sup.7 to R.sup.9, a five membered heterocyclic
connected to R.sup.7 by either a single bond or by a ring fusion;
R.sup.9 is optionally substituted heterocycle, optionally
substituted aryl, optionally substituted piperazinyl-R11,
optionally substituted morpholinyl-R.sup.11 or optionally
substituted or --C(.dbd.O)A; R.sup.10 is optionally substituted
alkyl, optionally substituted cycloalkyl, hydroxy, aryl, cyano,
halogen, --C(.dbd.O)NH.sub.2--, methylthio, --NHA, --NA.sub.2,
--NHC(.dbd.O)A, --C(.dbd.O)NHA, --C(.dbd.O)NA.sub.2 or OA; R.sup.11
is --H, alkyl, AOH, --SO.sub.2A, --SO.sub.2NH.sub.2, --SO.sub.2NHA,
--SO.sub.2NA.sub.2, --SO.sub.2NHAR.sup.9, --C(.dbd.O)R.sup.9,
-alkylR.sup.9, C(.dbd.O)A, C(.dbd.O)NH.sub.2, C(.dbd.O)NHA,
C(.dbd.O)NA.sub.2, and C(.dbd.O)OA; or a pharmaceutically
acceptable salt of said compound.
[0009] The term "hydrocarbyl" refers to any structure comprising
only carbon and hydrogen atoms up to 14 carbon atoms.
[0010] The term "alkyl" used alone or as a suffix or prefix, refers
to straight or branched chain hydrocarbyl radicals comprising 1 to
about 12 carbon atoms.
[0011] The term "alkenyl" refers to straight or branched chain
hydrocarbyl radicals having at least one carbon-carbon double bond
and comprising at least 2 up to about 12 carbon atoms.
[0012] The term "alkynyl" refers to straight or branched chain
hydrocarbyl radicals having at least one carbon-carbon triple bond
and comprising at least 2 up to about 12 carbon atoms.
[0013] The term "cycloalkyl" refers to ring-containing hydrocarbyl
radicals comprising at least 3 up to about 12 carbon atoms.
[0014] The term "cycloalkenyl" refers to ring-containing
hydrocarbyl radicals having at least one carbon-carbon double bond
and comprising at least 3 up to about 12 carbon atoms.
[0015] The term "cycloalkynyl" refers to ring-containing
hydrocarbyl radicals having at least one carbon-carbon triple bond
and comprising about 7 up to about 12 carbon atoms.
[0016] The term "aromatic" refers to hydrocarbyl radicals having
one or more polyunsaturated carbon rings having aromatic character,
(e.g., 4n+2 delocalized electrons) and comprising 6 up to about 14
carbon atoms.
[0017] The term "aryl" refers to aromatic radicals including both
monocyclic aromatic radicals comprising 6 carbon atoms and
polycyclic aromatic radicals comprising up to about 14 carbon
atoms.
[0018] The term "alkylene" refers to divalent alkyl moieties,
wherein said moiety serves to link two structures together.
[0019] The term "heterocycle" or "heterocyclic" or "heterocyclic
moiety" refers to ring-containing monovalent and divalent radicals
having one or more heteroatoms, independently selected from N, O
and S, as part of the ring structure and comprising at least 3 and
up to about 20 atoms in the rings preferably 5 and 6 membered
rings. Heterocyclic moieties may be saturated or unsaturated,
containing one or more double bonds, and heterocyclic moieties may
contain more than one ring.
[0020] The term "heteroaryl" refers to heterocyclic monovalent and
divalent radicals having aromatic character.
[0021] Heterocyclic moieties include for example monocyclic
moieties such as: aziridine, oxirane, thiirane, azetidine, oxetane,
thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine,
dioxolane, sulfolane 2,3-dihydrofuran, 2,5-dihydrofuran
tetrahydrofuran, thiophane, piperidine,
1,2,3,6-tetrahydro-pyridine, piperazine, morpholine,
thiomorpholine, pyran, thiopyran, 2,3-dihydropyran,
tetrahydropyran, 1,4-dihydropyridine, 1,4-dioxane, 1,3-dioxane,
dioxane, homopiperidine, 2,3,4,7-tetrahydro-1H-azepine
homopiperazine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and
hexamethylene oxide. In addition heterocyclic moieties include
heteroaryl rings such as: pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,
oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl,
tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,
1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,
1,3,4-thiadiazolyl, and 1,3,4oxadiazolyl. Additionally,
heterocyclic moieties encompass polycyclic moieties such as:
indole, indoline, quinoline, tetrahydroquinoline, isoquinoline,
tetrahydroisoquinoline, 1,4-benzodioxan, coumarin, dihydrocoumarin,
benzofuran, 2,3-dihydrobenzofuran, 1,2-benzisoxazole,
benzothiophene, benzoxazole, benzthiazole, benzimidazole,
benztriazole, thioxanthine, carbazole, carboline, acridine,
pyrolizidine, and quinolizidine.
[0022] In addition to the polycyclic heterocycles described above,
heterocyclic moieties include polycyclic heterocyclic moieties
wherein the ring fusion between two or more rings comprises more
than one bond common to both rings and more than two atoms common
to both rings. Examples of such bridged heterocycles include
quinuclidine, diazabicyclo[2.2.1]heptane and
7-oxabicyclo[2.2.1]heptane.
[0023] The term "halo" or "halogen" refers to fluorine, chlorine,
bromine and iodine radicals.
[0024] The term "alkoxy" refers to radicals of the general formula
--O--R, wherein R is selected from a hydrocarbyl radical. Alkoxy
moieties include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and
propargyloxy.
[0025] The term amine or amino refers to radicals of the general
formula --NRR', wherein R and R' are independently selected from
hydrogen or a hydrocarby radical.
DETAILED DESCRIPTION OF THE INVENTION
[0026] In a further aspect of the invention, A, R.sup.1 and
R.sup.3, each independently, as an alkyl, alkenyl, alkynyl and as a
cycloalkyl, may optionally be substituted with halogen, nitro,
cyano, hydroxy, trifluoromethyl, amino, carboxy, carboxamido,
amidino, carbamoyl, mercapto, sulfamoyl, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, C.sub.3-6
cycloalkenyl, C.sub.1-4 alkoxy, C.sub.1-4 alkanoyl, C.sub.1-4
alkanoyloxy, NH(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2,
C.sub.1-4 alkanoylamino, (C.sub.1-4 alkanoyl).sub.2amino,
N--(C.sub.1-4 alkyl)carbamoyl, N,N--(C.sub.1-4
alkyl).sub.2carbamoyl, (C.sub.1-4)S, (C.sub.1-4 alkyl)S(O),
(C.sub.1-4alkyl)S(O).sub.2, (C.sub.1-4) alkoxycarbonyl,
N--(C.sub.1-4 alkyl)sulfamoyl, N,N--C.sub.1-4 alkyl)sulfamoyl,
C.sub.1-4 alkylsolfonylamino, and heterocyclic.
[0027] Examples of optional substituents for aryl and heterocyclic
groups, when not otherwise defined, are halogen, nitro, cyano,
hydroxy, trifluoromethyl, amino, carboxy, carboxamido, amidino,
carbamoyl, mercapto, sulfamoyl, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl,
C.sub.1-4 alkoxy, C.sub.1-4 alkanoyl, C.sub.1-4 alkanoyloxy,
N--(C.sub.1-4 alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4
alkanoylamino, (C.sub.1-4 alkanoyl).sub.2amino, N--(C.sub.1-4
alkyl)carbamoyl, N,N--(C.sub.1-4 alkyl).sub.2carbamoyl,
(C.sub.1-4)S, (C.sub.1-4 alkyl)S(O), (C.sub.1-4alkyl)S(O).sub.2,
(C.sub.1-4) alkoxycarbonyl, N--(C.sub.1-4 alkyl)sulfamoyl,
N,N--C.sub.1-4 alkyl)sulfamoyl, C.sub.1-4 alkylsolfonylamino, and
heterocyclic.
[0028] A, R.sup.1 and R.sup.3 each independently as an alkyl,
alkenyl or alkynyl may be straight or branched, preferably having
1-6 carbon atoms. A, R.sup.1 and R.sup.3 preferably have 3-6 atoms
when each are independently a cyclic alkyl. Other preferable values
for A, R.sup.1 and R.sup.3 when each are an alkyl include methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,
cyclopentyl, neopentyl and cyclohexyl. Preferable values for
R.sup.1 when R.sup.1 is a halogen are fluorine, chlorine, and
bromine. Other preferable values for R.sup.1 when R.sup.1 is at
position 6 on the bicyclic ring are methyl, ethyl, ethoxy and
methoxy. Preferable values for R.sup.1 when R.sup.1 is at position
5 on the bicyclic ring are --H, methyl, ethyl and methoxy. When
R.sup.1 is at position 5-on the bicyclic ring, R.sup.1 is more
preferably --H. When R.sup.1 is at position 7- on the bicyclic
ring, R.sup.1 is preferably --H.
[0029] R.sup.2 is preferably represented by Formula i. Preferably
R.sup.2 is represented by formula i, wherein n equals 2. Most
preferably R.sup.2 is represented by N-methyl piperazinyl.
[0030] R.sup.3 is preferably represented by hydrogen, methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
R.sup.3 is most preferably represented by methyl.
[0031] R.sup.4 is preferably represented by hydrogen, methyl,
ethyl, n-propyl, isopropyl and trimethylsilanyl-ethoxymethoxy.
R.sup.4 is most preferably represented by methyl.
[0032] R.sup.6 is preferably represented by H.
[0033] Y represents a linking group. Y is preferably
--C(.dbd.O)N(CH.sub.3)--, when Y is --C(.dbd.O)N(A)-. Y may also be
--C(.dbd.O)-piperazine. When Y represents a five-membered
heterocyclic ring, Y may be represented by, for example, pyrrole,
thiophene, furan, imidazole, thiazole, oxazole, pyrazole,
isothiazole, isoxazole, 1,2,3-triazole, 1,2,3-thiadiazole,
1,2,3-oxadiazole, 1,2,4-triazole, 1,2,4-thiadiazole,
1,2,4-oxadiazole, 1,3,4-triazole, 1,3,4-thiadiazole or
1,3,4-oxadiazole.
[0034] More preferably, Y is --C(.dbd.O)NH--.
[0035] Examples of R.sup.7 that represent monocyclic or bicyclic
aromatic ring or a heterocycle include, but are not limited to,
phenyl; 1- and 2-naphthyl; 2-, 3- and 4-pyridyl; 2- and 3-thienyl;
2- and 3-furyl; 1-, 2- and 3-pyrrolyl; imidazolyl; thiazolyl;
oxazolyl; pyrazolyl; isothiazolyl; isoxazolyl; 1,2,3-triazolyl;
1,2,3-thiadiazolyl; 1,2,3-oxadiazolyl; 1,2,4-triazolyl;
1,2,4-thiadiazolyl; 1,2,4-oxadiazolyl; 1,3,4-triazolyl;
1,3,4-thiadiazolyl; 1,3,4oxadiazolyl; quinolyl; isoquinolyl;
indolyl; benzothienyl; benzofuryl; benzimidazolyl; benzthiazolyl;
benzoxazolyl; or triazinyl. R.sup.7 may also be represented by the
Formula (v): ##STR12## R.sup.7 may further be represented by the
Formula (vi): ##STR13## When the values for R.sup.7 are as set
forth above, R.sup.8 may be a single bond as tether, --C(.dbd.O)--,
--CH.sub.2--, --C(.dbd.O)--, --SO.sub.2--, --S(.dbd.O)--, --S--,
--O--, --C(.dbd.O)NH--, --SO.sub.2NH--, or a five membered
heterocycle connected to R.sup.7 by a single bond or by ring
fusion; and R.sup.9 may represent an aryl, heterocyclic or
heteroaryl each independently optionally substituted with halogen,
nitro, cyano, hydroxy, trifluoromethyl, amino, carboxy, carbamoyl,
mercapto, sulfamoyl, C.sub.1-4 alkyl, C.sub.2-4alkenyl, C.sub.2-4
alkynyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.1-4
alkoxy, C.sub.1-4 alkanoyl, C.sub.1-4 alkanoyloxy, N--(C.sub.1-4
alkyl), N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 alkanoylamino,
(C.sub.1-4 alkanoyl).sub.2amino, N--(C.sub.1-4alkyl)carbamoyl,
N,N--(C.sub.1-4).sub.2carbamoyl, C.sub.1-4)S, C.sub.1-4S(O),
(C.sub.1-4alkyl)S(.dbd.O).sub.2, (C.sub.1-4) alkoxycarbonyl,
N--(C.sub.1-4 alkyl)sulfamoyl, N,N--C.sub.1-4 alkyl)sulfamoyl,
C.sub.1-4 alkylsolfonylamino, or heterocyclic. Preferably R.sup.9
is a an optionally substituted heterocyclic moiety.
[0036] More preferably R.sup.9 represents piperazine,
thiomorpholine or morpholine each independently optionally
substituted on carbon with at least one substituent selected from
A. R.sup.8 may be a five membered heterocycle, incorporating at
least one heteroatom selected from N, O, or S and it may be
connected to R.sup.7 by a ring fusion, preferably when R.sup.7 is
phenyl. When R.sup.8 is a single bond as tether, R.sup.9 is
preferably methoxy, cyano, a five-membered heterocycle optionally
substituted with at least one substituent represented by A or
R.sup.11 for example compounds represented by the Formulas (vii),
(viii) and (ix): ##STR14##
[0037] When R.sup.8 is represented by a 5-membered heterocyclic
comprising N and further when it is connected to R.sup.7 by a ring
fusion, R.sup.9 is preferably --C(.dbd.O)A attached at the nitrogen
atom, R.sup.9 is most preferably --C(.dbd.O)CH.sub.2CH.sub.3.
[0038] When R.sup.7 is phenyl or a 6-membered heterocyclic ring,
R.sup.9 is attached via the R.sup.8 tether at the 2-, 3- or
4-position of the phenyl or a 6-membered heterocyclic ring.
Preferably, R.sup.9 is attached via the R.sup.8 tether at the 3- or
4-position of the phenyl or a 6-membered heterocyclic ring. More
preferably, R.sup.9 is attached via the R.sup.8 tether at the 4
position of the phenyl or a 6-membered heterocyclic ring.
[0039] R.sup.10 may be represented by alkyl or cycloalkyl each
independently optionally substituted with halogen, nitro, cyano,
hydroxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto,
sulfamoyl, C.sub.1-4 alkyl, C.sub.2-4alkenyl, C.sub.2-4 alkynyl,
C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkenyl, C.sub.1-4 alkoxy,
C.sub.1-4 alkanoyl, C.sub.1-4 alkanoyloxy, N--(C.sub.1-4 alkyl),
N(C.sub.1-4 alkyl).sub.2, Cl.sub.4 alkanoylamino, (C.sub.1-4
alkanoyl).sub.2-amino, N--(C.sub.1-4alkyl)carbamoyl,
N,N--(C.sub.1-4).sub.2carbamoyl, C.sub.1-4)S, C.sub.1-4S(O),
(C.sub.1-4alkyl)S(O).sub.2, (C.sub.1-4) alkoxycarbonyl,
N--(C.sub.1-4 alkyl)sulfamoyl, N,N--C.sub.1-4 alkyl)sulfamoyl,
C.sub.1-4 alkylsulfonylamino, or heterocyclic. R.sup.10 is
preferably a halogen, preferably chlorine or fluorine, cyano, or
--OCH.sub.3. When R.sup.10 is a halogen it is preferably chlorine
or fluorine. When R.sup.7 is a phenyl or 6-membered heteroaromatic
ring, R.sup.10 is attached at the 2-, 3- or 4-position of the
phenyl or a 6-membered heterocyclic ring. Preferably, R.sup.10 is
attached at the 2- or 3-position of the phenyl or a 6-membered
heterocyclic ring when R.sup.9 is attached via the R.sup.8 tether
at the 4-position of the phenyl or a 6-membered heterocyclic ring.
More preferably, R.sup.10 is attached at the 3-position of the
phenyl or a 6-membered heterocyclic ring when R.sup.9 is attached
via the R.sup.8 tether at the 4-position of the phenyl or a
6-membered heterocyclic ring.
[0040] When R.sup.8 is represented by a single bond as tether,
R.sup.9 is preferably represented by an optionally substituted
heterocyclic, optionally substituted on carbon with at least one
substituent selected from A and further substituted on a heteroatom
opposite to the heteroatom attached to the tether, with a
substituent represented by R.sup.11 (see e.g., Formulas (vii),
(viii) and (ix)). The preferred heterocyclic compounds for R.sup.8
are piperazine, morpholine, or thiomorpholine
[0041] When R.sup.11 represents SO.sub.2A it is preferably
represented by an alkylsulfonyl, more preferably
--SO.sub.2CH.sub.3, --SO.sub.2CH.sub.2CH.sub.3,
SO.sub.2-n-C.sub.3H.sub.7, SO.sub.2-i-C.sub.3H.sub.7,
SO.sub.2-n-C.sub.4H.sub.10, --SO.sub.2-i-C.sub.4H.sub.10, or
--SO.sub.2-t-C.sub.4H.sub.10. When R.sup.11 represent C(.dbd.O)A,
it is preferably represented by an alkylcarbonyl more preferably
--C(.dbd.O)CH.sub.3, --C(.dbd.O)CH.sub.2CH.sub.3,
C(.dbd.O)-n-C.sub.4H.sub.10, --C(.dbd.O)-i-C.sub.4H.sub.10,
--C(.dbd.O)-t-C.sub.4H.sub.10, or --C(.dbd.O)C.sub.3H.sub.7--. When
R.sup.11 is represented by C(.dbd.O)NHA or C(.dbd.O)NA.sub.2 it is
preferably an alkyl or dialkyl carbamoyl more preferably
C(.dbd.O)NCH.sub.2CH.sub.3, C(.dbd.O)NH-cycloC.sub.6H.sub.12, or
C(.dbd.O)NH-cycloC.sub.5H.sub.10. When R.sup.11 is represented by
C(.dbd.O)R.sup.9 it is preferably --C(.dbd.O)-pyrrolidine, or
--C(.dbd.O)-morpholine. When R.sup.11 is represented by
SO.sub.2NA.sub.2 it is preferably SO.sub.2N(CH.sub.3).sub.2. When
R.sup.11 is represented by AOH, it is preferably represented by,
CH.sub.2CH.sub.2OH or --C(.dbd.O)CH.sub.2CH.sub.2OH. R.sup.11 may
also be represented by C(.dbd.O)OC.sub.4H.sub.10.
[0042] In preferred embodiments, when Y is represented by
--C(.dbd.O)NH: [0043] (a) R.sup.1 is halogen or methoxy, most
preferably fluorine, at the 6.sup.th position of the bicyclic ring,
and is preferably hydrogen, methyl, ethyl or methoxy at the
5.sup.th position of the bicyclic ring, and is hydrogen at the
7.sup.th position on the bicyclic ring; [0044] (b) R.sup.2 is
methyl piperazine; [0045] (c) R.sup.6 is hydrogen; [0046] (d)
R.sup.7 is phenyl substituted with R8-R9 [0047] (e) R.sup.8 is a
single bond as tether; [0048] (f) R.sup.9 is a heterocyclic moiety,
preferably morpholine or piperazine attached to R.sup.8 by nitrogen
and optionally substituted on the other nitrogen (for piperazine)
with R.sup.11 or optionally substituted on the oxygen with R.sup.11
when R.sup.9 is morpholine; [0049] (g) R.sup.11 is AOH or
--SO.sub.2A wherein A is represented by methyl or ethyl.
[0050] The compounds provided herein are useful in the form as a
free base, but may also be provided in the form of a
pharmaceutically acceptable salt, and/or in the form of a
pharmaceutically acceptable hydrate. For example pharmaceutically
acceptable salts of compounds of Formula I, Formula II, Formula
III, Formula IV or Formula V include those derived from mineral
acids such as for example: hydrochloric acid, nitric acid,
phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid,
nitrous acid, and phosphorous acid. Pharmaceutically acceptable
salts may also be developed with organic acids including aliphatic
mono and dicarboxylates and aromatic acids. Other
pharmaceutically-acceptable salts of compounds of the present
invention include for example hydrochloride, sulfate, pyrosulfate,
bisulfate, bisulfite, nitrate, and phosphate.
[0051] Processes for the manufacture of the compounds of Formula I,
Formula II, Formula III, Formula IV and Formula V are provided as
further features of the invention. Many of the Compounds described
herein can be made by processes known in the chemical arts for the
production of structurally analogous compounds. Accordingly, the
compounds of this invention may be prepared by employing procedures
known in the literature starting from known compounds or readily
prepared intermediates. For example, the core bicyclic,
heterocyclic structure may be made by first preparing a chromone,
quinolone or quinoline.
[0052] For compounds of the present invention that have Y as an
amide linker, the compounds are preferably made by the general
procedure for amide coupling, that is by coupling an anime with an
acid hydrochloride. The amines used in the current invention if not
commercially available may be made by known techniques. For example
as a first step in the process of making compound of Formula I,
Formula II, Formula M, Formula IV or Formula V, a nitro compound
may be reduced to an amine. The nitro compound may be a nitrophenyl
compound. The resulting amines may be reacted with an acid
hydrochloride. Provided herein is a process for preparation of a
precursor compound or use in practicing aspects of the present
invention by reacting a compound of Formula (VIa): ##STR15##
(R.sup.1, R.sup.2, R.sup.3, R.sup.7, and X. are as defined for
Formula I unless otherwise specified), with for example a compound
represented by: ##STR16## wherein R' is represented by alkyl,
preferably lower alkyl (e.g., C.sub.1-C.sub.6) most preferably
methyl or ethyl, to form a precursor compound of Formula (VIb):
##STR17## R.sup.1 is preferably fluorine, chlorine, methyl,
methoxy, ethoxy or hydrogen. The Halogen is preferably Chlorine or
Bromine. The reaction may be carried out in the presence of a
catalyst such as tetrabultyammonium fluoride in THF. The reaction
may be stirred for example at room temperature and refluxed with
heat.
[0053] Further provided herein is a process for the preparation of
a precursor compound comprising hydrolyzing the esters of compound
(VIb) to form intermediate (VIc): ##STR18## This reaction may be
carried our for example by reacting a compound of Formula (VIb)
with a base such as sodium hydroxide (aqueous). Also provided here
is a process for the preparation of an intermediate by the
cyclization of compound (VIc) to form intermediate (VId)
##STR19##
[0054] Intermediate compound (VId) may be formed by refluxing a
compound of Formula (VIc) with a strong acid (e.g., H.sub.2SO) and
further refluxed with heat and an alkyl alcohol for example R''OH
wherein R'' is C.sub.1-C.sub.4alkyl, preferably ethyl.
[0055] In an additional aspect of the invention, a process is
provided for the preparation of an intermediate by reacting a
compound of Formula (VId) with an amine of R.sup.2 in the presence
of a catalyst and a base to form intermediate Formula (VIe):
##STR20## In a further embodiment of the invention, a compound of
Formula (VId) is reacted with a catalyst selected from the group
consisting of nickel and palladium. Preferably the palladium is
provided in the presence of a phosphine ligand for example
2,2'-bis(diphenylphosphino)-1,1'-binapthyl. The palladium may be
provided as tris(dibenzylideneacetone) dipalladium. The base is
preferably selected from the group consisting of potassium
carbonate, sodium carbonate, cesium carbonate and triethylamine and
mixtures thereof.
[0056] Further provided herein is an acid hydrochloride of a
compound of Formula (VIe) which is intermediate Formula (VIf):
##STR21## The intermediate Formula (VIf) may be formed for example
by heating a compound of Formula (VIe) in the presence of an acid
and water (e.g., HCL/H.sub.2O). In another aspect of the invention
provided is intermediate Formula (VIg): ##STR22## Thus, in another
aspect of the invention, a leaving group is added to the
carboxylate of a compound of Formula (VIf). L is a leaving group.
This intermediate is useful in that the acid is activated to
provide an electrophile. L is preferably represented by chlorine in
intermediate Formula (VIg) which is prepared by reacting a compound
of Formula (VIf) with thionyl chloride (SOCl.sub.2). Provided
herein is a compound of Formula (VIh): ##STR23## Methods for
reacting amines with acid chlorides may be used to prepare
compounds of formula I such as a compound of Formula (VIh) For
example, a method for the preparation of (VIh) may include reacting
a compound of Formula (VIg) with H.sub.2N--R.sup.7 in the presence
of DIPEA.
[0057] Alternatively, compounds of Formula (VIh) may also be
prepared by reacting a compound of Formula (VIf) with
H.sub.2N--R.sup.7 in the presence for example
1-hydroxybenzotriazole (HOBT),
O-(1H-Benzotriazol-1-yl)-N,N,N'N'-pentamethylene-uronium
tetrafluorborate (TBTU), and (dimethylamino)pyridine, preferably in
that order.
[0058] Compounds of Formulas (VIe), (VIf), and (VIg), and (VIh) may
also comprise a pharmaceutically acceptable salt of said
compounds.
[0059] The compounds and processes above may also be used to
prepare the chroman derivatives of Formula (I) via the saturation
of the double bond (4H-chromene) in the bicyclic compound.
Depending on the reduction conditions, the 4-oxo derivative may or
may not be obtained.
[0060] A method for preparing the acid hydrochlorides useful in
synthesis of a chromone is set forth in Scheme 1 below:
##STR24##
[0061] Alternatively, the chromone-2-carboxylic acid may be
converted to the acid chloride and reacted immediately with an
appropriate amine, as depicted in Scheme 2, below: ##STR25##
[0062] Additional functional group manipulations include, but are
not limited to, O-dealkylation and N-dealkylation (Scheme 3).
##STR26##
[0063] Quinoline and quinolone compounds of the present invention
are prepared and derivatized via synthetic routes similar to those
employed for synthesis of the chromone-2-carboxamides described
above and in Schemes 1-3. These synthetic routes to quinoline and
quinolone compounds of the present invention are depicted in Scheme
4, infra. ##STR27##
[0064] It will be appreciated by those skilled in the art that
certain compounds of the present invention contain for example
asymmetrically substituted carbon and/or sulfur atoms, and
accordingly may exist in and be isolated in, optically-active and
racemic forms. Some compounds may exhibit polymorphism, thus it is
to be understood that the present invention encompasses racemic,
optically-active, polymorphic or stereoisomeric forms, or mixtures
thereof, which forms possess properties useful in the treatment of
the disorders set forth below. Preparation of optically active
forms is well known in the art how (for example by resolution of
racemic forms by recrystallization techniques, synthesis from
optically-active starting materials, chiral synthesis, or by
chromatographic separation using a chiral stationary phase) and how
to determine efficacy for the treatment of the disorder described
above.
[0065] Compounds of Formula I, Formula II, Formula IV and Formula V
have been found by the inventors to be useful as 5-HT.sub.1B and
5HT.sub.1D antagonists. The compounds of Formula I, Formula I,
Formula IV and Formula V, and their pharmaceutically acceptable
salts, may also be used in a method for the treatment of
depression, generalized anxiety, eating disorders, dementia, panic
disorder, sleep disorders, gastrointestinal disorders, motor
disorders, endocrine disorders, vasospasm and sexual dysfunction.
The treatment of these disorders comprises administering to a
warm-blooded animal, preferably a mammal, more preferably a human,
in need of such treatment, an effective amount of a compound of
Formula I, Formula II, Formula IV or Formula V, or a
pharmaceutically acceptable salt of said compound.
[0066] Compounds of Formula III have been found to be 5-HT.sub.1B
and 5HT.sub.1D agonists. The compounds of Formula III, and their
pharmaceutically acceptable salts, may also be used in a method for
the treatment of migraine. The treatment of this disorder comprises
administering to a warm-blooded animal, preferably a mammal, more
preferably a human, in need of such treatment, an effective amount
of a compound of Formula III or a pharmaceutically acceptable salt
of said compound.
[0067] Further provided herein are compounds of Formula I, Formula
II, Formula IV or Formula V, and their pharmaceutically acceptable
salts, for use in the treatment of depression, generalized anxiety,
eating disorders, dementia, panic disorder, sleep disorders,
gastrointestinal disorders, motor disorders, endocrine disorders,
vasospasm and sexual dysfunction of a warm-blooded animal,
preferably a mammal, more preferably a human, in need of such
therapy.
[0068] Further provided herein is a method of treatment of a
warm-blooded animal, preferably a mammal, more preferably a human,
suffering from disorders such as depression, generalized anxiety,
eating disorders, dementia, panic disorder, sleep disorders,
gastrointestinal disorders, motor disorders, endocrine disorders,
vasospasm and sexual dysfunction comprising administering to such
animal an effective amount of a compound of Formula I, Formula II,
Formula IV or Formula V, or a pharmaceutically acceptable salt of
the compound.
[0069] Further provided is the use of a compound of Formula I,
Formula II, Formula IV or Formula V in the preparation of a
medicament for the treatment of a disorder such as depression,
generalized anxiety, eating disorders, dementia, panic disorder,
sleep disorders, gastrointestinal disorders, motor disorders,
endocrine disorders, vasospasm and sexual dysfunction in a
warm-blooded animal, preferably a mammal, more preferably a human,
suffering from such disorder.
[0070] Further provided is the use of a compound of Formula III in
the preparation of a medicament for the treatment of a disorder
such as migraine in a warm-blooded animal, preferably a mammal,
more preferably a human, suffering from such disorder.
[0071] The invention further provides a pharmaceutical composition
suitable for the treatment of the above describe disorders
comprising administering to a warm-blooded animal having such
disorder an effective amount of a pharmaceutical composition of a
compound of Formula I, Formula II, Formula III, Formula IV or
Formula V, or a pharmaceutically acceptable salt.
[0072] The invention also provides a pharmaceutical composition
comprising a compound of Formula I, Formula II, Formula II, Formula
IV or Formula V as defined herein, or a pharmaceutically acceptable
salt, in combination with a pharmaceutically acceptable carrier.
Preferred compounds of Formula I, Formula II, Formula III, Formula
IV and Formula V for use in the compositions of the invention are
as described above.
[0073] All compounds described herein demonstrate binding
affinities (observed Ki values), in an assay described below, of
less than about 10 .mu.M. Further, compounds of the present
invention not only demonstrate 5HT.sub.1B antagonist activity by
reversing 5HT.sub.1B agonist-induced hypothermia in the guinea pig,
these compounds are considered to be orally active, and hence, they
are the preferred compounds. Examples 1, 10, 11, 31, 32, 34, 44,
55, 56, 57, 71 and 72, infra, demonstrate 5HT.sub.1B antagonist
activity in a dosage range of 0.006-5.5 mg/kg. In addition,
compounds described herein demonstrate activity in the learned
helplessness assay for antidepressant/antianxiety activity.
Examples 31, 44, 71 and 72, infra, demonstrate activity in the
learned helplessness assay. In addition, compounds were tested for
maximal intrinsic activity (IA), and were found to have measured
IA's of negative 50% to positive 150% in the GTP.gamma.S assay
described below, thus demonstrating a range of response from
agonism (low percentages) to antagonism (high percentages).
[0074] The compounds described herein may be provided or delivered
in a form suitable for oral use, for example in a tablet, lozenge,
hard and soft capsule, aqueous solution, oily solution, emulsion,
and suspension. The compounds may be also be provided for topical
administration, for example, as a cream, ointment, gel, spray, or
aqueous solutions, oily solutions, emulsions or suspensions. The
compounds described herein may also be provided in a form suitable
for nasal administration for example, as a nasal spray, nasal
drops, or dry powder. The compositions may also be administered to
the vagina or rectum in the form of a suppository. The compounds
described herein may also be administered parentally, for example
by intravenous, intravesicular, subcutaneous, or intramuscular
injection or infusion.
[0075] The compounds may be administered by insufflation (for
example as a finely divided powder). The compounds may also be
administered transdermally or sublingually.
[0076] The compositions of the invention may accordingly be
obtained by conventional procedures using conventional
pharmaceutical excipients, well known in the art. Thus,
compositions intended for oral use may contain, for example, one or
more coloring, sweetening, flavoring and/or preservative
agents.
[0077] The amount of active ingredient that is combined with one or
more excipients to produce a single dosage form will necessarily
vary depending upon the host treated and the particular route of
administration. The size of the dose for therapeutic or
prophylactic purposes of a compound of the Formula I, Formula II,
Formula III, Formula IV or Formula V will naturally vary according
to the nature and severity of the conditions, the age and sex of
the animal or patient and the route of administration, according to
well known principles of medicine. Various assays and in vivo tests
are known for determining the utility of the compounds in the
disorders noted above and specifically as agonists and antagonists
of 5HT.sub.1B and 5HT.sub.1D.
[0078] The utility of the compounds for example to treat depression
may be shown via a learned helplessness test in guinea pigs, which
is used extensively as correlative to antidepressant activity in
humans. The learned helplessness test may be carried out as
follows: Seventy male Hartley guinea pigs, each weighing about
350-425 gm are fed ad lib, and are housed under a 12-hour
light/dark cycle. The procedure consists of two phases: The
induction phase and the avoidance training phase. In the induction
phase, subjects are placed into standard shuttle cages (20
L.times.16 W.times.21 centimeters H) which are fitted with a grid
floor. Electrical stimulation (1.25 mA, 10 sec duration) is
delivered to the floor of the cage every 90-sec during 1 hour daily
sessions. Subjects have no opportunity to escape or to avoid
shocks. Induction is conducted for 2 consecutive days.
[0079] In avoidance training, testing is also conducted in the
shuttle cages, except that the subjects are not returned to the
same chamber in which induction had occurred. Additionally, all
cages are fitted with a partition with an arch in the center of the
cage, through which animals can pass between the left and right
halves of the cage. The procedure employed is a standard shuttle
avoidance procedure in which a compound, conditioned stimulus (a
10-sec presentation of a tone and turning on of a lamp on the side
of the cage that the guinea pig was occupying) serves to indicate
presentation of electrical current to the floor of the cage. Shock
is presented for a 5 sec period, 5 sec after initiation of the
conditioned stimulus. Entry into the opposite side of the shuttle
cage via the arched partition prior to shock onset results in the
end of the trial (avoidance response). If shock is delivered, entry
into the opposite side of the cage results in termination of the
shock and CS (escape). Reversal of learned helplessness in the
induction subjects correlates to antidepressant activity of the
test compound.
[0080] Avoidance training, 45-min in duration, is conducted on 2
consecutive days, beginning 48 hr after the final induction
session. Seventy subjects are assigned to 1 of 6 groups of 11-12
animals. The groups are as follows:
[0081] 1) No induction group. The subjects are placed into the
shuttle cages but are not given inescapable shock, the animals are
subsequently trained in the avoidance procedure and the vehicle is
administered;
[0082] 2) Induction vehicle control group;
[0083] 3) Imipramine 17.8 mg/kg;
[0084] 4) 0.3 mg/kg compounds;
[0085] 5) 1 mg/kg compounds; and
[0086] 6) 5 mg/kg compounds.
[0087] Groups 2-6 are given induction and avoidance training
sessions. Injections are administered immediately following
induction sessions and 1 hour prior to avoidance training sessions.
A second injection is administered 7-8 hours following the first
injection, for a total of 9 injections administered over 5 days. No
injections are administered following the final avoidance training
session.
[0088] Compounds of the present invention may be administered in a
volume of 1 mL/kg bwt. Imipramine is dissolved in DI water. The
compounds are dissolved in DI water, to which was added a few drops
of lactic acid (pH 5.5). The vehicle control is DI water prepared
with lactic acid to the same pH as the-treated groups.
[0089] The primary dependent variable is escape failure during
avoidance training. 2-way analysis of variance (ANOVA) is used to
assess overall treatment effect, with Dunn's post hoc analysis used
to compare the vehicle-treated group with the drug-treated groups.
The no-induction group is used to gauge whether learned
helplessness is established, by comparison to the vehicle treated
group.
[0090] An alternative method for determining the utility of the
compounds of the present invention is to investigate the in vivo
activity of the compounds using a guinea pig hypothermia test (J.
Med. Chem., 41: 1218-1235 (1998)). Compounds that bind to
5-HT.sub.1B receptors are known to be useful in treating disorders
described above (e.g., depression, generalized anxiety, eating
disorders, dementia, panic disorder, sleep disorders,
gastrointestinal disorders, motor disorders, endocrine disorders,
vasospasm and sexual dysfunction. While not wishing to be bound to
any theory, it is believed that 5-HT.sub.1B receptors on nerve
terminals control the amount of release of s5-ht into the synapse.
Thus, it can be shown that compounds of Formula I, Formula II,
Formula IV and Formula V, and their pharmaceutically acceptable
salts, are able to act as 5-HT.sub.1B antagonists and block the
agonist-induced effect of hypothermia (a drop in body temperature
of about 2.degree. C. observed within 0.5-1.5 hours following
administration of a 5-HT.sub.1B agonist) as a method for assessing
whether the novel compounds are effective as antagonists at the
5-HT.sub.1B receptor.
[0091] The hypothermia test is conducted as follows: A
tele-thermometer fitted with a flexible probe will be used. The tip
of the probe is immersed in a test tube containing a lubrication
agent between usage. Core temperature is measured by inserting the
probe into the rectum and by waiting for the temperature to
stabilize, which occurs within the 20-60 seconds. Core temperature
is measured once (pretest) prior to administration of the test
substance in order to establish a baseline temperature for all
animals. Guinea pigs are then dosed with the test substance
(candidate 5-ht1b antagonist) either subcutaneously or
intraperitoneally. In general, 30 min following dosing with
antagonist, agonist is administered subcutaneously. The temperature
is then recorded 30-, 60, 90-min following agonist. In some
studies, in order to record time course of antagonist activity, up
to 12 hours may be allowed to elapse between administration of
antagonist and agonist. The drugs may either be injected
subcutaneously, intraperitoneally or orally (using a flexible
plastic gavage tube, or a stainless steel gavage tube). In
addition, animals may be observed on the days following drug
administration in order to monitor for unexpected toxicity. The
body temperature of the guinea pigs is recorded separately for each
guinea pig at each test time point, and submitted to a ANOVA with
one between subjects factor: dose, and one within subject factor:
time. Following a significant two-way interaction (p<0.05),
Dunnett's t-test is performed to compare the drug treatment with
either the saline or the effects of treatment with the hypothermic
agent.
[0092] Male Guinea Pig (Dunkin-Hartley), maximum 3 animals per
cage, are used. The animals may be grouped in sets of 5 during
testing. The animals will not be deprived of food or water during
their time in the laboratory. The routes of administration are:
S.C., I.P., P.O. The maximum dose (volume) is 2 ml/kg s.c. or i.p.,
5 ml/kg P.O. three times daily.
[0093] This method may function as a primary in vivo screen for
compounds having an affinity for 5-ht.sub.1b receptors as a
determination of antagonist activity. Each experiment may consist
of separate groups of 5 subjects per treatment level. One group is
given vehicle prior to agonist administration and may serve as the
control group, i.e., hypothermia will be unaltered by introduction
of an antagonist. The other groups are administered different doses
of antagonist prior to agonist administration, but no more than 5
groups are tested at a time. In order to determine full dose effect
functions for compounds (to determine drug potency) 4-6 doses of
each compound are evaluated. That results in about 25-35 animals
per drug to be evaluated. Dose-response curves are generated and
ED50 values are determined. ED50 values for compounds of the
present invention range from 0.006-5.5 mg/kg.
[0094] Other assays that may be used to measure for example
affinity of compounds of the present invention for 5HT.sub.1B and
5HT.sub.1D receptors are described in J. Med. Chem. 41:1218-1235,
1228 (1998) and J. Med. Chem. 42:4981-5001, (1999) and incorporated
by reference herein. These assays may be used with some
modifications: Frozen membrane preparations of a stably transfected
chinese hamster ovary (CHO) cell line expressing 5-HT.sub.1B
receptors and 5-HT.sub.1D receptors are thawed rapidly, briefly
vortexed, and diluted in assay buffer (AB) containing 50 mM
Tris-HCl, 4 mM MgCl.sub.2, 4 mM CaCl.sub.2, 1 mM EDTA, and adjusted
to pH 7.4 with NaOH. Final protein concentrations are -0.185 mg/ml
for 5-HT.sub.1B, and 0.4 mg/ml for 5-HT.sub.1D membranes. Test
compounds are evaluated in competition assays using
[.sup.3H]-GR125743 (Amersham). The ligand concentration in both
assays was 0.27 nM. Kd for [.sup.3H]-GR125743 may vary from 0.15 nM
to 0.25 nM. The 5-HT.sub.1B and 5-HT.sub.1D assays are performed
simultaneously on one 96-well assay plate, one drug/compound per
plate. Ten serial dilutions (1 uM to 4 pM, final concentration) of
compound are prepared in DMSO from 10 mM stock solutions.
Incubation mixtures are prepared in quadruplicate in 96-deep well
assay plates (Matrix 1 ml). Final assay volumes per well are 10
.mu.l compound/nonspecific; 100 .mu.l membranes; 100 .mu.l
[3H]-GR125743; and 790 .mu.l AB. Specific binding is defined by
using 10 uM Methiothepine. The assay plates are shaken for 5 min.,
and then incubated for an additional 55 min. Then the assay plates
are filtered through Beckman GF/B filters (soaked >2 hrs. in
PEI) using a Packard Filtermate 196. Filters are washed 2.times.
with 1 ml ice-cold wash buffer (5 mM Tris-HCl--pH7.4 with NaOH).
After the filters are dried, 35 .mu.l of Microscint20 is added to
each well. The plates are then counted on a Packard TopCount to
determine CPM's per well. Ki values are determined for each test
compound utilizing the graphic and analytical software package,
GraphPad Prism. Compounds are then ranked in order of potency, and
selectivity for 5 HT.sub.1B over 5-HT.sub.1D receptors.
[0095] A method that may be used to determine a compound's affinity
for 5-HT.sub.1B and 5HT.sub.1D receptors is a guinea pig cortical
test. This assay is described in detail by Roberts, et al, Br. J.
Pharmacol., 1996, 117, 384-388, which is incorporated by reference
herein. The test is carried out as follows: Guinea pigs are
decapitated and the cortici is dissected out, weighed and
homogenized in 50 mM Tris-HCl, pH 7.7 with an Ultra-Turrax followed
by centrifugation for 10 min at 48000.times.g and 5.degree. C. The
pellet is resuspended and recentrifuged. The final pellet is
suspended in 0.32 M sucrose buffer to a concentration of 0.5 g
original wet weight per mL and stored frozen at -70.degree. C. The
radioligand binding assay is carried out as follows:
[.sup.3H]GR125743 saturation studies are tested in duplicate with
34 mg w.w. per tube in 5 mL buffer (50 mM Tris, 4 mM CaCl2, 4 mM
MgCl2 and 1 mM EDTA at pH 7.7), and a concentration range of
0.012-2 nM (10-12 concentrations) for the radioligand. Non-specific
binding is determined in the presence of 10 mM methiothepin. In
competition experiments 4-8 mg w.w. per tube and a radioligand
concentration of 0.2 nM are used with 10-12 concentrations of the
competing drug. The assays are run for 24 hours at 30.degree. C.
and terminated by rapid filtration through Whatman GF/B filters
(pretreated with 0.1% polyethyleneimine) using a Brandel cell
harvester. Bovine serum albumin (0.1%) is added to the washing
buffer to reduce non-specific binding. Data from the experiments
may be analyzed using the iterative non-linear curve-fitting
program LIGAND. The K.sub.d values obtained from the saturation
studies are used in the calculation of the Ki values by the LIGAND
program. The K.sub.d value of [.sup.3H]GR125743 may result in a
measurement of 46.+-.4 pM and the B.sub.max in a measurement of
4.9.+-.0.2 .mu.mol/g w.w.
[0096] A GTP.gamma.S binding assay may used to determine whether a
compound is a 5HT.sub.1B or 5HT.sub.1D agonist or antagonist. One
assay available measures agonist stimulated GTP binding for example
as set forth by Lazareno, S. (1999) Methods in Molecular Biology
106: 231-245. Membrane preparations of a stably transfected CHO
cell line expressing human 5-HT.sub.1B receptors are purchased for
example from Unisyn, Hopkinton, Mass. Frozen membranes are thawed,
briefly sonicated, and diluted to 167 .mu.g/ml protein in assay
buffer containing 20 mM HEPES, 100 mM NaCl, 1 mM MgCL.sub.2 and 1
.mu.M GDP, pH adjusted to 7.4 with NaOH. Diluted membranes are
briefly homogenized with a Polytron and allowed to equilibrate at
room temperature for at least 15 minutes before use. Serial
dilutions (10 .mu.M to 1 pM, final concentration) of test compounds
are prepared in buffer with and without 100 nM 5-HT (final
concentration) from 10 mM DMSO stock solutions. Incubation mixtures
are prepared in quadruplicate in 96-well, deep-well plates and
consisted of 180 .mu.L of membranes (30 .mu.g protein) and 40 .mu.L
of compound with or without 5-HT. After an incubation period of 15
minutes at room temperature, 20 .mu.L of [.sup.35S]GTP.gamma.S
(NEN; 100 pM final concentration) is added to begin the assay.
Mixtures are shaken for 2 minutes and incubated at room temperature
for an additional 28 minutes. The reaction is stopped by rapid
filtration through Beckman GF/B glass fiber filters using a 96-well
Packard cell harvester. Filters are washed four times with 1 mL
ice-cold water. The filter plates are nominally dried and 30 .mu.L
of scintillation cocktail (MicroScint 40, Packard) is added to each
well. CPMs for each well is determined using a TopCount
Scintillation Counter (Packard). Maximum stimulation of
[.sup.35S]GTP.gamma.S binding is defined in the presence of 100 nM
5-HT. Basal [.sup.35S]GTP.gamma.S binding is defined in buffer
alone. IC50 values are defined as the concentration of compound at
which 50% of the 100 nM 5-HT response was obtained. Maximal
intrinsic activity (IA) of a compound is defined as the percent
maximal 5-HT-induced stimulation by 10 .mu.M compound in the
absence of 5-HT. As an inter-assay standard, a concentration
response curve of 5-HT (1 .mu.M to 1 pM final) in the absence of
compounds was included in each assay and an EC.sub.50 was
determined.
[0097] Preferred compounds of the present invention include, but
are not limited to, the following compositions listed in Table 1 on
the following pages. TABLE-US-00001 TABLE 1 Compounds. Example #
Structure Name 1 ##STR28## 8-(4-methyl-1-piperazinyl)-N-[4-(4-
morpholinyl)phenyl]-4-oxo-4H- chromene-2-carboxamide 2 ##STR29##
2-{1-[4-(2-Methoxy-phenyl)- piperazin-1-yl]-methanoyl}-8-(4-
methyl-piperazin-1-yl)-chromen-4- one 3 ##STR30##
2-{1-[4-(1-Acetyl-2,3-dihydro-1H- indol-6-yl)-piperazin-1-yl]-
methanoyl}-8-(4-methyl-piperazin- 1-yl)-chromen-4-one 4 ##STR31##
2-Chloro-5-(4-{1-[8-(4-methyl- piperazin-1-yl)-4-oxo-4H-chromen-
2-yl]-methanoyl}-piperazin-1-yl)- benzonitrile 5 ##STR32##
2-{1-[4-(4-Methoxy-phenyl)- piperazin-1-yl]-methanoyl}-8-(4-
methyl-piperazin-1-yl)-chromen-4- one 6 ##STR33##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
(5- furan-2-yl-1H-pyrazol-3-yl)-amide 7 ##STR34##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
(4- imidazol-1-yl-phenyl)-amide 8 ##STR35##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
(4- [1,2,3]thiadiazol-5-yl-phenyl)- amide 9 ##STR36##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid 4-
[1,2,3]thiadiazol-5-yl-benzylamide 10 ##STR37##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
[4- (4-acetyl-piperazin-1-yl)-phenyl]- amide 11 ##STR38##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
[4- (4-methanesulfonyl-piperazin-1-yl)- phenyl]-amide 12 ##STR39##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
(2- methoxy-4-morpholin-4-yl-phenyl)- amide 13 ##STR40##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
(3- chloro-4-morpholin-4-yl-phenyl)- amide 14 ##STR41##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
(4- thiomorpholin-4-yl-phenyl)-amide 15 ##STR42##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
(2,5-diethoxy-4-morpholin-4-yl- phenyl)-amide 16 ##STR43##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
(4- cyanomethyl-phenyl)-amide 17 ##STR44##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
(1H-indol-5-yl)-amide 18 ##STR45##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
[4- (1-morpholin-4-yl-methanoyl)- phenyl]-amide 19 ##STR46##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
[4- (2,6-dimerhyl-morpholin-4-yl)- phenyl]-amide 20 ##STR47##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
[4- (4-fluoro-phenoxy)-phenyl]-amide 21 ##STR48##
8-(4-Methyl-piperazin-1-yl)-2-(6- morpholin-4-yl-benzooxazol-2-yl)-
chromen-4-one 22 ##STR49## 8-(4-Methyl-piperazin-1-yl)-4-oxo-
4H-chromene-2-carboxylic acid (2- hydroxy-4-morpholin-4-yl-phenyl)-
amide 23 ##STR50## 8-(4-Methyl-piperazin-1-yl)-4-oxo-
4H-chromene-2-carboxylic acid (5- ethoxy-benzothiazol-2-yl)-amide
24 ##STR51## 8-(4-Methyl-piperazin-1-yl)-4-oxo-
4H-chromene-2-carboxylic acid (4- bromo-phenyl)-amide 25 ##STR52##
8-(4-Methylpiperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
methyl-(4-morpholin-4-yl- phenyl)amide 26 ##STR53##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
(3- morpholin-4-yl-phenyl)-amide 27 ##STR54##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
(3- cyano-4-morpholin-4-yl-phenyl)- amide 28 ##STR55##
8-(4-Methyl-piperazin-1-yl)-4-oxo- 4H-chromene-2-carboxylic acid
(3- fluoro-4-morpholin-4-yl-phenyl)- amide 29 ##STR56##
4-[4-({1-[8-(4-Methyl-piperazin-1- yl)-4-oxo-4H-chromen-2-yl]-
methanoyl}-amino)-phenyl]- piperazine-1-carboxylic acid tert- butyl
ester 30 ##STR57## 8-(4-Methyl-piperazin-1-yl)-4-oxo-
4H-chromene-2-carboxylic acid (4- piperazin-1-yl-phenyl)-amide 31
##STR58## 6-Methoxy-8-(4-methyl-piperazin-
1-yl)-4-oxo-4H-chromene-2- carboxylic acid (4-morpholin-4-yl-
phenyl)-amide 32 ##STR59## 6-Methoxy-8-(4-methyl-piperazin-
1-yl)-4-oxo-4H-chromene-2- carboxylic acid [4-(4-
methanesulfonyl-piperazin-1-yl)- phenyl]-amide 33 ##STR60##
6-Methoxy-8-(4-Methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid (3-chloro-4- morpholin-4-yl-phenyl)-amide 34
##STR61## 6-Methoxy-8-(4-methyl-piperazin-
1-yl)-4-oxo-4H-chromene-2- carboxylic acid (3-fluoro-4-
morpholin-4-yl-phenyl)-amide 35 ##STR62##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid (2-methoxy-4- morpholin-4-yl-phenyl)-amide 36
##STR63## 6-Methoxy-8-(4-methyl-piperazin-
1-yl)-4-oxo-4H-chromene-2- carboxylic acid (4-thiomorpholin-4-
yl-phenyl)-amide 37 ##STR64## 6-Methoxy-8-(4-methyl-piperazin-
1-yl)-4-oxo-4H-chromene-2- carboxylic acid [4-(2,6-dimethyl-
morpholin-4-yl)-phenyl]-amide 38 ##STR65##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid (3-morpholin-4-yl- phenyl)-amide 39 ##STR66##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid {4-[4-(2-hydroxy- ethyl)-piperazin-1-yl]-phenyl}-
amide 40 ##STR67## 6-Methoxy-8-(4-methyl-piperazin-
1-yl)-4-oxo-4H-chromene-2- carboxylic acid [4-(1-morpholin-4-
yl-methanoyl)-phenyl]-amide 41 ##STR68##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid (3-cyano-4- morpholin-4-yl-phenyl)-amide 42
##STR69## 4-[4-({1-[6-Methoxy-8-(4-methyl-
piperazin-1-yl)-4-oxo-4H-chromen- 2-yl]-methanoyl}-amino)-phenyl]-
piperazine-1-carboxylic acid tert- butyl ester 43 ##STR70##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid (4-piperazin-1-yl- phenyl)-amide 44 ##STR71##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid [4-(4-propionyl- piperazin-1-yl)-phenyl]-amide 45
##STR72## 6-Methoxy-8-(4-methyl-piperazin-
1-yl)-4-oxo-4H-chromene-2- carboxylic acid [4-(4-ethane
sulfonyl-piperazin-1-yl)-phenyl]- amide 46 ##STR73##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid [4-(4-dimethyl sulfamoyl-piperazin-1-yl)-phenyl]-
amide 47 ##STR74## 4-[4-({1-[6-Methoxy-8-(4-methyl-
piperazin-1-yl)-4-oxo-4H-chromen- 2-yl]-methanoyl}-amino)-phenyl]-
piperazine-1-carboxylic acid dimethylamide 48 ##STR75##
4-[4-({1-[6-Methoxy-8-(4-methyl- piperazin-1-yl)-4-oxo-4H-chromen-
2-yl]-methanoyl}-amino)-phenyl]- piperazine-1-carboxylic acid
ethylamide 49 ##STR76## 4-[4-({1-[6-Methoxy-8-(4-methyl-
piperazin-1-yl)-4-oxo-4H-chromen- 2-yl]-methanoyl}-amino)-phenyl]-
piperazine-1-carboxylic acid cyclohexylamide 50 ##STR77##
4-[4-({1-[6-Methoxy-8-(4-methyl- piperazin-1-yl)-4-oxo-4H-chromen-
2-yl]-methanoyl}-amino)-phenyl]- piperazine-1-carboxylic acid
cyclopentylamide 51 ##STR78## 6-Methoxy-8-(4-methyl-piperazin-
1-yl)-4-oxo-4H-chromene-2- carboxylic acid {4-[4-(1-pyrrolidin-
1-yl-methanoyl)-piperazin-1-yl]- phenyl}-amide 52 ##STR79##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid {4-[4-(propane-2-
sulfonyl)-piperazin-1-yl]-phenyl}- amide 53 ##STR80##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid {4-[4-(2-methyl-
propanoyl)-piperazin-1-yl]-phenyl}- amide 54 ##STR81##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid {4-[4-(1-morpholin-
4-yl-methanoyl)-piperazin-1-yl]- phenyl}-amide 55 ##STR82##
6-Fluoro-8-(4-methyl-piperazin-1- yl)-4-oxo-4H-chromene-2-
carboxylic acid (4-morpholin-4-yl- phenyl)-amide 56 ##STR83##
6-Fluoro-8-(4-methyl-piperazin-1- yl)-4-oxo-4H-chromene-2-
carboxylic acid [4-(4- methanesulfonyl-piperazin-1-yl)-
phenyl]-amide 57 ##STR84## 6-Fluoro-8-(4-methyl-piperazin-1-
yl)-4-oxo-4H-chromene-2- carboxylic acid [4-(4-acetyl-
piperazin-1-yl)-phenyl]-amide 58 ##STR85##
6-Fluoro-8-(4-methyl-piperazin-1- yl)-4-oxo-4H-chromene-2-
carboxylic acid (3-chloro-4- morpholin-4-yl-phenyl)-amide 59
##STR86## 6-Fluoro-8-(4-methyl-piperazin-1-
yl)-4-oxo-4H-chromene-2- carboxylic acid (3-fluoro-4-
morpholin-4-yl-phenyl)-amide 60 ##STR87##
6-Fluoro-8-(4-methyl-piperazin-1- yl)-4-oxo-4H-chromene-2-
carboxylic acid (3-cyano-4- morpholin-4-yl-phenyl)-amide 61
##STR88## 6-Fluoro-8-(4-methyl-piperazin-1-
yl)-4-oxo-4H-chromene-2- carboxylic acid [4-(1-morpholin-4-
yl-methanoyl)-phenyl]-amide 62 ##STR89##
6-Methyl-8-(4-methyl-piperazin-1- yl)-4-oxo-4H-chromene-2-
carboxylic acid (4-morpholin-4-yl- phenyl)-amide 63 ##STR90##
6-Methyl-8-(4-methyl-piperazin-1- yl)-4-oxo-4H-chromene-2-
carboxylic acid [4-(1-morpholin-4- yl-methanoyl)-phenyl]-amide 64
##STR91## 6-Methyl-8-(4-methyl-piperazin-1-
yl)-4-oxo-4H-chromene-2- carboxylic acid (3-fluoro-4-
morpholin-4-yl-phenyl)-amide 65 ##STR92##
6-Chloro-8-(4-methyl-piperazin-1- yl)-4-oxo-4H-cbromene-2-
carboxylic acid (4-morpholin-4-yl- phenyl)-amide 66 ##STR93##
5-Methyl-8-(4-methyl-piperazin-1- yl)-4-oxo-4H-chromene-2-
carboxylic acid (4-morpholin-4-yl- phenyl)-amide 67 ##STR94##
5-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid (4-morpholin-4-yl- phenyl)-amide 68 ##STR95##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-4H-chromene-2-
carboxylic acid {4-[4-(3-hydroxy-
propanoyl)-piperazin-1-yl]-phenyl}- amide 69 ##STR96##
4-[4-({1-[6-Fluoro-8-(4-methyl- piperazin-1-yl)-4-oxo-4H-chromen-
2-yl]-methanoyl}-amino)-phenyl]- piperazirie-1-carboxylic acid
tert- butyl ester 70 ##STR97## 4-[4-({1-[6-Fluoro-8-(4-methyl-
piperazin-1-yl)-4-oxo-4H- chromene-2-carboxylic acid (4-
piperazin-1-yl-phenyl)-amide 71 ##STR98##
6-Fluoro-8-(4-methyl-piperazin-1- yl)-4-oxo-4H-chromene-2-
carboxylic acid [4-(4-ethane sulfonyl-piperazin-1-yl)-phenyl]-
amide 72 ##STR99## 6-Fluoro-8-(4-methyl-piperazin-1-
yl)-4-oxo-4H-chromene-2- carboxylic acid [4-(4-propionyl-
piperazin-1-yl)-phenyl]-amide 73 ##STR100##
6-Fluoro-8-(4-methyl-piperazin-1- yl)-4-oxo-4H-chromene-2-
carboxylic acid {4-[4-(3-hydroxy-
propanoyl)-piperazin-1-yl]-phenyl}- amide 74 ##STR101##
N-[8-(4-Methyl-piperazin-1-yl)-4- oxo-4H-chromen-2-yl]-4-
morpholin-4-yl-benzamide 75 ##STR102## 8-(4-Methyl-piperazin-1-yl)-
chroman-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide
76 ##STR103## (+)-8-(4-Methyl-piperazin-1-yl)- chroman-2-carboxylic
acid (4- morpholin-4-yl-phenyl)-amide 77 ##STR104##
(-)-8-(4-Methyl-piperazin-1-yl)- chroman-2-carboxylic acid (4-
morpholin-4-yl-phenyl)-amide 78 ##STR105##
racemic-8-(4-methyl-piperazin-1- yl)-4-oxo-chroman-2-carboxylic
acid (4-morpholin-4-yl-phenyl)- amide 79 ##STR106##
8-(4-Methyl-piperazin-1-yl)-4-oxo- chroman-2-carboxylic acid (4-
morpholin-4-yl-phenyl)-amide (faster running isomer) 80 ##STR107##
8-(4-Methyl-piperazin-1-yl)-4-oxo- chroman-2-carboxylic acid (4-
morpholin-4-yl-phenyl)-amide (slower running isomer). 81 ##STR108##
4-[4-({1-[6-Fluoro-8-(4-methyl- piperazin-1-yl)-4-oxo-4H-chromen-
2-yl]-methanoyl}-amino)-phenyl]- piperazine-1-carboxylic acid
ethylamide 82 ##STR109## 6-Methoxy-8-(4-methyl-
[1,4]diazepan-1-yl)-4-oxo-4H- chromene-2-carboxylic acid (4-
morpholin-4-yl-phenyl)-amide 83 ##STR110##
6-Ethoxy-8-(4-methyl-piperazin-1- yl)4-oxo-4H-chromene-2-
carboxylic acid (4-morpholin-4-yl- phenyl)-amide 84 ##STR111##
6-Ethoxy-8-(4-methyl-piperazin-1- yl)-4-oxo-4H-chromene-2-
carboxylic acid [4-(4-propionyl- piperazin-1-yl)-phenyl]-amide 85
##STR112## 6-Methoxy-4-oxo-8-piperazin-1-yl-
4H-chromene-2-carboxylic acid (4- morpholin-4-yl-phenyl)-amide 86
##STR113## 6-Hydroxy-8-(4-methyl-piperazin-
1-yl)-4-oxo-4H-chromene-2- carboxylic acid (4-morpholin-4-yl-
phenyl)-amide 87 ##STR114## 6-Methoxy-8-(4-methyl-
[1,4]diazepan-1-yl)-4-oxo-1,4- dihydro-quinoline-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide 88 ##STR115##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-1,4-dihydro-quinoline-
2-carboxylic acid (4-morpholin-4- yl-phenyl)-amide 89 ##STR116##
6-Methoxy-8-(4-methyl-piperazin- 1-yl)-4-oxo-1,4-dihydro-quinoline-
2-carboxylic acid [4-(4-propionyl- piperazin-1-yl)-phenyl]-amide 90
##STR117## 6-Fluoro-8-(4-methyl-piperazin-1-
yl)-4-oxo-1,4-dihydro-quinoline-2- carboxylic acid
(4-morpholin-4-yl- phenyl)-amide 91 ##STR118##
6-Fluoro-8-(4-methyl-piperazin-1-
yl)-4-oxo-1,4-dihydro-quinoline-2- carboxylic acid [4-(4-propionyl-
piperazin-1-yl)-phenyl]-amide 92 ##STR119##
8-[(2-Dimethylamino-ethyl)- methyl-amino]-6-methoxy-4-oxo-
1,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-
amide 93 ##STR120## 8-[(3-Dimethylamino-propyl)-
methyl-amino]-6-methoxy-4-oxo- 1,4-dihydro-quinoline-2-carboxylic
acid (4-morpholin-4-yl-phenyl)- amide 94 ##STR121##
8-((3R)-(+)-3-Dimethylamino- pyrrolidin-1-yl)-6-methoxy-4-oxo-
1,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-
amide 95 ##STR122## 8-((3S)-(-)-3-Dimethylamino-
pyrrolidin-1-yl)-6-methoxy-4-oxo-
1,4-dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-
amide 96 ##STR123## 6-Methoxy-8-[methyl-(1-methyl-
pyrrolidin-3-yl)-amino]-4-oxo-1,4- dihydro-quinoline-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide 97 ##STR124##
8-[Ethyl-(1-ethyl-pyrrolidin-3-yl)- amino]-6-methoxy-4-oxo-1,4-
dihydro-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide
98 ##STR125## 4-dimethylamino-6-methoxy-8-(4-
methyl-piperazin-1-yl)-quinoline-2- carboxyhc acid
(4-morpholin-4-yl- phenyl)-amide 99 ##STR126##
6-methoxy-4-methylamino-8-(4- methyl-piperazin-1-yl)-quinoline-2-
carboxylic acid (4-morpholin-4-yl- phenyl)-amide 100 ##STR127##
6-fluoro-4-methoxy-8-(4-methyl- piperazin-1-yl)-quinoline-2-
carboxylic acid (4-morpholin-4-yl- phenyl)-amide 101 ##STR128##
6-Fluoro-4-oxo-8-piperazin-1-yl- 4H-chromene-2-carboxylic acid (4-
morpholin-4-yl-phenyl)-amide
[0098] Also provided herein are the pharmaceutically acceptable
salts of the compounds set forth in Table 1.
[0099] The following reference examples illustrate the making of
intermediates in the synthesis of the compounds of the present
invention, and are not intended to limit the invention in any
manner.
REFERENCE EXAMPLE 1
Preparation of Reference Example 1
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride
REFERENCE EXAMPLE 1a
(E,Z)-2-(2-Bromo-phenoxy)-but-2-enedioic Acid Diethyl Ester
[0100] Diethyl acetylenedicarboxylate (20 ml, 0.162 mol) was added
to 2-bromophenol (28 g, 0.162 mol), in anhydrous 2-propanol (60 ml)
followed by the addition of a catalytic amount of
tetrabutylammonium fluoride (0.5 ml, 1.0 M in THF). The solution
was stirred at room temperature four hours and was then heated to
reflux for one hour. The mixture was cooled to room temperature,
then concentrated under vacuum to an oil (51 g=91%).
REFERENCE EXAMPLE 1b
(E,Z)-2-(2-Bromo-phenoxy)-but-2-enedioic Acid
[0101] (E,Z)-2-(2-Bromo-phenoxy)-but-2-enedioic acid diethyl ester
(51 g, 148 mmol) as prepared in Reference Example 1a was suspended
in ethanol (95 ml) and a solution of sodium hydroxide (12.9 g,
0.323 mol) in water (95 ml) was added. The solution was refluxed
for 1 h to give a clear orange solution. The mixture was cooled to
room temperature and acidified with 6 M HCl (50 ml). The mixture
was then concentrated under vacuum and the residue azeotroped
(4.times.) with ethanol. The solid was filtered, washed with water
and dried to give (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic
acid as a light orange solid (24.3 g, 88% yield). This crude
product was used without further purification.
REFERENCE EXAMPLE 1c
Ethyl-8-Bromo-4-oxo-4H-chromene-2-carboxylate
[0102] Sulfuric acid (95 mL) was added to crude
(E,Z)-2-(2-Bromo-phenoxy)-but-2-enedioic acid as prepared in
Reference Example 1b. After heating the mixture with a heat gun for
45 min an orange milky solution was obtained. This solution was
slowly added to refluxing absolute ethanol (500 mL). After the
addition, the reaction was refluxed for 30 min then allowed to
cool. Crystals started to form after 20 min and the reaction was
put in the refrigerator overnight. The solid was filtered, washed
with cold ethanol/water 9:1 and dried to give ethyl
8-bromo-4-oxo-4H-chromene-2-carboxylate as an off-white solid (11.7
g, 24% yield, mp 124-126.degree. C.).
REFERENCE EXAMPLE 1d
Ethyl-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromenec-2-carboxylic
Acid
[0103] Ethyl 8-bromo-4-oxo-4H-chromene-2-carboxylate as prepared in
Reference Example 1c (Davies, Stephen et al., J. Chem. Soc. Perkin
Trans I p 2597, 1987) (3.0 g, 10.1 mmol) was azeotroped with
anhydrous toluene then the white solid was dissolved in 100 mL
anhydrous toluene and transferred to the reaction vessel. The
mixture was subjected to vacuum/argon (.times.2) and the following
were added in order (positive argon pressure): N-methylpiperazine
(1.3 ml, 11.1 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
(0.75 g, 1.2 mmol,), tris(dibenzylideneacetone) dipalladium (0)
(0.48 g, 0.5 mmol) then cesium carbonate (4.6 g, 14.1 mmol). The
mixture was again subjected to vacuum/argon and was heated at
80.degree. C. overnight.
[0104] The cooled reaction mixture was filtered through
diatomaceous earth and the toluene solution was applied directly to
a 600 ml filter funnel (silica 230-400 mesh ASTM packed in ethyl
acetate) and then washed with ethyl acetate (2 l). The product was
eluted with 5-8% methanol/chloroform and the desired was collected
to give 2.5 g of a slightly impure orange yellow solid (mp
120-123.degree. C.). The impure product was chromatographed on a
Waters Delta Prep 4000 using 1 PrepPak cartridge (Porasil 37-55
.mu.m 125 .ANG.) eluting with 3-5% methanol/chloroform. The product
was collected and dried to give ethyl
8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylate as a
yellow solid (2.25 g, 70% yield mp 124-125.degree. C.). GC/MS (EI,
M+) m/z 316.
REFERENCE EXAMPLE 1e
8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylic Acid
Hydrochloride
[0105] Ethyl
8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylate as
prepared in Reference Example 1d (1.01 g. 3.19 mmol) was suspended
in 6 M HCl (60 ml) and to reflux for 1.5 h (after 20 min a clear
solution was obtained).
[0106] The reaction was allowed to cool. The solution was
concentrated in vacuo and anhydrous toluene was added (.times.3)
and the solution was again concentrated in vacuo to give
8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride as a yellow powder (1.02 g, quantitative yield).
LC/MS (M+1) m/z 289.
REFERENCE EXAMPLE 2
[0107] ##STR129##
Preparation of
6-Methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Hydrochloride
REFERENCE EXAMPLE 2a
Diethyl (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate
[0108] Ethyl acetylenedicarboxylate (17.8 ml, 0.145 mol) was added
to 2-bromo-4-methoxyphenol (Synlett p 1241, 1997) (27.3 g, 0.134
mol), in anhydrous 2-propanol (55 ml) followed by the addition of a
catalytic amount of tetrabutylammonium fluoride (0.4 ml, 1.0 M in
THF). The solution was stirred at room temperature overnight and
was then heated to reflux for 30 min. Upon cooling a precipitate
formed. The solution was cooled and filtered to give diethyl
(2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate as a yellow solid
(29.9 g, 62% yield). Note: the solid contains 10% of diethyl
(2E)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate. GC/MS (EI, M+)
m/z 344 and 346.
REFERENCE EXAMPLE 2b
(2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic Acid
[0109] Diethyl (2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioate
(29.9 g, 86.6 mmol) as prepared in Reference Example 2a was
suspended in ethanol (55 ml) and a solution of sodium hydroxide
(7.0 g, 0.175 mol) in water (55 ml) was added. The solution was
refluxed for 1 h to give a clear orange solution. Most of the
ethanol was removed in vacuo then 6 M HCl (50 ml) was added. The
solid was filtered, washed with water and dried to give
(2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic acid as a light
orange solid (24.3 g, 88% yield).
REFERENCE EXAMPLE 2c
Ethyl-6-methoxy-8-bromo-4-oxo-4H-chromene-2-carboxylate
[0110] Sulfuric acid (50 ml) was added to
(2Z)-2-(2-bromo-4-methoxyphenoxy)-2-butenedioic acid (24.3 g, 86.6
mmol; as prepared in Reference Example 2b above). After heating the
mixture with a heat gun for 5-10 min a clear deep brown solution
was obtained. This solution was slowly added to refluxing absolute
ethanol (250 ml). After the addition the reaction was refluxed for
30 min then allowed to cool. Crystals started to form after 20 min
and the reaction was put in the refrigerator overnight. The solid
was filtered, washed with cold ethanol/water 9:1 and dried to give
ethyl 8-bromo-6-methoxy-4-oxo-4H-chromene-2-carboxylate as an
off-white solid (12.3 g, 50% yield, mp 159-161.degree. C.).
REFERENCE EXAMPLE 2d
Ethyl-6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylat-
e
[0111] Ethyl 8-bromo-4-oxo-4H-chromene-2-carboxylate (9.2 g, 28.1
mmol), as prepared in Example 2c above, was azeotroped with
anhydrous toluene then the white solid was dissolved in 300 ml
anhydrous toluene in a 500 mL single-neck round bottom flask. The
mixture was degassed by alternating argon sparge and vacuum
(3.times.), and the following were added in order:
N-methylpiperazine (4.0 ml, 35.1 mmol),
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (1.05 g, 1.69 mmol,),
tris(dibenzylideneacetone) dipalladium (0) (0.50 g, 0.56 mmol) then
cesium carbonate (12.8 g, 39.3 mmol). The mixture was again
degassed via alternating argon sparge and vacuum and was heated at
80.degree. C. for 17 h. Additional tris(dibenzylideneacetone)
dipalladium (0) (0.10 g, 0.11 mmol) and
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.20 g, 0.32 mmol,)
was added and the reaction was stirred at 80.degree. C. for another
55 h at which time the conversion was essentially complete.
[0112] The cooled reaction mixture was diluted with tetrahydrofuran
(250 mL), filtered and concentrated under vacuum. The residue was
purified by chromatography on a silica column eluted with 2-5%
methanol/chloroform and the desired fractions were collected and
concentrated under vacuum and the residue triturated with methylene
chloride to give 7.4 g (76%) of a yellow powder.
REFERENCE EXAMPLE 2e
6-Methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid
[0113]
Ethyl-6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-ca-
rboxylate (1.0 g. 2.89 mmol), as prepared in Reference Example 2d
above, was suspended in 6 M HCl (60 ml) and methanol (10 mL) and
warmed to reflux for 3.0 h. The reaction was allowed to cool. The
solution was concentrated in vacuo and anhydrous toluene was added
(.times.3) and the solution was again concentrated in vacuo. The
residue was dried under vacuum (17 h) to yield
6-methoxy-8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride as a yellow powder (1.0 g, quantitative
yield).
REFERENCE EXAMPLE 3
[0114] ##STR130##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Hydrochloride
REFERENCE EXAMPLE 3a
Diethyl (EZ)-2-(2-bromo-4-fluorophenoxy)-2-butenedioate
[0115] This compound was synthesized from 2-bromo-4-fluorophenol
and diethylacetylenedicarboxylate, using the same synthetic
procedures and the same stoichiometry as demonstrated in Reference
Example 1a above.
REFERENCE EXAMPLE 3b
(EZ)-2-(2-Bromo-4-fluorophenoxy)-2-butenedioic Acid
[0116] This compound was synthesized from diethyl
(EZ)-2-(2-bromo-4-fluorophenoxy)-2-butenedioate, as prepared in
Reference Example 3a above, using the same synthetic procedures and
the same stoichiometry as demonstrated in Reference Example 1b
above.
REFERENCE EXAMPLE 3c
Ethyl-6-fluoro-8-bromo-4-oxo-4H-chromene-2-carboxylate
[0117] This compound was synthesized from
(EZ)-2-(2-bromo-4-fluorophenoxy)-2-butenedioic acid, as prepared in
Reference Example 3b above, using the same synthetic procedures and
the same stoichiometry as demonstrated in Reference Example 1c
above.
REFERENCE EXAMPLE 3d
Ethyl-6-fluoro-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylate
This compound was synthesized from
ethyl-6-fluoro-8-bromo-4-oxo-4H-chromene-2-carboxylate, as prepared
in Reference Example 3c above, using the same synthetic procedures
and the same stoichiometry as demonstrated in Reference Example 1d
above.
REFERENCE EXAMPLE 3e
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Hydrochloride
[0118] This compound was synthesized starting from
ethyl-6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxyla-
te, as prepared in Example 3d, using the same synthetic procedures
and the same stoichiometry as demonstrated in Reference Example 1e
above.
REFERENCE EXAMPLE 4
[0119] ##STR131##
Preparation
6-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Hydrochloride
REFERENCE EXAMPLE 4a
Diethyl (E,Z)-2-(2-bromo-4-methylphenoxy)-2-butenedioate
[0120] 2-Bromo-4-methyl phenol (10 mL, 83 mmol) was dissolved in
diethyl ether (90 mL). To this was added dropwise triethyl amine
(13.7 mL, 98 mmol) followed by dimethyl acetylene dicarboxylate
(11.2 mL, 91 mmol). The resulting mixture was stirred overnight at
room temperature. The reaction was worked up by adding diethyl
ether (200 mL) and tetrahydrofuran (50 mL) and washing the
resulting mixture with 1N HCl (200 mL), water (200 mL) and brine
(100 mL). The organic phase was then dried (Na.sub.2SO.sub.4),
filtered and concentrated to a red-brown oil which was used without
further purification.
REFERENCE 4b
(2E,Z)-2-(2-Bromo-4-fluorophenoxy)-2-butenedioic Acid
[0121] This compound was synthesized from diethyl
(E,Z)-2-(2-bromo-4-methylphenoxy)-2-butenedioate, as prepared in
Reference Example 4a above, using the same synthetic procedures and
the same stoichiometry as demonstrated in Example 1b above.
REFERENCE EXAMPLE 4c
Ethyl-6-methyl-8-bromo-4-oxo-4H-chromene-2-carboxylate
[0122] This compound was synthesized from
(2Z)-2-(2-bromo-4-methylphenoxy)-2-butenedioic acid, as prepared in
Reference Example 4b above, and using the same synthetic procedures
and the same stoichiometry as demonstrated in Reference Example 1c
above.
REFERENCE EXAMPLE 4d
Ethyl-6-methyl-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylate
[0123] This compound was synthesized from
ethyl-6-methyl-8-bromo-4-oxo-4H-chromene-2-carboxylate, as prepared
in Reference Example 4c above, using the same synthetic procedures
and the same stoichiometry as demonstrated in Reference Example 1d
above.
REFERENCE EXAMPLE 4e
6-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Hydrochloride
[0124] This compound was synthesized starting with
ethyl-6-methyl-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylat-
e, as prepared in Reference Example 4d, using the same synthetic
procedures and the same stoichiometry as demonstrated in Reference
Example 1e above.
REFERENCE EXAMPLE 5
[0125] ##STR132##
Preparation of
6-Chloro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Hydrochloride
REFERENCE EXAMPLE 5a
Diethyl (E,Z)-2-(2-bromo-4-chlorophenoxy)-2-butenedioate
This compound was prepared from 2-bromo-4-chloro phenol and
dimethyl acetylenedicarboxylate by the same synthetic procedures
and in the same stoichiometry as the preparation described in
Reference Example 4a.
REFERENCE EXAMPLE 5b
(2E,Z)-2-(2-Bromo-4-chlorophenoxy)-2-butenedioic Acid
This compound was synthesized from diethyl
(E,Z)-2-(2-bromo-4-chlorophenoxy)-2-butenedioate, as prepared in
Reference Example 5a above, as using the same synthetic procedures
and the same stoichiometry as demonstrated in Reference Example 1b
above.
REFERENCE EXAMPLE 5c
Ethyl-6-chloro-8-bromo-4-oxo-4H-chromene-2-carboxylate
[0126] This compound was synthesized from
(2E,Z)-2-(2-bromo-4-chlorophenoxy)-2-butenedioic acid, as prepared
in Reference Example 5b above, using the same synthetic procedures
and the same stoichiometry as demonstrated in Example 1c above.
REFERENCE EXAMPLE 5d
Ethyl-6-chloro-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylate
[0127] This compound was synthesized from
ethyl-6-chloro-8-bromo-4-oxo-4H-chromene-2-carboxylate, as prepared
in Reference Example 5c above, using the same synthetic procedures
and the same stoichiometry as demonstrated in Example 1d above.
REFERENCE EXAMPLE 5e
6-Chloro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Hydrochloride
[0128] This compound was synthesized starting with
ethyl-6-chloro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylat-
e, prepared in Reference Example 5d above, using the same synthetic
procedures and the same stoichiometry as demonstrated in Reference
Example 1e above.
REFERENCE EXAMPLE 6
[0129] ##STR133##
Preparation of
5-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Hydrochloride
REFERENCE EXAMPLE 6a
Diethyl (E,Z)-2-(2-chloro-5-methylphenoxy)-2-butenedioate
[0130] This compound was prepared from 2-chloro-5-methylphenol and
dimethyl acetylenedicarboxylate by the same synthetic procedures
and in the same stoichiometry as the preparation described in
Reference Example 1a.
REFERENCE EXAMPLE 6b
(2E,Z)-2-(2-chloro-5-methylphenoxy)-2-butenedioic Acid
[0131] This compound was synthesized from diethyl
(E,Z)-2-(2-chloro-5-methylphenoxy)-2-butenedioate, as prepared in
Reference Example 6a above, using the same synthetic procedures and
the same stoichiometry as demonstrated in Reference Example 1b
above.
REFERENCE EXAMPLE 6c
Ethyl-5-methyl-8-chloro-4-oxo-4H-chromene-2-carboxylate
This compound was synthesized from
(2Z)-2-(2-chloro-5-methylphenoxy)-2-butenedioic acid, as prepared
in Reference example 6b, using the same synthetic procedures and
the same stoichiometry as demonstrated in Reference Example 1c
above.
REFERENCE EXAMPLE 6d
Ethyl-5-methyl-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylate
[0132] Ethyl 5-methyl-8-chloro-4-oxo-4H-chromene-2-carboxylate (1.0
g, 3.6 mmol) as prepared in Reference Example 6c above, was
azeotroped with anhydrous toluene then the white solid was
dissolved in 100 ml anhydrous toluene in a 250 mL single-neck round
bottom flask. The mixture was degassed by alternating argon sparge
and vacuum (3.times.), and the following were added in order:
N-methylpiperazine (0.6 ml, 5.37 mmol),
(2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (JACS
1998, 120, p 9722) (40 mg, 0.1 mmol,), tris(dibenzylideneacetone)
dipalladium (0) (66 mg, 0.072 mmol) then cesium carbonate (1.6 g,
5.37 mmol). The mixture was again degassed via alternating argon
sparge and vacuum and was heated at 80.degree. C. for 17 h.
Additional tris(dibenzylideneacetone) dipalladium (0) (66 mg, 0.072
mmol) and (2'-dicyclopentylphosphanyl-biphenyl-2-yl)-dimethyl-amine
(40 g, 0.1 mmol,) were added and the reaction was stirred at
80.degree. C. for another four days at which time the conversion
was still only about 50% complete by HPLC. Tetrahydrofuran (100 mL)
was added, and the combined mixture was filtered, concentrated
under vacuum and purified by chromatography on silica eluted with
2.5% methanol in chloroform. The desired fractions were
concentrated under vacuum to yield a yellow powder (250
mg=21%).
REFERENCE EXAMPLE 6e
5-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Hydrochloride
[0133] This compound was synthesized starting with
ethyl-5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylat-
e, as prepared in Reference Example 6d, and using the same
synthetic procedures and the same stoichiometry as demonstrated in
Example 1e above.
REFERENCE EXAMPLE 7
[0134] ##STR134##
Preparation of
5-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Hydrochloride
REFERENCE EXAMPLE 7a
(E,Z)-2-(2-Bromo-5-methoxyphenoxy)-2-butenedioate
[0135] This compound was prepared from 2-bromo-5-methoxyphenol and
dimethyl acetylenedicarboxylate by the same synthetic procedures
and in the same stoichiometry as the preparation described in
Reference Example 1a.
REFERENCE EXAMPLE 7b
(E,Z)-2-(2-Bromo-5-methoxyphenoxy)-2-butenedioic Acid
[0136] This compound was synthesized from diethyl
(E,Z)-2-(2-bromo-5-methoxyphenoxy)-2-butenedioate, as prepared in
Reference Example 7a, using the same synthetic procedures and the
same stoichiometry as demonstrated in Reference Example 1b
above.
REFERENCE EXAMPLE 7c
Ethyl-5-methoxy-8-bromo-4-oxo-4H-chromene-2-carboxylate
This compound was synthesized from
(E,Z)-2-(2-bromo-5-methoxyphenoxy)-2-butenedioic acid, as prepared
in Reference Example 7b above, using the same synthetic procedures
and the same stoichiometry as demonstrated in Reference Example 1c
above.
REFERENCE EXAMPLE 7d
Ethyl-5-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylat-
e
[0137] This compound was synthesized from
ethyl-5-methoxy-8-bromo-4-oxo-4H-chromene-2-carboxylate, as
prepared in Reference Example 7c above, using the same synthetic
procedures and the same stoichiometry as demonstrated in Reference
Example 1d above.
REFERENCE EXAMPLE 7e
5-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Hydrochloride
[0138] This compound was prepared from
ethyl-5-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxyla-
te, as prepared in Reference Example 7d above, using the same
method as the preparation in 1e.
REFERENCE EXAMPLE 8
[0139] ##STR135##
Preparation of
1-(6-piperazin-1-yl-2,3-dihydro-indol-1-yl)-ethanone
REFERENCE EXAMPLE 8a
1-[5-(4-Benzyl-piperazin-1-yl)-2,3-dihydro-indol-1-yl]-ethanone
[0140] 1-acetyl-5-bromoindoline (3.0 g, 12.5 mmol) was dissolved in
toluene (60 mL). To this was added, sodium t-butoxide (1.68 g, 17.5
mmol), N-benzylpiperazine (2.4 mL, 13.8 mmol), S-BINAP (0.93 g, 1.5
mmol) and Pd.sub.2(dba).sub.3 (0.46 g, 0.5 mmol). The mixture was
degassed via three cycles of vacuum and nitrogen sparge and then
stirred at 95.degree. C. until GC analysis confirmed that the
reaction was complete (1 h). The mixture was diluted with ethyl
acetate (150 mL), washed with water and extracted with 2N HCl
(2.times.100 mL). The combined aqueous extract was basified with
concentrated ammonium hydroxide and extracted with ethyl acetate
(2.times.100 mL). The combined organic extract was dried
(MgSO.sub.4) and concentrated to yield a solid (2.7 g) which was
purified by chromatography to yield a white solid (1.81 g, 43%).
Mp=150.5-152.8.degree. C.
REFERENCE EXAMPLE 8b
1-(6-piperazin-1-yl-2,3-dihydro-indol-1-yl)-ethanone
[0141]
1-[5-(4-Benzyl-piperazin-1-yl)-2,3-dihydro-indol-1-yl]-ethanone
(0.37 g, 1.1 mmol), as prepared in Reference Example 8a above, was
dissolved in methanol (5 mL). Pd/C (90 mg, 10%) and ammonium
formate (0.9 g, 14 mmol) was added and the resulting mixture was
heated to 65.degree. C. for two hours. The mixture was filtered and
the filter cake washed with hot methanol. The combined filtrate was
concentrated to yield the desired product (0.26 g, 90%).
REFERENCE EXAMPLE 9
[0142] ##STR136##
Preparation of 2-chloro-5-piperazin-1-yl benzonitrile
REFERENCE EXAMPLE 9a
3-Cyano-4-chloroaniline
[0143] 2-Chloro-5-nitrobenzonitrile (25 g, 137 mmol) was dissolved
in ethanol (275 mL). Stannous chloride dihydrate (154.5 g, 0.685 M)
was added and the mixture stirred at 70.degree. C. for 30 min. The
mixture was then cooled to room temperature and poured into crushed
ice. The mixture was made basic with solid sodium hydroxide. This
mixture was extracted with ethyl acetate (3.times.100 mL). The
extracts were combined, washed with brine, dried (MgSO.sub.4),
concentrated and the residue dried under vacuum and recrystallized
from ethanol to yield light brown needles (10.6 g, 51%).
REFERENCE EXAMPLE 9b
2-chloro-5-piperazin-1-yl benzonitrile
[0144] 3-Cyano-4-chloroaniline (10.1 g, 66 mmol), as prepared in
Reference Example 9a, was dissolved in n-butanol (300 mL)
bis-(2-chloroethyl)amine hydrochloride (23.2 g, 130 mmol) and
potassium iodide (50 mg, catalytic) were added. The mixture was
heated at reflux for three days, then cooled in a refrigerator
overnight. A solid precipitate was collected by filtration, washed
with cold n-butanol and dried. The crude product was distributed
between methylene chloride and 2N ammonium hydroxide. The organic
layer was separated, dried (Na.sub.2SO.sub.4) and concentrated to
yield a light yellow solid (9.1 g, 59%) which gave a single peak by
GC and TLC analysis.
REFERENCE EXAMPLE 10
[0145] ##STR137##
Preparation of 4-[1,2,3]thiadiazol-5-yl-phenylamine
[0146] SnCl.sub.2.H.sub.20 (3.21 g, 5 eq) was added to a slurry of
(5-(4-Nitrophenyl)-1,2,3-thiadiazole (Lancaster Synthesis) (0.59 g,
2.8 mmol) in absolute EtOH (50 mL) and the reaction heated to
70.degree. C. for 2 h. The reaction was allowed to cool to room
temperature and pour into saturated NaHCO.sub.3 and ice. The
product was extracted with EtOAc (2.times.) the solution dried
(MgSO.sub.4) and evaporated to dryness in vacuo to yield 0.47 g of
a light yellow solid mp 126-128.degree. C.
REFERENCE EXAMPLE 11
[0147] ##STR138##
Preparation of 1-[4-(4-Amino-phenyl)-piperazin-1-yl]-ethanone
REFERENCE EXAMPLE 11a
4-(4-Nitrophenyl)-1-acetylpiperazine
[0148] 1-(4-Nitrophenyl)piperazine (2.5 g, 12.1 mmol) was dissolved
in dichloromethane (100 ml). Triethylamine (2.0 ml, 14.5 mmol) was
added and the reaction was cooled to 0.degree. C. Acetic anhydride
(1.25 ml, 13.3 mmol) was added dropwise and the reaction was
stirred at 0.degree. C. for 1 h. Saturated sodium bicarbonate was
added and the reaction was extracted (.times.3) with
dichloromethane, dried (MgSO.sub.4), filtered and concentrated in
vacuo to give 4-(4-nitrophenyl)-1-acetylpiperazine as a yellow
solid (3.01 g,). GC/MS (EI, M+) m/z=249.
REFERENCE EXAMPLE 11b
1-[4-(4-Amino-phenyl)-piperazin-1-yl]-ethanone
[0149] 4-(4-Nitrophenyl)-1-acetylpiperazine (3.0 g, 12.0 mmol), as
prepared in Reference Example 11a above, was mixed in methanol (100
ml) and 2 M ammonia in methanol (50 ml) and 10% palladium on carbon
(300 mg) was added. The mixture was hydrogenated on a Paar
apparatus (50 psi) for 1.5 h.
[0150] The reaction was allowed to cool, the catalyst was filtered
and the solution was concentrated in vacuo. The crude solid was
recrystallized from ethyl acetate to give
4-(4-acetyl-1-piperazinyl)benzenamine as a light purple solid (1.86
g, 70% yield, mp 149.5-150.5.degree. C.). GC/MS (EI, M+)
m/z=219
REFERENCE EXAMPLE 12
[0151] ##STR139##
Preparation of 4-(4-methanesulfonyl-piperazin-1-yl)-phenylamine
REFERENCE 12a
4-(4-Nitrophenyl)-1-methylsulfonylpiperazine
[0152] 1-(4-Nitrophenyl)piperazine (2.79 g, 13.5 mmol) was
dissolved in dichloromethane (100 ml). Triethylamine (2.25 ml, 16.2
mmol) was added and the reaction was cooled to 0.degree. C.
Methanesulfonyl chloride (1.15 ml, 14.9 mmol) was added dropwise
and the reaction was stirred at 0.degree. C. for 1 h. Saturated
sodium bicarbonate was added and the reaction was extracted
(.times.3) with dichloromethane, dried (MgSO.sub.4), filtered and
concentrated in vacuo to give
4-(4-nitrophenyl)-1-methylsulfonylpiperazine as a yellow solid
(3.83 g, quantitative yield). GC/MS (EI, M+) m/z=285.
REFERENCE EXAMPLE 12b
4-(4-methanesulfonyl-piperazin-1-yl)-phenylamine
[0153] 4-(4-Nitrophenyl)-1-methylsulfonylpiperazine (3.83 g, 13.4
mmol), as prepared in Reference Example 12a above, was mixed in
methanol (100 ml) and 2 M ammonia in methanol (50 ml) and 10%
palladium on carbon (400 mg) was added. The mixture was
hydrogenated on a Paar apparatus (50 psi) for 3 h. The reaction was
allowed to cool, the catalyst was filtered, washed with methanol
then washed with chloroform. The chloroform portion contained a
minor amount of the desired but looked purer. The chloroform
portion was concentrated in vacuo and was recrystallized ethyl
acetate to give 4-[4-(methylsulfonyl)-1-piperazinyl]benzenamine as
a shiny brown solid (0.94 g, 27% yield, mp 192-193.degree. C.).
GC/MS (EI, M+) m/z=255.
REFERENCE EXAMPLE 13
[0154] ##STR140##
Preparation of 4-Thiomorpholin-4-yl-phenylamine
REFERENCE EXAMPLE 13a
4-(4-Nitro-phenyl)-thiomorpholine
[0155] 4-Fluoronitrobenzene (3.0 g, 21.3 mmol) was dissolved in
toluene (25 mL). Thiomorpholine (2.4 mL, 23.4 mmol) was added and
the mixture stirred overnight at 100.degree. C. At 17 h, the
mixture was distributed between ethyl acetate (100 mL) and
saturated sodium bicarbonate (50 mL). The organic layer was
separated, dried (Na.sub.2SO.sub.4), filtered and concentrated
under vacuum. The residue was triturated with hexane to yield a
bright yellow solid.
REFERENCE EXAMPLE 13b
4-Thiomorpholin-4-yl-phenylamine
[0156] 4-(4-Nitro-phenyl)-thiomorpholine (3.0 g, 13.4 mmol), as
prepared in Reference Example 13a above, was dissolved in ethanol
(250 mL) and 10% palladium on carbon (250 mg) was added. This
mixture was shaken on a Paar hydrogenator for 3 h. The reaction
mixture was then filtered through diatomaceous earth and
concentrated under vacuum. The residue was triturated with hexane
to yield an gray solid (2.1 g).
REFERENCE EXAMPLE 14
[0157] ##STR141##
Preparation of 1-(4-Amino-phenyl)-1-morpholin-4-yl-methanone
REFERENCE EXAMPLE 14a
1-Morpholin-4-yl-1-(4-nitro-phenyl)-methanone
[0158] 4-Nitrobenzoyl chloride (5 g, 27 mmol) in tetrahydrofuran
(10 mL) was added slowly to a solution of morpholine (5 g, 88 mmol)
and triethylamine (2.7 g, 27 mmol) in tetrahydrofuran (50 mL), and
stirred at room temperature for four hours. Ethyl acetate (200 mL)
was added to the mixture and the combined mixture was washed with
water (25 mL), 1N HCl (25 mL), water (25 mL), saturated sodium
bicarbonate (25 mL), water (25 mL) and brine (25 mL). The mixture
was dried (Na2SO4), filtered and concentrated under vacuum and the
residue used without further purification.
REFERENCE EXAMPLE 14b
1-(4-Amino-phenyl)-1-morpholin-4-yl-methanone
[0159] This compound was prepared from
1-morpholin-4-yl-1-(4-nitro-phenyl)-methanone as prepared in
Reference Example 13b.
REFERENCE EXAMPLE 15
[0160] ##STR142##
Preparation of 5-Amino-2-morpholin-4-yl-benzonitrile
REFERENCE EXAMPLE 15a
2-Morpholin-4-yl-5-nitro-benzonitrile
[0161] 3-Cyano-4-fluoronitrobenzene (3.3 g, 19.9 mmol) was
dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol),
and N,N-diisopropylethylamine (3.5 mL, 20 mmol) were added and the
mixture stirred overnight at room temperature. At 17 h, additional
ethyl acetate (150 mL) was added and the combined mixture was
washed with water (50 mL) and brine (50 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated under vacuum. The
residue was used without further purification.
REFERENCE EXAMPLE 15b
5-Amino-2-morpholin-4-yl-benzonitrile
[0162] This compound was prepared from
2-Morpholin-4-yl-5-nitro-benzonitrile (as prepared in Reference
Example 15a above), as prepared in Reference Example 13b.
REFERENCE EXAMPLE 16
[0163] ##STR143##
Preparation of 3-Fluoro-4-morpholin-4-yl-phenylamine
REFERENCE EXAMPLE 16a
4-(2-Fluoro-4-nitro-phenyl)-morpholine
[0164] 3,4-Difluoronitrobenzene (3.7 g, 23.2 mmol) was dissolved in
ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and
N,N-diisopropylethylamine (4 mL, 23 mmol) were added and the
mixture stirred overnight at room temperature. At 17 h, additional
ethyl acetate (150 mL) was added and the combined mixture was
washed with water (50 mL) and brine (50 mL), dried
(Na.sub.2SO.sub.4), filtered and concentrated under vacuum. The
residue was used without further purification.
REFERENCE EXAMPLE 16b
3-Fluoro-4-morpholin-4-yl-phenylamine
This compound was prepared from
4-(2-Fluoro-4-nitro-phenyl)-morpholine, (as prepared in Reference
Example 16a above) as prepared in Reference Example 13b.
REFERENCE EXAMPLE 17
[0165] ##STR144##
Preparation of 4-(4-Amino-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester
REFERENCE EXAMPLE 17a
4-(4-Nitro-phenyl)-piperazine-1-carboxylic Acid Tert-Butyl
Ester
[0166] 4-Fluoronitrobenzene (4.8 g, 34 mmol) was dissolved in ethyl
acetate (25 mL). Piperazine-1-carboxylic acid tert-butyl ester (6.7
g, 36 mmol) and N,N-diisopropylethylamine (6.3 mL, 36 mmol) were
added and the mixture was stirred at 65.degree. C. for five days
and cooled to room temperature. Ether (100 mL) was added and the
combined mixture was washed with water (25 mL) and brine (25 mL),
dried (Na2SO4), filtered and concentrated under vacuum. The residue
was triturated with hexane to yield a bright yellow solid (8 g,
77%).
REFERENCE EXAMPLE 17b
4-(4-Amino-phenyl)-piperazine-1-carboxylic Acid Tert-Butyl
Ester
[0167] 4-(4-Amino-phenyl)-piperazine-1-carboxylic acid tert-butyl
ester was prepared from 4-(4-Nitro-phenyl)-piperazine-1-carboxylic
acid tert-butyl ester, (as prepared in Reference Example 17a) as
prepared in Reference Example 13b.
REFERENCE EXAMPLE 18
[0168] ##STR145##
Preparation of 3-Morpholin-4-yl-phenylamine
REFERENCE EXAMPLE 18a
4-(3-Nitro-phenyl)-morpholine
[0169] 3-Fluoronitrobenzene (10 g, 71 mmol) was dissolved in
acetonitrile (100 mL). Morpholine (30 mL, 350 mmol) was added and
the mixture was reacted 18 h at 150.degree. C./80 psi in a pressure
reactor. The reaction was cooled to room temperature, concentrated
under vacuum and 5 g of the total mixture was purified by column
chromatography on silica eluted with CH.sub.2Cl.sub.2. The product
(3.6 g) was isolated as a bright yellow oil.
REFERENCE EXAMPLE 18b
3-Morpholin-4-yl-phenylamine
[0170] 3-Morpholin-4-yl-phenylamine was prepared from
4-(3-Nitro-phenyl)-morpholine, (as prepared in Reference Example
18a), as prepared in Reference Example 13b.
REFERENCE EXAMPLE 19
[0171] ##STR146##
Preparation of 2-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanol
REFERENCE EXAMPLE 19a
2[4-(4-nitrophenyl)piperazine-1-yl]-ethanol
[0172] 2[4-(4-nitrophenyl)piperazine-1-yl]-ethanol is prepared from
commercially available 4-fluoronitrobenzene (Aldrich) and
commercially available N-(2-hydroxyethyl)piperazine (Aldrich) via
the same procedure as described in Reference Example 13a above.
REFERENCE EXAMPLE 19b
2-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanol
[0173] 2-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanol is prepared by
catalytic hydrogenation of
2[4-(4-nitrophenyl)piperazine-1-yl]-ethanol (prepared as in
Reference Example 19a) as described in Reference Example 13b
REFERENCE EXAMPLE 20
[0174] ##STR147##
Preparation of 4-Morpholin-4-yl-phenylamine
[0175] 4-(4-Nitrophenyl)morpholine (10.3 g, 49.5 mmol;) (Lancaster
Synthesis) was suspended in methanol (130 ml) and 2 M ammonia in
methanol (70 mL) and 5% palladium on carbon (100 mg) was added. The
mixture was hydrogenated on a Paar apparatus (50 psi) for 1 h. The
reaction was allowed to cool, the catalyst was filtered and the
solution was concentrated in vacuo. The crude solid was
recrystallized from ethyl acetate/hexane to give
4-(4-morpholinyl)aniline as a light purple solid (6.2 g, 70% yield,
mp 132-133.degree. C.). GC/MS (EI, M+) m/z=178.
REFERENCE EXAMPLE 21
[0176] ##STR148##
Preparation of 4-Amino-3-hydroxyphenylmorpholine
[0177] 4-Nitro-3-hydroxyphenylmorpholine (Maybridge Chemical) (3.34
g, 14.9 mmol) was dissolved in 59 ml of ethanol at 30.degree. C.
The mixture was stirred at 25.degree. C. and treated with tin (II)
chloride dihydrate (16.8 grams, 74.5 mmol) with stirring. The
yellow suspension was heated to reflux over a 30 minute period. TLC
showed reaction progress over several hours. The mixture was
refluxed for 18 hours, cooled to room temperature, and concentrated
to remove most of the ethanol to give a yellow slurry. The mixture
was treated with saturated aqueous sodium bicarbonate until it was
basic. The mixture was extracted with ethyl acetate, filtered, and
the organic layer was separated. The aqueous layer was extracted
twice more with ethyl acetate. The extracts were combined, dried
over magnesium sulfate, filtered, and concentrated to give 1.02
grams of a purple solid. Proton NMR and CI mass spectral analyses
were consistent for the desired product (m/z=195 base peak by
positive ion CI and m/z=193 base peak by negative ion CI).
REFERENCE EXAMPLE 22
[0178] ##STR149##
Preparation of
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid
REFERENCE EXAMPLE 22a
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Ethyl Ester
[0179] Into a 250 mL 3 neck round bottom flask equipped with a
reflux condenser, nitrogen inlet and magnetic stirrer is placed 1.5
g (4.59 mmol, 1.0 equiv.) of
8-Bromo-6-methoxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester
(Reference Example 2c), 84 mg (0.092 mmol, 0.02 equiv.) of tris
dibenzylidineacetone dipalladium, 342 mg (0.55 mmol, 0.12 equiv.)
of racemic 2,2'-bis(diphenylphosphino)-1,1'-binapthyl and 2 g of 4
A molecular sieves. To this suspension is added 150 mL of dry
toluene. To the stirred suspension is then added 628 mg, 684 .mu.L,
(5.50 mmol, 1.2 equiv.) of 1-methylhomopiperazine, followed by 2.05
g (6.3 mmol, 1.4 equiv.) of cesium carbonate. The mixture is then
heated to 80.degree. C. for 3 days. At the end of this time
completion was monitored by LC/MS analysis of an aliquot. When the
reaction was determined to be complete it was cooled to room
temperature then filtered through a plug of diatomaceous earth with
toluene washing to remove solid by products. Purification by flash
chromatography, using a gradient of 5 to 20% methanol in methylene
chloride as eluent, yielded 1.0 g, (60%) of the desired
product.
[0180] Mass Spec.: calc. for
[C.sub.19H.sub.24N.sub.2O.sub.5+H].sup.+ Theor. m/z=361;
Obs.=361
REFERENCE EXAMPLE 22b
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid
[0181] Into a 125 mL erlenmeyer equipped with a magnetic stirrer is
placed 319 mg (0.89 mmol, 1.0 equiv.) of
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid ethyl ester. This material is dissolved in 30 mL of THF, then
30 mL of methanol are added. To this stirring solution is added 30
mL of a water containing 41 mg (0.97 mmol, 1.1 equiv.) of lithium
hydroxide. This mixture is stirred at room temperature for 2 hr.
Completion of the reaction is monitored by LC/MS, then 10 mL of 2N
HCl is added. This mixture is then concentrated, dried and
triturated with ether to give the product as the hydrochloride salt
in quantitative yield.
[0182] Mass Spec.: calc. for
[C.sub.17H.sub.20N.sub.2O.sub.5+H].sup.+ Theor. m/z=333;
Obs.=333
REFERENCE EXAMPLE 23
[0183] ##STR150##
Preparation of
6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carbonyl
Chloride
REFERENCE EXAMPLE 23a
8-Bromo-6-hydroxy-4-oxo-4H-chromene-2-carboxylic Acid Ethyl
Ester
[0184] The hydroxy compound,
8-Bromo-6-hydroxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester,
is formed as a side product during the synthesis of
8-Bromo-6-methoxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester.
It can be separated from the crude methoxy compound by flash
chromatography using a step gradient of 20% ethyl acetate in
methylene chloride to the same solvent containing 2% methanol. The
hydroxy compound, which elutes last, is concentrated to give the
pure compound. Mass Spec.: calc. for
[C.sub.12H.sub.9BrO.sub.5+H].sup.+ Theor. m/z=313, 315; Obs.=313,
315
REFERENCE EXAMPLE 23b
8-Bromo-6-ethoxy-4-oxo-4H-chromene-2-carboxylic Acid Ethyl
Ester
[0185] Into a 100 mL 3 neck round bottom flask equipped with a
reflux condenser, nitrogen inlet and magnetic stirrer is added 700
mg (2.24 mg, 1.0 equiv.) of
8-Bromo-6-hydroxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester
(Reference Example 23a). This material is dissolved in 50 mL of
toluene, then 689 mg, 586 .mu.L (4.47 mmol, 2.0 equiv.) of diethyl
sulfate and 309 mg (2.24 mmol, 1.0 equiv.) of K.sub.2CO.sub.3 were
added. The reaction was then heated to reflux for 24 hr. At the end
of this time, monitoring by LC/MS reveals that the reaction is
>than 95% complete. The reaction is then cooled, 100 mL of ethyl
acetate is added and the organic layer is washed with 0.5N HCl
solution, dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residues were subjected to flash chromatography, using 40%
ethyl acetate in hexane as eluent. The purified fractions were
concentrated to yield 500 mg (65%) of a colorless solid.
[0186] Mass Spec.: calc. for [C.sub.14H.sub.13BrO.sub.5+H].sup.+
Theor. m/z=341, 343; Obs.=341, 343
REFERENCE EXAMPLE 23c
6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid Ethyl Ester
[0187] Into a 100 mL, 3 neck round bottom flask equipped with a
reflux condenser, magnetic stirrer and nitrogen inlet is added 350
mg (1.03 mmol, 1.0 equiv.) of
8-Bromo-6-ethoxy-4-oxo-4H-chromene-2-carboxylic acid ethyl ester
(Reference Example 23b), 18.9 mg (0.02 mmol, 0.02 equiv.) of tris
dibenzylidineacetone dipalladium, 77 mg (0.123 mmol, 0.12 equiv.)
of racemic 2,2'-bis(diphenylphosphino)-1,1'-binapthyl and 1 g of 4
A molecular sieves and 60 mL of dry toluene. To the stirred
suspension is then added 113 mg, 1255 .mu.L, (1.13 mmol, 1.1
equiv.) of 1-methylpiperazine, followed by 470 mg (1.44 mmol, 1.4
equiv.) of cesium carbonate. The mixture is then heated to
80.degree. C. for 3 days. At the end of this time completion was
monitored by LC/MS analysis of an aliquot. When the reaction was
determined to be complete it was cooled to room temperature then
filtered through a plug of diatomaceous earth, with toluene washing
to remove solid by products. Purification by flash chromatography,
using a gradient of 5 to 40% methanol in methylene chloride as
eluent, yielded 350 mg (75%) of the desired product as a yellow
solid. Mass Spec.: calc. for
[C.sub.19H.sub.24N.sub.2O.sub.5+H].sup.+ Theor. m/z=361;
Obs.=361
REFERENCE EXAMPLE 23d
6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
Acid
[0188] Into a 125 mL Erlenmeyer equipped with a magnetic stirrer is
placed 500 mg (1.39 mmol, 1.0 equiv.) of
6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid ethyl ester (Reference Example 23c). This material is
dissolved in 30 mL of THF, then 30 mL of methanol are added. To
this stirring solution is added 30 mL of a water containing 64.2 mg
(1.53 mmol, 1.1 equiv.) of lithium hydroxide. This mixture is
stirred at room temperature for 2 hr. Completion of the reaction is
monitored by LC/MS, then 10 mL of 2N HCl is added. This mixture is
then concentrated, dried and triturated with ether to give the
product as the hydrochloride salt in quantitative yield.
[0189] Mass Spec.: calc. for [C.sub.17H.sub.20N.sub.2OS+H].sup.+
Theor. m/z=333; Obs.=333
REFERENCE EXAMPLE 23e
6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carbonyl
Chloride
[0190] Into a 100 mL round bottom flask equipped with a reflux
condenser, nitrogen inlet and magnetic stirrer is placed 250 mg
(0.68 mmol, 1.0 equiv.) of
6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride salt (Reference Example 23d) and 20 mL of
methylene chloride. To the stirring suspension is then added 129.5
mg, 164 .quadrature.L (1.02 mmol, 1.5 equiv.) of oxalyl chloride
followed by addition of one drop of DMF from a 50 microliter
syringe to act as catalyst. The mixture is stirred for 2 hours,
then concentrated to dryness on a rotary evaporator under a
nitrogen atmosphere, followed by drying under high vacuum. The
completeness of the reaction was ascertained by analysis of an
aliquot, which was quenched with a THF solution of methylamine, by
LC/MS. The crude material was used as obtained in the subsequent
amidation reaction.
REFERENCE EXAMPLE 24
[0191] ##STR151##
Preparation of
8-Bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carbox-
ylic Acid Methyl Ester
REFERENCE EXAMPLE 24a
2-(2-Bromo-4-methoxy-phenylamino)-but-2-enedioic Acid Dimethyl
Ester
[0192] A solution of 2-bromo-4-methoxy aniline (6.02 g, 29.8 mmol)
in 125 mL anhydrous methanol was treated with dimethyl
acetylenedicarboxylate (3.70 mL, 30.2 mmol) and the solution was
heated at reflux under nitrogen for 8 hours. The reaction mixture
was cooled, concentrated, and redissolved in hot methanol. Yellow
crystals were obtained by filtration (6.93 g, 68%). A second crop
of crystals was obtained from ethanol (0.942 g, 9%). The filtrates
were combined and purified by flash chromatography on silica gel
using 4:1 hexanes:ethyl acetate to afford an additional 1.63 g
(16%) for a total yield of 93%. .sup.1H NMR (300 MHz, DMSO,
d.sub.6) .delta. 9.60 (s, 1H, NH), 7.26 (d, 1H, J.sub.m=2.7 Hz,
ArH.sub.3), 6.93 (dd, 1H, J.sub.o=8.7, J.sub.m=2.7 Hz, ArH.sub.5),
6.87 (d, 1H, J.sub.o=8.7 Hz, ArH.sub.6), 5.34 (s, 1H, C.dbd.CH),
3.76 (s, 3H, OCH.sub.3), 3.68 (s, 3H, CHCO.sub.2CH.sub.3), 3.66 (s,
3H, CNCO.sub.2CH.sub.3); Mass Spec.: calc. for
[C.sub.13H.sub.14BrNO.sub.5+H].sup.+ Theor. m/z=344, 346; Obs. 344,
346.
REFERENCE EXAMPLE 24b
8-Bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic Acid
Methyl Ester
[0193] Dow-Therm (175 mL) was heated to 244.degree. C. and the
2-(2-bromo-4-methoxy-phenylamino)-but-2-enedioic acid dimethyl
ester (9.50 g, 27.6 mmol) was added as a solid in portions over 7
minutes while maintaining a temperature of 230-240.degree. C. The
brown reaction mixture was heated at 240-245.degree. C. for 45
minutes and then cooled to room temperature. A yellow precipitate
formed upon cooling. Approximately 100 mL of hexanes were added to
the mixture and the solids were isolated by filtration, washed with
additional hexanes, and dried under high vacuum to afford the
product as a yellow solid (6.73 g, 78%). .sup.1H NMR (300 MHz,
DMSO, d.sub.6) .delta. 12.01 (s, 1H, NH), 7.86 (d, 1H, J.sub.m=2.7
Hz, ArH.sub.5), 7.52 (s, 1H, C.dbd.CH), 7.48 (d, 1H, J.sub.m=2.7
Hz, ArH.sub.7), 3.93 (s, 6H, OCH.sub.3 and CO.sub.2CH.sub.3); Mass
Spec.: calc. for [C.sub.12H.sub.10BrNO.sub.4+H].sup.+ Theor.
m/z=312, 314; Obs. 312, 314.
REFERENCE EXAMPLE 24c
8-Bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxy-
lic Acid Methyl Ester
[0194] A brown solution of
8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid
methyl ester (6.73 g, 21.6 mmol) in 100 mL N-methylpyrrolidinone
was treated with sodium hydride (60% dispersion in oil, 1.028 g,
25.7 mmol). Gas evolution and warming were observed. The reaction
was stirred for 10 minutes at room temperature under nitrogen.
Addition of 2-(trimethylsilyl)ethoxymethyl chloride (5.00 mL, 28.3
mmol) resulted in a slightly cloudy, light brown solution. After
2.5 hours at room temperature, the reaction mixture was poured into
800 mL water and stirred for 15 minutes. The resulting cream
colored precipitate was isolated by filtration, washed with water,
and dried under high vacuum to afford the product as a cream
colored solid (9.70 g, quantitative yield). .sup.1H NMR (300 MHz,
DMSO, d.sub.6) .delta. 7.976 (d, 1H, J.sub.m=2.7 Hz, ArH.sub.7),
7.79 (s, 1H, C.dbd.CH), 7.53 (d, 1H, J.sub.m=2.7 Hz, ArH.sub.5),
5.70 (s, 2H, OCH.sub.2O), 3.99 (s, 6H, OCH.sub.3 and
CO.sub.2CH.sub.3), 3.88 (t, 2H, J=8.0 Hz, OCH.sub.2CH.sub.2Si),
0.97 (t, 2H, J=8.0 Hz, OCH.sub.2CH.sub.2Si),), -0.04 (s, 9H,
Si(CH.sub.3).sub.3; Mass Spec.: calc. for
[C.sub.18H.sub.24BrNO.sub.5Si+H].sup.+ Theor. m/z=442, 444; Obs.
442, 444.
REFERENCE EXAMPLE 25
[0195] ##STR152##
Preparation of
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-1,4-dihydro-quinoline-2-c-
arboxylic Acid
REFERENCE EXAMPLE 25a
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-(2-trimethylsilanyl-ethoxymeth-
oxy)-quinoline-2-carboxylic Acid Methyl Ester
[0196] To a clear, light brown solution of
2-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carbox-
ylic acid methyl ester (1.01 g, 2.28 mmol), N-methylhomopiperazine
(0.32 mL, 2.57 mmol), and 4 .ANG. sieves in 30 mL anhydrous toluene
was added Pd.sub.2 (dba).sub.2 (43.8 mg, 0.048 mmol) and BINAP
(169.8 mg, 0.27 mmol). The resulting wine colored solution was
treated with cesium carbonate (1.124 g, 3.45 mmol). The reaction
mixture was heated at reflux under nitrogen for 21 hours. The pea
green reaction mixture was cooled to room temperature and
concentrated. The crude mixture was purified by flash
chromatography on silica gel using a gradient of 95:5 to 40:60
methylene chloride:methanol to afford the desired product as a
yellow foam (1.004 g, 92%). .sup.1H NMR (300 MHz, DMSO, d.sub.6)
.delta. 7.67 (s, 1H, ArH.sub.3), 6.94 (d, 1H, J.sub.m=2.4 Hz,
ArH.sub.5), 6.66 (d, 1H, J.sub.m=2.4 Hz, ArH.sub.7), 5.60 (s, 2H,
OCH.sub.2O), 3.94 (s, 3H, CO.sub.2CH.sub.3), 3.88 (s, 3H,
OCH.sub.3), 3.82 (t, 2H, J=8.0 Hz, OCH.sub.2CH.sub.2Si), 3.75 (bs,
4H, ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3 &
ArNCH.sub.2CH.sub.2N--CH.sub.3), 3.45 (bs, 2H,
ArNCH.sub.2CH.sub.2NCH.sub.3), 3.31 (bs, 2H,
ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3), 2.83 (s, 3H, NCH.sub.3),
2.28 (bs, 2H ArNCH.sub.2CH.sub.2 CH.sub.2NCH.sub.3), 0.92 (t, 2H,
J=8.0 Hz, OCH.sub.2CH.sub.2Si), -0.04 (s, 9H, Si(CH.sub.3).sub.3;
Mass Spec.: calc. for [C.sub.24H.sub.37N.sub.3OsSi+H].sup.+ Theor.
m/z=476; Obs. 476.
REFERENCE EXAMPLE 25b
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-1,4-dihydro-quinoline-2-ca-
rboxylic Acid
[0197] To a light brown solution of
6-methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-(2-trimethylsilanyl-ethoxymet-
hoxy)-quinoline-2-carboxylic acid methyl ester (1.00 g, 2.10 mmol)
in 18 mL 3:1:1 tetrahydrofuran:methanol:water was added lithium
hydroxide monohydrate (0.267 g, 6.35 mmol). The reaction mixture
was stirred at room temperature for 5 hours, acidified to pH 4 with
1 N HCl, and stirred an additional 20 minutes. The reaction mixture
was concentrated and dried under high vacuum to afford an orange
foam. .sup.1H NMR (300 MHz, DMSO, d.sub.6) .delta. 11.06 (s, 1H,
NH), 7.53 (s, 1H, C.dbd.CH), 7.00 (d, 1H, J.sub.m=2.4 Hz,
ArH.sub.5), 6.70 (d, 1H, J.sub.m=2.4 Hz, ArH.sub.7), 4.05-3.99 (m,
2H, ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3), 3.87 (s, 3H, OCH.sub.3),
3.68-3.60 (m, 2H, ArNCH.sub.2CH.sub.2NCH.sub.3), 3.54-3.47 (m, 2H,
ArNCH.sub.2CH.sub.2NCH.sub.3), 3.41-3.26 (m, 2H,
ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3), 2.82 (d, 3H, J=4.8 Hz,
NCH.sub.3), 2.46-2.41 (m, 1H ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3),
2.30-2.25 (m, 1H ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3); Mass Spec.:
calc. for [C.sub.17H.sub.21N.sub.3O.sub.4+H].sup.+ Theor. m/z=332;
Obs. 332.
REFERENCE EXAMPLE 26
[0198] ##STR153##
Preparation of
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-2-carbox-
ylic Acid
This compound was prepared via the same procedure described for
preparation of Reference Example 25.
REFERENCE EXAMPLE 27
[0199] ##STR154##
Preparation of
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-(2-trimethylsilanyl-ethoxymet-
hoxy)-quinoline-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide
REFERENCE EXAMPLE 27a
8-Bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic Acid
[0200] To a light brown solution of
8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carbox-
ylic acid methyl ester (Reference Example 24c) (4.98 g, 11.3 mmol)
in 75 mL 3:1:1 tetrahydrofuran:methanol:water was added lithium
hydroxide monohydrate (1.367 g, 32.6 mmol). The reaction was
stirred at room temperature for 5 hours. The reaction mixture was
concentrated and then poured into water. The solution was acidified
to pH 2 with 1 N HCl and the resulting solids were isolated by
filtration. The solids were then suspended in methanol and filtered
to afford the desired product (2.6732 g, 80%). An additional 0.5768
g (17%) of product was obtained from the methanol filtrates.
.sup.1H NMR (300 MHz, DMSO, d.sub.6, TFA Shake) .delta. 7.86 (d,
1H, J.sub.m=2.7 Hz, ArH.sub.5), 7.55 (d, 1H, J.sub.m=2.7 Hz,
ArH.sub.7), 7.32 (s, 1H, C.dbd.CH), 3.94 (s, 3H, OCH.sub.3); Mass
Spec.: calc. for [C.sub.11H.sub.8BrNO.sub.4+H].sup.+ Theor.
m/z=298, 300; Obs.=298, 300.
REFERENCE EXAMPLE 27b
8-Bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide
[0201] To a yellow suspension of
8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid
(Reference Example 27a) (3.446 g, 11.56 mmol), TBTU (9.039 g, 28.15
mmol), and HOBt (3.757 g, 27.8 mmol) in 100 mL dimethylformamide
was added 4-morpholinoaniline (2.733 g, 15.3 mmol) and
diisopropylethyl amine (8.2 mL, 50.2 mmol). The resulting marroon
solution was stirred at room temperature under nitrogen for 16
hours during which time the reaction became greenish brown and
formed a large amount of precipitate. The reaction mixture was
filtered and the solids washed with dimethylformamide, water, and
methanol. Drying under high vacuum afforded the desired product as
a yellow solid (3.09 g, 58%). .sup.1H NMR (300 MHz, DMSO, d.sub.6)
.delta. 12.13 (s, 1H, NH), 10.18 (s, 1H, C(O)NH), 7.90 (d, 1H,
J.sub.m=2.7 Hz, ArH.sub.5), 7.68 (d, 2H, J.sub.o=9.0 Hz,
ArH.sub.2'& H.sub.6'), 7.63 (s, 1H, C.dbd.CH), 7.51 (d, 1H,
J.sub.m=2.7 Hz, ArH.sub.7), 7.00 (d, 2H, J.sub.o=9.0 Hz,
ArH.sub.3'& H.sub.5'), 3.94 (s, 3H, OCH.sub.3), 3.75 (t, 4H,
J=4.8 Hz, OCH.sub.2CH.sub.2N), 3.10 (t, 4H, J=4.8 Hz,
OCH.sub.2CH.sub.2N); Mass Spec.: calc. for
[C.sub.21H.sub.20BrN.sub.3O.sub.4+H].sup.+ Theor. m/z=458, 460;
Obs.=458, 460.
REFERENCE EXAMPLE 27c
8-Bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxy-
lic acid (4-morpholin-4-yl-phenyl)-amide
[0202] A yellow suspension of
8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide (Reference Example 27b) (3.092 g,
6.75 mmol) in 40 mL N-methylpyrrolidinone was treated with sodium
hydride (60% dispersion in oil, 0.410 g, 10.24 mmol). Gas evolution
and warming were observed and the suspension became light brown and
almost clear. The reaction was stirred for 10 minutes at room
temperature under nitrogen. Addition of the
2-(trimethylsilyl)ethoxymethyl chloride (1.6 mL, 9.1 mmol) resulted
in a slightly cloudy, lighter brown solution. After 4.5 hours at
room temperature, the reaction mixture was poured into 300 mL
water, stirred for 15 minutes and then stored at 0.degree. C.
overnight. The solids were isolated by filtration, suspended in
methanol, filtered again, and dried under high vacuum to afford the
product as a yellow solid (3.190 g, 80%). .sup.1H NMR (300 MHz,
DMSO, d.sub.6) .delta. 10.18 (s, 1H, C(O)NH), 7.95 (d, 1H,
J.sub.m=2.4 Hz, ArH.sub.7), 7.83 (s, 1H, ArH.sub.3), 7.69 (d, 2H,
J.sub.o=9.0 Hz, ArH.sub.2'& H.sub.6'), 7.51 (d, 1H, J.sub.m=2.7
Hz, ArH.sub.5), 7.00 (d, 2H, J.sub.o=9.0 Hz, ArH.sub.3'&
H.sub.5'), 5.69 (s, 2H, OCH.sub.2O), 3.95 (s, 3H, OCH.sub.3), 3.85
(t, 2H, J=8.0 Hz, OCH.sub.2CH.sub.2Si), 3.75 (t, 4H, J=4.7 Hz,
OCH.sub.2CH.sub.2N), 3.10 (t, 4H, J=4.7 Hz, OCH.sub.2CH.sub.2N),
0.94 (t, 2H, J=8.0 Hz, OCH.sub.2CH.sub.2Si), -0.04 (s, 9H,
Si(CH.sub.3).sub.3; Mass Spec.: calc. for
[C.sub.27H.sub.34BrN.sub.3O.sub.5Si+H].sup.+ Theor. m/z=588, 590;
Obs.=588, 590.
REFERENCE EXAMPLE 27d
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-(2-trimethylsilanyl-ethoxymeth-
oxy)-quinoline-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide
[0203] To a yellow-green suspension of
8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carbox-
ylic acid (Reference Example 27c) (4-morpholin-4-yl-phenyl)-amide
(1.155 g, 1.96 mmol), N-methyl homopiperazine (0.39 mL, 3.14 mmol),
and 4 .ANG. sieves in 30 mL anhydrous toluene was added Pd.sub.2
(dba).sub.2 (90.0 mg, 0.098 mmol) and BINAP (0.358 g, 0.58 mmol).
The resulting reddish brown mixture became lighter in color upon
treatment with cesium carbonate (2.544 g, 7.81 mmol). The reaction
mixture was heated at reflux under nitrogen for 17 hours. The clear
brown solution was cooled to room temperature, concentrated, and
then purified by flash chromatography on silica gel using a slow
gradient of 95:5 to 50:50 methylene chloride:methanol to afford the
desired product (0.989 g, 81%). .sup.1H NMR (300 MHz, DMSO,
d.sub.6) .delta. 9.88 (s, 1H, NH), 7.73 (s, 1H, ArH.sub.3), 7.68
(d, 2H, J.sub.o=8.9 Hz, ArH.sub.2'& H.sub.6'), 7.00 (d, 2H,
J.sub.o=8.9 Hz, ArH.sub.3'& H.sub.5'), 6.94 (d, 1H, J.sub.m=2.7
Hz, ArH.sub.5), 6.66 (d, 1H, J.sub.m=2.7 Hz, ArH.sub.7), 5.62 (s,
2H, OCH.sub.2O), 3.87 (s, 3H, OCH.sub.3), 3.80 (t, 2H, J=8.0 Hz,
OCH.sub.2CH.sub.2Si), 3.73 (t, 4H, J=4.7 Hz, OCH.sub.2CH.sub.2N),
3.63 (t, 2H, J=5.9 Hz, ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3), 3.33
(bs, 2H, ArNCH.sub.2CH.sub.2NCH.sub.3), 3.09 (t, 4H, J=4.7 Hz,
OCH.sub.2CH.sub.2N), 2.97 (bs, 2H, ArNCH.sub.2CH.sub.2NCH.sub.3),
2.69 (bs, 2H, ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3), 2.35 (s, 3H,
NCH.sub.3), 2.09 (bs, 2H ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3),
0.94 (t, 2H, J=8.0 Hz, OCH.sub.2CH.sub.2Si), -0.03 (s, 9H,
Si(CH.sub.3).sub.3; Mass Spec.: calc. for
[C.sub.33H.sub.47N.sub.5O.sub.5Si+H].sup.+ Theor. m/z=622;
Obs.=622.
REFERENCE EXAMPLE 28
[0204] ##STR155##
Preparation of
8-Bromo-4-dimethylamino-6-methoxy-quinoline-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide
REFERENCE EXAMPLE 28a
8-Bromo-4-chloro-6-methoxy-quinoline-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide
[0205] A suspension of
8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid
(Reference Example 27b) (1.75 mmol) in 20 mL methylene chloride was
treated with oxalyl chloride (1.5 mL, 17.2 mmol) and catalytic
dimethylformamide (3 drops). The reaction mixture bubbled
vigorously and became clearer. The reaction was heated at reflux
for 2 hours, cooled to room temperature, and concentrated to a pale
yellow solid (kept under nitrogen).
[0206] To a yellow solution of the acid chloride in 20 mL methylene
chloride was added 4-morpholinoaniline (0.347 g, 1.94 mmol) and
diisopropylethyl amine (1.0 mL, 6.1 mmol). The solution became
orange and gas evolution was observed. Within 30 minutes, solids
began to precipitate from the solution. The reaction was stirred at
room temperature for 1 hour. The solids were isolated by filtration
and dried under high vacuum to afford the desired product (0.406 g,
49%). .sup.1H NMR (300 MHz, DMSO, d.sub.6) .delta. 10.15 (s, 1H,
C(O)NH), 8.33 (s, 1H, ArH.sub.3), 8.10 (d, 1H, J.sub.m=2.7 Hz,
ArH.sub.7), 7.70 (d, 2H, J.sub.o=9.0 Hz, ArH.sub.2'& H.sub.6'),
7.56 (d, 1H, J.sub.m=2.7 Hz, ArH.sub.5), 7.01 (d, 2H, J.sub.o=9.0
Hz, ArH.sub.3'& H.sub.5'), 4.06 (s, 3H, OCH.sub.3), 3.75 (t,
4H, J=4.8 Hz, OCH.sub.2CH.sub.2N), 3.11 (t, 4H, J=4.8 Hz,
OCH.sub.2CH.sub.2N); Mass Spec.: calc. for
[C.sub.21H.sub.19BrClN.sub.3O.sub.3+H].sup.+ Theor. m/z=476, 478;
Obs.=476, 478.
REFERENCE EXAMPLE 28b
8-Bromo-4-dimethylamino-6-methoxy-quinoline-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide
[0207] A solution of
8-bromo-4-chloro-6-methoxy-quinoline-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide (Reference Example 28a) (0.1512 g,
0.317 mmol) in 100 mL 2.0 M dimethyl amine in tetrahydrofuran was
heated at 100.degree. C. in a Paar bomb. The initial pressure was
75-80 psi and then remained at approximately 60 psi. After 18
hours, the reaction was cooled to room temperature, concentrated
and dried to afford the crude product as a brown solid.
Purification on silica gel using a gradient of 100:0 to 95:5
methylene chloride:methanol afforded the clean product (0.142 g,
92%). .sup.1H NMR (300 MHz, DMSO, (16) .delta. 10.20 (s, 1H,
C(O)NH), 7.90 (d, 1H, J.sub.m=2.7 Hz, ArH.sub.5), 7.69 (d, 2H,
J.sub.o=9.0 Hz, ArH.sub.2'& H.sub.6'), 7.60 (s, 1H, ArH.sub.3),
7.41 (d, 1H, J.sub.m=2.7 Hz, ArH.sub.7), 7.01 (d, 2H, J.sub.o=9.0
Hz, ArH.sub.3'& H.sub.5'), 3.96 (s, 3H, OCH.sub.3), 3.75 (t,
4H, J=4.8 Hz, OCH.sub.2CH.sub.2N), 3.10 (t, 4H, J=4.8 Hz,
OCH.sub.2CH.sub.2N), 3.08 (s, 6H, N(CH.sub.3).sub.2); Mass Spec.:
calc. for [C.sub.21H.sub.19BrClN.sub.3O.sub.3+H].sup.+ Theor.
m/z=485, 487; Obs.=485, 487
REFERENCE EXAMPLE 29
[0208] ##STR156##
Preparation of
6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylic
acid
REFERENCE EXAMPLE 29a
8-Bromo-6-fluoro-4-methoxy-quinoline-2-carboxylic Acid Methyl
Ester
[0209] Into a 150 mL 3 neck round bottom flask equipped with a
reflux condenser, magnetic stirrer and nitrogen inlet is placed 2.0
g (6.76 mmol, 1.0 equiv.) of
8-Bromo-6-fluoro-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid
methyl ester. This material is then dissolved in 50 mL of NMP. Then
300 mg (7.44 mmol, 1.1 equiv.) of a 60% dispersion of sodium
hydride in oil is cautiously added portion-wise to the solution at
room temperature. A yellow color then develops, indicating that
formation of the anion has occurred, with hydrogen evolution.
Stirring of the anion solution is continued for one hour, then 1.14
g, 500 .mu.L (8.04 mmol, 1.2 equiv.) of iodomethane is added via
syringe. The mixture is allowed to react for two hours additional,
then is cautiously quenched with 20 mL of water. The solids, which
precipitate upon dilution in 1 L of water, are collected by
filtration, then washed with water to give the pure 0 methylated
material as 2.1 g (98%) of a colorless solid.
[0210] Mass Spec.: calc. for [C.sub.12H.sub.9BrFNO.sub.3+H].sup.+
Theor. m/z=314, 316; Obs.=314, 316
[0211] Alternatively, into a 100 mL 3 neck round bottom flask
equipped with a reflux condenser, nitrogen inlet and magnetic
stirrer is placed 350 mg (1.17 mmol, 1.0 equiv.) of
8-Bromo-6-fluoro-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid
methyl ester and 242 mg (1.75 mmol, 1.5 equiv.) of K.sub.2CO.sub.3.
This material is suspended in 20 mL of DMSO then heated to
70.degree. C. for 1 hr. The anion formation of the anion is
apparent when the mixture becomes cloudy. The mixture is allowed to
cool to 35.degree. C. then 331 mg, 145 .mu.L (2.33 mmol, 2.0
equiv.) of methyl iodide are added and stirring is continued for 2
hr. At the end of this time it is determined if the reaction is
complete by LC/MS. Upon completion the mixture is poured into 200
mL of water and the solids which form are collected by filtration
and washed with water to give 340 mg (93%) of the O-methylated
product after drying.
REFERENCE EXAMPLE 29b
6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylic
Acid Methyl Ester
[0212] Into a 250 mL, 3 neck round bottom flask equipped with a
reflux condenser, magnetic stirrer and nitrogen inlet is added 2.1
g (6.68 mmol, 1.0 equiv.) of
8-Bromo-6-fluoro-4-methoxy-quinoline-2-carboxylic acid methyl ester
(Reference Example 29a) (122 mg, 0.134 mmol, 0.02 equiv.) of tris
dibenzylidineacetone dipalladium, 499 mg (0.802 mmol, 0.12 equiv.)
of racemic 2,2'-bis(diphenylphosphino)-1,1'-binapthyl and 1 g of 4
A molecular sieves and 80 mL of dry toluene. To the stirred
suspension is then added 736 mg, 815 .mu.L, (7.35 mmol, 1.1 equiv.)
of 1-methylpiperazine, followed by 3.05 g (9.35 mmol, 1.4 equiv.)
of cesium carbonate. The mixture is then heated to 80.degree. C.
for 36 hr. At the end of this time completion was monitored by
LC/MS analysis of an aliquot. When the reaction was determined to
be complete it was cooled to room temperature then filtered through
a plug of celite, with toluene washing to remove solid by products.
Purification by flash chromatography using a gradient of 5 to 20%
methanol in methylene chloride as eluent yielded 2.0 g, (90%) of
the desired product. Mass Spec.: calc. for
[C.sub.17H.sub.20FN.sub.3O.sub.3+H].sup.+ Theor. m/z=334;
Obs.=334
REFERENCE EXAMPLE 29c
6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylic
Acid
[0213] Into a 125 mL erlenmeyer flask containing 30 mL of THF and
30 mL of methanol is placed 2.1 g (6.3 mmol) of
6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylic
acid methyl ester (Reference Example 29b). To this solution is
added with stirring 30 mL of water in which is dissolved 291 mg
(6.9 mmol, 1.1 equiv.) of lithium hydroxide monohydrate. This
solution is allowed to react for 1 hr then is quenched with 10 mL
of 2N HCl solution. The solution is then filtered and the solids
washed with 10 mL of 0.5 N HCl solution. The combined filtrates are
then concentrated to give 2.15 g, (95%) of the solid yellow product
as the hydrochloride salt. Mass Spec.: calc. for
[C.sub.16H.sub.18FN.sub.3O.sub.3+H].sup.+ Theor. m/z=320;
Obs.=320
EXAMPLE 1
[0214] ##STR157##
8-(4-methyl-1-piperazinyl)-N-[4-(4-morpholinyl)phenyl]-4-oxo-4H-chromene-2-
-carboxamide
[0215] 8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 1) (400 mg, 1.23 mmol) was
suspended in anhydrous N,N-dimethylformamide (20 ml) and
triethylamine (0.69 ml, 4.92 mmol) was added to give a clear
solution. The following were added in order: 1-hydroxybenzotriazole
(HOBt (205 mg, mol)),
O-(1H-Benzotriazol-1-yl)-N,N,N',N'-pentamethylene-uronium
tetrafluoroborate (TBTU (435 mg, 3.1 mmol)) then
4-(dimethylamino)pyridine (25 mg). After stirring for 5 min at room
temperature, 4-(4-morpholinyl)aniline (Reference Example 21) (220
mg, mmol). The reaction stirred overnight at room temperature. The
solution was concentrated in vacuo, the remains were partitioned
between chloroform/saturated sodium bicarbonate, extracted
(.times.3) with chloroform, dried (MgSO.sub.4) and concentrated in
vacuo to give the crude product.
[0216] Chromatography on silica (230-400 mesh ASTM) and eluting
ethyl acetate followed by 2.5-5% methanol/chloroform gave 190 mg (%
yield) of
8-(4-methyl-1-piperazinyl)-N-[4-(4-morpholinyl)phenyl]-4-oxo-4H-benzochro-
mene-2-carboxamide as a yellow solid (mp 217-218.degree.
decomposition and melt 244-247 C). LC/MS (M+1) m/z=449.
EXAMPLE 2
[0217] ##STR158##
2-{1-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-methanoyl}-8-(4-methyl-piperazi-
n-1-yl)-chromen-4-one
[0218] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
1-(2-Methoxy-phenyl)-piperazine (Aldrich) via the same procedure
used in example 1, yielding a yellow solid. MS (M+H) m/z=463.
EXAMPLE 3
[0219] ##STR159##
2-{1-[4-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-piperazin-1-yl]-methanoyl}-8--
(4-methyl-piperazin-1-yl)-chromen-4-one
[0220] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and
1-(6-piperazin-1-yl-2,3-dihydro-indol-1-yl)-ethanone (Reference
Example 8) as prepared in Example 1, yielding a yellow solid. MS
(M+H) m/z=516.
EXAMPLE 4
[0221] ##STR160##
2-Chloro-5-(4-{1-[8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-metha-
noyl}-piperazin-1-yl)-benzonitrile
[0222] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and 2-chloro-5-piperazin-1-yl
benzonitrile (Reference Example 9) as prepared in Example 1,
yielding a yellow solid. MS (M+H) m/z=493.
EXAMPLE 5
[0223] ##STR161##
2-{1-[4-(4-Methoxy-phenyl)-piperazin-1-yl]-methanoyl}-8-(4-methyl-piperazi-
n-1-yl)-chromen-4-one
[0224] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
(Aldrich) 1-(4-Methoxy-phenyl)-piperazine as prepared in example 1,
yielding a yellow solid. MS (M+H) m/z=463.
EXAMPLE 6
[0225] ##STR162##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(5-furan-2-yl-1H-pyrazol-3-yl)-amide
[0226] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
5-furan-2-yl-1H-pyrazol-3-ylamine (Maybridge) as prepared in
example 1, yielding a yellow solid. MS (M+H) m/z=420.
EXAMPLE 7
[0227] ##STR163##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(4-imidazol-1-yl-phenyl)-amide
[0228] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
4-imidazol-1-yl-phenylamine (Aldrich) as prepared in Example 1,
yielding a yellow solid. MS (M+H) m/z=430.
EXAMPLE 8
[0229] ##STR164##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(4-[1,2,3]thiadiazol-5-yl-phenyl)-amide
[0230] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and
4-[1,2,3]thiadiazol-5-yl-phenylamine (Reference Example 10) as
prepared in Example 1, yielding a yellow solid. MS (M+H)
m/z=448.
EXAMPLE 9
[0231] ##STR165##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
4-[1,2,3]thiadiazol-5-yl-benzylamide
[0232] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
(Maybridge) 4-[1,2,3]thiadiazol-5-yl-benzylamine as prepared in
Example 1, yielding a yellow solid. MS (M+H) m/z=462.
EXAMPLE 10
[0233] ##STR166##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
[4-(4-acetyl-piperazin-1-yl)-phenyl]-amide
[0234] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and
1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (Reference Example
11) as prepared in Example 1, yielding a yellow solid.
[0235] MS (M+H) m/z=499.
EXAMPLE 11
[0236] ##STR167##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-amide
[0237] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and
4-(4-methanesulfonyl-piperazin-1-yl)-phenylamine (Reference Example
12) as prepared in Example 1, yielding a yellow solid. MS (M+H)
m/z=526.
EXAMPLE 12
[0238] ##STR168##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(2-methoxy-4-morpholin-4-yl-phenyl)-amide
[0239] 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 1) (0.10 g, 0.35 mmol), HOBt
(0.10 g, 0.7 mmol), TBTU (0.225 g, 0.7 mmol), 4-(dimethylamino)
pyridine (0.01 g, catalytic amount), triethylamine (0.15 mL, 1.04
mmol), and commercially available
2-methoxy-4-morpholin-4-yl-phenylamine (SALOR) (0.08 g, 0.38 mmol)
were dissolved in dimethylformamide (2.5 mL) and stirred at room
temperature overnight. Ethyl acetate (150 mL) was added and the
resulting mixture was washed with water (3.times.50 mL), dried
(Na.sub.2SO.sub.4), filtered, concentrated under vacuum and
triturated with ether to yield a yellow solid (85 mg, 54%). LCMS:
m/z=480.3
EXAMPLE 13
[0240] ##STR169##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(3-chloro-4-morpholin-4-yl-phenyl)-amide
[0241] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
3-chloro-4-morpholin-4-yl-phenylamine (Maybridge) as prepared in
Example 12, yielding a yellow solid. (110 mg=73%),
LCMS-m/z=483.5
EXAMPLE 14
[0242] ##STR170##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(4-thiomorpholin-4-yl-phenyl)-amide
[0243] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and
4-thiomorpholin-4-yl-phenylamine (Reference Example 13) as prepared
in Example 12, yielding a yellow solid. (55 mg=38%),
LCMS-m/z=465.5
EXAMPLE 15
[0244] ##STR171##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(2,5-diethoxy-4-morpholin-4-yl-phenyl)-amide
[0245] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
2,5-diethoxy-4-morpholin-4-yl-phenylamine (Aldrich) as prepared in
Example 12, yielding a yellow solid. (80 mg=50%),
LCMS-m/z=537.6
EXAMPLE 16
[0246] ##STR172##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(4-cyanomethyl-phenyl)-amide
[0247] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
(4-amino-phenyl)-acetonitrile (Aldrich) as prepared in Example 12,
yielding a yellow solid. (65 mg=54%), LCMS-m/z=403.5
EXAMPLE 17
[0248] ##STR173##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(1H-indol-5-yl)-amide
[0249] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
1H-indol-5-ylamine (Aldrich) as prepared in Example 12, yielding a
yellow solid. (35 mg=29%), LCMS-m/z=401.6
EXAMPLE 18
[0250] ##STR174##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
[4-(1-morpholin-4-yl-methanoyl)-phenyl]-amide
[0251] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and
1-(4-amino-phenyl)-1-morpholin-4-yl-methanone (Reference Example
14) as prepared in Example 12, yielding a yellow solid. (21
mg=15%), LCMS-m/z=477.6
EXAMPLE 19
[0252] ##STR175##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
[4-(2,6-dimethyl-morpholin-4-yl)-phenyl]-amide
[0253] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
4-(2,6-dimethyl-morpholin-4-yl)-phenylamine (Maybridge) as prepared
in Example 12, yielding a yellow solid. (60 mg=42%),
LCMS-m/z=477.6
EXAMPLE 20
[0254] ##STR176##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
[4-(4-fluoro-phenoxy)-phenyl]-amide
[0255] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
4-(4-fluoro-phenoxy)-phenylamine (Maybridge) as prepared in Example
12, yielding a yellow solid. (110 mg=77%), LCMS-m/z=475.6
EXAMPLE 21
[0256] ##STR177##
8-(4-Methyl-piperazin-1-yl)-2-(6-morpholin-4-yl-benzooxazol-2-yl)-chromen--
4-one
[0257] 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 1) (0.532 g, 1.85 mmol) was
placed in a 25 mL 3-neck flask under nitrogen and treated with PPA
(6 g). The mixture was then treated with the prepared intermediate
4-amino-3-hydroxyphenylmorpholine (0.43 g of -85% pure, .about.2
mmol). The mixture was stirred and heated in an oil bath to
205.degree. C. for 3 hours to give a dark liquid. The mixture was
cooled to room temperature and treated with 10 mL of water to give
a dark solution. The solution was slowly neutralized with 1N
aqueous sodium hydroxide to pH.about.7 as a solid formed. The solid
was collected, washed several times with water, air dried, and
vacuum dried at room temperature to give 0.65 g of a black solid.
TLC (10% MeOH in CHCl.sub.3 on SiO.sub.2) showed 2 major components
at R.sub.f.about.0.5 and several lower R.sub.f minor components.
The solid was triturated with saturated aqueous sodium bicarbonate
at room temperature. It was filtered off, washed several times with
water, and air dried to give 0.65 g of a dark gray solid. TLC
showed the same components seen previously. Mass spectral analysis
showed m/e=447 by positive ion CI and m/e=446 by negative ion CI.
The solid was dissolved in 2% methanol in chloroform and it was
chromatographed on a Megabond Elute silica gel column (10 g of
SiO.sub.2) using 2% methanol in chloroform. The slightly faster
R.sub.f yellow component was concentrated to give 0.0188 g of a
yellow solid. CI mass spectral analysis showed m/e=447 as the base
peak by positive ion CI. The solid was recrystallized in methanol
to give 0.0178 g of a yellow solid with a melting point of
158.1-158.8.degree. C. Proton NMR (CDCl.sub.3) and CI mass spectral
analyses were consistent for the desired product (m/z=447 base peak
by positive ion CI and m/z=446 base peak by negative ion CI).
EXAMPLE 22
[0258] ##STR178##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(2-hydroxy-4-morpholin-4-yl-phenyl)-amide
[0259] 8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 1) (0.3768 g, 1.16 mmol) was
placed in a 100 mL 3-neck flask under nitrogen and it was dissolved
in 20 mL of DMF. The solution was treated with triethylamine (0.49
mL, 3.5 mmol) followed by HOBT hydrate (0.36 g, 2.3 mmol) followed
by TBTU (0.74 g, 2.3 mmol) and then followed by DMAP (0.020 g). The
mixture was stirred for 10 minutes and then it was treated with
4-amino-3-hydroxyphenylmorpholine (Reference example 21) (0.228 g,
1.17 mmol). The mixture was stirred for 15 minutes and then it was
treated with triethylamine (0.17 mL, 1.2 mmol). The mixture was
stirred at room temperature for 42 hours and then it was added to a
solution of 50 mL of saturated aqueous sodium bicarbonate and 50 mL
of water. The mixture was extracted 4 times with ethyl acetate,
dried over magnesium sulfate, filtered, and concentrated to give
0.834 gram of a purple oil. The oil was dissolved in 2 percent
methanol in chloroform and it was placed on a silica gel column
(5.5 cm diameter by 10.5 cm long) and eluted with 2 percent
methanol in chloroform followed by 5 percent methanol in
chloroform. The yellow fraction was concentrated to give 0.2031
gram of an orange-yellow solid. The solid was dissolved in
methanol, filtered through a medium sintered glass funnel, and
concentrated to a few ml volume as a solid formed. The solid was
filtered off, washed with methanol, and air dried to give 0.1613
gram of a tan solid with MP of 248.4-249.6.degree. C. Proton COSY
NMR and CI mass spectral analyses were consistent for the desired
product (m/z=465 by positive ion CI and m/z=463 by negative ion
CI).
EXAMPLE 23
[0260] ##STR179##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(5-ethoxy-benzothiazol-2-yl)-amide
[0261] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
5-ethoxy-benzothiazol-2-ylamine (SALOR) as prepared in Example 12,
yielding a yellow solid. (55 mg=39%), LCMS-m/z=465.3
EXAMPLE 24
[0262] ##STR180##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(4-bromo-phenyl)-amide
[0263] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and commercially available
4-bromo-phenylamine (Aldrich) as prepared in Example 12, yielding a
yellow solid. (1.0 g=75%), LCMS-m/z=442.4
EXAMPLE 25
[0264] ##STR181##
8-(4-Methylpiperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
methyl-(4-morpholin-4-yl-phenyl)amide
[0265] 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide (Example 1) (0.1046 g, 0.2332
mmol) was placed in a 10 mL single neck round flask under nitrogen.
The solid was dissolved in 2.8 mL of anhydrous DMF. The yellow
solution was stirred at room temperature and treated with one
portion of sodium hydride (0.011 g of 95%, 0.44 mmol). The mixture
evolved gas and became a red solution. It was stirred under
nitrogen for 20 minutes and then it was treated with iodomethane
(0.015 mL, 0.033 g, 0.233 mmol). The mixture was sealed and stirred
at room temperature for 18 hours.
[0266] The reaction mixture was concentrated to remove most of the
DMF (35 C bath @ 0.5 mm) to give a dark semisolid. It was treated
with a few drops of water followed by 10 mL of ethyl acetate. The
mixture was dried over magnesium sulfate, filtered, and
concentrated to give 0.0564 gram of a yellow glass. The glass was
triturated with diethyl ether, filtered off, and dried under high
vacuum to give 0.0302 g of a tan solid with MP of 245.0-246.8 C.
Proton NMR and CI mass spectral analyses were consistent for the
desired product (m/z=463 by positive ion CI).
EXAMPLE 26
[0267] ##STR182##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(3-morpholin-4-yl-phenyl)-amide
[0268] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and
3-morpholin-4-yl-phenylamine (Reference Example 18) as prepared in
Example 12, yielding a yellow solid. (120 mg=86%),
LCMS-m/z=449.5
EXAMPLE 27
[0269] ##STR183##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(3-cyano-4-morpholin-4-yl-phenyl)-amide
[0270] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and
5-amino-2-morpholin-4-yl-benzonitrile (Reference Example 15) as
prepared in Example 12, yielding a yellow solid. (120 mg=82%),
LCMS-m/z=474.5
EXAMPLE 28
[0271] ##STR184##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(3-fluoro-4-morpholin-4-yl-phenyl)-amide
[0272] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and
3-fluoro-4-morpholin-4-yl-phenylamine (Reference Example 16) as
prepared in example 12, yielding a yellow solid. (120 mg=83%),
LCMS-m/z=467.6
EXAMPLE 29
[0273] ##STR185##
4-[4-({1-[8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-methanoyl}-am-
ino)-phenyl]-piperazine-1-carboxylic Acid Tert-Butyl Ester
[0274] This compound was prepared from
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
hydrochloride (Reference Example 1) and
4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
(Reference Example 17) as prepared in example 12, yielding a yellow
solid. (260 mg=53%), LCMS-m/z=548.6
EXAMPLE 30
[0275] ##STR186##
8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid
(4-piperazin-1-yl-phenyl)-amide
[0276]
4-[4-({1-[8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-metha-
noyl}-amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester
(Example 29) (160 mg, 0.3 mmol) was dissolved ethyl acetate (20 mL)
and cooled to 0.degree. C. HCl gas was bubbled in slowly for 2
minutes. A solid began to precipitate. Methanol (3-4 mL) was added
to dissolve this solid and HCl gas was bubbled in for another 2
minutes. The mixture was concentrated under reduced pressure and
triturated with ether and dried under vacuum to yield a tan solid
(100 mg, 76%). LCMS/m/z=448.6
EXAMPLE 31
[0277] ##STR187##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide
[0278]
6-Methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxyl-
ic acid hydrochloride (Reference Example 2) (3.0 g, 8.5 mmol), TBTU
(5.5 g, 17 mmol), 1-hydroxybenztriazole (2.6 g, 17 mmol),
4-dimethylaminopyridine (0.05 g, catalytic) and commercially
available 4-morpholin-4-yl-aniline (1.66 g, 9.3 mmol) were
dissolved in dimethylformamide (100 mL). Triethylamine (3.5 mL, 25
mmol was added and this mixture stirred at room temperature for 17
hours. The reaction mixture was concentrated under vacuum and the
residue was partitioned between chloroform (400 mL) and saturated
aqueous sodium bicarbonate (50 mL). The organic layer was
separated, dried (Na.sub.2SO.sub.4), vacuum-filtered and
concentrated under vacuum. The residue was purified by
chromatography on silica eluted with 2-5% methanol in chloroform
and then triturated with ether to yield a yellow powder. (1.6
g=39%) LCMS-m/z=479.5 mp=234-236.degree. C.
EXAMPLE 32
[0279] ##STR188##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-amide
[0280] This compound was prepared from
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 2) and
4-(4-methanesulfonyl-piperazin-1-yl)-phenylamine (Reference Example
12) as prepared in example 1, yielding a yellow solid. GC/MS (EI,
M+) m/z=556
EXAMPLE 33
[0281] ##STR189##
6-Methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (3-chloro-4-morpholin-4-yl-phenyl)-amide
[0282] This compound was prepared from
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 2) and commercially available
3-chloro-4-morpholin-4-yl-phenylamine (Maybridge) as prepared in
Example 12, yielding a yellow solid. (45 mg=31%) LCMS-m/z=513.5
EXAMPLE 34
[0283] ##STR190##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (3-fluoro-4-morpholin-4-yl-phenyl)-amide
[0284] This compound was prepared from
6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 2) and
3-fluoro-4-morpholin-4-yl-phenylamine (Reference Example 16) as
prepared in Example 12, yielding a yellow solid. (55 mg=61%),
LCMS-m/z=497.5
EXAMPLE 35
[0285] ##STR191##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (2-methoxy-4-morpholin-4-yl-phenyl)-amide
[0286] This compound was prepared from
6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 2) and commercially available
2-methoxy-4-morpholin-4-yl-phenylamine (SALOR) as prepared in
Example 12, yielding a yellow solid. (55 mg=38%),
LCMS-m/z=510.5
EXAMPLE 36
[0287] ##STR192##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-thiomorpholin-4-yl-phenyl)-amide
[0288] This compound was prepared from
6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 2) and
4-thiomorpholin-4-yl-phenylamine (Reference Example 13) as prepared
in Example 12, yielding a yellow solid. (99 mg=71%),
LCMS-m/z=495.5
EXAMPLE 37
[0289] ##STR193##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(2,6-dimethyl-morpholin-4-yl)-phenyl]-amide
[0290] This compound was prepared from
6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 2) and commercially available
4-(2,6-dimethyl-morpholin-4-yl)-phenylamine (Maybridge) as prepared
in Example 12, yielding a yellow solid. (70 mg=49%),
LCMS-m/z=507.5
EXAMPLE 38
[0291] ##STR194##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (3-morpholin-4-yl-phenyl)-amide
[0292] This compound was prepared from
6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 2) and
3-morpholin-4-yl-phenylamine (Reference Example 18) as prepared in
Example 12, yielding a yellow solid. (80 mg=60%),
LCMS-m/z=479.5
EXAMPLE 39
[0293] ##STR195##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid {4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenyl}-amide
[0294] This compound was prepared from
6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 2) and
2-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanol (Reference Example
19) as prepared in Example 12, yielding a yellow solid. (80
mg=60%). mp=211.5-212.2 (dec.), MS-base peak at m/z=492 by positive
ion and m/z=490 by negative ion CI
EXAMPLE 40
[0295] ##STR196##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(1-morpholin-4-yl-methanoyl)-phenyl]-amide
[0296] This compound was prepared from
6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 2) and
1-(4-amino-phenyl)-1-morpholin-4-yl-methanone (Reference Example
14) as prepared in Example 12, yielding a yellow solid. (170
mg=80%), LCMS-m/z=507.5
EXAMPLE 41
[0297] ##STR197##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (3-cyano-4-morpholin-4-yl-phenyl)-amide
[0298] This compound was prepared from
6-methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 2) and
5-amino-2-morpholin-4-yl-benzonitrile (Reference Example 15) as
prepared in Example 12, yielding a yellow solid. (120 mg=57%),
LCMS-m/z=504.5
EXAMPLE 42
[0299] ##STR198##
4-[4-({1-[6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-met-
hanoyl}-amino)-phenyl]-piperazine-1-carboxylic Acid Tert-Butyl
Ester
[0300] The
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 2) (1.04 g, 2.93 mmol) was
placed in a 250 ml 3-neck flask under nitrogen and it was dissolved
in 50 ml of DMF. The solution was treated with triethylamine (1.22
mL, 8.79 mmol) followed by HOBT hydrate (0.90 g, 5.9 mmol) followed
by TBTU (1.88 g, 5.9 mmol) and then followed by DMAP (0.056 g, 0.46
mmol). The mixture was stirred for 10 minutes and then it was
treated with 4-(4-Amino-phenyl)-piperazine-1-carboxylic acid
tert-butyl ester (Reference Example 17) (0.81 g, 2.9 mmol). The
mixture was stirred for 15 minutes and then it was treated with
triethylamine (0.41 mL, 2.9 mmol). The mixture was stirred at room
temperature for 18 hours and then it was concentrated (1 mm Hg
pressure, 45 C bath) to give a dark liquid. The concentrate was
treated with 80 mL of saturated aqueous sodium bicarbonate and
extracted with ethyl acetate forming a suspended yellow solid in
the organic layer. The solid was filtered off, washed with diethyl
ether, washed with water, and vacuum dried (0.1 mm Hg @ 25 C) to
give 0.36 gram of a yellow solid, M.P.=232.3-232.8 C.
Proton NMR and CI mass spectral analyses were consistent for the
desired product (m/e=578 by positive ion CI and m/e=576 by negative
ion CI).
[0301] The aqueous layer was extracted twice with ethyl acetate,
dried over magnesium sulfate, filtered, and concentrated to give
1.35 gram of a dark semisolid. It was triturated with diethyl ether
and allowed to stand at room temperature as a solid formed. The
solid was filtered off, washed with diethyl ether, and vacuum dried
at room temperature to give 0.4816 gram of a yellow solid. CI mass
spectral analyses was consistent for the desired product (M/Z=578
BY positive ion CI AND MIZ=576 by negative ion CI).
EXAMPLE 43
[0302] ##STR199##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide
[0303] The
4-[4-({1-[6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-me-
thanoyl}-amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl
ester (Example 42) (0.792 gram, 1.37 mmol) was placed in a 50 ml
round flask under nitrogen and it was dissolved in 15 ml of
methylene chloride. The solution was treated with 15 ml of
trifluoroacetic acid (195 mmol) to give a dark solution and it was
stirred at room temperature for 18 hours. It was concentrated to
give a brown foam. The foam was treated with 30 ml of saturated
aqueous sodium bicarbonate and it was stirred at room temperature
as a yellow solid formed. The solid was filtered off, washed
several times with water, air dried and dried under high vacuum
(0.1 mm Hg pressure) to give 0.493 gram of a yellow solid,
M.P.=203.6-204.7 C.
[0304] Proton NMR and CI mass spectral analyses were consistent for
the desired product (m/z=478 by positive ion CI and m/z=476 by
negative ion CI).
EXAMPLE 44-54
[0305] The following examples were prepared in parallel by
acylation of
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide (Example 43) in an Argonaut
Quest synthesizer.
[0306] The piperazine side chain was derivatized in parallel
fashion using eleven different commercially available acylating and
sulfonating reagents. The resins used were Argonaut Tech
polystyrene amine resins. Each 5 ml Quest tube was charged with
0.010 gram (0.021 mmol) of the starting N--H piperazine and 3 ml of
methylene chloride followed by 4 equivalents (0.08 mmol) of PS-DIEA
resin (diisopropylbenzyl amine PS resin) to scavenge HCl. Each tube
was then treated with an acyl chloride, sulfonyl chloride, or
isocyanate (2 equivalents of each) followed by a little more
methylene chloride. The tubes were sealed under nitrogen, and
stirred for 3 hours at room temperature. The mixtures were then
opened and treated with about 4 equivalents (0.08 mmol) of
PS-trisamine resin (primary amine PS resin) to scavenge any excess
acylating or sulfonating reagent. The mixtures were sealed and
stirred for 1.5 hours and then filtered directly into vials and
concentrated to give the products. The products were characterized
by HPLC mass spectral analysis and were found to be greater than
90% pure by HPLC. The compounds were submitted to the 5-HT1b
binding assay for determination of 5-HT receptor binding affinities
and selectivities.
EXAMPLE 44
[0307] ##STR200##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide
[0308] This compound was prepared from
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially
available propionyl chloride (Aldrich) via the parallel synthesis
described above. MS-base peak at m/z=534 by positive ion CI
EXAMPLE 45
[0309] ##STR201##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(4-ethane sulfonyl-piperazin-1-yl)-phenyl]-amide
[0310] This compound was prepared from
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially
available ethanesulfonyl chloride (Aldrich) via the parallel
synthesis described above. MS-base peak at m/z=570 by positive ion
CI, mp=232-234.degree. C.
EXAMPLE 46
[0311] ##STR202##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(4-dimethyl sulfamoyl-piperazin-1-yl)-phenyl]-amide
[0312] This compound was prepared from
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially
available dimethylsulfamoyl chloride (Aldrich) via the parallel
synthesis described above. MS--base peak at f/z=585 by positive ion
CI
EXAMPLE 47
[0313] ##STR203##
4-[4-({1-[6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-met-
hanoyl}-amino)-phenyl]-piperazine-1-carboxylic Acid
Dimethylamide
[0314] This compound was prepared from
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially
available dimethylcarbamyl chloride (Aldrich) via the parallel
synthesis described above. MS--base peak at m/z=549 by positive ion
CI
EXAMPLE 48
[0315] ##STR204##
4-[4-({1-[6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-met-
hanoyl}-amino)-phenyl]-piperazine-1-carboxylic Acid Ethylamide
[0316] This compound was prepared from
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially
available ethyl isocyanate (Aldrich) via the parallel synthesis
described above. MS-base peak at m/z=549 by positive ion CI.
EXAMPLE 49
[0317] ##STR205##
4-[4-({1-[6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-met-
hanoyl}-amino)-phenyl]-piperazine-1-carboxylic Acid
Cyclohexylamide
[0318] This compound was prepared from
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially
available cyclohexyl isocyanate (Aldrich) via the parallel
synthesis described above. MS--base peak at m/z=603 by positive ion
CI
EXAMPLE 50
[0319] ##STR206##
4-[4-({1-[6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-met-
hanoyl}-amino)-phenyl]-piperazine-1-carboxylic acid
cyclopentylamide
[0320] This compound was prepared from
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially
available cyclopentanecarbonyl chloride (Aldrich) via the parallel
synthesis described above. MS-base peak at m/z=574 by positive ion
CI.
EXAMPLE 51
[0321] ##STR207##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid
{4-[4-(1-pyrrolidin-1-yl-methanoyl)-piperazin-1-yl]-phenyl}-amide
[0322] This compound was prepared from
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially
available 1-pyrrolidinecarbonyl chloride (Aldrich) via the parallel
synthesis described above. MS-base peak at m/z=575 by positive ion
CI.
EXAMPLE 52
[0323] ##STR208##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid {4-[4-(propane-2-sulfonyl)-piperazin-1-yl]-phenyl}-amide
[0324] This compound was prepared from
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially
available isopropylsulfonylonyl chloride (Aldrich) via the parallel
synthesis described above. MS-base peak at m/z=584 by positive ion
CI.
EXAMPLE 53
[0325] ##STR209##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid {4-[4-(2-methyl-propanoyl)-piperazin-1-yl]-phenyl}-amide
[0326] This compound was prepared from
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially
available isobutyryl chloride (Aldrich) via the parallel synthesis
described above. MS-base peak at m/z=548 by positive ion CI.
EXAMPLE 54
[0327] ##STR210##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid
{4-[4-(1-morpholin-4-yl-methanoyl)-piperazin-1-yl]-phenyl}-amide
[0328] This compound was prepared from
6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially
available morpholine-4-carbonyl chloride (Aldrich) via the parallel
synthesis described above. MS-base peak at m/z=591 by positive ion
CI.
EXAMPLE 55
[0329] ##STR211##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide
[0330] This compound was prepared from
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 3) and
4-morpholin-4-yl-phenylamine (Reference Example 20) as prepared in
Example 1, yielding a yellow solid. MS (M+H) m/z=467
EXAMPLE 56
[0331] ##STR212##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-amide
[0332] This compound was prepared from
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 3) and
4-(4-methanesulfonyl-piperazin-1-yl)-phenylamine (Reference Example
12) as prepared in Example 1, yielding a yellow solid. MS (M+H)
m/z=544
EXAMPLE 57
[0333] ##STR213##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(4-acetyl-piperazin-1-yl)-phenyl]-amide
[0334] This compound was prepared from
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 3) and
1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (Reference Example
11) as prepared in Example 1, yielding a yellow solid. MS (M+H)
m/z=508
EXAMPLE 58
[0335] ##STR214##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (3-chloro-4-morpholin-4-yl-phenyl)-amide
[0336]
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxyli-
c acid hydrochloride (Reference Example 3) (150 mg, 0.43 mmol),
1-hydroxybenzotriazole (140 mg, 0.9 mmol),
O-(1H-Benzotriazol-1-yl)-N,N,N',N'-pentamethylene-uronium
tetrafluoroborate (290 mg, 0.9 mmol), 4-(dimethylamino)pyridine (10
mg, catalytic), triethylamine (0.2 mL, 1.5 mmol), and commercially
available 3-chloro-4-morpholin-4-yl-phenylamine (Maybridge) were
dissolved in dimethylformamide (2.5 mL) and stirred at room
temperature overnight. At 17 h, water (20 mL) was added and the
resulting mixture was stirred for 15-30 min. The mixture was
vacuum-filtered and the residue washed with water and air-dried to
yield a yellow powder (220 mg=quantitative yield).
LC/MS-m/z=501.5
EXAMPLE 59
[0337] ##STR215##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (3-fluoro-4-morpholin-4-yl-phenyl)-amide
[0338] This compound was prepared from
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 3) and
3-fluoro-4-morpholin-4-yl-phenylamine (Reference Example 16) as
prepared in Example 58, yielding a yellow solid (210 mg=99%).
LC/MS-m/z=485.5
EXAMPLE 60
[0339] ##STR216##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (3-cyano-4-morpholin-4-yl-phenyl)-amide
[0340] This compound was prepared from
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 3) and
5-amino-2-morpholin-4-yl-benzonitrile (Reference Example 15) as
prepared in Example 58, yielding a yellow solid (210 mg=99%).
LC/MS-m/z=492.5
EXAMPLE 61
[0341] ##STR217##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(1-morpholin-4-yl-methanoyl)-phenyl]-amide
[0342] This compound was prepared from
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 3) and
1-(4-amino-phenyl)-1-morpholin-4-yl-methanone (Reference Example
14) as prepared in Example 58, yielding a yellow solid (220
mg=quantitative yield). LC/MS-m/z=495.5
EXAMPLE 62
[0343] ##STR218##
6-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide
[0344] This compound was prepared from
6-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 4) and
4-morpholin-4-yl-phenylamine (Reference Example 20) as prepared in
Example 1, yielding a yellow solid. LCMS-m/z=463.6
EXAMPLE 63
[0345] ##STR219##
6-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(1-morpholin-4-yl-methanoyl)-phenyl]-amide
[0346] This compound was prepared from
6-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 4) and
1-(4-amino-phenyl)-1-morpholin-4-yl-methanone (Reference Example
14) as prepared in Example 1, yielding a yellow solid.
LCMS-m/z=491.6
EXAMPLE 64
[0347] ##STR220##
6-Methyl 8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (3-fluoro-4-morpholin-4-yl-phenyl)-amide
[0348] This compound was prepared from
6-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 4) and
3-fluoro-4-morpholin-4-yl-phenylamine (Reference Example 16) as
prepared in Example 1, yielding a yellow solid. LCMS-m/z=504.5
EXAMPLE 65
[0349] ##STR221##
6-Chloro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide
[0350] This compound was prepared from
6-chloro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 5) and
4-morpholin-4-yl-phenylamine (Reference Example 20) as prepared in
Example 1, yielding a yellow solid. LCMS-m/z=483.3
EXAMPLE 66
[0351] ##STR222##
5-Methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide
[0352] This compound was prepared from
5-methyl-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 6) and
4-morpholin-4-yl-phenylamine (Reference Example 20) as prepared in
Example 1, yielding a yellow solid (116 mg=84%) LCMS-m/z=463.5
EXAMPLE 67
[0353] ##STR223##
5-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide
[0354] This compound was prepared from
5-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 7) and
4-morpholin-4-yl-phenylamine (Reference example 20) as prepared in
Example 1, yielding a yellow solid (149 mg=50%) LCMS-m/z=479.4
The following additional examples incorporate 4-substituted
piperazine-1-yl-phenyl amides similar in structure to Examples
44-54
EXAMPLE 68
[0355] ##STR224##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid{4-[4-(3-hydroxy-propanoyl)-piperazin-1-yl]-phenyl}-amide
[0356]
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxyl-
ic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) (1.5 gram,
2.12 mmol) was placed in a 100 mL flask with 50 mL of
CH.sub.2Cl.sub.2. This suspension was treated with triethylamine (4
equivalents, 1.2 mL, 8.5 mmol) and O-propionylactone (0.2 mL, 3.2
mmol) and the reaction stirred at room temperature for 2 hours,
then heated to 50.degree. C. for 2 hours. Then 0.8 mL more of
b-propionylactone was added and the reaction heated for 4 hours
more. The reaction was allowed to cool to room temperature and then
concentrated (1 mm Hg pressure). The concentrate was treated with
saturated aqueous sodium bicarbonate and the resulting solid
collected by vacuum filtration. The residue was purified by
chromatography on silica eluting with 2% methanol in chloroform,
then concentrated (1 mm Hg pressure). Then triturated with either
to yield a yellow powder with was dried under high vacuum for 48 h
at 50.degree. C. (100 mg) LCMS-m/z 550, mp=195-197.degree. C.
EXAMPLE 69
[0357] ##STR225##
4-[4-({1-[6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-meth-
anoyl}-amino)-phenyl]-piperazine-1-carboxylic Acid Tert-Butyl
Ester
[0358] This compound was prepared from
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride (Reference Example 3) and
4-(4-Amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester
(Reference Example 17) according to the method of Example 42 to
yield (1.65 grams, 64%) of a yellow powder LCMS-m/z=556;
mp=219-220.degree. C.
EXAMPLE 70
[0359] ##STR226##
4-[4-({1-[6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxy-
lic acid (4-piperazin-1-yl-phenyl)-amide
[0360] This compound was prepared from
4-[4-({1-[6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-met-
hanoyl}-amino)-phenyl]-piperazine-1-carboxylic acid tert-butyl
ester, as prepared in Example 69, using the method of Example 43 to
yield a yellow solid LCMS-m/z=466.
EXAMPLE 71
[0361] ##STR227##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(4-ethane sulfonyl-piperazin-1-yl)-phenyl]-amide
[0362]
4-[4-({1-[6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-
-carboxylic acid (4-piperazin-1-yl-phenyl)-amide ditrifluoroacetate
(the free acid of which was prepared as in Example 70) (4.0 grams,
5.77 mmol) was placed in a flask with 50 mL of CH.sub.2Cl.sub.2 and
triethylamine (3.2 mL and 23 mmol) and ethylsulfonyl chloride was
added (0.6 mL, 6.35 mmol) portionwise (0.1 mL at a time) over 15
minutes and allowed to stir at room temperature for 20 hours. The
reaction was concentrated (1 mm Hg pressure) and then saturated
aqueous sodium bicarbonate was added and extracted with CHCl.sub.3.
The organic fractions were combined, washed with saturated sodium
chloride, dried (MgSO.sub.4) concentrated (1 mm Hg pressure) to
give a yellow solid which was recrystallized from methanol to give
1.33 grams of product LCMS-m/z=558, mp=233-234.degree. C.
EXAMPLE 72
[0363] ##STR228##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide
[0364]
4-[4-({1-[6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-
-carboxylic acid (4-piperazin-1-yl-phenyl)-amide ditrifluoroacetate
(the free acid of which was prepared as in Example 70) (0.69 grams,
1.00 mmol) was placed in a flask with 25 mL of CH.sub.2Cl.sub.2 and
triethylamine (0.56 mL and 4 mmol) and propionyl chloride was added
(0.95 mL, 1.1 mmol) and the reaction allowed to stir at room
temperature for 20 hours. The residue was purified by
chromatography on silica eluting with 2% methanol in chloroform,
then concentrated (1 mm Hg pressure). The residue was triturated
with either then digested with CHCl.sub.3 and the CHCl.sub.3
concentrated to yield a yellow powder which was dried under high
vacuum for 48 h at 45.degree. C. (260 mg) LCMS-m/z=522,
mp=244-245.degree. C.
EXAMPLE 73
[0365] ##STR229##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid {4-[4-(3-hydroxy-propanoyl)-piperazin-1-yl]-phenyl}-amide
[0366] This compound was prepared from
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-piperazin-1-yl-phenyl)-amide and .beta.-propionylactone
using the method described above in Example 68 to yield 65 mg of a
yellow powder LCMS-m/z=538, mp=195-199.degree. C.
The following exemplifies a substituted chromene-2-"reverse amide"
(or substituted chromene-2-yl-benzamide).
EXAMPLE 74
[0367] ##STR230##
N-[8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-4-morpholin-4-yl-ben-
zamide
[0368] 8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride Reference Example 1 (227 mg, 0.69 mmol),
triethylamine (2 equivalents, 1.389 mmol, 0.193 mL) and
diphenylphosphoryl azide (0.69 mmol, 0.15 mL) were stirred in
toluene (10 mL) at 65.degree. C. for 30 minutes. The reaction was
allowed to cool to 22.degree. C. and 4-morpholinobenzonoic acid
(0.7 mmol, 145 mg), more triethylamine (0.051 mL, 0.7 mmol), and
CH.sub.3CN (5 mL) were added and the reaction heated to reflux for
1 hour. The reaction was concentrated (1 mm Hg pressure) the
residue was partitioned between 1N methanesulfonic acid and ether.
The acid layer was then basified with solid K.sub.2CO.sub.3 and the
product extracted in to CHCl.sub.3. The organic layer was dried
(MgSO.sub.4) and concentrated under reduced pressure to leave a
yellow solid which was further purified with silica chromatography
using CHCl.sub.3 to 4% CH.sub.3OH in CHCl.sub.3. Concentration of
the fractions containing product yielded 13 mg of product
LC/MS-m/z=449.
[0369] Enantiomers of
8-(4-Methyl-piperazin-1-yl)-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide.
EXAMPLE 75
[0370] ##STR231##
racemic-8-(4-Methyl-piperazin-1-yl)-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide
[0371] racemic-8-(4-Methyl-1-piperazin-1-yl)-chroman-2-carboxylic
acid hydrochloride (Example 75a) (1.04 mmol) was dissolved in
anhydrous N,N-dimethylformamide (40 ml) and the following were
added in order: HOBt (0.17 g, 1.14 mmol), TBTU (0.37 g, 1.14 mmol)
then triethylamine (0.6 ml, 4.2 mmol). After stirring for 5 min at
room temperature, 4-(4-morpholinyl)aniline (reference example 20)
(0.185 g, 1.14 mmol) was added and the reaction stirred overnight
at room temperature.
The solution was concentrated in vacuo, the remains were
partitioned between chloroform/saturated sodium bicarbonate,
extracted (.times.3) with chloroform, dried (MgSO.sub.4) and
concentrated in vacuo to give the crude product.
[0372] The crude product was chromatographed on a Waters Delta Prep
4000 using 1 PrepPak cartridge (Porasil 37-55 .mu.m 125 .ANG.)
eluting with 2.5% methanol/chloroform. The product was collected to
give a yellow oil. Ethyl acetate was added to the oil. The solution
was refluxed then cooled the yellow solid was filtered to give 55
mg (12% yield) of
racemic-8-(4-methyl-piperazin-1-yl)-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide (mp 215-216.degree. C.). The mother
liquor contained 76 mg that was used in the chiral separation
described below. LC/MS (M+1) m/z=437.
EXAMPLE 75a
racemic-8-(4-Methyl-1-piperazin-1-yl)-chroman-2-carboxylic Acid
Hydrochloride
[0373] Ethyl
8-(4-methyl-1-piperazin-1-yl)-4-oxo-4H-chromen-2-carboxylate
(Reference Example 1) (0.74 g, 2.3 mmol) was dissolved in glacial
acetic acid (50 ml) and 10% palladium on carbon (80 mg) was added.
The mixture was hydrogenated on a Paar apparatus (50 psi) at
70.degree. C. for 3 h. Then, concentrated HCl and 10% palladium on
carbon (100 mg) were added and the mixture was again subjected to
hydrogenation (50 psi) at 70.degree. C. for 1 h. The reaction was
allowed to cool, the catalyst was filtered and the solution was
concentrated in vacuo. Toluene was repeatedly added and the
solution concentrated to give
racemic-8-(4-Methyl-1-piperazin-1-yl)-chroman-2-carboxylic acid
hydrochloride as a foam that was used without further purification
in the next reaction. LC/MS (M+1) m/z=277.
EXAMPLE 76
[0374] ##STR232##
(+)-8-(4-Methyl-piperazin-1-yl)-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide
[0375] The enantiomers of
racemic-8-(4-Methyl-piperazin-1-yl)-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide (Example 75) (0.52 g, 1.19 mmol)
were separated by the use of a chiral column (ChiralPak AD, 5
cm.times.50 cm, 20.mu.). The faster (+) isomer (example 76) was
eluted with 45% isopropanol/hexane and the slower (-)isomer
(example 77) was eluted with 75% isopropanol/hexane.
[0376] The faster (+) isomer (example 76) was obtained as a white
solid (250 mg, mp 206-207.degree. C., .alpha..sub.D+92.66 in
dichloromethane). LC/MS (M+1) m/z=437.
EXAMPLE 77
[0377] ##STR233##
(-)-8-(4-Methyl-piperazin-1-yl)-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide
[0378] The enantiomers of
racemic-8-(4-Methyl-piperazin-1-yl)-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide (Example 75) (0.52 g, 1.19 mmol)
were separated by the use of a chiral column (ChiralPak AD, 5
cm.times.50 cm, 20.mu.). The faster (+) isomer (example 76) was
eluted with 45% isopropanol/hexane and the slower (-)isomer
(example 77) was eluted with 75% isopropanol/hexane.
[0379] The slower (-) isomer (example 77) was obtained as obtained
as a light purple solid (260 mg, mp 205.5-207.degree. C.,
.DELTA..sub.D-91.08 in dichloromethane). LC/MS (M+1) m/z=437.
[0380] Enantiomers of
8-(4-methyl-piperazin-1-yl)-4-oxo-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide.
EXAMPLE 78
[0381] ##STR234##
racemic-8-(4-methyl-piperazin-1-yl)-4-oxo-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide
[0382]
Racemic-8-(4-methyl-1-piperazin-1-yl)-4-oxo-chroman-2-carboxylic
acid hydrochloride (Example 78a) (1.04 mmol) was dissolved in
anhydrous N,N-dimethylformamide (40 ml) and the following were
added in order: HOBt (0.17 g, 1.14 mmol), TBTU (0.37 g, 1.14 mmol)
then triethylamine (0.6 ml, 4.2 mmol). After stirring for 5 min at
room temperature, 4-(4-morpholinyl)aniline (reference example 20)
(0.185 g, 1.14 mmol) was added and the reaction stirred overnight
at room temperature.
The solution was concentrated in vacuo, the remains were
partitioned between chloroform/saturated sodium bicarbonate,
extracted (.times.3) with chloroform, dried (MgSO.sub.4) and
concentrated in vacuo to give the crude product.
[0383] The crude product was chromatographed on a Waters Delta Prep
4000 using 1 PrepPak cartridge (Porasil 37-55 .mu.m 125 .ANG.)
eluting with 2.5% methanol/chloroform. The product was collected to
give a yellow oil. Ethyl acetate was added to the oil. The solution
was refluxed then cooled the yellow solid was filtered to give 55
mg (12% yield) of
racemic-8-(4-methyl-piperazin-1-yl)-4-oxo-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide (mp 215-216.degree. C.). The mother
liquor contained 76 mg that was used in the chiral separation
described below. LC/MS (M+1) m/z=451.
EXAMPLE 78a
racemic-8-(4-Methyl-1-piperazin-1-yl)-4-oxo-chroman-2-carboxylic
Acid Hydrochloride
[0384]
racemic-Ethyl-8-(4-methyl-1-piperazinyl)-4-oxo-chroman-2-carboxyla-
te (Example 78b) (0.33 g, 1.04 mmol) was dissolved in 6 M HCl (20
ml) and heated to 100.degree. C. for 1.5 h. The reaction was
allowed to cool. The solution was concentrated in vacuo and
anhydrous toluene was added (.times.3) and the solution was again
concentrated in vacuo to give
racemic-8-(4-Methyl-1-piperazin-1-yl)-4-oxo-chroman-2-carboxylic
acid hydrochloride as a yellow foam (0.44 g, quantitative yield)
that was used as is in the next reaction. LC/MS (M+1) m/z=291.
EXAMPLE 78b
racemic-Ethyl-8-(4-methyl-1-piperazin-1-yl)-4-oxo-chroman-2-carboxylate
[0385]
Racemic-Ethyl-8-(4-methyl-1-piperazin-1-yl)-4-hydroxy-chroman-2-ca-
rboxylate (Example 78c) (0.43 g, 1.3 mmol) was dissolve in
anhydrous dichloromethane (35 ml) and manganese dioxide (1.2 g, 13
mmol) was added. The reaction stirred at room temperature
overnight.
[0386] The reaction was filtered through diatomaceous earth and the
solvent was removed in vacuo to give
racemic-Ethyl-8-(4-methyl-1-piperazin-1-yl)-4-oxo-chroman-2-carboxylate
as a white solid (0.37 g, 86% yield) that was used as is in the
next reaction. GC/MS (EI, M+) m/z=318.
EXAMPLE 78c
racemic-Ethyl-8-(4-methyl-1-piperazin-1-yl)-4-hydroxy-chroman-2-carboxylat-
e
[0387] Ethyl
8-(4-methyl-1-piperazin-1-yl)-4-oxo-4H-chroman-2-carboxylate
(reference example 1) (0.48 g, 1.5 mmol) was dissolved in glacial
acetic acid (50 ml) and 10% palladium on carbon (100 mg) was added.
The mixture was hydrogenated on a Paar apparatus (50 psi) at
70.degree. C. for 3 h.
[0388] The reaction was allowed to cool, the catalyst was filtered
and the solution was concentrated in vacuo. Ethyl acetate/saturated
sodium bicarbonate was added to the remains and the mixture was
extracted (.times.3) with ethyl acetate, dried (MgSO.sub.4) and
stripped to give
racemic-Ethyl-8-(4-methyl-1-piperazin-1-yl)-4-hydroxy-chroman-2-carboxyla-
te (0.43 g, 90% yield) as a yellow oil. GC/MS (EI, M+) m/z=320.
EXAMPLE 79
[0389] ##STR235##
8-(4-Methyl-piperazin-1-yl)-4-oxo-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide (Faster Running Isomer)
[0390] The enantiomers of the
racemic-8-(4-methyl-piperazin-1-yl)-4-oxo-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide (Example 78) (100 mg, 0.22 mmol)
were separated by the use of a chiral column (ChiralPak AD, 5
cm.times.50 cm, 20.mu.). The isomers were eluted with a gradient of
35-55% isopropanol/hexane. The faster isomer was obtained as a
light yellow solid (40 mg, mp 216.degree. C. dec.) LC/MS (M+1)
m/z=451.
EXAMPLE 80
[0391] ##STR236##
8-(4-Methyl-piperazin-1-yl)-4-oxo-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide (Slower Running Isomer)
[0392] The enantiomers of the
racemic-8-(4-methyl-piperazin-1-yl)-4-oxo-chroman-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide (100 mg, 0.22 mmol) were separated
by the use of a chiral column (ChiralPak AD, 5 cm.times.50 cm,
20.mu.). The isomers were eluted with a gradient of 35-55%
isopropanol/hexane. The slower isomer was obtained as an off white
solid (32 mg, mp 215.degree. C. dec.) LC/MS (M+1) m/z=451.
EXAMPLE 81
[0393] ##STR237##
4-[4-({1-[6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromen-2-yl]-meth-
anoyl}-amino)-phenyl]-piperazine-1-carboxylic Acid Ethylamide
[0394]
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxyli-
c acid (4-piperazin-1-yl-phenyl)-amide (Example 71) (150 mg, 0.216
mmol) was placed in a 50 mL flask with 10 mL of CH.sub.2Cl.sub.2.
This suspension was treated with triethylamine (0.1 mL, 0.67 mmol)
and ethylisocyanate (0.21 mL, 18.7 mg, 0.26 mmol) and the reaction
stirred at room temperature for 18 hours. The reaction was
concentrated (1 mm Hg pressure) and the concentrate purified by
chromatography on silica eluting with 1% methanol in chloroform,
then concentrated (1 mm Hg pressure). Then triturated with either
to yield a yellow powder with was dried under high vacuum for 48 h
at 50.degree. C. (79 mg) LCMS-AP+537.4, mp=236-238.degree. C.
EXAMPLE 82
[0395] ##STR238##
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide
[0396] Into a 100 mL round bottom flask equipped with a nitrogen
inlet and magnetic stirrer is added 327 mg (0.89 mmol, 1.0 equiv.)
of
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid hydrochloride salt (Reference Example 23). This material is
dissolved in 20 mL of DMF and then 189 mg (1.06 mmol, 1.2 equiv.)
of 4-morpholinoaniline is added. To the stirred solution is quickly
added simultaneously added 568 mg (1.77 mmol, 2.0 equiv.) of TBTU
and 239 mg (1.77 mmol, 2.0 equiv.) of HOBT. At this point 457 mg,
577 .mu.L (25.2 mmol, 4.0 equiv.) is added via syringe over 5
minutes. The reaction is allowed to stir at room temperature for 18
hrs, then is concentrated on a rotary evaporator under high vacuum
in order to remove the DMF. The residue is triturated with methanol
and the crude solids are recovered by filtration. These residues
are then purified by flash chromatography using a gradient of 5-10%
methanol in methylene chloride as eluent. The eluted material,
which is obtained from chromatography, is concentrated, dried under
high vacuum, suspended in methylene chloride, dried over
K.sub.2CO.sub.3, concentrated, then crystallized from methanol to
give the free base of the pure product as 345 mg (79%) of a yellow
solid. Mass Spec.: calc. for
[C.sub.27H.sub.32FN.sub.4O.sub.5+H].sup.+ Theor. m/z=393;
Obs.=393
EXAMPLE 83
[0397] ##STR239##
6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide
[0398] Into a 100 mL flask equipped with a nitrogen inlet and
magnetic stirrer is placed 133 mg (0.748 mmol, 1.1 equiv.) of
4-morpholinoaniline, which is then dissolved in 20 mL of methylene
chloride. To this mixture is then added 290 mg, 367 .mu.L (2.24
mmol, 3.3 equiv.) of ethyldiisopropyl amine, followed by addition
of a solution of 250 mg (0.68 mmol, 1.0 equiv.) of
6-ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carbonyl
chloride (Reference Example 23) which has been dissolved in 10 ml
of methylene chloride. The reaction is allowed to stir for 4 hr,
after which no further formation of product was seen by LC/MS. The
crude reaction was concentrated on a rotary evaporator, then
triturated with 10 mL of methanol. The crude solids were collected
by filtration, then subjected to flash chromatography using a
gradient of from 2 to 20% methanol in methylene chloride.
Recrystallization from methylene chloride and hexanes afforded 55
mg (16%) of the pure product as a yellow solid.
[0399] Mass Spec.: calc. for
[C.sub.27H.sub.32N.sub.4O.sub.5+H].sup.+ Theor. m/z=493;
Obs.=493
EXAMPLE 84
[0400] ##STR240##
6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(4-propionyl-piperazin-1-yl)-phenyl)]-amide
[0401] This compound was prepared from 250 mg (0.68 mmol, 1.0
equiv.) of
6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carbonyl
chloride (Reference Example 23) and 175 mg (0.748 mmol, 1.1 equiv.)
of 1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-1-one by an
analogous procedure to that used to prepare the 4-morpholino
aniline derivative, to give 45 mg (12%) of the desired product as a
yellow solid.
[0402] Mass Spec.: calc. for
[C.sub.30H.sub.37N.sub.5O.sub.5+H].sup.+ Theor. m/z=548;
Obs.=548
EXAMPLE 85
[0403] ##STR241##
6-Methoxy-4-oxo-8-piperazin-1-yl-4H-chromene-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide
[0404] Into a 50 mL round bottom flask equipped with a reflux
condenser, nitrogen inlet and magnetic stirrer is placed 50 mg
(0.115 mmol, 1.0 equiv.) of
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide (Example 31) and 10 mL of 1, 2
dichloroethane. To this solution is then added via syringe 49 mg,
37 .mu.L (0.345 mmol, 3.0 equiv.) of 1-chloroethyl chloroformate. A
precipitate forms, indicating formation of an intermediate. The
reaction is heated to reflux for 3 days, whereupon an analysis of
an aliquot by LC/MS indicates only a trace of product has formed.
At this time 52 mg (0.345 mmol, 3.0 equiv.) of sodium iodide are
added to the refluxing reaction. LC/MS analyses then progressively
show formation of demethylated product over 5 additional days. The
reaction is then cooled, concentrated on a rotary evaporator, then
dried over K.sub.2CO.sub.3 as a suspension in methylene chloride
containing methanol, removal of solids by filtration, followed by
flash chromatography of the solution, using a gradient of 5 to 20%
methanol in methylene chloride, gives 34 mg (64%) of the pure
product as a reddish solid. Mass Spec.: calc. for
[C.sub.25H.sub.28N.sub.4O.sub.5+H].sup.+ Theor. m/z=465;
Obs.=465
EXAMPLE 86
[0405] ##STR242##
6-Hydroxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide
[0406] Into a 50 mL round bottom flask equipped with a reflux
condenser, nitrogen inlet and magnetic stirrer is placed 50 mg
(0.115 mmol, 1.0 equiv.) of
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide (Example 31) and 20 mL of
methylene chloride. To this solution is added 1 mL of a 1N solution
of boron tribromide in methylene chloride. The reaction is stirred
at room temperature for 2.5 days at which time it is complete by
LC/MS. The reaction is concentrated on a rotary evaporator, then
methanol is added. The methanol is concentrated and readded 5
times, until the BBr.sub.3 is removed as HBr and trimethyl borate.
The solid hydrobromide salt residue, which is obtained, is >85%
pure product by LC/MS. Mass Spec.: calc. for
[C.sub.25H.sub.28N.sub.4O.sub.5+H].sup.+ Theor. m/z=465;
obs.=465
EXAMPLE 87
Method 1
[0407] ##STR243##
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-1,4-dihydro-quinoline-2-ca-
rboxylic Acid (4-morpholin-4-yl-phenyl)-amide
[0408] To a solution of
6-methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-1,4-dihydro-quinoline-2-c-
arboxylic acid (2.10 mmol) (Reference Example 25b) and
diisopropylethyl amine (1.4 mL, 8.6 mmol) in 34 mL
dimethylformamide was added TBTU (1.40 g, 4.36 mmol) and HOBt
(0.588 g, 4.35 mmol) followed by the addition of
4-morpholinoaniline (0.463 g, 2.60 mmol). The resulting dark brown
solution was stirred at room temperature under nitrogen for 19
hours. The reaction was concentrated in vacuo and the resulting
crude product was taken up in methylene chloride/methanol.
Filtration of the resulting mixture afforded some product as a
yellow solid. The filtrates were concentrated and partitioned
between methylene chloride and saturated aqueous sodium
bicarbonate. The organic layer was washed with saturated sodium
bicarbonate, dried (MgSO4), and concentrated under vacuum to afford
a brown solid. This was suspended in methanol and filtered to
afford the desired product as a yellow solid (0.714 g, 69%).
.sup.1H NMR (300 MHz, DMSO, do) .delta. 9.97 (bs, 1H, NH), 7.67 (d,
2H, J.sub.o=8.8 Hz, ArH.sub.2'& H.sub.6'), 7.47 (bs, 1H,
ArH.sub.5), 7.00 (s, 1H, C.dbd.CH), 6.99 (d, 2H, J.sub.o=8.8 Hz,
ArH.sub.3'& H.sub.5'), 6.71 (bs, 1H, ArH.sub.7), 3.85 (s, 3H,
OCH.sub.3), 3.75 (t, 4H, J=4.6 Hz, OCH.sub.2CH.sub.2N), 3.70 (bs,
2H, ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3), 3.55 (bs, 2H,
ArNCH.sub.2CH.sub.2NCH.sub.3), 3.09 (t, 4H, J=4.6 Hz,
OCH.sub.2CH.sub.2N), 2.95 (bs, 2H, ArNCH.sub.2CH.sub.2NCH.sub.3),
2.73 (bs, 2H, ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3), 2.36 (s, 3H,
NCH.sub.3), 2.07 (bs, 2H ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3);
Mass Spec.: calc. for [C.sub.27H.sub.33N.sub.5O.sub.4+H].sup.+
Theor. m/z=492; Obs. 492.
EXAMPLE 87
Method 2
[0409] ##STR244##
6-Methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-oxo-1,4-dihydro-quinoline-2-ca-
rboxylic acid (4-morpholin-4-yl-phenyl)-amide
[0410] A solution of
6-methoxy-8-(4-methyl-[1,4]diazepan-1-yl)-4-(2-trimethylsilanyl-ethoxymet-
hoxy)-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide
(Reference Example 27d) (0.989 g, 1.59 mmol) in 20 mL methanol was
poured into 300 mL 0.05 N hydrochloric acid. The clear dark yellow
solution became cloudy within 5 minutes. The mixture was stirred at
room temperature for 45 minutes and then adjusted to pH 7 with 10%
sodium hydroxide. The resulting yellow precipitate was isolated by
filtration, washed with water, and dried under high vacuum to
afford the desired product as a yellow solid (0.629 g, 80%).
.sup.1H NMR (300 MHz, DMSO, d.sub.6) .delta. 9.97 (bs, 1H,C(O)NH),
7.67 (d, 2H, J.sub.o=8.8 Hz, ArH.sub.2'& H.sub.6'), 7.47 (bs,
1H, ArH.sub.5), 7.00 (s, 1H, C.dbd.CH), 6.99 (d, 2H, J.sub.o=8.8
Hz, ArH.sub.3'& H.sub.5'), 6.71 (bs, 1H, ArH.sub.7), 3.85 (s,
3H, OCH.sub.3), 3.75 (t, 4H, J=4.6 Hz, OCH.sub.2CH.sub.2N), 3.70
(bs, 2H, ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3), 3.55 (bs, 2H,
ArNCH.sub.2CH.sub.2NCH.sub.3), 3.09 (t, 4H, J=4.6 Hz,
OCH.sub.2CH.sub.2N), 2.95 (bs, 2H, ArNCH.sub.2CH.sub.2NCH.sub.3),
2.73 (bs, 2H, ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3), 2.36 (s, 3H,
NCH.sub.3), 2.07 (bs, 2H ArNCH.sub.2CH.sub.2CH.sub.2NCH.sub.3);
Mass Spec.: calc. for [C.sub.27H.sub.33N.sub.5O.sub.4+H].sup.+
Theor. m/z=492; Obs.=492. Analysis for
C.sub.27H.sub.33N.sub.5O.sub.4.1.0 eqHCl. 0.3 eqH.sub.2O:
Calculated C, 60.79; H, 6.54; N, 13.13. Found C, 60.82; H, 6.53; N,
13.17.
EXAMPLE 88
[0411] ##STR245##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-2-carbox-
ylic acid (4-morpholin-4-yl-phenyl)-amide
[0412] The title compound was prepared from
8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carbox-
ylic acid methyl ester (Reference Example 24c) according to the
procedures described in Reference Example 25a and in Example 87
(Method 1). A yellow solid was obtained. Mass Spec.: calc. for
[C.sub.26H.sub.31N.sub.5O.sub.4+H].sup.+ Theor. m/z=478; Obs.
478.
EXAMPLE 89
[0413] ##STR246##
6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-2-carbox-
ylic acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide
[0414] The title compound was prepared from
8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carbox-
ylic acid methyl ester (Reference Example 24c) according to the
procedures described in Reference Example 25a and in Example 87
(Method 1), except that the amide was formed from
1-[4-(4-amino-phenyl)-piperazin-1-yl]-propan-1-one. A yellow solid
was obtained. Mass Spec.: calc. for
[C.sub.29H.sub.36N.sub.6O.sub.4+H].sup.+ Theor. m/z=533; Obs.
533.
EXAMPLE 90
[0415] ##STR247##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-2-carboxy-
lic acid (4-morpholin-4-yl-phenyl)-amide
[0416] The title compound was prepared from
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-2-carbox-
ylic acid hydrochloride salt (Reference Example 26) using the
procedure described in Example 87 (Method 1). After chromatography,
it is then crystallized from methanol to give the pure product as
150 mg (55%) of a yellow solid. Mass Spec.: calc. for
[C.sub.25H.sub.28FN.sub.5O.sub.3+H].sup.+ Theor. m/z=466;
Obs.=466.
EXAMPLE 91
[0417] ##STR248##
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-2-carboxy-
lic acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide
[0418] The title compound was prepared from
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-2-carbox-
ylic acid hydrochloride salt (200 mg, 0.59 mmol) (Reference Example
26) using the procedure described in Example 87 (Method 1). 31%
yield. Mass Spec.: calc. for
[C.sub.28H.sub.33FN.sub.6O.sub.3+H].sup.+ Theor. m/z=521;
Obs.=521.
EXAMPLE 92
[0419] ##STR249##
8-[(2-Dimethylamino-ethyl)-methyl-amino]-6-methoxy-4-oxo-1,4-dihydro-quino-
line-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide
[0420] The title compound was prepared from
8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carbox-
ylic acid methyl ester (Reference Example 24c) according to the
procedures described in Reference Example 25a and in Example 87
(Method 2), using N,N,N'-trimethyl ethylenediamine for the Pd
catalysed coupling. A yellow solid was obtained. Mass Spec.: calc.
for [C.sub.26H.sub.33N.sub.5O.sub.4+H].sup.+ Theor. m/z=480;
Obs.=480.
EXAMPLE 93
[0421] ##STR250##
8-[(3-Dimethylamino-propyl)-methyl-amino]-6-methoxy-4-oxo-1,4-dihydro-quin-
oline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide
[0422] The title compound was prepared from
8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carbox-
ylic acid methyl ester (Reference Example 24c) according to the
procedures described in Reference Example 25a and in Example 87
(Method 2), using N,N,N'-trimethyl-1,3-propanediamine for the Pd
catalysed coupling. A yellow solid was obtained. Mass Spec.: calc.
for [C.sub.27H.sub.35N.sub.5O.sub.4+H].sup.+ Theor. m/z=494;
Obs.=494.
EXAMPLE 94
[0423] ##STR251##
8-((3R)-(+)-3-Dimethylamino-pyrrolidin-1-yl)-6-methoxy-4-oxo-1,4-dihydro-q-
uinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide
[0424] The title compound was prepared from
8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carbox-
ylic acid methyl (Reference Example 24c) according to the
procedures described in Reference Example 25a and in Example 87
(Method 2), using (3R)-(+)-3-(dimethylamino)pyrrolidine for the Pd
catalysed coupling. A yellow solid was obtained. Mass Spec.: calc.
for [C.sub.27H.sub.33N.sub.5O.sub.4+H].sup.+ Theor. m/z=492;
Obs.=492.
EXAMPLE 95
[0425] ##STR252##
8-((3S)-(-)-3-Dimethylamino-pyrrolidin-1-yl)-6-methoxy-4-oxo-1,4-dihydro-q-
uinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide
[0426] The title compound was prepared from
8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carbox-
ylic acid methyl ester (Reference Example 24c) according to the
procedures described in Reference Example 25a and in Example 87
(Method 2), using (3S)-(-)-3-(dimethylamino)pyrrolidine for the Pd
catalysed coupling. A yellow solid was obtained. Mass Spec.: calc.
for [C.sub.27H.sub.33N.sub.5O.sub.4+H].sup.+ Theor. m/z=492;
Obs.=492.
EXAMPLE 96
[0427] ##STR253##
6-Methoxy-8-[methyl-(1-methyl-pyrrolidin-3-yl)-amino]-4-oxo-1,4-dihydro-qu-
inoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide
[0428] The title compound was prepared from
8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carbox-
ylic acid methyl ester (Reference Example 24c) according to the
procedures described in Reference Example 25a and in Example 87
(Method 2), using N,N'-dimethyl-3-aminopyrrolidine for the Pd
catalysed coupling. A yellow solid was obtained. Mass Spec.: calc.
for [C.sub.27H.sub.33N.sub.5O.sub.4+H].sup.+ Theor. m/z=492;
Obs.=492.
EXAMPLE 97
[0429] ##STR254##
8-[Ethyl-(1-ethyl-pyrrolidin-3-yl)-amino]-6-methoxy-4-oxo-1,4-dihydro-quin-
oline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide
[0430] The title compound was prepared from
8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carbox-
ylic acid methyl ester (Reference Example 24c) according to the
procedures described in Reference Example 25a and in Example 87
(Method 2), using 3-diethylaminopyrrolidine for the Pd catalyzed
coupling. A yellow solid was obtained. Mass Spec.: calc. for
[C.sub.29H.sub.37N.sub.5O.sub.4+H].sup.+ Theor. m/z=520;
Obs.=520.
EXAMPLE 98
[0431] ##STR255##
4-Dimethylamino-6-methoxy-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxyl-
ic acid (4-morpholin-4-yl-phenyl)-amide
[0432] To a suspension of
8-bromo-4-dimethylamino-6-methoxy-quinoline-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide (Reference Example 28b) (139.9 mg,
0.288 mmol), N-methylpiperazine (48 .mu.L, 0.43 mmol), and 4 .ANG.
sieves in 15 mL anhydrous toluene was added Pd.sub.2 (dba).sub.2
(15.3 mg, 16.7 .mu.mol), BINAP (63.0 mg, 0.101 mmol) and cesium
carbonate (0.436 g, 1.345 mmol). The resulting wine colored mixture
was heated at reflux under nitrogen for 20 hours. The reaction
mixture was cooled to room temperature and concentrated. The crude
mixture was purified by flash chromatography on silica gel using a
gradient of 100:0 to 95:5 methylene chloride:methanol to afford the
desired product as a yellow solid (96.9 mg, 67%). .sup.1H NMR (300
MHz, DMSO, d.sub.6) .delta. 10.06 (s, 1H, C(O)NH), 7.69 (d, 2H,
J.sub.m=9.0 Hz, ArH.sub.2'& H.sub.6'), 7.58 (s, 1H, ArH.sub.3),
7.58 (d, 2H, J.sub.o=9.0 Hz, ArH.sub.3'& H.sub.5'), 6.95 (d,
1H, J.sub.m=2.7 Hz, ArH.sub.5), 6.76 (d, 1H, J.sub.m=2.7 Hz,
ArH.sub.7), 3.90 (s, 3H, OCH.sub.3), 3.75 (t, 4H, J=4.8 Hz,
OCH.sub.2CH.sub.2N), 3.37 (bs, 4H, ArNCH.sub.2CH.sub.2N), 3.10 (t,
4H, J=4.8 Hz, OCH.sub.2CH.sub.2N), 3.01 (s, 6H, N(CH.sub.3).sub.2),
2.71 (bs, 4H, ArNCH.sub.2CH.sub.2N), 2.35 (s, 3H,
R.sub.2NCH.sub.3); Mass Spec.: calc. for
[C.sub.28H.sub.36N.sub.6O.sub.3+H].sup.+ Theor. m/z=505;
Obs.=505.5.
EXAMPLE 99
[0433] ##STR256##
6-Methoxy-4-methylamino-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide
[0434] The title compound was prepared from
8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid
(Reference Example 27b) according to the procedure described for
Example 98 using N-methyl amine to prepare
8-bromo-4-methylamino-6-methoxy-quinoline-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide. A glassy orange solid was
obtained. Mass Spec.: calc. for
[C.sub.27H.sub.34N.sub.6O.sub.3+H].sup.+ Theor. m/z=491;
Obs.=491.5.
EXAMPLE 100
[0435] ##STR257##
6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylic
acid (4-morpholin-4-yl-phenyl)-amide
[0436] Into a 250 mL round bottom flask equipped with a nitrogen
inlet and magnetic stirrer is added 2.01 g (6.3 mmol, 1.0 equiv.)
of
6-Fluoro-4-methoxy-8-(4-methyl-piperazin-1-yl)-quinoline-2-carboxylic
acid hydrochloride salt. This material is dissolved in 20 mL of DMF
and then 1.35 g (7.56 mmol, 1.2 equiv.) of 4-morpholinoaniline is
added. To the stirred solution is quickly added simultaneously
added 4.05 g (12.6 mmol, 2.0 equiv.) of TBTU
(2-(1H-benzotriazole-1-yl)-1,1,3,3tetramethyluroniumtetrafluoroborate)
and 1.7 g (12.6 mmol, 2.0 equiv.) of HOBT (1-hydroxybenzotriaole
hydrate). At this point 3.25 g, 4.11 mL (25.2 mmol, 4.0 equiv.) is
added via syringe over 5 minutes. The reaction is allowed to stir
at room temperature for 18 hrs, then is concentrated on a rotary
evaporator under high vacuum in order to remove the DMF. The
residue is triturated with methanol and the crude solids are
recovered by filtration. The material is then dissolved in
methylene chloride and extracted with 10% sodium bicarbonate
solution. The organic layer is dried and then concentrated. These
residues are then purified by flash chromatography using a gradient
of 5-10% methanol in methylene chloride as eluent. The material
which is obtained from chromatography, is then crystallized from
methanol to give the pure product as 2.83 g (93%) of a yellow
solid.
[0437] Mass Spec.: calc. for
[C.sub.26H.sub.30FN.sub.5O.sub.3+H].sup.+ Theor. m/z=480;
Obs.=480
EXAMPLE 101
6-Fluoro-4-oxo-8-piperazin-1-yl-4H-chromene-2-carboxylic acid
(4-morpholin-4-yl-phenyl)-amide
Made According to the General Method of Howarth et. al.
Tetrahedron, 1998, 54, 10899-10914
[0438] Dry
6-fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic
acid [4-(4-propionyl-piperazin-1-yl)-phenyl]-amide (Example 72) (1
g 1.9 mmol) was added to 100 mL of rigorously dried
1,2-dichloroethane in a flask under N.sub.2 atmosphere and magnetic
stirring. The mixture was cooled to 0.degree. C. and freshly
distilled 1-chloroethyl chloroformate (650 ul, 858 mg, 6 mmol, 3
eq) was added drop wise. The reaction was then heated under reflux
for 5 hours at which time LC/MS revealed complete consumption of
starting material. NaI (1 g, 1 eq) was added and heating continued
for 2 days more. The reaction was then allowed to cool and filtered
and evaporated to dryness under reduced pressure. MeOH (100 mL) was
added and heated to reflux for 4 h, filtered hot and evaporated to
dryness. The product was isolated by chromatography using silica
gel and CHCl3/5% MeOH as an eluent. This gave 700 mg of the product
HCl salt as a yellow solid. LCMS-m/z=508.
* * * * *