U.S. patent application number 10/807918 was filed with the patent office on 2005-05-05 for substituted indian derivatives.
Invention is credited to Berg, Stefan, Florvall, Lennart, Ross, Svante, Thorberg, Seth-Olov.
Application Number | 20050096326 10/807918 |
Document ID | / |
Family ID | 20408299 |
Filed Date | 2005-05-05 |
United States Patent
Application |
20050096326 |
Kind Code |
A1 |
Berg, Stefan ; et
al. |
May 5, 2005 |
Substituted indian derivatives
Abstract
The present invention relates to new piperidyl- or
piperazinyl-substituted indan derivatives of the formula I 1 as
(R)-enantiomers, (S)-enantiomers, or racemates in the form of a
free base or pharmaceutically acceptable salts or solvates thereof.
The present invention further relates to a process for the
preparation of the compounds, to pharmaceutical compositions
containing the compounds and to methods of treatment of
5-hydroxytryptamine-mediated disorders comprising administering the
compounds.
Inventors: |
Berg, Stefan; (Ekero,
SE) ; Florvall, Lennart; (Sodertalje, SE) ;
Ross, Svante; (Sodertalje, SE) ; Thorberg,
Seth-Olov; (Strangnas, SE) |
Correspondence
Address: |
WHITE & CASE LLP
PATENT DEPARTMENT
1155 AVENUE OF THE AMERICAS
NEW YORK
NY
10036
US
|
Family ID: |
20408299 |
Appl. No.: |
10/807918 |
Filed: |
March 24, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10807918 |
Mar 24, 2004 |
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10339477 |
Jan 9, 2003 |
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10339477 |
Jan 9, 2003 |
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09171575 |
Oct 21, 1998 |
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6548498 |
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09171575 |
Oct 21, 1998 |
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PCT/SE98/01605 |
Sep 9, 1998 |
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Current U.S.
Class: |
514/252.13 ;
514/255.03; 514/319; 514/326; 544/359; 546/205 |
Current CPC
Class: |
A61P 25/14 20180101;
A61P 25/16 20180101; A61P 25/34 20180101; A61P 25/28 20180101; A61P
3/04 20180101; C07D 295/155 20130101; C07D 295/135 20130101; A61P
35/00 20180101; A61P 15/10 20180101; A61P 1/04 20180101; A61P 25/32
20180101; A61P 29/00 20180101; A61P 9/12 20180101; A61P 25/00
20180101; A61P 25/18 20180101; A61P 25/06 20180101; A61P 15/00
20180101; A61P 9/10 20180101; A61P 25/22 20180101 |
Class at
Publication: |
514/252.13 ;
514/255.03; 514/319; 514/326; 544/359; 546/205 |
International
Class: |
A61K 031/496; A61K
031/495; A61K 031/454 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 18, 1997 |
SE |
9703379-9 |
Claims
1. A compound having of the formula I 9wherein X is CH; Y is
NR.sub.2CH.sub.2, CH.sub.2NR.sub.2, NR.sub.2CO, CONR.sub.2 or
NR.sub.2SO.sub.2 wherein R.sub.2 is H or C.sub.1-C.sub.6 alkyl;
R.sub.1 is H, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl;
R.sub.3 is C.sub.1-Cr alkyl, C.sub.3-C.sub.6 cycloalkyl or
(CH.sub.2).sub.n-aromatic ring, wherein the aromatic ring is phenyl
or a heteroaromatic ring containing one or two heteroatoms selected
from the group consisting of N, O and S and wherein the aromatic
ring may be mono- or di-substituted with R.sub.4 and/or R.sub.5;
wherein R.sub.4 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, halogen, CN, CF.sub.3, OH, C.sub.1-C.sub.6 alkoxy,
NR.sub.6R.sub.7, OCF.sub.3, SO.sub.3CH.sub.3, SO.sub.3CF.sub.3,
SO.sub.2NR.sub.6R.sub.7, phenyl, phenyl-C.sub.1-C.sub.6 alkyl,
phenoxy, C.sub.1-C.sub.6 alkylphenyl, an optionally substituted
heterocyclic ring containing one or two heteroatoms selected from
the group consisting of N, O, S, SO and SO.sub.2 wherein the
substituent(s) is(are) selected from the group consisting of
C.sub.1-C.sub.6 alkyl C.sub.3-C.sub.6 cycloalkyl and
phenyl-C.sub.1-C.sub.6 alkyl, an optionally substituted
heteroaromatic ring containing one or two heteroatoms selected from
the group consisting of N, O and S, wherein the substituent(s) is
(are) selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl and phenyl-C.sub.1-C.sub.6 alkyl, or
COR.sub.8; wherein R.sub.6 is H, C.sub.1-C.sub.6 alkyl or
C.sub.3-C.sub.6 cycloalkyl; R.sub.7 is H, C.sub.1-C.sub.6 alkyl or
C.sub.3-C.sub.6 cycloalkyl; and R.sub.8 is C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, CF.sub.3, NR.sub.6R.sub.7, phenyl, a
heteroaromatic ring containing one or two heteroatoms selected from
the group consisting of N, O and S, or a heterocyclic ring
containing one or two heteroatoms selected from the group
consisting of N, O, S, SO and SO.sub.2; wherein R.sub.5 is H, OH,
CF.sub.3, OCF.sub.3, halogen, C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.6 alkoxy; n is 0-4; R.sub.9 is H, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, halogen, CN, CF.sub.3, OH, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkoxy-C.sub.1-C.sub.6 alkyl, NR.sub.6R.sub.7,
SO.sub.3CH.sub.3, SO.sub.3CF.sub.3, SO.sub.2NR.sub.6R.sub.7, an
unsubstituted or substituted heterocyclic or heteroaromatic ring
containing one or two heteroatoms selected from the group
consisting of N, O and S, wherein the substituent(s) is(are)
C.sub.1-C.sub.6 alkyl; or COR.sub.8; wherein R.sub.6, R.sub.7 and
R.sub.8 are as defined above, wherein the compound is an
(R)-enantiomer, an (S)-enantiomer, or a racemate in the form of a
free base or a pharmaceutically acceptable salt or solvate
thereof.
2. The compound according to claim 1 wherein Y is NR.sub.2CO or
CONR.sub.2.
3. (canceled)
4. The compound according to claim 1 wherein R.sub.1 is H or
C.sub.1-C.sub.6 alkyl.
5. The compound according claim 1 wherein R.sub.3 is
(CH.sub.2).sub.n-aromatic ring.
6. The compound according to claim 5 wherein the aromatic ring of
substituent R.sub.3 is substituted with R.sub.4, and R.sub.4 is an
optionally substituted heterocyclic or heteroaromatic ring
containing one or two heteroatoms selected from the group
consisting of N, O and S; or COR.sub.8.
7. The compound according to claim 5 or 6 wherein n is 0.
8. The compound according to claim 6 wherein R.sub.8 is
NR.sub.6R.sub.7 or a heterocyclic ring containing two heteroatoms
selected from N and 0.
9. The compound according to claim 1 wherein R.sub.9 is H,
C.sub.1-C.sub.6 alkyl, OCHF.sub.2, halogen or C.sub.1-C.sub.6
alkoxy.
10. The compound according to claim 1 wherein Y is NR.sub.2CO and
R.sub.9 is C.sub.1-C.sub.6 alkoxy.
11. The compound according to claim 10 wherein R.sub.4 is
morpholino or COR.sub.8.
12. The compound according to claim 1 wherein Y is NR.sub.2CO and
R.sub.9 is C.sub.1-C.sub.6 alkyl.
13. The compound according to claim 12 wherein R.sub.4 is
morpholino or COR.sub.8.
14. The compound according to claim 1 wherein Y is NR.sub.2CO and
R.sub.9 is H.
15. The compound according to claim 14 wherein R.sub.4 is
morpholino or COR.sub.8.
16. (canceled)
17. A pharmaceutical formulation comprising as active ingredient a
therapeutically effective amount of the compound of claim 1,
wherein the compound is an enantiomer or racemate in the form of a
free base or a pharmaceutically acceptable salt or solvate thereof
optionally in association with diluents, excipients or inert
carriers.
18. A method for the treatment of 5-hydroxytryptamine-mediated
disorders, comprising administering to a patient in need of such
treatment a therapeutically effective amount of the pharmaceutical
formulation of claim 17.
19. A method for the treatment of mood disorders, anxiety
disorders, personality disorders, obesity, anorexia, bulimia,
premenstrual syndrome, sexual disturbances, alcoholism, tobacco
abuse, autism, attention deficit, hyperactivity disorder, migraine,
memory disorders, pathological aggression, schizophrenia, endocrine
disorders, stroke, dyskinesia, Parkinson's disease,
thermoregulatory disorders, pain, hypertension, urinary
incontinence or vasospasm; or for inhibition of tumor growth,
comprising administering to a patient in need of such treatment a
therapeutically effective amount of the pharmaceutical formulation
of claim 17.
20. (canceled)
21. A method for the treatment of 5-hydroxytryptamine-mediated
disorders in the central nervous system, comprising administering
to a patient in need of such treatment a therapeutically effective
amount of the pharmaceutical formulation of claim 17.
22-29. (canceled)
30. A method for the treatment of 5-hydroxytryptamine-mediated
disorders in the central nervous system and/or urinary incontinence
or vasospasm, or for inhibition of tumor growth, comprising
administering to a patient in need of such treatment a
therapeutically effective amount of a compound defined in claim
1.
31. The method according to claim 30 for the treatment of mood
disorders, anxiety disorders, personality disorders, obesity,
anorexia, bulimia, premenstrual syndrome, sexual disturbances,
alcoholism, tobacco abuse, autism, attention deficit, hyperactivity
disorder, migraine, memory disorders, pathological aggression,
schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's
disease, thermoregulatory disorders, pain or hypertension.
32. (canceled)
33. A method for the treatment of 5-hydroxytryptamine-mediated
disorders which require treatment with an h5-HT.sub.1B antagonist,
comprising administering to a patient in need of such treatment a
therapeutically effective amount of a compound defined in claim
1.
34. A process for the preparation of the compound of formula I
according to claim 1, comprising reacting, in the case wherein Y is
CONR.sub.2 and R.sub.1, R.sub.2, R.sub.3 and R.sub.9 are as defined
in claim 1, a compound of formula A 10with a compound of formula
VII, wherein X is a leaving group.
35. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to new piperidyl- or
piperazinyl-substituted indan derivatives as (R)-enantiomers,
(S)-enantiomers or racemates in the form of free base or
pharmaceutically acceptable salts or solvates thereof, a process
for their preparation, pharmaceutical compositions containing said
therapeutically active compounds and to the use of said active
compounds in therapy.
[0002] An object of the invention is to provide compounds for
therapeutic use, especially compounds having a selective effect at
a subgroup of 5-hydroxytryptamine receptors, designated the
h5-HT.sub.1B-receptor (previously called the
5-HT.sub.1D.beta.-receptor) in mammals including man.
[0003] It is also an object of the invention to provide compounds
with a therapeutic effect after oral administration.
BACKGROUND OF THE INVENTION
[0004] Various central nervous system disorders such as depression,
anxiety, etc. appear to involve the disturbance of the
neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine
(5-HT), the latter also known as serotonin. The drugs most
frequently used in the treatment of depression are believed to act
by improving the neurotransmission of either or both of these
physiological agonists. It appears that the enhancement of 5-HT
neurotransmission primarily affects the depressed mood and anxiety,
whereas the enhancement of noradrenaline neurotransmission affects
the retardation symptoms occurring in depressed patients. The
invention concerns compounds which have an effect on 5-HT
neurotransmission.
[0005] Serotonin, or 5-HT, activity is believed to be involved in
many different types of psychiatric disorders. For instance it is
believed that an increase in 5-HT activity is associated with
anxiety, while a decrease in 5-HT release is associated with
depression. Serotonin has in addition been implicated in such
diverse conditions as eating disorders, gastrointestinal disorders,
cardiovascular regulation disorders and sexual disturbances.
[0006] The 5-HT Receptors
[0007] The various effects of 5-HT may be related to the fact that
serotonergic neurons stimulate the secretion of several hormones,
e.g. cortisol, prolactin, .beta.-endorphin, vasopressin and others.
The secretion of each of these other hormones appears to be
regulated on a specific basis by several different 5-HT (serotonin)
receptor subtypes. With the aid of molecular biology techniques, to
date these receptors have been classified as 5-HT.sub.1,
5-HT.sub.2, 5-HT.sub.3, 5-HT.sub.4, 5-HT.sub.5, 5-HT.sub.6 and
5-HT.sub.7 with the 5-HT.sub.1 receptor further divided into the
5-HT.sub.1A, 5-HT.sub.1B, 5-HT.sub.1D, 5-HT.sub.1E and 5-HT.sub.1F
subtypes. Each receptor subtype is involved in a different
serotonin function and has different properties.
[0008] Regulation of the 5-HT Transmission
[0009] The release of 5-HT is feedback-regulated by two different
subtypes of 5-HT receptors. Inhibitory 5-HT.sub.1A autoreceptors
are located on the cell bodies in the raphe nuclei which upon
stimulation by 5-HT decrease the impulse propagation in the 5-HT
neurons and thereby reducing the 5-HT released at the nerve
terminals. Another subtype of inhibitory 5-HT receptors is located
on the 5-HT nerve terminals, the h5-HT.sub.1B receptors (in rodents
the r5-HT.sub.1B receptors) which regulate the synaptic
concentration of 5-HT by controlling the amount of 5-HT that is
released. An antagonist of these terminal autoreceptors thus
increases the amount of 5-HT released by nerve impulses which has
been shown in both in vitro and in vivo experiments.
[0010] The use of an antagonist of the terminal h5-HT.sub.1B
autoreceptor will accordingly increase the synaptic 5-HT
concentration and enhance the transmission in the 5-HT system. It
would thus produce an antidepressant effect making it useful as a
medication for depression.
[0011] Other localizations of h5-HT.sub.1B receptor subtype also
exist. A large part of these postsynaptic receptors appear to be
located on nerve terminals of other neuronal systems (so called
heteroreceptors). Since the h5-HT.sub.1B receptor mediates
inhibitory responses an antagonist of this receptor subtype might
also increase the release of other neurotransmitters than 5-HT.
[0012] Compounds having h5-HT.sub.1B activity may according to well
known and recognised pharmacological tests be divided into full
agonists, partial agonists and antagonists.
DISCLOSURE OF THE INVENTION
[0013] The object of the present invention is to provide compounds
having a selective effect at the h5-HT.sub.1B receptor, preferably
antagonistic properties, as well as having a good bioavailability.
The effect on the other receptors chosen from, for example, the
5-HT.sub.1A, 5-HT.sub.2A, D.sub.1, D.sub.2A, D.sub.3, .alpha..sub.1
and .alpha..sub.2 receptor has been investigated.
[0014] Accordingly, the present invention provides compounds of the
formula I 2
[0015] wherein
[0016] X is N or CH;
[0017] Y is NR.sub.2CH.sub.2, CH.sub.2NR.sub.2, NR.sub.2CO,
CONR.sub.2 or NR.sub.2SO.sub.2 wherein R.sub.2 is H or
C.sub.1-C.sub.6 alkyl;
[0018] R.sub.1 is H, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6
cycloalkyl;
[0019] R.sub.3 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl
or (CH.sub.2).sub.n-aryl,
[0020] wherein aryl is phenyl or a heteroaromatic ring containing
one or two heteroatoms selected from N, O and S and which may be
mono- or disubstituted with R.sub.4 and/or R.sub.5;
[0021] wherein R.sub.4 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, halogen, CN, CF.sub.3, OH, C.sub.1-C.sub.6-alkoxy,
NR.sub.6R.sub.7, OCF.sub.3, SO.sub.3CH.sub.3, SO.sub.3CF.sub.3,
SO.sub.2NR.sub.6R.sub.7, phenyl, phenyl-C.sub.1-C.sub.6 alkyl,
phenoxy, C.sub.1-C.sub.6 alkylphenyl, an optionally substituted
heterocyclic ring containing one or two heteroatoms selected from
N, O, S, SO and SO.sub.2 wherein the substituent(s) is(are)
selected from C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl and
phenyl-C.sub.1-C.sub.6 alkyl, an optionally substituted
heteroaromatic ring containing one or two heteroatoms selected from
N, O and S herein the substituent(s) is(are) selected from
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl and
phenyl-C.sub.1-C.sub.6 alkyl, or COR.sub.8;
[0022] wherein R.sub.6 is H, C.sub.1-C.sub.6 alkyl or
C.sub.3-C.sub.6 cycloalkyl;
[0023] R.sub.7 is H, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6
cycloalkyl; and
[0024] R.sub.8 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl
CF.sub.3, NR.sub.6R.sub.7, phenyl, a heteroaromatic ring containing
one or two heteroatoms selected from N, O and S or a heterocyclic
ring containing one or two heteroatoms selected from N, O, S, SO
and SO.sub.2;
[0025] wherein R.sub.5 is H, OH, CF.sub.3, OCF.sub.3, halogen,
C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 alkoxy;
[0026] n is 0-4;
[0027] R.sub.9 is H, C I--C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyL
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, halogen, CN, CF.sub.3, OH,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxy- C.sub.1-C.sub.6
alkyl, NR.sub.6R.sub.7, SO.sub.3CH.sub.3, SO.sub.3CF.sub.3,
SO.sub.2NR.sub.6R.sub.7, an unsubstituted or substituted
heterocyclic or heteroaromatic ring containing one or two
heteroatoms selected from N, O and S wherein the substituent(s)
is(are) C.sub.1-C.sub.6 alkyl; or COR.sub.8; wherein R.sub.6,
R.sub.7 and R.sub.8 are as defined above,
[0028] as (R)-enantiomers, (S)-enantiomers or a racemate in the
form of a free base or a pharmaceutically acceptable salt or
solvate thereof which possess a high selective effect at the
h5-HT.sub.1B receptor and also show sufficient bioavailability
after oral administration.
[0029] In the present context C.sub.1-C.sub.6 alkyl may be straight
or branched. C.sub.1-C.sub.6 alkyl may be methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl,
t-pentyl, neo-pentyl, n-hexyl or i-hexyl.
[0030] In the present context C.sub.1-C.sub.6 alkoxy may be
straight or branched. C.sub.1-C.sub.6 alkoxy may be methoxy,
ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy,
t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy, neo-pentyloxy,
n-hexyloxy or i-hexyloxy.
[0031] In the present context C.sub.3-C.sub.6 cycloalkyl may be
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
[0032] In the present context halogen may be fluoro, chloro, bromo
or iodo.
[0033] In the present context the heteroaromatic ring containing
one or two heteroatoms selected from N, O and S preferably is a 5-
or 6-membered heteroaromatic ring and may be furyl, imidazolyl,
isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl,
pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl or thienyl.
The heteroaromatic ring can be either substituted or
unsubstituted.
[0034] In the present context the heterocyclic ring containing one
or two heteroatoms selected from N, O, S, SO and SO.sub.2 may
optionally contain a carbonyl function and is preferably a 5-, 6-
or 7-membered heterocyclic ring and may be imidazolidinyl,
imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl,
pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,
tetrahydropyranyl, thiomorpholinyl, preferably piperidim),
1-piperazinyl, morpholino, thiomorpholino and 4-piperidon-1-yl.
[0035] A preferred embodiment of the invention relates to compounds
of formula I wherein Y is NHCO or CONH i.e. amides. Of these
compounds, the compounds wherein R.sub.9 is H, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, OCHF.sub.2 or OCH.sub.2F and R.sub.3
is unsubstituted phenyl, or mono- or di-substituted phenyl, and
especially ortho-, meta- or para-substituted phenyl, and
particularly these wherein the substituent R.sub.4 is phenyl,
phenyl-C.sub.1-C.sub.6 alkyl, cyclohexyl, piperidino,
1-piperazinyl, morpholino, CF.sub.3, 4-piperidon-1-yl, n-butoxy or
COR.sub.8 wherein R.sub.8 is phenyl, cyclohexyl, 4-piperidon-1-yl,
1-piperazinyl, morpholino, CF.sub.3, piperidino or NR.sub.6R.sub.7,
are preferred.
[0036] Examples of Combinations of Substituents Are:
[0037] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0038] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 and R.sub.9
are H;
[0039] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is phenyl, phenylmethyl or phenylethyl, R.sub.5 is H,
R.sub.9 is OCH.sub.3;
[0040] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or
phenylethyl, R.sub.5 and R.sub.9 are H;
[0041] X is CH, Y is CONR.sub.2, R is H, CH.sub.3, C.sub.2H.sub.5
or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is CH.sub.2-phenyl,
R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0042] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H,
R.sub.9 is OCH.sub.3;
[0043] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is piperidino, R.sub.5 and R.sub.9 are H;
[0044] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.9 is OCH.sub.3;
[0045] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0046] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or phenylethyl,
R.sub.5 and R.sub.9 are H;
[0047] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0048] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is piperidino, R.sub.5 and R.sub.9 are H;
[0049] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3, C.sub.2Hs
or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0050] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.5 and R.sub.9 are H;
[0051] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or phenylethyl,
R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0052] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.5 and R.sub.9 are H;
[0053] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0054] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H,
R.sub.9 is OCH.sub.3;
[0055] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or phenylethyl,
R.sub.5 and R.sub.9 are H;
[0056] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0057] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is morpholino, R.sub.5 and R.sub.9 are H;
[0058] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is COR.sub.8. R.sub.8 is cyclohexyl, R.sub.9 is CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0059] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is morpholino, R.sub.5 and R.sub.9 are H;
[0060] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is
OCH3;
[0061] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7.
[0062] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H,
R.sub.9 is OCH.sub.3;
[0063] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is piperidino, R.sub.5 is H, R.sub.5 is OCH.sub.3;
[0064] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is piperidino, R.sub.5 and R.sub.9 are H;
[0065] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is phenyl, phenylmethyl or phenylethyl, R.sub.5 is H,
R.sub.9 is OCH.sub.3;
[0066] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 and R.sub.9 are
H;
[0067] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is
OCH.sub.3;
[0068] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or
phenylethyl, R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0069] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 and R.sub.9 are
H;
[0070] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.9 is OCH.sub.3;
[0071] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 and R.sub.9
are H;
[0072] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0073] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.9 is H;
[0074] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H, R.sub.9, is
OCH.sub.3;
[0075] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R is morpholino, R.sub.5 and R.sub.9 are H;
[0076] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is phenyl, phenylmethyl or phenylethyl, R.sub.5 is H,
R.sub.9 is OCH.sub.3;
[0077] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3, C.sub.2HS
or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl, R.sub.4 is
piperidino, R.sub.5 and R.sub.9 are H;
[0078] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3, C.sub.2Hs
or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl, R.sub.9 is
OCH.sub.3;
[0079] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl;
[0080] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3, C.sub.2Hs
or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl, R.sub.4 is
morpholino, R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0081] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is phenyl, phenylmethyl or phenylethyl, R.sub.5 and R.sub.9
are H;
[0082] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0083] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.9 is H;
[0084] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is
CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0085] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H. R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H,
R.sub.9 is OCH.sub.3;
[0086] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 and R.sub.9 are
H;
[0087] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0088] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 and R.sub.9
are H;
[0089] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.9 is OCH.sub.3;
[0090] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is phenyl, phenylmethyl or phenylethyl, R.sub.5 and R.sub.9
are H;
[0091] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or
phenylethyl, R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0092] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is morpholino, R.sub.5 and R.sub.9 are H;
[0093] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or
phenylethyl, % is H, R.sub.9 is CH.sub.3, C.sub.2HS or
C.sub.3H.sub.7;
[0094] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3, C.sub.2Hs
or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is CH.sub.2-phenyl,
R.sub.4 is piperidino, R.sub.5 and R.sub.9 are H;
[0095] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3, C.sub.2Hs
or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl, R.sub.4 is
phenyl, phenylmethyl or phenylethyl, R.sub.5 is H, R.sub.9 is
OCH.sub.3;
[0096] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl;
[0097] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0098] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is
OCH.sub.3;
[0099] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 and R.sub.9
are H;
[0100] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is
OCH.sub.3;
[0101] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is COR.sub.8, R.sub.8 is morpholino, R.sub.9 is H;
[0102] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is COR.sub.8, R.sub.8 is morpholino, R.sub.9 is
OCH.sub.3;
[0103] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H,
R.sub.9 is OCH.sub.3;
[0104] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or phenylethyl,
R.sub.5 and R.sub.9 are H;
[0105] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H,
R.sub.9 is OCH.sub.3;
[0106] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 and R.sub.9
are H;
[0107] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or phenylethyl,
R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0108] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or
phenylethyl, R.sub.5 and R.sub.9 are H;
[0109] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3, C.sub.2Hs
or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl, R.sub.4 is
COR.sub.8, R.sub.8 is morpholino, R.sub.9 is OCH.sub.3;
[0110] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is phenyl, phenylmethyl or phenylethyl, R.sub.5 and R.sub.9
are H;
[0111] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.9 is OCH.sub.3;
[0112] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 and R.sub.9 are
H;
[0113] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.9 is R.sub.9 is OCH.sub.3;
[0114] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is COR.sub.8, R.sub.8 is NR.sub.6R.sub.7,
R.sub.6R.sub.7CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7 and
R.sub.9 is H;
[0115] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0116] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is phenyl, phenylmethyl or phenylethyl, R.sub.5 and R.sub.9
are H;
[0117] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or
phenylethyl, R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0118] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 and R.sub.9
are H;
[0119] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or phenylethyl,
R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0120] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.9 is H;
[0121] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0122] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H; R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or
phenylethyl, R.sub.5 and R.sub.9 are H;
[0123] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.9 is OCH.sub.3;
[0124] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 and R.sub.9 are
H;
[0125] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is COR.sub.8, R.sub.8 is cyclohexyl, R.sub.9 is
OCH.sub.3;
[0126] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is COR.sub.8, R.sub.8 is morpholino, R.sub.9 is H;
[0127] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.9 is OCH.sub.3;
[0128] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.9 is H;
[0129] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is COR.sub.8, R.sub.8 is NR.sub.6R.sub.7,
R.sub.6R.sub.7CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.9
is OCH.sub.3;
[0130] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or
phenylethyl, R.sub.5 and R.sub.9 are H;
[0131] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.9 is OCH.sub.3.
[0132] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 and R.sub.9 are
H;
[0133] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0134] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.9 is H;
[0135] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is
OCH.sub.3;
[0136] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.9 is H;
[0137] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.9 is OCH.sub.3;
[0138] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0139] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 and R.sub.9 are
H;
[0140] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0141] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or phenylethyl,
R.sub.5 and R.sub.9 are H;
[0142] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0143] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 and R.sub.9
are H;
[0144] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.9 is OCH.sub.3;
[0145] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0146] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is
OCH.sub.3;
[0147] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 and R.sub.9
are H;
[0148] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or phenylethyl,
R.sub.5 is H, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0149] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is COR.sub.8, R.sub.8 is NR.sub.6R.sub.7,
R.sub.6R.sub.7CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.9
is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0150] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 and R.sub.9
are H;
[0151] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or phenylethyl,
R.sub.5 is H, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0152] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is
CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0153] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is
OCH.sub.3;
[0154] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is COR.sub.8, R.sub.8 is cyclohexyl, R.sub.9 is H;
[0155] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0156] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0157] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0158] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3, C.sub.2Hs
or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is CH.sub.2-phenyl,
R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0159] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.9 is H;
[0160] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3, C.sub.2Hs
or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or
phenylethyl, R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0161] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.9 is OCH.sub.3;
[0162] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is
CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0163] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0164] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.9 is H;
[0165] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0166] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7
[0167] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is phenyl, phenylmethyl or phenylethyl, R.sub.5 is H,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0168] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0169] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0170] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is phenyl, phenylmethyl or phenylethyl, R.sub.5 is H,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0171] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is phenyl, phenylmethyl or phenylethyl, R.sub.5 is H,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0172] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is CH.sub.3, C.sub.2Hs
or C.sub.3H.sub.7;
[0173] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is
CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0174] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0175] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is CH.sub.2
phenyl, R.sub.4 is phenyl, phenylmethyl or phenylethyl, R.sub.5 is
H, R.sub.9 is OCH.sub.3;
[0176] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is COR.sub.8, R.sub.8 is morpholino, R.sub.9 is CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0177] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0178] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0179] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or
phenylethyl, R.sub.5 is H, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0180] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is OCH.sub.3;
[0181] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is phenyl, phenylmethyl or phenylethyl, R.sub.5 is H,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0182] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.4 is COR.sub.8, R.sub.8 is morpholino, R.sub.9 is CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0183] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0184] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or
phenylethyl, R.sub.5 is H, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0185] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is phenyl,
R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0186] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or phenylethyl,
R.sub.5 is H, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0187] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H, R.sub.9 is
CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0188] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H,
R.sub.9 is OCH.sub.3;
[0189] X is N, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is morpholino, R.sub.5 is H,
R.sub.9 is OCH.sub.3;
[0190] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, R.sub.4 is phenyl, phenylmethyl or
phenylethyl, R.sub.5 is H, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0191] X is N, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R.sub.4 is piperidino, R.sub.5 is H, R.sub.9 is
CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7;
[0192] X is CH, Y is CONR.sub.2, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
(CH.sub.2).sub.2-phenyl, Rgis CH.sub.3, C.sub.2H.sub.5 or
C.sub.3H.sub.7;
[0193] X is CH, Y is NR.sub.2CO, R.sub.1 is H, CH.sub.3,
C.sub.2H.sub.5 or C.sub.3H.sub.7, R.sub.2 is H, R.sub.3 is
CH.sub.2-phenyl, R is phenyl, phenylmethyl or phenylethyl, R.sub.5
is H, R.sub.9 is CH.sub.3, C.sub.2H.sub.5 or C.sub.3H.sub.7.
[0194] A preferred compound is
4-(4-methylpiperazin-1-yl).sub.4V-(4-morpho-
linophenyl)-indan-2-carboxamide.
[0195] The compounds of the present invention are in the form of
the racemate or the (R)- or (S)-enantiomer in the form of a free
base or a pharmaceutically acceptable salt or solvate thereof.
Compounds in the form of the (R)-enantiomer are believed to be
preferred ones.
[0196] Both organic and inorganic acids can be employed to form
non-toxic pharmaceutically acceptable acid addition salts of the
compounds of this invention. Illustrative acids are sulfuric,
nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromic,
citric, acetic, lactic, tartaric, dibenzoyltartaric,
diacetyltartaric, palmoic, ethanedisulfonic, sulfarnic, succinic,
propionic, glycolic, malic, gluconic, pyruvic, phenylacetic,
4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic,
4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,5-dihydroxybenzoic,
3-hydroxy-2-naphthoic, nicotinic, methanesulfonic, ethanesulfonic,
hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic,
sulfanilic, naphthalenesulfonic, ascorbic, cyclohexylsulfamic,
fumaric, maleic and benzoic acids. These salts are readily prepared
by methods known in the art.
[0197] The preferred solvates of the compounds of this invention
are the hydrates.
[0198] Pharmaceutical Formulations
[0199] In a second aspect the present invention provides a
pharmaceutical formulation comprising as active ingredient a
therapeutically effective amount of the compound of formula I as an
enantiomer or a racemate in the form of a free base or a
pharmaceutically acceptable salt or solvate thereof, optionally in
association with diluents, excipients or inert carriers.
[0200] According to the present invention the compound of the
invention will normally be administered orally, rectally or by
injection, in the form of pharmaceutical formulations comprising
the active ingredient either as a free base or a pharmaceutically
acceptable non-toxic acid addition salt, e.g. the hydrochloride,
hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate,
citrate, tartrate, oxalate and the like, in a pharmaceutically
acceptable dosage form. The dosage form may be a solid, semisolid
or liquid preparation. Usually the active substance will constitute
between 0.1 and 99% by weight of the preparation, more specifically
between 0.5 and 20% by weight for preparations intended for
injection and between 0.2 and 50% by weight for preparations
suitable for oral administration.
[0201] To produce pharmaceutical formulations containing the
compound of the invention in the form of dosage units for oral
application, the selected compound may be mixed with a solid
excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches
such as potato starch, corn starch or amylopectin, cellulose
derivatives, a binder such as gelatine or poly-vinylpyrrolidone,
and a lubricant such as magnesium stearate, calcium stearate,
polyethylene glycol, waxes, paraffin, and the like, and then
compressed into tablets. If coated tablets are required, the cores,
prepared as described above, may be coated with a concentrated
sugar solution which may contain e.g. gum arabic, gelatine, talcum,
titanium dioxide, and the like. Alternatively, the tablet can be
coated with a polymer known to the person skilled in the art,
dissolved in a readily volatile organic solvent or mixture of
organic solvents. Dyestuffs may be added to these coatings in order
to readily distinguish between tablets containing different active
substances or different amounts of the active compound.
[0202] For the preparation of soft gelatine capsules, the active
substance may be admixed with e.g. a vegetable oil or poly-ethylene
glycol. Hard gelatine capsules may contain granules of the active
substance using either the above mentioned excipients for tablets
e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato
starch, corn starch or amylopectin), cellulose derivatives or
gelatine. Also liquids or semisolids of the drug can be filled into
hard gelatine capsules.
[0203] Dosage units for rectal application can be solutions or
suspensions or can be prepared in the form of suppositories
comprising the active substance in a mixture with a neutral fatty
base, or gelatine rectal capsules comprising the active substance
in admixture with vegetable oil or paraffin oil. Liquid
preparations for oral application may be in the form of syrups or
suspensions, for example solutions containing from about 0.1% to
about 20% by weight of the active substance herein described, the
balance being sugar and mixture of ethanol, water, glycerol and
propylene glycol. Optionally such liquid preparations may contain
colouring agents, flavouring agents, saccharine and
carboxymethyl-cellulose as a thickening agent or other excipients
known to the person skilled in the art.
[0204] Solutions for parenteral applications by injection can be
prepared in an aqueous solution of a water-soluble pharmaceutically
acceptable salt of the active substance, preferably in a
concentration of from about 0.1% to about 10% by weight. These
solutions may also contain stabilizing agents and/or buffering
agents and may conveniently be provided in various dosage unit
ampoules.
[0205] Suitable daily doses of the compound of the invention in
therapeutical treatment of humans are about 0.01-100 mg/kg
bodyweight at peroral administration and 0.001-100 mg/kg bodyweight
at parenteral administration.
[0206] The compounds of the invention may be used in a combination
with a 5-HT reuptake inhibitor, such as fluoxetine, paroxetine,
citalopram, clomipramine, sertraline, alaproclate or fluvoxamin,
preferably paroxetine or citalopram. Another possible combination
is to use the compound of the invention together with a monoamine
oxidase inhibitor, such as moclobemide, tranylcypramine,
brofaromide or phenelzine, preferably moclobemide or phenelzine.
Still another possible combination is the compound of the invention
together with a 5-HT.sub.1A antagonist, such as the compounds
disclosed in WO 96/33710, preferably
(R)-5-carbamoyl-3-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzo-
pyran.
[0207] Medical and Pharmaceutical Use
[0208] In a further aspect the present invention provides the use
of the compounds of formula I in therapy as a h5-HT.sub.1B
antagonist, partial agonist or full agonist, preferably as an
antagonist and the use in the treatment of 5-hydroxytryptamine
mediated disorders. Examples of such disorders are disorders in the
CNS such as mood disorders (depression, major depressive episodes,
dysthymia, seasonal affective disorder, depressive phases of
bipolar disorder), anxiety disorders (obsessive compulsive
disorder, panic disorder with/without agoraphobia, social phobia,
specific phobia, generalized anxiety disorder, posttraumatic stress
disorder), personality disorders (disorders of impulse control,
trichotellomania), obesity, anorexia, bulimia, premenstrual
syndrome, sexual disturbances, alcoholism, tobacco abuse, autism,
attention deficit, hyperactivity disorder, migraine, memory
disorders (age associated memory impairment, presenile and senile
dementia), pathological aggression, schizophrenia, endocrine
disorders (e g hyperprolactinaemia), stroke, dyskinesia,
Parkinson's disease, thermoregulation, pain and hypertension. Other
examples of hydroxytryptamine mediated disorders are urinary
incontinence, vasospasm and growth control of tumors (e g lung
carcinoma).
[0209] Methods of Preparation
[0210] The present invention also relates to processes for
preparing the compound of formula I. Throughout the following
description of such processes it is understood that, where
appropriate, suitable protecting groups will be added to, and
subsequently removed from, the various reactants and intermediates
in a manner that will be readily understood by one skilled in the
art of organic synthesis. Conventional procedures for using such
protecting groups as well as examples of suitable protecting groups
are described, for example, in "Protective Groups in Organic
Synthesis" T. W. Greene, Wiley-Interscience, New York, 1991.
[0211] Methods of Preparation of Intermediates 3
[0212] (i) Cyclization of the compound of formula II, where R.sub.9
is hydrogen, to a compound of formula III, where R.sub.9 is
hydrogen, may be carried out in a suitable solvent such as
N,N-dimethylformamide or dimethylsulfoxide in the presence of ethyl
cyanoacetate and a suitable base such as K.sub.2CO.sub.3 or KOH.
The reaction may occur between +20.degree. C. and 100.degree. C.
4
[0213] (ii) Conversion of a compound of formula III, where R.sub.9
is hydrogen, to a compound of formula IV, where R.sub.9 is
hydrogen, may be carried by hydrolysis followed by decarboxylation
under acidic conditions using acids such as HCl, HBr or
H.sub.2SO.sub.4 in a suitable solvent such as acetic acid, water or
mixtures thereof. The reaction may occur between +20.degree. C. and
reflux. Hydrolysis under basic conditions may be carried out by
using bases such as NaOH or KOH in a suitable solvent such as
water, ethanol, methanol or mixtures thereof followed by
decarboxylation under acidic conditions using acids such as HCl,
HBr or H.sub.2SO.sub.4 in a suitable solvent such as acetic acid,
water or mixtures thereof. The reaction may occur between
+20.degree. C. and reflux. 5
[0214] (iii) Conversion of a compound of formula IV, where R.sub.9
is hydrogen, to a compound of formula V, where Y is CONR.sub.2 and
R.sub.9 is hydrogen, may be carried out by activation of the acid
function of a compound of formula IV as an acid halide such as an
acid chloride with a suitable base such as a trialkylamine, e.g.
triethylamine, or by using an activating reagent such as
N,N'-carbonyldiimidazole, N,N-dicyclohexylcarbodiimide or
diphenylphosphinic chloride with a suitable base such as
N-methylmorpholine in a suitable solvent, e.g. methylene chloride,
chloroform, toluene, N,N-dimethylformamide, dioxane or
tetrahydrofuran, followed by the addition of an appropriate amine
or aniline HNR.sub.2R.sub.3, where R.sub.2 and R.sub.3 are as in
formula I above and the reaction may occur between 0.degree. C. and
+120.degree. C. 6
[0215] (iv) Conversion of a compound of formula V to a compound of
formula VI, where Y is CONR.sub.2, R.sub.2 and R.sub.3 are as in
formula I above, may be carried out by hydrogenation using a
catalyst containing palladium, platina, nickel or rhodium in a
suitable solvent such as ethanol, methanol or acetic acid at a
reaction temperature between +20.degree. C. and +120.degree. C.; or
by reduction with a suitable reductive reagent such as sodium
dithionite in a suitable solvent such as NA-dimethylformamide at a
reaction temperature between +20.degree. C. and +120.degree. C.
[0216] Methods of Preparation of End Products
[0217] Another object of the invention is a process for the
preparation of the compound of general formula I by
[0218] reacting, in the case where Y is CONR.sub.2; R.sub.1,
R.sub.2, R.sub.3 and R.sub.9 are as defined in general formula I
above, a compound of formula A 7
[0219] with a compound of formula VII wherein X is a leaving
group.
[0220] Thus, the reaction according to the process A may be carried
out with a compound of formula VII wherein X is a leaving group,
e.g. a halogen such as chlorine or bromine or an alkane- or
arenesulfonyloxy group such as p-toluenesulfonyloxy group. The
process may be carried out in a suitable solvent such as ethanol,
butanol, N,N-dimethylformarnmide, acetonitrile or a mixture of
water and acetonitrile with or without a suitable base, e.g.
K.sub.2CO.sub.3, NaHCO.sub.3 or KOH, and the reaction may occur
between +20.degree. C. and +150.degree. C.
[0221] Intermediates
[0222] Another object of the invention is a compound having the
formula 8
[0223] wherein
[0224] Y is CONR.sub.2 wherein R.sub.2 is H or C.sub.1-C.sub.6
alkyl,
[0225] R.sub.3 is C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl
or (CH.sub.2).sub.n-aryl,
[0226] wherein aryl is phenyl or a heteroaromatic ring containing
one or two heteroatoms selected from N, O and S and which may be
mono- or di-substituted with R.sub.4 and/or R.sub.5; wherein
R.sub.4, R.sub.5 and n are as defined above;
[0227] R.sub.9 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl OCF.sub.3, OCHF.sub.2, OCH.sub.2F, halogen, CN,
CF.sub.3, OH, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkoxy-C.sub.1-C.sub.6 alkyl, NR.sub.6R.sub.7, SO.sub.3CH.sub.3,
SO.sub.3CF.sub.3, SO.sub.2NR.sub.6R.sub.7, an unsubstituted or
substituted heterocyclic or heteroaromatic ring containing one or
two heteroatoms selected from N and O, wherein the substituent(s)
is(are) C.sub.1-C.sub.6 alkyl; or COR.sub.8; wherein R.sub.6,
R.sub.7 and R.sub.8 are as defined above.
[0228] The invention is illustrated but not restricted to the
following working examples.
WORKING EXAMPLES
Example 1
2-Cyano-2-ethoxycarbonyl-4-nitroindan
[0229] A mixture of 2,3-di(bromomethyl)nitrobenzene (34 g, 0.11
mol; described in: EP 0529 636 A1), potassium carbonate (35 g, 0.25
mol) and ethyl cyanoacetate (12 mL, 0.11 mmol) in
N,N-dimethylformamide (50 mL) was stirred at room temperature for
48 h. The solvent was evaporated in vacuo and the residue was
stirred with ethyl acetate. The mixture was filtered and the
filtrate was washed with water and dried over sodium sulfate. The
solvent was evaporated in vacuo to yield 29 g of the title compound
as an oil (94% GC purity): EIMS (70 eV) m/z (relative intensity)
260 (4, M+).
Example 2
4-Nitroindan-2-carboxylic Acid
[0230] A mixture of 2-cyano-2-ethoxycarbonyl-4-nitroindan (21 g, 81
mmol), acetic acid (290 mL), hydrochloric acid (37%, 130 mL) and
water (140 mL) was stirred under reflux temperature over night. The
acid was evaporated in vacuo and the residue was made alkaline with
a 2 M sodium hydroxide solution. The mixture was stirred at room
temperature, insoluble matter was filtered and the filtrate was
acidified with hydrochloric acid. The obtained precipitate was
filtered and washed with water to afford 18 gram of the crude acid:
mp .about.140.degree. C.; EIMS (70 eV) m/z (relative intensity) 207
(40, M.sup.+).
Example 3
4-Amino-N-(4-morpholinophenyl)indan-2-carboxamide
[0231] A mixture of 4-nitroindan-2-carboxylic acid (2.2 g, 11
mmol), thionyl chloride (8.0 mL) and a catalytical amount of
N,N-dimethylformamide in methylene chloride (20 mL) was stirred at
reflux for 45 minutes. The solvent was evaporated in vacuo and the
residue was dissolved in dry tetrahydrofuran and added, while
stirring, to a mixture of 4-anilino-morpholine (1.7 g, 9 mmol) and
potassium carbonate (3.0 g, 22 mmol) in acetonitrile (20 mL). The
mixture was stirred for 1 h at 50.degree. C. After the addition of
water (250 mL), the obtained precipitate was filtered, washed with
water and dried to afford 2.9 g (78% yield) of crude
4-nitro-N-(4-morpholinophenyl)indan-2-carboxamide: EIMS (70 eV) m/z
(relative intensity) 367 (100, M.sup.+).
[0232] To a solution of the crude nitro compound (3.5 g) in
N,N-dimethylformamide (25 mL) and water (3 mL) was added, in
portions, sodium dithionite (7.0 g, 40 mmol). The mixture was
stirred at 90.degree. C. for 3 hours. The solvent was evaporated in
vacuo and water (200 mL) was added. The mixture was made alkaline
with 2 M sodium hydroxide and extracted with chloroform. The phases
were separated and the organic phase was dried (Na.sub.2SO.sub.4),
filtered and evaporated in vacuo to give 1.1 g of the crude product
(GC purity 89%): EIMS (70 eV) m/z (relative intensity) 337 (100,
M.sup.+).
Example 4
4-(4-Methylpiperazin-1-yl)-N-(4-morpholinophenyl)indan-2-carboxamide
[0233] A mixture of
4-amino-N-(4-morpholinophenyl)indan-2-carboxamide (11.1 g, 3 mmol),
N-methyl-bis-(2-chloroethyl)amine hydrochloride (2.0 g, 10 mmol)
and sodium hydrogen carbonate (8.0 g, 95 mmol) in 1-butanol (100
mL) was stirred over night at 120.degree. C. The mixture was
filtered and the solvent was evaporated in vacuo. The crude residue
(oil) was purified on a silica gel column using methylene chloride
as the eluent to afford 100 mg of the title compound: mp
248-249.degree. C.; EIMS (70 eV) m/z (relative intensity) 420 (47,
M.sup.+).
[0234] Pharmacology
[0235] Electrical field stimulation of [.sup.3H]-5-HT release from
occipital cortex of guinea pigs
[0236] [.sup.3H]-5-HT is released by electrical field stimulation
from slices of occipital cortex of guinea pigs which have been
pre-incubated with [.sup.3H]-5-HT. This release is similar to that
caused by nerve stimulation, i.e. exocytotic release from
serotonergic nerve terminals, depending on the presence of
Ca.sup.2+in the incubation medium. The 5-HT release is regulated at
the level of the nerve terminals by autoreceptors, in the guinea
pigs (like in humans) belonging to the h5-HT.sub.1B receptor
subtype. Thus, agonists of h5-HT.sub.1B receptors reduce the amount
of [.sup.3H]-5-HT released by electrical field stimulation whereas
the release is increased by antagonists of this receptor type.
Testing compounds with this method is accordingly a convenient
screening technique for determining the potency and functional
effect of new h5-HT.sub.1B receptor agonists and antagonists.
[0237] Methods and Materials
[0238] Buffer composition (mM) NaHCO.sub.3 (25), NaH.sub.2PO.sub.4.
H.sub.2O (1.2), NaCl (117), KCl(6),
MgSO.sub.4.times.7H.sub.2O(1.2), CaCl.sub.2(1.3), EDTA
Na.sub.2(0.03). The buffer is gassed for at least 30 min before
use. The pH of the buffer is about 7.2 at room temperature but it
rises to about 7.4 at 37.degree. C.
[0239] Preparation of Occipital Cortical Slices
[0240] Guinea pigs (200-250 g) were decapitated and the whole brain
was removed. The occipital cortex was dissected and cut to slices
0.4.times.4 mm with McIlwain chopper machine. The white part of the
tissue should be removed carefully with a tweezer before slicing.
The slices were incubated in 5 ml buffer in the presence of 5 mM
pargyline chloride. After incubation with 0.1 mM [.sup.3H]-5-HT for
another 30 min the slices were transferred to a test tube and
washed three times with same volume buffer. The slices were
transferred to the superfusion chambers with a plastic pipette and
were washed for 40 min with the buffer in the presence of uptake
inhibitor citalopram 2.5 .mu.M with a flow 0.5 ml/min.
[0241] Electrical Stimulation of 5-HT Release
[0242] The superfused buffer was collected in 2 mL/fraction. The
slices were stimulated by electricity with a train of pulses of
frequency 3 Hz, duration 2 ms and current 30 mA for 3 min at the
4th and 13th fractions. The tested drugs were added from the 8th
fraction to the end of experiment.
[0243] Results
[0244] A first electrical (or K.sup.+) stimulation results in a
standard amount of [.sup.3H]-5-HT released (S.sub.1). Before the
first and the second stimulation the h5-HT.sub.1B antagonist is
added to the media which results in a dose depending increase of
the release(S.sub.2) after the second stimulation. See FIG. 1.
[0245] The S.sub.2/S.sub.1 ratio which is the percent of released
[.sup.3H]-5-HT at the second stimulation (S.sub.2) divided by that
of the first stimulation (S.sub.1) was used to estimate drug
effects on transmitter release.
* * * * *