U.S. patent application number 10/005491 was filed with the patent office on 2002-11-21 for indole derivatives for the treatment of osteoporosis.
This patent application is currently assigned to Smith Kline Beecham SpA. Invention is credited to Farina, Carlo, Gagliardi, Stefania, Nadler, Guy Marguerite Marie Gerard.
Application Number | 20020173659 10/005491 |
Document ID | / |
Family ID | 27268385 |
Filed Date | 2002-11-21 |
United States Patent
Application |
20020173659 |
Kind Code |
A1 |
Farina, Carlo ; et
al. |
November 21, 2002 |
Indole derivatives for the treatment of osteoporosis
Abstract
A compound of formula (I): 1 or a salt thereof, or a solvate
thereof, wherein Ra represents a group R.sub.5 which is hydrogen,
alkyl or optionally substituted aryl and Rb represents a moiety of
formula (a): 2 wherein X represents a hydroxy or an alkoxy group
wherein the alkyl group may be substituted or unsubstituted or X
represents a group NR.sub.sR.sub.t wherein R.sub.s and R.sub.t each
independently represent hydrogen, alkyl, substituted alkyl,
optionally substituted alkenyl, optionally substituted aryl,
optionally substituted arylalkyl, an optionally substituted
heterocyclic group or an optionally substituted heterocyclylalkyl
group, or R.sub.s and R.sub.t together with the nitrogen to which
they are attached form a heterocyclic group; RI represents an alkyl
or a substituted or unsubstituted aryl group; and R.sub.2, R.sub.3
and R.sub.4 each independently represent hydrogen, alkyl, aryl or
substituted aryl R.sub.6 and R.sub.7 each independently represents
hydrogen, hydroxy, amino, alkoxy, optionally substituted aryloxy,
optionally substituted benzyloxy, alkylamino, dialkylamino, halo,
trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy,
carbalkoxy, carbamoyl, alkylcarbamoyl, or R.sub.6 and R.sub.7
together represent methylenedioxy, carbonyldioxy or
carbonyldiamino; and R.sub.8 represents hydrogen, hydroxy,
alkanoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl,
carbalkoxyalkyl, carbamoyl or aminosulphonyl; a process for
preparing such a compound, a pharmaceutical composition containing
such a compound and the use of such a compound in medicine
Inventors: |
Farina, Carlo; (Milan,
IT) ; Gagliardi, Stefania; (Milan, IT) ;
Nadler, Guy Marguerite Marie Gerard; (Rennes, FR) |
Correspondence
Address: |
SMITHKLINE BEECHAM CORPORATION
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
Smith Kline Beecham SpA
|
Family ID: |
27268385 |
Appl. No.: |
10/005491 |
Filed: |
December 4, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10005491 |
Dec 4, 2001 |
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09704410 |
Nov 2, 2000 |
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09704410 |
Nov 2, 2000 |
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09214693 |
Apr 23, 1999 |
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09214693 |
Apr 23, 1999 |
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PCT/EP97/03577 |
Jul 3, 1997 |
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Current U.S.
Class: |
546/201 ;
548/507 |
Current CPC
Class: |
C07D 401/14 20130101;
C07D 471/08 20130101; C07D 401/12 20130101; C07D 209/18 20130101;
C07D 451/04 20130101; C07D 471/04 20130101; C07D 451/02 20130101;
C07D 413/12 20130101; C07D 403/12 20130101; C07D 455/02 20130101;
A61P 19/08 20180101 |
Class at
Publication: |
546/201 ;
548/507; 514/323; 514/419 |
International
Class: |
C07D 41/02; A61K
031/454; A61K 031/405; C07D 209/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 9, 1996 |
GB |
9614367.2 |
Dec 23, 1996 |
GB |
9626697.8 |
Dec 23, 1996 |
GB |
9626700.0 |
Claims
1. A selective inhibitor of the biological activity of human
osteoclast cells, providing that such an inhibitor does not include
any specific Example disclosed in WO 96/21644.
2. An inhibitor according to claim 1, which is selective for the
vacuolar H.sup.+-ATPase located on the ruffled border of human
osteoclasts.
3. An inhibitor according to claim 1 or claim 2, which interacts
specifically with the 16 kDa subunit or the 116 kDa subunit of the
vacuolar H.sup.+-ATPase located on the ruffled border of human
osteoclasts.
4. A compound of formula (I): 99or a salt thereof, or a solvate
thereof, wherein: Ra represents a group R.sub.5 which is hydrogen,
alkyl or optionally substituted aryl and Rb represents a moiety of
formula (a): 100 wherein X represents a hydroxy or an alkoxy group
wherein the alkyl group may be substituted or unsubstituted or X
represents a group NR.sub.sR.sub.t wherein R.sub.s each
independently represent hydrogen, alkyl, substituted alkyl,
optionally substituted alkenyl, optionally substituted aryl,
optionally substituted arylalkyl, an optionally substituted
heterocyclic group or an optionally substituted heterocyclylalkyl
group, or R.sub.s and R.sub.ttogether with the nitrogen to which
they are attached form a heterocyclic group; R.sub.1 represents an
alkyl or a substituted or unsubstituted aryl group; and R.sub.2,
R.sub.3 and R.sub.4 each independently represent hydrogen, alkyl,
aryl or substituted aryl R.sub.6 and R.sub.7 each independently
represents hydrogen, hydroxy, amino, alkoxy, optionally substituted
aryloxy, optionally substituted benzyloxy, alkylamino,
dialkylamino, halo, trifluoromethyl, trifloromethoxy, nitro, alkyl,
carboxy, carbalkoxy, carbamoyl alkylcarbamoyl, or R.sub.6 and
R.sub.7 together represent methylenedioxy, carbonyldioxy or
carbonyldiamino; and R.sub.8 represents hydrogen, hydroxy,
alkanoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl,
carbalkoxyalkyl, carbamoyl or aminosulphonyl; providing that such
an inhibitor does not include any specific Example disclosed in WO
96/21644.
5. A compound according to claim 4, wherein R.sub.1 represents
methyl.
6. A compound according to claim 4 or claim 5, wherein R.sub.2,
R.sub.3 and R.sub.4 each independently represent hydrogen, alkyl or
phenyl.
7. A compound according to any one of claims 4 to 6, wherein
R.sub.5 is hydrogen.
8. A compound according to any one of claims 4 to 7, wherein
R.sub.6 and R.sub.7 are hydrogen, halo, trifluoromethyl and
alkoxy.
9. A compound according to any one of claims 4 to 8, wherein
R.sub.6 is 5-chloro and R.sub.7 is 6-chloro.
10. A compound according to any one of claims 4 to 9, wherein
R.sub.8 represents hydrogen.
11. A compound according to any one of claims 4 to 10, wherein X
represents NR.sub.sR.sub.t.
12. A compound according to claim 11, wherein R.sub.s and R.sub.t
each independently represent hydrogen, alkyl, substituted alkyl,
optionally substituted alkenyl, optionally substituted aryl,
optionally substituted arylalkyl, an optionally substituted
heterocyclic group or an optionally substituted heterocyclylalkyl
group.
13. A compound according to claims 11 or 12, wherein R.sub.s and
R.sub.t together represent a heterocyclic group.
14. A compound according to claim 13, wherein R.sub.s and R.sub.t
together represent is a moiety of formula (H1): 101wherein Z.sub.1
is N or CX.sub.5 wherein X.sub.5 is selected from hydrogen, alkyl,
alkoxy, alkylcarbonyl, aryl, aryloxy or arylcarbonyl and Z.sub.2,
X.sub.3 and X.sub.4 are each independently selected from hydrogen,
alkyl, aryl, cyano, amino, heterocyclyloxy, alkoxy
carbonylalkyloxy, carboxyalkyloxy, aminoalkyloxy, aminoalkylamino,
aminoalkenylamino (especially aminomethyleneamino) and
alkanoylamino.
15. A compound according to claim 13, wherein R.sub.s and R.sub.t
together represent a group of formula (H2): 102wherein X.sub.6,
X.sub.7, X.sub.8, X.sub.9, X.sub.10, X.sub.11, X.sub.12 and
X.sub.13 are each independently selected from hydrogen, hydroxy,
alky, suitably C.sub.1-6 alkyl, cycloalkyl (suitably
spirocondensed), mono or poly hydroxyalkyl, alkoxyalkyl,
hydroxy-alkoxyalkyl, alkanoyl, alkoxycarbonyl, aminoalkyl
(optionally alkylated or acylated at nitrogen); or one of X.sub.6
with X.sub.12 and X.sub.8 with X.sub.10 represents a C.sub.2-4
alkylene chain and the remaining variables X.sub.7, X.sub.13,
X.sub.9 and X.sub.11 each independently represent hydrogen,
hydroxy, alkyl , suitably C.sub.1-6 alkyl, cycloalkyl (suitably
spirocondensed), mono or poly hydroxyalkyl, alkoxyalkyl,
hydroxy-alkoxyalkyl, alkanoyl, alkoxycarbonyl, aminoalkyl
(optionally alkylated or acylated at nitrogen); and X.sub.14
represents hydrogen or lower alkyl, mono or polyhydroxyalkyl, mono
or diaminoalkyl, aminocarbonyl, alkyl, carboxyalkyl,
carbalkoxyalkyl, aryl, heterocyclyl, acyl, carbamoyl,
alkylamino(cyanimidoyl), aminoalkanoyl, hydroxyalkanoyl. X.sub.6,
X.sub.7, X.sub.12 and X.sub.13 each represent hydrogen.
16. A compound according to claim 15, wherein X.sub.8, and X.sub.9
each independently represent hydrogen or alkyl.
17. A compound according to claim 15, wherein X.sub.10 and X.sub.11
each independently represent hydrogen or alkyl.
18. A compound according to claim 15, wherein X.sub.14 represents
alkyl
19. A compound according to claim 15, wherein X.sub.8, X.sub.9,
X.sub.10 and X.sub.11 each independently represent methyl and
X.sub.6, X.sub.7, X.sub.12 and X.sub.13 each represent
hydrogen.
20. A compound according to claim 1, wherein R.sub.1 is C.sub.1-6
alkyl, R.sub.2, R.sub.3, R.sub.4 and R.sub.8 are hydrogen, R.sub.6
is 5-halo, R.sub.7 is 6-halo, and X is a moiety NR.sub.sR.sub.t
wherein R.sub.t is hydrogen and R.sub.s is a moiety of formula (f)
or a moiety (H1) or (H2).
21. A compound according to claim 1, being selected from any one of
examples 1 to 79; or a salt thereof, or a solvate thereof.
22. A compound according to claim 1, being selected from examples,
31, 32 34, 35, 47, 51, 55, 56, 59, 68 and 74; or a salt thereof, or
a solvate thereof.
23. A process for the preparation of a compound of formula (I) or a
salt thereof or a solvate thereof, which process comprises reacting
a compound of formula (II): 103wherein R.sub.2, R.sub.3, R.sub.4,
R.sub.6, R.sub.7 and R.sub.8 are as defined in relation to formula
(I), with a reagent capable of converting a moiety of formula
104into a moiety of the above defined formula (a); and thereafter,
as necessary, carrying out one or more of the following reactions:
(i) converting one compound of formula (I) into another compound of
formula (I); (ii) removing any protecting group; (iii) preparing a
salt or a solvate of the compound so formed.
24 A pharmaceutical composition comprising a selective inhibitor of
the pharmacological activity of human osteoclast cells according to
claim 1, and a pharmaceutically acceptable carrier therefor.
25. An inhibitor of a mammalian osteoclasts according to claim 1,
for use as an active therapeutic substance.
26. The use of a selective inhibitor of the biological activity of
human osteoclast cells according to claim 1, for the manufacture of
a medicament for the treatment and/or prophylaxis of diseases
associated with over activity of osteoclasts in mammals.
27. A method for the treatment and/or prophylaxis of diseases
associated with over activity of osteoclasts in mammals which
method comprises the administration of an effective non-toxic,
pharmaceutically amount of a selective inhibitor of mammalian
osteoclasts according to claim 1.
Description
[0001] This invention relates to certain novel compounds, to a
process for preparing such compounds, to pharmaceutical
compositions containing such compounds and to the use of such
compounds and compositions in medicine.
[0002] Co-pending International Application, application number
PCT/EP96/00157, publication number WO 96/21644, discloses certain
indole derivatives of formula (A): formula (I): 3
[0003] or a salt thereof, or a solvate thereof, wherein
[0004] either: (i) R'a represents a group R'.sub.5 which is
hydrogen, alkyl or optionally substituted aryl and R'b represents a
moiety of formula (a'): 4
[0005] wherein X' represents a hydroxy or an alkoxy group wherein
the alkyl group may be substituted or unsubstituted or X'
represents a group NR'.sub.sR'.sub.t wherein R'.sub.s and R'.sub.t
each independently represent hydrogen, alkyl, substituted alkyl,
optionally substituted alkenyl, optionally substituted aryl,
optionally substituted arylalkyl, an optionally substituted
heterocyclic group or an optionally substituted heterocyclylalkyl
group, or R'.sub.s and R'.sub.t together with the nitrogen to which
they are attached form a heterocyclic group; R'.sub.1 represents an
alkyl or a substituted or unsubstituted aryl group; and R'.sub.2,
R'.sub.3 and R'.sub.4 each independently represent hydrogen, alkyl,
aryl or substituted aryl
[0006] or (ii) R'a represents a moiety of the above defined formula
(a) and R'b represents the above defined R'.sub.5;
[0007] R'.sub.6 and R'.sub.7 each independently represents
hydrogen, hydroxy, amino, alkoxy, optionally substituted aryloxy,
optionally substituted benzyloxy, alkylamino, dialkylamino, halo,
trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy,
carbalkoxy, carbamoyl, alkylcarbanoyl, or R'.sub.6 and R'.sub.7
together represent methylenedioxy, carbonyldioxy or
carbonyldiamino; and
[0008] R'.sub.8 represents hydrogen, hydroxy, alkanoyl, alkyl,
aminoalkyl, hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl
or aminosulphonyl, which compounds are indicated interalia to
reduce bone resorption by inhibiting osteoclast H.sup.+-ATPase.
[0009] Diseases associated with loss of bone mass are known to be
caused by over activity of osteoclast cells. It is also known that
certain compounds, usually related to bafilomycin, are useful for
treating such diseases: For example International Patent
Application, publication number WO 91/06296 discloses certain
bafilomycin macrolides for the treatment of bone affecting
diseases.
[0010] However, bafilomycin derivatives are not selective for
osteoclasts in humans. The use of these compounds is therefore
associated with unacceptable toxicity due to generalised blockade
of other essential v-ATPases. Indeed, to date there is no known
treatment which is selective for the human osteoclasts.
[0011] The search for a successful treatment for diseases
associated with loss of bone mass in humans is further complicated
in that the nature of the therapeutic target for the selective
inhibition of the osteoclasts is controversial. Thus Baron et al
(International Patent Application publication number WO93/01280)
indicate that a specific vacuolar ATPase (V-ATPase) has been
identified in osteoclasts as a potential therapeutic target.
However, the Baron work was carried out in chickens and Hall et al
(Bone and Mineral 27, 1994, 159-166), in a study relating to
mammals, conclude that in contrast to avian osteoclast V-ATPase,
mammalian osteoclast V-ATPase is pharmacologically similar to the
v-ATPase in other cells and, therefore, it is unlikely to be a good
therapeutic target.
[0012] We have now found a group of novel compounds from within the
scope of WO 96/21644 which are especially selective for mammalian
osteoclasts, especially human osteoclasts, acting to selectively
inhibit their bone resorbing activity. These compounds are
therefore considered to be particularly useful for the treatment
and/or prophylaxis of diseases associated with loss of bone mass,
such as osteoporosis and related osteopenic diseases, Paget's
disease, hyperparathyroidism and related diseases. These compounds
are also considered to possess anti-tumour activity, antiviral
activity (for example against Semliki Forest, Vesicular Stomatitis,
Newcastle Disease, Influenza A and B, HIV viruses), antiulcer
activity (for example the compounds may be useful for the treatment
of chronic gastritis and peptic ulcer induced by Helicobacter
pylori), immunosupressant activity, antilipidemic activity,
antiatherosclerotic activity and to be useful for the treatment of
AIDS and Alzheimer's disease. In a further aspect, these compounds
are also considered useful in inhibiting angiogenesis, i.e. the
formation of new blood vessels which is observed in various types
of pathological conditions (angiogenic diseases) such as rheumatoid
arthritis, diabetic retinopathy, psoriasis and solid tumours.
[0013] Accordingly, in its broadest aspect the the present
invention provides a selective inhibitor of the biological activity
of human osteoclast cells, in particular the bone resorption
activity of human osteoclast cells associated with abnormal loss of
bone mass, providing that such an inhibitor does not include any
specific Example disclosed in WO 96/21644. In a further aspect the
invention provides a selective inhibitor of the biological activity
of human osteoclast cells, in particular the bone resorption
activity of human osteoclast cells associated with abnormal loss of
bone mass, providing that such an inhibitor does not include a
compound of the hereinbefore defined compound of formula (A). A
particular inhibitor of human osteoclast cells is a selective
inhibitor of the vacuolar H.sup.+-ATPase located on the ruffled
border of human osteoclasts.
[0014] In one particular aspect the selective inhibitor interacts
specifically with the 16 kDa subunit of the vacuolar H.sup.+-ATPase
located on the ruffled border of human osteoclasts whose function
and structure is similar to other known 16 kDa subunits, for
example that reported in P. C. Jones et al., Membrane Dynamics and
Transport, 22, 805-809 (1994).
[0015] In a further particular aspect, the selective inhibitor
interacts specifically with the 116 kDa subunit of the vacuolar
H+-ATPase located on the ruffled border of human osteoclasts (for
example the protein reported in Y-P. Li et al., Biochem. Biophys.
Res. Commun., 218, 813-821(1996)).
[0016] In particular, the invention provides a compound of formula
(I): 5
[0017] or a salt thereof, or a solvate thereof, wherein
[0018] Ra represents a group R.sub.5 which is hydrogen, alkyl or
optionally substituted aryl and Rb represents a moiety of formula
(a): 6
[0019] wherein X represents a hydroxy or an alkoxy group wherein
the alkyl group may be substituted or unsubstituted or X represents
a group NR.sub.sR.sub.t wherein R.sub.s and R.sub.t each
independently represent hydrogen, alkyl, substituted alkyl,
optionally substituted alkenyl, optionally substituted aryl,
optionally substituted arylalkyl, an optionally substituted
heterocyclic group or an optionally substituted heterocyclylalkyl
group, or R.sub.s and R.sub.t together with the nitrogen to which
they are attached form a heterocyclic group; R.sub.1 represents an
alkyl or a substituted or unsubstituted aryl group; and R.sub.2,
R.sub.3 and R.sub.4 each independently represent hydrogen, alkyl,
aryl or substituted aryl
[0020] R.sub.6 and R.sub.7 each independently represents hydrogen,
hydroxy, amino, alkoxy, optionally substituted aryloxy, optionally
substituted benzyloxy, alkylamino, dialkylamino, halo,
trifluoromethyl, trifluoromethoxy, nitro, alkyl, carboxy,
carbalkoxy, carbamoyl, alkylcarbamoyl, or R.sub.6 and R.sub.7
together represent methylenedioxy, carbonyldioxy or
carbonyldiamino; and
[0021] R.sub.8 represents hydrogen, hydroxy, alkanoyl, alkyl,
aminoalkyl, hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl
or aminosulphonyl.
[0022] In one aspect R.sub.1 represents alkyl or substituted or
unsubstituted phenyl.
[0023] Suitably R.sub.1 represents alkyl.
[0024] Favourably, R.sub.1 represents a C.sub.1-4-alkyl group, for
example methyl or ethyl
[0025] Preferably, R.sub.1 represents methyl.
[0026] In one aspect, R.sub.2, R.sub.3 and R.sub.4 each
independently represent hydrogen, alkyl or phenyl.
[0027] Examples of R.sub.2 include hydrogen and methyl.
[0028] Suitably, R.sub.2 represents hydrogen.
[0029] Examples of R.sub.3 include hydrogen and methyl or
ethyl.
[0030] Suitably, R.sub.3 represents hydrogen.
[0031] Examples of R.sub.4 include hydrogen, propyl and phenyl,
especially hydrogen and phenyl.
[0032] Suitably, R.sub.4 represents hydrogen.
[0033] In one aspect, R.sub.5 is hydrogen, alkyl or substituted or,
suitably, unsubstituted phenyl.
[0034] Examples of R.sub.5 include hydrogen, ethyl and
4-methoxyphenyl, especially hydrogen and ethyl.
[0035] Suitably, R.sub.5 is hydrogen.
[0036] In one aspect R.sub.6 and R.sub.7 each independently
represents hydrogen, hydroxy, amino, alkoxy, optionally substituted
phenyloxy, optionally substituted benzyloxy, alkylamino,
dialkylamino, halo, trifluoromethyl, nitro, alkyl, carboxy,
carbalkoxy, carbamoyl, alkylcarbamoyl, or R.sub.6 and R.sub.7
together represent methylenedioxy, carbonyldioxy or
carbonyldiamino.
[0037] Suitably, R.sub.6 and R.sub.7 each independently represents
alkoxy, halo, trifluoromethyl, nitro, and alkyl.
[0038] When R.sub.6 or R.sub.7 represents alkoxy, said alkoxy group
is suitably a C.sub.1-6 alkoxy for example methoxy.
[0039] When R.sub.6 or R.sub.7 represents halo, said halo group is
suitably a fluoro, chloro or bromo group, especially a chloro or
bromo group.
[0040] When R.sub.6 or R.sub.7 represents alkyl, said alkyl group
is suitably a C.sub.1-6 alkyl for a example butyl group.
[0041] Suitable positions for substitution for R.sub.6 or R.sub.7
are the 4, 5, 6 or 7 position, favourably the 5 or 6 position.
[0042] When neither of R.sub.6 or R.sub.7 represent hydrogen then
favoured positions for bis-substitution are 5 and 6 positions.
[0043] Favoured values for R.sub.6 and R.sub.7 are hydrogen, halo,
trifluoromethyl and alkoxy.
[0044] In one aspect R.sub.6 is hydrogen and R.sub.6 or R.sub.7
represents hydrogen alkoxy, halo, nitro, trifluoromethyl and
alkyl.
[0045] In a further aspect R.sub.6 and R.sub.7 are each selected
from hydrogen, halo and alkoxy, examples include: R.sub.6 is halo
and R.sub.7 is halo; R.sub.6 is halo and R.sub.7 is alkyl; R.sub.6
is alkoxy and R.sub.7 is alkoxy.
[0046] In a preferred aspect R.sub.6 is halo, especially 5-halo,
and R.sub.7 is halo, especially 6-halo.
[0047] Most preferably R.sub.6 is chloro, especially 5-chloro, and
R.sub.7 is chloro, especially 6-chloro.
[0048] Examples of R.sub.8 include hydrogen, methyl and
t-butoxycarbonylmethyl.
[0049] A further example of R.sub.8 is a carboxymethyl group.
[0050] Suitably, R.sub.8 represents hydrogen.
[0051] When X represents an alkoxy group, the alkyl group thereof
is preferably an unsubstituted alkyl group.
[0052] Suitably, X represents the above defined group N
R.sub.sR.sub.t.
[0053] In one aspect, R.sub.s and R.sub.t each independently
represent hydrogen, alkyl, substituted alkyl, optionally
substituted alkenyl, optionally substituted aryl, optionally
substituted arylalkyl, an optionally substituted heterocyclic group
or an optionally substituted heterocyclylalkyl group.
[0054] R.sub.s and R.sub.t can also each independently represent
cycloalkyl or substituted cycloalkyl.
[0055] In a further aspect, R.sub.s and R.sub.t together represent
a heterocyclic group.
[0056] When R.sub.s or R.sub.t represent alkyl or substituted
alkyl, suitable alkyl groups are C.sub.1-6 alkyl groups, for
example C.sub.1, C.sub.2, C.sub.3, C.sub.4 and C.sub.5 alkyl
groups, favourably ethyl, propyl or butyl.
[0057] When R.sub.s or R.sub.t represent substituted alkyl,
favoured groups are 2-(dialkylamino)ethyl or 3-(dialkylamino)propyl
or 4-(dialkylamino)butyl or heterocyclylmethyl or heterocyclylethyl
or heterocyclylpropyl groups.
[0058] A further favoured group for R.sub.s or R.sub.t is
heterocyclylalkyl, especially heterocyclyl-C.sub.1-6 alkyl, in
particular heterocyclyl-(CH.sub.2)2- or
heterocyclyl-(CH.sub.2).sub.3-.
[0059] One favoured heterocyclyl substituent for alkyl groups, such
as heterocyclylmethyl, heterocyclylethyl or heterocyclyipropyl
groups include piperazinyl groups.
[0060] Further favoured heterocyclyl substituents for alkyl groups,
such as heterocyclylmethyl, heterocyclylethyl or heterocyclyipropyl
groups include homopiperazinyl groups.
[0061] When R.sub.s or R.sub.t represent cycloalkyl or substituted
cycloalkyl, suitable cycloalkyl groups are C.sub.5-9 cycloalkyl
groups, for example a cyclopentyl or cyclohexyl group. When R.sub.s
or R.sub.t represent alkenyl or substituted alkenyl, suitable
alkenyl groups are C.sub.2-6 alkenyl groups, for example a C.sub.5
alkenyl group.
[0062] When R.sub.s or R.sub.t represent aryl or substituted aryl,
suitable aryl groups are phenyl groups.
[0063] In one favoured aspect R.sub.t is hydrogen.
[0064] Suitable heterocyclic groups include single ring saturated
heterocyclic groups, single ring unsaturated heterocyclic groups,
fused ring heterocyclic groups.
[0065] Fused ring heterocyclic groups include spiro heterocyclic
groups.
[0066] Suitable single ring unsaturated heterocyclic groups
comprise 5-, 6- or 7-membered rings.
[0067] Suitable 5-membered single ring unsaturated heterocyclic
groups are furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,
triazolyl, tetrazolyl, oxazolyl, isoxazolyl, furazanyl, thiazolyl
and isothiazolyl groups; or partially saturated derivatives
thereof, such as 4,5-dihydro-1,3-thiazol-- 2-yl, 1H-imidazolinyl,
pyrrolinyl, pyrazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl
groups.
[0068] Suitable 6-membered single ring unsaturated heterocyclic
groups are pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,
tetrazinyl, 1,2- or 1,3- or 1,4-oxazinyl, 1,2-or 1,3- or
1,4-thiazinyl and pyranyl groups, or partially saturated
derivatives thereof such as 1,2- or 1,3- or 1,4- dihydrooxazinyl,
1,4-dihydropyridyl, dihydropyridazinyl, dihydropyrazinyl or
dihydropyrimidinyl.
[0069] A further suitable 6-membered single ring unsaturated
heterocyclic group is a pyridin-2-one-5-yl group.
[0070] Suitable 7-membered single ring unsaturated heterocyclic
groups are azepinyl, oxepinyl, diazepinyl, thiazepinyl, oxazepinyl
or partially saturated derivatives thereof.
[0071] Suitable, single ring saturated heterocyclic groups comprise
5-, 6- or 7-membered rings.
[0072] Suitable 5-membered single ring saturated heterocyclic
groups are pyrrolidinyl, imidazolidinyl, pyrazolidinyl,
oxazolidinyl, isoxazolidinyl and terahydroftiranyl groups.
[0073] Suitable 6-membered single ring saturated heterocyclic
groups are piperidinyl, piperazinyl, tetrahydropyranyl,
1,3-dioxacyclohexyl, tetrahydro-1,4-thiazinyl, morpholinyl and
morpholino groups.
[0074] Suitable piperazinyl groups are 1-piperazinyl groups,
especially 1-piperazinyl groups substituted in the 4 position with
an acyl group, suitably a phenylcarbonyl group, or a heterocyclic
group, such as a pyrimidyl group, or an optionally substituted
phenyl group, such as a phenyl group with 1, 2, or 3 subsitutents
selected from alkoxy and halogen.
[0075] Suitable 7-membered single ring saturated heterocyclic
groups are hexamethyleniminyl, oxepanyl and thiepanyl.
[0076] Suitable fused ring heterocyclic groups include fused
saturated rings, fused unsaturated rings and saturated rings fused
to unsaturated rings.
[0077] Preferred fused ring heterocyclic groups include those
comprising two or three rings wherein each ring comprises 4 to 8
ring atoms including 1, 2 or 3, especially 1 or 2, hetero
atoms.
[0078] Suitable hetero atoms are nitrogen atoms.
[0079] Suitable groups having fused saturated rings are polycyclic
groups wherein the rings share a single atom, one bond or more than
one bond, for example 2 bonds or three bonds. Suitable groups
having fused saturated rings are quinuclidyl,
8-azabicyclo[3.2.1]octyl, 9-azabicyclo[3.3.1]nonyl,
1-azabicyclo[3.3.3]undecyl, 1,9-diazabicyclo[3.3.1] and
1,5-diazabicyclo[3.3.1]nonyl groups.
[0080] Further suitable groups having fused saturated rings are
decahydro-pyrrolo[2.1.5-cd]indolizinyl, octahydroindolizinyl,
octahydro-2H-quinolizinyl and tricyclo[3.3.1.1.sup.3.7]decyl
groups.
[0081] A further suitable group comprising a fused saturated ring
is a nonyl 1-azabicyclo[3.3.1]nonyl, 3,7-diazabicyclo[3.3.1]nonyl
group.
[0082] Suitable groups having fused unsaturated rings are
pyrazo[3.4-d]pyrimidinyl, 1,2,5-thiadiazolo[3,4-b]pyridyl,
isoxazolo[4,5-b]pyridyl, thiazolo[4,5-b]pyridyl,
oxazolo[4,5-d]pyrimidiny- l, 7H-purin-2-yl, quinolyl, isoquinolyl,
benzo[b]thienyl, benzofuranyl, isobenzofuranyl, benzoxazolyl,
benzothiazolyl, indolizinyl, indolyl, isoindolyl, indazolyl,
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,
cinnolinyl, pteridinyl and .beta.-carbolinyl groups.
[0083] Suitable groups having saturated rings fused to unsaturated
rings includes groups which are fused to benzene rings such as
tetrahydroquinolyl, 4H-quinolizinyl, tetrahydroisoquinolyl,
dihydrobenzofuryl, chromenyl, chromanyl, isochromanyl, indolinyl
and isoindolinyl groups.
[0084] Suitable spiro heterocyclic groups include
oxaspiro[4.5]decyl, azaspiro[4.5]decyl,
1,2,4-triazaspiro[5.5]undecyl, 1,4-dioxa-9-azaspiro[4.7]dodecyl and
1-azaspiro[5.5]undecyl.
[0085] Suitable values for R.sub.s include hydrogen, C.sub.1-5
alkyl, mono- di- and tri-hydroxyalkyl, alkoxyalkyl, carboxyalkyl,
carbalkoxyalkyl, bisphosphonylalkyl,
(substituted)amino-carboxyalkyl, biscarbethoxy-hydroxyalkenyl,
dialkylaminoalkylpyridyl, mono- di- and tri-alkoxypyridyl,
dialkylaminoalkoxypyridyl, aryloxypyridyl, aminopyridyl,
substituted piperazinyl, quinuclidyl, saturated heterocyclylalkyl,
substituted piperidinyl, (di)azabicycloalkyl, substituted phenyl,
substituted benzyl, substituted phenylethyl, 1-imidazolylalkyl,
thiazolinyl, (2-tetrahydroisoquinolinyl)alkyl,
1H-pyrazolo[3,4-d]pyrimidin-4-yl, 7H-purin-2-yl, pyridylalkyl,
(2-pyrimidinyl)piperazin-1-ylalkyl, substituted pyridazinyl,
substituted pyrazinyl, substituted pyrimidinyl, quinolyl,
isoquinolyl, tetrahydroisoquinolyl, tetrahydroquinolyl.
[0086] Other suitable valuse for Rs include ,
(4-substituted)piperazinoalk- yl and aminopyrimidiniyl.
[0087] Preferred values for R.sub.s include diethylaminopropyl,
3-amino-3-carboxypropyl, 4-amino-4-carboxybutyl, 3-pyridyl,
diethylaminoethyl, 3quinuclidyl (or 1-azabicyclo[2.2.2]octan-3-yl),
morpholinopropyl, piperidinopropyl, 1-methyl-2-pyrrolidinylethyl,
2,2,6,6-tetramethyl-4-piperidinyl, 2-methoxy-5-pyridyl,
2-methylpiperidinopropyl,
8-methyl-8-azabicyclo[3.2.1]oct-3.beta.-yl, 1-methyl-4-piperidinyl,
1H-pyrazolo[3,4-d]pyrimidin-4-yl,
2,2,5,5-tetramethyl-3-pyrrolidinylmethyl, 2-methoxy-4-pyridyl,
1-ethyl-3-piperidinyl,
3-[4-(2-pyrimidinyl)piperazin-1-yl]propyl.
[0088] Other preferred values for R.sub.s include
dimethylaminopropyl, dibutylaminopropyl, 2-methoxy-pyrimidin-5-yl,
3-[4-(3-chlorophenyl)pipera- zin-1-yl]propyl,
3-[4-(2-phenyl)piperazin-1-yl]propyl,
3-[2,6-dimethyl-4-(2-pyrimidinyl)piperazin-1-yl]propyl],
3-dimethylamino-cyclohexyl,
1-(2-hydroxyethyl)-2,6-dimethylpiperidin-4-yl- , 8a
.beta.H-5.alpha.-methyl-octahydroindolizin-7.alpha.-yl,
3-[4-(2-pyridyl)piperazin-1-yl]propyl,
3-[4-(2-methoxyphenyl)piperazin-1-- yl]propyl and
3-[4-(2-pyrimidinyl)homopiperazin-1-yl]propyl].
[0089] Other preferred values for R.sub.s include
1,2,2,6,6pentamethyl-4-p- iperidinyl, 1,2,6-trimethyl-4-piperidinyl
and 1,2,2,6-tetramethyl-4-piperi- dinyl groups.
[0090] Suitable values for R.sub.t include hydrogen, methyl,
C.sub.2-5 alkyl, 2-hydroxyethyl, 2-methoxyethyl, carboxymethyl,
carbomethoxymethyl, 4-hydroxybutyl and 2,3-dihydroxypropyl,
especially hydrogen.
[0091] In one preferred aspect R.sub.t represents hydrogen.
[0092] A particular 6 membered single ring unsaturated heterocyclic
group is a moiety of formula (H1): 7
[0093] wherein Z.sub.1 is N or CX.sub.5 wherein X.sub.5 is selected
from hydrogen, alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy or
arylcarbonyl and Z.sub.2, X.sub.3 and X.sub.4 are each
independently selected from hydrogen, alkyl, aryl, cyano, amino,
heterocyclyloxy, alkoxy carbonylalkyloxy, carboxyalkyloxy,
aminoalkyloxy, aminoalkylamino, aminoalkenylamino (especially
aminomethyleneamino) and alkanoylamino. A particularly preferred
compound of the invention is a compound of formula (I) wherein:
R.sub.a is a group R.sub.5 wherein R.sub.5 is as defined in
relation to formula (I); R.sub.b is a moiety of formula (a) wherein
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined in relation to
formula (I) and X is a moiety NR.sub.sR.sub.t wherein R.sub.s is a
group (H1) as defined above, and R.sub.t is hydrogen.
[0094] A favoured moiety NR.sub.sR.sub.t, is an optionally
substituted piperidinyl group, especially wherein one of the
substituents is an N-alkyl group.
[0095] Particular substituents for piperidinyl groups are alkyl
groups, especially when attached to one or, favourably, both of the
carbon atoms alpha to the ring nitrogen atom.
[0096] Piperidinyl groups of especial interest are those wherein
one or, favourably, both of the carbon atoms alpha to the ring
nitrogen atom are substitued with one or, favourably, two alkyl
groups.
[0097] Further particular substituents for piperidinyl groups are
alkylene groups, especially when attached to one, favourably both,
of the carbon atoms alpha to the ring nitrogen atom.
[0098] A particular 6 membered, saturated heterocyclic group is a
group of formula (H2): 8
[0099] wherein X.sub.6, X.sub.7, X.sub.8, X.sub.9, X.sub.10,
X.sub.11, X.sub.12 and X.sub.13 are each independently selected
from hydrogen, hydroxy, alkyl, suitably C.sub.1-6 alkyl, cycloalkyl
(including spirocondensed), mono or poly hydroxyalkyl, alkoxyalkyl,
hydroxy-alkoxyalkyl, alkanoyl, alkoxycarbonyl, aminoalkyl
(optionally alkylated or acylated at nitrogen);
[0100] or one of X.sub.6 with X.sub.12 and X.sub.8 with X.sub.10
represents a C.sub.2-4 alkylene chain and the remaining variables
X.sub.7, X.sub.13, X.sub.8 and X.sub.11 each independently
represent hydrogen, hydroxy, alkyl, suitably C.sub.1-6 alkyl,
cycloalkyl (including spirocondensed), mono or poly hydroxyalkyl,
alkoxyalkyl, hydroxy-alkoxyalkyl, alkanoyl, alkoxycarbonyl,
aminoalkyl (optionally alkylated or acylated at nitrogen); and
X.sub.14 represents hydrogen or alkyl, especially C.sub.1-6 alkyl,
mono or polyhydroxyalkyl, mono or diaminoalkyl, aminocarbonyl,
alkylcarboxyalkyl, carbalkoxyalkyl, aryl, heterocyclyl, acyl,
carbamoyl, alkylamino(cyanimidoyl), aminoalkanoyl,
hydroxyalkanoyl.
[0101] Suitably, X.sub.6, X.sub.7, X.sub.12 and X.sub.13 each
represent hydrogen.
[0102] Suitably, X.sub.8, and X.sub.9 each independently represent
hydrogen or alkyl, especially alkyl, for example methyl.
[0103] Suitably, X.sub.10 and X.sub.11 each independently represent
hydrogen or alkyl, especially alkyl, for example methyl.
[0104] Suitably, X.sub.14 represents alkyl, for example methyl.
[0105] In one preferred aspect X.sub.8, X.sub.9, X.sub.10 and
X.sub.11 each independently represent alkyl, especially methyl, and
X.sub.6, X.sub.7, X.sub.12 and X.sub.13 each represent
hydrogen.
[0106] In a most preferred aspect X.sub.8, X.sub.9, X.sub.10 and
X.sub.11 each independently represent alkyl, especially methyl, and
X.sub.6, X.sub.7, X.sub.12 and X.sub.13 each represent hydrogen and
X.sub.14 represents alkyl, especially methyl.
[0107] A preferred compound of the invention is a compound of
formula (I) wherein R.sub.a is a group R.sub.5 wherein R.sub.5 is
as defined in relation to formula (I); R.sub.b is a moiety of
formula (a) wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as
defined in relation to formula (I) and X is a moiety
NR.sub.sR.sub.t wherein R.sub.s is a moiety of formula (I) defined
below, especially a moiety (f) wherein k is zero and H.sub.0 is a
moiety (a) as defined below, or a moiety (H1) or (H2) as defined
above, and R.sub.t is hydrogen, suitably wherein R.sub.s is a
moiety of formula (H1) or (H2) and R.sub.6, R.sub.7 and R.sub.8 are
as defined in relation to formula (I).
[0108] A particularly preferred compound of the invention is a
compound at formula (I) wherein R.sub.a is a group R.sub.5 wherein
R.sub.5 is as defined in relation to formula (I); R.sub.b is a
moiety of formula (a) wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4
are as defined in relation to formula (I) and X is a moiety
NR.sub.sR.sub.t wherein R.sub.s is a group (H2), as defined above,
and R.sub.t is hydrogen and R.sub.6, R.sub.7 and R.sub.8 are as
defined in relation to formula (I).
[0109] Of particular mention are the compounds wherein R.sub.1 is
C.sub.1-6 alkyl, especially methyl, R.sub.2, R.sub.3, R.sub.4 and
R.sub.8 are hydrogen, R.sub.6 is 5-halo, especially 5-chloro,
R.sub.7 is 6-halo, especially 6-chloro, and X is a moiety
NR.sub.sR.sub.t wherein R.sub.t is hydrogen and R.sub.s is a moiety
of formula (f) defined below or a moiety (H1) or (H2) as defined
above, suitably wherein R.sub.s is a moiety of formula (H1) or
(H2).
[0110] Of particular mention are the compounds wherein R.sub.1 is
C.sub.1-6 alkyl, especially methyl, R.sub.2, R.sub.3, R.sub.4 and
R.sub.8 are hydrogen, R.sub.6 is 5-halo, especially 5-chloro,
R.sub.7 is 6-halo, especially 6-chloro, and X is a moiety
NR.sub.sR.sub.t wherein R.sub.t is hydrogen and R.sub.s is a moiety
(f), especially a moiety (f) wherein k is zero and Ho is a moiety
(a).
[0111] Of particular mention are the compounds wherein R.sub.1 is
C.sub.1-6 alkyl, especially methyl, R.sub.2, R.sub.3, R.sub.4 and
R.sub.8 are hydrogen, R.sub.6 is 5-halo, especially 5-chloro,
R.sub.7 is 6-halo, especially 6-chloro, and X is a moiety
NR.sub.sR.sub.t wherein R.sub.t is hydrogen and R.sub.s is a moiety
(H1).
[0112] Of particular mention are the compounds wherein R.sub.1 is
C.sub.1-6 alkyl, especially methyl, R.sub.2, R.sub.3, R.sub.4 and
R.sub.8 are hydrogen, R.sub.6 is 5-halo, especially 5-chloro,
R.sub.7 is 6-halo, especially 6-chloro, and X is a moiety
NR.sub.sR.sub.t wherein R.sub.t is hydrogen and Rs is a moiety
(H2).
[0113] Particular examples of the invention are the compounds of
example numbers 1, 31, 32 34, 35, 47, 48, 51, 55, 56, 59, 61, 62,
63, 68, 74 and 75.
[0114] Most particularly should be mentioned the compounds of
example numbers 1, 55, 62, 68, 74 and 75.
[0115] The present invention does not encompass the examples per se
of above mentioned co-pending International Application,
application number PCT/EP96/0015 publication number WO 96/21644.
Thus each of the examples of WO 96/21644 numbered 1 to 104 and each
of the examples disclosed on page 50 are excluded from the present
invention. Thus the invention excludes Examples 49, 51, 53, 59, 67,
69, 83, 84, 97 and 100 of WO 96/21644. Also, the invention excludes
examples 33, 44, 48, 57, 65, 73, 91, 95, 98, 99, 101 and 10 of WO
96/21644. In addition the invention excludes examples 47, 56, 66
and 70 of WO 96/21644.
[0116] As used herein, the term "alkyl" includes straight or
branched chain alkyl groups having from 1 to 12, suitably 1 to 6,
preferably 1 to 4, carbon atoms, such as methyl, ethyl, n- and
iso-propyl and n- iso-, tert-butyl and pentyl groups, and also
includes such alkyl groups when forming part of other groups such
as alkoxy or alkanoyl groups.
[0117] Suitable optional substituents for any alkyl group include
hydroxy; alkoxy; a group of formula NR.sub.uR.sub.v wherein R.sub.u
and R.sub.v each independently represent hydrogen, optionally
substituted alkyl, optionally substituted cycloalkyl, optionally
substituted aryl, optionally substituted arylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
carboxy, carboxyalkyl, or alkoxycarbonyl, nitro, or R.sub.u and
R.sub.v together with the nitrogen to which they are attached form
an optionally substituted heterocyclic ring; carboxy;
alkoxycarbonyl; alkoxycarbonylalkyl; alkylcarbonyloxy;
alkylcarbonyl; mono-and di-alkylphosphonate; optionally substituted
aryl; and optionally substituted heterocyclyl.
[0118] A preferred alkyl substituent is NR.sub.uR.sub.v, wherein
R.sub.u and R.sub.v each independently represent hydrogen,
optionally substituted aryl, optionally substituted arylalkyl,
optionally substituted heterocyclyl, optionally substituted
heterocyclylalkyl or R.sub.u and R.sub.v together with the nitrogen
to which they are attached form an optionally substituted
heterocyclic ring.
[0119] When R.sub.s or R.sub.t represents substituted alkyl,
especially C.sub.1-4 alkyl, particular substituent values are the
moieties of formulae (a), (b), (c), (d) and (e): 9
[0120] wherein A represents a bond or alkylene, suitably C.sub.1-3
alkylene, A.sub.1 is alkylene, suitably C.sub.1-4 alkylene, and
R.sub.a, R.sub.b, R.sub.c, R.sub.d, R.sub.e, R.sub.f and R.sub.g
each independently represent hydrogen, alkyl, optionally
substituted aryl or an optionally substituted heterocyclic group
and R.sub.u and R.sub.v are as defined above.
[0121] One suitable alkyl substituent value is moiety (a).
[0122] One suitable alkyl substituent value is moiety (b).
[0123] One suitable alkyl substituent value is moiety (c).
[0124] One suitable alkyl substituent value is moiety (d).
[0125] One suitable alkyl substituent value is moiety (e).
[0126] In moiety (a), one preferred value for NR.sub.uR.sub.v is a
1-piperazinyl group, preferably substituted in the 4 position with
an acyl group, suitably a phenylcarbonyl group, or a heterocyclic
group, such as a pyrimidyl group, or an optionally substituted
phenyl group, such as a phenyl group with 1, 2 or 3 subsitutents
selected from alkoxy, alkyl, trifluoromethyl, and halogen, for
example chlorine and methoxy.
[0127] Thus one preferred value of R.sub.s or R.sub.t is a moiety
of formula (f):
--(CH.sub.2).sub.k--(HO) (f)
[0128] wherein k is zero and H.sub.0 is a moiety (a) or k is an
integer 2 or 3 and H.sub.0 is a moiety (b), (c), (d) and (e).
[0129] Preferably in moiety (f), k is zero and H.sub.0 is a moiety
(a).
[0130] As used herein, the term "alkenyl" includes straight or
branched chain alkenyl groups having from 2 to 12, suitably 2 to 6
carbon and also includes such groups when forming part of other
groups, an example is a butenyl group, such as a 2-butenyl
group.
[0131] Suitable optional substituents for any alkenyl group
includes the alkyl substituents mentioned above.
[0132] As used herein, the term "aryl" includes phenyl and
naphthyl, especially phenyl.
[0133] Suitable optional substituents for any aryl group include up
to 5 substituents, suitably up to 3 substituents, selected from
alkyl, substituted alkyl, alkoxy, hydroxy, halogen,
trifluoromethyl, acetyl, cyano, nitro, amino, mono-and
di-alkylamino and alkylcarbonylamino.
[0134] Preferred optional substituents for any aryl group are
selected from isobutyl, hydroxy, methoxy, phenoxy,
diethylaminoethoxy, pyrrolidinoethoxy, carboxymethoxy, pyridyloxy,
fluoro, chloro, amino, dimethylamino, aminomethyl, morpholino,
bis(carbethoxy)hydroxymethyl, Suitable arylalkyl groups include
aryl-C.sub.1-3-alkyl groups such as phenylethyl and benzyl groups,
especially benzyl.
[0135] Preferably, substituted aralkyl groups are substituted in
the aryl moiety.
[0136] As used herein, the terms "heterocyclyl" or "heterocyclic"
include saturated or unsaturated single or fused, ring heterocyclic
groups, each ring having 4 to 11 ring atoms, especially 5 to 8,
preferably 5, 6 or 7 which ring atoms include 1, 2 or 3 heteroatoms
selected from O, S, or N.
[0137] As used herein `fused ring heterocyclic group` includes
polycyclic heterocyclic groups which share a single atom, such as a
spiro ring system, one bond, as in an octahydroindolizinyl group,
or more than one bond, as in an azabicyclo[3.2.1]oct-3-alpha-yl
group.
[0138] Suitable optional substituents for any heterocyclyl or
heterocyclic group include up to 5 substituents, suitably up to 3
substituents, selected from alkyl, substituted alkyl, alkoxy,
hydroxy, halo, amino, mono- or di-alkyl amino, alkoxycarbonyl,
hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkoxyalkyloxyalkyl,
aryl, aryloxy and heterocyclyl.
[0139] Preferred optional substituents for any heterocyclyl or
heterocyclic group are selected from isobutyl, hydroxy, methoxy,
phenoxy, diethylaminoethoxy, pyrrolidinoethoxy, carboxymethoxy,
pyridyloxy, fluoro, chloro, amino, dimethylamino, aminomethyl,
morpholino, bis(carbethoxy)hydroxymethyl.
[0140] Further optional substituents for any heterocyclyl or
heterocyclic group include up to 5, suitably up to 3, substituents
selected from the list consisting of: isopropyl, cyano, oxo,
arylcarbonyl, heterocyclyloxy, alkoxyalkoxy,
alkoxycarbonylalkyloxy, carboxyalkyloxy, aminoalkyloxy,
aminoalkylamino, aminoalkenylamino (especially
aminomethyleneamino), alkanoylamino, alkoxyamino, aryl, acetamido,
2-(dimethylamino)ethylamino, 2-methoxyethoxy, 3-carboxyprop-2-oxy
and 2-pyrazinyl.
[0141] Additional optional substituents for any hetrocyclyl or
heterocyclic group include up to 5, suitably up to 3, substituents
selected from the list consisting of: carbonylaminoalkyl,
aminocarbonylalkyl and alkylcarbonylaminoalkyl.
[0142] For the avoidance of doubt a reference herein to
"heterocyclic" includes a reference to "heterocyclyl".
[0143] As used herein, the term "halo" includes fluoro, chloro,
bromo and iodo, suitably fluoro and chloro, favourably chloro.
[0144] Certain of the carbon atoms of the compounds of formula
(I)--such as those compounds wherein R.sub.1-R.sub.8 contains
chiral alkyl chains are chiral carbon atoms and may therefore
provide stereoisomers of the compound of formula (I). The invention
extends to all stereoisomeric forms of the compounds of formula (I)
including enantiomers and mixtures thereof, including racemates.
The different stereoisomeric forms may be separated or resolved one
from the other by conventional methods or any given isomer may be
obtained by conventional stereospecific or asymmetric
syntheses.
[0145] The compounds of formula (I) also possess two double bonds
and hence can exist in one or more geometric isomers. The invention
extends to all such isomeric forms of the compounds of formula (I)
including mixtures thereof. The different isomeric forms may be
separated one from the other by conventional methods or any given
isomer may be obtained by conventional synthetic methods. Suitable
salts of the compounds of the formula (I) are pharmaceutically
acceptable salts. A preferred isomer is the 2Z, 4E isomer.
[0146] Certain of the compounds herein can exist in various
tautomeric forms, for example when hydroxy is a substituent on an
aryl or heteroaryl ring; it is to be understood that the invention
encompasses all such tautomeric forms.
[0147] Suitable pharmaceutically acceptable salts include acid
addition salts and salts of carboxy groups.
[0148] Suitable pharmaceutically acceptable acid addition salts
include salts with inorganic acids such, for example, as
hydrochloric acid, hydrobromic acid, orthophosphoric acid or
sulphuric acid, or with organic acids such, for example as
methanesulphonic acid, toluenesulphonic acid, acetic acid,
propionic acid, lactic acid, citric acid, fumaric acid, malic acid,
succinic acid, salicylic acid, maleic acid, glycerophosphoric acid
or acetylsalicylic acid.
[0149] Suitable pharmaceutically acceptable salts of carboxy groups
include metal salts, such as for example aluminiumn, alkali metal
salts such as sodium or potassium and lithium, alkaline earth metal
salts such as calcium or magnesium and ammonium or substituted
ammonium salts, for example those with C.sub.1-6 alkylamines such
as triethylamine, hydroxy-C.sub.1-6 alkylamines such as
2-hydroxyethylamine, bis (2-hydroxyethyl)-amine or
tri-(2-hydroxyethyl)amine, cycloalkylamines such as
dicyclohexylamine, or with procaine, 1,4-dibenzylpiperidine,
N-benzyl-.beta.-phenethylamine, dehydroabietylamine,
N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases
of the pyridine type such as pyridine, collidine or quinoline.
[0150] Suitable solvates of the compounds of the formula (I) are
pharmaceutically acceptable solvates, such as hydrates.
[0151] The salts and/or solvates of the compounds of the formula
(I) which are not pharmaceutically acceptable may be useful as
intermediates in the preparation of pharmaceutically acceptable
salts and/or solvates of compounds of formula (I) or the compounds
of the formula (I) themselves, and as such form another aspect of
the present invention.
[0152] A compound of formula (I) or a salt thereof or a solvate
thereof, may be prepared:
[0153] (a) for compounds of formula (I) wherein Ra represents
hydrogen, alkyl or optionally substituted aryl and R.sub.b
represents a moiety of the above defined formula (a), by reacting a
compound of formula (II): 10
[0154] wherein R.sub.2, R.sub.3, R.sub.4, R.sub.6, R.sub.7 and
R.sub.8 are as defined in relation to formula (I), with a reagent
capable of converting a moiety of formula 11
[0155] into a moiety of the above defined formula (a); or
[0156] (2) for compounds of formula (I) where R.sub.a represents a
moiety of the above defined formula (a) and R.sub.b represents
hydrogen, alkyl or optionally substituted aryl , by treating a
compound of formula (III): 12
[0157] wherein R.sub.4, R.sub.6, R.sub.7 and R.sub.8 are as defined
in relation to formula (I) with a compound of formula (IV): 13
[0158] wherein R.sub.1, R.sub.2, R.sub.3 and X are as defined in
relation to the compounds of formula (I) and R.sub.9 is a C.sub.1-4
alkyl group; and thereafter, as necessary, carrying out one or more
of the following reactions:
[0159] (i) converting one compound of formula (I) into another
compound of formula (I);
[0160] (ii) removing any protecting group;
[0161] (iii) preparing a salt or a solvate of the compound so
formed.
[0162] In reaction (a) above, a suitable reagent capable of
converting a moiety of the above defined formula 14
[0163] into a moiety of the above defined formula (a), includes
conventional reagents used to convert C.dbd.O bonds into carbon
carbon double bonds, such as Wittig or Horner-Emmons reagents, for
example those of formula (V): 15
[0164] wherein R.sub.1 is as defined in relation to the compounds
of formula (I), X.sub.1 represents X as defined in relation to
formula (I) or a group convertible thereto and X.sub.2 represents a
moiety (R.sub.9O).sub.2P(O)-- wherein R.sub.9 is as defined above
or a group Ph.sub.3P--.
[0165] The reaction between the compounds of formula (II) and the
reagent capable of converting the group of formula 16
[0166] into the moiety of formula (a), may be carried out under the
appropriate conventional conditions, depending upon the particular
reagent chosen, for example:
[0167] When the reagent is a compound of formula (V) wherein
X.sub.2 is a moiety (R.sub.9O).sub.2P(O)--, then the reaction is
carried out under conventional Horner-Emmons conditions, using any
suitable, aprotic solvent for example an aromatic hydrocarbon such
as benzene, toluene or xylene, DMF, DMSO, chloroform, dioxane,
dichloromethane, preferably, THF, acetonitrile,
N-methylpyrrolidone, and the like or mixtures thereof, preferably
an anhydrous solvent, at a temperature providing a suitable rate of
formation of the required product, conveniently at ambient
temperature or at an elevated temperature, such as a temperature in
the range of from 30.degree. C. to 120.degree. C.; preferably the
reaction is conducted in the presence of a base.
[0168] Suitable bases for use in the last above mentioned reaction
include organic bases, such as butyl lithium, lithium
diisopropylamide (LDA), N,N-diisopropylethylamine,
1,5-diazabicyclo[4.3.0]-5-nonene (DBN),
1,5-diazabicyclo[5.4.0]-5-undecene (DBU),
1,5-diazabicyclo[2.2.2]octane (DABCO), and inorganic bases, such as
sodium hydride; preferably sodium hydride, and generally the
reaction is carried out in an inert atmosphere such as
nitrogen.
[0169] When the reagent is a compound of formula (V) wherein
X.sub.2 is a moiety Ph.sub.3P--, then the reaction is carried out
under conventional Wittig conditions. Usually, the reaction is
carried out in the presence of a base, in any suitable aprotic
solvent. Suitable bases are organic bases such as triethylamine,
trimethylamine, N,N-diisopropylethylamine (DIPEA), pyridine,
N,N-dimethylaniline, N-methylmorpholine,
1,5-diazabicyclo[4.3.0]-5-nonene (DBN),
1,5-diazabicyclo[5.4.0]-5-undecen- e (DBU),
1,5-diazabicyclo[2.2.2]octane (DABCO) and inorganic bases such as
sodium hydride, caesium carbonate, potassium carbonate, preferably
sodium hydride. Suitable solvents are conventional solvents for use
in this type of reaction, such as aromatic hydrocarbons such as
benzene, toluene or xylene or the like; DMF, DMSO, chloroform,
dioxane, dichioromethane, THF, ethyl acetate, acetonitrile,
N-methylpyrrolidone or mixtures thereof, preferably
dichloromethane. This reaction is carried out at any temperature
providing a suitable rate of formation of the required product,
conveniently at ambient temperature or at an elevated temperature,
such as a temperature in the range of from -20.degree. C. to
140.degree. C., preferably in the range of from about room
temperature to the reflux temperature of the solvent.
[0170] The reaction between the compounds of formula (III) and the
Horner Emmons reagent of formula (TV) may be carried out under
conventional Horner Emmons conditions such as those described
above.
[0171] A compound of formula (II) may be prepared according to the
reaction sequences shown in Schemes (Ia-c) below 17
[0172] wherein, subject to any qualification mentioned below,
R.sub.a, R.sub.2, R.sub.3, R.sub.4, R.sub.6, R.sub.7 and R.sub.8
are as defined in relation to the compounds of formula (I).
[0173] Compounds of formula (II) may be prepared using either
Wittig or Horner-Emmons reactions of keto derivatives of formula
(VIII) with the appropriate phosphonium salt or phosphonate using
the reaction conditions which are known in the art and described,
for example in "The Wittig Reaction", R. Adams Ed., Vol. 14, p. 270
(1965) or in Angew. Chem. Int. Ed. Engl., 4, 645 (1965).
[0174] When R.sub.2 is other than --H , e.g. alkyl, a compound of
formula (II) is obtained directly from a compound of formula (VIII)
by Wittig or Horner-Emmons reaction with the appropriate
phosphonium salts or phosphonates according to Scheme (Ia).
[0175] When a compound of formula (VIII) is reacted with the above
mentioned phosphonates using the Horner-Emmons reaction, the
experimental conditions used are conventional conditions such as
those reported, in Tetrahedron Lett. 1981, 461; Can. J. Chem., 55,
562 (1977); J. Am. Chem. Soc., 102, 1390 (1980); J. Org. Chem., 44,
719 (1979); Synthesis, 1982, 391; and Tetrahedron Lett. 1982,
2183.
[0176] The reaction of compounds of formula (VIII) with the above
mentioned phosphonium salts are carried out in the presence of a
base in any suitable solvent.
[0177] Suitable bases include organic bases, such as triethylamine,
trimethylamine, N,N-diisopropylethylamine (DIPEA), pyridine,
N,N-dimethylaniline, N-methylmorpholine,
1,5-diazabicyclo[4.3.0]-5-nonene (DBN),
1,5-diazabicyclo[5.4.0]-5-undecene (DBU), 1,5-diazabicyclo[2.2.2]o-
ctane (DABCO) and inorganic bases, such as sodium hydride, caesium
carbonate, potassium carbonate. Suitable solvents include
conventionally used solvents, for example aromatic hydrocarbons
such as benzene, toluene or xylene or the like; DMF, DMSO,
chloroform, dioxane, dichloromethane, THF, ethyl acetate,
acetonitrile, N-methylpyrrolidone and the like or mixtures thereof.
Preferably, the reaction is carried out at a reaction temperature
of in the range of about -20.degree. C. to 140.degree. C.,
preferably about room temperature to the reflux temperature of the
solvent.
[0178] The reaction of compounds of formula (VIII) with
phosphonates are carried out under conventional Horner-Emmons
conditions, using any suitable, aprotic solvent for example an
aromatic hydrocarbon such as benzene, toluene or xylene, DMF, DMSO,
chloroform, dioxane, dichioromethane, preferably, THF,
acetonitrile, N-methylpyrrolidone, and the like or mixtures
thereof, preferably an anhydrous solvent, at a temperature
providing a suitable rate of formation of the required product,
conveniently at ambient temperature or at an elevated temperature,
such as a temperature in the range of from 30.degree. C. to
120.degree. C.; preferably the reaction is conducted in the
presence of a base.
[0179] Suitable bases for use in the last above mentioned reaction
include organic bases, such as butyl lithium, lithium
diisopropylamide (LDA), N,N-diisopropylethylamine,
1,5-diazabicyclo[4.3.0]-5-nonene (DBN),
1,5-diazabicyclo[5.4.0]-5-undecene (DBU),
1,5-diazabicyclo[2.2.2]octane (DABCO), and inorganic bases, such as
sodium hydride; preferably sodium hydride, and generally the
reaction is carried out in an inert atmosphere such as
nitrogen.
[0180] When R.sub.2.dbd.H, aldehyde (VII) is reacted with aliphatic
aldehydes of formula (VI) in presence of bases such as sodium or
potassium hydroxide affording compound (II) as in Scheme (Ib),
using the appropriate conventional procedure.
[0181] In a further aspect, when R.sub.2.dbd.H, a compound of
formula (VIII) is reacted with a substituted
carbethoxymethylphosphonium salt or carbethoxymethylphosphonate
(Scheme (Ic)), the carboxylic ester obtained (XIV) is then
converted into the corresponding alcohol with a reducing agent,
suitably a complex metal reducing agent such as lithium aluminium
hydride (LiAlH.sub.4), diisobutyl aluminum hydride (DIBAH) or
lithium borohydride (LiBH.sub.4), in any suitable aprotic solvent
for example methylene dichloride, chloroform, dioxane, diethyl
ether or THF, at any temperature providing a suitable rate of
formation of the required product, such as a temperature in the
range of from -30.degree. C. to 60.degree. C., for example at room
temperature. Then, the intermediate alcohol is oxidised to aldehyde
(II) with an oxidising agent such as manganese dioxide, periodinane
(Dess-Martin reagent), pyridinium chlorochromate (PCC) or
pyridinium dichromate (PDC) or a combination of oxalyl chloride and
DMSO (Swern reaction), preferably manganese dioxide in methylene
dichloride.
[0182] A compound of formula (IV) may be prepared according to the
reaction sequence shown in Scheme (II) below. 18
[0183] wherein, subject to any qualification mentioned below,
R.sub.1, R.sub.2 and R.sub.3 are as defined in relation to formula
(I), R.sub.9 is as defined in relation to formula (IV) and X.sub.1
is as defined in relation to formula (V).
[0184] Compounds of formula (X) are prepared by reaction of,
preferably anhydrous, chloroaldehydes or chloroketones of formula
(IX) with suitable phosphonium compounds using the appropriate
conventional procedure as described above for the Wittig reaction;
conversion of intermediate compound (X) into the desired compound
(IV) may be effected by reaction with a suitable trialkylphosphite
(R.sub.9O).sub.3P wherein R.sub.9 is as defined above, and the
reaction is performed in any conventionally used solvent,
preferably the trialkyl phosphite, and at a suitable reaction
temperature, preferably at the boiling point of the solvent. For
example from Scheme (II): the chloroacetaldehyde (IX) was treated
with methyl 2-methoxy-2-(triphenylphosphonium)acetate bromide in
the presence of DIPEA in chloroform and the intermediate (X) so
obtained was converted into compound (IV) by refluxing in trimethyl
phosphite.
[0185] The compounds of formula (V) can be prepared according to
the reaction sequence shown in Scheme (III) below: 19
[0186] wherein, subject to any qualification mentioned below,
R.sub.1 and R.sub.9 are as defined in relation to formula (I) and
XI is as defined in relation to formula (V).
[0187] The starting material is an .alpha.-alkoxycarboxylic ester
of formula (XI) which is commercially available or which is
prepared according to the methods known in the art, for example
those reported in Rodd's Chemistry of Organic Compounds, Vol ID, p.
96 (1965), S. Coffey Ed., Elseviers. The compound of formula (XI)
is reacted with an N-haloimide, for example N-bromosuccinimide in
the presence of a radical producing agent such as
azobisisobutyrronitrile or benzoyl peroxide in a suitable solvent
such as carbon tetrachloride, benzene, for example carbon
tetrachloride and at a reaction temperature in the range of from
-30.degree. C. and 80.degree. C., for example at room temperature;
examples of such a reaction may be found in the literature, for
example J. Org. Chem., 41, 2846 (1976). The halocompound obtained,
of formula (XII), is then reacted either with triphenylphosphine or
with a trialkyl phosphite P(OR.sub.9).sub.3 to give the required
compound of formula (V) as shown in scheme (III).
[0188] When the compound of formula (XII) is reacted with
triphenylphosphine, the reaction is performed in any conventionally
used solvent, for example diethyl ether, dioxane, tetrahydrofuran,
benzene, xylene or, preferably, toluene at a suitable reaction
temperature in the range of from -30.degree. C. to 80.degree. C.,
for example at room temperature (examples of this conversion are
reported in the literature, for example in Chem. Ber., 97, 1713
(1964)).
[0189] When the compound of formula (XII) is reacted with trialkyl
phosphite P(OR.sub.9).sub.3, the reaction is performed in any
conventionally used solvent, preferably the trialkyl phosphite, and
at a suitable reaction temperature, preferably at the boiling point
of the solvent (examples of this conversion are reported in the
literature, for example in Liebigs Ann. Chem., 699, 53 (1966)).
[0190] Alternatively, a compound of formula (V) in which R.sub.2 is
(R.sub.9O).sub.2PO may be prepared using the procedure depicted in
Scheme (III), by reacting a diazophosphonoacetates of formula
(XIII) with an alcohol or phenol of formula R.sub.1 OH, wherein
R.sub.1 is as defined in relation to formula (I), in the presence
of rhodium (II) acetate as described in the literature, for example
in Tetrahedron, 50, 3177 (1994) or in Tetrahedron, 48, 3991
(1992).
[0191] The compounds of formula (III), (VII) and (VIII), are known
compounds or they are prepared using methods analogous to those
used to prepare known compounds, such as those described in J. Org.
Chem., 47, 757 (1982); Heterocycles, 22, 1211 (1984); Tetrahedron,
44, 443 (1988), Liebigs Ann. Chem., 1986, 438; Chem. Pharm. Bull.,
20, 76,1972.
[0192] The compounds of formula (VI), (IX) and (XI) are known
compounds or they are prepared using methods analogous to those
used to prepare known compounds, such as those described in J.
March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley
Interscience.
[0193] Suitable conversions of one compound of formula (I) into
another compound of formula (I) includes converting a compound of
formula (I) wherein X represents a hydroxy group or an alkoxy group
into a compound of formula (I) wherein X represents a different
alkoxy group or a moiety of the above defined formula
NR.sub.sR.sub.t. Such conversions are shown below in Scheme (IV):
20
[0194] wherein, subject to any qualification mentioned below,
R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and X
are as defined in relation to the compounds of formula (I),
R.sub.s' is R.sub.s or a protected form thereof, R.sub.t' is
R.sub.t or a protected form thereof and R' is X when X is an alkoxy
group.
[0195] The conversion of one compound of formula (I) into another
compound of formula (I) may be carried out using the appropriate
conventional procedure; for example, the above mentioned conversion
of a compound wherein X represents a hydroxy group or an alkoxy
group into a compound wherein X represents a moiety of the above
defined formula NR.sub.sR.sub.t or another alkoxy group may be
carried out as follows:
[0196] (i) when X is alkoxy, by basic hydrolysis, using for example
potassium hydroxide, to provide a compound of formula (I) wherein X
is hydroxy, and thereafter(a) for preparing compounds wherein X
represents a moiety of the above defined formula NR.sub.sR.sub.t,
treating with a compound of formula HNR.sub.s'R.sub.t' wherein
R.sub.s' and R.sub.t' are as defined above or (b) for preparing
compounds of formula (I) wherein X represents alkoxy, by treating
with a compound of formula R'OH wherein R' is the required alkyl
group; and thereafter optionally deprotecting; or
[0197] (ii) when X is hydroxy, by using analogous procedures to
those mentioned above in (i).
[0198] Preferably the reaction with the compounds of formula
HNR.sub.s'R.sub.t' or with compounds of formula R'OH takes place
after activation of the carboxylic group.
[0199] A carboxyl group may be activated in conventional manner,
for example, by conversion into an acid anhydride, acid halide,
acid azide or an activated ester such as cyanomethyl ester,
thiophenyl ester, p-nitrophenyl ester, p-nityrothiophenyl ester,
2,4,6-trichlorophenyl ester, pentachlorophenyl ester,
pentafluorophenyl ester, N-hydroxyphthalimido ester,
8-hydroxypiperidine ester, N-hydroxysuccinimide ester,
N-hydroxybenzotriazole ester, or the carboxyl group may be
activated using a carbodiimide such as
N,N'-dicyclohexylcarbodiimide (DCC) or
1-ethyl-3-[3-(dimethylamino)propyl- ]-carbodiimide hydrochloride
(WSC), either in the presence or the absence of
hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt);
or it may be activated using N,N'-carbonyldiimidazole, Woodward-K
reagent, Castro's reagent or an isoxazolium salt.
[0200] Condensation of an activated carboxyl group with an amino
group or with an alcoholic group may be carried out in the presence
of a base, in any suitable solvent. Suitable bases include organic
bases, such as triethylamine, trimethylamine,
N,N-diisopropylethylamine (DIPEA), pyridine, N,N-dimethylaniline,
4-dimethylaminopyridine (DMAP), N-methylmorpholine,
1,5-diazabicyclo[4.3.0]-5-nonene (DBN),
1,5-diazabicyclo[5.4.0]-5-undecene (DBU),
1,5-diazabicyclo[2.2.2]octane (DABCO), and inorganic bases, such as
potassium carbonate. Suitable solvents include conventionally used
solvents, for example DMF, dimethyl sulfoxide (DMSO), pyridine,
chloroform, dioxane, dichloromethane, THF, ethyl acetate,
acetonitrile, N-methylpyrrolidone and hexamethylphosphoric triamide
and mixtures thereof. The reaction temperature may be within the
usual temperature range employed in this type of condensation
reaction, and generally in the range of about -40.degree. C. to
about 60.degree. C., preferably from about -20.degree. C. to about
40.degree. C.
[0201] When the reaction is carried out in the presence of a
suitable condensing agent, for example a carbodiimide,
N,N'-carbonyldiimidazole, Woodward-K reagent, Castro's reagent or
the like, the condensing agent is preferably employed in an amount
from equimolar to about 5 times the molar quantity of the starting
material and the reaction is performed in a suitable solvent for
example a halogenated hydrocarbon such as dichloromethane,
chloroform, carbon tetrachloride, tetrachloroethane or the like; an
ether such as dioxane, THF, dimethoxyethane or the like, a ketone
such as acetone, methyl ethyl ketone or the like; acetonitrile,
ethyl acetate, DMF, dimethylacetamide, DMSO or the like. Preferably
the condensation is carried out in an anhydrous solvent, and at a
reaction temperature in the range of from about -10.degree. C. to
60.degree. C., preferably about 0.degree. C. to room
temperature.
[0202] Alternatively, conversion of one compound of formula (I) in
which X is O-alkyl into another compound of formula (I) in which X
is NR.sub.sR.sub.t may be effected by treating the said compound of
formula (I) directly with a compound of formula HNR.sub.s'R.sub.t'
in the presence of a trialkylaluminium reagent such as
trimethylaluminium or triethylaluminium, according to known
procedures, such as those disclosed in Tetrahedron Lett., 48, 4171
(1977); and, if necessary, deprotecting or converting the compound
of formula (I) in which X is NR.sub.s'R.sub.t' into a compound of
formula (I) in which X is NR.sub.sR.sub.t.
[0203] The trialkylaluminium reagent is generally employed in the
above mentioned reactions in an amount of from equimolar to about 5
times the molar quantity of the starting material, preferably 2-3
times the molar quantity of the starting material and the reaction
is performed in a suitable solvent for example a halogenated
hydrocarbon such as dichloromethane, chloroform, carbon
tetrachloride, tetrachloroethane or the like; an ether such as
dioxane, THF, dimethoxyethane or the like. Preferably the
condensation is carried out in an anhydrous solvent, and at a
reaction temperature of about, generally -20.degree. C. to
120.degree. C., preferably about 0.degree. C. to the reflux
temperature of the solvent.
[0204] Amines of general formula HNR.sub.sR.sub.t may be prepared
using the methods known in the art for the preparation of amines,
for example as taught in Houben-Weil, Methoden der Organischen
Chemie, Vol. XI/1 (1957) and Vol. E16d/2 (1992), Georg Thieme
Verlag, Stuttgart.
[0205] In particular, amines of the general formula
HNR.sub.sR.sub.t wherein one of R.sub.s and R.sub.t represents
hydrogen and the other represents a moiety (a), (b), (c), (d) (e)
as defined above or a particular example thereof, are prepared
according to the methods summarised in Scheme (V) below: 21
[0206] wherein R is an alkyl or aryl group, R.sub.u and R.sub.v are
as defined above, X.sub.6 to X.sub.14 are as defined for (H2), A is
a bond or an alkylene chain, R.sub.10 is hydrogen (in (ii) and
(vii)) or halogen (in (iii)) and R.sub.11 is an alkyl group,
R.sub.12 is alkyl or aryl, L and L.sub.1 are leaving groups, for
example halogen or mesylate, Y is halogen, Y.sub.1 is a leaving
group, for example a halogen and and Y.sub.1 and Y.sub.2 are
leaving groups such as halogens, for example Y.sub.1 is chloride
and Y.sub.2 is bromine, Z.sub.1 is N or CY.sub.3 wherein Y.sub.3 is
selected from hydrogen, alkyl, alkoxy, alkylcarbonyl, aryl, aryloxy
or arylcarbonyl.
[0207] The reactions of condensation in (i) are performed under
conventional reaction conditions as described in J. March, Advanced
Organic Chemistry, 3rd Edition, 1985, Wiley Interscience.
[0208] The reduction of the amide function in (i) is suitably
carried out using known methods, for example by using mixed hydride
reducing agents, such as lithium aluminium hydride and methods
described in Org Synth Coll Vol 4 564.
[0209] Protection of the primary amino group in (i) can entail the
use of classical carbamate protecting agents such as
t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or
fluorenylmethoxycarbonyl (Fmoc), or of the phthalimido protecting
group. The synthesis and the removal of such protective groups is
described in, for example, in Protective Groups in Organic
Synthesis, T. W Greene Ed., Wiley, New York, 1981.
[0210] The reduction of the nitrile in (i) is suitably carried out
using known methods, for example following the procedure described
in J. Med. Chem., 39, 1514, (1996).
[0211] The reduction of the nitropyridine in (ii) is suitably
carried out using the method described in J. Org. Chem. 58, 4742
(1993).
[0212] The alkylation of the hydroxy-nitropyridine in (ii) may be
effected by using the method described in J. Org. Chem 55, 2964
(1990).
[0213] The displacement reaction in (iii) and (vii) is suitably
carried out using the method described in Helvetica Chemica Acta 47
(2), 45 (1964).
[0214] The reduction of the nitrile in (v) is suitably carried by
catalytic hydrogenation over platinium oxide.
[0215] The reduction of nitro group in (vii) is suitably carried
out using the method described in J. Org. Chem. 58, 4742
(1993).
[0216] The reaction of acid halide NC--A--COY to provide the
dialkylphosphonate in (iv) is effected by following the procedure
described in J Org Chem 36, 3843 (1971).
[0217] The reaction of the azide with triphenylphosphine in (v) is
carried out in wet tetrahydrofuran as described in Bull Soc Chim Fr
1985, 815.
[0218] The azides in (v) are prepared as shown using
azidotrimethylsilane, following the procedure described in
Synthesis 1995, 376.
[0219] The reaction of compound Y.sub.1--A--Y.sub.2 and the amine
derivative in (v) proceeds under conventional displacement reaction
conditions.
[0220] The reactions in (vi) can be performed using known,
conventional methods, as described in J. March, Advanced Organic
Chemistry, 3rd Edition, 1985, Wiley Interscience. For example,
oxidation can be performed using oxidising agents such as chromic
acid (Jones reagent); reductive amination of the ketone in can be
performed with benzylamine to give an imine intermediate which is
then reduced using known methods and reducing agents such as sodium
borohydride or lithium aluminium hydride. Debenzylation can then be
performed again using conventional methods, for example with
hydrogen in the presence of a catalyst such as palladium on
charcoal. Protection of ketone as the ethylene ketal can be
performed with ethylene glycol under acidic catalysis; acylations
or alkylations can be performed by treating the suitable piperidine
derivatives with acyl or alkyl halides in the presence of an
inorganic or organic base; deprotection of the dioxolane to the
ketone can be effected by acidic treatment in aqueous or alcoholic
solvents. Protection on the primary amino group in 4
aminopiperidines can entail the use of classical carbamate
protecting agents such as t-butoxycarbonyl (Boc), benzyloxycarbonyl
(Cbz) or fluorenylmethoxycarbonyl (Fmoc), or of the phthalimido
protecting group: the synthesis and the removal of such protective
groups is described in, for example, in Protective Groups in
Organic Synthesis, T. W Greene Ed., Wiley, New York, 1981.
4-Oxopiperidines can be converted into the corresponding oximes by
treatment with hydroxyl- or alkoxyl-amine in a suitable solvent;
reduction of the oxime to amine can be performed using conventional
reducing agents such as lithium aluminium hydride or sodium
cyanoborohydryde.
[0221] The starting materials in the above reactions (i), (ii),
(iii), (iv), (v), (vi) and (vii) are known, commercially available
compounds.
[0222] A compound of formula (I) or a solvate thereof may be
isolated from the above mentioned processes according to standard
chemical procedures.
[0223] The preparation of salts and/or solvates of the compounds of
formula (I) may be performed using the appropriate conventional
procedure.
[0224] If required mixtures of isomers of the compounds of the
invention may be separated into individual stereoisomers and
diastereoisomers by conventional means, for example by the use of
an optically active acid as a resolving agent. Suitable optically
active acids which may be used as resolving agents are described in
"Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971,
Allinger, N. L. and Eliel, W. L. Eds.
[0225] Alternatively, any enantiomer of a compound of the invention
may be obtained by stereospecific synthesis using optically pure
starting materials of known configuration.
[0226] The absolute configuration of compounds may be determined by
conventional methods such as X-ray crystallographic techniques.
[0227] The protection of any reactive group or atom, may be carried
out at any appropriate stage in the aforementioned processes.
Suitable protecting groups include those used conventionally in the
art for the particular group or atom being protected. Protecting
groups may be prepared and removed using the appropriate
conventional procedure, for example OH groups, including diols, may
be protected as the silylated derivatives by treatment with an
appropriate silylating agent such as
di-tert-butylsilylbis(trifluoromethanesulfonate): the silyl group
may then be removed using conventional procedures such as treatment
with hydrogen fluoride, preferably in the form of a pyridine
complex and optionally in the presence of alumina, or by treatment
with acetyl chloride in methanol. Alternatively benyloxy groups may
be used to protect phenolic groups, the benzyloxy group may be
removed using catalytic hydrogenolysis using such catalysts as
palladium (II) chloride or 10% palladium on carbon.
[0228] Amino groups may be protected using any conventional
protecting group, for example tert-butyl esters of carbamic acid
may be formed by treating the amino group with
di-tert-butyldicarbonate, the amino group being regenerated by
hydrolysing the ester under acidic conditions, using for example
hydrogen chloride in ethyl acetate or trifluoroacetic acid in
methylene dichloride. An amino group may be protected as a benzyl
derivative, prepared from the appropriate amine and a benyl halide
under basic conditions, the benzyl group being removed by catalytic
hydrogenolysis, using for example a palladium on carbon
catalyst.
[0229] Indole NH groups and the like may be protected using any
conventional group, for example benzenesulphonyl, methylsulphonyl,
tosyl, formyl, acetyl (all of them removable by treatment with
alkaline reagents), benzyl (removable either with sodium in liquid
ammonia or with AlCl.sub.3 in toluene), allyl (removable by
treatment with rhodium (III) chloride under acidic conditions),
benzyloxycarbonyl (removable either by catalytic hydrogenation or
by alkaline treatment), trifluoroacetyl (removable by either
alkaline or acidic treatment), t-butyldimethylsilyl (removable by
treatment with tetrabutylammonium fluoride),
2-(trimethylsilyl)ethoxymethyl (SEM) (removable by treatment with
tetrabutylammonium fluoride in the presence of ethylendiamine),
methoxymethyl (MOM) or methoxyethyl (MEM) groups (removed by mild
acidic treatment).
[0230] Carboxyl groups may be protected as alkyl esters, for
example methyl esters, which esters may be prepared and removed
using conventional procedures, one convenient method for converting
carbomethoxy to carboxyl is to use aqueous lithium hydroxide.
[0231] A leaving group or atom is any group or atom that will,
under the reaction conditions, cleave from the starting material,
thus promoting reaction at a specified site. Suitable examples of
such groups unless otherwise specified are halogen atoms, mesyloxy,
p-nitrobenzensulphonylox- y and tosyloxy groups.
[0232] The salts, esters, amides and solvates of the compounds
mentioned herein may as required be produced by methods
conventional in the art: for example, acid addition salts may be
prepared by treating a compound of formula (I) with the appropriate
acid.
[0233] Esters of carboxylic acids may be prepared by conventional
esterification procedures, for example alkyl esters may be prepared
by treating the required carboxylic acid with the appropriate
alkanol, generally under acidic conditions.
[0234] Amides may be prepared using conventional amidation
procedures, for example amides of formula CONR.sub.sR.sub.t may be
prepared by treating the relevant carboxylic acid with an amine of
formula HNR.sub.sR.sub.t wherein R.sub.s and R.sub.t are as defined
above. Alternatively, a C.sub.1-6 alkyl ester such as a methyl
ester of the acid may be treated with an amine of the above defined
formula HNR.sub.sR.sub.t to provide the required amide.
[0235] As mentioned above the compounds of the invention are
indicated as having useful therapeutic properties:
[0236] The present invention therefore provides a method for the
treatment and/or prophylaxis of diseases associated with over
activity of osteoclasts in mammals which method comprises the
administration of an effective non-toxic amount of a selective
inhibitor of mammalian osteoclasts.
[0237] A suitable selective inhibitor of a mammalian osteoclast is
a selective inhibitor of the vacuolar ATPase located on the ruffled
border of mammalian osteoclasts.
[0238] One particular selective inhibitor of mammalian vacuolar
ATPase is a compound of formula (I), or a pharmaceutically
acceptable salt thereof, or a pharmaceutically acceptable solvate
thereof.
[0239] Thus, the present invention further provides a method for
the treatment of osteoporosis and related osteopenic diseases in a
human or non-human mammal, which comprises administering an
effective, non-toxic, amount of a compound of formula (I) or a
pharmaceutically acceptable solvate thereof, to a human or
non-human mammal in need thereof.
[0240] In a further aspect, the present invention provides an
inhibitor of a mammalian, especially human, osteoclasts, for
example a compound of formula (I) or a pharmaceutically acceptable
salt thereof, or a pharmaceutically acceptable solvate thereof, for
use as an active therapeutic substance.
[0241] The preferred mammal is human. Mammalian osteoclasts are
preferably human osteoclasts.
[0242] In particular the present invention provides a compound of
formula (I) or a pharmaceutically acceptable salt thereof and/or a
pharmaceutically acceptable solvate thereof, for use in the
treatment of and/or prophylaxis of osteoporosis and related
osteopenic diseases.
[0243] Of particular interest is the osteoporosis associated with
the peri and post menopausal conditions. Also encompassed are the
treatment and prophylaxis of Paget's disease, hypercalcemia
associated with bone neoplasms and all the types of osteoporotic
diseases as classified below according to their etiology:
[0244] Primary Osteoporosis
[0245] Involutional
[0246] Type I or postmenopausal
[0247] Type II or senile
[0248] Juvenile
[0249] Idiopathic in young adults
[0250] Secondary Osteoporosis
[0251] Endocrine abnormality
[0252] Hyperthyroidism
[0253] Hypogonadism
[0254] Ovarian agenesis or Turner's syndrome
[0255] Hyperadrenocorticism or Cushing's syndrome
[0256] Hyperparathyroidism
[0257] Bone marrow abnormalities
[0258] Multiple myeloma and related disorders
[0259] Systemic mastocytosis
[0260] Disseminated carcinoma
[0261] Gaucher's disease
[0262] Connective tissue abnormalities
[0263] Osteogenesis imperfecta
[0264] Homocystinuria
[0265] Ehlers-Danlos syndrome
[0266] Marfan's syndrome
[0267] Menke's syndrome
[0268] Miscellaneous causes
[0269] Immobilisation or weightlessness
[0270] Sudeck's atrophy
[0271] Chronic obstructive pulmonary disease
[0272] Chronic alcoholism
[0273] Chronic heparin administration
[0274] Chronic ingestion of anticonvulsant drugs
[0275] In addition the invention encompasses the treatment of
tumours, especially those related to renal cancer, melanoma, colon
cancer, lung cancer and leukemia, viral conditions (for example
those involving Semliki Forest virus, Vesicular Stomatitis virus,
Newcastle Disease virus, Influenza A and B viruses, HIV virus),
ulcers (for example chronic gastritis and peptic ulcer induced by
Helicobacter pylori), for use as immunosupressant agents in
autoimmune diseases and transplantation, antilipidemic agents for
the treatment and/or prevention of hypercholesterolemic and
atherosclerotic diseases and to be useful for the treatment of AIDS
and Alzheimer's disease. These compounds are also considered useful
in treating angiogenic diseases, i.e. those pathological conditions
which are dependent on angiogenesis, such as rheumatoid arthritis,
diabetic retinopathy, psoriasis and solid tumours.
[0276] A selective inhibitor of the pharmacological activity of
human osteoclast cells such as a compound of formula (I), or a
pharmaceutically acceptable salt thereof and/or a pharmaceutically
acceptable solvate thereof, may be administered per se or,
preferably, as a pharmaceutical composition also comprising a
pharmaceutically acceptable carrier.
[0277] Accordingly, the present invention also provides a
pharmaceutical composition comprising a selective inhibitor of the
pharmacological activity of human osteoclast cells, in particular
the bone resorption activity of human osteoclast cells associated
with abnormal loss of bone mass, and a pharmaceutically acceptable
carrier thereof.
[0278] A particular inhibitor of human osteoclast cells is a
selective inhibitor of human osteoclast vacuolar ATPase such as a
compound of formula (I), or a pharmaceutically acceptable salt
thereof, or a pharmaceutically acceptable solvate thereof, and a
pharmaceutically acceptable carrier thereof.
[0279] Active compounds or a pharmaceutically acceptable salt
thereof and/or a pharmaceutically acceptable solvate thereof is
normally administered in unit dosage form.
[0280] An amount effective to treat the disorders hereinbefore
described depends upon such factors as the efficacy of the active
compounds , the particular nature of the pharmaceutically
acceptable salt or pharmaceutically acceptable solvate chosen, the
nature and severity of the disorders being treated and the weight
of the mammal. However, a unit dose will normally contain 0.01 to
50 mg, for example 1 to 25 mg, of the compound of the invention.
Unit doses will normally be administered once or more than once a
day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to
3 or 2 to 4 times a day such that the total daily dose is normally
in the range, for a 70 kg adult of 0.01 to 250 mg, more usually 1
to 100 mg, for example 5 to 70 mg, that is in the range of
approximately 0.0001 to 3.5 mg/kg/day, more usually 0.01 to 1.5
mg/kg/day, for example 0.05 to 0.7 mg/kg/day.
[0281] At the above described dosage range, no toxicological
effects are indicated for the compounds of the invention.
[0282] The present invention also provides a method for the
treatment of tumours, especially those related to renal cancer,
melanoma, colon cancer, lung cancer and leukemia, viral conditions
(for example those involving Semliki Forest, Vesicular Stomatitis,
Newcastle Disease, Influenza A and B, HIV viruses), ulcers (for
example chronic gastritis and peptic ulcer induced by Helicobacter
pylori), autoimmune diseases and transplantation, for the treatment
and/or prevention of hypercholesterolemic and atherosclerotic
diseases, AIDS and Alzheimer's disease, angiogenic diseases, such
as rheumatoid arthritis, diabetic retinopathy, psoriasis and solid
tumours, in a human or non-human mammal, which comprises
administering an effective, non-toxic, amount of a compound of
formula (I) or a pharmaceutically acceptable solvate thereof, to a
human or non-human mammal in need thereof.
[0283] In such treatments the active compound may be administered
by any suitable route, e.g. by the oral, parenteral or topical
routes. For such use, the compound will normally be employed in the
form of a pharmaceutical composition in association with a human or
veterinary pharmaceutical carrier, diluent and/or excipient,
although the exact form of the composition will naturally depend on
the mode of administration.
[0284] Compositions are prepared by admixture and are suitably
adapted for oral, parenteral or topical administration, and as such
may be in the form of tablets, capsules, oral liquid preparations,
powders, granules, lozenges, pastilles, reconstitutable powders,
injectable and infusable solutions or suspensions, suppositories
and transdermal devices. Orally administrable compositions are
preferred, in particular shaped oral compositions, since they are
more convenient for general use.
[0285] Tablets and capsules for oral administration are usually
presented in a unit dose, and contain conventional excipients such
as binding agents, fillers, diluents, tabletting agents,
lubricants, disintegrants, colourants, flavourings, and wetting
agents. The tablets may be coated according to well known methods
in the art.
[0286] Suitable fillers for use include cellulose, mannitol,
lactose and other similar agents. Suitable disintegrants include
starch, polyvinylpyrrolidone and starch derivatives such as sodium
starch glycollate. Suitable lubricants include, for example,
magnesium stearate. Suitable pharmaceutically acceptable wetting
agents include sodium lauryl sulphate.
[0287] These solid oral compositions may be prepared by
conventional methods of blending, filling, tabletting or the like.
Repeated blending operations may be used to distribute the active
agent throughout those compositions employing large quantities of
fillers. Such operations are, of course, conventional in the
art.
[0288] Oral liquid preparations may be in the form of, for example,
aqueous or oily suspensions, solutions, emulsions, syrups, or
elixirs, or may be presented as a dry product for reconstitution
with water or other suitable vehicle before use. Such liquid
preparations may contain conventional additives such as suspending
agents, for example sorbitol, syrup, methyl cellulose, gelatin,
hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate
gel or hydrogenated edible fats, emulsifying agents, for example
lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles
(which may include edible oils), for example, almond oil,
fractionated coconut oil, oily esters such as esters of glycerine,
propylene glycol, or ethyl alcohol; preservatives, for example
methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired
conventional flavouring or colouring agents.
[0289] For parenteral administration, fluid unit dose forms are
prepared containing a compound of the present invention and a
sterile vehicle. The compound, depending on the vehicle and the
concentration, can be either suspended or dissolved. Parenteral
solutions are normally prepared by dissolving the compound in a
vehicle and filter sterilising before filling into a suitable vial
or ampoule and sealing. Advantageously, adjuvants such as a local
anaesthetic, preservatives and buffering agents are also dissolved
in the vehicle. To enhance the stability, the composition can be
frozen after filling into the vial and the water removed under
vacuum.
[0290] Parenteral suspensions are prepared in substantially the
same manner except that the compound is suspended in the vehicle
instead of being dissolved and sterilised by exposure to ethylene
oxide before suspending in the sterile vehicle. Advantageously, a
surfactant or wetting agent is included in the composition to
facilitate uniform distribution of the active compound.
[0291] For topical administration, the composition may be in the
form of a transdermal ointment or patch for systemic delivery of
the active compound and may be prepared in a conventional manner,
for example, as described in the standard textbooks such as
`Dermatological Formulations`--B. W. Barry (Drugs and the
Pharmaceutical Sciences--Dekker) or Harrys Cosmeticology (Leonard
Hill Books).
[0292] The present invention also provides the use of a selective
inhibitor of the biological activity of human osteoclast cells, in
particular the bone resorption activity of human osteoclast cells
associated with abnormal loss of bone mass, compound of formula
(I), or a pharmaceutically acceptable salt thereof, or a
pharmaceutically acceptable solvate thereof, for the manufacture of
a medicament for the treatment and/or prophylaxis of diseases
associated with over activity of osteoclasts in mammals, such as
the treatment and/or prophylaxis of osteoporosis and related
osteopenic diseases.
[0293] The present invention also provides the use of a selective
inhibitor of the biological activity of human osteoclast cells, in
particular the bone resorption activity of human osteoclast cells
associated with abnormal loss of bone mass, for the manufacture of
a medicament for the treatment of tumours, especially those related
to renal cancer, melanoma, colon cancer, lung cancer and leukemia,
viral conditions (for example those involving Semliki Forest,
Vesicular Stomatitis, Newcastle Disease, Influenza A and B, HIV
viruses), ulcers (for example chronic gastritis and peptic ulcer
induced by Helicobacter pylori), autoimmune diseases and
transplantation, for the treatment and/or prevention of
hypercholesterolemic and atherosclerotic diseases, AIDS and
Alzheimer's disease, angiogenic diseases, such as rheumatoid
arthritis, diabetic retinopathy, psoriasis and solid tumours.
[0294] In one preferred aspect the inventions herein comprising
compositions, treatment methods and pharmaceutical uses of a
selective inhibitor of the biological activity of mammalian,
including human, osteoclast cells exclude the compositions,
treatment methods and pharmaceutical uses of the compounds of
formula (I) of WO96/21644 and in another aspect the specific
examples of WO96/21644.
[0295] No unacceptable toxicological effects are expected with
compounds of the invention when administered in accordance with the
invention. As is common practice, the compositions will usually be
accompanied by written or printed directions for use in the medical
treatment concerned.
[0296] The following, descriptions, examples and pharmacological
methods illustrate the invention but do not limit it in any
way.
[0297] Preparation 1
[0298] Ethyl
Alpha-oxo-3-(2-nitro-4,5-dichlorophenyl)propanoate.
[0299] To a suspension of potassium (49.2 g, 1.26 mol) in anhydrous
diethyl ether (500 ml), a solution of absolute EtOH (319 ml) and
anhydrous diethyl ether (260 ml) was added dropwise under nitrogen
during a period of four hours. The resulting solution was diluted
with anhydrous diethyl ether (1200 mL) and then diethyl oxalate
(171 ml, 1.26 mol) was added dropwise in about 30 minutes. To the
resulting yellow mixture, a solution of 2-nitro-4,5-dichlorotoluene
(260 g, 1.26 mmol), prepared as described by Cohen and Dakin in J.
Chem. Soc., 79, 1133, in anhydrous diethyl ether (450 ml) was added
dropwise in one hour at RT. Stirring was continued for additional
three hours and the dark-brown mixture was settled at RT for two
days. The potassium salt was collected by suction and dried to give
a dark-brown powder. This was suspended in a mixture of water (400
ml) and ethyl acetate (400 ml), then acidified with 10% HCl. The
organic phase was washed with brine, aqueous sat. NaHCO.sub.3 and
again brine, then it was dried with MgSO.sub.4. Evaporation
produced 239 g of title compound (781 mmol, yield 62.0%) as a light
brown solid that was used as such for the next step,
m.p.=92-94.degree. C.
[0300] Preparation 2
[0301] Ethyl 5,6dichloroindole-2-carboxylate.
[0302] A mixture of ethyl
alpha-oxo-3-(2-nitro-4,5-dichlorophenyl)propanoa- te (200 g, 653
mmol) and iron powder (320 g, 5.75 mol) in EtOH/AcOH 1/1 (2.5 l)
was refluxed for two hours. After cooling, the resulting mixture
was evaporated under vacuum and the solid residue was dissolved in
THF (4 l). The solid residue was filtered on Fluosil and then
washed with additional THF (2 l). The pooled organic phases were
concentrated to give a dark residue (203 g). This was treated with
AcOEt/CH.sub.2Cl.sub.2 and the remaining solid was filtered off.
Evaporation produced 120 g of title compound (465 mmol, yield
71.2%) that was used as such for the next step,
m.p.=215-218.degree. C.
[0303] Preparation 3
[0304] 5,6-Dichloroindole-2-methanol.
[0305] To an ice cold stirred 1 M solution of LiAlH.sub.4 in
anhydrous THF (800 ml, 800 mmol) under argon, ethyl
5,6dichloroindole-2-carboxylate (118 g, 457 mmol), dissolved in
anhydrous THF (1 l), was added dropwise while keeping the
temperature below 5.degree.. Stirring at 0.degree. was continued
for one hour, then the reaction was quenched with water (35 ml),
15% aq. NaOH (35 ml) and water (70 ml). The mixture was filtered on
a Celite pad and washed with THF (2.times.500 ml). The organic
phase was dried (MgSO.sub.4) and concentrated to give a residue (80
g) that was chromatographed with AcOEt/n-heptane 1/2 to give 52.0 g
of pure title compound (241 mmol, yield 52.7%) as an oil.
[0306] Preparation 4
[0307] 5,6-Dichloroindole-2-carboxaldehyde.
[0308] A solution of 5,6-dichloroindole-2-methanol (43 g, 199 mmol)
in diethyl ether (1.3 l) was treated with activated MnO.sub.2 (64
g, 730 mmol) and stirred for 15 hours at room temperature.
Additional MnO.sub.2 (20 g, 230 mmol) was added and stirring
continued for 5 h. The suspension was filtered on a Celite pad,
then the pad was washed with diethyl ether and warm acetone. The
pooled organic phases were concentrated to give 38.5 g of the title
compound (180 mmol, yield 90.4%) that was used as such in the next
step, m.p.=207-208.degree. C.
[0309] Preparation 5
[0310] Method A). Ethyl
(E)-3-(5,6-dichloroindol-2-yl)-2-propenoate.
[0311] 5,6-Dichloro indole-2-carboxaldehyde (35 g, 164 mmol) was
dissolved in toluene (1.5 l) under argon, then
(ethoxycarbonylmethylene)triphenylph- osphorane (60 g, 176 mmol)
was added and the solution was refluxed for 3 h. The solvent was
evaporated under reduced pressure and the residue chromatographed
on silicagel with AcOEt/n-heptane 1/4 to give 28.0 g of pure title
compound, m.p.=188-190.degree. C. (yield 60.1%).
[0312] Method B). Ethyl
(E)-3-(5,6dichloroindol-2-yl)-2-propenoate.
[0313] To a solution of triethyphosphonoacetate (32.9 g, 147 mmol)
in THF (150 ml), NaH (5.95, 148 mmol) was added portionwise under
nitrogen maintaining the temperature between 0-5.degree. C. in 30
min. After reaching room temperature,
5,6-dichloro-1H-indol-2-carboxaldehyde (29 g, 135.5 mmol),
dissolved in THF (200 ml), was added dropwise maintaining the
internal temperature around 20.degree. C. (about 1 h). The solvent
was evaporated under reduced pressure and the residue was treated
with H.sub.2O (200 ml) and EtOAc (500 ml). The organic layer was
washed with brine, dried over Na.sub.2SO.sub.4 and evaporated to
dryness obtaining a residue that was triturated with hexane,
filtered and dried under vacuum affording 34.5 g of the title
compound, m.p.=188-190.degree. C. (yield=89.6%).
[0314] Preparation 6
[0315] (E)-3-(5,6-Dichloroindol-2-yl)-2-propen-1-ol.
[0316] To a solution of ethyl
(E)3-(5,6-dichloroindol-2-yl)-2-propenoate (28 g, 98.5 mmol) in dry
THF (500 ml) stirred under argon at -20.degree. DIBAL (1 M solution
in hexane, 200 mmol) was added dropwise while keeping the
temperature below -20.degree.. The stirring was continued for one
hour, then the reaction was quenched with water (70 m). After
warming to RT diethyl ether (350 m) was added and the suspension
was filtered on a Celite pad. The pad was washed with diethyl ether
(3.times.100 ml), then the pooled organic phase was dried
(MgSO.sub.4) and evaporated to give 23.85 g of the title compound
(98.5 mmol, yield 100%) that was used as such in the next step.
[0317] Preparation 7
[0318] (E)-3-(5,6-Dichloroindol-2-yl)-2-propenaldehyde.
[0319] To a solution of (E)
3-(5,6-dichloroindol-2-yl)-2-propen-1-ol (23.8 g, 98.3 mmol) in
diethyl ether (800 ml) activated MnO.sub.2 (71 g, 8.76 mol) and
NaCl (60 g) were added and the resulting suspension stirred for one
day at RT. It was then filtered on a Celite pad repeatedly washed
with AcOEt and the organic phase dried (MgSO.sub.4) and evaporated
to give 21.0 g of the title compound (87.5 mmol, yield 89.0%) that
was used as such in the next step.
[0320] Preparation 8
[0321] Methyl
(2Z,4E)-5-(5,6-dichloroindol-2-yl)-2-methoxy-2,4-pentadienoa-
te.
[0322] A solution of (E)3-(5,6-dichloroindol-2-yl)-2-propenaldehyde
(15 g, 62.5 mmol), methyl 2-methoxy-2-(triphenylphosphonium)acetate
bromide (31 g, 69.6 mmol) and DBU (10.5 mL, 70.1 mmol) was refluxed
for 4 h. The solvent was evaporated and the crude chromatographed
on silicagel with AcOEt/n-heptane 1/4 to give 14.5 g of pure title
compound (44.5 mmol, yield 71.1%) after trituration with
diisopropyl ether, m.p.=203-204.degree. C.
[0323] Preparation 9
[0324] (2Z,4E)-5-(5,6-Dichloroindol-2-yl)2-methoxy-2,4-pentadienoic
Acid.
[0325] A suspension of methyl
(2Z,4E)-5-5,6-dichloroindol-2-yl)-2-methoxy-- 2,4-pentadienoate (10
g, 30.7 mmol) and KOH (3.6 g, 64.2 mmol) in EtOH/water 1/1 (460 ml)
was refluxed for 3 h. The suspension after cooling to RT was poured
into water (1.5 l), it was acidified with 2N HCl and extracted with
AcOEt (2.times.l). The organic phase was washed with water and
dried (MgSO.sub.4), then concentrated and the residue taken up with
CH.sub.2Cl.sub.2. Filtration and drying in the oven at 50.degree.
produced 9.5 g of pure title compound (30.4 mmol, yield 99.1%),
m.p.=249-250.degree. C.
[0326] .sup.1H-NMR (DMSO-d.sub.6): 11.81 (bs, 1H); 7.77 (s, 1H);
7.53 (s, 1H); 7.20 (dd, 1H); 6.95 (d, 1H); 6.84 (d, 1H); 6.61 (s,
1H); 3.74 (s, 3H)
[0327] Preparation 10
[0328] 1,2,2,6,6-Pentamethyl-4-piperidone hydroiodide.
[0329] A solution of 2,2,6,6-tetramethyl-4-piperidone monohydrate
(40 g, 23.1 mmol) and methyl iodide (98.31 g, 69.3 mmol) in
isopropyl alcohol (25 mL) was stirred at RT for 48 hours. The
resulting suspension was filtered, the solid residue was dried and
recrystallized from MeOH. After filtration and repeated washings
with MeOH the solid was dried giving pure title compound (31.6 g,
10.6 mmol, yield 46.0%) as pale brown crystals.
[0330] Preparation 11
[0331] 1,2,2,6,6-Pentamethyl-4-piperidone Oxime.
[0332] A suspension of 1,2,2,6,6-pentamethyl-4-piperidone
hydroiodide (3 g, 10.1 mmol) and hydroxylamine hydrochloride (980
mg, 14 mmol) in water (6 ml) was stirred at RT for 15 minutes.
Solid NaOH was added until basic pH and thickening of the
suspension. Water (3 ml) was added and stirring at RT was continued
overnight. The suspension was filtered and the solid washed with
water (few ml) and dried. The solid was then dissolved in
Et.sub.2O, the solution was dried (MgSO.sub.4) and concentrated to
give after drying pure title compound (1.55 g, 8.41 mmol, yield
83.3%) as white crystals.
[0333] Preparation 12
[0334] 4-Amino-1,2,2,6,6-pentamethyl-4-piperidine.
[0335] LiAlH.sub.4 (925 mg, 24.4 mmol) was added under stirring at
0.degree. under Ar to anhydrous THF (100 ml), followed by
1,2,2,6,6-pentamethyl-4-piperidone oxime (1.50 g, 8.14 mmol). The
suspension was refluxed for 2 hours, then cooled to RT and stirred
overnight. After cooling to 0.degree. water (0.9 ml), 15% aq. NaOH
(0.9 ml) and water (2.8 ml) were carefully added dropwise. The
suspension was stirred for 15 min at RT, then MgSO.sub.4 was added
and stirring continued for 30 minutes. After filtration, the liquid
was concentrated and the oily residue chromatographed on silicagel
(CH.sub.2Cl.sub.2/MeOHl- aq.NH.sub.3 95/5/1). The collected
fractions were pooled and concentrated to give pure title compound
(750 mg, 4.40 mmol, yield 54.1%) as a yellow oil.
[0336] Preparation 13
[0337] (2Z,4E)-5-(Indol-2-yl)-2-methoxy-2,4-pentadienoic acid was
prepared from 2-indolecarbaldehyde (Heterocycles, 1984, 22, 1211)
using the reaction sequence described in Preparations 5-9.
m.p.=189-190.degree. C.
[0338] Preparation 14
[0339] Ethyl 5-trifluoromethyl-2-indolecarboxylate.
[0340] 5-Trifluoromethylphenylhydrazine (5 g, 28.4 mmol) was
treated with ethyl pyruvate (3.3 ml, 30 mmol) in ethanol (15 ml)
giving, after filtration, 5.4 g of the corresponding
phenylhydrazone as a white powder, m.p.=134-137.degree. C. This
compound (5.4 g, 19.7 mmol) was refluxed for 3 h in toluene (150
ml) in the presence of anhydrous p-toluensulfonic acid (6 g, 34.8
mmol) obtaining 0.9 g (18%) of the title compound as a yellow
powder, m.p.=153-154.degree. C.
[0341] Preparation 15
[0342]
(2Z,4E)-5-(5-Trifluoromethylindol-2-yl)-2-methoxy-2,4-pentadienoic
acid was prepared from ethyl 5-trifluoromethyl-2-indolecarboxylate
using the reaction sequence described in Preparations 3-9.
m.p.=191-193.degree. C.
[0343] Preparation 16
[0344] Ethyl 5-bromo-2-indolecarboxylate was prepared from
5-bromophenylhydrazine and ethyl piruvate using the procedure
described in Preparation 14, m.p.=160-164.degree. C.
[0345] Preparation 17
[0346] (2Z,4E)-5-(5Bromoindol-2-yl)-2-methoxy-2,4-pentadienoic acid
was prepared from ethyl 5-bromo-2-indolecarboxylate using the
reaction sequence described in Preparations 3-9,
m.p.=208-210.degree. C.
[0347] Preparation 18
[0348] 2,6-Dimethyl-4-(2-pyrimidinyl)piperazine Dihydrochloride
[0349] A solution of 1.71 g (15 mmol) of 2,6-dimethylpiperazine and
1.14 g (10 mmol) of 2-chloropyrimidine in 25 ml ethanol was
refluxed for 16 hours. The reaction mixture was concentrated under
reduced pressure, dissolved in 25 ml of water and extracted twice
with 50 ml of methylene chloride. The organic phase was dried over
MgSO.sub.4 and concentrated under reduced pressure. The residue was
dissolved in acetonitrile and treated with a solution of anhydrous
HCl in ethanol. The salt was filtered and dried in vacuo to afford
1.70 g of the title compound.
[0350] Preparation 19
[0351]
3-[2,6-Dimethyl-4-(2-pyrimidinyl)piperazin-1-yl]propylamide.
[0352] A mixture of 1.1 g (4.1 mmol) of
2,6-dimethyl-4-(2-pyrimidinyl)pipe- razine dihydrochloride, 0.45 g
(4.1 mmol) of 3-chloropropionamide, 3 g of 30% KF on Clarcel.RTM.
in 25 ml acetonitrile was heated for 72 hours at 150.degree. C. in
a close vessel. After cooling to room temperature the mixture was
filtered over a filtration aid and concentrated under reduced
pressure.
[0353] The residue was dissolved in water, alkalinised with aqueous
1N NaOH and extracted twice with 25 ml methylene chloride. The
organic phase was dried over MgSO.sub.4 and concentrated under
reduced pressure. The residue was then purified by chromatography
on silicagel (AcOEt, EtOH, NH.sub.4OH: 45, 5, 1) to afford 0.2 g of
the title compound, mp.=125.degree. C.
[0354] Preparation 20
[0355]
3-[2,6-Dimethyl-4-(2-pyrimidinyl)piperazin-1-yl]propylamine.
[0356] 50 mg (1.54 mmol) of LiAlH.sub.4 were added to a solution of
0.2 g (0.77 mmol) of
3-[2,6-dimethyl-4-(2-pyrimidinyl)piperazin-1-yl]propylamid- e in 5
ml of diethylether and 5 ml of THF. The mixture was stirred one
hour at room temperature and one additional hour at reflux, then
the reaction was quenched by successive addition of 50 ul of water,
50 ul of 15% aqueous NaOH and 3.times.50 ul water. The mixture was
diluted with diethyl ether, filtered, dried over MgSO.sub.4 and
concentrated under reduced pressure. The residue was purified by
column chromatography on silicagel (CH.sub.2Cl.sub.2, EtOH,
NH.sub.4OH: 45, 5, 1) to afford 0.037 g of the title compound.
[0357] Preparation 21
[0358] 3-[4-(2,6-Dimethylphenyl)pipernazin-1-yl]propylamine.
[0359] 4-(2,6-Dimethylphenyl) piperazine (1 g, 5.23 mmol) in MeOH
(10 ml) was cooled to 0.degree. and 0.305 g (5.73 mmol) of
acrilonitrile was added. The reaction was stirred overnight at room
temperature and evaporated under vacuum affording 1 g of crude
3-[4(2,6-dimethylphenyl)pi- perazin-1-yl]propionitrile as a waxy
solid. This compound was dissolved in MeOH (60 ml), 2 ml 37% HCl
and hydrogenated under pressure (40 psi) with 0.2 g of 10% PdC. The
reaction was filtered and evaporated to dryness obtaining 1 g of
the title compound, as a hydrochloride salt, that was used without
further purification for the following reaction.
EXAMPLE 1
[0360]
(2Z,4E)(5,6-Dichloro-1H-indol-2yl)-2-methoxy-N-(1,2,2,6,-pentamethy-
l Piperidin-4-yl)-2,4-pentadienamide.
[0361] A solution of
(2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-- pentadienoic
acid (736 mg, 3.65 mmol), 4-amino-1,2,2,6,6-pentamethylpiperi- dine
(620 mg, 3.65 mmol), 1-hydroxy-7-azabenzotriazole hydrate (474.5
mg, 3.65 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (693.5 mg, 3.65 mmol) in DMF (2 ml) was stirred at RT
overnight. The solution was poured into brine (20 ml) and
repeatedly extracted with EtOAc. The organic phase was washed with
5% aq. CaCO.sub.3, dried (MgSO.sub.4) and evaporated under vacuum.
The residue was chromatographed on silica gel using ethyl
acetate:methanol:aq. ammonia (32%) 90:10:2 as eluent mixture. The
collected fractions produced the pure title compound (0.8, yield
73%) as yellow crystals, m.p.=212.degree. C.
[0362] .sup.1H-NMR (200 MHz, DMSO-d.sub.6): 1.02 (s, 6H); 1.08 (s,
6H); 1.44(t, 2H); 1.62 (m, 2H); 2.18 (s, 3H); 3.70 (s, 3H); 4.07
(m, 1H); 6.6 (m, 2H); 6.84 (d, 1H); 7.14 (dd, 1H); 7.51 (s, 1H);
7.75 (s, 1H); 7.91 (d, 1H); 11.74 (s, 1H, exch with D2O).
[0363] Two other isomers were isolated from the column
chromatography:
[0364]
(2E,4E)-5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-N-(1,2,2,6,6-penta-
methyl Piperidin-4-yl)-2,4-pentadienamide
[0365] .sup.1H-NMR (200 MHz, THF-d.sub.8,): 10.76 (s br, 1H); 8.19
(dd, 1H); 7.54 (s, 1H); 7.40 (s, 1H); 6.93 (d br, 1H); 6.51 (d,
1H); 6.32 (d, 1H); 5.92 (d, 1H); 4.25-4.12 (m, 1H); 3.70 (s, 3H);
2.25 (s, 3H); 1.72 (m, 2H); 1.32 (dd, 2H); 1.10 (s, 12H).
[0366]
(2Z,4Z)-5-(5,6-Dichloro-1H-indol-2-yl)2-methoxy-N-(1,2,2,6,6-pentam-
ethyl piperidin-4-yl)-2,4-pentadienamide
[0367] .sup.1H-NMR (200 MHz, THF-d.sub.8,): 10.48 (s br, 1H); 7.58
(s, 1H); 7.44 (s, 1H); 7.22 (d, 1H); 6.99 (d br, 1H); 6.61 (s br,
1H); 6.59 (dd, 1H); 6.42 (d, 1H); 4.25-4.12 (m, 1H); 3.75 (s, 3H);
2.28 (s, 3H); 1.72 (m, 2H); 1.33 (dd, 2H); 1.11 (s, 12H).
[0368] The following compounds were prepared according to the
procedure of Example 1
1 22 Ex. No Name Rs Rt R1 R2 R3 R4 Ra R6 R7 R8 M.P. (.degree. C.)
N.M.R. 2 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(6-
ethoxy-pyridin-3-yl)-2,4- pentadienamide 23 H Me H H H H 5Cl 6Cl H
273 .sup.1H NMR (DMSO-d.sub.6): 1.30 (t, 3H); 3.82 (s, 3H); 4.27
(q, 2H); 6.62 (s, 1H); 6.77-6.98 (s, 3H); 7.25 (dd, 1H); 7.53 (s,
1H); 7.77 (s, 1H); 8.04 (dd, 1H); 8.49 (d, 1H); 10.04 (s, 1H, exch
with D.sub.2O); 11.81 (s, 1H, exch with D.sub.2O). 3
(2Z,4E)-N-(5-Chloropyridin- 2-yl)-56-(5,6-dichloro-1H-
indol-3-(yl)-2-methoxy-2,4- pentadienamide 24 H Me H H H H 5Cl 6Cl
H 284 dec. .sup.1H NMR (DMSO-d.sub.6): 3.84 (s, 3H); 6.64 (s, 1H);
6.90 (d, 1H); 7.00 (d, 1H); 7.25 (dd, 1H); 7.54 (s, 1H); 7.77 (s,
1H); 7.97 (dd, 1H); 8.16 (d, 1H); 8.43 (d, 1H); 10.13 (s, 1H, exch
with D.sub.2O); 11.82 (s, 1H, exch with D.sub.2O) 4
(2Z,4E)-5-(5,6-Dichloro-1H- - indol-2-yl)-2-methoxy-N-
[(2,4-dimethoxy)pyridin-3- yl]-2,4-pentadienamide 25 H Me H H H H
5Cl 6Cl H 175 .sup.1H NMR (DMSO-d.sub.6): 3.42 (s, 3H); 3.81 (s,
6H); 6.33 (d, 1H); 6.59 (s, 1H); 6.67 (d, 1H); 6.87 (d, 1H); 7.22
(dd, 1H); 7.53 (s, 1H); 7.73 (m, 2H); 8.77 (s, 1H, exch with
D.sub.2O); 11.83 (s, 1H, exch with D.sub.2O) 5
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(2-
methoxy-pyrimidin-5-yl)-2,4- pentadienamide 26 H Me H H H H 5Cl 6Cl
H 290-291 .sup.1H NMR (DMSO-d.sub.6): 3.84 (s, 3H); 3.90 (s, 3H);
6.64 (s, 1H); 6.88 (d, 1H); 6.96 (d, 1H); 7.25 (dd, 1H); 7.54 (s,
1H); 7.77 (s, 1H); 8.91 (s, 2H); 10.25 (s, 1H, exch with D.sub.2O);
11.82 (s, 1H, exch with D.sub.2O) 6 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-2-methoxy-N-(5- methoxy-pyridin-3-yl)-2,4-
pentadienamide 27 H Me H H H H 5Cl 6Cl H 235-236 .sup.1H NMR
(DMSO-d.sub.6): 3.64 (s, 3H); 3.85 (s, 3H); 6.64 (s, 1H); 6.87 (d,
1H); 6.97 (d, 1H); 7.27 (dd, 1H); 7.54 (s, 1H); 7.77 (s, 1H); 7.96
(m, 1H); 8.11 (d, 1H); 8.67 (d, 1H); 10.27 (s, 1H, exch with
D.sub.2O); 11.84 (s, 1H, exch with D.sub.2O) 7
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-[3-
(4-benzoylpiperazin-1- yl)propyl]-2,4- pentadienamide 28 H Me H H H
H 5Cl 6Cl H 232 .sup.1H NMR (DMSO-d.sub.6): 1.64 (m, 2H); 2.35 (m,
6H); 3.19-3.26 (m, 4H); 3.44--3.62 (m, 2H); 3.72 (s, 3H); 6.58 (s,
1H); 6.65 (d, 1H); 6.85 (d, 1H); 7.17 (dd, 1H); 7.36-7.46 (m, 5H);
7.51 (s, 1H); 7.75 (s, 1H); 8.25 (t, 1H, exch with D.sub.2O); 11.75
(s, 1H, exch with #D.sub.2O) 8 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-N-[6-(2- hydroxyethoxy)-pyridin-3- yl]-2-methoxy-2,4-
pentadienamide 29 H Me H H H H 5Cl 5Cl H 228 dec. .sup.1H NMR
(DMSO-d.sub.6): 3.70 (m, 2H); 3.82 (s, 3H); 4.22 (t, 2H); 4.82 (m,
1H, exch with D.sub.2O); 6.62 (s, 1H); 6.80-6.98 (m, 3H); 7.24 (dd,
1H); 7.53 (s, 1H); 7.77 (s, 1H); 8.04 (m, 1H); 8.49 (d, 1H); 10.04
(s, 1H, exch with D.sub.2O) 11.80 (s, 1H, exch with #D.sub.2O) 9
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(2-
pyridyloxy-5-pyridyl)-2,4- pentadienamide hydrochloride 30 H Me H H
H H 5Cl 6Cl H 208-210 .sup.1H NMR (DMSO-d.sub.6): 11.85 (s, 1H);
10.21 (s, 1H); 8.64 (d, 1H); 8.53 (s, 1H); 8.52 (m, 1H); 8.29 (dd,
1H); 7.89 (m, 1H); 7.76 (s, 1H); 7.67 (dd, 1H); 7.52 (s, 1H); 7.27
(dd, 1H); 7.20 (d, 1H); 6.95 (d, 1H); 6.85 (d, 1H); 6.64 (s, 1H);
3.82 (s, 3H) 10 (S,2Z,4E)-5-(5,6- Dichloro-2-yl)-N-[2-(1-
carbethoxy)-ethoxy-5- pyridyl]-2-methoxy-2,4- pentadienamide 31 H
Me H H H H 5Cl 6Cl H 228-230 .sup.1H NMR (DMSO-d.sub.6): 11.75 (s,
1H); 10.00 (s, 1H); 8.42 (d, 1H); 8.06 (dd, 1H); 7.77 (s, 1H); 7.52
(s, 1H); 7.23 (dd, 1H); 6.93 (d, 1H); 6.90 (d, 1H); 6.82 (d, 1H);
6.62 (s, 1H); 5.19 (q, 1H); 4.11 (q, 2H); 3.81 (s, 3H); 1.50 (d,
3H); 1.16 (t, 3H) 11 (S,2Z,4E)-5-(5,6- Dichloroindol-2-yl)-N-[2-(1-
carboxy)ethoxy-5-pyridyl]-- 2- methoxy-2,4- pentadienamide 32 H Me
H H H H 5Cl 6Cl H 239-240 .sup.1H NMR (DMSO-d.sub.6); 11.80 (s,
1H); 10.00 (s, 1H); 8.42 (d, 1H); 8.05 (dd, 1H); 7.76 (s, 1H); 7.52
(s, 1H); 7.25 (dd, 1H); 6.94 (d, 1H); 6.87 (d, 1H); 6.81 (d, 1H);
6.61 (s, 1H); 5.18 (q, 1H); 3.82 (s, 3H); 1.50 (d, 3H) 12
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-[6- -
(1-methyl-ethoxy)pyridin-3- yl]-2,4-pentadienamide 33 H Me H H H H
5Cl 6Cl H 263 dec .sup.1H NMR (DMSO-d.sub.6): 1.28 (s, 6H); 3.82
(s, 3H); 5.19 (m, 1H); 6.62 (s, 1H); 6.72-6.98 (m, 3H); 7.24 (dd,
1H); 7.54 (s, 1H); 7.77 (s, 1H); 8.00 (dd, 1H); 8.50 (d, 1H); 10.03
(s, 1H, exch with D.sub.2O); 11.81 (s, 1H, exch with D.sub.2O) 13
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(6-
dimethylaminpyridin-3-yl)- 2,4-pentadienamide 34 H Me H H H H 5Cl
6Cl H 260-290 .sup.1H NMR (DMSO-d.sub.6): 3.00 (s, 6H); 3.82 (s,
3H); 6.61 (s, 1H); 6.64 (d, 1H); 6.78 (d, 1H); 6.91 (d, 1H); 7.23
(dd, 1H); 7.53 (s, 1H); 7.76 (s, 1H); 7.85 dd, 1H); 8.41 (d, 1H);
9.81 (s, 1H, exch with D.sub.2O); 11.78 (s, 1H, exch with D.sub.2O)
14 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(1-
azobicyclo-[3.3.1]nonan-4- beta-yl)-2,4- pentadienamide 35 H Me H H
H H 5Cl 6Cl H 230 .sup.1H NMR (DMSO-d.sub.6) 1.10-2.25 (bm, 7H);
2.80-3.05 (m, 6H), 3.73 (s, 3H); 4.15 (m, 1H); 6.57 (s, 1H); 6.59
(d, 1H); 6.85 (d, 1H); 7.17 (dd, 1H); 7.51 (s, 1H); 7.75 (s, 1H);
8.06 (d, 1H, exch with D.sub.2O); 11.76 (s, 1H, exch with D.sub.2O)
15 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-methoxy-N-(9- methyl-9-
azabicyclo[3.3.1]nonan-3- alpha-yl)-2,4-pentadienamide 36 H Me H H
H H 5Cl 6Cl H 293 .sup.1H NMR (DMSO-d.sub.6): 0.86-2.15 (bm, 10H);
2.38 (s, 3H); 2.84-3.04 (m, 2H); 3.71 (s, 3H); 4.20 (m, 1H); 6.57
(s, 1H); 6.63 (d, 1H); 6.84 (d, 1H); 7.17 (dd, 1H); 7.51 (s, 1H);
7.75 (s, 1H); 7.87 (d, 1H, exch with D.sub.2O); 11.75 (s, 1H, exch
with D.sub.2O) 16 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-2-methoxy-N-[8- methyl-8- azabicyclo[3.2.1]oct-
3alpha-yl)-2,4- pentadienamide 37 H Me H H H H 5Cl 6Cl H 262
.sup.1H NMR (DMSO-d.sub.6): 1.98-2.46 (m, 8H); 2.59 (s, 3H); 3.74
(m, 2H); 3.76 (s, 3H); 3.78 (m, 1H); 6.58 (s, 1H); 6.60 (d, 1H);
6.88 (d, 1H); 7.21 (dd, 1H); 7.53 (s, 1H); 7.75 (s, 1H); 7.95 (m,
1H, exch with D.sub.2O); 11.89 (s, 1H, exch with D.sub.2O) 17
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[6-(2-
methoxyethoxy)-pyridin-3- - yl]-2-methoxy-2,4- pentadienamide 38 H
Me H H H H 5Cl 6Cl H 233 dec. .sup.1H NMR (DMSO-d.sub.6): 11.80 (s,
1H, exch with D.sub.2O); 10.01 (s, 1H, exch with D.sub.2O); 8.50
(d, 1H); 7.77 (s, 1H); 7.54 (s, 1H); 7.24 (dd, 1H); 6.81-6.99 (m,
3H); 6.62 (s, 1H0; 4.34 (t, 2H); 3.82 (s, 3H); 3.64 (t, 2H); 3.29
(s, 3H). 18 (2Z,4E)-5-[2-(1- Carboxymethyl-5,6-
dichloro)indolyl]-2-methoxy- N-[5-(2-methoxypyridinyl]- -
2,4-pentadienamide hydrochloride 39 H Me H H H H 5Cl 6Cl CH.sub.2-
COOH >250 .sup.1H NMR (DMSO-d.sub.6); 10.04 (s, 1H); 9.01 (d,
1H); 8.04 (dd, 1H); 7.82 (s, 1H); 7.78 (s, 1H); 7.60 (d, 1H); 7.40
(s, 1H); 7.26 (dd, 1H); 6.86 (d, 1H); 6.82 (d, 1H); 5.18 (s, 2H);
3.82 (s, 3H) 19 (2Z,4-E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[6-(2-
diethylaminoethoxy)-pyrid- 3-yl]-2-methoxy-2,4- pentadienamide
hydrochloride 40 H Me H H H H 5Cl 6Cl H 201-204 .sup.1H NMR
(DMSO-d.sub.6): 11.86 (s, 1H); 10.10 (s, 1H); 9.80 (s br, 1H0; 8.55
(d, 1H); 8.11 (dd, 1H); 7.76 (s, 1H); 7.54 (s, 1H); 7.26 (dd, 1H);
6.95 (d, 1H); 6.90 (d, 1H); 6.82 (d, 1H); 6.61 (s, 1H); 4.59 (t,
2H); 3.83 (s, 3H); 3.50 (dt, 2H); 3.20 (m, 4H); #1.22 (t, 6H). 20
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-(1-methylethyl-
6-oxopyridin-3-yl)-2- methoxy-2,4- pentadienamide 41 H Me H H H H
5Cl 6Cl H 165-168 dec .sup.1H NMR (DMSO-d.sub.6): 11.81 (s, 1H,
exch with D.sub.2O); 9.86 (s, 1H, exch with D.sub.2O); 8.21 (d,
1H); 7.77 (s, 1H0; 7.68 (dd, 1H); 7.54 (s, 1H); 7.23 (dd, 1H); 6.92
(d, 1H); 6.81 (d, 1H); 6.62 (s, 1H); 6.40 (d, 1H); 5.07 (m, 1H);
3.81 (s, 3H); 1.28 (d, 6H). 21 (2Z,4E)-5-(1H-indol-2-yl)-2-
methoxy-N-[4-(2,2,6,6-nl tetramethyl)-piperidinyl]-2,4-
pentadienamide hydrochloride 42 H Me H H H H H H H >250 .sup.1H
NMR (DMSO-d.sub.6): 11.41 (s, 1H); 9.09 (d br 1H); 8.19 (d, 1H);
8.01 (d br, 1H); 7.49 (d, 1H); 7.32 (d, 1H); 7.12 (dd, 1H); 7.11
(dd, 1H); 6.97 (dd, 1H); 6.85 (d, 1H); 6.65 (d, 1H); 6.56 (s, 1H);
4.22 (m, 1H); 3.71 (s, 3H); 1.85 (dd, 1H); 1.65 (dd, 1H); 1.43 (s,
6H); 1.41 (s, #6H). 22 (2Z,4E)-5-(5,6-Dichloro-3-
ethyl-1H-indol-2-yl)-2- methoxy-N-[4-(2,2,6,6-
tetramethyl)piperidinyl]-2- ,4- pentadienamide hydrochloride 43 H
Me H H H Et 5Cl 6Cl H >250 .sup.1H NMR (DMSO-d.sub.6): 11.52 (s,
1H); 9.00 (d br, 1H); 8.20 (d, 1H); 7.99 (d br, 1H); 7.75 (s, 1H);
7.46 (s, 1H); 7.13 (dd, 1H); 6.98 (d, 1H); 6.70 (d, 1H); 4.12 (m,
1H); 3.71 (s, 3H); 2.78 (m, 2H); 1.85 (d br, 2H); 1.61 (dd br, 2H);
1.44 (s, 6H); 1.40 (s, #6H); 1.13 (t, 3H). 23
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[6-(2-
dimethylaminoethylamino)- pyrid-3-yl]-2-methoxy-2,4- pentadienamide
hydrochloride 44 H Me H H H H 5Cl 6Cl H >250 .sup.1H NMR (DMSO-
d.sub.6+TFA); 11.86 (s, 1H0; 10.32 (s, 1H); 10.05 (s br, 1H); 8.55
(d, 1H); 8.26 (dd, 1H); 7.75 (s, 1H); 7.53 (s, 1H); 7.26 (dd, 1H);
7.16 (d, 1H); 6.96 (d, 1H); 6.88 (d, 1H); 6.62 (s, 1H); 3.82 (s,
3H); 3.79 (t, 2H); 3.36 (t br, 2H); 2.85 #(s, 6H). 24
(2Z,4E)-5-[(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-[3-
piperazin-1-yl)-propyl]-2,4- pentadienamide 45 H Me H H H H 5Cl 6Cl
H 200 .sup.1H NMR (DMSO-d.sub.6): 1.61 (m, 2H); 2.19-2.43 (m, 6H);
2.80 (m, 4H); 3.20 (m, 2H); 3.72 (s, 3H); 6.57 (s, 1H); 6.64 (d,
1H); 6.85 (d, 1H); 7.17 (dd, 1H); 7.52 (s, 1H); 7.75 (s, 1H); 8.27
(t, 1H, exch with D.sub.2O); 11.79 (s, 1H, exch with D.sub.2O). 25
(2Z,4E)-5-(5,6-Dichloro-1- methylindol-2-yl)-2-
methoxy-N-[4-(2,2,6,6- tetramethyl)piperidinyl]-2,4- pentadienamide
46 H Me H H H H 5Cl 6Cl Me 210-213 .sup.1H NMR (DMSO): 7.90 (m br,
1H); 7.80 (s, 1H); 7.74 (s, 1H); 7.19 (dd, 1H); 7.05 (d, 1H); 6.93
(s, 1H); 6.67 (d, 1H); 4.19 (m br, 1H); 3.79 (s, 3H); 3.71 (s, 3H);
1.65 (m, 2H); 1.20 (m, 2H); 1.20 (s, 6H); 1.09 (s, 6H). 26
(2Z,4E)-5-(5- Trifluoromethylindol-2-yl)- -2-
methoxy-N-[4-(2,2,6,6- tetramethyl)piperidinyl]-2,4- pentadienamide
hydrochloride 47 H Me H H H H 5CF.sub.3 H H >250 .sup.1H-NMR
(DMSO-d.sub.6): 11.90 (s, 1H); 8.99 (d br, 1H); 8.23 (d, 1H); 7.96
(d br, 1H); 7.89 (s, 1H); 7.50 (d, 1H); 7.49 (d, 1H); 7.21 (dd,
1H); 6.90 (d, 1H); 6.72 (s, 1H); 6.64 (d, 1H); 4.23 (m, 1H); 3.71
(s, 3H); 1.88 (d br, 2H); 1.62 (dd br, 2H); 1.42 (s, #6H); 1.40 (s,
6H). 27 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-
(3,7-dimethyl-3,7- diazabicyclo[3.3.1]nonan-9-
yl)-2,4-pentadienamide 48 H Me H H H H 5Cl 6Cl H 200 .sup.1H NMR
(DMSO-d.sub.6): 2.26 (m, 2H); 2.39 (s, 3H); 2.53 (s, 3H); 2.66-3.33
(m, 8H); 3.76 (s, 3H); 3.88 (m, 1H); 6.58 (s, 1H); 6.64 (d, 1H);
6.87 (d, 1H); 7.20 (dd, 1H); 7.53 (s, 1H); 7.75 (s, 1H); 8.12 (d,
1H, exch with D.sub.2O); 11.88 (s, 1H, exch with D.sub.2O). 28
Exo-(2Z,4E)-5-(5,6- Dichloro-1H-indol-2-yl)- -2-
methoxy-N-[(8-methyl-8- azabicyclo[3.2.1]oct-3- yl)methyl]-2,4-
pentadienamide 49 H Me H H H H 5Cl 6Cl H 255 .sup.1H NMR
(DMSO-d.sub.6): 1.10-1.98 (m, 9H); 2.13 (s, 3H); 2.97 (bs, 2H);
3.22 (m, 2H); 3.70 (s, 3H); 6.57 (s, 1H); 6.63 (d, 1H); 6.84 (d,
1H); 7.16 (dd, 1H), 7.51 (s, 1H); 7.74 (s, 1H); 8.24 (t, 1H, exch
with D.sub.2O); 11.76 (s, 1H, exch with D.sub.2O). 29
Endo-(2Z,4E)-5-(5,6- Dichloro-1H-indol-2-yl)-2-
methoxy-N-[(8-methyl-8- azabicyclo[3.2.1]oct-3- yl)methyl]-2,4-
pentadienamide 50 H Me H H H H 5Cl 6Cl H 180-198 .sup.1H NMR
(DMSO-d.sub.6): 1.16-2.03 (m, 9H); 2.12 (s, 3H); 2.98 (m, 2H); 3.22
(m, 2H); 3.70 (s, 3H); 6.57 (s, 1H); 6.62 (d, 1H); 6.84 (d, 1H);
7.16 (dd, 1H); 7.51 (s, 1H); 7.74 (s, 1H); 8.24 (t, 1H, exch with
D.sub.2O); 11.75 (s, 1H, exch with #D.sub.2O). 30
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-(1,2,3,4- tetrahydro-2,4-
dioxopyrimidin-5-yl)-2- methoxy-2,4- pentadienamide 51 H Me H H H H
5Cl 6Cl H >330 .sup.1H NMR (DMSO-d.sub.6): 3.85 (s, 3H); 6.61
(s, 1H); 6.84 (d, 1H); 6.96 (d, 1H); 7.21 (dd, 1H); 7.52 (s, 1H);
7.76 (s, 1H); 8.10 (s, 1H); 8.69 (s, 1H, exch with D.sub.2O); 11.25
(bm, 2H, exch with D.sub.2O); 11.80 (s, 1H, exch with D.sub.2O). 31
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-
(2alpha-hydrocy-8-methyl)- 8-azabicyclo[3.2.1]oct- 3beta-yl)-2,4-
pentadienamide 52 H Me H H H H 5Cl 6Cl H 290 .sup.1H NMR
(DMSO-d.sub.6): 1.53-2.25 (m, 6H); 2.58 (s, 3H); 3.42-3.85 (m, 3H);
3.73 (s, 3H); 3.94 (m, 1H); 5.33 (bs, 1H, exch with D.sub.2O); 6.57
(s, 1H); 6.63 (d, 1H); 6.85 (d, 1H); 7.19 (dd, 1H); 7.52 (s, 1H);
7.74 (s, 1H); 8.02 (d, 1H, exch with #D.sub.2O); 11.82 (bs, 1H,
exch with D.sub.2O). 32 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-2-methoxy-N-[2- (1-methylethoxy)-pyrimidin-
5-yl]-2,4-pentadienamide 53 H Me H H H H 5Cl 6Cl H 253-254 .sup.1H
NMR (DMSO-d.sub.6): 1.31 (d, 6H); 3.83 (s, 3H); 5.16 (m, 1H); 6.64
(s, 1H); 6.87 (d, 1H); 6.98 (d, 1H); 7.25 (dd, 1H), 7.54 (s, 1H);
7.77 (s, 1H); 8.87 (s, 2H); 10.21 (bs, 1H, exch with D.sub.2O);
11.82 (bs, 1H, exch with D.sub.2O). 33 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-2-methoxy-N-[5- (dimethylamino-
methyleneamino)pyrimidin- 2-yl)-2,4-pentadienamide 54 H Me H H H H
5Cl 6Cl H 275 .sup.1H NMR (DMSO-d.sub.6): 2.95 (s, 3H); 3.05 (s,
3H); 3.81 (s, 3H); 6.62 (s, 1H); 6.78 (d, 1H); 6.92 (d, 1H); 7.23
(dd, 1H); 7.53 (s, 1H); 7.76 (s, 1H); 7.94 (s, 1H); 8.33 (s, 2H);
10.12 (s, 1H, exch with D.sub.2O); 11.80 (bs, 1H, exch with
D.sub.2O). 34 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-2-methoxy-N-(8- phenyl-8- azabicyclo[3.2.1]oct-3beta-
yl)-2,4-pentadienamide 55 H Me H H H H 5Cl 6Cl H 233 .sup.1H NMR
(DMSO-d.sub.6): 1.42-2.08 (m, 8H); 3.62 (s, 3H); 4.16-4.46 (m, 3H);
6.49-6.68 (m, 3H); 6.73-6.88 (m, 3H); 7.02-7.27 (m, 3H); 7.49 (s,
1H); 7.74 (s, 1H); 7.98 (d, 1H, exch with D.sub.2O); 11.71 (bs, 1H,
exch with D.sub.2O). 35 (2Z,4E)-5-(5,6-Dichloro-- 1H-
indol-2-yl)-2-methoxy-N-(2- dimethyl-aminopyridin-5-
yl)-2,4-pentadienamide 56 H Me H H H H 5Cl 6Cl H 299 .sup.1H NMR
(DMSO-d.sub.6): 3.10 (s, 6H); 3.82 (s, 3H); 6.62 (s, 1H); 6.83 (d,
1H); 6.93 (d, 1H); 7.24 (dd, 1H); 7.53 (s, 1H); 7.76 (s, 1H); 8.62
(s, 2H); 9.93 (s, 1H, exch with D.sub.2O); 11.80 (bs, 1H, exch with
D.sub.2O). 36 (2Z,4E)-N-(2- Acetylaminopyrimidin-5-yl)-
5-(5,6-dichloro-1H-indol-2- yl)-2-methoxy-2,4- pentadienamide 57 H
Me H H H H 5Cl 6Cl H 307 .sup.1H NMR (DMSO-d.sub.6): 2.15 (s, 3H);
3.84 (s, 3H); 6.64 (s, 1H); 6.89 (d, 1H); 6.98 (d, 1H0; 7.25 (dd,
1H); 7.54 (s, 1H); 7.77 (s, 1H); 8.98 (s, 2H); 10.29 (s, 1H, exch
with D.sub.2O); 10.54 (s, 1H, exch with D.sub.2O); 11.82 (bs, 1H,
exch with D.sub.2O). 37 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-N-[2-(1H- imidazol-4-yl)ethyl]-2- methoxy-2,4-
pentadienamide 58 H Me H H H H 5Cl 6Cl H 140 .sup.1H NMR
(DMSO-d.sub.6): 2.71 (t, 2H); 3.40 (q, 2H); 3.70 (s, 3H); 6.58 (s,
1H); 6.65 (d, 1H); 6.85 (s, 1H); 6.86 (s, 1H); 7.16 (dd, 1H); 7.52
(s, 1H); 7.61 (s, 1H); 7.75 (s, 1H); 8.27 (t, 1H, exch with
D.sub.2O); 11.76 (bs, exch with D.sub.2O). 38
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-
[(bicyclo[3.3.1.1.(3,7)]-de- c- 1-yl)amino]propyl]-2- methoxy-2,6-
pentadienamide 59 H Me H H H H 5Cl 6Cl H 220 .sup.1H NMR
(DMSO-d.sub.6): 1.57 (m, 14H); 1.21 (m, 3H); 1.92 (t, 2H); 1.16 (q,
2H); 3.84 (s, 3H); 6.58 (s, 1H); 6.65 (d, 1H); 6.85 (d, 1H); 7.17
(dd, 1H); 7.51 (s, 1H); 7.75 (s, 1H); 8.53 (t, 1H, exch with
D.sub.2O); 11.76 (bs, 1H, exch with D.sub.2O). 39
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-(5-
pyridimidinyl)-2,4- pentadienamide 60 H Me H H H H 5Cl 6Cl H 293
.sup.1H NMR (DMSO-d.sub.6): 3.85 (s, 3H0; 6.65 (s, 1H0; 6.92 (d,
1H); 7.00 (d, 1H); 7.27 (dd, 1H); 7.55 (s, 1H); 7.78 (s, 1H); 8.92
(s, 1H); 9.17 (s, 2H); 10.41 (s, 1H, exch with D.sub.2O); 11.83
(bs, 1H, exch with D.sub.2O). 40 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-2-methoxy-N-(2- phenyl-5-pyrimidinyl)-2,4-
pentadienamide 61 H Me H H H H 5Cl 6Cl H 299 .sup.1H NMR
(DMSO-d.sub.6): 3.87 (s, 3H); 6.66 (s, 1H); 6.94 (d, 1H); 7.01 (d,
1H); 7.28 (dd, 1H); 7.46-7.60 (m, 4H); 7.78 (s, 1H); 8.36 (m, 2H);
9.28 (s, 2H); 10.49 (s, 1H, exch with D.sub.2O); 11.85 (bs, 1H,
exch with D.sub.2O). 41 (2Z,4E)-N-(2-Amino-5-
pyrimidinyl)-5-(5,6-dichloro- 1H-indol-2-yl)-2-methoxy-
2,4-pentadienamide 62 H Me H H H H 5Cl 6Cl H 305 .sup.1H NMR
(DMSO-d.sub.6): 11.80 (bs, 1H, exch with D.sub.2O); 9.87 (s, 1H,
exch with D.sub.2O); 8.50 (s, 2H); 7.77 (s, 1H); 7.54 (s, 1H); 7.24
(dd, 1H); 6.94 (d, 1H); 6.81 (d, 1H); 6.63 (s, 1H); 6.53 (s, 2H,
exch with D.sub.2O); 3.81 (s, 3H). 42 (2Z,4E)-N-[(5,6-Dichloro-1H-
indol-2-yl)-N-[3-[4-(4- benzoyl)benzoyl]piperazin-
1-yl]propyl]-2-methoxy-2,4- pentadienamide 63 H Me H H H H 5Cl 6Cl
H 198-200 .sup.1H NMR (DMSO-d.sub.6): 11.70 (s, 1H); 8.19 (t, 1H);
7.80-7.71 (m, 5H); 7.70 (dd, 1H); 7.60-7.51 (m, 5H); 7.17 (dd, 1H);
6.84 (d, 1H); 6.63 (d, 1H); 6.59 (s, 1H); 3.71 (s, 3H); 3.65 (m,
2H); 3.33 (m, 2H); 3.22 (dt, 2H); 2.60-2.30 (m, 6H); 1.66 (m, 2H).
43 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-(2-cyano-5-
pyrimidinyl)-2-methoxy-2,4- pentadienamide 64 H Me H H H H 5Cl 6Cl
H 292 .sup.1H NMR (DMSO-d.sub.6): 11.84 (bs, 1H, exch with
D.sub.2O); 10.54 (s,
1H, exch with D.sub.2O); 9.15 (s, 2H); 7.78 (s, 1H0; 7.55 (s, 1H);
7.27 (dd, 1H); 7.01 (d, 1H); 6.93 (d, 1H); 6.66 (s, 1H); 3.85 (s,
3H). 44 (2Z,4E)-5-(1H-indol-2-yl)-N- (3-diethylaminopropyl)-2-
methoxy-2,4-pentadienamide 65 H Me H H H H H H H 134-137 .sup.1H
NMR (DMSO-d.sub.6): 11.40 (s, 1H); 8.23 (t br, 1H); 7.48 (d, 1H);
7.31 (d, 1H), 7.14 (dd, 1H); 7.10 (dd, 1H); 6.96 (dd, 1H); 6.84 (d,
1H); 6.66 (d, 1H); 6.55 (s, 1H); 3.76 (s, 3H); 3.25 (m, 2H); 2.52
(m, 6H); 1.63 (m, 2H); 1.00 (t, 6H). 45
(2Z,4E)-5-(1H-indol-2-yl)-2- methoxy-N-(1,2,2,6,6-
pentamethyl-piperidin-4-yl)- 2,4-pentadienamide 66 H Me H H H H H H
H 198-201 .sup.1H NMR (DMSO-d.sub.6): 11.40(s, 1H); 7.81 (d br,
1H); 7.47 (d, 1H); 7.32 (d, 1H); 7.12 (dd, 1H); 7.00 (dd, 1H); 6.96
(dd, 1H); 6.81 (d, 1H); 6.61 (d, 1H); 6.55 (s, 1H); 4.09 (m, 1H);
3.70 (s, 3H); 2.20 (s, 3H); 1.62 (d br, 2H); 1.46 (dd br, 2H); 1.09
(s, 6H); 1.02 (s, 5H). 46 Ethyl (2Z,4E)-5-(5,6-
Dichloro-1H-indol-2-yl)-[(2- methoxy-penta-2,4- dienoyl)amino]-2-
azabicyclo[2.2.2]octane-2- carboxylate 67 H Me H H H H 5Cl 6Cl H
168-170 .sup.1H NMR (DMSO-d.sub.6): 1.10-1.28 (m, 3H); 1.38-2.23
(m, 7H); 3.09-3.59 (m, 2H); 3.71 and 3.73 (2s, 3H); 3.85-4.12 (m,
4H); 6.58 (s, 1H); 6.60 (d, 1H); 6.85 (d, 1H); 7.18 (dd, 1H); 7.52
(s, 1H); 7.75 (s, 1H); 8.17 (2d, 1H, exch with #D.sub.2O) 11.75 (s,
broad, 1H, exch with D.sub.2O) 47 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-2-methoxy-N- (1,2,6-trimethylpiperidin-4-
yl)-2,4-pentadienamide 68 H Me H H H H 5Cl 6Cl H 217 .sup.1H NMR
(DMSO-d.sub.6): 1.04 (d, 6H); 1.32 (m, 2H); 1.65 (m, 2H); 1.96-2.21
(m, 2H); 2.12 (s, 3H); 3.70 (s, 3H); 3.74 (m, 1H); 6.57 (s, 1H);
6.60 (s, 1H); 6.84 (d, 1H); 7.17 (dd, 1H); 7.51 (s, 1H); 7.75 (s,
1H); 7.96 (d, 1H, exch with D.sub.2O); 11.75 (s, 1H, exch with
D.sub.2O) 48 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-
]2-[4-(2- methoxyphenyl)piperazin-1- yl]ethyl] 2,4- pentadienamide
69 H Me H H H H 5Cl 6Cl H 227-229 .sup.1H NMR (DMSO-d.sub.6):
2.45-2.60 (m, 6H); 2.96 (m, 4H); 3.25-3.35 (m, 2H); 3.74 (s, 3H);
3.77 (s, 3H); 6.59 (s, 1H); 6.66 (d, 1H); 6.85 (d, 1H);6.84-6.97
(m, 4H); 7.18 (dd, 1H); 7.51 (s, 1H); 7.74 (s, 1H); 8.01 (t br,
1H); 11.7 (s br, 1H). 49 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-N-(8a betaH-5 alpha-methyl- octahydroindolizin-7-alpha-
yl)-2-methoxy-2,4- pentadiene 70 H Me H H H H 5Cl 6Cl H 231 .sup.1H
NMR (DMSO-d.sub.6): 11.74 (s, broad band, 1H exch with D.sub.2O);
8.00 (d, 1H exch with D.sub.2O); 7.74 (s, H); 7.51 (s, 1H); 7.17
(dd, 1H); 6.84 (d, 1H); 6.60 (d, 1H); 6.57 (s, 1H); 3.74 (m, 1H);
3.70 (s, 3H); 3.08 (m, 1H); 1.50-2.14 (m, 8H); 1.13-1.42 #(m, 3H);
1.03 (d, 3H) 50 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[1-(2-
hydroxyethyl)piperidin-4-yl)- 2-methoxy-2,4- pentadienamide 71 H Me
H H H H 5Cl 6Cl H 218 .sup.1H NMR (DMSO-d.sub.6): 11.73 (s, broad
band, 1H, exch with D.sub.2O); 7.95 (d, 1H exch with D.sub.2O);
7.75 (s, 1H); 7.51 (s, 1H); 7.17 (dd, 1H); 6.83 (d, 1H); 6.60 (d,
1H); 6.57 (s, 1H); 4.35 (t, 1H exch with D.sub.2O); 3.71 (s, 3H);
3.62 (m, 1H); 3.48 (q, 2H); 2.84 (m, 2H); #2.36(t, 2H); 2.00 (m,
2H); 1.43-1.74 (m, 4H) 51 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-N-[1-(2,3- dihydroxypropyl)piperidin-
4-yl)-2-methoxy-2,4- pentadienamide hydrochloride 72 H Me H H H H
5Cl 6Cl H 275 .sup.1H NMR (DMSO-d.sub.6): 11.8 (s, broad band, 1H
exch with D.sub.2O); 9.49 (broad band, 2H, exch with D.sub.2O);
8.29 (d, 1H exch with D.sub.2O); 7.75 (s, 1H ar); 7.52 (s, 1H);
7.20 (dd, 1H); 6.85 (d, 1H); 6.65 (d, 1H); 6.58 (s, 1H); 5.53 (d,
1H, exch with D2O); #4.98 (m, 1H); 4.36 (m, 1H); 3.93 (m, 2H); 3.73
(s, 3H); 2.87-3.62 (m, 6H); 1.94 (m, 4H) 52 Ethyl
(2Z,4E)-[[4-[5-(5,6- Dichloro-1H-indol-2-yl)-2- methoxy-penta-2,4-
dienoyl]amino]- piperidineacetate 73 H Me H H H H 5Cl 6Cl H 237
.sup.1H NMR (DMSO-d.sub.6): 11.75 (s, broad band, 1H, exch with
D.sub.2O); 7.99 (d, 1H, exch with D.sub.2O); 7.75 (s, 1H); 7.52 (s,
1H); 7.17 (dd, 1H); 6.85 (d, 1H); 6.61 (d, 1H); 6.58 (s, 1H); 4.09
(q, 2H); 3.72 (s, 3H); 3.65 (m, H); 3.19 (s, 2H); 2.83 (m, 2H);
2.22 (m, 2H); #1.46-1.75 (m, 4H); 1.19 (t, 3H) 53
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[8-(2-
acetyloxyethane)-8- azabicyclo[3.2.1]oct-3beta- yl]2-methoxy-2,4-
pentadienamide 74 H Me H H H H 5Cl 6Cl H 118-120 .sup.1H NMR
(DMSO-d.sub.6): 11.7 (s, broad band 1H exch with D.sub.2O); 7.9 (d,
1H, exch with D.sub.2O); 7.75 (s, 1H); 7.51 (s, 1H); 7.16 (dd, 1H);
6.83 (d, 1H); 6.60 (d, 1H); 6.56 (s, 1H); 4.06 (m, 3H); 3.69 (s,
3H); 3.23 (m, H); 2.65 (t, 2H); 2.02 (s, #3H); 5.81-1.96 (m, 8H) 54
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-(2a beta, 4a alpha, 6
alpha, 7a alpha- decahydro-pyrrolo[2.1.5- cd]indolizyn-6-yl)-2-
methoxy-2,4- penadienamide 75 H Me H H H H 5Cl 6Cl H 226 .sup.1H
NMR (DMSO-d.sub.6): 11.75 (s, broad band, 1H exch with D.sub.2O);
7.91 (d, 1H, exch with D.sub.2O); 7.75 (s, 1H ar); 7.51 (s, 1H ar);
7.17 (dd, 1H); 6.84 (d, 1H); 6.61 (d, 1H); 6.57 (s, 1H); 3.73 (m,
1H); 3.70 (s, 3H); 3.08 (m, #3H); 5.26 (m, 2H)l 1.04-1.81 (m, 10H)
55 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-(2a beta, 4a alpha, 6
beta, 7a alpha- decahydro-pyrrolo[2.1.5- cd]indolizyn-6-yl)-2-
methoxy-2,4- pentadienamide 76 H Me H H H H 5Cl 6Cl H 238 .sup.1H
NMR (DMSO-d.sub.6): 11.7 (s, broad band, 1H, exch with D.sub.2O);
7.75 (s, 1H); 7.62 (d, 1H exch with D.sub.2O); 7.52 (s, 1H); 7.19
(dd, 1H); 6.85 (d, 1H); 6.60 (d, 1H); 6.58 (s, 1H); 4.04 (m, 1H);
3.76 (s, 3H); 3.24 (m, 3H); 1.00 #(m, 2H); 1.03-1.85 (m, 10H) 56
(2Z,4E)-5-(5,6-Dichloro-1- H- indol-2-yl)-N-[8-(2-ethanol)-
8-azabicyclo[3.2.1]oct- 3beta-yl]2-methoxy-2,4- pentadienamide 77 H
Me H H H H 5Cl 6Cl H 267-270 .sup.1H-NMR (DMSO-d.sub.6): 11.79 (s,
broad band, 1H exch with D.sub.2O); 7.92 (d, 1H exch with
D.sub.2O); 7.74 (s, 1H); 7.52 (s, 1H); 7.17 (dd, 1H); 6.83 (d, 1H);
6.59 (d, 1H); 6.57 (s, 1H); 4.34 (m, 1H, exch with D.sub.2O); 4.03
(m, 1H); 3.69 (s, 3H); 3.45 (m, #2H); 3.21 (m, 2H); 2.48 (t, 2H);
1.40-1.97 (m, 8H) 57 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-2-methoxy-N-(2- alpha, 6 beta 9a aplha)-
octahydro-6-methyl-2H- quinolizin-2-yl]-2,4- pentadienamide 78 H Me
H H H H 5Cl 6Cl H 200-202 .sup.1H NMR (DMSO-d.sub.6); 11.79 (s,
1H); 7.74 (s, 1H); 7.73 (s, 1H); 7.54 (s, 1H); 7.13 (dd, 1H); 6.84
(d, 1H); 6.60 (m, 2H); 3.95 (s, 1H); 3.73 (s, 3H); 3.11 (m, 1H);
2.60-2.15 (m, 3H); 1.90-1.15 (m, 10H); 1.08 (d, 3H). 58
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-
[1,2,6-trimethylpiperidin-4- yl]-2,4-pentadienamide 79 H Me H H H H
5Cl 6Cl H 214 .sup.1H NMR (DMSO-d.sub.6): 11.74 (s, broad band,
1H); 7.90 (d, 1H); 7.74 (s, 1H); 7.51 (s, 1H); 7.17 (dd, 1H); 6.83
(d, 1H); 6.60 (d, 1H); 6.56 (s, 1H); 4.01 (m, 1H); 3.70 (s, 3H);
3.05 (m, 1H); 2.52 (m, 1H); 2.18 (s, 3H); 1.85-1.1 (m, 4H); 0.96
(2d, 6H). 59 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[1-(2-
hydroxyethyl)-2,6- dimethylpiperidin-4-yl]-2- methoxy-2,4-
pentadienamide 80 H Me H H H H 5Cl 6Cl H 150 .sup.1H NMR
(DMSO-d.sub.6): 11.75 (s, broad band, 1H); 7.93 (d, 1H); 7.75 (s,
1H); 7.51 (s, 1H); 7.16 (dd, 1H); 6.84 (d, 1H); 6.60 (d, 1H); 6.57
(s, 1H); 4.38 (s, broad band, 1H); 3.70 (s, 3H); 3.36 (t, 2H);
2.80-2.30 (m, 5H); 1.77-1.49 (m, 2H); 1.38-1.10 (m, 2H); 1.05 (d,
6H). 60 (2Z,4E)-5-(5-Bromo-1H- indol-2-yl)-N--2-methoxy-
(1,2,2,6,6-pentamethyl- piperidin-4-yl)-2,4- pentadienamide 81 H Me
H H H H 5Br H H 225-226 .sup.1H NMR (DMSO-d.sub.6): 11.61 (s br,
1H); 7.83 (d, 1H); 7.68 (d, 1H); 7.29 (d, 1H); 7.19 (dd, 1H); 7.15
(dd, 1H); 6.82 (d, 1H); 6.59 (d, 1H); 6.55 (d, 1H); 4.15-4.02 (m,
1H); 3.71 (s, 3H); 2.18 (s, 3H); 1.62 (dd, 2H); 1.44 (dd, 2H); 1.08
(s, 6H); 1.02 (s, 6H). 61 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-N-(3- dimethylamino-cyclohexyl)- 2-methoxy-2,4-
pentadienamide 82 H Me h h h 5Cl 6Cl H 200-201 .sup.1H NMR
(DMSO-d.sub.6): 11.75 (s, broad band, 1H); 7.80 (s, broad band,
1H); 7.75 (s, 1H); 7.51 (s, 1H); 7.17 (dd, 1H); 6.83 (d, 1H); 6.59
(d, 1H); 6.57 (s, 1H); 4.06 (m, 1H); 3.71 (s, 3H); 2.30-2.20 (m,
1H); 2.16 (s, 6H); 2.45-1.05 (m, 8H). 62
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-[2,6- dimethyl-4-(2-
pyrimidinyl)piperazin-1- yl]propyl]-2-methoxy-2,4- pentadienamide
hydrochloride 83 H Me H H H H 5Cl 6Cl H 245 .sup.1H NMR
(DMSO-d.sub.6): 11.80 (s, broad band, 1H); 10.40 (s, broad band,
1H); 8.43 (d, 2H); 8.39 (m, 1H); 7.76 (s, 1H); 7.53 (s, 1H); 7.19
(dd, 1H); 6.87 (d, 1H); 6.76 (t, 1H); 6.69 (d, 1H); 6.59 (s, 1H);
4.74 (m, 2H); 3.74 (s, 3H); 3.50- # 3.00 (m, 8H); 1.82 (m, 2H);
1.35 (d, 6H). 63 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-2-methoxy-N-[3- [-4-(2- methoxyphenyl]piperazin-1-
yl]propyl] 2,4- pentadienamide 84 H Me H H H H 5Cl 6Cl H 181-182
.sup.1H NMR (DMSO-d.sub.6): 11.72 (s br, 1H); 8.25 (t, 1H); 7.72
(s, 1H), 7.50 (s, 1H); 7.18 (dd, 1H); 6.98-6.81 (m, 5H); 6.64 (d,
1H); 6.58 (s, 1H); 3.76 (s, 3H); 3.73 (s, 3H); 3.27 (dt, 2H), 2.99
(m, 4H); 2.50 (m, 4H); 2.39 (t, 2H); 1.73-1.62 (m, 2H). 64
(2Z,4E)-5-(5,6-Dichloro-1H- - indol-2-yl)-2-methoxy-N-[3-
[-4-(phenyl)piperazin-1- yl]propyl 2,4- pentadienamide 85 H Me H H
H H 5Cl 6Cl H 223-225 .sup.1H NMR (DMSO-d.sub.6): 11.75 (s br, 1H);
8.26 (t, 1H); 7.74 (s, 1H); 7.51 (s, 1H); 7.20 (dd, 2H); 7.17 (dd,
1H); 6.92 (d, 2H); 6.84 (d, 1H); 6.79 (dd, 1H); 6.65 (d, 1H); 6.57
(d, 1H); 3.73 (s, 3H); 3.26 (dt, 2H); 3.13 (m, 4H); 2.50 (m, 4H);
2.39 (t, 2H); 1.73-1.62 #(m, 2H). 65 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-2-methoxy-4- methyl-N-(1,2,2,6,6-
pentamethyl-piperidin-4-yl)- 2,4-pentadienamide 86 H Me H Me H H
5Cl 6Cl H 131-132 .sup.1H NMR (DMSO-d.sub.6): 11.35 (s br, 1H);
7.89 (d, 1H); 7.78 (s, 1H); 7.56 (s, 1H); 6.73 (s, 1H); 6.62 (s,
1H); 6.37 (s, 1H); 4.15-4.00 (m, 1H); 3.60 (s, 3H); 2.29 (s, 3H);
2.18 (s, 3H); 1.62 (dd, 2H); 1.43 (dd, 2H); 1.09 (s, 6H); 1.02 (s,
6H). 66 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-
(dimethylamino)propyl]-2- methoxy-2,4- pentadienamide 87 H Me H H H
H 5Cl 6Cl H 181-183 .sup.1H NMR (DMSO-d.sub.6): 11.71 (s br, 1H);
8.25 (t, 1H); 7.73 (s, 1H); 7.51 (s, 1H); 7.18 (dd, 1H); 6.83 (d,
1H); 6.64 (d, 1H); 6.58 (s, 1H); 3.76 (s, 3H); 3.70 (s, 3H); 3.20
(dt, 2H); 2.24 (t, 2H); 2.13 (s, 6H); 1.66-1.56 (m, 2H). 67
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[(3-
dimethylamino)phenyl]-2- methoxy-2,4- pentadienamide 88 H Me H H H
H 5Cl 6Cl H 140-141 .sup.1H NMR (DMSO-d.sub.6): 11.78 (s br, 1H);
9.70 (s, 1H); 7.76 (s, 1H); 7.52 (s, 1H); 7.23 (dd, 1H); 7.20-7.08
(m, 3H); 6.91 (d, 1H); 6.77 (d, 1H); 6.61 (s, 1H0; 6.48 (d br, 1H);
3.81 (s, 3H); 2.89 (s, 6H). 68 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-N-[3-[4-(3- chlorophenyl)piperazin-1-
yl]propyl]-2-methoxy-2,4- pentadienamide 89 H Me H H H H 5Cl 6Cl H
192-193 .sup.1H NMR (DMSO-d.sub.6): 11.73 (s br, 1H); 8.24 (t, 1H);
7.74 (s, 1H); 7.50 (s, 1H); 7.20 (dd, 2H); 7.15 (dd, 1H); 6.95-6.88
(m, 2H); 6.83 (d, 1H); 6.78 (d, 1H); 6.63 (d, 1H); 6.58 (s, 1H);
3.70 (s, 3H); 3.26 (dt, 2H); 3.18 (m, 4H); 2.50 (m, 4H); 2.39 (t,
2H); #1.72-1.63 (m, 2H). 69 (2Z,4E)-5-(5,6-Dichloro-1H-
indol-2-yl)-N-[3-[4-(4- chlorophenyl)piperazin-1-
yl]propyl]-2-methoxy-2,4- pentadienamide 90 H Me H H H H 5Cl 6Cl H
218-219 .sup.1H NMR (DMSO-d.sub.6): 11.72 (s br, 1H); 8.23 (t, 1H);
7.73 (s, 1H); 7.50 (s, 1H); 7.21 (d, 2H); 7.16 (dd, 1H); 6.93 (d,
2H); 6.84 (d, 1H); 6.64 (d, 1H); 6.58 (s, 1H); 3.73 (s, 3H); 3.24
(dt, 2H); 3.11 (m, 4H); 2.50 (m, 4H); 2.39 (t, 2H); 1.71-1.62 (m,
2H). 70 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3[4-(2-
chlorophenyl)piperazin-1- yl]propyl]-2-methoxy-2,4- -
pentadienamide 91 H Me H H H H 5Cl 6Cl H 193-194 .sup.1H NMR
(DMSO-d.sub.6): 11.71 (s, 1H); 8.23 (t, 1H); 7.74 (s, 1H); 7.51 (s,
1H); 7.40 (dd, 1H); 7.29 (ddd, 1H); 7.16 (dd, 1H); 7.15 (dd, 1H);
7.02 (ddd, 1H); 6.85 (d, 1H); 6.65 (d, 1H); 6.59 (s, 1H); 3.74 (s,
3H); 3.25 (dt, 1H); 3.00 (m, 4H); 2.55 (m, 4H); 2.40 (t, #2H);
2.22-2.13 (m, 2H). 71 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-
(dibutylamino)propyl]-2- methoxy-2,4- pentadienamide 92 H Me H H H
H 5Cl 6Cl H 144-146 .sup.1H NMR (DMSO-d.sub.6): 11.72 (s br, 1H);
8.18 (t, 1H); 7.74 (s, 1H); 7.51 (s, 1H); 7.17 (dd, 1H); 6.84 (d,
1H); 6.63 (d, 1H); 6.58 (s, 1H); 3.72 (s, 3H); 3.18 (dt, 2H);
2.40-2.31 (m, 6H), 1.63-1.54 (m, 2H); 1.40-1.21 (m, 8H); 0.87 (t,
6H). 72 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-[4-(2,6-
dimethylphenyl)piperazin- 1-yl]propyl]-2-methoxy-2,4-
pentadienamide 93 H Me H H H H 5Cl 6Cl H 228-230 .sup.1H NMR
(DMSO-d.sub.6): 11.71 (s br, 1H); 8.20 (t, 1H); 7.74 (s, 1H); 7.52
(s, 1H); 7.17 (dd, 1H); 6.97-6.89 (m, 3H); 6.85 (d, 1H); 6.65 (d,
1H); 6.58 (s, 1H); 3.75 (s, 3H); 3.25 (dt, 2H); 3.02 (m, 4H); 2.47
(m, 4H); 2.39 (t, 2H); 2.27 (s, 6H); 1.73-1.63 #(m, 2H). 73
(2Z,4E)-5-(5,6-Dichloro-1H- - indol-2-yl)-2-methoxy-N-[3-
(pyrrolidin-2-one)propyl]- 2,4-pentadienamide 94 H Me H H H H 5Cl
6Cl H 165-167 .sup.1H NMR (DMSO-d.sub.6): 11.79 (s br, 1H); 8.14
(t, 1H); 7.74 (s, 1H); 7.52 (s, 1H); 7.18 (dd, 1H); 6.85 (d, 1H);
6.66 (d, 1H); 6.58 (s, 1H); 3.75 (s, 3H); 3.34 (t, 2H); 3.20 (t,
2H); 3.14 (dt, 2H); 2.22 (t, 2H); 1.97-1.87 (m, 2H); 1.69-1.60 (m,
2H) 74 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-[4-(2-
pyridinyl)homopiperazin- 1-yl]propyl]-2-methoxy-2- ,4-
pentadienamide 95 H Me H H H H 5Cl 6Cl H 220-222 .sup.1H NMR
(DMSO-d.sub.6): 11.71 (s, 1H); 8.32 (d, 2H); 8.17 (t br, 1H); 7.74
(s, 1H); 7.51 (s, 1H); 7.16 (dd, 1H); 6.84 (d, 1H); 6.63 (d, 1H);
6.57 (s br, 1H); 6.55 (dd, 1H); 3.83-3.77 (m, 2H); 3.74 (t, 2H);
3.72 (s, 3H); 3.19 (dt, 2H); 2.73-2.66 (m, 2H); #2.58-2.51 (m, 2H);
2.45 (t, 2H); 1.88-1.77 (m, 2H); 1.67-1.55 (m, 2H). 75
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-N-[3-[4-(2-
pyridyl)piperazin-1- yl]propyl -2-methoxy-2,4- pentadienamide 96 H
Me H H H H 5Cl 6Cl H 219-220 .sup.1H NMR (DMSO-d.sub.6): 11.80 (s
br, 1H); 8.25 (t br, 1H); 8.10 (dd, 1H); 7.72 (s, 1H); 7.51 (s,
1H); 7.51 (ddd, 1H); 7.19 (dd, 1H); 6.82 (d, 1H); 6.80 (d, 1H);
6.64 (d, 1H); 6.81 (dd, 1H); 6.58 (s, 1H); 3.71 (s, 3H); 3.46 (m,
4H); 3.23 (dt, 2H); 2.46 (m, 4H); 2.39 (t, #2H); 1.73-1.63 (m, 2H).
76 (2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-[3- [-4-(3-
methoxyphenyl)piperazin-1- yl]propyl] 2,4- pentadienamide 97 H Me H
H H H 5Cl 6Cl H 172-173 .sup.1H NMR (DMSO-d.sub.6): 11.70 (s br,
1H); 8.25 (t br, 1H); 7.72 (s, 1H); 7.50 (s, 1H); 7.16 (dd, 1H);
7.10 (dd, 1H); 6.84 (d, 1H); 6.64 (d, 1H); 6.57 (s, 1H); 6.52 (dd,
1H); 6.44 (dd, 1H); 6.36 (dd, 1H); 3.72 (s, 3H); 3.24 (dt, 2H);
3.13 (m, 4H); 2.50 (m, #4H); 2.40 (t br, 2H); 1.73-1.64 (m, 2H). 77
(2Z,4E)-5-(5,6-Dichloro-1H- indol-2-yl)-2-methoxy-N-[3- [-4-(4-
methoxyphenyl)piperazin-1- yl]propyl] 2,4- pentadienamide 98 H Me H
H H H 5Cl 6Cl H 197-199 .sup.1H NMR (DMSO-d.sub.6): 11.70 (s br,
1H); 8.25 (t br, 1H); 7.74 (s, 1H); 7.51 (s, 1H); 7.16 (dd, 1H);
6.88-6.80 (ABq, 4H); 6.84 (d, 1H); 6.65 (d, 1H); 6.57 (s br, 1H);
3.73 (s, 3H); 3.67 (s, 3H); 3.25 (dt, 2H); 3.02 (m, 4H); 2.51 (m,
4H); 2.39 (t, 2H); #1.72-1.63 (m, 2H)
List of Abbreviations Used in the Above Preparations and
Examples
[0369] Florisil Registered trademark
[0370] Celite Registered trade mark for dicalite
[0371] DMF Dimethylformamide
[0372] EI Electron Impact
[0373] AcOEt Ethyl acetate
[0374] FAB POS Fast Atom Bombardment/Positive ions detection
[0375] MS Mass Spectrum
[0376] THF Tetrahydrofuran
[0377] TSP ThermoSpray
[0378] Biological Assays
[0379] Background.
[0380] It is known that, upon attachment to bone, an electrogenic
H.sup.+-adenosine triphosphatase (ATPase) is polarised to the
osteoclast-bone interface. The pump transports massive quantities
of protons into the resorption microenvironment to effect
mobilisation of the bone mineral and to create the acidic pH
required by collagenases to degrade the bone matrix.
[0381] The vacuolar nature of the osteoclast proton pump was
originally recognised by Blair [H. C. Blair at al., Science, 245,
855 (1989)1 and than confirmed by Bekker [P. J. Bekker et al., J.
Bone Min. Res., 5, 569 (1990)] and Vnnen [K. K. Vnnen et al., J.
Cell. Biol., 111, 1305 (1990)]. Evidence was based upon
preparations of ruffled membrane fragments from avian osteoclasts
(obtained from the medullar bone of calcium-starved egg-laying
hens). The resulting membrane vesicles acidify in response to ATP,
which is easily assessed by measuring the fluorescence quench of
acridine orange, a weak base which accumulates into acidic
compartments.
[0382] The biochemical pattern indicated that the osteoclast proton
pump belonged to the vacuolar-like ATPases since proton transport
was inhibited by N-ethylmaleimide (NEM), a sulphydryl reagent, and
by bafilomycin A.sub.1, a selective inhibitor of vacuolar
H.sup.+-ATPases [J. E. Bowman et al., Proc. Natl. Acad Sci. USA,
85, 7972 (1988)], whilst it was not inhibited by ouabain, an
inhibitor of Na.sup.+/K.sup.+-ATPases- ; sodium orthovanadate, an
inhibitor of p-ATPases, or by omeprazole or SCH 28080, both of
which are inhibitors of gastric H.sup.+/K.sup.+-ATPase (J. P.
Mattson et al., Acta Physiol. Scand., 146, 253 (1992)].
[0383] It is known that specific inhibitors of vacuolar ATPases,
such as bafilomycin A.sub.1, are able to inhibit bone resorption in
osteoclast cultures [K. Sundquist et al., Biochem. Biophys. Res.
Commun. 168, 309-313 (1990)].
[0384] Inhibition of Proton Transport and v-ATPase Activity in
Membrane Vesicles
[0385] Preparation of Crude Bone Microsomes from Calcium-starved
Egg-laying Hens.
[0386] Vesicles were prepared from medullar bone obtained from
tibiae and femurs of egg-laying hens which were calcium-starved for
at least 15 days. Briefly, bone fragments were scraped with a 24
scalpel blade, suspended in 40 ml of isolation medium (0.2 M
sucrose, 50 mM KCl, 10 mM Hepes, 1 mM EGTA, 2 mM dithiotheitrol, pH
7.4) and filtered through a 100 lm pore size nylon mesh. The whole
procedure was performed at 4.degree. C. After homogenisation in a
potter (20 strokes) in 40 ml of isolation medium an initial
centringation (6,500.times. g.sub.max.times.20 min) was performed
to remove mitochondria and lysosomes. The supernatant was
centrifuged at 100,000.times. g.sub.max for 1 hr and the pellet was
collected in 1 ml of isolation medium, divided into 200 .mu.l
aliquots, immediately frozen in liquid nitrogen and stored at
-80.degree. C. The protein content was determined using a Biorad
colourimetric kit according to Bradford [M. Bradford, Anal.
Biochem., 72, 248 (1976)]. For the proton transport assay, 5-10
.mu.l of membranes were used.
[0387] Purification of Osteoclast Membranes.
[0388] 1 ml of crude microsomal vesicles prepared above were
applied (about 0.2 ml per tube ) on the top of a sucrose
step-gradient consisting of 3.5 ml of 15%, 30% and 45% (w/w)
sucrose in isolation medium and centrifuged at 280,000 g.sub.max
for 2 hours (SW 41 Ti rotor). After centrifugation the 30-45%
sucrose interfaces were collected, diluted approx. 20-fold in
isolation medium and pelletted at 100,000 g.sub.max for 1 hour (SW
28 rotor). The pellet was then resuspended in 1 ml of isolation
medium, aliquoted and frozen in liquid N.sub.2 and stored at
-80.degree. C. until used.
[0389] Human kidney membranes were obtained from the cortex of a
human kidney, frozen immediately after surgery, according to the
method reported in the literature for bovine kidney (S. Gluck, J.
Biol. Chem., 265, 21957 (1990)).
[0390] Proton transport in membrane vesicles was assessed,
semi-quantitatively, by measuring the initial slope of fluorescence
quench of acridine orange (excitation 490 nm; emission 530) after
addition of 5-20 .mu.l of membrane vesicles in 1 ml of buffer
containing 0.2 M sucrose, 50 mM KCl, 10 mM Hepes pH 7.4, 1 mM
ATP.Na.sub.2, 1 mM CDTA, 5 .mu.M valinomycin and 4 .mu.M acridine
orange. The reaction was started by addition of 5 mM MgSO.sub.4.
Results were expressed as the percent of the mean of two
controls.
[0391] Inhibition of bafilomycin-sensitive ATPase activity was
assessed in purified membrane vesicles by measuring the release of
inorganic phosphate (Pi) during 30 min of incubation at 37.degree.
C. in a 96-well plate either in the presence or in the absence of
bafilomycin A1. The reaction medium contained 1 mM ATP, 10 mM
HEPES-Tris pH 8, 50 mM KCl, 5 uM valinomycin, 5 uM nigericin, 1 mM
CDTA-Tris, 100 uM ammonium molybdate, 0.2 M sucrose and membranes
(20 ug protein/ml). The reaction was initiated by MgSO.sub.4 (8-arm
pipette) and stopped, after 30 min, by addition of 4 volumes of the
malachite green reagent (96-arm pipette) prepared according to Chan
[Anal. Biochem. 157, 375 (1986)]. Absorbance at 650 nm was measured
after 2 min using a microplate reader. Results are expressed as
Mmol (Pi).times.mg protein.sup.-1.times.hour.sup.-1 and, for each
experiment, represent the mean.+-.sem of triplicates.
[0392] Pharmacological Data:
[0393] Inhibition of Baflomycin-sensitive ATPase in Chicken
Osteoclasts
[0394] The compounds of the present invention are able to inhibit
bafilomycin-sensitive ATPase in chicken osteoclast in a range from
18 nM to 1000 nM. In particular:
2 Ex. No IC.sub.50 (nM) ATPase assay 1 24 55 23 59 24 61 41 62 30
64 67 68 18 74 42 75 30
[0395] Inhibition of Bone Resorption
[0396] In vivo Assays
[0397] 1) Bone resorption by disaggregated rat osteoclasts can be
assessed as described previously in the literature [T. J. Chambers
et al., Endocrinology, 1985, 116, 234]. Briefly, osteoclasts were
mechanically disaggregated from neonatal rat long bones into
Hepes-buffered medium 199 (Flow, UK). The suspension was agitated
with a pipette, and the larger fragments were allowed to settle for
30 sec. The cells were then added to two wells of a multiwell dish
containing slices (each measuring 12 mm.sup.2). After 15 min at
37.degree. C. the bone slices were removed, washed in medium 199
and placed in individual wells of a 96-well plate. These were
incubated for 24 hrs in a total volume of 2 ml of culture medium,
consisting of 10% foetal calf serum in Hanks-buffered MEM, in the
presence or absence of drug. The number of osteoclasts and bone
resorption were quantified by confocal laser scanning microscopy
(CLSM): the bone slices were fixed with 2% glutaraldehyde in 0.2 M
cacodylate buffer and the osteoclasts on each bone slice were
stained for tartrate-resistant acid phosphatase. After counting the
number of large, multinucleated, red-stained cells, the bone slices
were immersed in 10% sodium hypochlorite for 5 min to remove cells,
washed in distilled water and sputter-coated with gold. The entire
surface of each bone slice was then examined in CLSM. The number
and the size of the osteoclastic excavations, the plain area and
the volume of bone resorbed was recorded. Results were expressed as
mean pit number per bone slice, mean pit number per osteoclast,
mean area per osteoclast or mean volume per osteoclast.
[0398] 2) Bone resorption by human osteoclasts can be assessed
using a modification of the method above. Briefly, human
osteoclasts are purified from human giant cell tumours by negative
selection using Pan Human HLA II antibodies in conjunction with
Dynal magnetic beads. Osteoclasts are seeded onto bovine bone
slices in Hepes-buffered medium 199 (Flow, UK). After 30 minutes,
the bone slices are transferred into a 24-well multi-plate (4
slices per well) containing 2 ml/well of medium, consisting of 10%
foetal calf serum in D-MEM. One hour later, vehicle (DMSO) or test
compounds at different concentrations in DMSO were added and
incubation was continued for 47 hours. Bone slices were then
treated and analysed as described above for the rat osteoclast
assay.
[0399] 3) Inhibition of PTH-stimulated .sup.45Ca.sup.2+ Release
from Prelabelled Foetal Rat Long Bone.
[0400] The assay is based on that described by Raisz (J. Clin.
Invest. 44:103-116, 1965). Time-mated Sprague-Dawley rats were
injected subcutaneously with 200 mCi of .sup.45CaC12 on the 18th
day of gestation. On the following day, the foetuses were removed
aseptically and the radii and ulnae were dissected free of adjacent
soft tissue and the cartilaginous ends, and then cultured for 24 hr
at 37.degree. C. in BGJ medium containing 1 mg/ml BSA. The bones
were then transferred to fresh medium containing the test compounds
(0.1-50 .mu.M) with and without PTH (12 nM) and were incubated for
an additional 48 hr. The media were collected and the bones
extracted to determine the mean % calcium release by scintillation
counting. Results were expressed as the % inhibition compared to
the amount of calcium released from cultures incubated with PTH
alone
[0401] In vivo Assays
[0402] Prevention of Retinoid-induced Hypercalcaemia.
[0403] The method used was that described by Trechsel et al., (J.
Clin. Invest. 80:1679-1686, 1987). Briefly, male Sprague-Dawley
rats weighing 160-200 g (10 per group) were
thyroparathyroidectomised and were treated subcutaneously with the
retinoid Ro 13-6298 (30 .mu.g/day) for three days and this was
found to significantly increase blood serum calcium by 4-5 mg/100
ml. For inhibition of this effect, rats were treated simultaneously
with test compounds i.v. or p.o. at 0.1-100 mg/kg, or vehicle and
blood calcium was measured as described above, before treatment and
one day after the last administration. Results were expressed as %
inhibition with respect to vehicle-treated animals.
[0404] Prevention of Bone Loss in Osteoporosis Induced by
Ovariectomy and Immobilisation.
[0405] Seven groups of 10 Sprague-Dawley rats (200 g) underwent
ovariectomy plus neurectomy of the sciatic nerve in the right hind
limb, while one group was sham-operated according to the method
described by Hayashi et al., (Bone 10:25-28, 1989). It was
demonstrated that a steady-state was attained in the amount of
trabecular bone lost 6-12 weeks after the operations. During a
6-week period, the operated animals received the test compounds
(0.1 -100 mg/kg p.o. u.i.d.), or vehicle. At the end of this
treatment period, the animals were sacrificed and the tibia and
femur of the hind limb removed. The tibia wet and dry weight were
determined, and the density (displacement of water) and ashes
content (total weight, calcium and phosphorous content) also
measured. The femur were fixed in 10% formalin, de-mineralised in
5% formic acid and the coronal midshaft and longitudinal section of
the distal metaphysis cut and stained with haematoxilin and cosin.
Histomorphometric evaluation was made using a semi-automated image
analyser (Immagini & Computer, Milan, Italy). In the distal
metaphysis, the % trabecular bone area in the secondary spongiosa
(which is the trabecular bone 1 mm from the epiphyseal growth plate
to about 4 mm towards the midshaft giving a total area of 5
mm.sup.2) and the number of trabeculae (according to Parfitt et
al., J. Bone Min. Res. 2: 595, (1987)) were determined in all
animals. In the midshaft, the medullary, cortical (CA) and total
(TA) cross-sectional area was measured and the cortical index (CI)
determined from the formula CI=CA/TA.
[0406] Prevention of Bone Loss in Ovariectomised Mature Rats.
[0407] The methodology employed is based on that described by
Wronsky et al. [J. Bone Min. Res.,6, 387 (1991)]. The bone loss,
prevalently cancellous, occuring after the surgery is monitored by
dual emission X-ray absorptiometry (DEXA) measurements of bone
mineral density (BMD) of long bones and by HPLC measurements of
urinary levels of products of bone collagen breakdown, such as the
cross-link residues pyridinoline (PYD), deoxypyridinoline (DPD) and
lysine glycosides, i.e. galactosyl-hydroxylysine (GHYL) and
glucosyl-galactosyl-hydroxylysine (GGHYL). Groups of 7-10 female
Sprague-Dawley rats, about 90 days old and weighing 200-250 g are
used. Rats are anesthetised by sodium pentobarbital (35 mg/kg
i.v.), laparotomy is performed and ovaries are bilaterally removed
. Wounds are adequately disinfected and sutured. A group is sham
operated. During a 4-week experimental period, the operated animals
receive test compounds in the appropiate vehicle (0.1-100 mg/kg
p.o. u.i.d.) or vehicle alone. Twenty-four-hr urine samples are
collected for PYD, DPD, GHYL and OGHYL determinations before and 2,
4, 8, 11, 15, 18, 22 and 25 days after surgery. The aliquots of
urine are frozen and stored at -20.degree. C. until HPLC
analysis.
[0408] Before and at the end of the experimental period, the bone
metaphyseal mineral densities of left distal femur and proximal
tibia were evaluated in vivo using lightly anaesthetised animals.
Results are expressed as % of prevention of bone loss versus
vehicle treated animals, using the following equation, where BMD
indicates the bone mineral density at the end of the experimental
period and is expressed as the percent of pre-ovariectomy baseline:
1 Percent prevention = BMD ( treatment ) - BMD ( vehicle ) BMD (
sham ) - BMD ( vehicle ) .times. 100
[0409] Biological Data for Compound of Example 1
3 Human Osteoclast Resorption Assay IC.sub.50 = 3.4 nM Human Kidney
ATPase assay IC.sub.50 = 363 nM Protection of bone loss in
ovariectomised mature 76% rats at 10 mg/kg p.o.
[0410] Other Therapeutic Utilities:
[0411] The activity of the compounds of the invention for the other
utilities mentioned herein may be determined by according to the
following methods which are incorprated herein:
[0412] 1. Antitumor activity may be determined according to the
methods disclosed in published International Application,
Publication number 93/18652; in particular the screen employed,
experimental details and bibliography of M. R. Boyd et al., Status
of the NCI preclinical antitumor drug discovery screen; principles
and practices of Oncology, 3, issue 10, Oct. 1989, Lippincott.
[0413] 2. Antiviral activity may be assessed using the in vitro
assays reported by H. Ochiai et al., Antiviral Research, 27,
425-430 (1995) or by C. Serra et al., Pharmacol. Res., 29, 359
(1994). Anti-HIV activity can be assessed as reported in the
literature, for example by S. Velsquez et al., J. Med. Chem., 38,
1641-1649 (1995)
[0414] 3. Antiulcer activity may be assessed in vivo using the
methods reported in the literature, for example, as described by C.
J. Pfeiffer, Peptic Ulcer, C. J. Pfeiffer Ed., Munksgaard Publ.,
Copenaghen, 1971. In vitro assays for inhibition of vacuolization
induced by Helicobacter pylori are described, for example, by E.
Papini et al., FEMS Microbiol. Lett., 113, 155-160 (1993)
[0415] 4. Usefulness in treating Alzheimer's disease may be
determined using models in vitro such as inhibition of
amiloyd-.beta. production as descrided in the literature by J.
Knops et al., J. Biol. Chem., 270,2419-2422 (1995) or by models in
vivo: such as the transgenic mouse model overexpressing human APP
reported by D. Games et al., Nature, 373, 523-527 (1995).
[0416] 5. Immunosuppressant activity can be assessed as reported in
the literature, for example by M. -K. Hu et al., J. Med. Chem., 38,
4164-4170 (1995)
[0417] 6.Antilipidemic activity can be assessed as reported in the
literature, for example by E. A. L. Biessen et al., J. Med. Chem.,
38, 1846-1852 (1995). Antiatherosclerotic activity may be assessed
by using animal models of atherosclerosis, such as the
atherosclerotic rabbit model, which are reported in the literature,
for example by R. J. Lee et al., J. Pharm. Exp. Ther., 184, 105-112
(1973).
[0418] 7. Angiostatic activity may be assessed using the methods
reported in the literature, for example as described by T. Ishii et
al., J. Antibiol., 48, 12 (1995).
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