U.S. patent application number 11/842674 was filed with the patent office on 2007-12-13 for 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9h-pyrido (3,4-b) indole-3-carboxylic acid esters/amides useful as antithrombotic agents.
This patent application is currently assigned to Council of Scientific and Industrial Research. Invention is credited to Zahid Ali, Mohammed Salim Ansari, Kanta Bhutani, Madhu Dikshit, Anshuman Dixit, Zeeshan Fatima, Stuti Gaur, Kapil Kapoor, Anil Kumar Saxena, William Rascan Surin.
Application Number | 20070287723 11/842674 |
Document ID | / |
Family ID | 36612578 |
Filed Date | 2007-12-13 |
United States Patent
Application |
20070287723 |
Kind Code |
A1 |
Gaur; Stuti ; et
al. |
December 13, 2007 |
2-ALKYL/ARYL SULPHONYL-1,2,3,4-TETRAHYDRO-9H-PYRIDO (3,4-B)
INDOLE-3-CARBOXYLIC ACID ESTERS/AMIDES USEFUL AS ANTITHROMBOTIC
AGENTS
Abstract
The present invention relates to antithrombotic compounds
2-alkyl aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)
indole-3-carboxylic acid esters/amides, pharmaceutically acceptable
salts and compositions thereof to be used in the treatment of
intravascular thrombosis such as myocardial ischemia and stroke.
The compound has the following general structure ##STR1## wherein R
represents methyl ester or amide and R.sub.1 represents alkyl, aryl
and heteroaryl moiety.
Inventors: |
Gaur; Stuti; (Uttar Pradesh,
IN) ; Fatima; Zeeshan; (Uttar Pradesh, IN) ;
Dixit; Anshuman; (Uttar Pradesh, IN) ; Ali;
Zahid; (Uttar Pradesh, IN) ; Surin; William
Rascan; (Uttar Pradesh, IN) ; Kapoor; Kapil;
(Uttar Pradesh, IN) ; Bhutani; Kanta; (Uttar
Pradesh, IN) ; Ansari; Mohammed Salim; (Uttar
Pradesh, IN) ; Dikshit; Madhu; (Uttar Pradesh,
IN) ; Saxena; Anil Kumar; (Uttar Pradesh,
IN) |
Correspondence
Address: |
OSTROLENK FABER GERB & SOFFEN
1180 AVENUE OF THE AMERICAS
NEW YORK
NY
100368403
US
|
Assignee: |
Council of Scientific and
Industrial Research
|
Family ID: |
36612578 |
Appl. No.: |
11/842674 |
Filed: |
August 21, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11023915 |
Dec 28, 2004 |
|
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11842674 |
Aug 21, 2007 |
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Current U.S.
Class: |
514/292 ;
546/85 |
Current CPC
Class: |
A61P 7/02 20180101; A61P
9/10 20180101; C07D 471/04 20130101 |
Class at
Publication: |
514/292 ;
546/085 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61P 7/02 20060101 A61P007/02; A61P 9/10 20060101
A61P009/10; C07D 471/04 20060101 C07D471/04 |
Claims
1. A process for the preparation of a 2-alkyl/aryl
sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic
acid ester of formula I ##STR7## wherein R is selected from methyl
ester and amide; and R.sub.1 is selected from the group consisting
of alkyl, aryl, and heteroaryl moiety, the process comprising
condensing an alkyl or aryl sulphonyl chloride with dimethyl-1, 2,
3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate of formula
2 ##STR8## in the presence of a base and an organic solvent to
obtain a corresponding 2-alkyl/aryl sulphonyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indo.le-3-carboxylic acid ester of
formula 1.
2. A method as claimed in claim 1 wherein the aryl is selected from
the group consisting of substituted phenyl substituted by hydrogen,
halogen, alkyl or alkoxy, sunstituted napthyl substituted by
hydrogen or dimethyl amino; and heteroaryl.
3. A method as claimed in claim 2 wherein the heteraryl is
quinoline.
4. A method as claimed in claim 1 wherein the reaction is carried
out at a temperature in the range of 30.degree. C. to 120.degree.
C. and for 8 to 24 hours.
5. A method as claimed in claim 2 wherein the halogen is selected
from the group consisting of chlorine, bromine fluorine, iodine,
and mixtures thereof; alkoxy is selected from the group consisting
of C.sub.1-C.sub.10 oxy; alkyl is selected from the group
consisting of C.sub.1-C.sub.10 alkyl, and heteroaryl is selected
from the group consisting of C.sub.4-C.sub.10 heteroaryl.
6. A method for the preparation of 2-alkyl/aryl
sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic
acid amide of formula I ##STR9## wherein R is selected from methyl
ester and amide; and R.sub.1 is selected from the group consisting
of alkyl, aryl, and heteroaryl moiety by condensing an alkyl or
aryl sulphonyl chloride wherein aryl is selected from the group
consisting of substituted phenyl substituted by hydrogen, halogen,
alkyl or alkoxy; substituted napthyl substituted by hydrogen or
dimethyl amino; and heteroaryl consisting of quinoline with dl 1,
2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide of formula 3
##STR10## in the presence of a base and an organic solvent to
obtain a corresponding 2-alkyl/aryl sulphonyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid amide.
7. A method as claimed in claim 6 wherein the reaction is carried
out at a temperature in the range of 30.degree. C. to 120.degree.
C. for 8 to 24 hours.
8. A method as claimed in claim 6 wherein the halogen is selected
from the group consisting of chlorine, bromine fluorine, iodine,
and mixtures thereof, alkoxy is selected from the group consisting
of C.sub.1 to C.sub.10 oxy; alkyl is selected from the group
consisting of C.sub.1 to C.sub.10 alkyl, and heteroaryl is selected
from the group consisting of C.sub.4-C.sub.10 heteroaryl.
9. A method for the preparation of 2-alkyl/aryl sulphonyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid amides
comprising reacting a 2-alkyl/aryl sulphonyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid ester with
methanolic ammonia for 24 to 48 hours to obtain the corresponding
2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid amide.
10. A process as claimed in claim 1 wherein the reaction is carried
out in the presence of a solvent selected from the group consisting
of acetone, DMF, THF and dioxane; a base selected from the group
consisting of TEA, K.sub.2CO.sub.3. Na.sub.2CO.sub.3, pyridine or
any combination thereof and at a temperature in the range of
30.degree. C. to 120.degree. C. and a period of 8 to 24 hours.
11. A process as claimed in claim 1 wherein molar ratio of
substituted sulphonyl chloride to dl methyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylate/dl 1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indole-3-amide is 1:2.
12. A process as claimed in claim 10 wherein the amount of solvent
is in the range of 0.8-2.2 ml per mmol.
13. A process as claimed in claim 10 wherein molar ratio of the
base to the dl methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)
indole-3-carboxylate/dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)
indole-3-amide is 1:4.
14. A pharmaceutical composition comprising a pharmaceutically
effective amount of 2-alkyl/aryl
sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic
acid ester/amide of formula 1 ##STR11## wherein R is selected from
the methyl ester and amide; and R.sub.1 is selected from the group
consisting of alkyl, aryl, and heteroaryl moiety, and a
pharmaceutically acceptable carrier.
15. A method for the treatment of intravascular thrombosis in
mammals comprising administering to a patient in need thereof a
therapeutically effective amount of a pharmaceutical composition
consisting of a pharmaceutically effective amount of 2-alkyl/aryl
sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic
acid amide of formula 1 ##STR12## wherein R is selected from methyl
ester and amide; and R.sub.1 is selected from the group consisting
of alkyl, aryl and heteroaryl moiety, with a pharmaceutically
acceptable carrier.
16. A method for the treatment of myocardial ischemia in mammals,
comprising by administering to a patient in need thereof a
therapeutically effective amount of a pharmaceutical composition
consisting of a pharmaceutically effective amount of 2-alkyl/aryl
sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic
acid ester/amide of formula 1 ##STR13## wherein R is selected from
methyl ester and amide; and R.sub.1 is selected from the group
consisting of alkyl, aryl and heteroaryl moiety, with a
pharmaceutically acceptable carrier.
17. A method for the treatment of stroke in mammals, comprising
administering to a patient in need thereof a therapeutically
effective amount of a pharmaceutical composition consisting of a
pharmaceutically effective amount of 2-alkyl/aryl
sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic
acid ester/amide of formula 1 ##STR14## wherein R is selected from
methyl ester and amide; and R.sub.1 is selected from the group
consisting of alkyl, aryl and heteroaryl moiety, with a
pharmaceutically acceptable carrier.
18. A method for treating a condition in mammals, selected from the
group consisting of myocardial ischemia, intravascular thrombosis
and stroke, which comprises administering to a mammal in need
thereof a therapeutically effective amount of a pharmaceutical
composition consisting of a pharmaceutically effective amount of
2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid ester/amide of formula 1 ##STR15## wherein
R is selected from methyl ester and amide; and R.sub.1 is selected
from the group consisting of alkyl, aryl and heteroaryl moiety,
with or without a pharmaceutically acceptable carrier.
19. The method as claimed in claim 15 wherein the amount of
compound of formula 1 is in the range of 10 .mu.M to 30 .mu.M per
kilogram body weight of subject.
20. The method as claimed in claim 16 wherein the amount of
compound of formula 1 is in the range of 10 .mu.M to 30 .mu.M per
kilogram body weight of subject.
21. The method as claimed in claim 17 wherein the amount of
compound of formula 1 is in the range of 10 .mu.M to 30 .mu.M per
kilogram body weight of subject.
22. The method as claimed in claim 18 wherein the amount of
compound of formula 1 is in the range of 10 .mu.M to 30 .mu.M per
kilogram body weight of subject.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to antithrombotic compounds
2-alkyl aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)
indole-3-carboxylic acid esters/amides, pharmaceutically acceptable
salts and compositions thereof useful in treatment of intravascular
thrombosis such as myocardial ischemia and stroke. The compound has
the following general structure ##STR2## wherein R represents
methyl ester or amide and R.sub.1 represents alkyl, aryl and
heteroaryl moiety. The present invention particularly relates to
novel compounds 2-alkyl/aryl sulphonyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid
esters/amides, which are potent antithrombotic agents and can be
useful in treatment of intravascular thrombosis, such as myocardial
ischemia and stroke. The present invention also relates to
processes for preparing the said novel compounds. More particularly
the present invention relates to 2-alkyl/aryl sulphonyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid
esters/amides, processes for preparing the said compounds and to
their use in medicine.
BACKGROUND OF THE INVENTION AND PRIOR ART
[0002] Cardiovascular diseases associated with intravascular
thrombosis are the most common cause of death in both developed and
developing countries. Arterial and venous thromboses are the
principal causes for the evolution of myocardial infarction,
thromboembolic stroke and deep vein thrombosis. Approximately three
million individuals die each year in the United States only from
venous (deep vein thrombosis and pulmonary embolism) or arterial
thrombosis (acute myocardial infarction and unstable angina).
[0003] Initiation of thrombosis is a complex process. The final
event i.e. the thrombus formation, however, is primarily due to the
activation of platelets and coagulation cascade. Clinical and
experimental studies indicate that abnormalities in the normal
blood flow, activation of platelets, coagulation cascade or
fibrinolysis contribute to the pathogenesis of intravascular
thrombosis/thromboembolism. Though the treatment strategy for
thrombosis has improved with newer diagnostic and surgical tools
but effective antithrombotic therapy with minimal side effects
still poses a challenge to scientists around the globe.
[0004] Antithrombotic agents have been researched and developed for
use in treating cardiovascular and other diseases. Presently
established antithrombotic agents include heparin, coumarin, and
aspirin. There are, however, limitations with these agents. For
example, both heparin.sup.1 and coumarin.sup.2 have a
highly-variable dose-related response, and their anticoagulant
effects must be closely monitored to avoid a risk of serious
bleeding. The erratic anticoagulant response of heparin is likely
due to its propensity to bind non-specifically to plasma proteins.
Aspirin has a limited efficacy and at high doses presents a risk of
gastrointestinal bleeding.
[0005] Tissue plasminogen activators.sup.3,4, platelet GPIIb/IIIa
antagonists.sup.5, ADP receptor antagonists.sup.6, are also being
currently used to treat thrombosis, however, these drugs have some
inherent problems and limitations. Therefore, new search is taken
up to develop next generation anti-thrombotic agents such as direct
thrombin inhibitors.sup.7, tissue factor pathway inhibitors.sup.8,
Factor Xa inhibitors.sup.9, collagen antagonists.sup.10 and gene
therapy. The search of a potent orally active and specific
anti-thrombotic agent with minimal danger of bleeding or unrelated
side effects is thus an area of interest. Moreover, the high cost
of anticoagulant and antithrombotic therapy necessitates the search
for efficacious new chemical entities.
[0006] 1. Circulation 1998, 98, 1575-82.
[0007] 2. Drugs 1994, 48,185-97.
[0008] 3. J Intern Med 1994, 236, 425-32.
[0009] 4. J Antibiot 1996,49,1014-21.
[0010] 5. Current Pharmaceutical Design 2003.9(28) 2317-2322.
[0011] 6. Current Pharmaceutical Design 2003.9(28) 2303-2316.
[0012] 7. Expert Opinion on Investigational Drugs 2004,13(5)
465-477.
[0013] 8. Drugs News and Perspective 2003,16(6) 363-369.
[0014] 9. Current Pharmaceutical Design 2003.9(28) 2337-23247.
[0015] 10. Drugs of the future 2003 28(l),61-67.
OBJECTS OF THE INVENTION
[0016] The main object of the invention is to provide novel
molecules 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido
(3,4-b) indole-3-carboxylic acid esters/amides that exhibit better
therapeutic efficacy to treat intravascular thrombosis, myocardial
ischemia and stroke over the existing antithrombotic agents.
[0017] It is another object of the invention to provide novel
2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid esters/amides exhibiting activity against
intravascular thrombosis for which there is/are no/few agent/agents
available till date.
[0018] It is another object of the invention to provide
2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid esters/amides as therapeutic agents for
diseases arising out of alterations/impairment in intravascular
thrombosis leading to myocardial ischemia and stroke.
[0019] It is another object of the invention to provide a process
for preparing novel 2-alkyl/aryl
sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic
acid esters/amides.
[0020] It is another object of the invention to provide a
pharmaceutical composition comprising 2-alkyl/aryl sulphonyl-1, 2,
3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid
esters/amides and pharmaceutically acceptable additive(s) and a
process for preparing such composition.
[0021] It is another object of the invention to provide for the use
of compounds of the present invention in the treatment or
prevention of primary arterial thrombotic complications of
atherosclerosis such as thrombotic stroke, peripheral vascular
disease, and myocardial infarction without thrombolysis.
[0022] It is another object of the invention to provide for the use
of compounds of the invention for the treatment or prevention of
arterial thrombotic complications due to interventions in
atherosclerotic disease such as angioplasty, endarterectomy, stent
placement, coronary and other vascular graft surgery.
[0023] It is another object of the invention to provide for the use
of the compounds of the invention for the treatment or prevention
of thrombotic complications of surgical or mechanical damage such
as tissue salvage following surgical or accidental trauma,
reconstructive surgery including skin flaps, and "reductive"
surgery such as breast reduction.
[0024] It is another object of the invention to provide for the use
of compounds of the present invention for the prevention of
mechanically-induced platelet activation in vivo such as
cardiopulmonary bypass (prevention of microthromboembolism),
prevention of mechanically-induced platelet activation in vitro
such as the use of the compounds in the preservation of blood
products, e.g. platelet concentrates, prevention of shunt occlusion
such as renal dialysis and plasmapheresis, thrombosis secondary to
vascular damage/inflammation such as vasculitis, arteritis,
glomerulonephritis and organ graft rejection.
[0025] It is another object of the invention to provide for the use
of compounds of the present invention for the indicating with a
diffuse thrombotic/platelet consumption component such as
disseminated intravascular coagulation, thrombotic thrombocytopenic
purpura, hemolytic uremic syndrome, heparin-induced
thrombocytopenia and pre-eclampsia/eclampsia.
[0026] It is another object of the invention to provide for the use
of compounds of the present invention for the treatment or
prevention of venous thrombosis such as deep vein thrombosis,
veno-occlusive disease, hematological conditions such as
thrombocythemia and polycythemia, and migraine.
[0027] It is another object of the invention to provide for the use
of compounds of the present invention in treatment of unstable
angina, coronary angioplasty and myocardial infarction.
[0028] It is another object of the invention to provide for the use
of compounds of the present invention for adjunctive therapy in the
prevention of coronary arterial thrombosis during the management of
unstable angina, coronary angioplasty and acute myocardial
infarction, i.e. perithrombolysis.
[0029] It is another object of the invention to provide for a
method of treating mammals to alleviate the pathological effects of
atherosclerosis and arteriosclerosis, acute MI, chronic stable
angina, unstable angina, transient ischemic attacks and strokes,
peripheral vascular disease, arterial thrombosis, preeclampsia,
embolism, restenosis or abrupt closure following angioplasty,
carotid endarterectomy, and anastomosis of vascular grafts.
[0030] It is another object of the invention to provide for the use
of compounds of the present invention in vitro to inhibit the
aggregation of platelets in blood and blood products, e.g. for
storage, or for ex vivo manipulations such as in diagnostic or
research use.
[0031] It is another object of the invention to provide for the use
of compounds of the present invention for the to inhibit platelet
aggregation and clot formation in a mammal, especially a human,
which comprises the internal administration.
[0032] It is another object of the invention to provide for the use
of compounds of the present invention for the treatment of chronic
or acute states of hyperaggregability, such as disseminated
intravascular coagulation (DIC), septicemia, surgical or infectious
shock, post-operative and post-partum trauma, cardiopulmonary
bypass surgery, incompatible blood transfusion, abruptio placenta,
thrombotic thrombocytopenic purpura (TTP), snake venom and immune
diseases, which are likely to be responsive to these compounds.
[0033] It is another object of the invention to provide for the use
of compounds of the present invention in a method for inhibiting
the reocclusion of an artery or vein following fibrinolytic
therapy, which comprises internal administration of compound and a
fibrinolytic agent.
[0034] It is another object of the invention to provide for the use
of compounds of the present invention for extracorporeal
circulation, which is routinely used for cardiovascular surgery in
order to oxygenate blood. Platelets adhere to surfaces of the
extracorporeal circuit.
[0035] It is another object of the invention to provide for the use
of compounds of the present invention for prevention of platelet
thrombosis, thromboembolism and reocclusion during and after
thrombolytic therapy and prevention of platelet thrombosis,
thromboembolism and reocclusion after angioplasty of coronary and
other arteries and after coronary artery bypass procedures.
[0036] To achieve the above and other objects the present invention
provides novel pharmacologically active compounds, specifically new
2-alkyl aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)
indole-3-carboxylic acid esters/amides which are used as potential
therapeutic agents for intravascular thrombosis, myocardial
ischemia and stroke and other disorders as mentioned above.
SUMMARY OF THE INVENTION
[0037] Accordingly the present invention relates to 2-alkyl/aryl
sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic
acid esters/amides having formula 1: ##STR3## wherein R is selected
from methyl ester and amide; and R.sub.1 is selected from the group
consisting of alkyl, aryl, and heteroaryl moiety.
[0038] In one embodiment of the invention, the compound comprises
at least one of: [0039] a. 2[-2,5 dichlorobenzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester [0040] b. 2[2,4,6, trimethyl benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester [0041] c. 2[2,nitrobenzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester [0042] d.
2[1-napthyl sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester [0043] e. 2-4-metoxy benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3 ,4-b]
indole-3-carboxylic acid ester [0044] f. 2[8-quinoline
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
0 acid ester [0045] g. 2-[dansyl sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester [0046] h.
2[2,4,6 tri isopropyl benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester [0047] i.
2[4-floro benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester [0048] j. 2[2-tri floro methyl
benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester [0049] k. 2[methyl
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester [0050] l. 2-[2-napthalene sulfonyl]-1, 2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester [0051] m.
2[benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester [0052] n. 2[4-methyl benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester
[0053] In other embodiment the compound includes at least one of:
[0054] o. 2[-2,5 dichlorobenzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide [0055] p.
2[-4-methoxy benzene sulfonyl]-1,2,3 ,4,-tetra hydro-9H-pyrido[3
,4-b] indole-3-carboxylic acid amide [0056] q.
2[-1-napthylsulfonyl]-1,2,3 ,4,-tetra hydro-9H-pyrido[3 ,4-b]
indole-3-carboxylic acid amide [0057] r. 2[8-quinoline
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide [0058] s. 2[-4-floro benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide [0059] t.
2[methane sulphonyl sulfonyl-1, 2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid amide [0060] u. 2[3-nitro benzene
sulfonyl-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide [0061] v. 2[2,4,6 trimethyl benzene
sulfonyl-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide [0062] w. 2-[2-napthalene sulfonyl]-1 ,2,3,4,-tetra
hydro-9H-pyrido[3 ,4-b] indole-3-carboxylic acid amide
[0063] The present invention also provides a process for synthesis
of 2-alkyl/aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid esters/amides of formula 1: ##STR4##
wherein R is selected from methyl ester and amide; and R.sub.1 is
selected from the group consisting of alkyl, aryl, and heteroaryl
moiety, the process comprising condensing an alkyl or aryl
sulphonyl chloride wherein aryl includes substituted phenyl
substituted by group selected from the group consisting of
hydrogen, halogens, alkyl and alkoxy, substituted napthyl
substituted by group selected from the group consisting of hydrogen
and dimethyl amino; and heteroaryl like quinoline with dimethyl-l,
2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate Formula
2 in the presence of a base and an organic solvent at temperature
ranging from 30.degree. C. to 120.degree. C. for 8 to 24 hours to
produce the corresponding 2-alkyl/aryl sulphonyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esters.
[0064] In another embodiment, the invention relates to a process
for the synthesis of the above compounds by condensing an alkyl or
aryl sulphonyl chloride where in aryl includes, substituted phenyl
by groups like hydrogens, halogens, alkyl, alkoxy etc., substituted
napthyl by hydrogen, di methyl amino, and heteroaryl like quinoline
with dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide
formula 3 in the presence of a base and an organic solvent at
temperature ranging from 30.degree. C. to 120.degree. C. for 8 to
24 hours to produce the corresponding 2-alkyl/aryl sulphonyl-l, 2,
3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid
amides.
[0065] In another embodiment, the invention relates to a process
for the synthesis of the above compounds wherein 2-alkyl/aryl
sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid esters is treated with methanolic ammonia
for 24 to 48 hours hrs to obtain the corresponding 2-alkyl/aryl
sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid amides.
[0066] In another preferred embodiment, the synthesis of
2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid esters/amide of formula 1 includes the
presence of one of the organic solvent selected from a group of
acetone, DMF, THF, dioxane, a base including at least one of TEA,
K.sub.2CO.sub.3, Na.sub.2CO.sub.3, pyridine and a temperature of
about 30.degree. C. to 120.degree. C. for 8 to 24 hours.
[0067] In another embodiment, the molar ratios of the substituted
sulphonyl chloride to dl methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,
4-b) indole-3-carboxylate/dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3,
4-b) indole-3-amide is about 1:2. In yet another preferred
embodiment the organic solvents include acetone, DMF, THF, dioxane
and the organic solvent is present about 0.8-2.2 ml per mmol.
[0068] In another embodiment, the molar ratio of the base to the dl
methyl-I, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)
indole-3-carboxylate/dli 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)
indole-3-amide is about 1:4.
[0069] The invention also relates to pharmaceutical compositions
having the compound of formula 1 described above in a mixture with
a pharmaceutically acceptable carrier. The invention further
relates to a process for preparing the pharmaceutical composition
by bringing the compound into association with a pharmaceutically
acceptable additive.
[0070] The invention also relates to method of treating various
diseases with the pharmaceutical compositions of the present
invention. In one embodiment, the method involves treating
intravascular thrombosis in mammals by administering to a patient
in need thereof a therapeutically effective amount of the
pharmaceutical composition. In one embodiment, the method involves
treating myocardial ischemia in mammals, by administering to a
patient in need thereof a therapeutically effective amount of the
pharmaceutical composition In one embodiment, the method involves
treating stroke in mammals, by administering to a patient in need
thereof a therapeutically effective amount of the pharmaceutical
composition.
[0071] In a preferred embodiment, the diseases treated are selected
to be intravascular thrombosis, myocardial ischemia and stroke or a
combination thereof. In another preferred embodiment the
intravascular diseases are selected to include as mentioned above.
In another preferred embodiment halogen of the compound is selected
from the group of chlorine, bromine fluorine and iodine, and
mixtures thereof, the alkoxy is selected to be a C.sub.1-C.sub.10
oxy, the alkyl is selected to be C.sub.1-C.sub.10 alkyl, and the
heteroaryl is selected to be a C.sub.4-C.sub.10 heteroaryl.
BRIEF DESCRIPTION OF THE DRAWINGS
[0072] FIG. 1 is a graphical representation of the effect of
compound (i) on human platelet aggregation.
DETAILED DESCRIPTION OF THE INVENTION
[0073] The compound of the present invention achieves the following
objects: [0074] i) providing novel molecules 2-alkyl/aryl
sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid esters/amides that may exhibit better
therapeutic efficacy to treat intravascular thrombosis, myocardial
ischemia and stroke over the existing antithrombotic agents. [0075]
ii) providing novel 2-alkyl/aryl sulphonyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid
esters/amides exhibiting activity against intravascular thrombosis
for which there is/are no/few agent/agents available till date to
the best of the applicants knowledge. [0076] iii) providing
2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid esters/amides as therapeutic agents for
the diseases arising out of alterations/impairment in intravascular
thrombosis leading to myocardial ischemia and stroke. [0077] iv)
providing processes for preparing novel 2-alkyl/aryl sulphonyl-1,
2, 3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid
esters/amides. [0078] v) providing a pharmaceutical composition
comprising 2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido
(3,4-b) indole-3-carboxylic acid esters/amides. And
pharmaceutically acceptable additive (s) and a process for
preparing such composition. [0079] vi) providing for use of the
compounds in the treatment or prevention of primary arterial
thrombotic complications of atherosclerosis such as thrombotic
stroke, peripheral vascular disease, and myocardial infarction
without thrombolysis. [0080] vii) providing for the use of the
compounds of the invention for the treatment or prevention of
arterial thrombotic complications due to interventions in
atherosclerotic disease such as angioplasty, endarterectomy, stent
placement, coronary and other vascular graft surgery. [0081] viii)
providing for the use of the compounds of the invention for the
treatment or prevention of thrombotic complications of surgical or
mechanical damage such as tissue salvage following surgical or
accidental trauma, reconstructive surgery including skin flaps, and
"reductive" surgery such as breast reduction. [0082] ix) providing
for the use of the compounds of the invention for the prevention of
mechanically-induced platelet activation in vivo such as
cardiopulmonary bypass (prevention of microthromboembolism),
prevention of mechanically-induced platelet activation in vitro
such as the use of the compounds in the preservation of blood
products, e.g. platelet concentrates, prevention of shunt occlusion
such as renal dialysis and plasmapheresis, thrombosis secondary to
vascular damage/inflammation such as vasculitis, arteritis,
glomerulonephritis and organ graft rejection. [0083] x) providing
for the use of the compounds of the invention as indicators with a
diffuse thrombotic/platelet consumption component such as
disseminated intravascular coagulation, thrombotic thrombocytopenic
purpura, hemolytic uremic syndrome, heparin-induced
thrombocytopenia and pre-eclampsia/eclampsia. [0084] xi) providing
for the use of the compounds of the invention for the treatment or
prevention of venous thrombosis such as deep vein thrombosis,
veno-occlusive disease, hematological conditions such as
thrombocythemia and polycythemia, and migraine. [0085] xii)
providing for the use of the compounds of the invention for the
treatment of unstable angina, coronary angioplasty and myocardial
infarction. [0086] xiii) providing for the use of the compounds of
the invention for the adjunctive therapy in the prevention of
coronary arterial thrombosis during the management of unstable
angina, coronary angioplasty and acute myocardial infarction, i.e.
perithrombolysis. Agents commonly used for adjunctive therapy in
the treatment of thrombotic disorders can be used, for example
heparin and/or aspirin, just to mention a few. [0087] xiv)
providing for the use of the compounds of the invention for a
method of treating mammals to alleviate the pathological effects of
atherosclerosis and arteriosclerosis, acute MI, chronic stable
angina, unstable angina, transient ischemic attacks and strokes,
peripheral vascular disease, arterial thrombosis, preeclampsia,
embolism, restenosis or abrupt closure following angioplasty,
carotid endarterectomy, and anastomosis of vascular grafts. [0088]
xv) providing for the use of the compounds of the invention for the
in vitro to inhibit the aggregation of platelets in blood and blood
products, e.g. for storage, or for ex vivo manipulations such as in
diagnostic or research use. This invention also provides a method
of inhibiting platelet aggregation and clot formation in a mammal,
especially a human, which comprises the internal administration.
[0089] xvi) providing for the use of the compounds of the invention
for treatment of chronic or acute states of hyperaggregability,
such as disseminated intravascular coagulation (DIC), septicemia,
surgical or infectious shock, post-operative and post-partum
trauma, cardiopulmonary bypass surgery, incompatible blood
transfusion, abruptio placenta, thrombotic thrombocytopenic purpura
(TTP), snake venom and immune diseases, which are likely to be
responsive to these compounds. [0090] xvii) providing for the use
of the compounds of the invention in a method for inhibiting the
reocclusion of an artery or vein following fibrinolytic therapy,
which comprises internal administration of compound and a
fibrinolytic agent. When used in the context of this invention, the
term fibrinolytic agent is intended to mean any compound, whether a
natural or synthetic product, which directly or indirectly causes
the lysis of a fibrin clot. Plasminogen activators are a well known
group of fibrinolytic agents. Useful plasminogen activators
include, for example, anistreplase, urokinase (UK), pro-urokinase
(pUK), streptokinase (SK), tissue plasminogen activator (tPA) and
mutants, or variants thereof, which retain plasminogen activator
activity, such as variants which have been chemically modified or
in which one or more amino acids have been added, deleted or
substituted or in which one or more functional domains have been
added, deleted or altered such as by combining the active site of
one plasminogen activator or fibrin binding domain of another
plasminogen activator or fibrin binding molecule. [0091] xviii)
providing for use of the compounds of the invention for
extracorporeal circulation, which is routinely used for
cardiovascular surgery in order to oxygenate blood. Platelets
adhere to surfaces of the extracorporeal circuit. Platelets
released from artificial surfaces show impaired hemostatic
function. Compounds of the invention can be administered to prevent
adhesion. [0092] xix) providing for the use of the compounds of the
invention for other applications including prevention of platelet
thrombosis, thromboembolism and reocclusion during and after
thrombolytic therapy and prevention of platelet thrombosis,
thromboembolism and reocclusion after angioplasty of coronary and
other arteries and after coronary artery bypass procedures.
[0093] To achieve the above and other objects the present invention
provides novel pharmacologically active compounds, specifically new
2-alkyl aryl sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b)
indole-3-carboxylic acid esters/amides which are used as potential
therapeutic agents for intravascular thrombosis, myocardial
ischemia and stroke and other disorders as mentioned above.
[0094] The compound of the invention has the formula 1 ##STR5##
wherein R represents methyl ester or amide and R.sub.1 represents
alkyl, aryl and heteroaryl moiety. Representative compounds
include: [0095] a. 2[-2,5 dichlorobenzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester [0096] b.
2[2,4,6, trimethyl benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester [0097] c.
2[2,nitrobenzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester [0098] d. 2[1-napthyl
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester [0099] e. 2-4-metoxy benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3 ,4-b] indole-3-carboxylic acid ester [0100] f.
2[8-quinoline sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester [0101] g. 2-[ dansyl
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester [0102] h. 2[2,4,6 tri isopropyl benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester [0103] i. 2[4-floro benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester [0104] j.
2[2-tri floro methyl benzene sulfonyl]-l,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester [0105] k.
2[methyl sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester [0106] l. 2-[2-napthalene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester [0107] m. 2[benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester [0108] n.
2[4-methyl benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester [0109] o. 2[-2,5 dichlorobenzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide [0110] p. 2[-4-methoxy benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide [0111] q.
2[-1-napthylsulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid amide [0112] r. 2[8-quinoline
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide [0113] s. 2[-4-floro benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide [0114] t.
2[methane sulphonyl sulfonyl-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid amide [0115] u. 2[3-nitro benzene
sulfonyl-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide [0116] v. 2[2,4,6 trimethyl benzene
sulfonyl-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide [0117] w. 2-[2-napthalene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide
[0118] In the specification in formula 1, R designates methylester
and amide R.sub.1 designates alkyl group includes methyl, aryl
group includes naphthyl and phenyl group substituted by alky,
alkoxy, halogen groups and heteroaryl group includes quinoline.
[0119] A preferred group of compound comprises those in which
R=methyl ester/amide and R.sub.1=methyl, benzene, 4-methyl benzene,
2-napthalene, 2,5 dichlorobenzene, 2,4,6, trimethyl benzene,
2,nitrobenzene, 1-napthyl, 4-metoxy benzene, 8-quinoline, dansyl,
2,4,6 tri isopropyl benzene, 4-floro benzene, tri floro methyl
benzene.
[0120] The invention also provides a pharmaceutical composition
comprising a compound of formula 1 in a mixture with a
pharmaceutically acceptable conventional carriers and a process for
the preparation of a pharmaceutical composition which comprises
bringing a compound of the formula 1 into association with a
pharmaceutically acceptable conventional carrier.
[0121] In addition, the invention provides a method of treating
intravascular thrombosis and myocardial ischemia and stroke in
mammals, that comprises administering to a subject in need thereof
an effective amount of a compound of formula 1.
[0122] The compounds of the invention are useful in therapy,
particularly in the prevention of platelet aggregation. The
compounds of the invention have shown to possess antithrombotic
activity in different test models. The compounds of the present
invention are thus useful as anti-thrombotic agents, and are thus
useful in the treatment or prevention of unstable angina, coronary
angioplasty and myocardial infarction. The compounds prevent
intravascular thrombosis, its progression or recurrence. They may
be useful as additive or synergistic therapy to reduce the
incidence of myocardial ischemia, acute myocardial infarction,
unstable angina, during and after angioplasty or stent replacement,
prevent cerebrovascular events, secondary prevention of stroke and
pulmonary thromboembolism. These agents may also be used in
combination with antithrombotic drugs and anticoagulants in
patients undergoing angioplasty or stenting for coronary artery
disease and also in conjunction with fibrinolysis protocols.
[0123] Diseases or conditions associated with platelet aggregation
are disorders or procedures characterized by thrombosis, primary
arterial thrombotic complications of atherosclerotic disease,
thrombotic complications of interventions of atherosclerotic
disease, thrombotic complications of surgical or mechanical damage,
mechanically-induced platelet activation, shunt occlusion,
thrombosis secondary to vascular damage and inflammation,
indications with a diffuse thrombotic/platelet consumption
component, venous thrombosis, coronary arterial thrombosis,
pathological effects of atherosclerosis and arteriosclerosis,
platelet aggregation and clot formation in blood and blood products
during storage, chronic or acute states of hyper-aggregability,
reocclusion of an artery or vein following fibrinolytic therapy,
platelet adhesion associated with extracorporeal circulation,
thrombotic complications associated with thrombolytic therapy,
thrombotic complications associated with coronary and other
angioplasty, or thrombotic complications associated with coronary
artery bypass procedures.
[0124] Disorders or procedures associated with thrombosis are
unstable angina, coronary angioplasty, or myocardial infarction;
said primary arterial thrombotic complications of atherosclerosis
are thrombotic stroke, peripheral vascular disease, or myocardial
infarction without thrombolysis; said thrombotic complications of
interventions of atherosclerotic disease are angioplasty,
endarterectomy, stent placement, coronary or other vascular graft
surgery; said thrombotic complications of surgical or mechanical
damage are associated with tissue salvage following surgical or
accidental trauma, reconstructive surgery including skin flaps, or
reductive surgery; said mechanically-induced platelet activation is
caused by cardiopulmonary bypass resulting in microthromboembolism
and storage of blood products; said shunt occlusion is renal
dialysis and plasmapheresis; said thromboses secondary to vascular
damage and inflammation are vasculitis, arteritis,
glomerulonephritis or organ graft rejection; said indications with
a diff-use thrombotic/platelet consumption component are
disseminated intravascular coagulation, thrombotic thrombocytopenic
purpura, hemolytic uremic syndrome, heparin-induced
thrombocytopenia, or pre-eclampsialeclampsia; said venous
thrombosis are deep vein thrombosis, veno-occlusive disease,
hematological conditions, or migraine; and said coronary arterial
thrombosis is associated with unstable angina, coronary angioplasty
or acute myocardial infarction.
[0125] Pathological effects of atherosclerosis and arteriosclerosis
are arteriosclerosis, acute myocardial infarction, chronic stable
angina, unstable angina, transient ischemic attacks, strokes,
peripheral vascular disease, arterial thrombosis, preeclampsia,
embolism, restenosis or abrupt closure following angioplasty,
carotid endarterectomy, or anastomosis of vascular grafts; said
chronic or acute states of hyper-aggregability is caused by DIC,
septicemia, surgical or infectious shock, post-operative trauma,
post-partum trauma, cardiopulmonary bypass surgery, incompatible
blood transfusion, abruptio placenta, thrombotic thrombocytopenic
purpura, snake venom or immune diseases. A method of preparation of
the inventive compounds consists of the condensation of different
alkyl/aryl sulphonyl chlorides with dl methyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate/dl -1, 2, 3,
4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide to get the compounds
of formula 1 (2-alkyl/aryl sulphonyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid
esters/amides) as shown in scheme 1 of the accompanying
drawings.
[0126] The compounds of the present invention can be used as
pharmaceutical compositions comprising compounds of the present
invention with a suitable pharmaceutical career. Preferably, these
compositions are used to produce intravascular antithrombotic
activity and contain an effective amount of the compounds useful in
the method of the invention. The most preferred compounds of the
invention are [0127] 1. 2[-2,5 dichlorobenzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester. [0128] 2. 2[-4-methoxy benzene sulfonyl]-1, 2, 3,
4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.
[0129] 3. 2-[2-napthalene sulfonyl]-l, 2, 3, 4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.
[0130] The reaction leading to 2-alkyl/aryl sulphonyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid
esters/amides is shown in scheme 1 which represents the reaction
sequence resulting in 2-alkyl aryl
sulphonyl-1,2,3,4-tetrahydro-9H-pyrido(3,4-b) indole-3-carboxylic
acid esters/amides, according to the present invention.
##STR6##
[0131] It will be noted that according to the foregoing scheme the
methods that lead to the synthesis of 2-alkyl/aryl sulphonyl-1, 2,
3, 4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid
esters/amides of formula 1 as shown earlier are as follows
[0132] The method involves in the synthesis of the compounds of
formula 1 wherein R is methyl ester comprises of condensation of an
alkyl or aryl sulphonyl chloride with dimethyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate of formula 2
in the presence of a base selected from trimethylamine, potassium
carbonate, pyridine in organic solvent selected from THF, DMF,
acetone, dioxane at a temperature ranging from 30.degree. C. to
120.degree. C. for 8 to 24 hours to produce the corresponding
2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid esters.
[0133] Two methods were used for the synthesis of 2-alkyl/aryl
sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid amides.
[0134] The first method relates to a process for the synthesis of
the above compounds by condensing a alkyl or aryl sulphonyl
chloride with dli 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)
indole-3-amide formula 3 in the presence of a base selected from
trimethylamine and an organic solvent DMF at temperature 30.degree.
C. to 120.degree. C. for 8 to 12 hours to produce the corresponding
2-alkyl/aryl sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid amide of formula 1 wherein
R.dbd.CONH.sub.2.
[0135] The second method involves 2-alkyl/aryl sulphonyl-1, 2, 3,
4-tetrahydro-9H-pyrido (3,4-b) indole-3-carboxylic acid esters
synthesized as described previously, treated with methanolic
ammonia for 24-32 hours at 32.degree. C. to obtain 2-alkyl/aryl
sulphonyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3,4-b)
indole-3-carboxylic acid amide.
[0136] The compounds of the invention show marked antithrombotic
activity and can be used as therapeutic agents for the treatment of
intravascular thrombosis, myocardial ischemia and stroke as shown
for instance by the following data of the compounds [0137] (i)
2-[2,5-dichlorobenzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester, [0138] (ii)
2-[4-methoxy benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3
,4-b] indole-3-carboxylic acid amide. [0139] (iii) 2-[2-napthalene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide, Pharmacological Activity (1) Methods:
[0140] 1.1 Effect on mouse thrombosis: Pulmonary thromboembolism
was induced by following a method of Diminno and Silver .sup.(1).
Test compounds (30 .mu.M/Kg) or vehicle were administered orally 60
min prior to the thrombotic challenge. A mixture of collagen (150
.mu.g/ml) and adrenaline (50 .mu.g/mL) was administered by the
rapid intravenous injection into the tail vein to induce hind limb
paralysis or death. A group of 10 animals were used to evaluate the
effect of test compound, while 5 mice were used to assess effect of
a standard drug, aspirin and a group of vehicle treated (n=5) mice
was also used in each experiment. % Protection was expressed as: (
P control - P test ) P control .times. 100 ##EQU1##
[0141] P.sub.test is the number of animals paralyzed/dead in the
test compound-treated group, and P.sub.contol is the number of
animals paralyzed/dead in vehicle treated group.
[0142] 1.2 Effect on mouse-tail bleeding time: Mice tail bleeding
time was performed by method of Dejna et al, .sup.(2). The tail 2
mm from tip was incised and the blood oozed was soaked with filter
paper till the bleeding stops. The time elapsed from the tip
incision to the stoppage of bleeding was determined as the bleeding
time. Test compound (30 .mu.M/kg), aspirin or vehicle was given
orally 60 min prior to the tail incision. Each group consisted of 5
mice.
[0143] 1.3 Evaluation of compounds on platelet aggregation:
Platelet aggregation was monitored according to the protocol
described earlier .sup.(3). Sprague Dawley rats (wt 250-300 gm)
were anaesthetized with ether and blood (9 mL) was drawn from the
heart into a plastic syringe containing 1 ml of 1.9% tri-
[0144] Sodium citrate: The blood was centrifuged at 275.times.g for
20 min and the platelet rich plasma (PRP) was collected. The
remaining blood was further centrifuged at 1500 g for 15 min at
20.degree. C. to obtain platelet poor plasma (PPP). The platelet
count in the PRP was adjusted to 2.times.10.sup.8 cells/ml by.
using PPP. Adenosine-5'-diphosphate (ADP), thrombin, collagen,
calcium ionophore A23187 or phorbol myristate ester (PMA) induced
aggregation was monitored on a dual channel aggregometer
(Chrono-log, USA). The test compound was incubated with PRP for 5
min before the addition of aggregation inducing agent. Percent
inhibition of the test compounds at various concentrations was
calculated as follows: % .times. .times. .times. Inhibition = [
Aggregation vehicle - Aggregation test ] Aggregation vehicle
.times. 100 ##EQU2##
[0145] 1.4 Evaluation of coagulation parameters: Blood was
collected by cardiac puncture from ether-anaesthetized rat using a
syringe containing 3.2% tri-sodium citrate (9:1,v/v). Plasma was
obtained by centrifugation of citrated blood at 2500.times.g for 15
min at 20.degree. C. Stock solutions of the test compounds were
prepared freshly in DMSO and were diluted in DMSO. Thrombin time
(TT), prothrombin time (PT) and activated partial thromboplastin
time (aPTT) were evaluated according to manufacturer's instructions
supplied with kits (Stago, France) and measured by Coagulometer
(Stago, France) .sup.(4). In each set of experiment effect of DMSO
on these parameters was also assessed and was used to calculate
change in TT, PT or aPTT.
[0146] 1.5 Rabbit venous thrombosis model: Experiments were
performed on New Zealand white strain rabbits (2-3 kg) either sex.
Escherichia coli LPS strain 1055:B5 (Sigma Chemicals, USA) was
injected intravenously via ear vein (1 .mu.g/kg) .sup.(5,6).
Jugular veins on both sides were exposed and dissected free from
surrounding tissue. Two loose sutures were placed 1.5 cm apart and
all collateral veins were ligated. Four hours after E. Coli
endotoxin injection (animal is watched for any signs of
hypersensitivity reaction during this period), stasis was
established and maintained for 45 min by tightening the two
sutures. Ligated segments were removed and opened longitudinally
and the thrombus was carefully removed and weighed. Heparin sodium
(Beparine from beef intestinal mucosa .gtoreq.140 USP units/mg;
Biological E. Limited, India) was given in doses of (0.5, 0.25, 0.1
mg/kg i.v., via ear vein) 5 min before stasis.
[0147] 1.6 Effect of compound (i) on human platelet aggregation in
vitro.: Platelet aggregation study was done on human platelets
following isolation of PRP from the human blood as described above
(1.3). Aggregation was induced by collagen (10 .mu.g/ml, 5
.mu.g/ml), ADP (10 .mu.M) and thrombin (0.5U/ml).
[0148] 2. Results: Effect of test compounds is indicated in the
following table (1) against collagen and epinephrine induced
thrombosis in mice, which is a primary screening model to detect
antithrombotic efficacy of the test agents. At the same dose these
compounds were also evaluated for their effect on the bleeding time
in mouse (Table 1).
[0149] Since compound (i), (ii) and (iii) exhibited significant
protection these compounds were further analysed in greater details
for the anti-thrombotic activity in various test systems, as
indicated below.
[0150] Effect on venous thrombosis model in rabbit: The selected
compounds were evaluated at 10 .mu.M/Kg and 30 .mu.M/kg dose for
their efficacy against stasis induced thrombosis in LPS treated
rabbits. (i) was found to be most effective as it inhibited
thrombus formation significantly at both 30 and 10 .mu.M/Kg, while
n and a inhibited thrombus formations only at 30 .mu.M/Kg. heparin
was used as standard drug in this model and the results obtained
are shown in the Table 2.
[0151] Ex vivo effect of selective compounds on rat platelet
aggregation: Blood was collected in sodium citrate to obtain PRP
and evaluate the ex vivo effect of selective compounds ((i), (ii)
,(iii) at 30 .mu.M/kg administered by the ip route) against ADP,
collagen, phorbol myristate ester (PMA) calcium ionophore (A23187),
or thrombin induced aggregation. It was observed that all these
compounds were consistent against collagen-induced platelet
aggregation (Table 3). (iii) inhibited ADP(10 .mu.M), collagen (10
.mu.g/ml), PMA (1.5 .mu.M), and thrombin (0.64U/ml) induced
platelet aggregation while no inhibition was found against calcium
ionophore A23187 (2.5 .mu.g/ml) induced platelet aggregation.
Compound (ii) inhibited only ADP (10 .mu.M), collagen (10
.mu.g/ml), PMA (1.5 .mu.M), and A23187 (2.5 .mu.g/ml) induced
platelet aggregation however it did not inhibit thrombin (0.64U/ml)
induced platelet aggregation. Compound(i) inhibited ADP (10 .mu.M),
collagen (10 .mu.g/ml), and A23187 (2.5 .mu.g/ml) induced platelet
aggregation but had no inhibitory effect against thrombin
(0.64U/ml) and PMA (1.5 .mu.M) induced platelet aggregation.
[0152] Effect on clotting parameters: The selected compounds were
also tested in vitro for their effect on thrombin time (TT),
prothrombin time (PT) and activated partial thromboplastin time
(aPTT) at 100 .mu.g/ml and 200 .mu.g/ml in vitro (Table 4). The
test compounds at 100 .mu.g/ml had no significant effect of on
these parameters. Some effect was though seen on PT at 200 .mu.g/ml
concentration, but the concentration seems to be quite high.
[0153] Effect of compound(i) on human platelet aggregation in human
PRP in vitro: Since the compound(i) exhibited promising profile
against venous thrombosis model in rabbits as well as in other test
systems; it was therefore further studied for inhibition of
aggregation in human platelet rich plasma (PRP). It was found to be
a competitive inhibitor of collagen induced platelet aggregation,
collagen (10 .mu.g/ml) induced aggregation was not so significantly
reduced in presence of compound(i), while response of low
concentration of collagen (5 .mu.g/ml) was reduced significantly
(FIG. 1). TABLE-US-00001 TABLE 1 Antithrombotic Effect of the test
compounds on mice model and bleeding time Antithrombotic Sl
Compound No. activity (AT) Bleeding time (BT) no. (dose 30
.mu.M/kg) (% protection) % increase (1 hr) Control 0 -- 1 A
Compound(i) 60 .+-. 10 51 .+-. 14 (n = 4) (n = 5) 2 b 20 31 3 c 0
18 4 d 20 0 5 e 0 13 6 f 20 25 7 g 20 0 8 h 0 0 9 i 0 0 10 j 56 150
11 k 50 0 12 o 40 31 13 p Compound(ii) 70 .+-. 10 33 .+-. 12 (n =
3) (n = 3) 14 q 20 12 15 r 30 0 16 s 60 13 17 t 30 0 18 u 45 0 19 v
30 50 20 w Compound(iii) 70 .+-. 0 61 .+-. 16 (n = 3) (n = 3)
Aspirin (30 mg/Kg) 38 .+-. 3 125 .+-. 6 (n = 24) (n = 30)
Indomethacin (10 mg/kg) 55 .+-. 15 -- (n = 20) n = number of
groups
[0154] Number of mice used for AT testing were 10 in each group,
while 5 mice were used in each group to evaluate BT. Values are
mean .+-.SEM TABLE-US-00002 TABLE 2 Effect of Test compounds on
venous thrombosis model in rabbits: Test Thrombus % Thrombus %
Thrombus compounds wt. Reduction wt. Reduction wt. % Reduction 10
.mu.M/Kg dose 30 .mu.M/Kg dose Control 43 .+-. 13 (i) 26 .+-. 0 41
0.0 .+-. 0.0 100.0 (ii) 79 .+-. 9 -67 5 .+-. 4 88 (iii) -- -- 11
.+-. 5 57 0.5 mg/Kg dose 0.25 mg/kg dose 0.1 mg/Kg dose Heparin 1
.+-. 0.2 98 2 .+-. 0.3 95 4 .+-. 0.5 91 Values are Mean .+-. ;,
Compound (i); n = 2, Compound (ii); n = 4, Compound (iii); n = 4 [n
is no. pf observations in 2 or more animals at 10 .mu.M/Kg or 30
.mu.M/Kg p.o. administered 2 h prior to the stasis] or vehicle
control [n = 10 observations in five animals]. In heparin treated
group n = 6 observations for each dose in nine animals.
[0155] TABLE-US-00003 TABLE 3 Effect of Test compounds on the
platelet aggregation Compound(i) Compound(ii) Compound(iii)
Aggregation % % % % % % Inducers Aggregation Inhibition Aggregation
Inhibition Aggregation Inhibition ADP 37 .+-. 4 17 .+-. 6 35 .+-. 5
26 .+-. 10 2 .+-. 0.4 94 .+-. 0.2 (10 .mu.M) n = 12 n = 12 n = 8 n
= 8 n = 4 n = 4 Thrombin 45 .+-. 4 -9 .+-. 9 44 .+-. 10 4 .+-. 10
28 .+-. 3 40 .+-. 6 (0.64 U/ml) n = 10 n = 10 n = 4 n = 4 n = 6 n =
6 Collagen 22 .+-. 9 65 .+-. 13 5 .+-. 1 79 .+-. 7 2.5 .+-. 0 47
.+-. 13 (10 .mu.g/ml) n = 8 n = 8 n = 4 n = 4 n = 2 n = 2 A23187 51
.+-. 4 11 .+-. 4 51 .+-. 5 54 .+-. 4 57 .+-. 6 -25 .+-. 2 (2.5
.mu.g/ml) n = 8 n = 8 n = 6 n = 6 n = 4 n = 4 PMA 58 .+-. 6 -12
.+-. 9 44 .+-. 12 26 .+-. 0.3 38 .+-. 13 32 .+-. 5 (1.5 .mu.M) n =
6 n = 6 n = 2 n = 2 n = 2 n = 2 n = number of experiments which
consists of at least 6 or more observations
[0156] TABLE-US-00004 TABLE 4 Effect of test substances against
clotting parameters Compound Compound (i) Compound (ii) Compound
(iii) Conc. (.mu.g/ml) % Change Thrombin time (TT) 5 .+-. 5 9 .+-.
5 10 .+-. 4 100 9 .+-. 5 9 .+-. 4 6 .+-. 1 200 Prothrombin time
(PT) 19 .+-. 16 9 .+-. 5 -0.24 .+-. 0.8 100 14 .+-. 3 14 .+-. 7 9
.+-. 0.2 200 Activated partial 7 .+-. 5 13 .+-. 7 11 .+-. 4 100
thromboplastin time 4 .+-. 3 11 .+-. 4 10 .+-. 8 200 (aPTT) Values
are mean .+-. SEM (number of observation [n] = 3 in each case)
[0157] The following examples are provided by the way of
illustration of the present invention.
EXAMPLE 1
Preparation of 2-[-2,5 dichlorobenzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.
[0158] i) 2,5 dichlorobenzene sulphonyl chloride (0.541 gm, 2.2
mmol) in dry acetone (5 ml) was added to a stirred solution of dl
methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)
indole-3-carboxylate (0.46 gm,2.0 mmol)and dry triethylamine (0.56
ml, 4.0 mmol) in dry acetone (8 ml) during 15 min and was allowed
to stirr for 10 hrs. at room temperature(32.degree. C.). The
reaction mixture was concentrated under vaccum, the residue was
triturated with water (20 ml) to get 2-[2,5-dichlorobenzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester, crystallized with methanol, Yield=0.650 gm(74.03%).
m.p.=205.degree. C. Mass (FAB) m/z =440 (M.sup.+). IR(KBr
cm.sup.-1): 3412, 1730, 1600, 1446, 1343, 1271, 1162, 738.
H.sup.1NMR (200 MHz, CDCl.sub.3): .delta. 3.14-3.38 (m,2H), .delta.
3.61(s,3H), .delta.4.67-4.88 (m,2H), .delta.5.19 (d,1H), .delta.
7.08-7.21 (m,2H), .delta.7.44-7.49 (m,3H), .delta.7.79(d,
1H).delta. 8.16 (s,1H). Molecular
Formula=C.sub.19H.sub.16Cl.sub.2N.sub.2O.sub.4S.
EXAMPLE 2
Preparation of 2-[2,4,6, trimethyl benzenesulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.
[0159] i) 2,4,6, trimethyl benzene sulphonyl chloride (0.479 gm,2.2
mmol) in dry acetone (5 ml) was added to a stirred solution of dl
methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)
indole-3-carboxylate (0.46 gm,2.0 mmol) and dry triethylamine (0.56
ml ,4.0 mmol) in dry acetone (8 ml)during 15 min and was allowed to
stirr for 8 hrs. at room temperature (32.degree. C.). The reaction
mixture was concentrated under vaccum, the residue was triturated
with water (20 ml) to get 2-[2,4,6, trimethyl benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester, crystallized with methanol, Yield=0.521 gm(63.21%).
m.p.=160.degree. C. Mass (FAB) m/z=413 (M.sup.+). IR(KBr
cm.sup.-1): 3400, 2938, 1734, 1599, 1452, 1330, 1237, 1153, 738.
.sup.1HNMR (200 MHz, CDCl.sub.3): .delta. 2.29(s,3H),
.delta.2.63(s,6H), .delta.3.05-3.39 (m,2H), .delta.3.64 (s,3H),
.delta.4.50(d,1H), .delta. 4.79-4.93 (m,2H), .delta.6.95(s,
2H).delta.7.05-7.20 (m,2H), .delta.7.45(d,1H), .delta.7.78 (s,3H).
Molecular Formula=C.sub.22H.sub.24N.sub.2O.sub.4S.
EXAMPLE 3
Preparation of 2[2, nitrobenzenesulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester.
[0160] i) 2-nitrobenzenesulphonyl chloride (0.486 gm, 2.2 mmol) in
dry acetone (5 ml) was added to a stirred solution of dl methyl-1,
2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46
gm, 2 mmol )and dry triethylamine (0.56 ml,4.0 mmol) in dry acetone
(8 ml) during 15 min and was allowed to stirr for 8 hours at room
temperature(32.degree. C.). The reaction mixture was concentrated
under vaccum, the residue was triturated with water (20 ml) to get
2-[2,nitrobenzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester, crystallized with methanol,
Yield=0.42 gm (50.6% ), m.p.=225-230.degree. C. Mass (FAB) m/z=416
(M.sup.+). IR (KBr cm.sup.-1): 3424, 1743, 1598, 1363, 1229,
1166,753. .sup.1HNMR (200 MHz, CDCl.sub.3): .delta.
3.16-3.44(m,2H), .delta.3.55 (s, 3H), .delta.4.83 (s,2H),
.delta.5.20 ( d ,1H), .delta. 7.04-7.19 (m,2H), .delta. 7.33(d,1H),
.delta. 7.45-7.47 (m, 1H) .delta.7.69-7.79 ( m,3H), .delta.
8.10-8.18(m,1H). Molecular
Formula=C.sub.19H.sub.17N.sub.3O.sub.6S.
EXAMPLE 4
Preparation of 2[1-napthyl sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester.
[0161] i) 1-napthylsulphonyl chloride (0.497 gm, 2.2 mmol) in dry
acetone (5 ml) was added to a stirred solution of dl methyl-1, 2,
3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm,
2.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone
(8 ml)during 15 min and was allowed to stirr for 8 hrs. at room
temperature(32.degree. C.). The reaction mixture was concentrated
under vaccum, the residue was triturated with water (20 ml) to get
2-[1-napthyl sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester, crystallized with methanol,
Yield=0.55 gm (65%), m.p.=215.degree. C. Mass (FAB) m/z=421
(M.sup.+). IR (KBr cm.sup.-1):3402, 1736,, 1596, 1447, 1325, 1236,
1200, 1163, 733. .sup.1HNMR (200 MHz, CDCl.sub.3):
.delta.3.09-3.29(m,1H), .delta.3.35-3.40(m,4H), .delta.4.76(s,2H),
.delta.5.28(d,1H,), .delta.7.03-7.19(m,2H),.delta.7.40-7.70(m,5H),
.delta.7.90(d,1H), .delta.8.06 (d,1H), .delta.8.30 (d,1H),
.delta.8.68 (d,1H). Molecular
Formula=C.sub.23H.sub.20N.sub.20.sub.4S.
EXAMPLE 5
Preparation of 2-[4-methoxy benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b]indole-3-carboxylic acid ester.
[0162] i) 4-methoxy benzene sulphonyl chloride (0.453 gm, 2.2 mmol)
in dry acetone (5 ml) was added to a stirred solution of dl
methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)
indole-3-carboxylate (0.46 gm, 2.0 mmol) and dry triethylamine
(0.56 ml, 4.0 mmol) in dry acetone (8 ml) during 15 min and was
allowed to stirr for 8 hours at room temperature (32.degree. C.).
The reaction mixture was concentrated under vaccum, the residue was
triturated with water (20 ml) to get 2-[4-methoxy benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester, crystallized with methanol, Yield=0.682 gm (85.25%)
m.p.=215.degree. C. Mass (FAB) m/z=401 (M.sup.+). IR (KBr
cm.sup.-1) 3426,1748 , 1594, , 1450, 1344, 1256, 1155, 741.
.sup.1HNMR (200 MHz, CDCl.sub.3): .delta.3.05-3.37(m,2H),
.delta.3.47(s,3H), .delta.3.84 (s,3H), .delta.4.59-4.86(m,2H)
.delta.5.16(d,1H,), .delta.6.92-7.46(m,5H), .delta.7.82 (d,3H).
Molecular Formula=C.sub.20H.sub.20N.sub.2O.sub.5S.
EXAMPLE 6
Preparation of 2-[8-quinoline sulfonyl]-1, 2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.
[0163] i) 8-quinolinesulphonyl chloride (0.499 gm, 2.2 mmol) in dry
acetone (5 ml) was added to a stirred solution of dl methyl-1, 2,
3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46
gm,2.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry
acetone (8 ml) during 15 min and was allowed to stirr for 8 hours.
at room temperature(32.degree. C.). The reaction mixture was
concentrated under vaccum, the residue was triturated with water
(20 ml) to get 2-[8-quinoline sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester, crystallized
with methanol, Yield=0.619 gm ( 73.6%) , m.p.=235.degree. C.Mass
(FAB) m/z=422 (M.sup.+).IR (KBr cm.sup.-1) 3400, , 1733, 1621,1564,
1446, 1327, 1213, 1161, 743. .sup.1HNMR(200 MHz, CDCl.sub.3):
.delta.2.99-3.10( m,1H), .delta.3.31-3.44(m, 4H), .delta.4.80-5.01
(m, 2H), .delta.5.78 (d ,1H), .delta.7.00-7.18 (m, 2H),
.delta.7.39-7.49(m, 2H), .delta.7.60-.delta.7.80 (m, 2H),
.delta.8.02(d,1H), .delta.8.20 (d,1H), .delta.8.56 (d, 1H),
.delta.9.00(d, 1H). Molecular
Formula=C.sub.22H.sub.19N.sub.3O.sub.4S.
EXAMPLE 7
Preparation of 2-[dansyl sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.
[0164] i) 2-dansyl sulphonyl chloride (0.592 gm,2.2 mmol) in dry
acetone (5 ml) was added to a stirred solution of dl methyl-1, 2,
3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46
gm,2.0 mmol) and dry triethylamine (0.56 ml ,4.0 mmol) in dry
acetone (8 ml) during 15 min and was allowed to stirr for 8 hrs. at
room temperature(32.degree. C.). The reaction mixture was
concentrated under vaccum, the residue was triturated with water
(20 ml) to get 2-[dansyl sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester,crystallized
with acetone, Yield=0.364 gm(44.9%) m.p.=195.degree. C. Mass (FAB)
m/z=464 (M.sup.+). IR(KBr cm.sup.-1): 3407, 1741, 1595, 1451, 1345,
1201,1151,744. .sup.1HNMR (200 MHz, CDCl.sub.3) .delta.2.85
(s,6H),.delta.3.08-3.18(m,1H),.delta.3.33-3.45 (m,
4H),.delta.4.71-4.77(m,2H),.delta.5.28 (d,1H), .delta.7.10-7.16
(m,3H),.delta.7.39-7.58 (m,3H), .delta.7.75 (s,1H),.delta.8.29
(d,2H),.delta.8.51 (d,1H). Molecular
Formula=C.sub.25H.sub.25N.sub.3O.sub.4S.
EXAMPLE 8
Preparation of 2-[2,4,6 tri isopropyl benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester.
[0165] i) 2,4,6 tri isopropyl benzene sulphonyl chloride (0.664
gm,2.2 mmol) in dry acetone (5 ml) was added to a stirred solution
of dl methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)
indole-3-carboxylate (0.46 gm,2.0 mmol) and dry triethylamine (0.56
ml ,4.0 mmol) in dry acetone (8 ml) during 15 min and was allowed
to stirr for 24 hrs. at room temperature(32.degree. C.). The
reaction mixture was concentrated under vaccum, the residue was
triturated with water (20 ml) to get 2-[2,4,6 tri isopropyl benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester, crystallized with acetone, Yield=0.310 gm (31.25%)
m.p.=200.degree. C. Mass (FAB) m/z=497 (M.sup.+). IR (KBr
cm.sup.-1): 3408, 2960,1744, 1626, 1457, 1317, 1160, 1040, 934,
746. .sup.1HNMR (200 MHz, CDCl.sub.3) .delta.1.20-1.33(m,18H),
.delta.2.81-2.98(m,1H), .delta.3.10-3.40(m,2H), .delta.3.65(s,3H),
.delta.4.05-4.19(m,2H), .delta.4.45(d,1H), .delta.4.88(d,1H),
.delta.5.12 (d,1H), .delta.7.05-7.17(m,4H), .delta.7.46 (d,1H),
.delta.7.80 (s,1H). Molecular
Formula=C.sub.28H.sub.36N.sub.2O.sub.4S.
EXAMPLE 9
Preparation of 2-[4-floro benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.
[0166] i) 4-floro benzene sulphonyl chloride (0.427 gm,2.2 mmol) in
dry acetone (5 ml) was added to a stirred solution of dl methyl-1,
2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46
gm,2.0 mmol) and dry triethylamine (0.56 ml ,4.0 mmol) in dry
acetone (8 ml) during 15 min and was allowed to stirr for 8 hrs. at
room temperature(32.degree. C.). The reaction mixture was
concentrated under vaccum, the residue was triturated with water
(20 ml) to get 2-[4-floro benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester, crystallized
with acetone, Yield=0.666 gm (67.19%) m.p.=190.degree. C. Mass
(FAB) m/z=389 (M.sup.+). IR(KBr cm.sup.-1) 3430,1748,
1591,1489,1344, 1228, 1156,742. .sup.1 HNMR (200 MHz, CDCl.sub.3)
.delta.3.08-3.19 (m, 1H), .delta.3.32-3.47(m, 4H),
.delta.4.59-4.88(m,2H), .delta.5.16 (d,1H), .delta.7.10-7.32(m,4H),
.delta.7.45 (d,1H), .delta.7.83-7.90-(m,3H). Molecular
Formula=C.sub.19H.sub.17FN.sub.2O.sub.4S.
EXAMPLE 10
Preparation of 2-[2-tri floro methyl benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester.
[0167] i) 2-tri floro methyl benzene sulphonyl chloride (0.537 gm,
2.2 mmol) in dry acetone (5 ml) was added to a stirred solution of
dl methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)
indole-3-carboxylate (0.46 gm, 2.0 mmol) and dry triethylamine
(0.56 ml, 4.0 mmol) in dry acetone (8 ml) during 15 min and was
allowed to stirr for 8 hrs. at room temperature(32.degree. C.). The
reaction mixture was concentrated under vaccum, the residue was
triturated with water (20 ml) to get 2-[2-tri floro methyl benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester., crystallized with acetone, Yield=0.524 gm (59.8%),
m.p.=136.degree. C. Mass (FAB) m/z=439 (M.sup.+)
[0168] IR (KBr cm.sup.-1) 3400, 1741, 1563, 1449, 1347, 1308, 1272,
1218, 1169, 771. .sup.1HNMR (200 MHz, CDCl.sub.3): .delta.3.18-3.24
(m,1H), .delta.3.40-3.50(m,1H), .delta.3.56(s,3H,), .delta.4.75
(s,2H), .delta.5.20 (d,1H), .delta.7.11-7.15 (m,2H),
.delta.7.46-7.49(d,1H), .delta.7.68-7.91-(m,4H),
.delta.8.21-8.24(m, 1H). Molecular
Formula=C.sub.20H.sub.17F.sub.3N.sub.2O.sub.4S.
EXAMPLE 11
Preparation of 2-[methane sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.
[0169] i) Methane sulphonyl chloride (0.18 ml,2:4 mmol) in dry
acetone (5 ml) was added to a stirred solution of dl methyl-1, 2,
3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm,
2.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry acetone
(8 ml) during 15 min and was allowed to stirr for 8 hrs. at room
temperature(32.degree. C.). The reaction mixture was concentrated
under vaccum, the residue was triturated with water (20 ml) to get
2-[methyl sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester, crystallized with acetone.
Yield=0.480 gm (77.9%), m.p.=198.degree. C. Mass (FAB) m/z=309
(M.sup.+). IR (KBr cm.sup.-1),3384, 3026, 1736, 1632, 1278, 1234,
1152, 1016, 746. .sup.1HNMR (200 MHz, Acetone):
.delta.2.91(s.3H),.delta.2.97-3.35(m, 2H),
.delta.3.51(s,3H),.delta.4.52-4.74(m,2H),.delta.4.99 (d,1H),
.delta.6.85-7.00(m,2H), .delta.7.22 (d,1H), .delta.7.34 (d,1H),
.delta.10.00(s,1H). Molecular
Formula=C.sub.14H.sub.16N.sub.2O.sub.4S.
EXAMPLE 12
Preparation of 2-[2-napthalene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester.
[0170] i) 2-naphthyl sulphonyl chloride (0.497 gm, 2.2 mmol) in dry
acetone (5 ml) was added to a stirred solution of dl methyl-1, 2,
3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46
gm,2.0 mmol ) and dry triethylamine (0.56 ml, 4.0 mmol) in dry
acetone (10 ml) during 15 min and was allowed to stirr for 12 hours
at room temperature 32.degree. C. The reaction mixture was
concentrated under vaccum, the residue was triturated with water
(20 ml) to give 2-[2-napthalene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester, crystallized
with methanol, Yield=0.714 gm (85%). m.p-210.degree. C. Mass (FAB)
m/z=421 (M.sup.+). IR(KBr cm.sup.-1): 3418, 1748, 1594, 1451, 1362,
1158, 751. H.sup.1NMR (200 MHz, CDCl.sub.3): .delta.3.08-3.36(m,
5H), .delta.4.68-4.95 (m,2H), .delta.5.24 (d,1H), .delta.7.057.18
(m,2H), .delta.7.42(d,1H), .delta.7.60-7.63 (m,2H),.delta.7.77-7.98
(m,5H), .delta.8.45 (s,1H). Molecular
Formula=C.sub.23H.sub.20N.sub.20.sub.4S.
[0171] ii) 2-naphthyl sulphonyl chloride (0.272 gm, 1.2 mmol) in
dry acetone (3 ml) was added to a stirred solution of dl methyl-1,
2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.23
gm, 1.0 mmol) and dry pyridine (0.97 ml, 1.2 mmol) in dry acetone
(10 ml) during 15 min and was allowed to stirr for 12 hours at room
temperature(32.degree. C.). The reaction mixture was concentrated
under vaccum, water(10 ml) was added to the residue and extracted
with chloroform (3.times.10 ml).The extract was dried over
Na.sub.2SO.sub.4 and concentrated over reduced pressure to give
2-[2-napthalene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester, crystallized with methanol,
Yield=0.227 gm (54%), m.p-210.degree. C.
[0172] iii) 2-naphthyl sulphonyl chloride (0.272 gm, 1.2 mmol) in
dry acetone (3 ml) was added to a stirred solution of dl methyl-1,
2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.23
gm, 1.0 mmol) and K.sub.2CO.sub.3 (0.13 gm, 1.2 mmol) in dry
acetone (10 ml) during 15 min and was allowed to stirr for 8 hrs.
at room temperature(32.degree. C.). The reaction mixture was
concentrated under vaccum, water(10 ml) was added to the residue
and extracted with chloroform (3.times.10 ml).The extract was dried
over Na.sub.2SO.sub.4 and concentrated over reduced pressure to
give 2-[2-napthalene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester, crystallized
with methanol, Yield=0.29 gm.(68%) m.p-210.degree. C.
[0173] iv) 2-naphthyl sulphonyl chloride (0.272 gm, 1.2 mmol) in
dry acetone (3 ml) was added to a stirred solution of dl methyl-1,
2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.23
gm, 1.0 mmol) and dry triethylamine (0.12 ml, 1.2 mmol) in TBF (5
ml) during 15 min and was allowed to stirr for 8 hours at room
temperature(32.degree. C.). The reaction mixture was concentrated
under vaccum, the residue was triturated with water (20 ml) to get
obtain 2-[2-napthalene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester, crystallized
with methanol, Yield=0.32 gm.( 75% ), m.p-210.degree. C.
[0174] v) 2-naphthyl sulphonyl chloride (0.272 gm, 1.2 mmol) in dry
acetone (3 ml) was added to a stirred solution of dl methyl-1, 2,
3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.23 gm,
1.0 mmol) and dry triethylamine (0.12 ml, 1.2 mmol) in DMF (3 ml)
during 15 min and was allowed to stirr for 8 hrs. at room
temperature(32.degree. C.). The reaction mixture was concentrated
under vaccum, the residue was triturated with water (10 ml) then
extracted with chloroform (3.times.10 ml).The extract was dried
over Na.sub.2SO.sub.4 and concentrated over reduced pressure to
give 2-[2-napthalene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester to get obtain
2-[2-napthalene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester, crystallized with methanol,
Yield=0.21 gm. (50%), m.p-210.degree. C.
[0175] vi) 2-naphthyl sulphonyl chloride (0.272 gm, 1.2 mmol) in
dry acetone (3 ml) was added to a stirred solution of dl methyl-1,
2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate 0.23 gm,
1.0 mmol) and dry triethylamine (0.12 ml, 1.2 mmol) dry dioxane (5
ml) during 15 min and was allowed to stirr for 8 hours at room
temperature(32.degree. C.). Water(10 ml) was added to the residue
and extracted with chloroform (3.times.10 ml).The extract was dried
over Na.sub.2SO.sub.4 and concentrated over reduced pressure to
give 2-[2-napthalene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester, crystallized
with methanol, Yield=0.29 gm.( 70%), m.p-210.degree. C.
[0176] vii) 2-naphthyl sulphonyl chloride (0.272 gm,1.2 mmol) in
dry THF (3 ml) was added to a stirred solution of dl methyl-1, 2,
3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.23 gm,
1.0 mmol) and backed K.sub.2CO.sub.3 (0.13 gm, 1.2 mmol) in dry THF
and was allowed to stirr for 12 hours at 80.degree. C. temperature.
The reaction mixture was concentrated under vaccur, water(8 ml) was
added to the residue and extracted with chloroform (3.times.5
ml).The extract was dried over Na.sub.2SO.sub.4 and concentrated
over reduced pressure to give 2-[2-napthalene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester which was purified by column chromatography over silica
gel using methanol chloroform as eluent Yield=0.20 gm (48%),
m.p-210.degree. C.
[0177] viii) 2-naphthyl sulphonyl chloride (0.272 gm, 1.2 mmol) in
dry DMF (3 ml) was added to a stirred solution of dl methyl-1, 2,
3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.23 g,,
1.0 mmol) and backed K.sub.2CO.sub.3 (0.13 gm, 1.2 mmol) in dry DMF
and was allowed to stirr for 8 hours at 120.degree. C. temperature.
The reaction mixture was concentrated under vaccum, water(8 ml) was
added to the residue and extracted with chloroform (3.times.8
ml).The extract was dried over Na.sub.2SO.sub.4 and concentrated
over reduced pressure to give 2-[2-napthalene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid ester which was purified by column chromatography over silica
gel using methanol chloroform as eluent. Yield=0. 170 gm (40%),
m.p-210.degree. C.
EXAMPLE 13
[benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester
[0178] i) Benzene sulphonyl chloride (0.388 gm, 2.2 mmol) in dry
acetone (5 ml) was added to a stirred solution of dl methyl-1, 2,
3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-carboxylate (0.46 gm,
2.0 mmol) and dry triethylamine (0.56. ml, 4.0 mmol) in dry acetone
(8 ml) during 15 min and was allowed to stirr for 8 hrs. at room
temperature(32.degree. C.). The reaction mixture was concentrated
under vaccum, the residue was triturated with water (20 ml) to get
2-[benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester, crystallized with acetone.
Yield=0.371 gm (50%), m.p.=124.degree. C. Mass (FAB) m/z=371
(M.sup.+). IR (KBr cm.sup.-1) : 3838, 3024, 1742, 1442, 1342, 1052,
746. .sup.1HNMR (200 MHz, CDCl.sub.3): .delta.3.04-3.42(m, 5H),
.delta.3.30-3.42(m,4H), .delta.4.61-4.89(m, 2H), .delta.5.16(d,
1H), .delta.7.05-7.19(m,2H), .delta.7.42-7.60(m,4H),
.delta.7.83-7.91(m, 3H). Molecular
Formula=C.sub.19H.sub.18N.sub.2O.sub.4S.
EXAMPLE 14
2-[4-methyl benzene sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester
[0179] i) 4-methyl benzene sulphonyl chloride (0.419 gm, 2.2 mmol)
in dry acetone (5 ml) was added to a stirred solution of dl
methyl-1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b)
indole-3-carboxylate (0.46 gm, 2.0 mmol) and dry triethylamine
(0.56 ml, 4.0 mmol) in dry acetone (8 ml)during 15 min and was
allowed to stirr for 8 hrs. at room temperature(32.degree. C.). The
reaction mixture was concentrated under vaccum, the residue was
triturated with water (20 ml) to get 2-[4-methyl benzene
sulphonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid ester, crystallized with acetone.
Yield=0.400 gm (51%), m.p.=128.degree. C. Mass (FAB) m/z=385
(M.sup.+). IR (KBr cm.sup.-1): 3427, 1744, 1597, 1445, 1337, 1159,
1091, 1051, 1016, 935, 746. .sup.1HNMR (200 MHz, CDCl.sub.3):
.delta.2.40(s, 3H), .delta.3.05-3.45(m,5H), .delta.4.60-4.87(m,2H),
.delta.5.15(d,1H), .delta.6.96-7.46(m, 5H), .delta.7.70-7.85(m,3H).
Molecular Formula=C.sub.20H.sub.20N.sub.2O.sub.4S.
EXAMPLE 15
Preparation of 2-[2,5 dichlorobenzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.
[0180] i) 2,5 dichlorobenzene benzene sulphonyl chloride (0.590 gm,
2.4 mmol) in dry acetone(5 ml) was added to a stirred solution of
dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide (0.430
gm, 1.0 mmol) and dry triethylamine (0.56 ml, 4.0 mmol) in dry
DMF(5 ml)during 15 min and was allowed to stirr for 8 hrs. at room
temperature(32.degree. C.). Water was added to the reaction mixture
and triturated to give 2-[2,5 dichlorobenzene benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide which was purified by column chromatography over silica
gel using 2% methanol chloroform as eluent. Yield=0.400 gm
(47.17%)
[0181] ii) 2-[-2,5 dichlorobenzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester (0.220 gm,
0.5 mmol)was kept at room temperature (32.degree. C.) in methanolic
ammonia(25 ml) for 32 hours The reaction mixture was then
evaporated under vaccum to obtain to obtain 2-[-2,5 dichlorobenzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide, crystallized in methanol chloroform solution(2:1)
Yield=0.185 gm (87.26%). m.p.=220.degree. C. Mass (FAB)
m/z=425(M.sup.+). IR (KBr cm.sup.-1): 3456, 3332, 1693, 1602, 1450,
1337, 1160, 752. H.sup.1NMR (200 MHz, Acetone) .delta.3.06-3.73 (m,
2H), .delta.4.87(s, 2H), .delta.4.97(d, 1H), .delta.6.41(s, 1H),
.delta.7.01-6.84(m, 3H), .delta.7.32-7.21(m, 21H),
.delta.7.60-7.48(m, 2H), .delta.8.08-8.67(d,1H), 67 9.95(s,1H).
Molecular Formula=C.sub.18H.sub.15Cl.sub.2N.sub.3O.sub.3S.
EXAMPLE 16
Preparation of 2-[4-methoxy benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.
[0182] i) 4-methoxy benzene sulphonyl chloride (495 gm,2.4 mmol) in
dry acetone(5 ml) was added to a stirred solution of dl 1, 2, 3,
4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide (0.430 gm, 1.0 mmol)
and dry triethylamine (0.56 ml, 4.0 mmol) in dry DMF(5 ml)during 15
min and was allowed to stirr for 8 hrs. at room
temperature(32.degree. C.). Water was added to the reaction mixture
and triturated to give 2-[4-methoxy benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide,which was purified by column chromatography over silica
gel using 2% methanol chloroform as eluent. Yield=0.480 gm
(62.34%). imp. =178-180.degree. C.
[0183] ii) 2-[4-methoxy benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester (0.200 gm,0.5
mmol)was kept at room temperature(32.degree. C.) in methanolic
ammonia (30 ml) for 24 hrs. The reaction mixture was then
evaporated under vaccum to obtain 2-[4-methoxy benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide, crystallized in methanol (5 ml) Yield=0.170 gm (88%),
m.p.=178-180.degree. C. Mass (FAB) m/z=386 (M.sup.+). IR(KBr
cm.sup.1): 3375, 1698, 1595, 1495, 1447, 1342, 1256, 1151, 756.
H.sup.1NMR (200 MHz, CDCl.sub.3) .delta.2.43-2.54(m, 1H),
.delta.3.43-3.77(s,4H), .delta.4.80-4.96(m, 3H),
.delta.6.81-6.86(d, 2H), .delta.7.04-7.39(m,6H),
.delta.7.67-7.72(d,2H). Molecular
Formula=C.sub.19H.sub.19N.sub.3O.sub.4S.
EXAMPLE 17
Preparation of 2-[1-napthyl sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.
[0184] i) 2-[1-napthylsulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester (0.210 gm,
0.5 mmol) was kept at room temperature (32.degree. C.) in
methanolic ammonia(30 ml) for 24 hrs. The reaction mixture was then
evaporated under vaccum to obtain
2[-1-napthylsulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid amide, Yield=0.174 gm (85.7%).
m.p.=145-150.degree. C. Mass (FAB) m/z=406 (M.sup.+). IR (KBr
cm.sup.-1) 3397, ,1597, ,1447, 1349, 1204, 1160, 799, 750.
H.sup.1NMR(200 MHz, CDCl.sub.3): .delta.2.60-2.72 (m ,1H,),
.delta.3.56 (d,1H), .delta.4.60-5.00 (m,3H), .delta.5.39(s,1H),
.delta.6.61(s,1H), .delta.7.03-7.49 (m ,7H), .delta.7.88(d,1H),
.delta.8.06 (d,1H), .delta.8.30(d,1H), .delta.8.50(d,1H). Molecular
Formula=C.sub.22H.sub.19N.sub.3O.sub.3S.
EXAMPLE 18
Preparation of 2-[8-quinoline sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.
[0185] i) 2-[8-quinoline sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester (0.211 gm,
0.5 mmol) was kept at room temperature(32.degree. C.) in methanolic
ammonia(30 ml) for 48 hrs The reaction mixture was then evaporated
under vaccum to obtain 2-[8-quinoline sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide . This was
purified by column chromatography over silica gel using 2% methanol
chloroform as eluent. Yield=0.130 gm (64.04%). m.p.=160.degree. C.
Mass (FAB) m/z=407(M.sup.+). IR (KBr cm.sup.-1): 3426, 3338, 1686,
1617, 1493, 1450, 1328, 1161, 1139, 740. H.sup.1NMR(200 MHz,
CDCl.sub.3) .delta.2.33-2.45(m,1H), .delta.3.33-3.59(m,1H),
.delta.5.16-5.48(m,3H), .delta.6.96-7.42(m,6H),
.delta.7,61-7.83(m,2H), .delta.8.18-8.63(m,2H), .delta.8.56(d,1H),
.delta.8.80-8.32(d,1H). Molecular
Formula=C.sub.21H.sub.18N.sub.4O.sub.3S.
EXAMPLE 19
Preparation of 2-[4-floro benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.
[0186] i) 2-[4-floro benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester (0.388 gm,
0.5 mol)was kept at room temperature(32.degree. C.) in methanolic
ammonia (30 ml)for 24 hrs The reaction mixture was then evaporated
under vaccum to obtain 2-[4-floro benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide Yield=0.300
gm(80.41%). m.p.=220.degree. C.
[0187] Mass (FAB) m/z=374 (M.sup.+). IR (KBr cm.sup.-1): 3461,
3371, 1690, 1598, 1488, 1454, 1330, 1167, 764. H.sup.1NMR (200 MHz,
MeOH) .delta.2.69-2.80(m,1H) , .delta.2.86-2.99(m,1H),
.delta.4.66-5.05(m,3H), .delta.6.89-7.07(m,2H), .delta.7.14-7.3
1(m,5H), .delta.7.85-7.98(m,3H). Molecular
Formula=C.sub.18H.sub.16FN.sub.3O.sub.3S.
EXAMPLE 20
Preparation of 2-[ methane sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.
[0188] i) Methane sulphonyl chloride (0.18 ml,2.4 mmol) was added
to a stirred solution of dl 1, 2, 3, 4-tetrahydro-9H-pyrido (3,
4-b) indole-3-amide (0.430 gm,2.0 mmol) and dry triethylamine (0.56
ml ,4.0 mmol) in dry DMF (8 ml) during 15 min at room temperature
30.degree. C. The reaction mixture was allowed to stirr for 8 hrs.
at room temperature. Water(20 ml) was added to the reaction mixture
and extracted with chloroform(3.times.15 ml).The extract was dried
over Na.sub.2SO.sub.4 and concentrated over reduced pressure to
give 2-[methane sulphonyl ]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid amide which was purified by column
chromatography over silica gel using 2% methanol chloroform as
eluent. Yield=0.150 gm(25.60%). m.p.=234.degree. C. Mass (FAB)
m/z=294 (M.sup.+). IR(KBr cm.sup.-1): 3483, 3361, 1685, 1610, 1446,
1325, 1148, 756. H.sup.1NMR (200 MHz, CDCl.sub.3)
.delta.3.04(s,3H), .delta.3.20-3.63(m,2H), .delta.4.69-4.84(m,3H),
.delta.6.96-7.15(m,3H), .delta.7.32-7.53(m,3H), .delta.10.89(s,1H).
Molecular Formula=C.sub.13H.sub.15N.sub.3O.sub.3S.
EXAMPLE 2
Preparation of 2-[3-nitro benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.
[0189] i) 3-nitro benzene sulphonyl chloride (0.531 gm,2.4 mmol) in
dry acetone was added to a stirred solution of dl 1, 2, 3,
4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide (0.430 gm,2.0 mmol)
and dry triethylamine (0.56 ml, 4.0 mmol) in dry DMF (8 ml) during
15 min and was allowed to stirr for 8 hrs. at room temperature. The
reaction mixture was allowed to stirr for 8 hrs. at room
temperature. Water(20 ml) was added to the reaction mixture and
extracted with chloroform(3.times.15 ml).The extract was dried over
Na.sub.2SO.sub.4 and concentrated over reduced pressure to give
2-[3-nitro benzene sulfonyl-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b]
indole-3-carboxylic acid amide which was purified by column
chromatography over silica gel using 2% methanol chloroform as
eluent. Yield=0.400 gm(50%). m.p.=252.degree. C. Mass (FAB) m/z=401
(M.sup.+). IR(KBr cm.sup.-1): 3459, 3378, 1692, 1618, 1528, 1353,
1173, 760. H.sup.1NMR(200 MHz,CDCl.sub.3+DMSOd.sub.6):
.delta.2.88(m,1H), .delta.3.33(d,1H), .delta.4.73(d,1H),
.delta.4.93(d,1H), .delta.5.06(d,1H), .delta.6.41(s,1H),
.delta.6.89-7.31(m,3H), .delta.7.63-7.71(m,3H), .delta.8.13-8.17(d,
1H), .delta.8.30 (d,1H), .delta.8.59 (d,1H), .delta.10.27(s, 1H).
Molecular Formula=C.sub.18H.sub.16N.sub.4O.sub.5S.
EXAMPLE 22
Preparation of 2-[2, 4, 6 trimethyl benzene
sulfonyl]-1,2,3,4,-tetra hydro-9H-pyrido[3,4-b] indole-3-carboxylic
acid amide.
[0190] i) 2,4,6 trimethyl benzene sulphonyl chloride (0.524 gm,2.4
mmol) in dry acetone was added to a stirred solution of dl 1, 2, 3,
4-tetrahydro-9H-pyrido (3, 4-b) indole-3-amide (0.430 gm,2.0 mmol)
and dry triethylamine (0.56 ml, 4.0 mmol) in dry DMF (8 ml) during
15 min and was allowed to stirr for 8 hrs. at room temperature.
Water (20 ml) was added to the reaction mixture and extracted with
chloroform(3.times.15 ml). The extract was dried over
Na.sub.2SO.sub.4 and concentrated over reduced pressure to give
2-[2,4,6 trimethyl benzene sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide which was
purified by column chromatography over silica gel using 2% methanol
chloroform as eluent Yield=0.35 gm(44.08%) m.p.=212.degree. C. Mass
(FAB) m/z=398 (M.sup.+). IR(KBr cm.sup.-1): 3394, 3299, 1668, 1596,
1455, 1324, 115.5, 752. H.sup.1NMR (200 MHz, DMSO d6)
.delta.2.30(s,3H), .delta.2.56-2.74(m,7H), .delta.3.55-3.62(d,1H),
.delta.4.49-4.70(m,3H), .delta.5.17(s,1H), .delta.5.49(s,1H),
.delta.6.96-7.77(m, 6H). Molecular
Formula=C.sub.21H.sub.23N.sub.3O.sub.3S.
EXAMPLE 23
Preparation of 2-[2-napthyl sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide.
[0191] i) 2-[2-napthyl sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid ester (0.210 gm,
0.5 mol)was kept at room temperature(32.degree. C.) in methanolic
ammonia (30 ml)for 24 hrs The reaction mixture was then evaporated
under vaccum to obtain 2-[2-napthyl sulfonyl]-1,2,3,4,-tetra
hydro-9H-pyrido[3,4-b] indole-3-carboxylic acid amide Yield=0.142
gm(70%). m.p.=240.degree. C. Mass (FAB) m/z=406 (M.sup.+). IR (KBr
cm.sup.-1): 3489, 3372, 1694, 1604, 1444, 1328, 1160, 1078, 754.
H.sup.1NMR (200 MHz, Acetone): .delta.3.17-3.28(m,2H),
.delta.4.67-4.99(m,3H), .delta.6.35(s,1H), .delta.6.76-6.91(m,3H),
.delta.7.11-7.16(d,2H), .delta.7.48-7.55(m, 2H).
.delta.7.67-7.97(m, 4H), .delta.8.40(s,1H), .delta.9.86(s,1H).
Molecular Formula=C.sub.22H.sub.19N.sub.3O.sub.3S.
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