AP800A - Substituted sulfonic acid n-[{aminoiminomethyl)phenylalkyl] -azaheterocyclamide compounds. - Google Patents

Substituted sulfonic acid n-[{aminoiminomethyl)phenylalkyl] -azaheterocyclamide compounds. Download PDF

Info

Publication number
AP800A
AP800A APAP/P/1998/001305A AP9801305A AP800A AP 800 A AP800 A AP 800A AP 9801305 A AP9801305 A AP 9801305A AP 800 A AP800 A AP 800A
Authority
AP
ARIPO
Prior art keywords
optionally substituted
alkyl
group
aryl
formula
Prior art date
Application number
APAP/P/1998/001305A
Other versions
AP9801305A0 (en
Inventor
William R Ewing
Michael R Becker
Yong Mi Choi-Sledeski
Heinry W Pauls
Daniel G Mcgarry
Roderick S Davies
Alfred P Spada
Original Assignee
Aventis Pharmaceuticals Products Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aventis Pharmaceuticals Products Inc filed Critical Aventis Pharmaceuticals Products Inc
Publication of AP9801305A0 publication Critical patent/AP9801305A0/en
Application granted granted Critical
Publication of AP800A publication Critical patent/AP800A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • Urology & Nephrology (AREA)
  • Virology (AREA)
  • Vascular Medicine (AREA)
  • Oncology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)

Abstract

The compounds of formula (I) exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are inhibitors of the activity of Factor Xa. The present invention is directed to compounds of formula (I), compositions containing compounds of formula (I), and their use, which are for treating a patient suffering from, or subject to, physiological condition which can be ameliorated by the administration of an inhibitor of the activity of Factor Xa.

Description

SUBSTITUTED SULFONIC ACID N-[(AMINOIMINOMETHYL)PHENYLALKYL1-AZAHETEROCYCLAMIDE COMPOUNDS
This application is a continuation-in-part application of copending United States Patent Application Serial No. 08/761,414, filed December 6, 1996, which in turn is a continuation-in-part application of PCT US96/09816, filed June 7, 1996, which designates the United States, which in turn is a continuation-in-part application of United States Patent Application Serial No. 08/481,024, filed June 7, 1995. now United Stales Patent No. 5,612,353, issued March 18, 1997. This application is also a continuation-in-part of copending United States Patent Application Serial No. not assigned, filed November 21,1997, which in turn is a continuation application of PCT US96/09816, filed June 7, 1996
Field of the Invention
The compounds of formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More specifically, they are Factor Xa inhibitors. The present invention is directed to compounds of formula I, compositions containing compounds of formula I, and their use, which are for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of Factor Xa.
Factor Xa is the penultimate enzyme in the coagulation cascade. Both free factor Xa and factor Xa assembled in the prothrombinase complex (Factor Xa. Factor Va, calcium and phospholipid) are inhibited by compounds of formula I. Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin III. Effective factor Xa inhibition is achieved by administering the compounds either by oral administration, continuous intravenous infusion, bolus intravenous administration or any other parenteral route such that it achieves the desired effect of preventing the factor Xa induced formation of thrombin from prothrombin.
Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature. The diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and bypass grafting of the coronary (CABG) or peripheral arteries. Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long-term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus formation frequently occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT further predisposes the patient to a higher risk of pulmonary thromboembolism. A systemic, disseminated intravascular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer. This condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors resulting in the formation of life-threatening clots throughout the microvasculature of several organ systems. The indications discussed above include some, but not all, of the possible clinical situations where anticoagulant therapy is warranted. Those experienced in this field are well aware of the circumstances requiring either acute or chronic prophylactic anticoagulant therapy.
SUMMARY OF THE INVENTION
This invention is directed to the pharmaceutical use of a compound of formula I below for treating a patient suffering from a physiological disorder capable of being modulated by inhibiung the activity of Factor Xa, where formula I is as follows:
formula I is phenyl or'monocyclic heteroaryl; R is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl. R^CHj),-, R6O:C(CH1)I-,YIY2NC(O)(CH2)X-, or Y'Y2N(CH^-·, R, is hydrogen, alkyl, hydroxy, alkoxy, Y'Y:N-. halogen. -CO;R6, -C(O)NY‘Y2,
-(CH^OR^,-(CHJjNY'Y2, or-CN; R2 and R3are independently selected from hydrogen, hydroxy, alkoxy, Y’Y2N-, halogen, -CO2R6, -C(O)NY‘Y:, -(CH^OR^ -(CH2)XNY‘Y:, -CN, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted aralkenyl or optionally substituted heteroaralkenyl, or R, and R3 taken together with the carbon atoms through which they are linked form an optionally substituted 5 to 7 membered fused cycloalkyl, optionally substituted 5 to 7 membered fused heterocyclyl ring or an optionally substituted 6 membered fused aryl, or an optionally substituted 5 to 7 membered fused heteroaryl ring; R4 is hydrogen or optionally substituted lower alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl; X, and Xls are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl, or X, and Xlx taken together form oxo; X2 and X^ are hydrogen, or taken together form oxo; X3 is hydrogen, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or X3 and one of X, and Xls taken together with the carbon atoms through which X and one of X, and Xl3 are linked form a 4 to 7 membered cycloalkyl or heterocyclyl ring; X4 is hydrogen, optionally substituted alkyl or an optionally substituted aralkyl; X5 and X5j are hydrogen or taken together are =NR5; R; is hydrogen. R6O2C-, RJD-, cyano, R6CO-. optionally substituted lower alkyl, nitro or Y*Y2N-; Y1 and Y2 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y1 and Y2 taken together with the N through which Y' and Y2 are linked form a 4 to 7 membered heterocyclyl; X6 and X6, are independently hydrogen, R7R8N-, R,O-, R7R8NCO-, R7R8NSO2-. R7R8NSO2N -, R7R.SO:O-, R.CO-, -CO2R6, -C(O)NY'Y2, -(CH^COoRi, -(CH2)jC(O)NY'Y2, -(CH2)xOR6, -(CH2)xNY’Y2, halo, cyano or nitro; R6 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl; R7 and Rs are independently hydrogen or optionally substituted lower alkyl, or one of R7 and Rs is hydrogen and the other of R, and R8 is R,0(O)CCH:- or lower acyl; R, is hydrogen, optionally substituted lower alkyl, optionally substituted lower acyl or R10(O)CCH:-; R1(, is hydrogen, optionally substituted lower alkyl, optionally substituted alkoxy or hydroxy; A is S or -CH=CH-; m is 0, 1, 2 or 3; n is 0, 1, 2 or 3; and x is 1, 2. 3, 4, or 5, or a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings;
Definitions "Patient" includes both human and other mammals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. “Lower alkvl" means about 1 to about 4 carbon atoms in the chain which may be straight or branched. The alkyl may be substituted with one or more "alkyl group substituents” which may be the same or different, and include halo, cycloalkyl, hydroxy, alkoxy, amino, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkyloxycarbonyl. heteroaralkyloxycarbonyl or Y'Y2NCO-, wherein Y1 and Y2 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y' and Y2 taken together with the N through which Y1 and Y2 are. linked form a 4 to 7 membered heterocyclyl. Exemplary alkyl groups include methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, π-propyl, i-propyl, π-butyl, i-butyl, π-pentyl, 3-pentyl, methoxyethyl, carboxymethyl, methoxy carbonyl ethyl, benzyloxycarbonylmethyl, pyridylmethyloxycarbonylmethyl. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group is optionally partially unsaturated or optionally substituted with one or more cycloalkyl group substituents which may be the same or different, where "cycloalkyl group substituent" includes hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl. alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio. arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, fused cycloalkyl, fused heterocyclyl, arylazo, heteroaryl azo, Y'Y2N-, Y‘Y2NCO- or Y‘Y2NSO2-, wherein Y1 and Y2 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y' and Y2 taken together with the N through which Y1 and Y2 are linked form a 4 to 7 membered heterocyclyl. The aryl group substituents are as defined herein. Exemplary multicyclic cycloalkyl rings include 1-decalin, norbomyl, adamant-(l- or 2-)yl. "Heterocyclyl" means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 ring atoms. Preferred rings include about 5 to about 6 ring atoms wherein one of the ring atoms is oxygen, nitrogen or sulfur. The heterocyclyl is optionally partially unsaturated or optionally substituted with one or more heterocyclyl group substituents which may be the same or different, where " heterocyclyl group substituent" includes hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy,.aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl. aralkoxycarbonyl. acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio,.heteroaralkylthio, fused cycloalkyl, fused heterocyclyl, arylazo, heteroaryiazo, Y'Y2N-, Y’YTQCO- or Y‘Y2NSO2-, wherein Y' and Y2 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y' and Y2 taken together with the N through which Y1 and Y2 are linked form a 4 to 7 membered heterocyclyl. The heterocyclyl group substituents are as defined herein. Exemplary monocyclic rings include pyrrolidyl, piperidyl, tetrahydro fur anyl. tetrahydrothienyl and tetrahydrothiopyranvl. The thio or nitrogen moiety of the heterocyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. "Aryl" means a 6 to 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system. Exemplary aryl include phenyl or naphthyl, or phenyl substituted or naphthyl substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent" includes hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl. halo, nitro, cyano. carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl. heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, fused cycloalkyl, fused heterocyclyl, arylazo, heteroarylazo, Y'Y2N-, Y'Y2NC0- or Y‘Y2NSOj-, wherein Y' and Y2 are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y' and Y2 taken together with the N through which Y1 and Y2 are linked form a 4 to 7 membered heterocyclyl. The aryl group substituents are as defined herein. Preferred ary] groups are optionally substituted phenyl or optionally substituted naphthyl. Preferred aryl group substituents include hydrogen, alkyl, hydroxy, acyl, aryl aroyl, aryloxy, halo, nitro, alkoxy, cyano, alkoxycarbonyl, acylamino. alkylthio, Y'Y2N-, Y'Y2NCO- or Y‘Y2NSO2-, where Y1 and Y2 are independently optionally substituted alkyl, aryl, aralkyl or hetero aralkyl; preferred phenyl group substituents are hydroxy, halogen, alkyl, amino. e "Heteroaryl" means about a 5- to about a 10- membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the carbon atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. The "heteroaryl·' may also be substituted by one or more of the above-mentioned “aryl group substituents”. Exemplary heteroaryl groups include substituted pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl. thiazolyl, pyrazolyl, furazanyl, pyrrolyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolvl, azaindolyl, benzimidazolyl, benzothienvl, quinolinyl. imidazolvl and isoquinolinyl.
Where
is a monocylic heteroaryl. then preferred heteroarvls include thienyl or pyridyl.
‘Aralkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethvi and naphthalenemethyl. “Hetercaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl moiety. Exemplary heteroaraikv: groups may contain thienylmethyl. pyridylmethyl. imidazoiy Imethyl and pyrazinylmethyl. "Aralkenyl" means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl moiety . An exemplary aralkenyl group is 2-phenethenyl. “Heterc-aralkeny Γ means a heteroaryl-alkenyl- group in which the heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl moiety. Exemplary heteroaralkenyl groups may contain thienylethenyl, pyridylethenyl. imidazolylethenvl and pyrazinvletheny 1. "Hydroxyalky)" means a HO-alkyl- group in which alky l is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Exemplary hydroxyalky I groups include hydroxymethyl and 2-hydroxyethy 1. t "Acyl" means an H-CO- or alkyl-CO- group in which the alkyl group is as previously described. Preferred acyis contain a lower alky 1. Exemplary5 acy l groups include formy 1. acetyl, propanovl, 2-methylpropanoyl. butanoyl and palmitoyl. "Aroyl" means an ary 1-CO- group in which the ary I group is as previously described. Exemplary groups include benzoyl and 1- and 2-naphthoyl. “Heteroaroyp means an means an heteroary 1-CO- group in which the heteroaryl group is as previously described. Exemplary groups include thiophenoyl and pyridinoyl. "Alkoxy” means an alkyl-O- group in which the alkyl group is as previously described. Exemplary' alkoxy groups include methoxy, ethoxy, «-propoxy, /-propoxy, «-butoxy and heptoxy. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described.
Exemplary aryloxy groups include phenoxv and naphthoxy. "Aralkyloxy" means an aralkyl-O- group in which the aralkyl groups is as previously described. Exemplary aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio. ethylthio. i-propylthio and heptylthio. "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. An exemplary aralkylthio group is benzylthio. "Y'Y2N-" means a substituted or'unsubstituted amino group, wherein Y1 and Y2 are as previously described. Exemplary groups include amino (H2N-), methylamino, dimethylamino, diethylamino, pyrrolidine, piperidine, benzylamino, or phenethylamino. "Alkoxycarbonyl" means an alkyl-O-CO- group. Exemplary alkoxvcarboriyl groups include methoxycarbonyl, ethoxycarbonyl, or t-butyloxycarbonyl. t "Aryloxycarbonyl" means an aryl-O-CO- group. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxvcarbonyl. "Aralkoxycarbonyl” means an aralkyl-O-CO- group. An exemplary aralkoxycarbonyl group is benzvloxycarbonyl. "Υ'γ-NCO-" means a substituted or unsubstituted carbamoyl group, wherein Y! and Y2 are as previously described. Exemplary groups are carbamoyl (H2NCO-) and dimethylaminocarbamovl (Me2NC0-). "Y‘YhNSC>2-" means a substituted or unsubstituted sulfamoyl group, wherein Y1 and Y2 are as previously described. Exemplary groups are aminosulfamoyl (HgN'SOg-) and dimethvlaminosulfamoyl (Me2NSO2-). "Acylamino" is an acyl-NH- group wherein acyl is as defined herein. "Aroylamino" is an aroyl-NH- group wherein aroyl is as defined herein. "Alkylsulfonyl" means an alkyl-SO?- group. Preferred groups are those in which the alkyl group is lower alkyl. "Alkylsulfinyl" means an alkyl-SO- group. Preferred groups are those in which the alkyl group is lower alkyl. "Arylsulfonyl" means an aryl-SO?- group. "Arylsulfinyl" means an aryl-SO- group. "Halo” means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro.
Preferred Embodiments A preferred embodiment of the invention is a method for treating a patient suffering from a physiological disorder capable of being modulated by inhibiting an activity of Factor Xa by administering a therapeutically effective amount of a compound of formula I.
Another preferred compound aspect of the invention is the compound of formula I wherein n is 1. and m is 1.
Another preferred compound aspect of the invention is the compound of formula I wherein X, and X^ taken together are oxo.
Another preferred compound aspect of the invention is the compound of formula I wherein Xp X]? X< are hydrogen, and X3 is hydrogen or alkyl.
Another preferred compound aspect of the invention is the compound formula I wherein X5 and X53 taken together are =NR5 wherein R5 is R6O2C-.
Another preferred compound aspect of the invention is the compound formula 1 wherein X5 and X5l taken together are =NR5 wherein R5 is -OH.
Another preferred compound aspect of the invention is the compound of formula I wherein Xs and X5a taken together are =NR5 wherein R5 is H.
Another preferred compound aspect of the invention is the compound of formula I wherein
is phenyl and the carbon substituted with X5, X5a and Κ,ΗΝ- is attached meta relative to the attachment of the -(CH)„N- moiety to the phenyl.
Another preferred compound aspect of the invention is the compound of formula I wherein
is thienyl and the carbon substituted with X,, X5a and R„HN- is attached in the 2 position relative to the sulfur of the thienyl and the attachment of the -(CH)„N-moiety is to the 4 position of the thienyl.
Another preferred compound aspect of the invention is the compound of formula I wherein R is hydrogen, methyl, aralkyl, heteroaralkyl, HQ:CCH;-, H,NC(O)CH2-. or RJINC(O)CH2-.
Another preferred compound aspect of the invention is the compound of formula I wherein R, is hydrogen, alkyl, or halogen.
Another preferred compound aspect of the invention is the compound of formula I wherein R, and R3are independently hydrogen, halogen, alkyloxy. amino, aryl, or heteroaryl.
Another preferred compound aspect of the invention is the compound of formula I wherein R2 and R3 form an optionally substituted fused aryl or an optionally substituted fused heteroaryl ring wherein the substituent is halogen, alkyl, amino, hydroxy, or alkoxy.
Another preferred compound aspect of the invention is the compound of formula I wherein R, and R3 form an optionally substituted fused cycloalkyl or an optionally substituted fused heterocyclyl in which the heteroatom is nimogen wherein the substituent is hydrogen. Y‘Y2N, or alkyl..

Claims (1)

  1. Original document published without claims.
APAP/P/1998/001305A 1996-12-06 1997-12-01 Substituted sulfonic acid n-[{aminoiminomethyl)phenylalkyl] -azaheterocyclamide compounds. AP800A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US08/761,414 US5731315A (en) 1995-06-07 1996-12-06 Substituted sulfonic acid n- (aminoiminomethyl)phenylalkyl!-azaheterocyclamide compounds

Publications (2)

Publication Number Publication Date
AP9801305A0 AP9801305A0 (en) 1998-09-30
AP800A true AP800A (en) 2000-01-19

Family

ID=25062109

Family Applications (1)

Application Number Title Priority Date Filing Date
APAP/P/1998/001305A AP800A (en) 1996-12-06 1997-12-01 Substituted sulfonic acid n-[{aminoiminomethyl)phenylalkyl] -azaheterocyclamide compounds.

Country Status (21)

Country Link
US (1) US5731315A (en)
EP (1) EP0894088A4 (en)
JP (1) JP2000505815A (en)
KR (1) KR19990082323A (en)
CN (2) CN1093856C (en)
AP (1) AP800A (en)
AU (1) AU727810B2 (en)
BG (1) BG102725A (en)
BR (1) BR9707489A (en)
CA (1) CA2245699A1 (en)
CZ (1) CZ275798A3 (en)
EA (1) EA001739B1 (en)
HU (1) HUP9903336A3 (en)
IL (1) IL125677A0 (en)
NO (1) NO983603L (en)
OA (1) OA10823A (en)
PL (1) PL328618A1 (en)
SI (1) SI9720019A (en)
SK (1) SK122398A3 (en)
WO (1) WO1998024784A1 (en)
ZA (1) ZA9710968B (en)

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5958918A (en) * 1995-06-07 1999-09-28 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N- (aminominomethyl)phenylalkyl!-azaheterocyclylamide compounds
US6034093A (en) * 1995-06-07 2000-03-07 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds
US6602864B1 (en) * 1996-12-13 2003-08-05 Aventis Pharma Deutschland Gmbh Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide compounds
AR016817A1 (en) * 1997-08-14 2001-08-01 Smithkline Beecham Plc DERIVATIVES OF FENILUREA OR FENILTIOUREA, PROCEDURE FOR PREPARATION, COLLECTION OF COMPOUNDS, INTERMEDIARY COMPOUNDS, PHARMACEUTICAL COMPOSITION, METHOD OF TREATMENT AND USE OF SUCH COMPOUNDS FOR THE MANUFACTURE OF A MEDICINAL PRODUCT
WO1999011658A1 (en) 1997-08-29 1999-03-11 Proteus Molecular Design Ltd. Meta-benzamidine derivatives as serin protease inhibitors
KR20010015639A (en) 1997-09-30 2001-02-26 스즈키 다다시 Sulfonyl derivatives
US6747023B1 (en) * 1998-08-11 2004-06-08 Daiichi Pharmaceutical Co., Ltd. Sulfonyl derivatives
US20090311267A1 (en) * 1999-08-10 2009-12-17 University Of Wurzburg Inhibition of VWF - GPIb/V/IX interaction and platelet-collagen interaction for prevention and treatment of cerebral attacks
GB9918788D0 (en) * 1999-08-10 1999-10-13 Leuven K U Res & Dev Antithrombotic effect of platelet glycoprotein 1b blocking monoclonal Fab fragments
US6544981B2 (en) * 2000-06-09 2003-04-08 Bristol-Myers Squibb Company Lactam inhibitors of factor Xa and method
US6511973B2 (en) * 2000-08-02 2003-01-28 Bristol-Myers Squibb Co. Lactam inhibitors of FXa and method
WO2002100850A1 (en) * 2001-06-08 2002-12-19 Kuraray Co., Ltd. Processes for preparation of heterocyclic compounds
GB0130705D0 (en) * 2001-12-21 2002-02-06 Glaxo Group Ltd Chemical compounds
WO2003106445A1 (en) * 2002-06-12 2003-12-24 Qsi Pharma A/S Compounds and methods for controlling bacterial virulence
CA2393887A1 (en) * 2002-07-17 2004-01-17 Idelix Software Inc. Enhancements to user interface for detail-in-context data presentation
CA2507707C (en) 2002-12-03 2011-06-21 Axys Pharmaceuticals, Inc. 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors
WO2004110997A1 (en) * 2003-06-19 2004-12-23 Glaxo Group Limited 3- sulfonylamino- pyrrolidine- 2- one derivatives as inhibitors of factor xa
GB0314370D0 (en) * 2003-06-19 2003-07-23 Glaxo Group Ltd Chemical compounds
US7199149B2 (en) * 2003-10-01 2007-04-03 Bristol Myers Squibb Company Monocyclic and bicyclic lactams as factor Xa inhibitors
WO2005095386A1 (en) * 2004-03-30 2005-10-13 Chiron Corporation Substituted thiophene derivatives as anti-cancer agents
ME02461B (en) 2005-05-10 2017-02-20 Incyte Holdings Corp INDOLEAMINE 2,3-DIOXYGENASE MODULATORS AND METHODS FOR THE USE OF THE SAME
EP1971583B1 (en) 2005-12-20 2015-03-25 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
CL2007002650A1 (en) 2006-09-19 2008-02-08 Incyte Corp COMPOUNDS DERIVED FROM HETEROCICLO N-HIDROXIAMINO; PHARMACEUTICAL COMPOSITION, USEFUL TO TREAT CANCER, VIRAL INFECTIONS AND NEURODEGENERATIVE DISORDERS BETWEEN OTHERS.
US20080125470A1 (en) 2006-09-19 2008-05-29 Incyte Corporation N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
SG10201805844QA (en) 2008-07-08 2018-08-30 Incyte Holdings Corp 1,2,5-oxadiazoles as inhibitors of indoleamine 2,3-dioxygenase
CN103254265B (en) * 2012-02-21 2016-07-13 上海希迈医药科技有限公司 Abiraterone acetate trifluoroacetate and its preparation method and application
CA2929552C (en) 2013-11-08 2022-05-17 Incyte Holdings Corporation Process for the synthesis of an indoleamine 2,3-dioxygenase inhibitor
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4121947A1 (en) * 1991-07-03 1993-01-07 Basf Ag 2- (3- (4-AMIDINO-PHENYL)) - PROPIONIC ACID DERIVATIVES, THEIR PRODUCTION AND USE
US5612353A (en) * 1995-06-07 1997-03-18 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 119, no. 3, page 861, c1, ABSTRACT 28019n (MACK) *

Also Published As

Publication number Publication date
AP9801305A0 (en) 1998-09-30
OA10823A (en) 2001-07-24
WO1998024784A1 (en) 1998-06-11
KR19990082323A (en) 1999-11-25
EP0894088A1 (en) 1999-02-03
EA001739B1 (en) 2001-08-27
CN1213370A (en) 1999-04-07
PL328618A1 (en) 1999-02-01
NO983603D0 (en) 1998-08-05
ZA9710968B (en) 1998-07-22
EP0894088A4 (en) 2001-12-05
BR9707489A (en) 1999-07-27
SI9720019A (en) 1999-02-28
NO983603L (en) 1998-10-05
US5731315A (en) 1998-03-24
AU727810B2 (en) 2000-12-21
EA199800690A1 (en) 1999-02-25
BG102725A (en) 1999-03-31
IL125677A0 (en) 1999-04-11
CN1093856C (en) 2002-11-06
CA2245699A1 (en) 1998-06-11
AU6012198A (en) 1998-06-29
CZ275798A3 (en) 1999-01-13
SK122398A3 (en) 1999-01-11
HUP9903336A2 (en) 2000-12-28
CN1418882A (en) 2003-05-21
HUP9903336A3 (en) 2001-07-30
JP2000505815A (en) 2000-05-16

Similar Documents

Publication Publication Date Title
AP800A (en) Substituted sulfonic acid n-[{aminoiminomethyl)phenylalkyl] -azaheterocyclamide compounds.
AP861A (en) Substituted N-({Aminoiminomethyl or aminomethyl} phenyl] propyl amides.
AP1032A (en) Sulfonic acid or sulfonylamino n-(Heterorlkyl)-zheterocyclylmie compounds.
AP799A (en) Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N-[(aminoiminomethyl) phenylalkyl]-azaheterocyclylamide compounds.
AP1061A (en) Substituted N-[(Aminoiminomethyl or aminomethyl) Phenyl] Propyl amides.
US5801197A (en) Rotamase enzyme activity inhibitors
JP2003534325A (en) Caspase inhibitor and use thereof
IL155333A0 (en) Sulfanilide derivatives for use in medicine, certain such new derivatives and their preparation
JP2001527527A (en) Novel integrin receptor antagonist
DE19632772A1 (en) New benzamidines
JP2012140444A (en) Anti-inflammatory agent
DE69923444T2 (en) HETEROCYCLIC COMPOUNDS WITH FACTOR XA HARDENING EFFECT
EP3190111B1 (en) Pyrazolo[3,4-c]pyridine derivatives
CA2325471C (en) Piperididinyl and n-amidinopiperidinyl derivatives
Imura et al. Comparative antithrombotic effects of heparin, recombinant hirudin and argatroban in a hamster femoral vein platelet-rich mural thrombosis model.
RU2379288C2 (en) Novel pyrrolidine-3, 4-dicarboxamide drivatives
CN101917990B (en) Pharmaceutical composition, use of 2-iminopyrrolidine derivative for producing pharmaceutical composition, and kit for treating or improving cardiac disease
KR20080109866A (en) Dicarboxamide Derivatives
EP0959882A1 (en) N-linked ureas and carbamates of heterocyclic thioesters
JP2008509974A (en) Anti-inflammatory agent
MX2007016085A (en) Anti-inflammatory agents.
JPH02104568A (en) Nerve growth factor production promoting agent
JPH0169A (en) Novel prolinal derivatives
EP0342577B1 (en) Use of dihydropyridine derivatives for the prophylaxis or treatment of cerebral circulation disorders
BE1004874A4 (en) The depressant INHIBITOR ALPHA2-PLASMIN.