AP861A - Substituted N-({Aminoiminomethyl or aminomethyl} phenyl] propyl amides. - Google Patents

Substituted N-({Aminoiminomethyl or aminomethyl} phenyl] propyl amides. Download PDF

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AP861A
AP861A APAP/P/1998/001288A AP9801288A AP861A AP 861 A AP861 A AP 861A AP 9801288 A AP9801288 A AP 9801288A AP 861 A AP861 A AP 861A
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APAP/P/1998/001288A
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AP9801288A0 (en
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Kevin R Guertin
Scott I Klein
Alfred P Spada
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Aventis Pharma Inc
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    • 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
    • C07D207/32—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
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    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract

The compounds according to the invention are substituted N-[ (aminoiminomethyl or aminomethyl) phenyl]propyl amides of formula (I) herein which exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More especially, they are Factor Xa inhibitors. The present invention is directed to compounds of formula (I), compositions containing compounds of formula (I), methods for their preparation 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.

Description

SUBSTITUTED N-ffAMINQIMlNOMETHYL OR AMINOMETHYUPHENYL1PROPYL AMIDES
Field of the Invention
The compounds ot 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 especially, they are Factor Xa inhibitors. The present invention is directed to compounds of formula 1, compositions containing compounds of fo/mula 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 protnrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) are inhibited by compounds of formuia I. Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma cofactor antithrombin 111. 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 aneries 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 resuiting in the formation of life-threatening clots throughout the microvasculature of several organ systems. Tne indications discussed above include some, but not all, of the possible clinical situations where anticoagulant therapy*is warranted. Those experienced in this field aO 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 to inhibit the production or physiological effects of Factor Xa in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of Factor Xa, where formula I is as follows:
R-| and R2 are hydrogen or taken together are =NRg; R3 is -CO2R6, -C(O)Rg, -CONRgRg, -CH2OR7 or -CH2SR7; R4 is a group of formula
or R4 is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl; R5 is alkyl, alkenyl, optionally substituted aryl or optionally substituted heteroaryl; R6 is hydrogen or lower alkyl;
Ry is hydrogen, lower alkyl, lower acyl, aroyl or heteroaryl;
Rg is hydrogen*or lower alkyl;
Rg is wherein Rg is RiqO2C-, R10O-, HO-, cyano, R10CO-, HCO-, lower alkyl, nitro, or Y 1Y^N- , where R-jq is optionally substituted alkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl, and where Y and 2 Y 'are independently hydrogen or alkyl; A and B are hydrogen or taken together are a bond;
Ar is optionally substituted aryl or optionally substituted heteroaryl; and n is 0, 1 or 2; 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 15 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 alkyl" means about 1 to about 6 carbon atoms in the chain which may be straight or branched. The alkyl group may be substituted by one or more halo, cycloalkyi or cycloalkenyl. Exemplary alkyl groups include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, π-propyl, /-propyl, n-butyl, f-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl. “Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond and whictn may be straight or branched having about about 15 carbon atoms in the chain. 'Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 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 alkenyl chain. “Lower alkenyl" means about 2 to about 4 carbon atoms in the chain which may be straight or branched. The alkenyl group may be substituted by one or more halo. Exemplary alkenyl groups include ethenyl, propenyi, n-butenyl, /-butenyl, 3-methylbut-2-enyl, n-pentenyi, heptenyi, octenyl and decenyl. "Cycloalkyi" means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkyi rings include cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl. The y cycloalkyi group may be substituted by one or more halo, methylene (H2C=por alkyl. Exemplary .multicyclic cycloalkyi rings include 1-decalin, adamant-{1- or 2-)yl and norbornyl. "Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyi or cycloheptenyi. An exemplary.multicyclic cycloalkenyl ring is norbornylenyl. The cycloalkenyl group may be substituted by one or more halo, methylene (H2C=) or alkyl. "Heterocylyl" means a non-aromatic monocyclic or muiticyclic 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 heterocyclyi may be optionally substituted by one or more halo. Preferred monocyclic heterocyclyi rings include pyrrole, tetranydrothiophenyl and tetrahydrothiopyranyl. The thio or nitrogen moiety of the hetercyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. “Aryl’1 means aromatic carbocyciic radical containing about 6 to about 10 carbon atoms. Exemplary aryl include phenyl or naphthyl optionally substituted with one or more aryl group substituents which may be the same or different, where “aryl group substituent" includes hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryi, aralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, carboxy, acyl, aroyi, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryioxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsuifohyl, alkylsulfinyl, aryisulfinyl, alkylthio, arylthio, aralkyithio, Y1 Υ2Ν-, Υ1Υ2Ν-, Y1 Y2N-alkyl-, CO- or y1y2NSO2-, where Y1 and Y2 are independently hydrogen, alkyl, aryl, and aralkyl. Preferred aryl group substituents include hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyl, aroyi, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, Υ"'Υ2Ν-, Y^ Y2NCO- or Y"· Y2NSO2-, where Y-' and Y2 are independently hydrogen and alkyl. ’Heteroaryi" means about a 5- to about a 10- membered aromatic monocyclic or muiticyclic 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 "heteroaryi’ may also be substituted by one or more aryf group substituents. Exemplary heteroaryi groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, quinolinyl, indolyl, and isoquinolinyl. "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-p'nenethyl and naphthlenemethyl. “Hydroxyalkyl” means a HO-alkyl- group in which alky! is as previously defined. Preferred hydroxyaikyis contain lower alkyl. Exemplary hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. nAcyl“ means an H-CO- or alkyl-CO- group in which the alkyl group is as previously described. Preferred acyis contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methyipropanoyl, butanoyl and palmitoyl. "Aroyl" means an aryl-CO- group in which the alkyl group is as previously described. Exemplary groups include benzoyl and 1- and 2-naphthoyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, ethoxy, © n-propoxy, /-propoxy, n-butoxy and heptoxy. "Aryloxy" means an aryl-O- group in which the aryl group is as previously I described. Exemplary aryloxy groups include phenoxy 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 alkyi-S- group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, Apropylthio and heptylthio. Ay ) "Arylthio" means an aryi-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 5 previously described. An exemplary aralkylthio group is benzyithio. «γ1γ2Ν-“ means a substituted or unsubstituted amino group, wherein Y1 and Y2 are as previously described. Exemplary groups include amino (H2N-), methylamino, ethyimethylamino, dimethyiamino and diethylamino. "Aikoxycarbonyl" means an aikyl-O-CO- group. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl. "Aryloxycarbonyr means an aryl-O-CO- group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxycarbonyl. "Aralkoxycarbonyl" means an aralkyl-O-CO- group. An exemplary aralkoxycarbonyi group is benzyloxycarbonyl. nY1Y2NCO-° means a substituted or unsubstituted carbamoyl group, wherein Y1 and Y2 are as previously described. Exemplary groups are 'carbamoyl (H2NCO-) and dimethyiaminocarbamoyl (Me2NC0-). γ1γ2Ν502-" means a substituted or unsubstituted sulfamoyl group, wherein Y"1 and Y2 are as previously described. Exemplary groups are aminosulfamoyl (H2NSO2-) and dimethylaminosuifamoyl (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. "Alkylsuifonyl" means an alkyl-SO2- group. Preferred groups are those in which the alkyl group is lower alkyl. "Alkylsulfinyl" means an alkyi-SO- group.. Preferred groups are those in > which the aikyl group is lower alkyl. "Arylsuifonyl" means an aryl-SC>2- 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. "Pro-drug" means a compound which may or may not itself be biologically active but which may, by metabolic, solvolytic, or other physiological means be converted to a biologically active chemical entity.
Preferred Embodiments A preferred embodiment of the invention is a method for treating a disease state capable of being modulated by inhibiting production of Factor Xa to a patient suffering from said disease state an effective amount of the compound of formuia I . A preferred compound aspect of the invention is the compound of formula 1 wherein R-j and Rg taken together are =NH.
Another preferred compound aspect of the invention is the compound'! formula I wherein Rg is -COgRg, -CHgORy or-CHgSR7;
Another preferred compound aspect of the invention is the compound of formula I wherein n is 1.
Another preferred compound aspect of the invention is the compound of formula I wherein Rg is -COgRg and Rg is lower alkyl.
Another preferred compound aspect of the invention is the compound of formula I wherein Rg is -CHgORy or -CHgSRy and Ry is hydrogen or lower alkyl. <··
Another preferred compound aspect of the invention is the compound of formula I wherein R-] and Rg taken together are =NH and form an aminoiminomethyl on the phenyl moiety that is in the meta position to the position of attachment of the phenyl moiety to the propyl moiety.
Another preferred compound aspect of the invention is the compound of formula I wherein Ar is optionally substituted aryl.
Another preferred compound aspect of the invention is the compound of formula I wherein Ar is phenyl.
Another preferred compound aspect of the invention is the compound of formula I wherein R5 is optionally substituted phenyl, optionally substituted biphenyl, optionally substituted naphthyl, or optionally substituted heterobiphenyl.
Another preferred compound aspect of the invention is the compound of formula 1 wherein R10 is lower alkyl.
Included within the scope of formula I are compounds wherein R-j and R2 taken together are =NRg, wherein Rg is R-j^O2C-, R-jqO-, cyano, R-jqCO-, optionally substituted lower alkyl, nitro, or Y Y N-. Such derivatives may themselves comprise the biologically active compound useful for treating a * disease state capable of being modulated by inhibiting production of Factor Xa to a patient suffering from said disease state, or may act as pro-drugs to such biologically active compounds which are formed therefrom under physiological conditions.
Species according to the invention are selected from the following:

Claims (1)

  1. Original document published without claims.
APAP/P/1998/001288A 1996-01-02 1996-12-23 Substituted N-({Aminoiminomethyl or aminomethyl} phenyl] propyl amides. AP861A (en)

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