United States Patent [19]
`Ewing et al. (cid:9)
`
`[54] SUBSTITUTED (SULFINIC ACID, SULFONIC
`ACID, SULFONYLAMINO OR
`SULFINYLAMINO) N-
`[ (AMINOMINOMETHYL) PH ENY LALKYL]-
`AZAHETEROCYCLYLAMIDE COMPOUNDS
`
`[75]
`
`Inventors: William R. Ewing, Downingtown;
`Michael R. Becker, Norristown; Henry
`W. Pauls; Daniel L. Cheney, both of
`Collegeville; Jonathan Stephen
`Mason, Phoenixville; Alfred P. Spada,
`Lansdale; Yong Mi Choi-Sledeski,
`Collegeville, all of Pa.
`
`[73] Assignee: Rhone-Poulenc Rorer
`Pharmaceuticals Inc.
`
`[ * ] Notice: (cid:9)
`
`This patent is subject to a terminal dis-
`claimer.
`
`[21] Appl. No.: 08/976,034
`
`[22] Filed: (cid:9)
`
`Nov. 21, 1997
`
`Related U.S. Application Data
`
`[63] Continuation of application No. PCT/US96/09816, Jun. 7,
`1996, which is a continuation-in-part of application No.
`08/481,024, Jun. 7, 1995, Pat. No. 5,612,353.
`[51] Int. C1.6 ........................ C07D 401/02; A61K 31/40;
`A61K 31/435
`[52] U.S. Cl ........................... 514/212; 514/307; 514/309;
`514/329; 514/343; 514/422; 514/426; 540/606;
`546/141; 546/223; 546/281; 546/139; 546/276.4;
`548/527; 548/557
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111 I
`
`US005958918A
`
`i (cid:9)
`[451 Date of Patent: (cid:9)
`
`5,958.418
`*Sep. 28, 1999
`
`[58] Field of Search ............................. 540/606; 546/141,
`546/223, 281, 139, 276.4; 548/527, 557;
`514/212, 307, 309, 343, 320, 422, 426
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,612,353 3/1997 Ewing et al.
`5,731,315 3/1998 Ewing et al.
`
`OTHER PUBLICATIONS
`
`Valerio et al, Synthesis, vol. 10, pp. 786-789, 1988.
`
`Primary Examiner—Zinna Northington Davis
`Attorney, Agent, or Firm— Raymond S. Parker, III
`
`[57]
`
`ABSTRACT
`
`The compounds of formula I exhibit useful pharmacological
`activity and accordingly are incorporated into pharmaceuti-
`cal compositions and used in the treatment of patients
`suffering from certain medical disorders. More especially,
`they are inhibitors of the activity of Factor Xa. The present
`invention is directed to compounds of formula I, composi-
`tions 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.
`
`57 Claims, No Drawings
`
`MYLAN - EXHIBIT 1026
`
`(cid:9)
`

`
`5,958,918
`
`SUBSTITUTED (SULFINIC ACID, SULFONIC
`ACID, SULFONYLAMINO OR
`SULFINYLAMINO) N-
`[ (AMINOMINOMETHYL) PH ENYLALKYL]-
`AZAHETEROCYCLYLAMIDE COMPOUNDS
`
`5
`
`2
`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
`10 inhibiting an activity of Factor Xa, where formula I is as
`follows:
`
`15 (cid:9)
`
`20 (cid:9)
`
`
`X4
`
`R
`1
`N
`
`X (cid:9)
`3
`
`m (cid:9)
`
`R1
`xz'
`
`N (cid:9)
`
`X2
`
`X,
`Xl.
`
`X5
`X5'
`
`NHR2
`
`X6 (cid:9)
`
`Arl (cid:9)
`
`X6,
`
`25 Q is phenyl or monocyclic heteroaryl;
`
`This application is a continuation of copending Interna-
`tionalApplication No. PCT/US96109816, filed Jun. 7,1996,
`which designates the United States, which, in turn, is a
`continuation-in-part application of U.S. patent application
`Ser. No. 08/481,024, filed Jun. 7, 1995, now U.S. Pat. No.
`5,612,353.
`
`FIELD OF THE INVENTION
`
`The compounds of formula I exhibit useful pharmaco-
`logical activity and accordingly are incorporated into phar-
`maceutical compositions and used in the treatment of
`patients suffering from certain medical disorders. More
`especially, they are Factor Xa inhibitors. The present inven-
`tion 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. Effec-
`tive factor Xa inhibition is achieved by administering the
`compounds either by oral administration, continuous intra-
`venous 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 percuta-
`neous 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 benefi-
`cial 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 hemo-
`dialysis 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 throm-
`boembolism. A systemic, disseminated intravascular coagu-
`lopathy (DIC) commonly occurs in both vascular systems
`during septic shock, certain viral infections and cancer. This
`condition is characterized by a rapid consumption of coagu-
`lation factors and their plasma inhibitors resulting in the
`formation of life-threatening thrombin throughout the
`microvasculature of several organ systems. The indications
`discussed above include some, but not all, of the possible
`
`30 (cid:9)
`
`45 (cid:9)
`
`R is hydrogen, optionally substituted alkyl, optionally
`substituted aralkyl, optionally substituted heteroaralkyl or
`hydroxyalkyl;
`Ri is hydrogen, R3S(0)P or R3R4NS(0)P ;
`R2 is hydrogen, or when XS and Xs, taken together are
`35 =NR5, then R2 is hydrogen, optionally substituted lower
`alkyl, optionally substituted aralkyl or optionally substituted
`heteroaralkyl;
`R3 is optionally substituted alkyl, optionally substituted
`cycloalkyl, optionally substituted heterocyclyl, optionally
`40 substituted aryl, optionally substituted heteroaryl, optionally
`substituted aralkyl, optionally substituted heteroaralkyl,
`optionally substituted aralkenyl or optionally substituted
`heteroaralkenyl, or R and R3 taken together form a 5 to 7
`membered ring; and
`R4 is optionally substituted alkyl, optionally substituted
`cycloalkyl or optionally substituted aryl, optionally substi-
`tuted heteroaryl, optionally substituted aralkyl or optionally
`substituted heteroaralkyl, or R3 and R4 taken together with
`the nitrogen to which R3 and R4 are attached form an
`50 optionally substituted 4 to 7 membered heterocyclyl;
`Xl and X1, are independently selected from hydrogen,
`optionally substituted alkyl, optionally substituted aryl,
`optionally substituted aralkyl, optionally substituted
`heteroaryl, optionally substituted heteroaralkyl or
`55 hydroxyalkyl, or Xi and X1 taken together form oxo;
`X2 and X2, 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 Xl and X1. taken together
`form a 4 to 7 membered ring;
`X4 is hydrogen, optionally substituted alkyl, optionally
`substituted aralkyl, or hydroxyalkyl;
`X5 and X5, are hydrogen or taken together are
`RS is hydrogen, R602C—, R60—, cyano, R6CO—,
`optionally substituted lower alkyl, nitro or Y1'Y2'N—;
`
`60
`
`65 (cid:9)
`
`(cid:9)
`

`
`10
`
`30 (cid:9)
`
`3
`Y1' and Y2' are independently hydrogen, alkyl, aralkyl or
`heteroaralkyl;
`X6 and X6, are independently hydrogen, R7R8N—,
`R9O—, R7R8NCO—, R7R8NSO2 , R9CO—, halo, cyano
`or nitro;
`R6 is hydrogen, optionally substituted lower alkyl or
`optionally substituted aralkyl or optionally substituted het-
`eroaralkyl;
`R7 and R8 are independently hydrogen or optionally
`substituted lower alkyl, or one of R7 and R8 is hydrogen and
`the other of R7 and R8 is Rio(0)CCHz or lower acyl;
`R9 is hydrogen, optionally substituted lower alkyl, lower
`acyl or Rio(0)CCHz ;
`Rio is hydrogen, optionally substituted lower alkyl,
`alkoxy or hydroxy;
`m is 0, 1, 2 or 3;
`n is 1, 2 or 3; or
`p is 1 or 2,
`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 alkyl"
`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, alkoxy,
`amino, acylamino, aroylamino, carboxy, alkoxycarbonyl,
`aralkyloxycarbonyl, heteroaralkyloxycarbonyl or
`Y1'Y2'NCO—, where Y1' and Y2' are independently
`hydrogen, alkyl, aralkyl or heteroaralkyl. Exemplary alkyl
`groups include methyl, trifluoromethyl, cyclopropylmethyl,
`cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl,
`t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxymethyl,
`methoxycarbonylethyl, benzyloxycarbonylmethyl, pyridyl-
`methyloxycarbonylmethyl.
`"Cycloalkyl" means a non-aromatic mono- or multicyclic
`ring system of about 3 to about 10 carbon atoms. Exemplary
`monocyclic cycloalkyl rings include cyclopentyl,
`fluorocyclopentyl, cyclohexyl and cycloheptyl. The
`cycloalkyl group is optionally partially unsaturated or
`optionally substituted by one or more halo, methylene
`(H2C=), alkyl, fused ary or fused heteroaryl. Exemplary
`multicyclic cycloalkyl rings include 1-decalin, adamant-(1-
`or 2-)yl and norbornyl.
`"Heterocyclyl" means a non-aromatic monocyclic or mul-
`ticyclic 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 by one or more alkyl, halo, aryl,
`heteroaryl, fused aryl or fused heteroaryl. Exemplary mono-
`cyclic rings include pyrrolidyl, piperidyl, tetrahydrofuranyl,
`tetrahydrothienyl and tetrahydrothiopyranyl. The thio or
`
`5,958,918
`
`n
`nitrogen moiety of the heterocyclyl may also be optionally
`oxidized to the corresponding N-oxide, S-oxide or S,S-
`dioxide.
`"Aryl" means aromatic carbocyclic radical containing
`5 about 6 to about 10 carbon atoms. Exemplary aryl include
`phenyl or naphthyl, or phenyl substituted or naphthyl sub-
`stituted 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,
`15 aralkylthio, heteroaralkylthio, fused cycloalkyl, fused
`heterocyclyl, arylazo, heteroarylazo, Y1Y2 N—,
`YlY2NCO— or Y1Y2NSO2 , where Y1 and Y2 are inde-
`pendently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or
`Y1, Y2 and N taken together form a heterocyclyl. The aryl
`20 group substituents are as defined herein.
`Preferred aryl groups are optionally substituted phenyl or
`optionally substituted naphthyl. Preferred aryl group sub-
`stituents include hydrogen, alkyl, hydroxy, acyl, aryl aroyl,
`aryloxy, halo, nitro, alkoxy, cyano, alkoxycarbonyl,
`25 acylamino, alkylthio, Y1'Y2'N—, Y1'Y2'NCO— or
`Y1'Y2'NSO2 , where Y1' and Y2' are independently
`hydrogen, alkyl, aralkyl or heteroaralkyl; preferred phenyl
`group substituents are aryloxy and aryl; and preferred naph-
`thyl group substituents are nitro, alkoxy and amino.
`"Heteroaryl" means about a 5- to about a 10- membered
`aromatic monocyclic or multicyclic hydrocarbon ring sys-
`tem 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
`35 substituted by one or more of the above-mentioned "aryl
`group substituents". Exemplary heteroaryl groups include
`pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl,
`isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,
`pyrrolyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl,
`40 azaindolyl, benzimiddazolyl, benzothienyl, quinolinyl, imi-
`dazolyl and isoquinolinyl. Preferred heteroaryl groups in the
`R substituent include benzothienyl, thienyl, imidazolyl,
`pyridyl and quinolinyl all of which may be optionally
`substituted. Where
`
`45
`
`50
`
`il
`
`is monocylic heteroaryl, then preferred heteroaryls include
`thienyl, pyridyl and furanyl.
`"Aralkyl" means an aryl-alkyl- group in which the aryl
`and alkyl are as previously described. Preferred aralkyls
`55 contain a lower alkyl moiety. Exemplary aralkyl groups
`include benzyl, 2-phenethyl and naphthalenemethyl.
`"Heteroaralkyl" means a heteroaryl-alkyl- group in which
`the heteroaryl and alkyl are as previously described. Pre-
`ferred heteroaralkyls contain a lower alkyl moiety. Exem-
`60 plary heteroaralkyl groups may contain thienyl, pyridyl,
`imidazolyl and pyrazinyl.
`"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
`65 aralkenyl group is 2-phenethenyl.
`"Heteroaralkenyl" means a heteroaryl-alkenyl- group in
`which the heteroaryl and alkenyl are as previously
`
`

`
`5,958,918
`
`5
`described. Preferred heteroaralkenyls contain a lower alk-
`enyl moiety. Exemplary heteroaralkenyl groups may contain
`thienyl, pyridyl, imidazolyl and pyrazinyl.
`"Hydroxyalkyl" means a HO-alkyl- group in which alkyl
`is as previously defined. Preferred hydroxyalkyls contain
`lower alkyl. Exemplary hydroxyalkyl groups include
`hydroxymethyl and 2-hydroxyethyl.
`"Acyl" means an H—CO— or alkyl-CO— group in
`which the alkyl group is as previously described. Preferred
`acyls contain a lower alkyl. Exemplary acyl groups include
`formyl, acetyl, propanoyl, 2-methylpropanoyl, 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, i-propoxy, n-butoxy
`and heptoxy.
`"Aryloxy" means an aryl-O— group in which the aryl
`group is as previously described. Exemplary aryloxy groups
`include phenoxy and naphthoxy.
`"Aralkyloxy" means an aralkyl-O— group in which the
`aralkyl groups is as previously described. Exemplary aralky-
`loxy 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 hep-
`tylthio.
`"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.
`"Y3Y4N—" means a substituted or unsubstituted amino
`group, wherein Y3 and Y4 are as previously described.
`Exemplary groups include amino (H2N—), methylamino,
`ethylmethylamino, dimethylamino and diethylamino.
`"Alkoxycarbonyl" means an alkyl-O—CO— group.
`Exemplary alkoxycarbonyl groups include methoxy- and
`ethoxycarbonyl.
`"Aryloxycarbonyl" means an aryl-O—CO— group.
`Exemplary aryloxycarbonyl groups include phenoxy- and
`naphthoxycarbonyl.
`"Aralkoxycarbonyl" means an aralkyl-O—CO— group.
`An exemplary aralkoxycarbonyl group is benzyloxycarbo-
`nyl.
`"Y3Y4NCO—" means a substituted or unsubstituted car-
`bamoyl group, wherein Y3 and Y4 are as previously
`described. Exemplary groups are carbamoyl (H2NCO—)
`and dimethylaminocarbamoyl (Me2NCO—).
`"Y3Y4NSO2—" means a substituted or unsubstituted sul-
`famoyl group, wherein Y3 and Y4 are as previously
`described. Exemplary groups are aminosulfamoyl
`(H2NSO2 ) and dimethylaminosulfamoyl (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-S02 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-S02--- group.
`"Arylsulfinyl" means an aryl-SO— group.
`
`5 (cid:9)
`
`10 (cid:9)
`
`6
`"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.
`A preferred compound aspect of the invention is the
`compound of formula I wherein R3 is optionally substituted
`phenyl, optionally substituted naphthyl, optionally substi-
`tuted thienyl or optionally substituted benzothienyl.
`Another preferred compound aspect of the invention is the
`15 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 X2 and X2, taken together
`are oxo.
`Another preferred compound aspect of the invention is the
`compound of formula I wherein X1, X1, X3 and X4 are
`hydrogen.
`Another preferred compound aspect of the invention is the
`compound of formula I wherein XS and Xs, taken together
`are =NH.
`Another preferred compound aspect of the invention is the
`compound of formula I wherein XS and Xs, taken together
`are =NRS wherein R5 is R602C—.
`Another preferred compound aspect of the invention is the
`compound of formula I wherein
`
`20
`
`25 (cid:9)
`
`30
`
`Arl
`
`35 is phenyl and the carbon substituted with Xs, Xs, and
`HR2N— is attached to the 3-position of the phenyl.
`Another preferred compound aspect of the invention is the
`compound of formula I wherein
`
`40
`
`Arl
`
`45 is of the formula
`
`50 (cid:9)
`
`/ \ (cid:9)
`s
`
`NHZ.
`
`NH
`
`55 (cid:9)
`
`60 (cid:9)
`
`Another preferred compound aspect of the invention is the
`compound of formula I wherein R is hydrogen, methyl,
`aralkyl, heteroaralkyl, HO2CCH2 , HOC(0)CHz , H2NC
`(0)CH2—, (aralkyl)HNC(0)CH2— or (heteroaralkyl)HNC
`(0)CH2—.
`Another preferred compound aspect of the invention is the
`compound of formula I wherein Xl is hydrogen and X1. is
`carboxyalkyl, alkoxycarbonylalkyl or aryl, or Xl and X1.
`taken together form oxo.
`Another preferred compound aspect of the invention is the
`65 compound of formula I wherein Rl is R3SO2 .
`Another preferred compound aspect of the invention is the
`compound of formula I wherein Rl is R3R4NSO2 .
`
`

`
`5,958,918
`
`7
`Another preferred compound aspect of the invention is the
`compound of claim 1 wherein one of X6 and X6, is amino in
`a para position relative to the
`
`xs
`Xs
`
`NHR2
`
`moiety.
`Species according to the invention are selected from the
`group consisting of:
`Naphthalene-2-sulfonic acid {1-[3-(aminoiminomethyl)
`benzyl]-2-oxopyrrolidin-3-(S)-yl}amide trifluoroacetate;
`Dibenzofuran-2-sulfonic acid {1-[3-(aminoiminomethyl)
`benzyl]-5-oxopyrrolidin-3-yl}amide trifluoroacetate;
`Toluene-4-sulfonic acid {l-[3-(aminoiminomethyl)benzyl]-
`2-oxopyrrolidin-3-(S)-yl}amide trifluoroacetate;
`3,4-Dihydro-1H-isoquinoline-2-sulfonic acid { 1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`3'-Methoxy-biphenyl-4-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`Naphthalene-l-sulfonic acid {1-[3-(aminoiminomethyl)
`benzyl]-2-oxopyrrolidin-3-(S)-yl}amide trifluoroacetate;
`5-Pyrid-2-ylthiophene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`Biphenyl-4-sulfonic acid {1-[3-(aminoiminomethyl)
`benzyl]-2-oxopyrrolidin-3-(S)-yl}amide trifluoroacetate;
`7-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`7-Ethoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`5-Chloro-6-methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`5-Chloro-6,7-dimethoxynaphthalene-2-sulfonic acid {l-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`7-Aminonaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide bistrifluoroacetate;
`Naphthalene-2-sulfonic acid {1-[4-(aminoiminomethyl)
`benzyl]-2-oxopyrrolidin-3-(S)-yl}amide trifluoroacetate;
`7-Methoxynaphthalene-2-sulfonic acid [1-(3-
`aminomethylbenzyl)-2-oxopyrrolidin-3-(S)-yl]amide trif-
`luoroacetate;
`Naphthalene-2-sulfonic acid {1-[3-(aminoiminomethyl)
`benzyl]-2-oxopyrrolidin-3-(S)-yl}methyl amide trifluoro-
`acetate;
`Naphthalene-2-sulfonic acid {1-[3-(aminoiminomethyl)
`benzyl]pyrrolidin-3-(S)-yl}amide bistrifluoroacetate;
`7-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-3-(S) -
`yl}amide trifluoroacetate;
`Naphthalene-2-sulfonic acid {1-[3-(aminoiminomethyl)
`benzyl]-2-oxopiperidin-3-yl}amide trifluoroacetate;
`7-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-azepan-3-(S)-
`yl}amide trifluoroacetate;
`7-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}methyl amide trifluoroacetate;
`
`5 (cid:9)
`
`20 (cid:9)
`
`30
`
`8
`6-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`6-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}methyl amide trifluoroacetate;
`2-[{ 1 -[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl} -6-methoxynaphthalene-2-sulfonylamino]-N-
`phenethylacetamide trifluoroacetate;
`10 9,10-Dioxo-8a,9, 10,10a-tetrahydroanthracene-2-sulfonic
`acid {l-[3-(aminoiminomethyl)benzyl]-2-oxopyrrolidin-
`3-(S)-yl}amide trifluoroacetate;
`8-Chloro-7-methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)-benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`15 7-Methoxynaphthalene-2-sulfonic acid {1-[4-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`6,7-Dimethoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`Naphtho(2,3-d)-(1,3)dioxole-6-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`7-Benzyloxynaphthalene-2-sulfonic acid {1-[3-
`25 (aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`7-Hydroxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`6-Hydroxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid {l-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`35 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid {l-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}methyl amide trifluoroacetate;
`7-Methylnaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`7-Ethylnaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide trifluoroacetate;
`5-Chloro-6-aminonaphthalene-2-sulfonic acid {1-[3-
`aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide bistrifluoroacetate;
`7-Methylaminonaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}amide bistrifluoroacetate;
`so 2-Methyl-1,2,3,4-tetrahydroisoquinolinyl-7-sulfonic acid
`{ 1 -[3-(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl}amide bistrifluoroacetate;
`1,2,3,4-Tetrahydroisoquinolinyl-7-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-
`yl}methyl amide dihydrochloride;
`7-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoimino methyl)benzyl]-2-oxopyrrolidin-3-(S)-yl}-
`(4-nitrobenzyl)amide trifluoroacetate;
`7-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-yl}-
`(4-aminobenzyl)amide bistrifluoroacetate;
`7-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-yl}
`(3-nitrobenzyl)amide trifluoroacetate;
`65 7-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-yl)}
`(3-aminobenzyl)amide bistrifluoroacetate;
`
`40 (cid:9)
`
`45
`
`55 (cid:9)
`
`60
`
`

`
`5,958,918
`
`7-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-(S)-yl}-
`(2-nitrobenzyl)amide trifluoroacetate;
`3-[2-Oxo-3(S)-(2-phenylethenesulfonylamino)pyrrolidin-l-
`ylmethyl]-benzamidine trifluoroacetate;
`3-[2-Oxo-3(S)-(2-phenylethanesulfonylamino)pyrrolidin-l-
`ylmethyl]-benzamidine trifluoroacetate;
`[Imino-(3-{3-[7-Methoxynaphth ale ne-2-sulfonyl)
`methylamino]-2-oxo-3(S)-pyrrolidin-1-ylmethyl]phenyl)
`methyl]carbamic acid ethyl ester;
`3-[2-Oxo-3(S)-{2-(pyridin-4-ylamino)-
`ethanesulfonylamino}-pyrrolidin-1-ylmethyl]-
`benzamidine bistrifluoroacetate;
`2'-Methoxybiphenyl-4-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3(S)-
`yl}amide trifluoroacetate;
`5,6,7,8-Tetrahydrophenanthrene-3-sulfonic acid { 1 -[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}amide trifluoroacetate;
`Isoquinolinyl-5-sulfonic acid {l-[3-(aminoiminomethyl)
`benzyl]-2-oxo-3(S)-pyrrolidin-3-yl}amide bistrifluoroac-
`etate;
`5-Chlorothiophene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}amide trifluoroacetate;
`2,4-Diaminoquinazoline-6-sulfonic acid { 1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}amide trifluoroacetate;
`7-Methoxy-2-naphthalenesulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}ethylamide trifluoroacetate;
`7-Methoxy-2-napthalenesulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-yl}
`(3-fluorobenzyl)amide trifluoroacetate;
`7-Methoxy-2-napthalenesulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-yl}
`(4-methylbenzyl)amide trifluoroacetate;
`7-Methoxy-2-napthalenesulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-yl}
`(3-methylbenzyl)amide trifluoroacetate;
`7-M ethoxy-2-napthalenesulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}napthalene-2-ylmethylamide trifluoroacetate;
`7-Methoxy-2-napthalenesulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-yl}
`(3-phenylallyl)amide trifluoro acetate;
`7-Methoxy-2-napthalenesulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-yl}
`(3-methylbenzyl)amide trifluoroacetate;
`7-Methoxy-2-napthalenesulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-yl}
`(2-fluorobenzyl)amide trifluoroacetate;
`{ 1 -[3-
`acid (cid:9)
`2-F1uorobipheny1-4-su1fonic (cid:9)
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}methylamide trifluoroacetate;
`3-[ { 1-[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3
`(S)-3-yl}-(7-methoxynaphthalene-2-sulfonyl)amino]
`propionamide trifluoroacetate;
`2-[{ 1 -[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl}n aphthalene -2 -sulfonylamino]-N-
`phenethylacetamide trifluoroacetate;
`2-[{ 1 -[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl}biphenyl-4-sulfonylamino]-N-phenethylacetamide
`trifluoroacetate;
`2-[{ 1 -[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl} -7-methoxynaphthalene-2-sulfonylamino ]-N-
`phenethylacetamide trifluoroacetate;
`
`5 (cid:9)
`
`20 (cid:9)
`
`30
`
`10
`2-[{ 1 -[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl} -7-methoxynaphthalene-2-sulfonylamino]-N-
`ethylacetamide trifluoroacetate;
`2-[{1-[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl}-7-methoxynaphthalene-2-sulfonylamino]-N,N-
`dimethylacetamide trifluoroacetate;
`2-[{ 1 -[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl} -7-methoxynaphthalene-2-sulfonylamino]-N-
`benzylacetamide trifluoroacetate;
`10 2-[{ 1 -[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl}-7-methoxynaphthalene-2-sulfonylamino]-N-(2-p-
`toluylethyl)acetamide trifluoroacetate;
`2-[{1-[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl}-7-methoxynaphthalene-2-sulfonylamino]-N-(3-
`phenylpropyl)acetamide trifluoroacetate;
`15 2-[{1-[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl}-7-methoxynaphthalene-2-sulfonylamino]-N-(4-
`methylbenzyl)acetamide trifluoroacetate;
`2-[{1-[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl}-7-methoxynaphthalene-2-sulfonylamino]-N-[2-
`(3-fluorophenyl)ethyl]acetamide trifluoroacetate;
`2-[{ 1 -[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`(S)-yl} -7-methoxynaphthalene-2-sulfonylamino]-N-
`indan-2-ylacetamide trifluoroacetate;
`2-[{1-[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3-
`25 (S)-yl}-7-methoxynaphthalene-2-sulfonylamino]-N-(2-
`pyridin-3-yl-ethyl)acetamide bistrifluoroacetate;
`4,5-Dichlorothiophene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}amide trifluoroacetate
`4,5-Dichlorothiophene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}-methylamide trifluoroacetate;
`4,5-Dichlorothiophene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}benzylamide trifluoroacetate;
`35 7-Methoxy-2-napthalenesulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}-2-cyclopropylphenethylamide trifluoroacetate;
`3'-Methyl-biphenyl-4-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxopyrrolidin-3(S)-
`yl}amide trifluoroacetate;
`3-[{ 1 -[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3
`(S)-3-yl}-(7-methoxynaphthalene-2-sulfonyl)amino]
`acetamide trifluoroacetate;
`3-[{ 1 -[3-(Aminoiminomethyl)benzyl]-2-oxopyrrolidin-3
`(S)-3-yl}-(7-methoxynaphthalene-2-sulfonyl)amino]-2-
`methylacetamide trifluoroacetate;
`7-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-azetidin-3(S)-
`yl}amide trifluoroacetate;
`so 7-Methoxynaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-azetidin-3(S)-
`yl}benzylaraide trifluoroacetate;
`5,6,7,8-Tetrahydronaphthalene-2-sulfonic acid {1-[3-
`(aminoiminomethyl)-benzyl]-2-oxopyrrolidin-3(S)-
`yl}amide trifluoroacetate;
`7-Methoxy-2-napthalenesulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}-(2-methoxybenzyl)amide trifluoroacetate;
`7-Methoxy-2-napthalenesulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}-(3-methoxybenzyl)amide trifluoroacetate;
`7-Methoxy-2-napthalenesulfonic acid {1-[3-
`(aminoiminomethyl)benzyl]-2-oxo-3(S)-pyrrolidin-3-
`yl}-(4-methoxybenzyl)amide trifluoroacetate;
`65 7-Methoxy-2-napthalenesulfonic acid