Substituted sulfonic acid N-[(aminoiminomethyl) phenylalkyl] -azaheterocycleamide compounds

专利摘要:
Compounds of formula (I) exhibit useful pharmaceutical activity and are therefore formulated into pharmaceutical compositions and used to treat patients suffering from certain diseases. More particularly the compound is an activity inhibitor of Factor Xa. The present invention relates to a compound of formula (I), a composition containing a compound of formula (I), and use thereof, wherein a patient suffers from or is easily exposed to physiological conditions that can be recovered by administering an inhibitor of activity of factor Xa. To cure.
公开号:KR19990082323A
申请号:KR1019980706053
申请日:1997-12-01
公开日:1999-11-25
发明作者:윌리엄 알. 유잉；마이클 알. 벡커；영 미 최-슬레데스키；하인츠 더블유. 폴스；다니엘 지. 맥게리；로데릭 에스. 데이비스；알프레드 피. 스페이다
申请人:오흘러 로스 제이.；롱-프랑 로러 파마슈티칼즈 인코포레이티드；
IPC主号:

专利说明:

Substituted sulfonic acid N-[(aminoiminomethyl) phenylalkyl] -azaheterocycleamide compounds
This application is a partial consecutive application of US Patent Application No. 08 / 761,414, filed on December 6, 1996, and currently pending, which is an international application filed on June 7, 1996 and designated by the United States as a Designated Country [PCT / US96 / 09816, which is part of US Patent Application Serial No. 08 / 481,024, filed June 7, 1995, and is currently patented US Pat. No. 5,612,353, dated March 18,1997. This application is also a partial serial application of a pending US patent application, filed November 21, 1997, with no application number assigned, which is an international application filed on June 7, 1996 [PCT / US96 / 09816] It is a continuous application of.
Compounds of formula (I) exhibit useful pharmaceutical activity and are therefore formulated in pharmaceutical compositions and used to treat patients suffering from certain diseases. More particularly, the compound is a factor Xa inhibitor. The present invention relates to a compound of formula (I), a composition containing a compound of formula (I), and use thereof, wherein a patient suffers from or is easily exposed to physiological conditions that can be recovered by administering an inhibitor of activity of factor Xa. To cure.
Factor Xa is the second enzyme at the end in the blood coagulation stage. Both free factor Xa and factor Xa bound to the prothrombinase complexes (factor Xa, factor Va and phospholipids) are inhibited by compounds of formula (I). Factor Xa inhibition is caused by the formation of a direct complex between the inhibitor and the enzyme and thus is independent of plasma co-factor antithrombin III. Effective Factor Xa inhibition is achieved by administering the compound via oral administration, continuous intravenous infusion, bolus intravenous administration or other parenteral methods that achieve the desired effect of inhibiting Factor Xa induced thrombin formation from prothrombin.
Anticoagulant therapy is for treating and preventing various thrombus conditions in both veins and arteries. In the arterial system, abnormal thrombus formation is primarily associated with arteries of coronary, brain and peripheral blood vessels. Diseases associated with thrombotic occlusion of these vessels are mainly acute myocardial infarction (AMI), unstable angina, thromboembolism, treatment of thrombotic collapse and coronary angioplasty (PTCA) through percutaneous caliber, transient anemia Symptoms, seizures, intermittent claudication and bypass transplantation of coronary (CABG) or peripheral arteries. Long-term anticoagulant therapy may also be beneficial in preventing vascular stenosis that frequently occurs after PTCA and CABG, or in maintaining vascular inlet opening in long-term hemodialysis patients. In venous vessels, pathogenic thrombus formation often occurs in the veins of the extremities of the lower body after abdominal, knee and hip surgery (deep vein thrombosis, DVT). In addition, DVT makes patients at higher risk for pulmonary thromboembolism. Systemic diffuse coagulopathy (DIC) usually occurs in both the vascular system when suffering from septic shock, certain viral infections, and cancer. This condition is characterized by the rapid depletion of the coagulation factor and its plasma inhibitor, resulting in the formation of life-threatening clots across the microvascular vessels of some organ systems. The signs include some, but not all, possible clinical conditions for which anticoagulant therapy is justified. Those skilled in the art are well aware of situations that require acute or chronic prophylactic anticoagulant therapy.
Summary of the Invention
The present invention relates to the pharmaceutical use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof for treating a patient suffering from a physiological disease that can be modulated by inhibiting the activity of factor Xa. will be.
In the above formula,
Is phenyl or monocyclic heteroaryl;
R is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, R ₆ O (CH ₂ ) _x- , R ₆ O ₂ C (CH ₂ ) _x- , Y ¹ Y ² NC ( O) (CH ₂ ) _x -or Y ¹ Y ² N (CH ₂ ) _x- ;
R ₁ is hydrogen, alkyl, hydroxy, alkoxy, Y ¹ Y ² N-, halogen, -CO ₂ R ₆ , -C (O) NY ¹ Y ² ,-(CH ₂ ) _x OR ₆ ,-(CH ₂ ) _x NY ¹ Y ² or -CN;
R ₂ and R ₃ are independently hydrogen, hydroxy, alkoxy, Y ¹ Y ² N-, halogen, -CO ₂ R ₆ , -C (O) NY ¹ Y ² ,-(CH ₂ ) _x OR ₆ ,- (CH ₂ ) _x NY ¹ Y ² , -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 ₂ and R ₃ are optionally substituted with 5 to 7 membered fused cycloalkyl, together with the carbon atom to which they are linked, 5 To form a 7-membered fused heterocyclyl ring or an optionally substituted 6-membered fused aryl or an optionally substituted 5-7 membered fused heteroaryl ring;
R ₄ is hydrogen or optionally substituted lower alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl;
X ₁ and X _1a are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl, or X ₁ and X _1a together form oxo To;
X ₂ and X _2a are hydrogen or together form oxo;
X ₃ is hydrogen, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or one of X ₃ and X ₁ and X _1a is Together with the carbon atom to which it is linked form a 4-7 membered cycloalkyl or heterocyclyl ring;
X ₄ is hydrogen, optionally substituted alkyl or optionally substituted aralkyl;
X ₅ and X _5a are hydrogen or together form = NR ₅ ;
R ₅ is hydrogen, R ₆ O ₂ C-, R ₆ O-, cyano, R ₆ CO-, optionally substituted lower alkyl, nitro or Y ¹ Y ² N-;
Y ¹ and Y ² are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y ¹ and Y ² together with N to which they are linked 4 to 7 membered hetero To form a cyclyl;
X ₆ and X _6a are independently hydrogen, R ₇ R ₈ N-, R ₉ O-, R ₇ R ₈ NCO-, R ₇ R ₈ NSO _2- , R ₇ R ₈ NSO ₂ N-, R ₇ R ₈ SO ₂ O-, R ₉ CO-, -CO ₂ R ₆ , -C (O) NY ¹ Y ² ,-(CH ₂ ) _x CO ₂ R ₆ ,-(CH ₂ ) _x C (O) NY ¹ Y ² ,-(CH ₂ ) _x OR ₆ ,-(CH ₂ ) _x NY ¹ Y ² , halo, cyano or nitro;
R ₆ is hydrogen, optionally substituted alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl;
R ₇ and R ₈ are independently hydrogen or optionally substituted lower alkyl or one of R ₇ and R ₈ is hydrogen and the other is R ₁₀ (O) CCH ₂ — or lower acyl;
R ₉ is hydrogen, optionally substituted lower alkyl, optionally substituted lower acyl or R ₁₀ (O) CCH ₂ —;
R ₁₀ 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;
x is 1, 2, 3, 4 or 5.
As used above and throughout the specification of the present invention, the following terms have the following meanings, except in special cases.
Justice
"Patient" refers to both humans and other mammals.
"Alkyl" refers to an aliphatic hydrocarbon which may be present in the chain, either straight or branched, having from about 1 to 20 carbon atoms. Preferred alkyl groups have about 1 to 12 carbon atoms in the chain. Side chains indicate that at least one lower alkyl group, such as methyl, ethyl or propyl, is bonded to a straight chain alkyl chain. "Lower alkyl" refers to a case having from about 1 to 4 carbon atoms in the chain, which may be linear or branched. Alkyl is the same or different and is halo, cycloalkyl, hydroxy, alkoxy, amino, acylamino, aroylamino, carboxy, alkoxycarbonyl, aralkyloxycarbonyl, heteroaralkyloxycarbonyl or Y ¹ Y ² NCO May be substituted with one or more "alkyl group substituents", wherein Y ¹ and Y ² are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl Or Y ¹ and Y ² are joined together through N to form a 4 to 7 membered heterocyclyl. Typical alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, I-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, methoxyethyl, carboxy Methyl, methoxycarbonylethyl, benzyloxycarbonylmethyl, pyridylmethyloxycarbonylmethyl.
"Cycloalkyl" refers to a non-aromatic mono- or multicyclic ring system having about 3 to about 10 carbon atoms. Typical monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups are optionally partially unsaturated or optionally substituted with one or more cycloalkyl group substituents, which may be the same or different, wherein the "cycloalkyl group substituent" is hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroar Alkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroyl Amino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, fused cycloalkyl , fused heterocyclyl, aryl azo, azo-heteroaryl, Y ¹ Y ² N-, Y ¹ Y ² NCO- or Y ¹ Y _² NSO ² - and include, in which Y ¹ and Y ² is independently , Optionally form a substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y ¹ and Y ² are coupled to each other through N with 4 to 7 membered heterocyclyl. Aryl group substituents are as defined herein. Typical multicyclic cycloalkyl rings include 1-decalin, norbornyl and adamant- (1- or 2-) yl.
"Heterocyclyl" refers to a non-aromatic monocyclic or multicyclic ring system having from about 3 to about 10 ring atoms. Preferred rings contain from about 5 to 6 ring atoms, where one of the ring atoms is oxygen, nitrogen or sulfur. Heterocyclyl is optionally partially unsaturated or optionally substituted with one or more heterocyclyl group substituents, wherein “heterocyclyl group substituents” are 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 ¹ Y ² N-, Y ¹ Y ² NCO _2- , or Y ¹ Y ² NSO _2- , wherein Y ¹ and Y ² are independently hydrogen, optionally substituted alkyl , The righteousness form a substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or, Y ¹ and Y ² is bonded through N with 4 to 7 membered heterocyclyl. Heterocyclyl group substituents are as defined herein. Typical monocyclic rings include pyrrolidyl, piperidyl, tetrahydrofuranyl, tetrahydrothienyl and tetrahydrothiopyranyl. Thio or nitrogen moieties of heterocyclyl may also optionally be oxidized to form the corresponding N-oxide, S-oxide or S, S-dioxide.
"Aryl" refers to a 6 to 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system. Typical aryls include phenyl or naphthyl, phenyl or substituted naphthyl substituted using one or more aryl group substituents, which may be the same or different, wherein “aryl group substituents” are hydrogen, alkyl, aryl, heteroaryl, Aralkyl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonyl, Acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, akylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkyl Thio, fused cycloalkyl, fused heterocyclyl, arylazo, heteroarylazo, Y ¹ Y ² N-, Y ¹ Y ² NCO- or Y ¹ Y ² NSO _2- , wherein Y ¹ and Y ² are Independently hydrogen, optionally Hwandoen alkyl, optionally form a substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or, Y ¹ and Y ² is bonded through N with 4 to 7 membered heterocyclyl. Aryl group substituents are as defined herein. Preferred aryl groups are optionally substituted phenyl or optionally substituted naphthyl. Preferred aryl group substituents are hydrogen, alkyl, hydroxy, acyl, aryl, aroyl, aryloxy, halo, nitro, alkoxy, cyano, alkoxycarbonyl, acylamino, alkylthio, Y ¹ Y ² N-, Y ¹ Y ² NCO- or Y ¹ Y ² NSO _2- , wherein Y ¹ and Y ² are independently optionally substituted alkyl, aryl, aralkyl or heteroaralkyl; Preferred phenyl group substituents are hydroxy, halogen, alkyl or amino.
"Heteroaryl" refers to an about 5 to about 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system wherein at least one carbon atom of the ring system is an element other than carbon, such as nitrogen, oxygen, or sulfur. "Heteroaryl" may also be substituted by one or more of the "aryl group substituents" mentioned above. Typical heteroaryl groups include substituted pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, imidazo [2 , 1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl and isoquinolinyl.
When is monocyclic heteroaryl, preferred heteroaryls include thienyl or pyridyl.
"Aralkyl" refers to an aryl as described above and an aryl-alkyl- group in which alkyl is present. Preferred aralkyls include lower alkyl moieties. Typical aralkyl groups include benzyl, 2-phenethyl and naphthylenemethyl.
“Heteroaralkyl” refers to a heteroaryl-alkyl-group in which heteroaryl and alkyl as described above are present. Preferred heteroaralkyls include lower alkyl moieties. Typical heteroaralkyl groups may include thienylmethyl, pyridylmethyl, imidazolylmethyl and pyrazinylmethyl.
"Aralkenyl" refers to an aryl-alkenyl-group in which aryl and alkenyl as defined above are present. Preferred aralkenyls include lower alkenyl moieties. Typical aralkenyl groups are 2-phenethenyl.
"Heteroarkenyl" refers to a heteroaryl-alkenyl group having heteroaryl and alkenyl as defined above. Preferred heteroalalkenyls include lower alkenyl moieties. Typical heteroaralkenyl groups may include thienylethenyl, pyridylethenyl, imidazolyleethenyl and pyrazinylethenyl.
"Hydroxyalkyl" refers to a HO-alkyl-group in which alkyl as defined above is present. Preferred hydroxyalkyls include lower alkyl. Typical hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
"Acyl" refers to an H-CO- or alkyl-CO- group in which an alkyl group as defined above is present. Preferred acyls include lower alkyl. Typical acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
"Aroyl" refers to an aryl-CO- group in which an aryl group as defined above is present. Typical groups include benzoyl and 1- and 2-naphthoyl.
"Heteroaroyl" refers to a heteroaryl-CO- group in which a heteroaryl group as defined above is present. Typical groups include thiophenoyl and pyridinoyl.
"Alkoxy" refers to an alkyl-O- group in which an alkyl group as defined above is present. Typical alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
"Aryloxy" refers to an aryl-O- group in which an aryl group as defined above is present. Typical groups include phenoxy and naphthoxy.
"Aralkyloxy" refers to an aralkyl-O- group in which an aralkyl group as defined above is present. Typical aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
"Alkylthio" refers to an alkyl-S-group in which an alkyl group as defined above is present. Typical alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.
"Arylthio" refers to an aryl-S-group in which an aryl group as defined above is present. Typical arylthio groups include phenylthio and naphthylthio.
"Aralkylthio" refers to an aralkyl-S-group in which an aralkyl group as defined above is present. Typical aralkylthio groups are benzylthio.
"Y ¹ Y ² N-" represents a saturated or unsaturated amino group, wherein Y ¹ and Y ² are as defined above. Typical groups include amino (H ₂ N-), methylamino, dimethylamino, diethylamino, pyrrolidine, piperidine, benzylamino or phenethylamino.
"Alkoxycarbonyl" refers to an alkyl-O-CO- group. Typical alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl or t-butyloxycarbonyl.
"Aryloxycarbonyl" refers to an aryl-O-CO- group. Typical aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
"Aralkoxycarbonyl" refers to an aralkyl-O-CO- group. Typical aralkoxycarbonyl groups are benzyloxycarbonyl.
"Y ¹ Y ² NCO-" refers to a saturated or unsaturated carbamoyl group, wherein Y ¹ and Y ² are as defined above. Typical groups are carbamoyl (H ₂ NCO-) and dimethylaminocarbamoyl (Me ₂ NCO-).
"Y ¹ Y ² NSO _2- " refers to a saturated or unsaturated sulfamoyl group, wherein Y ¹ and Y ² are as defined above. Typical groups are aminosulfamoyl (H ₂ NSO _2- ) and dimethylaminosulfamoyl (Me ₂ NSO _2- ).
"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" refers to an alkyl-SO ₂ -group. Preferred groups are where the alkyl group is lower alkyl.
"Alkylsulfinyl" refers to an alkyl-SO- group. Preferred groups are where the alkyl group is lower alkyl.
"Arylsulfonyl" refers to an aryl-SO ₂ -group.
"Arylsulfinyl" refers to an aryl-SO- group.
"Halo" refers to fluoro, chloro, boromo or iodo. Preferred is fluoro, chloro or bromo and most preferred is fluoro or chloro.
Preferred Embodiment
A preferred embodiment of the invention is a method for treating a patient suffering from a physiological disease that can be controlled by inhibiting the activity of factor Xa by administering a therapeutically effective amount of a compound of formula (I).
Another preferred embodiment of the compounds of the invention is a compound of formula I, wherein n is 1 and m is 1.
Another preferred embodiment of the compounds of the invention is a compound of formula I, wherein X ₂ and X _2a together are oxo.
Another preferred embodiment of the compounds of the invention is a compound of formula I, wherein X ₁ , X _1a and X ₄ are hydrogen and X ₃ is hydrogen or alkyl.
Another preferred embodiment of the compounds of the invention is a compound of formula I, wherein X ₅ and X _5a together are = NR _5, wherein R ₅ is R ₆ O ₂ C-.
Another preferred embodiment of the compounds of the invention is a compound of formula I, wherein X ₅ and X _5a together are = NR _5, wherein R ₅ is -OH.
Another preferred embodiment of the compounds of the invention is a compound of formula I, wherein X ₅ and X _5a together are = NR _5, wherein R ₅ is H.
Other preferred embodiments of the compounds of the present invention Is phenyl and carbon substituted with X ₅ , X _5a or R ₄ HN- is attached at the meta position for attachment of the-(CH) _n N- residue of phenyl.
Other preferred embodiments of the compounds of the present invention Is thienyl, carbon substituted with X ₅ , X _5a or R ₄ HN- is attached at position 2 relative to the sulfur of thienyl and the-(CH) _n N-residue is attached at position 4 of thienyl Compound.
Another preferred embodiment of the compounds of the present invention are those of formula I, wherein R is hydrogen, methyl, aralkyl, heteroaralkyl, HO ₂ CCH _2- , H ₂ NC (O) CH ₂ or R ₅ HNC (O) CH _2- Compound.
Another preferred embodiment of the compounds of the invention is a compound of formula (I) wherein R ₁ is hydrogen, alkyl or halogen.
Another preferred embodiment of the compounds of the invention is a compound of formula (I) wherein R ₂ and R ₃ are independently hydrogen, halogen, alkyloxy, amino, aryl or heteroaryl.
Another preferred embodiment of the compounds of the present invention are those compounds of formula I, wherein R ₂ and R ₃ form an optionally substituted fused aryl or optionally substituted fused heteroaryl ring, wherein the substituents are halogen, alkyl, amino, hydroxy or alkoxy. to be.
Another preferred embodiment of the compounds of the present invention form R ₂ and R ₃ optionally substituted fused cycloalkyl or fused heterocyclyl wherein the optionally substituted heteroatom is nitrogen, wherein the substituent is hydrogen, Y ¹ Y ² N or alkyl Compound of formula (I).
Other preferred embodiments of the compounds of the present invention Is phenyl and X ₆ and X _6a are The compound of claim 1 which is amino or hydroxy in the para position relative to the residue.
Another preferred embodiment of the compounds of the invention is the compound of claim 1, wherein X ₆ and X _6a are hydrogen.
Another preferred embodiment of the compounds of the invention is that A is -CH = CH-; R ₂ and R ₃ together form an optionally substituted 5-6 membered heteroaryl ring, preferably a ring containing one or more heteroatoms N or optionally substituted 6-membered aryl ring, wherein the substituents are Preferably chloro, hydroxy or amino.
Another preferred embodiment of the compounds of the invention is that A is -CH = CH-; R ₂ is hydrogen; R ₃ is an optionally substituted heteroaryl ring, preferably a 5-6 membered heteroaryl ring, preferably a ring containing one or more heteroatoms N or S, or an optionally substituted 6-membered aryl ring, wherein the substituent is preferably chloro, The compound of claim 1 which is hydroxy or amino.
Another preferred embodiment of the compounds of the invention is the compound of claim 1 wherein A is S.
Another preferred embodiment of the compounds of the invention is A is S; R ₂ and R _{3 taken} together form a carbon atom, optionally substituted 5-6 membered heteroaryl ring, preferably a ring containing one or more heteroatoms N, or an optionally substituted 6-membered aryl ring, Wherein the substituent is a compound of claim 1 which is preferably chloro, hydroxy or amino.
Another preferred embodiment of the compounds of the invention is A is S; R ₂ is hydrogen; R ₃ forms an optionally substituted hetero ring, preferably a ring containing 5-6 membered hetero rings, preferably one or more heteroatoms N or S, or an optionally substituted 6-membered aryl ring, wherein the substituents are preferably Preferably chloro, hydroxy or amino.
The species according to the invention are selected from the following groups:
3- [3- (S)-(benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(benzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
4- [3- (S)-(benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxamidine trifluoro acetate;
4- [3- (S)-[Benzo [b] thiophene-2-sulfonyl] -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxamidine Trifluoroacetate;
3- [3- (S)-(4-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-(6-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(4-chlorobenzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
3- [3- (S)-[(6-chlorobenzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
3- [3- (S)-[(5-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(5-chlorobenzo [b] thiophene-2-sulfonyl) -methyl-amino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
3- [3- (S)-[(4-methylbenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(6-methylbenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(5-methylbenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoro acetate;
([3- [3- (S)-[(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -phenyl] -already Nomethyl) -carbamic acid 2,2,2-trichloroethyl ester;
4-amino-3- [3- (S)-(4,6-dichlorobenzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4-hydroxy-2- [3- (S)-(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dine trifluoroacetate;
3- [3- (S)-(6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
4-amino-3- [3- (S)-(6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
4-hydroxy-3- [3- (S)-(6-fluorobenzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4-amino-3- [3- (S)-(4-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
4-hydroxycin-3- [3- (S)-(4-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
3- [3- (S)-(4-Chloro-thieno [3,2-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
4-hydroxy-3- [3- (S)-(4-chloro-thieno [3,2-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate;
3- [3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
3- [3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine bistrifluoroacetate ;
3- [3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
3- {3- (S)-[(5-Chlorothieno [3,2-b] pyridine-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl} -benz Amidine trifluoroacetate;
3- [3- (S)-(6-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
3- [3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine bistrifluoroacetate ;
3- [3- (S)-(6-Chlorothieno [3,2-b] pyridine-2-methylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoro acetate;
4-hydroxy-3- [2-oxo-3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl]- Benzamidine trifluoroacetate;
4-hydroxy-3- [2-oxo-3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine Bistrifluoroacetate;
4-hydroxy-3- [2-oxo-3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl]- Hydroxybenzamidine trifluoroacetate;
4-amino-3- [2-oxo-3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benz Amidine trifluoroacetate;
4-Amino-3- [2-oxo-3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine bis Trifluoroacetate;
4- [3- (S)-(5-Chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2- Carboxamidine trifluoroacetate;
4- [3- (S)-(5-Chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2- Hydroxycarboxamidine trifluoroacetate;
4- {3- (S)-(5-Chlorothieno [3,2-b] pyridine-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl} -thiophene 2-carboxamidine trifluoroacetate;
3- {3- (S)-[5- (2-Methylsulfanyl-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl} Benzamidine trifluoroacetate;
3- {3- (S)-[5- (2-methoxy-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl}- Benzamidine trifluoroacetate;
3- {3- (S)-[5- (2-Amino-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl} -benz Amidine bistrifluoroacetate;
3- {3- (S)-[5- (2-Amino-pyrimidin-4-yl) -thiophene-2-sulfonyl] -methylamino] -2-oxo-pyrrolidin-1-ylmethyl } -Benzamidine bistrifluoroacetate;
3- [3- (S)-(5'-Chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
4-amino-3-[(3- (S) -benzo [b] thiophene-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] benzamidine trifluoroacetate;
4-amino-3-[(6-chlorobenzo [b] thiophen-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] benzamidine trifluoroacetate;
4-amino-3-[(6-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] hydrobenzamidine trifluoroacetate;
3- [2-oxo-2- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
4-Amino-3- [2-oxo-3- (S)-(5-pyridin-2-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
4-hydroxy-3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4-Hydroxy-3- [2-oxo-3- (S)-(5-pyridine-N-oxide-3-yl-thiophene-2-tfvhslfdkalsh) -pyrrolidin-1-ylmethyl] -benz Amidine trifluoroacetate;
3- [2-oxo-3- (S)-(5-pyridin-4-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-(4-Chloro-thiophene-2-sulfoniamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- {3- (S)-[4- (5-Chloropyridin-3-yl) -thiophene-2-sulfonylamino] -2-oxopyrrolidin-1-ylmethyl} benzamidine trifluor Low acetate;
3- [3- (S)-(4-chloro-5-pyridin-3-ylthiophen-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate ;
4-hydroxy-3- [3- (S)-(6-chlorobenzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamide trifluor Low acetate;
3- [3- (S)-(1-aminoisoquinoline-6-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
4-Fluoro-3- [3- (S)-(5-pyridin-3-yl-thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamide tri Fluoroacetates;
2-Chloroquinoline-6-sulfonic acid {1- [3- (aminoiminomethyl) -benzyl] -2-oxo-pyrrolidin-3- (S) -yl} -amide trifluoroacetate;
2-Aminoquinoline-6-sulfonic acid {1- [3- (aminoiminomethyl) -benzyl] -2-oxo-pyrrolidin-3- (S) -yl} -amide bistrifluoroacetate;
4-hydroxy-3- [3- (S)-(7-chloro-thieno [2,3-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate;
4-hydroxy-3- [3- (S)-(thieno [2,3-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Bistrifluoroacetate;
4-hydroxy-3- [3- (S)-(thieno [3,2-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4- [3- (6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxamidine hydrochloride;
4- {3- (S)-[(3-aminopropyl)-(6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl}- Thiophene-2-carboxamidine bistrifluoroacetate;
[[1- (5-carbamimidoyl-thiophen-3-ylmethyl-2-oxo-pyrrolidin-3-yl]-(6-fluorobenzo [b] thiophene-2-sulfonyl)- Amino] -acetic acid trifluoroacetate;
[Imino- (4- {3-[(7-methoxynaphthalene-2-sulfonyl) -pyridin-2-ylmethyl-amino] -2-oxo-pyrrolidin-1-ylmethyl} -thiophene -2-yl) -methyl] -carbamic acid ethyl ester;
4-amino-3- {3- (S)-[(7-methoxy-naphthalene-2-sulfonyl) -pyridin-2-ylmethyl-amino] -2-oxo-pyrrolidin-1-ylmethyl } -Benzamidine trifluoroacetate;
2-[[1- (2-Amino-5-carbamimidoyl-benzyl) -2-oxo-pyrrolidin-3- (S) -yl}-(7-methoxy-naphthalene-2-sulfonyl) -Amino] -acetamide trifluoroacetate;
[Imino (3- {3-[(7-methoxy-naphthalene-2-sulfonyl) -methylamino] -2-oxo-3- (S) -pyrrolidin-1-ylmethyl} -4- Amino-phenyl) -methyl] carbamic acid ethyl ester;
4-hydroxy-3- {3- (S)-[5- (1-hydroxy-pyridin-4-yl) -thienphen-2-sulfonyl amino] -2-oxo-pyrrolidine-1- Monomethyl} -benzamidine trifluoroacetate;
4-amino-3- [3- (S)-(5-chloro-thieno [3,2-b] pyridin-2-sulfoniamino) -2-oxo-pyrrolidin-1-ylmethyl]- Hydroxybenzamidine trifluoroacetate;
4-amino-3- [3- (S)-(5-methoxy-thieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate;
3- [3- (S)-(5-isoxazol-3-yl-thiophen-2-sulfonylamino-2-oxo-pyrrolidin-1-ylmethy] -benzamidine trifluoroacetate;
4-Amino-3- [3- (S)-(5-isoxazol-3-yl-thiophen-2-sulfonylamino) -2-oxo-piperidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4-hydroxy-3- [3- (S)-(5-isoxazol-3-yl-thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dine trifluoroacetate;
3- (S)-[3-([2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
4-amino-3- [3- (S)-([2,2 ']-bithiophenyl-5-sulfoniamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
4-Amino-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl]- Benzamidine trifluoroacetate;
4-hydroxy-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-4-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl} Benzamidine hydrochloride;
4-hydroxy-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Hydroxybenzamidine; And
4- [3- (S)-(6-Fluoro-benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -pyridine-2-carboxami Dean hydrochloride.
More preferred species according to the invention are selected from the following groups:
3- [3- (S)-[(benzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
4- [3- (benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxamidine trifluoroacetate;
3- [3- (S)-(6-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(6-chlorobenzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
3- [3- (4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzoamidine trifluoroacetate;
([3- [3- (S)-(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -phenyl] -imino Methyl) -carbamic acid 2,2,2-trichloroethyl ester;
3- [3- (6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
4-Amino-3- [2-oxo-3- (S)-(6-fluorobenzo [b] thiophene-2-sulfamylamino) -pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
4-hydroxy-3- [2-oxo-3- (S)-(6-fluorobenzo [b] thiophene-2-sulfamylamino) -pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4-hydroxy-3- [2-oxo-3- (S)-(4-chloro-thieno [3,2-c] pyridin-2-sulphylamino) -pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate;
3- [3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidine-1-ylmethy] -benzamidine bistrifluoroacetate ;
3- [3- (S)-(thieno [2,3-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine bistrifluoroacetate ;
4-Amino-3- [2-oxo-3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine bis Trifluoroacetate;
3- {3- (S)-[5- (2-Methylsulfanyl-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl} Benzamidine trifluoroacetate;
4-amino-3- [6-chlorobenzo [b] thiophen-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] benzamidine trifluoroacetate;
4-amino-3- [6-chlorobenzo [b] thiophen-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] hydroxybenzamidine trifluoroacetate;
3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-ylmethyl] -benzamidine trifluoroacetate;
4-hydroxy-3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4-hydroxy-3- [2-oxo-3- (S)-(5-pyridine-N-oxide-2-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate;
4-hydroxy-3- [3- (S)-(6-chloro-benzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl] benzamide trifluoro acetate;
4-hydroxy-3- [3- (S)-(7-chloro-thieno [2,3-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate;
4-hydroxy-3- [3- (S)-(thieno [2,3-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Bistrifluoroacetate;
4-hydroxy-3- [3- (S)-(thieno [3,2-c] pyridine-2-sulfoniamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4-hydroxy-3- {3- (S)-[5- (1-hydroxy-pyridin-4-yl) -thiophene-2-sulfonyl amino] -2-oxo-pyrrolidine-1- Monomethyl} -benzamidine trifluoroacetate;
4-amino-3- [3- (S)-(5-methoxy-thieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Benzamidine bistrifluoroacetate;
4-Amino-3- [3- (S)-(5-isoxazol-3-yl-thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4-hydroxy-3- [3- (S)-(5-isoxazol-3-yl-thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dine trifluoroacetate;
4-Amino-3- [3- (S)-([2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
4-Amino-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl]- Benzamidine trifluoroacetate; And
4-hydroxy-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Benzamidine hydrochloride.
The present invention also includes all combinations of the preferred embodiments of the invention mentioned herein.
Compounds of formula (I) can be prepared using applied methods or variations of known methods used to date and described in the literature.
Compounds of formula (I) may be prepared by treating compounds of formula (II) at about −40 to about 100 ° C. with or without a hydrogen halide gas such as HCl in an alcoholic solvent such as ethanol, with or without a co-solvent such as CH ₂ Cl ₂ . .
The imidates obtained are then treated with an ammonia gas in an alcoholic solvent (such as MeOH) so that R ₄ is hydrogen and X ₅ and X _5a together are NR ₅ , wherein R ₅ is hydrogen (amidine). Obtain the compound. In the case of compounds where R ₅ is OH, imidate is treated with hydroxyamine in alcoholic solvent. For compounds wherein R ₅ is C (O) OR ₆ , tertiary amines such as triethylamine, diisopropylethylamine, or N-methylpiperidine, after dissolving amidine in a DMF / CH ₂ Cl ₂ solution and Treatment at about −20 to about 100 ° C. with alkyl carbonate or alkyl chloroformate. Compounds of formula II wherein R is not H are treated with compounds of formula III with a strong base such as sodium hydride or potassium carbonate in an inert organic solvent such as THF, DMF or Et ₂ O, followed by an optionally substituted alkyl halide, optionally substituted Aralkyl halide or optionally substituted heteroaralkyl halide can be prepared by addition at a temperature of about -78 to about 100 ° C.
The compound of formula III is prepared by dissolving amine hydrochloride in an organic solvent such as CH ₂ Cl ₂ , THF or DMF containing a suitable base such as triethylamine or potassium carbonate, or dissolving amine hydrochloride in an organic base such as pyridine. It can be prepared from the amine of formula IV by adding sulfonyl chloride of V.
Sulfonyl chloride of formula V may be treated with a strong base such as n-BuLi at −78 ° C., followed by addition of SO ₂ gas or lithium heteroaryl sulfonate with a chloride such as NCS or SO ₂ Cl _2. Can be prepared by treatment.
end A phenyl group, a compound of formula (IV) is substituted, such as P is benzyl, t- butyl, allyl, with a compound of the silyl ethyl or trichloroethyl standard protecting moiety of the formula VII, such as ethyl and methyl halide of formula VIII THF, Et ₂ O Or by treatment in an inert organic solvent such as DNF in the presence of a strong base such as NaH, lithium hexamethyldisylylazide or lithium diisopropylamine.
The carbonate protecting group is then removed using one of the suitable deprotection methods such as acidic, basic, hydrogenolysis, palladium mediated deprotection, zinc promoted deprotection or fluorine anion mediated deprotection. Compounds of formula (VIII) may be prepared by treating compounds of formula (IX) with a chlorinating or brominating agent such as NCS or NBS.
When X ₆ is NH ₂ and X _6a is H, the corresponding nitrogen compound is reduced with SnCl ₂ and protected as a disubstituted alkyl, aryl or aralkyl imine. The protective material obtained is brominated with NBS to give the compound of formula VIII. When X ₆ is OH and X _6a is H, the hydroxyl group is protected as a silyl, MOM- or MEM- group. The compound obtained is then brominated with NBS.
end The compound of formula IV, which is a thienyl group substituted with, may be prepared by reacting bromine or iodine containing thiophene carboxaldehyde with a reducing agent such as sodium borohydride or lithium borohydride. The bromine or iodine containing thiophene methanol obtained is then converted to nitrile via a palladium mediated coupling reaction with a cyanide such as Zn (CN) ₂ . The cyano-thiophene-methanol obtained is then converted to the corresponding methylchloride or methylbromide by the compatibility of PPh ₃ with CCl ₄ or CBr ₄ .
Compounds of formula (IV), wherein X ₃ is H, are either commercially available or obtained from literature, or protected, optionally substituted diamino alkyl carboxylic acid, wherein the protection is located at the amino attached to the carbon forming the carboxylic acid; It can be obtained by treatment in an inert solvent such as CH ₂ Cl ₂ , THF or DMF with a peptide coupling agent such as BOP. Compounds wherein X ₃ is alkyl can be prepared using methods such as those described in JE Baldwin et al., Tetrahedran 46 (13), p4733, 1990.
Compounds of the formula (I) comprising a nitrogen ring, preferably a heteroaryl group comprising at least one imine (= N-), together with m-chloroperoxide acid in an inert solvent such as peracetic acid in acetic acid or dichloromethane By reacting under reflux at about room temperature to preferably elevated temperature, whereby at least one nitrogen ring atom of the heteroaryl moiety is oxidized to N-oxide.
The compounds of the present invention are useful in the form of free bases or acids or in the form of pharmaceutically acceptable salts thereof. All types are within the scope of the present invention.
When the compound of the present invention is substituted with a base moiety, acid addition salts are formed to make them easier to use; Usually the use of the salt form is essentially the same as the use of the free base form. Acids from which acid addition salts can be prepared are preferably salts which, when mixed with the free base, form a pharmaceutically acceptable salt, i.e. the salt's anion is a non-toxic salt to the patient in the pharmaceutical dosage form of the salt so that the free base thereof is Included are those salts in which the beneficial inhibitory effect on factor Xa activity inherently inherent is not countered by adverse effects due to anions. Although pharmaceutically acceptable salts of these basic compounds are preferred, all acid addition salts are used for the purpose of purifying and separating the salts by ion exchange methods or as intermediates for preparing pharmaceutically acceptable salts. As is the case, it is useful as a source in the form of the free base even if the particular salt itself is desired as an intermediate product. Pharmaceutically acceptable salts within the scope of the present invention include inorganic acids such as hydrochloric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid and sulfamic acid; And salts derived from organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfonic acid, quinic acid and the like. Corresponding acid addition salts are hydrohalides, for example hydrochloride and hydrobromide, trifluoroacetate, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxal Latex, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-B-hydroxynaphthoate, gentiate, mesylate, isethionate and di-p-toluoyltartarate Methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate.
According to a further aspect of the invention, acid addition salts of the compounds of the invention are prepared by reacting the free base with a suitable acid or by applying or modifying known methods. For example, acid addition salts of the compounds of the invention may be dissolved in an aqueous or aqueous-alcohol solution or other suitable solvent containing a suitable acid and the solution is evaporated to separate the salts, or by reacting the free base and acid in an organic solvent to form a salt. Is obtained by direct separation or by concentrating the solution.
The compounds of the present invention can regenerate acid addition salts by applying known methods or modifying the application. For example, the parent compounds of the present invention can be regenerated from acid addition salts by treatment with alkalis such as sodium bicarbonate solution or aqueous ammonia solution.
When the compound of the present invention is substituted with an acidic moiety, base addition salts may be formed and become easier to use; Usually the use of the salt form is essentially the same as the use of the free acid form. Bases that can be used to prepare base addition salts preferably form pharmaceutically acceptable salts when combined with free acid, ie their cations are free as salts which are non-toxic to animal organisms in pharmaceutical dosages of salts. Included are salts in which the beneficial inhibitory effect on the factor Xa activity inherently inherent in the acid is not countered by the adverse effects due to the cation. Within the scope of the present invention, pharmaceutically acceptable salts, including, for example, alkali and alkaline earth metal salts, include sodium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium Hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, di It is derived from ethanolamine, procaine, diethylamine, N-benzylphenethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetramethylammonia hydroxide, and the like.
Metal salts of the compounds of the present invention can be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of a metal selected from an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent used may be water or a mixture of water and an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran or an ester such as ethyl acetate. Such reactions are generally carried out at ambient temperature, but can be carried out with heating if desired.
Amine salts of the compounds of the present invention can be obtained by contacting amines with the compounds in an aqueous or organic solvent. Suitable aqueous solvents include water and mixtures of water and alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitriles such as acetonitrile or ketones such as acetone. Amino acid salts can be prepared in the same manner.
Base addition salts of compounds of the present invention can be regenerated from salts by applying known methods or by modifying the application. For example, the parent compounds of the present invention can be regenerated from their base addition salts by treatment with acids such as hydrochloric acid.
Salt formation according to the invention also includes compounds with quaternary nitrogen. Quaternary salts are formed by methods such as alkylation of sp ³ or sp ² hybridized nitrogen in compounds.
As will be apparent to those skilled in the art, some of the compounds of the present invention do not form stable salts. However, acid addition salts are most likely formed by compounds of the present invention having nitrogen-containing heteroaryl groups and / or wherein the compounds contain amino acids as substituents. Preferred acid addition salts of the compounds of the present invention are salts in which there are no labile acid groups.
In addition to being useful as an active compound per se, the salts of the compounds of the invention can be purified using compounds well known to those skilled in the art, for example salts and parent compounds, by-products and / or starting materials. It is useful for purification purposes using the difference in solubility of the liver.
Compounds of the invention may comprise an asymmetric center. These asymmetric centers may independently exist in the R or S configuration. It will also be apparent to those skilled in the art that some of the compounds of Formula I may exhibit geometric isomerism. Geometric isomers include cis and trans forms of the compounds of the invention having alkenyl or diazenyl (azo) residues. Compounds of the invention include their geometric isomers, stereoisomers and mixtures thereof.
The compounds of the present invention may also contain the following tautomeric structures.

The present invention includes various tautomeric structures and mixtures thereof.
Such isomers are separated from the mixture, for example by applying or modifying known techniques, such as chromatography and recrystallization techniques, or individually from suitable isomers of their intermediates, for example by applying or modifying the methods described herein. It can be prepared as.
Starting materials and intermediates are prepared by applying or modifying known methods such as, for example, the methods described in the Reference Examples and the obvious chemically equivalent methods thereof.
The invention is further demonstrated by, but not limited to, the following examples which illustrate the preparation of the compounds according to the invention.
In nuclear magnetic resonance spectra (NMR), chemical displacements are expressed in ppm compared to tetramethylsilane. The abbreviations have the following meanings: s = singlet; d = doublet; t = triplet; m = multiplet; dd = doublet of doublet; ddd = doublet of doublet of doublets; dt = doublet of triplets, b = broadcast, bs = broad singlet, q = quartet, AB = AB pattern.
Example 1
3- [3- (S)-(benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. (2-Oxo-pyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester
(S) -Boc-diaminobutyric acid (25 g, 115 mmol), triethylamine (35 g, 344 mmol) and 1-hydroxybenzotriazole hydrate (19.3 g, 143 mmol) are dissolved in 300 ml of THF. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (27.4 g, 143 mmol) is added to the solution. The solution is heated at 60 ° C. over 15 minutes. Once a white precipitate forms, the solution is kept at 60 ° C. for 4 hours. The solution is then filtered and the collected liquid is concentrated. The crude product is purified by column chromatography eluting with a gradient of 1% MeOH / CH ₂ Cl ₂ to 3% MeOH / CH ₂ Cl ₂ to afford the title compound (19.6 g, 98 mmol) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 6.17 (bs, 1H), 5.08 (bs, 1H), 4.12 (m, 1H), 3.33 (m, 2H), 2.65 (m, 1H), 2.00 (m, 1H), 1.42 (s, 9H).
B. [1- (3-Cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester
2-oxo-pyrrolidin-3- (S) -yl) -carbamic acid tert-butyl ester (9.0 g, 45 mmol) and α-bromo-m in 225 ml of THF / DMF (10: 1) at 0 ° C. To a solution of toluyl nitrile (9.3 g, 47 mmol) add 60% mineral oil dispersion of sodium hydride (1.8 g, 46 mmol). The reaction mixture is stirred for 0.5 h at 0 ° C. and warmed to ambient temperature. After 3 hours, the reaction mixture is quenched by addition of saturated NH ₄ Cl. The resulting solution is diluted with EtOAc. Separate the layers. The organic layer is washed with 1N HCl, H ₂ O and saturated NaCl. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc / hexanes to 40% EtOAc / hexanes to give the title compound (12.7 g, 40 mmol) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.55 (m, 4H), 5.18 (bs, 1H), 4.47 (AB, 2H), 4.18 (dd, 1H), 3.21 (m, 2H), 2.60 (m, 1H), 1.42 (s, 9H).
C. 3- (3- (S) -Amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride
To a solution of [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester (9.1 g. 29 mmol) in 150 ml EtOAc at 0 ° C. HCl gas is bubbled for 10 minutes. The solution is then stirred for 4 hours. The solution is concentrated to give the title compound (7.3 g, 29 mmol) as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.71 (bs, 3H), 7.85 (m, 2H), 7.70 (m, 2H), 4.58 (AB, 2H), 4.13 (m, 1H), 3.32 ( m, 2H), 2.44 (m, 1 H), 2.18 (m, 1 H).
D. Benzo [b] thiophene-2-sulfonyl chloride
To a solution of thianaphthalene (11.8 g. 88.1 mmol) in 400 ml THF at −78 ° C. is added n-Bui (55 ml 1.6M solution in hexane, 88.1 mmol). After 15 minutes, the solution is added to the cannula with a pre-cooled solution (-78 ° C.) of SO ₂ (200 g) in 100 ml of THF. After addition, the solution is warmed to ambient temperature. After 0.5 h the solution is concentrated. The residue is suspended in hexane (400 ml) and cooled to 0 ° C. To the solution is added SO ₂ Cl ₂ (12.5 g, 92.5 mmol). After stirring for 15 minutes the solution is concentrated. The residue is dissolved in EtOAc. The organic solution is washed with saturated NH ₄ Cl (aq), water and saturated NaCl (aq). The organic layer is dried over magnesium sulfate, filtered and then concentrated. The crude product is dissolved in CH ₂ Cl ₂ and filtered through a silica gel plug. The organic solution is concentrated. The resulting solution is triturated with hexanes to give the title compound (12.1 g, 38 mmol) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.16 (s, 1H), 7.97 (m, 2H), 7.57 (m, 2H).
E. Benzo [b] thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
To a solution of 3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride (0.36 g 1.43 mmol) in ₁₅ ml of CH ₂ Cl ₂ , benzo [b] thiophene 2-sulfonyl chloride (0.32 g, 1.38 mmol) is added. Triethylamine (0.29 g, 2.88 mmol) was added to the resulting solution. After 16 hours, the solution is diluted with EtOAc. The solution is washed with 1N HCl, saturated NaHCO ₃ and saturated NaCl. The organic layer is dried over magnesium sulfate, filtered and then concentrated. The title compound (0.45 g, 1.09 mmol) is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.95 (m, 2H), 7.62 (m, 1H), 7.42 (m, 6H), 5.49 (bs, 1H), 4.47 (AB, 2H), 3.90 (m, 1H), 3.24 (m, 2H), 2.63 (m, 1H), 2.10 (m, 1H).
F. 3- [3- (S)-(benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
Benzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3-yl in 20 ml of EtOH: CH ₂ Cl ₂ (1: 1) at 0 ° C. In a solution of] -amide (0.20 g, 0.49 mmol) is bubbled HCl gas for 5 minutes. Warm the solution to ambient temperature. After 16 hours, the solution is concentrated. The residue is dissolved in 20 ml of MeOH and NH ₃ gas is bubbled into the solution for 5 minutes. The solution is then heated at 60 ° C. After 2 hours, the solution is concentrated. The residue is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a solid.
¹ H NMR (DMSO, 300 MHz) δ 9.28 (bs, 2H), 9.02 (bs, 2H), 8.62 (m, 2H), 8.04 (s,
1H), 8.02 (m, 3H), 7.65 (m, 1H), 7.51 (m, 5H), 4.40 (AB, 2H), 4.22 (m, 1H), 3.09 (m, 2H), 2.14 (m, 1H ), 1.68 (m, 1 H).
FAB MS, [M + H] ⁺ = 479.
Elemental Analysis (with 1.5 mol of TFA)
Calculated: C 46.7%, H 3.62%, N 9.35%
Found: C 46.35%, H 3.83%, N 9.46%
Example 2
3- [3- (S)-[(benzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. Benzo [b] thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide
Benzo [b] thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide (0.25 g, 0.61 mmol) in 3 ml of DMF Methyl iodide (0.13 g, 0.91 mmol) is added to a solution of K ₂ CO ₃ (0.13 g, 0.91 mmol). The solution is stirred for 6 hours at ambient temperature. The solution is then diluted with H ₂ O and EtOAc. Separate the layers. The organic layer is washed with H ₂ O and saturated NaCl. The organic layer is dried over magnesium sulfate, filtered and then concentrated. The residue is triturated with Et ₂ O to afford the title compound (0.25 g, 0.59 mmol) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) 7.99 (s, 1H), 7.82 (m, 2H), 7.54 (m, 1H), 7.38 (m, 5H), 4.89 (m, 1H), 4.40 (AB, 2H ), 3.18 (m, 2H), 2.89 (s, 3H), 2.32 (m, 1H), 1.98 (m, 1H).
B. 3- [3- (S)-[(benzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoro acetate
Example 1 using benzo [b] thiophen-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide as starting material Prepare the title compound as described in step F of. The crude product is purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.30 (bs, 2H), 9.05 (bs, 2H), 8.07 (m, 2H), 8.00 (m, 1H), 7.65 (m, 1H), 7.53 (m , 5H), 4.93 (m, 1H), 4.42 (AB, 2H), 3.16 (m, 2H), 2.81 (s, 3H), 2.08 (m, 1H), 1.89 (m, 1H). FAB MS, [M + H] ⁺ = 443.
Elemental analysis (contains 1.5 mol of H ₂ O)
Calculation: C 47.34%, H 4.15%, N 9.35%
Found: C 47.26%, H 4.15%, N 9.35%
Example 3
4- [3- (S)-(benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxamidine trifluoro acetate
A. 5-iodo-thiophene-3-carboxaldehyde
To a solution of thiophene-3-carboxaldehyde (36 g, 321 mmol) in 80 ml of CCl ₄ and 60 ml of H ₂ O was added 2.5 ml of concentrated sulfuric acid in 160 ml of acetic acid. To the resulting solution is added HIO ₃ (14 g, 80 mmol) and I ₂ (38 g, 150 mmol). The solution is refluxed for 6 hours. The solution is then cooled to ambient temperature and 200 ml of CHCl _{3 are} added. Separate the layers. The aqueous layer is extracted with CHCl ₃ . The organic layers are combined and washed with 0.5M Na ₂ S ₂ O ₃ , saturated NaHCO ₃ and saturated NaCl. The organic layer is dried over magnesium sulfate, filtered and then concentrated. The crude product is purified by column chromatography eluting with a gradient of 2% EtOAc / hexanes to 5% EtOAc / hexanes to give the title compound (20 g, 84 mmol) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 9.78 (s, 1H), 8.10 (s, 1H), 7.69 (s, 1H).
B. (5-iodo-thiophen-3-yl) methanol
To a solution of 5-iodo-thiophene-3-carboxaldehyde (42 g, 176 mmol) in 800 ml THF is added NaBH ₄ (7.0 g, 185 mmol). After 1 hour, the reaction was quenched by addition of 100 ml of saturated NH ₄ Cl. The resulting solution is diluted with 1 L of EtOAc. Separate the layers. The organic layer is washed with H ₂ O and saturated NaCl. The organic layer is dried over magnesium sulfate, filtered and concentrated. The title compound (42 g, 175 mmol) is obtained as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.18 (s, 2H), 4.63 (s, 2H), 1.92 (bs, 1H).
C. 4-hydroxymethyl-thiophene-2-carbonitrile
Zinc cyanide (12.4 g, 106 mmol) and tetrakis (triphenylphosphine) palladium (0) (8.13 g) in a solution of (5-iodo-thiophen-3-yl) methanol (42 g, 176 mmol) in 150 ml DMF , 7.04 mmol). The solution is heated at 80 ° C. After 6 hours, the solution is diluted with 3 liters of EtOAc. The resulting solution is washed with 1N NH ₄ OH, H ₂ O and saturated NaCl. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc / hexanes to 30% EtOAc / hexanes to give the title compound (10 g, 72 mmol) as a clear oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.59 (s, 1H), 7.46 (s, 1H), 4.67 (s, 2H), 2.42 (bs, 1H).
D. 4-Bromomethyl-thiophene-2-carbonitrile
To a solution of 4-hydroxymethyl-thiophene-2-carbonitrile (10 g, 72 mmol) in 360 ml of THF is added triphenyl phosphine (18.3 g, 76 mmol) and carbon tetrabromide (25 g, 76 mmol). After 3 hours, the solution is filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc / hexanes to 10% EtOAc / hexanes to give the title compound (14 g, 69 mmol) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.62 (s, 1H), 7.49 (s, 1H), 4.42 (s, 2H).
E. 1-[(5-Cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester
(2-oxo-pyrrolidin-3- (S) -yl) -carbamic acid tert-butyl prepared as described in step A of Example 1 in 80 ml of THF / DMF (10: 1) at 0 ° C. To a solution of ester (3.2 g, 16 mmol) is added 4-bromomethyl-thiophene-2-carbonitrile (3.23 g, 16 mmol) and sodium hydride (60% dispersion in oil, 0.67 g, 16.8 mmol). After addition, the solution is warmed to ambient temperature. After 2 hours, the solution was quenched by addition of saturated NH ₄ Cl. The solution is diluted with H ₂ O and EtOAc. Separate the layers. The organic layer is washed with H ₂ O and saturated NaCl. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 20% EtOAc / CH ₂ Cl ₂ to 30% EtOAc / CH ₂ Cl ₂ to afford the title compound (4.0 g, 13.8 mmol) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.51 (s, 1H), 7.45 (s, 1H), 5.12 (bs, 1H), 4.42 (AB, 2H), 4.12 (m, 1H), 3.27 (m, 2H), 2.58 (m, 1 H), 1.93 (m, 1 H), 1.42 (s, 9 H).
F. 4- (3- (S) -Amino-2-oxo-pyrrolidin-1-ylmethyl) -thiophene-2-carbonitrile hydrochloride
[1- (5-Cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester (4.0 g, 13.8 mmol) was charged at 0 ° C. To a solution of 100 ml of EtOAc saturated with HCl gas. After 3 hours, the solution is concentrated. The title compound (3.3 g, 13.5 mmol) is obtained as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.61 (bs, 3H), 7.96 (s, 1H), 7.82 (s, 1H), 5.12 (bs, 1H), 4.42 (AB, 2H), 4.00 ( m, 1H), 3.27 (m, 2H), 2.31 (m, 1H), 2.03 (m, 1H).
G. Benzo [b] thiophene-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
4- (3- (S) -Amino-2-oxo-pyrrolidine-1 instead of 3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride Prepare the title compound as described in step E of Example 1 using -ylmethyl) -thiophene-2-carbonitrile hydrochloride. The crude product is triturated from Et ₂ O to afford the product as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.91 (m, 3H), 7.42 (m, 3H), 7.38 (s, 1H), 5.50 (bs, 1H), 4.42 (AB, 2H), 3.89 (m, 1H), 3.27 (m, 2H), 2.66 (m, 1H), 2.13 (m, 1H).
H. 4- [3- (S)-(Benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxamidine tri Fluoroacetate
Use of benzo [b] thiophene-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as starting material To prepare the title compound as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (CMSO-d ₆ , 300 MHz) δ 9.20 (bs, 2H0, 8.80 (bs, 2H), 8.55 (m, 1H), 8.00 (m, 3H), 7.86 (s, 1H), 7.78 (s , 1H), 7.46 (m, 2H), 4.37 (AB, 2H), 4.16 (m, 1H), 3.12 (m, 2H), 2.11 (m, 1H), 1.64 (m, 1H) .FAB MS, [ M + H] ⁺ = 435.
Example 4
4- [3- (S)-[(benzo [b] thiophene-2-sulfonyl] -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxami Dean trifluoroacetate
A. Benzo [b] thiophene-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide
Benzo [b] thiophen-2- instead of benzo [b] thiophen-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide As described in Step A of Example 2 using sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide Prepare the title compound. The crude product is triturated with Et ₂ O to afford the product as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.98 (s, 1H), 7.87 (m, 2H), 7.42 (m, 4H), 7.38 (s, 1H), 4.86 (dd, 1H), 4.38 (AB, 2H), 3.22 (m, 2H), 2.89 (m, 3H), 2.36 (m, 1H), 2.03 (m, 1H).
B. 4- [3- (S)-[(benzo [b] thiophene-2-sulfonyl] -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-ka Voxamidine trifluoroacetate
As starting material benzo [b] thiophene-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide To prepare the title compound as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.30 (bs, 2H), 9.05 (bs, 2H), 8.07 (m, 2H), 8.00 (m, 1H), 7.65 (m, 1H), 7.53 ( m, 5H), 4.93 (m, 1H), 4.42 (AB, 2H), 3.16 (m, 2H), 2.78 (s, 3H), 2.08 (m, 1H), 1.89 (m, 1H). FAB MS, [M + H] ⁺ = 449.
Elemental analysis (containing 1.5 mol of H ₂ O)
Calculated: C 42.78%, H 4.10%, N 9.50%
Found: C 42.83%, H 3.71%, N 9.27%
Example 5
3- [3- (S)-(4-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. 1-Chloro-3- (2,2-dimethoxy-ethyl-sulfanyl) -benzene
Bromoacetaldehyde dimethyl acetal (2.8 g, 16.6 mmol) is added to a solution of 3-chlorothiophenol (2.4 g, 16.6 mmol) in 200 ml of THF at 0 ° C. To the solution is added sodium hydride (60% mineral oil dispersion, 0.70 g, 17.4 mmol). The reaction is stirred for 16 h and quenched by addition of saturated NH ₄ Cl (aq.). Dilute the solution with EtOAc. The organic layer is washed with saturated NaCl (aq). The organic layer is dried over magnesium sulfate, filtered and then concentrated. The crude product is purified by column chromatography, eluting with hexanes. To give the title compound (3.7 g, 15.9 mmol) as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.32 (m, 1H), 7.25 (m, 1H), 7.12 (m, 1H), 4.47 (m, 1H), 3.07 (s, 3H), 3.02 (s, 3H).
B. 4-Chloro-benzo [b] -thiophene and 6-chloro-benzo [b] -thiophene
The solution containing 8 g of polyphosphoric acid and 50 ml of chlorobenzene is heated to reflux. A solution containing 50 ml of 1-chloro-3- (2,2-dimethoxy-ethyl-sulfanyl) -benzene in 5 ml of chlorobenzene was added dropwise to the reflux polyphosphoric acid solution. After 6 hours, the solution is cooled to ambient temperature. The solution is diluted with CH ₂ Cl ₂ and washed with water and saturated NaCl (aq). The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by column chromatography eluting with hexanes to give the title compound (2.4 g, 9.0 mmol) as a 1: 1 isomeric mixture.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.88 (m, 1H), 7.75 (m, 2H), 7.42 (m, 2H).
EIMS, [M] ⁺ = 168, 170, Cl pattern.
C. 4-Chlorobenzo [b] thiophene-2-sulfonyl chloride and 6-chlorobenzo [b] thiophene-2-sulfonyl chloride
The title compound is prepared as described in Step D of Example 1 using 4-chloro-benzo [b] -thiophene and 6-chloro-benzo [b] -thiophene instead of thianaphthalene. The crude product is purified by column chromatography eluting with hexanes to give 4-chlorobenzo [b] thiophene-2-sulfonyl chloride as a white solid as well as the title compound.
4-chlorobenzo [b] thiophene-2-sulfonyl chloride
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.32 (m, 1H), 7.81 (m, 1H), 7.53 (m, 2H).
6-chlorobenzo [b] thiophene-2-sulfonyl chloride
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.11 (s, 1H), 7.88 (m, 2H), 7.50 (m, 1H).
D. 4-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
The title compound is prepared as described in Step E of Example 1 using 4-chlorobenzo [b] thiophene-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride. The crude product is triturated with Et ₂ O to afford the product as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.09 (s, 1H), 7.73 (m, 1H), 7.58 (m, 1H0, 7.46 (m, 5H), 5.76 (bs, 1H), 4.48 (AB, 2H), 3.24 (m, 2H), 2.66 (m, 1H), 2.18 (m, 1H).
E. 3- [3- (S)-(4-Chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
Using 4-chlorobenzo [b] thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as starting material The title compound is prepared as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.28 (bs, 2H), 9.07 (bs, 2H), 8.78 (d, 1H), 8.08 (d, 1H), 8.01 (s, 1H), 7.66 ( m, 1H), 7.54 (m, 5H), 4.41 (AB, 2H), 4.29 (m, 1H), 3.13 (m, 2H), 2.18 (m, 1H), 1.70 (m, 1H). FAB MS, [M + H] ⁺ = 463, 465, Cl pattern.
Elemental analysis (containing 1.5 mol of H ₂ O)
Calculated: C 43.75%, H 3.84%, N 9.28%
Found: C 43.85%, H 3.50%, N 9.03%
Example 6
3- [3- (S)-(6-Chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. 6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
Prepare the title compound as described in Step E of Example 1 using 6-chlorobenzo [b] thiophene-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride. The crude product is triturated with Et ₂ O to afford the product as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.90 (s, 1H), 7.81 (m, 2H), 7.58 (m, 1H), 7.46 (m, 5H), 5.58 (bs, 1H), 4.46 (AB, 2H), 3.93 (m, 1H), 3.22 (m, 1H), 2.64 (m, 1H), 2.12 (m, 1H).
B. 3- [3- (6-Chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
Example 1, using 6-chlorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3-yl] -amide as starting material Prepare the title compound as described in step F. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.28 (bs, 2H), 9.16 (bs, 2H), 8.68 (d, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.98 ( d, 1H), 7.68 (m, 1H), 7.55 (m, 5H), 4.42 (AB, 2H), 4.21 (m, 1H), 3.10 (m, 2H), 2.14 (m, 1H), 1.68 (m , 1H).
FAB MS, [M + H] ⁺ = 463, 465, Cl pattern.
Elemental analysis (containing 1.5 mol of H ₂ O)
Calculated: C 43.75%, H 3.84%, N 9.28%
Found: C 43.85%, H 3.50%, N 9.03%
Example 7
3- [3- (S)-[(4-chlorobenzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Loacetate
A. 4-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3-yl] -methylamide
4-chlorobenzo [b] thiophene instead of benzo [b] thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide Title compound as described in step A of Example 2 using 2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide To prepare. The crude product is triturated with Et ₂ O to afford the product as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.12 (s, 1H), 7.73 (d, 1H), 7.58 (m, 1H), 7.42 (m, 5H), 4.90 (t, 1H), 4.41 (AB, 2H), 3.20 (m, 2H), 2.91 (s, 3H), 2.40 (m, 1H), 2.04 (m, 1H).
B. 3- [3- (S)-[(4-Chlorobenzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate
4-chlorobenzo [b] thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide was used as starting material To prepare the title compound as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.28 (bs, 2H), 9.10 (bs, 2H), 8.10 (d, 1H), 8.03 (s, 1H), 7.58 (m, 1H), 7.52 ( m, 5H), 4.97 (t, 1H), 4.40 (AB, 2H), 3.15 (m, 2H), 2.77 (s, 3H), 2.15 (m, 1H), 1.94 (m, 1H). FAB MS, [M + H] ⁺ = 477, 479, Cl pattern.
Elemental analysis (containing 1.5 mol of H ₂ O)
Calculated: C 44.70%, H 4.08%, N 9.06%
Found: C 44.67%, H 3.66%, N 8.91%
Example 8
3- [3- (S)-[(6-chlorobenzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Loacetate
A. 6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide
6-chlorobenzo [b] thiophen-2- instead of benzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3-yl] -amide Prepare the title compound as described in Step A of Example 2 using sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide do. The crude product is triturated with Et ₂ O to afford the product as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.95 (s, 1H), 7.84 (m, 2H), 7.58 (m, 1H), 7.43 (m, 4H), 4.90 (dd, 1H), 4.41 (AB, 2H), 3.20 (m, 2H), 2.89 (s, 3H), 2.38 (m, 1H), 2.04 (m, 1H).
B. 3- [3- (S)-[(6-Chlorobenzo [b] thiophen-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate
Use of 6-chlorobenzo [b] thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide as starting material To prepare the title compound as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.28 (bs, 2H), 8.98 (bs, 2H), 8.29 (d, 1H), 8.12 (s, 1H), 7.99 (d, 1H), 7.65 ( m, 1H), 7.52 (m, 4H), 4.89 (t, 1H), 4.40 (AB, 2H), 3.13 (m, 2H), 2.74 (s, 3H), 2.08 (m, 1H), 1.90 (m , 1H).
FAB MS [M + H] ⁺ = 477, 479, Cl pattern.
Elemental analysis (contains 2.0 mol of H ₂ O)
Calculated: C 44.05%, H 4.18%, N 8.93%
Found: C 44.13%, H 3.55%, N 8.61%
Example 9
3- [3- (S)-(5-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. 1-Chloro-4- (2,2-dimethoxy-ethyl-sulfanyl) -benzene
The title compound is prepared as described in Step A of Example 5 using 4-chlorothiolphenol instead of 3-chlorothiophenol. The crude product is purified by column chromatography eluting with 4% EtOAc / hexanes to 10% EtOAc / hexanes to afford the title compound as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.28 (m, 2H), 7.20 (m, 2H), 4.50 (t, 1H), 3.06 (s, 3H), 3.03 (s, 3H). EIMS, [M] ⁺ = 232, 234, Cl pattern.
B. 5-chlorobenzo [b] thiophene
Example 1 using 1-chloro-4- (2,2-dimethoxy-ethyl-sulfanyl) -benzene instead of 1-chloro-3- (2,2-dimethoxy-ethyl-sulfanyl) -benzene Prepare the title compound as described in step B. The crude product is purified by column chromatography eluting with hexanes to afford the title compound as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.78 (m, 2H), 7.50 (d, 1H), 7.28 (m, 2H).
EIMS, [M] ⁺ = 168, 170, Cl pattern.
C. 5-chlorobenzo [b] thiophene-2-sulfonyl chloride
Prepare the title compound as described in step D of Example 1 using 5-chlorobenzo [b] thiophene instead of thianaphthalene. The crude product is purified by column chromatography eluting with hexanes to afford the title compound as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.05 (s, 1H), 7.98 (s, 1H), 7.82 (d, 1H), 7.53 (d, 2H).
D. 5-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3-yl] -amide
The title compound is prepared as described in Step E of Example 1 using 5-chlorobenzo [b] thiophene-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc / CH ₂ Cl ₂₀ to 20% EtOAc / CH ₂ Cl ₂ to afford the product as a white solid.
¹ H NMR (DMSO, 300 MHz) δ 8.70 (d, 1H), 8.08 (m, 2H), 7.98 (s, 1H), 7.70 (m, 1H), 7.60 (m, 5H), 7.51 (m, 5H ), 4.36 (AB, 2H), 4.24 (m, 1H), 3.08 (m, 2H), 2.12 (m, 1H), 1.61 (m, 1H). FAB MS, [M + H] ⁺ = 446, 448, Cl pattern.
E. 3- [3- (S)-(5-Chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] benzamidine trifluoroacetate
5-chlorobenzo [b] thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide was used as starting material To prepare the title compound as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.28 (bs, 2H), 8.98 (bs, 2H), 8.69 (d, 1H), 8.10 (m, 2H), 7.99 (s, 1H), 7.68 ( m, 1H), 7.48 (m, 4H), 4.40 (AB, 2H), 4.21 (m, 1H), 3.10 (m, 2H), 2.13 (m, 1H), 1.68 (m, 1H). FAB MS, [M + H] ⁺ = 463, 465, Cl pattern.
Elemental analysis (contains 2.0 mol of H ₂ O)
Calculated: C 43.10%, H 3.95%, N 9.14%
Found: C 43.33%, H 3.45%, N 8.90%
Example 10
3- [3- (S)-[(5-chlorobenzo [b] thiophene-2-sulfonyl) -methyl-amino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetate
A. 5-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide
5-chlorobenzo [b] thio instead of benzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide As described in step A of Example 2 using offen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide Prepare the title compound. The crude product is triturated with Et ₂ O to afford the product as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.12 (s, 1H), 8.04 (m, 1H), 7.72 (m, 1H), 7.64 (s, 1H), 7.50 (m, 4H), 4.91 ( m, 1H), 4.37 (AB, 2H), 3.14 (m, 2H), 2.76 (s, 3H), 2.06 (m, 1H), 1.88 (m, H). FAB MS, [M + H] ⁺ = 460, 462, Cl pattern.
B. 3- [3- (S)-[(5-Chlorobenzo [b] thiophene-2-sulfonyl) -methyl-amino] -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dean trifluoroacetate
5-chlorobenzo [b] thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide was used as starting material To prepare the title compound as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.26 (bs, 2H), 8.95 (bs, 2H), 8.05 (m, 3H), 7.62 (m, 1H), 7.48 (m, 4H), 4.90 ( t, 1H), 4.39 (AB, 2H), 3.14 (m, 2H), 2.77 (s, 3H), 2.08 (m, 1H), 1.89 (m, 1H). FAB MS, [M + H] ⁺ = 477, 479, Cl pattern.
Elemental analysis (containing 1.25 mol of H ₂ O)
Calculated: C 45.10%, H 4.03%, N 9.15%
Found: C 44.97%, H 3.94%, N 8.91%
Example 11
3- [3- (S)-(4-Methylbenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. 3-Methyl-1- (2,2-dimethoxy-ethyl-sulfanyl) -benzene
Prepare the title compound as described in step A of Example 5 using 3-methylthiolphenol instead of 3-chlorothiophenol. The crude product is purified by column chromatography, eluting with a gradient of hexanes to 10% Et ₂ O / hexanes to afford the title compound as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.20 (m, 3H), 7.02 (m, 1H), 4.50 (m, 1H), 3.07 (s, 3H), 3.02 (s, 3H), 2.32 (s, 3H). EI MS, [M] ⁺ = 212.
B. 4-Methylbenzo [b] thiophene and 6-methylbenzo [b] thiophene
Example 5 was substituted with 3-methyl-1- (2,2-dimethoxy-ethyl-sulfanyl) -benzene instead of 1-chloro-3- (2,2-dimethoxy-ethyl-sulfanyl) -benzene Prepare the title compound as described in step B. The crude product is purified by column chromatography eluting with hexanes to afford the title compound as an inseparable (2: 1) mixture of oil.
EI MS, [M] ⁺ = 148.
C. 4-Methylbenzo [b] thiophene-2-sulfonyl chloride and 6-methylbenzo [b] thiophene-2-sulfonyl chloride
The title compound is prepared as described in Step D of Example 1 using 4-methylbenzo [b] thiophene and 6-methylbenzo [b] thiophene instead of thianaphthalene. The crude product was purified by column chromatography, eluting with hexanes to give 6-methylbenzo [b] thiophene-2-sulfonyl chloride as well as 4-methylbenzo [b] thiophene-2-sulfonyl chloride as a white solid. To obtain.
4-methylbenzo [b] thiophene-2-sulfonyl chloride
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.22 (s, 1H), 7.78 (d, 1H), 7.49 (t, 2H), 7.32 (d, 1H), 2.65 (s, 3H).
6-methylbenzo [b] thiophene-2-sulfonyl chloride
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.09 (s, 1H), 7.83 (d, 2H), 7.70 (s, 1H), 7.35 (d, 1H), 2.50 (s, 3H).
D. 4-Methylbenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
The title compound is prepared as described in Step E of Example 1 using 4-methylbenzo [b] thiophene-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride. The crude product is triturated with Et ₂ O to afford the product as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.02 (s, 1H), 7.68 (d, 1H), 7.57 (m, 1H), 7.42 (m, 4H), 7.23 (m, 1H), 5.49 (bs, 1H), 4.46 (AB, 2H), 3.90 (m, 1H), 3.23 (m, 2H), 2.68 (m, 1H), 2.62 (s, 3H), 2.16 (m, 1H).
E. 3- [3- (S)-(4-Methylbenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] benzamidine trifluoroacetate
Using 4-methylbenzo [b] thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as starting material The title compound is prepared as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.26 (bs, 2H), 9.00 (bs, 2H), 8.58 (m, 1H), 7.97 (m, 2H), 7.79 (s, 1H), 7.60 ( m, 1H), 7.49 (m, 3H), 7.31 (m, 1H), 4.40 (AB, 2H), 4.22 (m, 1H), 3.12 (m, 2H), 2.40 (s, 3H), 2.10 (m , 1H), 1.66 (m, 1H).
FAB MS, [M + H] ⁺ = 443.
Elemental analysis (contains 2.0 mol of H ₂ O)
Calculated: C 46.61%, H 4.59%, N 9.45%
Found: C 46.75%, H 4.14%, N 9.38%
Example 12
3- [3- (S)-(6-Methylbenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. 6-Methylbenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
Step E of Example 1 using 6-methylbenzo [b] thiophene-2-sulfonyl chloride prepared as described in Step C of Example 11 instead of benzo [b] thiophene-2-sulfonyl chloride. Prepare the title compound as described. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc / CH ₂ Cl ₂ to 15% EtOAc / CH ₂ Cl ₂ to afford the title compound as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.89 (s, 1H), 7.79 (d, 1H), 7.67 (s, 1H), 7.58 (m, 1H), 7.43 (m, 3H), 7.30 (m, 1H), 5.50 (bs, 1H), 4.2 (AB, 2H), 3.88 (m, 1H), 3.21 (m, 2H), 2.64 (m, 1H), 2.49 (s, 3H), 2.12 (m, 1H ).
B. 3- [3- (S)-(6-Methylbenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
Using 5-methylbenzo [b] thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as starting material The title compound is prepared as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.23 (bs, 2H), 9.00 (bs, 2H), 8.56 (d, 1H), 7.96 (s, 1H), 7.84 (m, 2H), 7.67 ( m, 1H), 7.53 (m, 3H), 7.28 (d, 1H), 4.42 (AB, 2H), 4.19 (m, 1H), 3.12 (m, 2H), 2.40 (s, 3H), 2.12 (m , 1H), 1.64 (m, 1H).
FAB MS [M + H] ⁺ = 443.
Elemental analysis (containing 0.50 mol of H ₂ O)
Calculated: C 48.84%, H 4.28%, N 9.91%
Found: C 48.89%, H 4.05%, N 9.73%
Example 13
3- [3- (S)-(5-methylbenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. 4-Methyl-1- (2,2-dimethoxy-ethyl-sulfanyl) -benzene
The title compound is prepared as described in Step A of Example 5 using 4-methylthiolphenol instead of 3-chlorothiophenol. The crude product is purified by column chromatography eluting with hexanes to afford the title compound as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.28 (m, 2H), 7.10 (m, 2H), 4.49 (t, 1H), 3.06 (s, 3H), 3.03 (s, 3H), 2.28 (s, 3H).
B. 5-Methylbenzo [b] thiophene
Example 4-5 using 4-methyl-1- (2,2-dimethoxy-ethyl-sulfanyl) -benzene instead of 1-chloro-3- (2,2-dimethoxy-ethyl-sulfanyl) -benzene Prepare the title compound as described in step B. The crude product is purified by column chromatography eluting with hexanes to afford the title compound as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.78 (d, 1H), 7.62 (s, 1H), 7.39 (d, 1H), 7.23 (d, 1H), 7.17 (d, 1H), 2.50 (s, 3H).
C. 5-Methylbenzo [b] thiophene-2-sulfonyl chloride
Prepare the title compound as described in step D of Example 1 using 5-chlorobenzo [b] thiophene instead of thianaphthalene. The crude product is purified by column chromatography eluting with hexanes to afford the title compound as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.08 (s, 1H), 7.78 (m, 2H), 7.39 (d, 1H), 2.51 (s, 3H).
D. 5-Methylbenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
The title compound is prepared as described in Step E of Example 1 using 5-methylbenzo [b] thiophene-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride. The crude product is triturated with Et ₂ O to afford the product as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.86 (s, 1H), 7.73 (m, 2H), 7.69 (s, 1H), 7.60 (m, 1H), 7.42 (m, 2H), 7.30 (s, 1H), 5.52 (bs, 1H), 4.43 (AB, 2H), 3.91 (m, 1H), 3.20 (m, 2H), 2.64 (m, 1H), 2.48 (s, 3H), 1.61 (m, 1H ).
E. 3- [3- (S)-(5-Methylbenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] benzamidine trifluoroacetate
Using 5-methylbenzo [b] thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as starting material The title compound is prepared as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.26 (bs, 2H), 9.00 (bs, 2H), 8.58 (m, 1H), 7.97 (m, 2H), 7.79 (s, 1H), 7.60 ( m, 1H), 7.49 (m, 3H), 7.31 (m, 1H), 4.40 (AB, 2H), 4.22 (m, 1H), 3.12 (m, 2H), 2.40 (s, 3H), 2.10 (m , 1H), 1.66 (m, 1H).
FAB MS, [M + H] ⁺ = 443.
Elemental analysis (contains 0.75 mol of H ₂ O)
Calculated: C 48.46%, H 4.33%, N 9.83%
Found: C 48.41%, H 3.98%, N 9.43%
Example 14
3- [3- (4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. 1,3-Dichloro-5- (2,2-dimethoxy-ethyl-sulfanyl) -benzene
Prepare the title compound as described in step A of Example 5 using 3,5-dichlorothiolphenol instead of 3-chlorothiophenol. The crude product is purified by column chromatography eluting with hexanes to afford the title compound as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.19 (s, 2H), 7.12 (s, 1H), 4.51 (m, 1H), 3.13 (s, 3H), 3.09 (s, 3H).
B. 4,6-dichlorobenzo [b] thiophene
Example using 1,3-dichloro-5- (2,2-dimethoxy-ethyl-sulfanyl) -benzene instead of 1-chloro-3- (2,2-dimethoxy-ethyl-sulfanyl) -benzene Prepare the title compound as described in step B of 5. The crude product is purified by column chromatography eluting with hexanes to afford the title compound as a white solid.
EI MS, [M] ⁺ = 202.
C. 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride
Prepare the title compound as described in step D of Example 1 using 4,6-dichlorobenzo [b] thiophene instead of thianaphthalene. The crude product is purified by column chromatography eluting with hexanes to afford the title compound as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.27 (s, 1H), 7.79 (s, 1H), 7.24 (s, 1H).
D. 4,6-Dichlorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
The title compound is prepared as described in Step E of Example 1 using 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride. The crude product is triturated with Et ₂ O to afford the product as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.01 (s, 1H), 7.70 (s, 1H), 7.58 (m, 1H), 7.42 (m, 4H), 5.66 (bs, 1H), 4.41 (AB, 2H), 3.95 (m, 1H), 3.22 (m, 2H), 2.62 (m, 1H), 2.12 (m, 1H).
E. 3- [3- (S)-(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] benzamidine trifluoro acetate
4,6-dichlorobenzo [b] thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as starting material To prepare the title compound as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.27 (bs, 2H), 9.18 (bs, 2H), 8.82 (m, 1H), 8.24 (d, 1H), 7.98 (d, 1H), 7.72 ( m, 1H), 7.63 (m, 1H), 7.52 (m, 3H), 4.39 (AB, 2H), 4.28 (m, 1H), 3.12 (m, 2H), 2.13 (m, 1H), 1.68 (m , 1H).
FAB MS, [M + H] ⁺ = 497, 499, Cl pattern.
Elemental analysis (containing 1.33 mol of H ₂ O)
Calculated: C 43.22%, H 3.44%, N 8.82%
Found: C 43.10%, H 3.18%, N 8.47%
Example 15
([3- [3- (S)-(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] phenyl] -iminomethyl ) -Carbamic acid 2,2,2-trichloroethyl ester
A. ([3- [3- (S)-(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] phenyl] -already Nomethyl) -carbamic acid 2,2,2-trichloroethyl ester
3- [3- (S)-(4,6-dichlorobenzo [b] thiophene-2-sulfonyl, prepared as in Step E of Example 14 in 4 ml of CH ₂ Cl ₂ : DMF (10: 1) Amino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate (0.25 g, 0.40 mmol) in a solution of N-methyl piperidine (0.12 g, 1.2 mmol) followed by triclo Low ethyl chloroformate (0.93 g, 0.44 mmol) is added. The solution is stirred for 16 hours. The solution is then diluted with EtOAc. The organic layer is washed with 1N HCl, H ₂ O, saturated NaCl. The organic layer is dried over magnesium sulfate, filtered and concentrated. The residue is purified by column chromatography eluting with a gradient of 1% MeOH / CH ₂ Cl ₂ to 3% MeOH / CH ₂ Cl ₂ to afford the title compound (0.20 g, 0.30 mmol) as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.23 (bs, 2H), 8.82 (d, 1H), 8.28 (s, 1H), 8.00 (s, 1H), 7.84 (d, 1H), 7.76 ( s, 1H), 7.72 (s, 1H), 7.40 (m, 2H), 4.83 (s, 2H), 4.38 (AB, 2H), 4.27 (m, 1H), 3.09 (m, 2H), 2.13 (m , 1H), 1.65 (m, 1H).
FAB MS, [M + H] ⁺ = 671, 673, 675, 5-Cl pattern.
Example 16
4-amino-3- [3- (S)-(4,6-dichlorobenzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate
A. 4-amino-3-methyl benzonitrile
To a solution of 3-methyl-4-nitrobenzonitrile (2.0 g, 12.3 mmol) in 100 ml EtOH is added SnCl ₂ (13.9 g, 61.7 mmol). The resulting solution is heated to reflux. After 2 hours, the solution is cooled to ambient temperature. Pour the solution into 150 ml of ice water. The pH of the solution is adjusted to> 7 with a solution of saturated NaHCO ₃ . The solution is diluted with EtOAc and the resulting mixture is filtered through celite. Separate the filtered solution. The organic layer is dried over magnesium sulfate, filtered and concentrated to give the title compound (1.57 g, 8.7 mmol) as an off-white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.30 (m, 2H), 6.63 (d, 1H), 4.10 (bs, 2H), 2.15 (m, 2H). EI MS, [M] ⁺ = 132.
B. 4- (Benzhydrylidene-amino) -3-benzonitrile
To a solution of 4-amino-3-methyl benzonitrile (1.20 g, 9.08 mmol) in 75 ml of toluene is added benzophenone (1.74 g, 9.53 mmol) and p-toluenesulfonic acid (0.43 g, 2.1 mmol). The reaction vessel is mounted in a Dean-Stark trap and the solution is heated to reflux. After 24 hours the solution is cooled to ambient temperature. The solution is concentrated. Crude material is purified by column chromatography, eluting with a gradient of 3% EtOAc / hexanes to 10% EtOAc / hexanes. To give the title compound (2.43 g, 8.2 mmol) as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.80 (m, 2H), 7.40 (m, 6H), 7.30 (s, 1H), 7.15 (d, 1H), 7.05 (bs, 2H), 6.50 (d, 1H), 2.20 (s, 3H). EI MS, [M] ⁺ = 296.
C. 4- (Benzhydrylidene-amino) -3-bromomethyl-benzonitrile
To a solution of 4- (benzhydrylidene-amino) -3-methyl-benzonitrile (1.36 g, 4.27 mmol) in 40 ml CCl ₄ , N-bromosuccinimide (0.84 g, 4.7 mmol) and benzoyl peroxide ( 0.22 g, 0.64 mmol) is added. The solution is heated to reflux for 16 hours. Cool the solution to ambient temperature. Dilute the solution with CH ₂ Cl ₂ . The solution is washed with 1N NaOH and saturated NaCl. The organic layer is dried over magnesium sulfate, filtered and concentrated. Crude material is purified by column chromatography, eluting with a gradient of 5% EtOAc / hexanes to 10% EtOAc / hexanes. To give the title compound (0.91 g, 2.43 mmol) as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.80 (m, 2H), 7.60 (d, 1H), 7.35 (m, 8H), 7.15 (dd, 1H), 6.35 (d, 1H), 4.55 (s, 2H). EI MS, [M] ⁺ = 374.
D. {1- [2- (Benzhydrylidene-amino) -5-cyano-benzyl] -2-oxo-pyrrolidin-3- (S) -yl} -carbamic acid tert-butyl ester
The title compound is prepared as described in Step B of Example 1 using 4- (benzhydrylidene-amino) -3-bromomethyl-benzonitrile instead of α-bromo-m-toluyl nitrile. Crude material is purified by column chromatography, eluting with a gradient of 30% EtOAc / hexanes to 40% EtOAc / hexanes. The title compound is obtained as a yellow solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.70 (bs, 2H), 7.40 (s, 1H), 7.38 (bs, 6H), 7.30 (d, 1H), 7.15 (bs, 2H), 6.48 (d, 1H), 5.00 (d, 1H), 4.45 (AB, 2H), 4.15 (m, 1H), 3.30 (m, 2H), 2.61 (m, 1H), 1.90 (m, 1H), 1.45 (s, 9H ).
E. 4-Amino [3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl)] -benzonitrile dihydrochloride
The title compound is prepared as described in Step C of Example 1. The title compound is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.68 (bs, 3H), 7.38 (s, 1H), 6.76 (d, 1H), 5.68 (bs, 3H), 4.25 (AB, 2H), 4.07 (m, 1H), 3.29 (m, 2H), 2.38 (m, 1H), 1.98 (m, 1H).
F. 4,6-Dichlorobenzo [b] thiophene-2-sulfonic acid [1- (2-amino-5-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amides
4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride and 3- (3- (S) -amino-2-oxo-pyrroli 4-amino- [3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl)]-benzonitrile dihydrochloride instead of din-1-ylmethyl) -benzonitrile hydrochloride To prepare the title compound as described in Step E of Example 1. The crude product is triturated with Et ₂ O to afford the product as a white solid.
¹ H NMR (CDCl ₃ + CD ₃ OD, 300 MHz) δ 7.97 (s, 1H), 7.68 (s, 1H), 7.40 (s, 1H), 7.27 (d, 1H), 7.21 (d, 1H), 6.55 (bs, 1H), 4.20 (AB, 2H), 4.00 (t, 1H), 3.14 (m, 2H), 2.45 (m, 1H), 1.90 (m, 1H).
G 4-Amino-3- [3- (S)-(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dean trifluoroacetate
Example using 4,6-dichlorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3-yl] -amide as starting material Prepare the title compound as described in step F of 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.27 (bs, 2H), 9.18 (bs, 2H), 8.82 (m, 1H), 8.24 (d, 1H), 7.98 (d, 1H), 7.72 ( m, 1H), 7.63 (m, 1H), 7.52 (m, 3H), 4.39 (AB, 2H), 4.28 (m, 1H), 3.12 (m, 2H), 2.13 (m, 1H), 1.68 (m , 1H).
FAB MS, [M + H] ⁺ = 497, 499, Cl pattern.
Elemental analysis (containing 1.33 mol of H ₂ O)
Calculated: C 43.22%, H 3.44%, N 8.82%
Found: C 43.10%, H 3.18%, N 8.47%
Example 17
4-hydroxy-3- [3- (S)-(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dean trifluoroacetate
A. 2-hydroxy-5-iodo-benzaldehyde
CH ₂ Cl ₂ 50ml and that the salicylic aldehyde (10g, 82mmol) 1M ICl solution in 22ml CH ₂ Cl ₂ to a solution of. The solution is stirred for 14 hours. Then, a saturated solution of sodium sulfite is added until decolorized. Dilute the solution with CH ₂ Cl ₂ . Separate the layers. The organic layer is washed with water. The organic layer is dried over magnesium sulfate, filtered and then concentrated. The resulting crude product is recrystallized from cyclohexane to give the title compound (7.2 g, 32 mmol) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 10.91 (s, 1H), 9.82 (s, 1H), 7.84 (d, 1H), 7.75 (dd, 1H), 6.75 (d, 1H). EI MS, [M] ⁺ = 248.
B. 5-iodo-2- (2-methoxy-ethoxymethoxy) -benzyl alcohol
To a solution of sodium hydride (1.2 g of 60% mineral oil dispersion, 52 mmol) in 25 ml of THF at 0 ° C., 2-hydroxy-5-iodo-benzaldehyde (7.0 g, 28 mmol) is added. To the resulting solution is added 2-methoxy-ethoxymethoxy chloride (3.4 ml, 30 mmol) and 4 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone. . Warm the solution to ambient temperature. After 45 minutes, the solution is cooled to -15 ° C and 6 ml of a 2M solution of sodium borohydride in THF is added. The solution is stirred for 10 minutes. Then 24 ml of a 2M HCl solution in water are added. The resulting solution is diluted with ether and washed with H ₂ O and saturated NaCl. The organic layer is dried over magnesium sulfate, filtered and concentrated. The resulting crude material is purified by column chromatography eluting with 40% EtOAc / hexanes to give the title compound (7.6 g, 22.5 mmol) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.64 (d, 1H), 7.52 (dd, 1H), 6.90 (d, 1H), 5.30 (s, 2H), 4.62 (d, 2H), 3.82 (m, 2H), 3.54 (m, 2H), 3.35 (s, 3H), 2.53 (t, 1H).
EI MS, [M] ⁺ = 338.
C. 5-iodo-2- (2-methoxy-ethoxymethoxy) -benzyl bromide
To a solution of 5-2- (2-methoxy-ethoxymethoxy) -benzyl alcohol (6.35 g, 24 mmol) in 60 ml THF at 15 ° C., triphenylphosphine (6.35 g, 24 mmol) followed by N-bromosuccine Amide (4.3 g, 24 mmol) is added. The solution is stirred for 5 minutes. Warm the solution to ambient temperature. After 20 minutes, the solution is concentrated. The crude product is purified by column chromatography, eluting with EtOAc: CH ₂ Cl ₂ : hexane (3: 1: 6).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.60 (d, 1H), 7.50 (dd, 1H), 6.91 (s, 1H), 5.30 (s, 2H), 4.43 (dd, 1H), 3.84 (m, 2H), 3.53 (m, 2H), 3.35 (s, 3H).
EI MS, [M] ⁺ = 400.
D. 3- (S)-(tert-butoxy-carbonyl-amino) -1- (5-iodo-2- (2-methoxy-ethoxymethoxy) -benzyl) -pyrrolidine- 2-on
Prepare the title compound as described in Step B of Example 1 using 5-iodo-2- (2-methoxy-ethoxymethoxy) -benzyl bromide instead of α-bromo-m-toluyl nitrile do. The crude product is purified by column chromatography, eluting with EtOAc: CH ₂ Cl ₂ : hexanes (3: 1: 1).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.53 (dd, 1H), 7.45 (d, 1H), 6.93 (d, 1H), 5.26 (s, 2H), 5.20 (bs, 1H), 4.50 (d, 1H), 4.45 (d, 1H), 4.19 (m, 1H), 3.80 (m, 2H), 3.53 (m, 2H), 3.37 (s, 3H), 3.22 (m, 2H), 2.62 (m, 1H ), 1.84 (m, 1 H), 1.45 (s, 9 H). Ion spray MS, [M + H] ⁺ = 521.
E. 3- (S)-(tert-butyl-carbonyl-amino) -1- (5-cyano-2- (2-methoxy-ethoxymethoxy) -benzyl-pyrrolidine-2- On
3- (S)-(tert-butoxy-carbonyl-amino) -1- (5-iodo-2- (2-methoxy-) instead of (5-iodo-thiophen-3-yl) methanol The title compound is prepared as described in Step C of Example 3 using ethoxymethoxy) -benzyl) -pyrrolidin-2-one. Crude material is purified by column chromatography, eluting with EtOAc: CH ₂ Cl ₂ : hexane (3: 1: 1).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.54 (dd, 1H), 7.45 (d, 1H), 7.20 (d, 1H), 5.35 (s, 2H), 5.20 (bs, 1H), 4.50 (d, 1H), 1.45 (s, 9H), 4.45 (d, 1H), 4.15 (m, 1H), 3.77 (m, 2H), 3.51 (m, 2H), 3.35 (s, 3H), 3.24 (m, 2H ), 2.60 (m, 1 H), 1.90 (m, 1 H). EI MS, [M] ⁺ = 420.
F. 3- (S)-[(3-amino-2-oxo-pyrrolidin-1-yl) -methyl] -4-hydroxy-benzonitrile hydrochloride
3- (S)-(tert-butyl-carbonyl instead of [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester -Amino) -1- (5-cyano-2- (2-methoxy-ethoxymethoxy) -benzyl-pyrrolidin-2-one as described in Step C of Example 1 Compound is prepared The title compound is obtained as a white solid.
_{^{1 H NMR (DMSO-d 6}} . 300 MHz) δ 8.50 (bs, 3H), 7.50 (dd, 1H), 7.40 (d, 1H), 7.00 (d, 1H), 4.26 (d, 2H), 4.00 ( m, 1H), 3.25 (m, 2H), 2.30 (m, 1H), 1.90 (m, 1H). EI MS, [M] ⁺ = 231.
G. 4,6-Dichlorobenzo [b] thiophene-2-sulfonic acid [1- (2-hydroxy-5-cyano-benzyl) -2-oxo-pyrrolidin-3-yl] -amide
To a solution of 3-[(3-amino-2-oxo-pyrrolidin-1-yl) -methyl] -4-hydroxy-benzonitrile hydrochloride (0.20 g, 0.75 mmol) in 3 ml pyridine at 0 ° C. , 6-dichlorobenzo [b] thiophene-2-sulfonyl chloride is added. The solution is warmed to ambient temperature and stirred for 6 hours. The solution is then concentrated. The residue is dissolved in CH ₂ Cl ₂ . The organic solution is washed with 1N HCl and saturated NaCl. The crude product is triturated with Et ₂ O to afford the title compound (0.22 g, 0.44 mmol) as a white solid.
¹ H NMR (CDCl ₃ + DMSO-d ₆ , 300 MHz) δ 7.97 (s, 1H), 7.73 (m, 1H), 7.67 (s, 1H), 7.57 (s, 1H), 7.45 (m, 2H) , 6.86 (bs, 1H), 4.31 (AB, 2H), 4.04 (m, 1H), 3.24 (m, 2H), 2.40 (m, 1H), 1.94 (m, 1H).
H. 4-hydroxy-3- [3- (S)-(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl]- Benzamidine trifluoroacetate
4,6-dichlorobenzo [b] thiophene-2-sulfonic acid [1- (2-hydroxy-5-cyano-benzyl) -2-oxo-pyrrolidine-3- (S)-as starting material Il] -amide is used to prepare the title compound as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 10.80 (bs, 1H), 9.00 (bs, 2H), 8.82 (d, 1H), 8.62 (bs, 2H), 8.29 (s, 1H), 7.57 ( m, 2H), 7.48 (m, 2H), 6.97 (d, 1H), 4.30 (AB, 2H), 4.26 (m, 1H), 3.22 (m, 2H), 2.23 (m, 1H), 1.74 (m , 1H).
FAB MS, [M + H] ⁺ = 513, 151, Cl ₂ pattern.
Example 18
3- [3- (S)-(6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. 1-Fluoro-3- (2,2-dimethoxy-ethyl-sulfanyl) -benzene
Prepare the title compound as described in step A of Example 5 using 3-fluorothiophenol instead of 3-chlorothiophenol. The crude product is purified by column chromatography, eluting with a gradient of hexanes to 10% EtOAc / hexanes to afford the title compound as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.21 (m, 1H), 7.09 (m, 2H), 6.82 (m, 2H), 4.51 (m, 1H), 3.09 (s, 31H), 3.07 (s, 3H).
B. 6-fluorobenzo [b] -thiophene
Example 5 using 1-fluoro-3- (2,2-dimethoxy-ethyl-sulfanyl) -benzene instead of 1-chloro-3- (2,2-dimethoxy-ethyl-sulfanyl) -benzene Prepare the title compound as described in step B of. The crude product is purified by column chromatography eluting with hexanes to afford the title compound as a white solid.
EI MS, [M] ⁺ = 152.
C. 6-fluorobenzo [b] thiophene-2-sulfonyl chloride
Prepare the title compound as described in step D of Example 1 using 6-fluorobenzo [b] -thiophene instead of thianaphthalene. The crude product is purified by column chromatography eluting with hexanes to afford the title compound as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.08 (s, 1H), 7.94 (dd, 1H), 7.58 (dd, 1H), 7.23 (dt, 1H).
D. 6-Fluorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
3-[(3- (S) -amino-2-oxo-pyrrolidin-1-yl) -methyl] -4-hydroxy-benzonitrile instead of 3-[(3- (S) -amino-2- 6-fluorobenzo [b] thiophene-2 instead of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride using oxo-pyrrolidin-1-yl) -methyl] -benzonitrile Prepare the title compound as described in step G of Example 17 using sulfonyl chloride. The crude product is triturated with Et ₂ O to afford the product as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.85 (s, 1H), 7.78 (m, 1H), 7.64 (m, 2H), 7.49 (m, 1H), 7.42 (m, 3H), 7.14 (dt, 1H), 4.42 (AB, 2H), 4.02 (t, 1H), 3.18 (m, 2H), 2.60 (m, 1H), 2.12 (m, 1H).
E. 3- [3- (S)-(6-Fluorobenzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoro acetate
Use of 6-fluorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as starting material To prepare the title compound as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.25 (bs, 4H), 8.63 (d, 1H), 8.03 (s, 1H), 8.00 (m, 2H), 7.63 (m, 1H), 7.51 ( m, 3H), 7.31 (dt, 1H), 4.38 (AB, 2H), 4.28 (m, 1H), 3.11 (m, 2H), 2.13 (m, 1H), 1.68 (m, 1H). FAB MS, [M + H] ⁺ = 447.
Elemental analysis (containing 1.0 mol of H ₂ O)
Calculated: C 45.67%, H 3.71%, N 9.68%
Found: C 45.52%, H 3.95%, N 9.31%
Example 19
4-amino-3- [3- (S)-(6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetate
A. 6-Fluorobenzo [b] thiophene-2-sulfonic acid [1- (2-amino-5-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl]- amides
3-[(3- (S) -amino-2-oxo-pyrrolidin-1-yl) -methyl] -4-hydroxy-benzonitrile instead of 3-[(3- (S) -amino-2- 6-fluorobenzo [b] thione using oxo-pyrrolidin-1-yl) -methyl] -4-amino-benzonitrile and instead of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride Offen-2-sulfonyl chloride is used to prepare the title compound as described in Step G of Example 17. The crude product is triturated with Et ₂ O to afford the product as a white solid.
FAB MS, [M + H] ⁺ = 445.
B. 4-Amino-3- [3- (S)-(6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dean trifluoroacetate
6-fluorobenzo [b] thiophene-2-sulfonic acid [1- (2-amino-5-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] as starting material Prepare the title compound as described in step F of Example 1 using -amide. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.74 (bs, 2H), 8.68 (d, 1H), 8.40 (bs, 2H), 8.01 (m, 3H), 7.53 (d, 1H), 7.36 ( m, 2H), 6.72 (d, 1H), 6.20 (bs, 2H), 4.28 (m, 1H), 4.26 (AB, 2H), 3.12 (m, 2H), 2.09 (m, 1H), 1.60 (m , 1H).
FAB MS, [M + H] ⁺ = 462.
Example 20
4-hydroxy-3- [3- (S)-(6-fluorobenzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate
A. 6-fluorobenzo [b] thiophene-2-sulfonic acid [1- (2-hydroxy-5-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amides
Title compound as described in Step G of Example 17 using 6-fluorobenzo [b] thiophene-2-sulfonyl chloride instead of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride To prepare. The crude product is triturated with Et ₂ O to afford the product as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.85 (s, 1H), 7.82 (m, 1H), 7.63 (m, 2H), 7.47 (m, 2H), 7.22 (dt, 1H), 6.93 (d, 1H), 4.32 (AB, 2H), 4.20 (t, 1H), 3.32 (m, 2H), 2.60 (m, 1H), 2.09 (m, 1H).
B. 4-hydroxy-3- [3- (S)-(6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benz Amidine trifluoroacetate
Use of 6-fluorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as starting material To prepare the title compound as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 10.87 (bs, 1H), 9.00 (bs, 2H), 8.68 (bs, 2H), 8.60 (d, 1H), 8.01 (s, 1H), 8.00 ( m, 2H), 7.54 (d, 1H), 7.38 (m, 2H), 6.92 (m, 1H), 4.30 (AB, 2H), 4.21 (m, 1H), 3.15 (m, 2H), 2.18 (m , 1H), 1.67 (m, 1H). FAB MS, [M + H] ⁺ = 463.
Example 21
4-amino-3- [3- (S)-(4-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Loacetate
A. 4-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (2-amino-5-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
3-[(3- (S) -amino-2-oxo-pyrrolidin-1-yl) -methyl] -4-hydroxy-benzonitrile instead of 3-[(3- (S) -amino-2- 4-chlorobenzo [b] thiophene instead of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride using oxo-pyrrolidin-1-yl) -methyl] -4-amino-benzonitrile Prepare the title compound as described in step G of Example 17 using 2-sulfonyl chloride. The crude product is triturated with Et ₂ O to afford the product as a white solid.
FAB MS, [M + H] ⁺ = 461, 463, Cl pattern.
B. 4-Amino-3- [3- (S)-(4-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate
4-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (2-amino-5-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl]-as starting material The amide is used to prepare the title compound as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.79 (d, 1H), 8.75 (bs, 2H), 8.36 (bs, 2H), 8.36 (bs, 2H), 8.07 (d, 1H), 8.03 ( s, 1H), 7.52 (d, 1H), 7.50 (m, 2H), 7.37 (m, 2H), 6.70 (d, 1H), 6.15 (bs, 2H), 4.27 (m, 1H), 4.13 (AB , 1H), 3.14 (m, 2H), 2.13 (m, 1H), 1.60 (m, 1H). FAB MS, [M + H] ⁺ = 478, 480, Cl pattern.
Example 22
4-hydroxy-3- [3- (S)-(4-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetate
A. 4-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (2-hydroxy-5-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl]- amides
The title compound was prepared as described in Step G of Example 17 using 4-chlorobenzo [b] thiophen-2-sulfonyl chloride instead of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride. Manufacture. The crude product is triturated with Et ₂ O to afford the product as a white solid.
FAB MS, [M + H] ⁺ = 461, 463, Cl pattern.
B. 4-hydroxy-3- [3- (S)-(4-chlorobenzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dean trifluoroacetate
Using 4-chlorobenzo [b] thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as starting material The title compound is prepared as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 10.87 (bs, 1H), 9.01 (bs, 2H), 8.74 (d, 2H), 8.60 (bs, 1H), 8.08 (d, 1H), 8.02 ( s, 1H), 7.53 (m, 3H), 7.38 (m, 2H), 6.92 (d, 1H), 4.30 (AB, 2H), 4.27 (m, 1H), 3.21 (m, 2H), 2.20 (m , 1H), 1.72 (m, 1H).
FAB MS, [M + H] ⁺ = 479, 481, Cl pattern.
Example 23
3- [3- (S)-(4-Chloro-thieno [3,2-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetate
A. 3-thiophen-2-yl-acrylic acid
To a solution of 2-thiophene carboxaldehyde (10 g, 89 mmol) in 300 ml of CH ₂ Cl ₂ is added methyl (triphenylphosphorylidene) acetate. The solution is stirred for 48 hours. The solution is then concentrated. The residue is dissolved in 1000 ml of H ₂ O: MeOH: THF (1: 1: 1). Lithium hydroxide (22.9 g, 547 mmol) was added to the resulting solution. The solution is stirred for 3 hours. The solution is then concentrated to one third of its volume. The remaining solution is washed with EtOAc. The aqueous solution is acidified to pH 5 with 1N HCl. White precipitate is formed. The solid is collected by filtration and dried over P ₂ O ₅ under vacuum.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.90 (d, 1H), 7.27 (d, 1H), 7.08 (d, 1H), 6.22 (d, 1H).
B. 5H-thieno [3,2-c] pyridin-4-one
Triethylamine (4.9 g, 47.9 mmol) is added to a solution of 3-thiophen-2-yl-acrylic acid (7.39 g, 47.9 mmol) in 200 ml of acetone. The resulting solution is cooled to 0 ° C. and ethyl chloroformate (5.7 g, 52.8 mmol) is added dropwise. After 2 hours, sodium azide (4.67 g, 71.9 mmol) in 25 ml of water is added. The solution is stirred at 0 ° C. for 1.5 h. Then the solution is poured into 300 ml of water. Once white precipitate is formed, it is collected by filtration. The resulting solid is dried over P ₂ O ₅ under vacuum. The solid is suspended in 20 ml of diphenyl ether. The solution is added dropwise to a solution of tributylamine (6.9 g, 37.4 mmol) in 200 ml of diphenyl ether at 190 ° C. After 2 hours, the solution is cooled to ambient temperature. The solution is diluted with 1000 ml of hexane and cooled to 0 ° C. The resulting solid is collected by filtration and the solid is washed with hexane. The title compound (3.6 g, 23.8 mmol) is obtained as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 6.71 (m, 2H), 6.42 (d, 1H), 6.13 (d, 1H).
C. 4-chloro-thieno [3,2-c] pyridine
5H-thieno [3,2-c] pyridin-4-one (1.0 g, 6.62 mmol) is dissolved in 30 ml of phosphorus oxychloride. The solution is heated to 100 ° C. After 4 hours, the solution is concentrated. The residue is dissolved in CH ₂ Cl ₂ . The resulting solution is washed with water and saturated NaCl. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by column chromatography, eluting with 40% CH ₂ Cl ₂ / hexanes to 60% CH ₂ Cl ₂ / hexanes. The title compound (1.0 g, 5.8 mmol) is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.24 (d, 1H), 7.76 (d, 1H), 7.66 (m, 2H).
EI MS, [M] ⁺ = 169, 171, Cl pattern.
D. 4-Chloro-thieto [3,2-c] pyridine-2-sulfonyl chloride
Prepare the title compound as described in step D of Example 1 using 4-chloro-thieno [3,2-c] pyridine instead of thianaphthalene. The crude product is purified by column chromatography, eluting with a gradient of 40% CH ₂ Cl ₂ / hexanes to 60% CH ₂ Cl ₂ / hexanes. The title compound is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.39 (d, 1H), 8.28 (s, 1H), 7.72 (d, 1H).
E. 4-Chloro-thieno [3,2-c] pyridine-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3-yl] -amide
3-[(3- (S) -amino-2-oxo-pyrrolidin-1-yl) -methyl] -4-hydroxy-benzonitrile instead of 3- (3- (S) -amino-2-oxo 4-chloro-thieno [3,2-c] pyridine- using pyrrolidin-1-yl) -methyl-benzonitrile and instead of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride Prepare the title compound as described in step G of Example 17 using 2-sulfonyl chloride. The crude product is purified by column chromatography, polishing with a gradient of 10% CH ₂ Cl ₂ / EtOAc to 20% CH ₂ Cl ₂ / EtOAc. The title compound is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.34 (m, 1H), 8.11 (s, 1H), 7.73 (m, 1H), 7.58 (m, 1H), 7.40 (m, 3H), 5.62 (bs, 1H), 4.46 (AB, 2H), 3.97 (m, 1H), 3.27 (m, 2H), 2.68 (m, 1H), 2.12 (m, 1H).
F. 3- [3- (S)-(4-Chloro-thieno [3,2-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dean trifluoroacetate
Using 4-chlorobenzo [b] thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as starting material The title compound is prepared as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.28 (bs, 2H), 9.18 (bs, 2H), 9.06 (d, 1H), 8.38 (d, 1H), 8.22 (d, 1H), 8.08 ( s, 1H), 7.68 (m, 1H), 7.52 (m, 3H), 4.41 (AB, 2H), 4.33 (m, 1H), 3.14 (m, 2H), 2.21 (m, 1H), 1.72 (m , 1H).
FAB MS, [M + H] ⁺ = 464, 466 Cl pattern.
Example 24
4-hydroxy-3- [3- (S)-(4-chloro-thieno [3,2-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate
A. 4-Chloro-thieno [3,2-c] pyridine-2-sulfonic acid [1- (2-hydroxy-5-cyano-benzyl) -2-oxo-pyrrolidine-3- (S ) -Yl] -amide
The procedure described in step G of Example 17 using 4-chloro-thieno [3,2-c] pyridine-2-sulfonyl chloride instead of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride Prepare the title compound as described. The crude product is purified by column chromatography with a gradient of 1% MeOH / CH ₂ Cl ₂ to 4% MeOH / CH ₂ Cl ₂ . The title compound is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 9.13 (s, 1H), 8.38 (d, 1H), 8.09 (s, 1H), 7.72 (d, 1H), 7.52 (dd, 1H), 7.38 (s, 1H), 6.96 (d, 1H), 5.44 (d, 1H), 4.32 (AB, 2H), 4.10 (m, 1H), 3.48 (m, 2H), 2.74 (m, 1H), 2.18 (m, 1H ).
B. 4-hydroxy-3- [3- (S)-(4-chloro-thieno [3,2-c] pyridin-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl Methyl] -benzamidine trifluoroacetate
Using 4-chlorobenzo [b] thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide as starting material The title compound is prepared as described in Step F of Example 1. The crude product is purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 10.91 (bs, 1H), 9.04 (bs, 2H), 8.93 (d, 1H), 8.78 (bs, 2H), 8.40 (d, 1H), 8.21 ( d, 1H), 8.08 (s, 1H), 7.62 (m, 1H), 7.41 (s, 1H), 6.97 (d, 1H), 4.31 (AB, 2H), 4.30 (m, 1H), 3.22 (m , 2H), 2.26 (m, 1 H), 1.78 (m, 1 H). FAB MS, [M + H] ⁺ = 480, 482, Cl pattern.
Example 25
3- [3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Loacetate
A. 5-chlorothieno [3,2-b] pyridine
See, J. Chem. Soc., Perkin Trans. I, 1981, 1531 to prepare the title compound from 3-acetyl thiophene according to the method described. The crude product is purified by column chromatography, eluting with a gradient of 10% EtOAc / hexa to 20% EtOAc / hexanes to give a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.12 (d, 1H), 7.80 (d, 1H), 7.51 (d, 1H), 7.28 (d, 1H). EI MS, [M] ⁺ = 169, 171, Cl pattern.
B. 5-Chlorothieno [3,2-b] pyridine-2-sulfonyl chloride
The title compound is prepared as described in Step D of Example 1 using 5-chlorothieno [3,2-b] pyridine instead of thianaphthalene. A crude product is obtained as a white solid, which has sufficient purity for use in the next step.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.25 (s, 1H), 8.23 (d, 1H), 7.53 (d, 1H).
EI MS, [M] ⁺ = 267, 269, Cl pattern.
C. 5-Chlorothieno [3,2-b] pyridin-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
3- (3 as described in Step E of Example 1 using 5-chlorothieno [3,2-b] pyridine-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride The title compound is prepared from-(S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride. The product is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.18 (d, 1H), 8.03 (s, 1H), 7.59 (m, 1H), 7.47 (d, 1H), 7.45 (m, 2H), 7.42 (d, 1H), 5.95 (bs, 1H), 4.48 (s, 2H), 3.99 (m, 1H), 3.28 (m, 2H), 2.67 (m, 1H), 2.14 (m, 1H).
D. 3- [3- (S)-(5-Chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate
5-Chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3- (S) as described in Example 1 -Yl] -amide is converted to the title compound. The crude product was purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate fractions were lyophilized The title compound is obtained as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.30 (bs, 2H), 9.17 (bs, 2H), 8.93 (d, 1H), 8.67 (d, 1H), 8.11 (s, 1H), 7.69 ( m, 1H), 7.64 (d, 1H), 7.55 (m, 3H), 4.43 (AB, 2H), 4.33 (m, 1H), 3.16 (m, 2H), 2.22 (m, 1H), 1.73 (m , 1H).
FAB MS, [M + H] ⁺ = 464, 466, Cl pattern.
Elemental analysis (containing 1.0 mol of H ₂ O)
Calculated: C 42.35%, H 3.55%, N 11.76%
Found: C 42.34%, H 3.30%, N 11.39%
Example 26
3- [3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
3- [3- (S)-(5-chlorothieno [3,2-b] pyridin-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl in 10 ml 1: 1 benzene / MeOH To a solution of methyl] -benzamidine trifluoroacetate (0.21 g, 0.36 mmol) is added 0.25 g of excess solid KOH and a catalytic amount of 10% palladium / activated carbon. The heterogeneous mixture is hydrogenated at room temperature for 5 days under H ₂ 70 psi on a Parr apparatus. The reaction mixture is filtered through a pad of celite, washed with MeOH and the filtrate is concentrated in vacuo. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate fractions were lyophilized The title compound (0.14 g, 0.21 mmol) is obtained as a white solid.
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 9.56 (bs, 2H), 9.35 (bs, 2H), 8.84 (d, 1H), 8.80 (d, 1H), 8.61 (d, 1H), 8.14 ( s, 1H), 7.72 (dt, 1H), 7.61 (s, 1H), 7.57 (dd, 1H), 7.56 (s, 1H), 7.54 (dd, 1), 4.44 (AB, 2H), 4.34 (m , 1H), 3.17 (m, 2H), 2.21 (m, 1H), 1.74 (m, 1H). IS MS. [M + H] ⁺ = 430.
Example 27
3- [3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -hydroxybenzamidine Trifluoroacetate
5-Chlorothieno [3,2-b] pyridin-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide (0.20 g 0.45 mmol) is dissolved in 10 ml of MeOH. The solution is cooled to 0 ° C. and HCl gas is bubbled into the solution for 5 minutes. The reaction mixture is warmed to ambient temperature and stirred for 16 hours. The solution is then concentrated in vacuo and anhydrous pumped under high vacuum. To the residue solution dissolved in 20 ml of MeOH was added hydroxylamine hydrochloride (0.78 g, 11.2 mmol) followed by triethylamine (2.23 g, 22.0 mmol). The resulting solution is heated to reflux for 2 hours. The solution was concentrated and the residue was purified by RP-HPLC, eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate fractions Lyophilization affords the title compound (0.17 g, 0.29 mmol) as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.94 (d, 1H), 8.78 (bs, 1H), 8.67 (d, 1H), 8.10 (s, 1H), 7.64 (d, 1H), 7.57 ( m, 2H), 7.50 (m, 2H), 4.43 (AB, 2H), 4.33 (m, 1H), 3.16 (m, 2H), 2.22 (m, 1H), 1.17 (m, 1H). FAB MS, [M + H] ⁺ = 480, 482, Cl pattern.
Elemental analysis (containing 1.4 mol of H ₂ O)
Calculated: C 40.74%, H 3.55%, N 11.31%
Found: C 40.75%, H 3.20%, N 10.86%
Example 28
3- {3- (S)-[(5-Chlorothieno [3,2-b] pyridine-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl} -benz Amidine trifluoroacetate
A. 5-Chlorothieno [3,2-b] pyridin-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide
5-Chlorothieno [3,2-b] pyridin-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide (0.25 g , 0.56 mmol) is dissolved in 6 ml of DMF and cooled to 0 ° C. To the solution is added methyl iodide (0.40 g, 2.82 mmol) and sodium hydride (25 mg of 60% dispersion in mineral oil, 0.62 mmol). The reaction mixture is warmed to ambient temperature and stirred for 2 hours. The solution is then diluted with water and EtOAc and the layers are separated. The organic layer is washed with 1N HCl, water, saturated NaHCO ₃ solution and saturated NaCl. The organic phase is dried over magnesium sulfate, filtered and concentrated to give the title compound (0.25 g, 0.54 mmol) as a solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.15 (d, 1H), 8.08 (s, 1H), 7.60 (m, 1H), 7.45 (m, 3H), 7.40 (d, 1H), 4.92 (m, 1H), 4.42 (AB, 2H), 3.24 (m, 2H), 2.92 (s, 3H), 2.43 (m, 1H), 2.06 (m, 1H).
B. 3- {3- (S)-[(5-chlorothieno [3,2-b] pyridine-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl} Benzamidine trifluoroacetate
5-Chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3- as described in Step F of Example 1 (S) -yl] -methylamide is converted to the title compound. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were freeze dried. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 9.32 (bs, 2H), 9.14 (bs, 2H), 8.69 (d, 1H), 8.24 (s, 1H), 7.70 (m, 1H), 7.66 ( d, 1H), 7.58 (m, 2H), 7.56 (s, 1H), 5.00 (m, 1H), 4.44 (AB, 2H), 3.24 (m, 1H), 3.19 (m, 1H), 2.83 (s , 3H), 2.17 (m, 1 H), 1.96 (m, 1 H). FAB MS, [M + H] ⁺ = 478, 480, Cl pattern.
Elemental analysis (containing 1.3 mol of H ₂ O)
Calculated: C 42.91%, H 3.87%, N 11.37%
Found: C 42.90%, H 3.52%, N 11.07%
Example 29
3- [3- (S)-[(6-chlorothieno [2,3-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetate
A. 2-bromo-6-chlorothieno [2,3-b] pyridine
See, J. Chem. Soc., Perkin Trans. I, 1981, 1531 to prepare the title compound from 2-bromo-5-acetyl thiophene according to the method described in. The crude product is purified by column chromatography eluting with 2% EtOAc / hexa to give a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.89 (d, 1H), 7.28 (d, 1H), 7.27 (d, 1H).
B. 6-chlorothieno [2,3-b] pyridine-2-sulfonyl chloride
Prepare the title compound as described in step D of Example 1 using 2-bromo-6-chlorothieno [2,3-b] pyridine instead of thianaphthalene. A crude product is obtained as a white solid, which has sufficient purity for use in the next step.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.22 (d, 1H), 8.09 (s, 1H), 7.52 (d, 1H).
EI MS, [M] ⁺ = 267, 269, Cl pattern.
C. 6-Chlorothieno [2,3-b] pyridin-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
3- (3) as described in Step E of Example 1 using 6-chlorothieno [2,3-b] pyridine-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride The title compound is prepared from-(S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc / CH ₂ Cl ₂ to 25% EtOAc / CH ₂ Cl ₂ to give a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.12 (d, 1H), 7.89 (s, 1H), 7.57 (m, 1H), 7.50 (s, 1H), 7.45 (m, 2H), 7.42 (d, 1H), 6.03 (bs, 1H), 4.48 (AB, 2H), 4.05 (m, 1H), 3.26 (m, 2H), 2.68 (m, 1H), 2.15 (m, 1H).
D. 3- [3- (S)-(6-Chlorothieno [2,3-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate
6-Chlorothieno [2,3-b] pyridine-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3- as described in Step F of Example 1 (S) -yl] -amide is converted to the title compound. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were freeze dried. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.29 (bs, 2H), 9.15 (bs, 2H), 8.88 (d, 1H), 8.48 (d, 1H), 8.08 (s, 1H), 7.68 ( m, 2H), 7.56 (m, 3H), 4.42 (AB, 2H), 4.30 (m, 1H), 3.16 (m, 2H), 2.22 (m, 1H), 1.73 (m, 1H). FAB MS, [M + H] ⁺ = 464, 466, Cl pattern.
Elemental analysis (containing 1.4 mol of H ₂ O)
Calculated: C 41.78%, H 3.65%, N 11.60%
Found: C 41.78%, H 3.28%, N 11.16%
Example 30
3- [3- (S)-(thieno [2,3-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
3- [3- (S)-(6-chlorothieno [2,3-b] pyridin-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl as described in Example 26 Methyl] -benzamidine trifluoroacetate is converted to the title compound. The reaction mixture is hydrogenated at room temperature for 3 days. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were lyophilized. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.22 (bs, 2H), 9.04 (bs, 2H), 8.73 (d, 1H), 8.64 (m, 1H), 8.37 (d, 1H), 7.99 ( s, 1H), 7.62 (m, 1H), 7.50 (m, 4H), 4.36 (AB, 2H), 4.21 (m, 1H), 3.08 (m, 2H), 2.13 (m, 1H), 1.67 (m , 1H).
IS MS, [M + H] ⁺ = 430.
Example 31
3- {3- (S)-[(6-chlorothieno [2,3-b] pyridine-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl} -benz Amidine trifluoroacetate
A. 6-Chlorothieno [2,3-b] pyridin-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide
5-Chlorothieno [3,2-b] pyridin-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide instead of 6- Example using chlorothieno [2,3-b] pyridin-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide Prepare the title compound as described in step A of 28. The crude product is purified by column chromatography eluting with a gradient of 5% EtOAc / CH ₂ Cl ₂ to 10% EtOAc / CH ₂ Cl ₂ to give a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.13 (d, 1H), 7.97 (s, 1H), 7.60 (m, 1H), 7.48 (m, 3H), 7.41 (d, 1H), 4.94 (m, 1H), 4.44 (AB, 2H), 3.25 (m, 2H), 2.93 (s, 3H), 2.44 (m, 1H), 2.09 (m, 1H).
B. 3- {3- (S)-[(6-chlorothieno [2,3-b] pyridine-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl} Benzamidine trifluoroacetate
6-Chlorothieno [2,3-b] pyridine-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3- as described in Step F of Example 1 (S) -yl] -methylamide is converted to the title compound. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were lyophilized. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 500 MHz) δ 9.30 (bs, 2H), 9.03 (bs, 2H), 8.49 (d, 1H), 8.17 (s, 1H), 7.70 (d, 1H), 7.68 ( m, 1H), 7.55 (m, 3H), 4.96 (m, 1H), 4.43 (AB, 2H), 3.19 (m, 2H), 2.81 (s, 3H), 2.15 (m, 1H), 1.97 (m , 1H).
FAB MS, [M + H] ⁺ = 478, 480, Cl pattern.
Example 32
4-hydroxy-3- [2-oxo-3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl]- Benzamidine trifluoroacetate
A. 5-Chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (5-cyano-2-hydroxybenzyl) -2-oxo-pyrrolidine-3- (S)- General] -amide
As described in Step F of Example 17, using 5-chlorothieno [3,2-b] pyridine-2-sulfonyl chloride instead of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride To provide the title compound. The product is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 9.40 (bs, 1H), 8.16 (d, 1H), 8.02 (s, 1H), 7.52 (dd, 1H), 7.43 (d, 1H), 7.38 (s, 1H), 6.96 (d, 1H), 5.65 (bs, 1H), 4.31 (AB, 2H), 4.10 (m, 1H), 3.46 (m, 2H), 2.68 (m, 1H), 2.15 (m, 1H ).
B. 4-hydroxy-3- [2-oxo-3- (S)-(5-chlorothieno [3,2-b] pyridin-2-sulfonylamino) -pyrrolidin-1-ylmethyl ] -Benzamidine trifluoroacetate
5-Chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (5-cyano-2-hydroxybenzyl) -2-oxo-pi as described in Step F of Example 1 Rollidin-3- (S) -yl] -amide is converted to the title compound. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were lyophilized. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.03 (bs, 2H), 8.93 (d, 1h), 8.75 (bs, 2H), 8.67 (d, 1H), 8.11 (s, 1H), 7.65 ( d, 1H), 7.59 (dd, 1H), 7.41 (s, 1H), 6.97 (d, 1H), 4.33 (AB, 2H), 4.29 (m, 1H), 3.21 (m, 2H), 2.22 (m , 1H), 1.74 (m, 1H).
IS MS, [M + H] ⁺ = 480, 482, Cl pattern.
Elemental analysis (contains 1.2 mol of H ₂ O)
Calculated: C 41.03%, H 3.49%, N 11.39%
Found: C 41.02%, H 3.24%, N 10.86%
Example 33
4-hydroxy-3- [2-oxo-3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine Bistrifluoroacetate
5- [3- (S)-(5-chlorothieno [3,2-b] pyridin-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl as described in Example 26 Methyl] -2-hydroxy-benzamidine trifluoroacetate is converted to the title compound. The reaction mixture is hydrogenated at room temperature for 7 days. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were freeze dried. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.03 (bs, 2H), 8.85 (bs, 2H), 8.83 (d, 1H), 8.78 (d, 1H), 8.60 (d, 1H), 8.12 ( s, 1H), 7.61 (d, 1H), 7.53 (dd, 1H), 7.42 (s, 1H), 6.97 (d, 1H), 4.33 (AB, 2H), 4.28 (m, 1H), 3.22 (m , 2H), 2.22 (m, 1 H), 1.76 (m, 1 H). FAB MS, [M + H] ⁺ = 446.
Example 34
4-hydroxy-3- [2-oxo-3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl]- Benzamidine trifluoroacetate
5-Chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (5-cyano-2-hydroxybenzyl) -2-oxo-pyrrolidine- as described in Example 27. 3- (S) -yl] -amide is converted to the title compound. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were lyophilized. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.93 (d, 1H), 8.89 (bs, 1H), 8.68 (d, 1H), 8.11 (s, 1H), 7.65 (d, 1H), 7.48 ( d, 1H), 7.30 (s, 1H), 6.97 (d, 1H), 4.32 (AB, 2H), 4.28 (m, 1H), 3.20 (m, 2H), 2.22 (m, 1H), 1.73 (m , 1H).
FAB MS, [M + H] ⁺ = 496, 498, Cl pattern.
Example 35
4-amino-3- [2-oxo-3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benz Amidine trifluoroacetate
A. 5-Chlorothieno [3,2-b] pyridin-2-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl ]-amides
As described in Step F of Example 17, using 5-chlorothieno [3,2-b] pyridine-2-sulfonyl chloride instead of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride The title compound is prepared from 4-amino-3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile dihydrochloride. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc / CH ₂ Cl ₂ to 25% EtOAc / CH ₂ Cl ₂ to give a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.16 (d, 1H), 8.03 (s, 1H), 7.44 (d, 1H), 7.38 (dd, 1H), 7.28 (dd, 1H), 6.60 (d, 1H), 5.55 (bs, 1H), 4.86 (bs, 2H), 4.29 (AB, 2H), 4.00 (m, 1H), 3.26 (m, 2H), 2.66 (m, 1H), 2.09 (m, 1H ).
B. 4-Amino-3- [2-oxo-3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate
5-Chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxo-pyrroli as described in Step F of Example 1 Din-3- (S) -yl] -amide is converted to the title compound. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 70% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were freeze dried. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.94 (d, 1H), 8.80 (bs, 2H), 8.68 (d, 1H), 8.40 (bs, 2H), 8.11 (s, 1H), 7.65 ( d, 1H), 7.54 (dd, 1H), 7.44 (s, 1H), 6.72 (d, 1H), 6.19 (bs, 2H), 4.33 (m, 1H), 4.20 (AB, 2H), 3.20 (m , 2H), 2.22 (m, 1 H), 1.70 (m, 1 H). FAB MS, [M + H] ⁺ = 479, 481, Cl pattern.
Elemental analysis (contains 2.0 mol of H ₂ O)
Calculations: C 40.00%, H 3.86%, N 13.34%
Found: C 40.03%, H 3.19%, N 12.67%
Example 36
4-Amino-3- [2-oxo-3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine bis Trifluoroacetate
4-Amino-3- [3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidine as described in Example 26 -1-ylmethyl] -benzamidine trifluoroacetate is converted to the title compound. The reaction mixture is hydrogenated at room temperature for 7 days. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were lyophilized. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.85 (d, 1H), 8.78 (bs, 3H), 8.60 (d, 1H), 8.39 (bs, 2H), 8.11 (s, 1H), 7.53 ( m, 1H), 7.52 (d, 1H), 7.42 (s, 1H), 6.71 (d, 1H), 6.17 (bs, 1H), 4.31 (m, 1H), 4.19 (AB, 1H), 3.19 (m , 2H), 2.20 (m, 1 H), 1.69 (m, 1 H). FAB MS, [M + H] ⁺ = 445.
Example 37
4- [3- (S)-(5-Chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2- Carboxamidine trifluoroacetate
A. 5-Chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidine-3- (S)- General] -amide
4- (3 as described in Step E of Example 1 using 5-chlorothieno [3,2-b] pyridine-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride The title compound is prepared from-(S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -thiophene-2-carbonitrile hydrochloride. The crude product is triturated with Et ₂ O / CH ₂ Cl ₂ / hexanes to give a white solid.
¹ H NMR (CDCl ₃ + CD ₃ OD, 300 MHz) δ 8.20 (d, 1H), 8.03 (s, 1H), 7.50 (s, 1H), 7.48 (s, 1H), 7.43 (d, 1H), 4.41 (AB, 2H), 4.08 (m, 1H), 3.27 (m, 2H), 2.58 (m, 1H), 2.05 (m, 1H).
B. 4- [3- (S)-(5-Chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene- 2-carboxamidine trifluoroacetate
5-Chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pi as described in Step F of Example 1 Rollidin-3- (S) -yl] -amide is converted to the title compound. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were lyophilized. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.26 (bs, 2H), 9.12 (bs, 2H), 8.92 (d, 1H), 8.67 (d, 1H), 8.10 (s, 1H), 7.89 ( s, 1H), 7.81 (s, 1H), 7.63 (d, 1H), 4.37 (AB, 2H), 4.28 (m, 1H), 3.19 (m, 2H), 2.22 (m, 1H), 1.73 (m , 1H).
FAB MS, [M + H] ⁺ = 470, 472, Cl pattern.
Elemental analysis (contains 2.1 mol of H ₂ O)
Calculated: C 36.70%, H 3.44%, N 11.26%
Found: C 36.70%, H 2.78%, N 10.38%
Example 38
4- [3- (S)-(5-Chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2- Hydroxycarboxamidine trifluoroacetate
5-Chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidine- as described in Example 27. 3- (S) -yl] -amide is converted to the title compound. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were lyophilized. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.91 (d, 1H), 8.68 (d, 1H), 8.11 (s, 1H), 7.65 (dd, 1H), 7.55 (s, 1H), 7.47 ( s, 1H), 4.33 (AB, 2H), 4.28 (m, 1H), 3.18 (m, 2H), 2.22 (m, 1H), 1.72 (m, 1H). FAB MS, [M + H] ⁺ = 486, 488, Cl pattern.
Elemental analysis (containing 1.5 mol of H ₂ O)
Calculated: C 36.42%, H 3.21%, N 11.18%
Found: C 36.43%, H 2.77%, N 10.83%
Example 39
4- {3- (S)-[(5-Chlorothieno [3,2-b] pyridine-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl} -thi Offen-2-carboxamidine trifluoroacetate
A. 5-Chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidine-3- (S)- General] -methylamide
5-Chlorothieno [3,2-b] pyridin-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide instead of 5- Chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide Prepare the title compound as described in step A of Example 28. Crude product is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.20 (d, 1H), 8.05 (s, 1H), 7.48 (s, 1H), 7.45 (s, 1H), 7.40 (d, 1H), 4.91 (m, 1H), 4.40 (AB, 2H), 3.30 (m, 2H), 2.90 (s, 3H), 2.40 (m, 1H), 2.05 (m, 1H).
B. 4- {3- (S)-[(5-Chlorothieno [3,2-b] pyridine-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl} -Thiophene-2-carboxamidine trifluoroacetate
5-Chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pi as described in Step F of Example 1 Ralidin-3- (S) -yl] -methylamide is converted to the title compound. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were lyophilized. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.25 (bs, 2H), 8.98 (bs, 2H), 8.70 (d, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.80 ( s, 1H), 7.66 (d, 1H), 4.95 (m, 1H), 4.36 (AB, 2H), 3.22 (m, 2H), 2.79 (s, 3H), 2.13 (m, 1H), 1.94 (m , 1H).
FAB MS, [M + H] ⁺ = 484, 486, Cl pattern.
Elemental analysis (containing 1.3 mol of H ₂ O)
Calculated: C 38.68%, H 3.50%, N 11.28%
Found: C 38.69%, H 2.99%, N 10.72%
Example 40
3- {3- (S)-[5- (2-Methylsulfanyl-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl} Benzamidine trifluoroacetate
A. 3- (3- (S) -Amino-2-oxo-pyrrolidin-1-ylmethyl) -benzamidine bistrifluoroacetate
[1- (3-Cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tert-butyl ester as described in Step F of Example 1 as the title compound Switch. The crude product was purified by RP-HPLC eluting with a gradient of 2% CH ₃ CN / H ₂ O (0.1% TFA) to 30% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were freeze dried. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.36 (bs, 2H), 9.28 (bs, 2H), 8.47 (bs, 3H), 7.75 (m, 1H), 7.65 (s, 1H), 7.62 ( m, 2H), 4.55 (AB, 2H), 4.13 (m, 1H), 3.33 (m, 2H), 2.40 (m, 1H), 1.94 (m, 1H). FAB MS, [M + H] ⁺ = 233.
Elemental analysis (contains 0.7 mol of H ₂ O)
Calculated: C 40.59%, H 4.14%, N 11.83%
Found: C 40.58%, H 3.92%, N 11.81%
B. 3- {3- (S)-[5- (2-Methylsulfanyl-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-pyrrolidin-1-yl Methyl} -benzamidine trifluoroacetate
As described in Step E of Example 1 using 5- [2- (methylthio) -pyrimidin-4-yl] thiophene-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride The title compound is prepared from 3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzamidine bistrifluoroacetate as described. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 80% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were lyophilized. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.28 (bs, 2H), 8.98 (bs, 2H), 8.71 (d, 1H), 8.62 (d, 1H), 8.09 (d, 1H), 7.80 ( d, 1H), 7.74 (d, 1H), 7.67 (m, 1H), 7.57 (m, 3H), 4.43 (AB, 2H), 4.25 (m, 1H), 3.14 (m, 2H), 2.25 (s , 3H), 2.18 (m, 1 H), 1.70 (m, 1 H). FAB MS, [M + H] ⁺ = 503.
Example 41
3- {3- (S)-[5- (2-methoxy-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl}- Benzamidine trifluoroacetate
A. [5- (2-Methylsulfanyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3- (S ) -Yl] -amide
As described in Step E of Example 1 using 5- [2- (methylthio) -pyrimidin-4-yl] thiophene-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride The title compound is prepared from 3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride as described. A crude product is obtained as a white solid, which has sufficient purity for use in the next step.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.55 (d, 1H), 7.70 (d, 1H), 7.65 (d, 1H), 7.60 (m, 1H), 7.50 (s, 1H), 7.46 (m, 2H), 7.23 (d, 1H), 5.84 (s, 1H), 4.48 (s, 2H), 3.97 (m, 1H), 3.28 (m, 2H), 2.66 (m, 1H), 2.60 (s, 3H ), 2.15 (m, 1 H).
B. [5- (2-Methylsulfinyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3- (S ) -Yl] -amide and [5- (2-methylsulfonyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine -3- (S) -yl] -amide
[5- (2-Methylsulfanyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine in 30 ml of CHCl ₃ at 0 ° C. To a solution of -3- (S) -yl] -amide (1.48 g, 3.05 mmol) is added dropwise a solution of 3-chloroperoxybenzoic acid (75%, 1.05 g, 4.58 mmol) in 50 ml of CHCl ₃ . The resulting solution is allowed to warm to room temperature and stirred for 16 hours. The reaction mixture is diluted with CH ₂ Cl ₂ and washed successively with saturated Na ₂ SO ₃ solution, 10% Na ₂ CO ₃ and water. The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo to afford a mixture of the title compound (1.46 g, 2.82 mmol) as a solid, which has sufficient purity for use in the next step.
FAB MS, [M + H] ⁺ = 502, 518.
C. [5- (2-Methoxy-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3- (S) -Yl] -amide
[5- (2-Methylsulfinyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3- (S)- Yl] -amide and [5- (2-methylsulfonyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3 A mixture of-(S) -yl] -amide (0.19 g, 0.37 mmol) is dissolved in 10 ml of MeOH and 1 ml of CH ₂ Cl ₂ and the NH ₃ gas is bubbled into the solution for 5 minutes. The resulting mixture is heated to reflux for 4 hours. The solution is then concentrated in vacuo to afford the title compound (0.17 g, 0.36 mmol) as a solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.70 (d, 1H), 8.09 (d, 1H), 7.75 (m, 3H), 7.66 (s, 1H), 7.55 (m, 3H), 4.42 ( AB, 2H), 4.27 (m, 1H), 3.95 (s, 3H), 3.15 (m, 2H), 2.17 (m, 1H), 1.68 (m, 1H).
D. 3- {3- (S)-[5- (2-methoxy-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl } -Benzamidine trifluoroacetate
[5- (2-Methoxy-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo- as described in Step F of Example 1 Pyrrolidin-3- (S) -yl] -amide is converted to the title compound. The crude product was purified by RP-HPLC eluting with a gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions were freeze dried. To give the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.29 (bs, 2H), 9.11 (bs, 2H), 8.70 (d, 1H), 8.62 (d, 1H), 8.09 (d, 1H), 7.75 ( m, 2H), 7.68 (m, 1H), 7.57 (m, 3H), 4.45 (AB, 2H), 4.25 (m, 1H), 3.95 (s, 3H), 3.16 (m, 2H), 2.18 (m , 1H), 1.70 (m, 1H).
FAB MS, [M + H] ⁺ = 487.
Elemental analysis (containing _2.5 mol of H ₂ O)
Calculated: C 42.70%, H 4.39%, N 12.99%
Found: C 42.69%, H 3.64%, N 12.28%
Example 42
3- [3- (S)-[5- (2-Amino-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-prolidin-1-ylmethyl} benzami Dean Bistrifluoroacetate
[5- (2-Methylsulfonyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3- (S)- Yl] -amide and [5- (2-methylsulfonyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3 A mixture of-(S) -yl] -amide (0.20 g, 0.39 mmol) is dissolved in 10 ml of EtoH and NH ₃ gas bubbles are injected into the solution for 5 minutes. The resulting mixture is heated at 90 ° C. for 3 hours in a stainless steel Parr high pressure reaction vessel. The solution was then cooled to room temperature and concentrated in vacuo to afford [5- (2-amino-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2- as crude product. Obtain oxo-pyrrolidin-3- (S) -yl] -amide (0.20 g). FAB MS, [M + H] ⁺ = 455. Unrefined [5- (2-amino-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3- (S) -Yl] -amide is converted to the title compound as described in F of Example 1. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.29 (bs, 2H), 9.08 (bs, 2H), 8.55 (d, 1H), 8.33 (d, 1H), 7.93 (d, 1H), 7.68 ( m, 2H), 7.57 (m, 3H), 7.20 (d, 1H), 7.01 (bs, 1H), 4.45 (AB, 2H), 4.22 (m, 1H), 3.15 (m, 2H), 2.15 (m , 1H), 1.68 (m, 1H).
FAB MS, [M + H] ⁺ = 472.
Example 43
3- {3- (S)-([5- (2-Amino-pyrimidin-4-yl) -thiophene-2-sulfonyl] -methylamino) -2-oxo-pyrrolidone-1-yl Methyl] -benzamidine bistrifluoroacetate
A. [5- (2-Methylsulfinyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3- (S ) -Yl] -methylamide and [5- (2-methylsulfonyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrroli Din-3- (S) -yl] -methylamide
The title compound was prepared as described in Example 28 A, 5-chlorothieno [3,2-b] pyridine-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine- [5- (2-methylsulfinyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2 in place of 3- (S) -yl] -amide -Oxo-pyrrolidin-3- (S) yl] amide and [5- (2-methylsulfonyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl ) -2-oxo-pyrrolidin-3- (S) -yl] -amide. A mixture of crude product is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.94 (d, 1H), 7.90 (d, 1H), 7.84 (d, 1H), 7.73 (m, 1H), 7.62 (m, 1H), 7.46 (m, 3H), 4.93 (m, 1H), 4.43 (AB, 2H), 3.43 (s, 3H), 3.27 (m, 2H), 2.97 (s, 3H), 2.41 (m, 1H), 2.06 (m, 1H ).
FAB MS, [M + H] ⁺ = 516, 532.
B. 3- {3- (S)-([5- (2-Amino-pyrimidin-4-yl) -thiophene-2-sulfonyl] -methylamino) -2 -oxo-pyrrolidine-1 -Ylmethyl] -benzamidine bistrifluoroacetate
The title compound was prepared as described in Example 42 [5- (2-methylsulfinyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo -Pyrrolidin-3- (S) -yl] -methylamide and [5- (2-methylsulfonyl-pyrimidin-4-yl) -thiophene-2-sulfonic acid [1- (3-cyano [5- (2-methylsulfinyl-pyrimidin-4-yl) -thiophen-2-sul on behalf of a mixture of benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide Phonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide and [5- (2-methylsulfonyl-pyrimidin-2-yl)- Prepared using a mixture of thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -methylamide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.29 (bs, 2H), 9.03 (bs, 2H), 8.36 (d, 1H), 7.98 (d, 1H), 7.75 (d, 1H), 7.68 ( m, 1H), 7.56 (m, 3H), 7.21 (d, 1H), 6.95 (bs, 1H), 4.88 (m, 1H), 4.44 (AB, 2H), 3.18 (m, 2H), 2.74 (s , 3H), 2.07 (m, 1 H), 1.89 (m, 1 H). IS MS, [M + H] ⁺ = 486.
Example 44
3- [3- (S)-(5'-Chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetate
A. 5-chloro- [2,2 '] bithiophenyl
The title compound is described in Bull. Chem. Soc. Japan, 1979, 1126] is prepared from 2-chloro-thiophene according to the method described. The crude product is eluted using column chromatography with a concentration gradient of 5% to 10% EtOAc / hexanes to give as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.24 (m, 1H), 7.11 (d, 1H), 7.03 (dd, 1H), 6.94 (d, 1H), 6.83 (d, 1H). EI MS, [M] ⁺ = 200, 202, Cl pattern.
B. 5'-Chloro- [2,2 '] bithiophenyl-5-sulfonyl chloride
The title compound is prepared using 5-chloro- [2,2 '] bithiophenyl in place of thianaphthalene as described in D of Example 1. The crude product is eluted using column chromatography with a concentration gradient of 5% to 10% EtOAc / hexanes to give as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.76 (d, 1H), 7.14 (d, 1H), 7.09 (d, 1H), 6.92 (d, 1H). EI MS, [M] ⁺ = 298, 300, Cl pattern.
C. 5'-Chloro- [2,2 ']-bithiophenyl] -5-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl]- amides
The title compound was prepared using 5'-chloro- [2,2 '] bithiophenyl-5-sulfonyl chloride in place of benzo [b] thiophen-2-sulfonyl chloride as described in Example 1 E. Prepared from 3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride. The crude product is triturated with EtOAc / CH ₂ Cl ₂ to give a medium solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.62 (m, 1H), 7.56 (d, 1H), 7.50 (m, 2H), 7.48 (d, 1H), 7.06 (d, 1H), 7.04 (d, 1H), 6.90 (d, 1H), 5.54 (s, 1H), 4.48 (s, 2H), 3.93 (m, 1H), 3.27 (m, 2H), 2.65 (m, 1H), 2.15 (m, 1H ).
D. 3- [3- (S)-(5'-Chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dean trifluoroacetate
5'-Chloro- [2,2 ']-bithiophenyl-5-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide Convert to the title compound as described in F of Example 1. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 80% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.30 (bs, 2H), 9.19 (bs, 2H), 8.56 (d, 1H), 7.68 (m, 1H), 7.62 (d, 1H), 7.58 ( m, 3H), 7.36 (d, 1H), 7.34 (d, 1H), 7.19 (d, 1H), 4.46 (AB, 2H), 4.22 (m, 1H), 3.17 (m, 2H), 2.18 (m , 1H), 1.70 (m, 1H).
FAB MS, [M + H] ⁺ = 495, 497, Cl pattern.
Elemental Analysis (Contains 0.9 mol of H ₂ O)
Calculated Value: C 42.23%, H 3.52%, N 8.95%
Found: C 42.22%, H 3.02%, N 8.62%
Example 45
4-amino-3- [3- (S) -benzo [b] thiophene-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] benzamidine trifluoroacetate
A. Benzo [b] thiophene-2-sulfonic acid [1- (4-amino-3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] amide
The title compound (0.131 g, 0.307 mmol) was 4-amino-3- (3- (S) -amino-2-oxo-pyrrolidin-1-yl in acetonitrile as described in E of Example 1 Prepared from methyl) benzonitrile dihydrochloride (0.135 g, 0.445 mol) and benzo [b] thiophene-2-sulfonyl chloride (0.114 g, 0.49 mmol).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.88-7.94 (m, 3H), 7.48 (m, 2H0, 7.36 (dd, 1H), 7.28 (d, 1H), 6.58 (d, 1H), 5.36 (d , 1H), 4.88 (bs, 2H), 4.30 (AB, 2H), 3.94 (m, 1H), 3.26 (m, 2H), 2.65 (m, 1H), 2.10 (m, 1H); FAB MS, [ M + H] ⁺ = 427.
B. 4-Amino-3- [3- (S) -benzo [b] thiophene-2-sulfonylamino-2-oxopyrrolidin-1-ylmethyl] benzamidine trifluoroacetate
The title compound was prepared as described in F of Example 1, benzo [b] thiophene-2-sulfonic acid [1- (4-amino-3-cyanobenzyl) -2-oxopyrrolidine-3- (S ) -Yl] amide (0.131 g, 0.307 mmol). The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 100% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to afford the title compound as a white solid. The appropriate fractions were lyophilized to yield 4-amino-3- [3- (S) -benzo [b] thiophene-2-sulfonylamino-2-oxopyrrolidin-1-ylmethyl] benzamidine as a white solid. Trifluoroacetate (0.08 g, 0.14 mmol) is obtained.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.80 (bs, 2H), 8.67 (d, 1H), 8.39 (bs, 2H), 8.0-8.12 (m, 3H), 7.47-7.57 (m, 3H ), 7.43 (m, 1H), 6.73 (d, 21 (bs, 2H), 4.28 (m, 1H), 4.22 (m, 2H), 3.18 (m, 2H), 2.17 (m, 1H), 1.67 ( m, 1 H).
FAB MS, [M + H] ⁺ = 444.
Elemental analysis (contains 1.6 mol of H ₂ O)
Calculated Value: C 45.06%, H 4.33%, N 11.94%
Found: C 45.41%, H 4.07%, N 11.47%
Example 46
4-amino-3- [6-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] benzamidine trifluoroacetate
A. 6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (4-amino-3-cyanobenzyl) -2-oxopyrrolidin-3- (S) -yl] amide
The title compound (0.133 g, 0.288 mmol) was prepared as described in E of Example 1, 4-amino-3- (3- (S) -amino-2-oxopyrrolidin-1-ylmethyl) benzonitrile ( 0.175 g, 0.758 mmol) and 6-chlorobenzo [b] thiophene-2-sulfonyl chloride (0.203 g, 0.758 mmol).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.89 (s, 1H), 7.86 (d, 1H), 7.82 (d, 1H), 7.45 (dd, 1H), 7.37 (dd, 1H), 7.29 (d, 1H), 6.60 (d, 1H), 5.41 (bs, 1H), 4.89 (bs, 2H), 4.28 (AB, 2H), 3.97 (m, 1H), 3.28 (m, 2H), 2.64 (m, 1H ), 2.09 (m, 1 H).
FAB MS, [M + H] ⁺ = 461, 463 Cl pattern.
B. 4-Amino-3- [6-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] benzamidine trifluoroacetate
The title compound was prepared as described in F of Example 1 6-chlorobenz [b] thiophene-2-sulfonic acid [1- (4-amino-3-cyanobenzyl) -2-oxo-pyrrolidine- Prepared from 3- (S) -yl] amide (0.131 g, 0.284 mmol) f. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 100% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to afford the title compound as a white solid. The appropriate fractions are lyophilized to afford the title compound (0.126 g, 0.207 mmol) as a solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.80 (bs, 2H), 8.73 (d, 1H), 8.43 (bs, 2H), 8.29 (s, 1H), 8.05 (s, 1H), 8.02 ( d, 1H), 7.57 (m, 2H), 7.44 (s, 1H), 6.73 (dd, 1H), 6.20 (bs, 2H), 4.1-4.25 (m, 3H), 3.20 (m, 2H), 2.18 (m, 1 H), 1.68 (m, 1 H). FAB MS, [M + H] ⁺ = 478, 480, Cl pattern.
Elemental Analysis (Contains 1.4 mol of H ₂ O)
Calculation: C 42.84%, H 3.88%, N 11.35%
Found: C 42.84%, H 3.74%, N 11.05%
Example 47
4-amino-3- [6-chlorobenz [b] thiophene-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] hydroxybenzamidine trifluoroacetate
6-chlorobenzo [b] thiophene-2-sulfonic acid [1- (4-amino-3-cyanobenzyl) -2-oxopyrrolidin-2-oxopyrrolidin-3- (S) -yl ] Amide (0.20 g, 0.434 mmol) is converted to the title compound (0.178 g, 0.36 mmol) using the method described in Example 37.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.27 (bs, 1H), 10.80 (bs, 1H), 8.98 (bs, 1H), 8.74 (d, 1H), 8.65 (bs, 2H), 8.28 ( s, 1H), 8.07 (s, 1H), 8.03 (d, 1H), 7.56 (dd, 1H), 7.39 (dd, 1H), 7.30 (s, 1H), 6.73 (d, 1H), 6.08 (bs , 1H), 4.12-4.28 (m, 3H), 3.18 (m, 2H), 2.17 (m, 1H), 1.68 (m, 1H) .; Ion spray MS, [M] ⁺ = 495.
Example 48
3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -pyridinin-1-ylmethyl] -benzamidinetrifluoroacetate
A. 2-thiophene boronic acid
To a solution of 2-bromothiophene (5.94 mL, 61.3 mmol) in 100 ml ether at 60 ° C. is added n-butyl lithium (40 ml of 1.6M in hexane, 64.4 mmol). After stirring for 30 minutes tributylborate (23.7 mL, 85.9 mmol) is added and the mixture is stirred for 3 hours. The reaction mixture is allowed to warm to rt overnight then treated with 150 ml of 1N HCl and washed with ether (2 × 150 mL). The mixed organic layer is extracted with 1N NaOH. Adjust to less than 7 with 1N HCl during the pHfmf precipitation formation time of the aqueous layer. The precipitate is collected and washed with hexane to give the product (3.95 g, 30.9 mmol) as a gray solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.64 (dd, 1H), 7.59 (dd, 1H), 7.21 (dd, 1H), 4.75 (s, 2H). EI, [M] ⁺ = 128.
B. 3-thiophen-2-yl-pyridine
A mixture of 3-bromopyridine (1.30 ml, 13.5 mmol) and tetrakis (triphenylphosphine) (0.468 g, 0.41 mmol) in 40 ml of dimethoxyethane is stirred under nitrogen at room temperature for 10 minutes. 2-thiophene boronic acid (1.90 g, 14.8 mmol) and 20 ml of 1N sodium carbonate are added and the resulting mixture is refluxed overnight. The solution is cooled to room temperature and filtered through celite. The filtrate is extracted with ether (2 x 30 ml). The combined organic layers are dried over MgSO ₄ , filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 10% to 20% EtOAc / hexanes to give the title compound (0.355 g, 2.20 mmol) as a pale yellow oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.89 (d, 1H), 8.52 (dd, 1H), 7.87 (ddd, 1H), 7.38 (s, 1H), 7.36 (d, 1H), 7.31 (m, 1H), 7.12 (dd, 1H). EI, [M] ⁺ = 161.
C. 5-pyridin-3-yl-thiophene-2-sulfonyl chloride
To a 3-thiophen-2-yl-pyridine solution (0.355 g, 2.20 mmol) in 15 ml THF at −78 ° C. add n-BuLi (1.64 1.44 ml. 2.31 mmol in hexanes). After stirring for 15 minutes, SO ₂ gas bubbles are injected into the solution for 30 minutes. The solution is warmed to room temperature and stirred overnight. The solution is concentrated to dryness and the solid obtained is suspended in 20 ml of hexane. Sulfuryl chloride (0.185 ml, 2.31 mmol) is added and the reaction mixture is stirred for 30 minutes, then a small amount of methylene chloride is added and the mixture is stirred for 30 minutes. The mixture is then concentrated to dryness, diluted with ethyl acetate and washed with saturated NaHCO ₃ (aq), water and brine. The organic layer is dried over MgSO ₄ and filtered and concentrated to give a brown solid as the title product (0.452 g, 1.74 mmol) which is used in the next step without further purification.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.95 (bs, 1H), 8.70 (bs, 1H), 7.95 (d, 1H), 7.90 (d, 1H), 7.45 (bs, 1H), 7.44 (d, 1H). EI, [M] ⁺ = 259, 261, Cl pattern.
D. 5-Pyridin-3-yl-thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
The title compound was CH ₂ Cl using 5-pyridin-3-yl-thiophene-2-sulfonyl chloride in place of benzo [b] thiophene-2-sulfonyl chloride as described in E of Example 1 Prepared in CH ₃ CN instead of ₂ . The crude product is obtained by diluting with ethyl acetate and washing with saturated sodium bicarbonate (aq), water and brine. The organic layer is dried over MgSO ₄ , filtered and concentrated. The title product is purified by column chromatography eluting with MeOH / CH ₂ Cl ₂ 5% to give a gray solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.90 (d, 1H), 8.63 (d, 1H), 7.85 (dd, 1H), 7.68 (d, 1H), 7.61 (m, 1H), 7.41-7.45 ( m, 3H), 7.34 (dd, 1H), 7.31 (d, 1H), 5.45 (s, 1H), 4.50 (s, 2H), 3.95 (m, 1H), 3.25 (m, 2H), 2.68 (m , 1H), 2.15 (m, 1H).
FAB MS, [M + H] ⁺ = 439.
E. 3- [2-Oxo-3- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine trifluoro acetate
The title compound was used as the starting material as described in F of Example 1 as 5-pyridin-3-yl-thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine- Prepared using 3-yl] -amide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.30 (s, 2H), 9.05 (s, 2H), 8.95 (s, 1H), 8.63 (d, 1H), 8.55 (d, 1H), 8.16 ( d, 1H), 7.65-7.71 (m, 3H), 7.48-7.60 (m, 4H), 4.48 (AB, 2H), 4.28 (m, 1H), 3.15 (m, 2H), 2.20 (m, 1H) , 1.71 (m, 1 H).
FAB MS, [M + H] ⁺ = 456.
Elemental Analysis (Contains 0.8mol H ₂ O)
Calculated Value: C 43.02%, H 3.55%, N 10.03%
Found: C 43.10%, H 3.85%, N 9.98%
Example 49
4-Amino-3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetate
A. 5-Pyridin-3-yl-thiophene-2-sulfonic acid [1- (2-amino-5-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl]- amides
The title compound was used 5-pyridin-3-yl-thiophene-2-sulfonyl chloride in place of benzo [b] thiophene-2-sulfonyl chloride as described in E of Example 1 and 3- ( 4-amino- [3- (3- (S) -amino-2-oxo-pyrroli instead of 3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride Prepare in CH ₃ CN instead of CH ₂ Cl ₂ using din-1-ylmethyl)]-benzonitrile dihydrochloride.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.85 (d, 1H), 8.61 (dd, 1H), 7.82 (m, 1H), 7.68 (d, 1H), 7.26-7.38 (m, 4H), 6.60 ( d, 1H), 5.35 (d, 1H), 4.89 (s, 2H), 4.30 (AB, 2H), 3.97 (m, 1H), 3.30 (m, 2H), 2.65 (m, 1H), 2.09 (m , 1H).
FAB MS, [M + H] ⁺ = 454.
B. 4-Amino-3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzami Dean trifluoroacetate
The title compound is 5-pyridin-3-yl-thiophene-2-sulfonic acid [1- (2-amino-5-cyano-benzyl) -2-oxo as starting material as described in F of Example 1 -Pyrrolidin-3-yl] -amide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.95 (d, 1H), 8.75 (s, 2H), 8.58 (d, 1H), 8.50 (d, 1H), 8.48 (s, 2H), 8.10 ( d, 1H), 7.70 (s, 2H), 7.50 (m, 2H), 7.40 (d, 1H), 6.71 (d, 1H), 6.20 (bs, 2H), 4.11-4.25 (m, 3H), 3.15 (m, 2H), 2.18 (m, 1H), 1.62 (m, 1H). FAB MS, [M + H] ⁺ = 471.
Example 50
4-hydroxy-3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate
A. 5-Pyridin-3-yl-thiophene-2-sulfonic acid {1- [5-cyano-2-hydroxy-benzyl] -2-oxo-pyrrolidin-3- (S) -yl} -amides
The title compound was substituted with 5-pyridin-3-yl-thiophene-2-sulfonyl chloride in place of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride as described in G of Silit Example 17. To manufacture. The solution is concentrated and purified by column chromatography eluting with MeOH / CH ₂ Cl ₂ 10% to give a brown oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.82 (bs, 1H), 8.61 (bs, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 7.63 (d, 1H), 7.55 (s, 1H), 7.53 (dd, 1H), 7.41 (d, 1H), 7.31 (m, 1H), 7.28 (d, 1H), 6.91 (d, 1H), 4.41 (s, 2H), 4.12 (m, 1H ), 3.35 (m, 2H), 2.55 (m, 1H), 2.09 (m, 1H). FAB MS, [M + H] ⁺ = 455.
B. 4-hydroxy-3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benz Amidine trifluoroacetate
The title compound is 5-pyridin-3-yl-thiophene-2-sulfonic acid {1- [5-cyano-2-hydroxy-benzyl] -2- as starting material as described in F of Example 1 Prepared using oxo-pyrrolidin-3-yl} -amide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 10.91 (s, 1H), 9.06 (s, 2H), 8.98 (s, 1H), 8.67 (s, 2H), 8.55 (d, 1H), 8.16 ( d, 1H), 7.71 (m, 2H), 7.60 (d, 1H), 7.51 (m, 1H), 7.42 (s, 1H), 7.00 (d, 1H), 4.35 (AB, 2H), 4.21 (m , 1H), 3.21 (m, 2H), 2.20 (m, 1H), 1.71 (m, 1H). FAB MS, [M + H] ⁺ = 472.
Example 51
4-hydroxy-3- [2-oxo-3- (S)-(5-pyridine-N-oxide-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate
A. 5-Pyridin-3-yl-thiophene-2-sulfonic acid {1- [2- (tert-butyl-dimethyl-silanyloxy) -5-cyanobenzyl] -2-oxo-pyrrolidine -3- (S) -yl} -amide
Imidazole (0.094 g, 1.37 mmol) and tert-butyldimethylchlorosilane (0.099 g, 0.66 mmol) were added to 5-pyridin-3-yl-thiophene-2-sulfonic acid in 10 ml of DMF. No-2-hydroxy-benzyl] -2-oxo-pyrrolidin-3-yl} -amide (0.25 g, 0.55 mmol) solution. The resulting mixture is stirred overnight then diluted with EtOAc and washed with saturated NaHCO ₃ (aq) and brine. The organic layer is dried over MgSO ₄ , filtered and concentrated. The product was purified by column chromatography eluting with MeOH / CH ₂ Cl ₂ 3% to give a brown oil (0.236 g, 0.41 mmol).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.90 (bs, 1H), 8.52 (bs, 1H), 7.79 (m, 1H), 7.60 (d, 1H), 7.56 (dd, 1H), 7.45 (d, 1H), 7.39 (m, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 6.80 (d, 1H), 6.70 (s, 1H), 4.40 (s, 2H), 4.03 (m, 1H ), 3.21 (m, 2H), 2.60 (m, 1H), 2.10 (m, 1H), 0.92 (s, 9H), 0.20 (s, 6H).
B. 5-Pyridine-N-oxide-3-yl-thiophene-2-sulfonic acid {1- [2- (tert-butyl-dimethyl-silanyloxy) -5-cyano-benzyl] -2- Oxo-pyrrolidin-3- (S) -yl} -amide
5-Pyridin-3-yl-thiophene-2-sulfonic acid {1- [2- (tert-butyl-dimethyl-silanyloxy) -5-cyano-benzyl] -2- in 10 ml of CH ₂ Cl _2. To a solution of oxo-pyrrolidin-3- (S) -yl} -amide (0.18 g, 0.32 mmol) is added m-chloroperbenzoic acid (0.17 g, 0.63 mmol). The mixture is stirred overnight, diluted with CH ₂ Cl ₂ and washed with saturated NaHCO ₃ (aq) and brine. The organic layer was dried over MgSO ₄ , filtered and concentrated to give the title product (0.18 g, 0.32 mmol) as a yellow oil which was used in the next step without further purification.
¹ H NMR (CDCl ₃ , 300 MHz) δ 10.70 (bs, 1H), 8.85 (s, 1H), 8.42 (d, 1H), 8.00 (s, 1H), 7.95 (d, 1H), 7.85 (s, 1H), 7.80 (d, 1H), 7.70 (m, 1H), 7.35 (d, 1H), 6.90 (d, 1H), 6.82 (d, 1H), 4.44 (s, 2H), 4.18 (m, 1H ), 3.31 (m, 2H), 2.62 (m, 1H), 2.20 (m, 1H), 0.92 (s, 9H), 0.25 (s, 6H). FAB MS, [M + H] ⁺ = 585.
C. 4-Hydroxy-3- [2-oxo-3- (S)-(5-pyridine-N-oxide-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-yl Methyl] -benzamidine trifluoroacetate
The title compound was prepared as described in F of Example 1 5-pyridine-N-oxide-3-yl-thiophene-2-sulfonic acid {1- [2-tert-butyl-dimethyl-silanyloxy)- 5-cyano-benzyl] -2-oxo-pyrrolidin-3- (S) -yl} -amide. The title compound is 5-pyridin-3-yl-thiophene-2-sulfonic acid [1- (2-amino-5-cyano-benzyl) -2-oxo as starting material as described in F of Example 1 -Pyrrolidin-3-yl] -amide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 10.91 (s, 1H), 9.05 (s, 2H), 8.75 (s, 1H), 8.65 (s, 2H), 8.60 (d, 1H), 8.21 ( d, 1H), 7.76 (d, 1H), 7.70 (d, 1H), 7.66 (d, 1H), 7.60 (dd, 1H), 7.49 (m, 1H), 7.41 (d, 1H), 6.98 (d , 1H), 4.35 (AB, 2H), 4.19 (m, 1H), 3.21 (m, 2H), 2.25 (m, 1H), 1.75 (m, 1H). FAB MS, [M + H] ⁺ = 488.
Example 52
3- [2-oxo-3- (S)-(5-pyridin-4-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. 4-thiophen-2-yl-pyridine
The title compound is prepared using 4-bromopyridine instead of 3-bromopyridine as described in Example 48B. The crude product is purified by column chromatography eluting with a concentration gradient of 20% to 40% EtOAc / hexanes to give the title product as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.60 (d, 2H), 7.51 (m, 1H), 7.49 (d, 2H), 7.42 (dd, 1H), 7.14 (dd, 1H). EI, [M] ⁺ = 161.
B. 5-Pyridin-4-yl-thiophene-2-sulfonyl chloride
The title compound is prepared using 4-thiophen-2-yl-pyridine in place of 3-thiophen-2-yl-pyridine as described in C of Example 48. The title compound is used in the next step without further purification.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.75 (d, 2H), 8.60 (d, 1H), 7.90 (d, 1H), 7.51 (d, 2H). EI, [M] ⁺ = 259, 261 Cl pattern.
C. 5-Pyridin-4-yl-thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
The title compound is prepared using 5-pyridin-4-yl-thiophene-2-sulfonyl chloride in place of benzo [b] thiophene-2-sulfonyl chloride as described in E of Example 1. The crude product is obtained by diluting with ethyl acetate and washing with saturated sodium bicarbonate (aq), water and brine. The organic layer is dried over MgSO ₄ , filtered and concentrated. The title product is purified by column chromatography eluting with MeOH / CH ₂ Cl ₂ to give a light brown solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.70 (d, 2H), 7.68 (d, 1H), 7.60 (m, 1H), 7.40-7.50 (m, 6H), 5.65 (bs, 1H), 4.48 ( AB, 2H), 3.98 (m, 1H), 3.28 (m, 2H), 2.68 (m, 1H), 2.17 (m, 1H). FAB MS, [M + H] ⁺ = 439.
D. 3- [2-oxo-3- (S)-(5-pyridin-4-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine trifluoro acetate
The title compound is 5-pyridin-4-yl-thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidine as starting material as described in F of Example 1 3-yl] -amide. The title compound is 5-pyridin-3-yl-thiophene-2-sulfonic acid [1- (2-amino-5-cyano-benzyl) -2-oxo as starting material as described in F of Example 1 -Pyrrolidin-3-yl] -amide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.30 (s, 2H), 9.05 (s, 2H), 8.69 (d, 2H), 8.67 (d, 1H), 7.89 (d, 1H), 7.85 ( d, 2H), 7.77 (d, 1H), 7.68 (m, 2H), 7.51-7.60 (m, 3H), 4.42 (AB, 2H), 4.26 (m, 1H), 3.18 (m, 2H), 2.21 (m, 1 H), 1.70 (m, 1 H). FAB MS, [M + H] ⁺ = 456.
Example 53
3- [3- (S)-(4-Chloro-thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. 4-Chloro-5-trimethylsilanyl-thiophene-2-sulfonyl chloride
The title compound is (3-chloro-thiophen-2-yl) -trimethylsilane (WO94 / 12505, PCT / US93 / 08613 instead of 3-thiophen-2-yl-pyridine as described in Example 48C). Prepared using the method as described in the above).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.10 (s, 1H), 0.30 (s, 9H). EI, [M] ⁺ = 288, 290, Cl pattern.
B. 4-Chloro-5-trimethylsilanyl-thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide and 4-Chloro-thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
The title compound was CH ₂ using 4-chloro-5-trimethylsilanyl-thiophene-2-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride as described in E of Example 1 Prepared in CH ₃ CN instead of Cl ₂ . The crude product is obtained by diluting with ethyl acetate and washing with saturated sodium bicarbonate (aq), water and brine. The organic layer is dried over MgSO ₄ , filtered and concentrated. The title product is purified by column chromatography eluting with MeOH / CH ₂ Cl ₂ to afford two products.
4-Chloro-5-trimethylsilanyl-thiophen-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.60 (m, 1H), 7.45-7.50 (m, 3H), 7.30 (s, 1H), 5.80 (bs, 1H), 4.50 (AB, 2H), 3.85 ( m, 1H), 3.28 (m, 2H), 2.62 (m, 1H), 2.15 (m, 1H), 0.35 (s, 9H). FAB MS, [M + H] ⁺ = 396, 398, Cl pattern.
4-Chloro-thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.69 (m, 1H), 7.56 (d, 1H), 7.50 (m, 3H), 7.08 (d, 1H), 5.83 (bs, 1H), 4.48 (s, 2H), 3.85 (s, 1H), 3.21 (m, 2H), 2.60 (m, 1H), 2.11 (m, 1H). FAB MS, [M + H] ⁺ = 468, 470, Cl pattern.
C. 3- [3- (S)-(4-Chloro-thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
The title compound was 4-chloro-thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidin-3-yl as starting material as described in F of Example 1 Prepared using] -amide. The title compound is 5-pyridin-3-yl-thiophene-2-sulfonic acid [1- (2-amino-5-cyano-benzyl) -2-oxo as starting material as described in F of Example 1 -Pyrrolidin-3-yl] -amide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.25 (bs, 2H), 8.91 (bs, 2H), 8.65 (m, 1H), 7.95 (d, 1H), 7.68 (m, 1H), 7.55 ( m, 2H), 7.22 (d, 1H), 4.41 (AB, 2H), 4.20 (m, 1H), 3.18 (m, 2H), 2.10 (m, 1H), 1.75 (m, 1H). MS, [M + H] ⁺ = 413, 415, Cl pattern.
Example 54
3- {3- (S)-[5- (5-chloropyridin-3-yl) -thiophene-2-sulfonylamino] -2-oxopyrrolidin-1-ylmethyl} benzamidine trifluor Loacetate
A. 5-chloro-3- (thiophen-2-yl) pyridine
The title compound (0.21 g, 1.08 mmol) is prepared from 3,5-dichloropyridine (1.0 g, 6.76 mmol) and 2-thiophene boronic acid (0.95 g, 7.43 mmol) as described in B of Example 48. .
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.73 (d, 1H), 8.47 (d, 1H), 7.83 (dd, 1H), 7.34 (two dd, 2H), 7.10 (dd, 1H).
B. 5- (5-chloropyridin-3-yl) thiophene-2-sulfonylchloride
5- (5-Chloropyridin-3-yl) thiophene-2-sulfonylchloride (0.21 g, 1.08 mmol) was added to 5-chloro-3- (thiophene-2- as described in Example 48C. From 1) pyridine.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.88 (d, 1H), 8.66 (d, 1H), 7.94 (m, 1H), 7.65 (AB, 2H); EI MS, [M] ⁺ = 293, 295.
C. 5- (5-Chloropyridin-3-yl) thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] amide
The title compound (0.012 g, 0.288 mmol) was added to 3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) benzonitrile in acetonitrile as described in Example 1 E. (0.039 g, 0.153 mmol) and 6-chlorobenzo [b] thiophene-2-sulfonyl chloride (0.045 g, 0.153 mmol).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.74 (d, 1H), 8.58 (d, 1H), 7.88 (dd, 1H), 7.61 (m, 1H), 7.52 (AB, 2H), 7.47 (m, 3H), 5.64 (bs, 1H), 4.47 (AB, 2H), 3.97 (dd, 3H), 3.27 (m, 2H), 2.64 (m, 1H), 2.16 (m, 1H); EI MS, [M] ⁺ = 473, 475, Cl pattern.
D. 3- {3- (S)-[5-Chloropyridin-3-yl) -thiophene-2-sulfonylamino] -2-oxopyrrolidin-1-ylmethyl] benzamidine trifluoro acetate
The title compound was prepared as described in F of Example 1 5- (5-chloropyridin-3-yl) thiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine Prepared from 3- (S) -yl] amide (0.012 g, 0.025 mmol). The title compound is 5-pyridin-3-yl-thiophene-2-sulfonic acid [1- (2-amino-5-cyano-benzyl) -2-oxo as starting material as described in F of Example 1 -Pyrrolidin-3-yl] -amide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 100% CH ₃ CN. The appropriate fractions were lyophilized to afford 3- {3- (S)-[5- (5-chloropyridin-3-yl) -thiophene-2-sulfonylamino] -2-oxopyrrolidin-1-ylmethyl } Benzamidine trifluoroacetate yields a white solid (0.005 g, 0.14 mmol).
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.28 (bs), 8.89 (bs), 8.60 (m), 8.37 (m), 7.75 (AB), 7.67 (m), 7.56 (m), 4.44 ( AB), 4.24 (m, 2 H), 3.17 (m), 2.20 (m), 1.69 (m). FAB MS, [M + H] ⁺ = 490, 492, Cl pattern.
Example 55
3- [3- (s)-(4-chloro-5-pyridin-3-yl] thiophene-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] -benzamidine trifluor Loacetate
A. (3-chlorothiophen-2-yl) pyridine
3-Chlorothiophene-2-boronic acid (1.5 g, 9.24 mmol), prepared as described in Example 48A, was treated with 3-bromopyridine (0.81 ml, 8.4 as described in B of Example 48). mmol) to afford the title compound (0.232 g, 1.19 mmol).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.89 (dd, 1H), 8.58 (dd, 1H), 7.98 (ddd, 1H), 7.36 (ddd, 1H), 7.19 (AB, 2H).
B. 3-Chloro-5-pyridin-3-ylthiophene-2-sulfonylchloride
(3-chlorothiophene) -2-yl) pyridine (0.232 g, 1.19 mmol) was reacted as described in Example 48 C to 3-chloro-5- (contaminated with some butylated material. Pyridin-3-yl) thiophene-2-sulfonylchloride (0.154 g, 0.612 mmol) is obtained.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.92 (bs, 1H), 8.87 (d, 1H), 8.05 (dd, 1H), 7.84 (s, 1H), 7.47 (dd, 1H); EI MS, [M] ⁺ = 293, 295, Cl pattern.
C. 4-Chloro-5-pyridin-3-ylthiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] amide
The title compound (0.063 g, 0.133 mmol) was added to 3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) benzonitrile in acetonitrile as described in Example 1 E. (0.154 g, 0.612 mmol) and 3-chloro-5-pyridin-3-ylthiophene-2-sulfonylchloride (0.180 g, 0.612 mmol).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.86 (bs, 1H), 8.70 (dd, 1H), 7.98 (ddd, 1H), 7.42-7.55 (m, 4H), 7.56-7.66 (m, 2H), 6.64 (bs, 1H), 4.50 (AB, 2H), 4.08 (dd, 3H), 3.28 (m, 2H), 2.67 (m, 1H), 2.18 (m, 1H).
D. 3- [3- (S)-(4-Chloro-5-pyridin-3-ylthiophene-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] -benzamidine trifluor Loacetate
The title compound was prepared as described in F of Example 1 4-chloro-5-pyridin-3-ylthiophene-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidine-3 Prepared from-(S) -yl] amide (0.063 g, 0.133 mmol). The crude product was purified using RP-HPLC, eluting with a concentration gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 100% CH ₃ CN to give 3- [3- (S)-( 4-Chloro-5-pyridin-3-ylthiophene-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate (0.076 g, 0.106 mmol) is obtained. .
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.32 (bs, 2H), 9.08 (bs, 2H), 8.88 (bs, 1H), 8.82 (d, 1H), 8.70 (d, 1H), 8.13 ( dd, 1H), 7.87 (s, 1H), 7.72 (m, 1H), 7.51 (m, 4H), 4.45 (AB, 2H), 4.31 (m, 1H), 3.21 (m, 2H), 2.33 (m , 1H), 1.79 (m, 1H).
Ion spray MS, [M + H] ⁺ = 490, 492, Cl pattern.
Example 56
4-hydroxy-3- [3- (S)-(6-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetate
A. 6-Chlorobenzo [b] thiophene-2-sulfonic acid [1- (5-cyano-2-hydroxy-benzyl) -2-oxo-pyrrolidin-3- (S) -yl]- amides
The title compound was prepared using 6-chlorobenzo [b] thiophene-2-sulfonyl chloride instead of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride as described in G of Example 17. Prepared from 3-[(3-amino-2-oxo-pyrrolidin-1-yl) -methyl] -4-hydroxy-benzonitrile hydrochloride. The crude product is triturated with Et ₂ O to afford the title compound as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.15 (d, 1H), 7.95 (s, 1H), 7.82 (m, 2H), 7.50 (s, 1H), 7.40 (m, 2H), 6.94 (d, 1H), 4.46 (d, 1H), 4.35 (d, 1H), 4.15 (t, 1H), 3.30 (m, 2H), 2.40 (m, 1H), 1.95 (m, 1H). FAB MS, [M + H] ⁺ = 462, 464, Cl pattern.
B. 4-hydroxy-3- [3- (S)-(6-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamide
The title compound was described as starting material in Example 1 F as 6-chlorobenzo [b] thiophene-2-sulfonic acid [1- (5-cyano-2-hydroxy-benzyl) -2-oxo as starting material. -Pyrrolidin-3- (S) -yl] amide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 80% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 10.80 (bs, 1H), 9.00 (bs, 2H), 8.82 (d, 1H), 8.62 (bs, 2H), 7.98 (m, 2H), 7.90 ( d, 1H), 7.47 (m, 2H), 6.65 (d, 1H), 4.49 (AB, 2H), 4.23 (m, 1H), 3.32 (m, 2H), 2.30 (m, 1H), 1.82 (m , 1H).
FAB MS [M + H] ⁺ = 479, 481, Cl pattern.
Example 57
3- [3- (S)-(1-aminoisoquinoline-6-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. 3- (3-bromophenyl) acrylic acid
3-Bromobenzaldehyde (10.0 g, 54 mmol), malonic acid (10.1 g, 97 mmol) and piperidine (0.267 ml, 2.7 mmol) are treated with pyridine (30 ml) and heated at 100 ° C. for 3.5 h. The reaction mixture is cooled to room temperature and poured into 200 ml of 20% hydrochloric acid at 0 ° C. The precipitate obtained is collected, washed with a small amount of water and dried overnight in a vacuum drier to give the title compound (11.64 g, 51 mmol).
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.55 (bs, 1H), 7.96 (s, 1H), 7.70 (d, 1H), 7.5-7.64 (m, 2H), 7.38 (m, 1H), 6.62 (d, 1 H). EI MS, M ⁺ = 226, 228, Br pattern.
B. 6-Bromoisoquinolin-1-one
3- (3-bromophenyl) acrylic acid (10.0 g, 44 mmol) was treated by the method described in Example 23B to yield 5.6 g of a yellow solid. The material is washed with hot ethanol / ethyl acetate to afford the title compound (2.54 g, 11 mmol) as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.30 (d, 1H), 8.19 (d, 1H), 8.04 (s, 1H), 7.78 (d, 1H), 7.52 (d, 1H), 7.27 ( s, 1 H), 6.49 (d, 1 H). EI MS, M ⁺ = 241, 243.
C. 6-Bromo-1-chloroisoquinoline
6-Bromoisoquinolin-1-one (2.54 g, 11 mmol) is converted to the title compound (2.69 g, 11 mmol) using the method as described in C of Example 23.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.30 (d, 1H), 8.19 (d, 1H), 8.04 (s, 1H), 7.78 (d, 1H), 7.52 (d, 1H), 7.27 (s, 1H), 6.49 (d, 1H). EI MS, M ⁺ = 241, 243.
D. 1-Chloroisoquinoline-2-sulfonyl chloride
6-Bromo-1-chloroisoquinoline (2.69 g, 11 mmol) was converted to the title compound using the method described in Example D, except that the crude product was washed with hexane to give a yellow solid (3.6 g). ) Is obtained and used without further purification.
EI MS, M ⁺ = 261, 263.
E. 1-Chloroisoquinoline-6-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] amide
3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) benzonitrile hydrochloride (1.7 g, 6.8 mmol) was prepared as described in Example 1 E as 1-chloroiso React with quinoline-2-sulfonyl chloride (3.54 g, 13.6 mmol). The crude product is purified by flash chromatography (2% MeOH / CH ₂ Cl ₂ ) to afford the title compound (1.14 g, 2.58 mmol).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.49 (m, 2H), 8.40 (d, 1H), 8.12 (dd, 1H), 7.74 (d, 1H), 7.57 (m, 1H), 7.45 (d, 1H), 7.39 (d, 1H), 5.83 (bs, 1H), 4.44 (AB, 2H), 3.90 (dd, 2H), 2.51 (m, 1H), 2.08 (m, 1H); FAB MS, [M + H] ⁺ = 441, 443.
F. 1-Aminoisoquinoline-6-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] amide
1-aminoisoquinoline-6-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] amide (0.20 g, 0.45 mmol) and phenol (3 g) Are heated together at 70 ° C. for 5 minutes, treated with ammonium acetate (2.5 g) and further heated to 115 ° C. for 7 hours. The reaction is cooled to room temperature, diluted with ethyl acetate and partitioned with 1N sodium hydroxide. The liquid layer is saturated with sodium chloride and washed with ethyl acetate (2 X 100 ml). The organic layers are mixed, dried (sodium sulfate), concentrated and chromatographed (5% MeOH / CH ₂ Cl ₂ ) to afford the title compound (0.108 g, 0.26 mmol).
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.28 (s, 1H), 8.03 (d, 1H), 7.92 (AB, 2H), 7.55 (m, 1H), 7.4-7.48 (m, 3H), 7.08 ( d, 1H), 5.50 (bs, 3H), 4.34 (AB, 2H), 3.89 (dd, 1H), 3.22 (m, 2H), 2.58 (m, 1H), 2.09 (m, 1H); FAB MS, [M + H] ⁺ = 422.
G. 3- [3- (S)-(1-Aminoisoquinoline-6-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] -benzamidinebistrifluoroacetate
1-aminoisoquinoline-6-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] amide (0.108 g, 0.26 mmol) was prepared as in Example 1 Treat as described in F and purify by HPLC to afford the title compound (0.10 g, 0.15 ml) as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.39 (bs, 2H), 9.21 (bs, 4H), 8.69 (d, 1H), 8.60 (d, 1H), 8.46 (d, 1H), 8.12 ( dd, 1H), 7.80 (d, 1H), 7.67 (d, 1H), 7.5-7.6 (m, 3H), 7.38 (d, 1H), 4.39 (bs, 2H), 4.26 (m, 1H), 3.14 (dd, 2H), 2.18 (m, 1 H), 1.67 (m, 1 H); FAB MS, [M + H] ⁺ = 439.
Elemental Analysis (Contains ₂ mol of H ₂ O)
Calculated Value: C 42.09%, H 4.13%, N 11.78%
Found: C 42.17%, H 3.90%, N 11.38%
Example 58
4-Fluoro-3- [3- (S)-(5-pyridin-3-yl-thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamide tri Fluoroacetate
A. 5-bromo-2-fluorobenzyl alcohol
To 0 ml of 5-bromo-2-fluoro-benzaldehyde (6.10 g, 30.0 mmol) in 30 ml THF is added 5 ml sodium borohydride (2.0 M solution in triglyme, 10.0 mmol). The reaction mixture is stirred at 0 ° C. for 25 minutes and then quenched by addition of 1N HCl. The mixture is diluted with EtOAc and the layers are separated. The organic layer is washed with H ₂ O and saturated NaCl. The organic layer is dried over MgSO ₄ , filtered and concentrated. The crude product is purified by column chromatography eluting with 15% EtOAc / hexanes to afford the title compound (6.00 g, 29.3 mmol).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.55 (dd, 1H), 7.36 (m, 1H), 6.89 (t, 1H), 4.71 (d, 2H), 2.11 (bs, 1H). EI MS, [M] ⁺ = 204, 206, Br pattern.
B. 5-Bromo-2-fluoro-benzyl bromide
Triphenyl phosphine (4.10 g, 15.6 mmol) in a solution of 5-bromo-2-benzyl alcohol (3.10 g, 15.1 mmol) in 30 ml THF at 10 ° C. followed by N-bromosuccinimide (2.67 g, 15.0 mmol) Add). The ice bath is removed and the resulting solution is stirred at room temperature for 20 minutes. The crude product is purified by column chromatography eluting with EtOAc / hexane 5% to afford the title compound (3.90 g, 14.5 mmol).
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.50 (dd, 1H), 7.37 (m, 1H), 6.92 (t, 1H), 4.42 (s, 2H). EI MS, [M] ⁺ = 266, 268, 270; 2 Br pattern.
C. 3- (S)-(tert-butoxy-carbonyl-amino) -1- (5-bromo-2-fluoro-benzyl) -pyrrolidin-2-one
The title compound is prepared using 5-bromo-2-fluorobenzyl bromide instead of α-bromo-m-toluyl nitrile as described in Example 1 B. Crude material is purified by column chromatography eluting with EtOAc: hexane: CH ₂ Cl ₂ 3: 1: 1.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.40 (m, 2H), 6.96 (t, 1H), 5.20 (bs, 1H), 4.50 (s, 2H), 4.18 (m, 1H), 3.28 (m, 2H), 2.64 (m, 1H), 1.90 (m, 1H), 1.45 (s, 9H).
EI MS, [M] ⁺ = 387, 389, Br pattern.
D. 3- (S)-(tert-butoxy-carbonyl-amino) -1- (5-cyano-2-fluoro-benzyl) -pyrrolidin-2-one
The title compound was prepared as 3- (S)-(tert-butoxy-carbonyl-amino) -1- instead of (5-iodo-thiophen-3-yl) methanol as described in Example C. Prepared using (5-bromo-2-fluoro-benzyl) -pyrrolidin-2-one. Crude material is purified by column chromatography eluting with EtOAc: hexane: CH ₂ Cl ₂ 3: 1: 1.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.70 (bd, 1H), 7.61 (m, 1H), 7.19 (t, 1H), 5.18 (bs, 1H), 4.63 (d, 1H), 4.50 (d, 1H), 4.18 (m, 1H), 3.32 (m, 2H), 2.64 (m, 1H), 2.00 (m, 1H), 1.47 (s, 9H). EI MS, [M] ⁺ = 334.
E. 3- (S)-[(3-amino-2-oxo-pyrrolidin-1-yl) methyl] -4-fluoro-benzonitrile hydrochloride
The title compound was used in place of [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tertiary butyl ester as described in Example C Prepared using-(S)-(tert-butoxycarbonyl-amino) -1- (5-cyano-2-fluoro-benzyl) -pyridin-2-one. The title compound is obtained as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.73 (bs, 3H), 7.92 (m, 1H), 7.86 (d, 1H), 7.50 (t, 1H), 4.54 (s, 2H), 4.10 ( m, 1H), 3.38 (m, 2H), 2.42 (m, 1H), 2.07 (m, 1H). EI MS, [M] ⁺ = 233.
F. 5-Pyridin-3-yl-thiophene-2-sulfonic acid [1- (5-cyano-2-fluoro-benzyl) -2-oxopyrrolidin-3- (S) -yl]- amides
The title compound was substituted with 5-pyridin-3-yl-thiophene-2-sulfonyl chloride in place of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride as described in G of Example 17. Prepared from 3- (S)-[3-amino-2-oxo-pyrrolidin-1-yl] -methyl] -4-fluorobenzonitrile hydrochloride. The crude product is triturated with Et ₂ O to afford the title compound as a white solid.
¹ H NMR (CDCl ₃ + CD ₃ OD, 300 MHz) δ 8.87 (s, 1H), 8.55 (d, 1H), 8.08 (d, 1H), 7.73 (m, 3H), 7.53 (m, 1H), 7.48 (d, 1H), 7.28 (t, 1H), 4.54 (AB, 2H), 4.20 (m, 1H), 3.34 (m, 2H), 2.49 (m, 1H), 1.98 (m, 1H). FAB MS, [M + H] ⁺ = 457.
G. 4-Fluoro-3- [3- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -2-oxo-pyrrolidone-1-ylmethyl] -benz Amide trifluoroacetate
The title compound was used as the starting material, as described in F of Example 1, 5-pyridin-3-yl-thiophene-2-sulfonic acid [1- (5-cyano-2-fluoro-benzyl) -2- Prepared using oxo-piperidin-3- (S) -yl] amide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to CH ₃ CN 80%. The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (CD ₃ OD, 300 MHz) δ 8.77 (s, 1H), 8.44 (d, 1H), 8.03 (d, 1H), 7.67 (m, 2H), 7.58 (d, 1H), 7.45 (d , 1H), 7.41 (m, 1H), 7.28 (t, 1H), 5.10 (s, 1H), 4.47 (s, 2H), 4.13 (m, 1H), 3.23 (m, 2H), 2.28 (m, 1H), 1.81 (m, 1H). FAB MS, [M + H] ⁺ = 473.
Example 59
2-Chloroquinoline-6-sulfonic acid {1- [3- (aminoiminomethyl) -benzyl] -2-oxo-pyrrolidin-3- (S) -yl} -amide trifluorocetate
A. 2-chloro-6-bromoquinoline
The title compound is described in J. Chem. Soc., Perkin Trans. I, 1972, 1648, prepared from 4-bromoaniline and cinnamoyl chloride. The crude 6-bromo-1H-quinolin-2-one intermediate obtained is triturated in Et ₂ O / hexanes and filtered to give a medium solid and used in the direct combustion step. The crude product is recrystallized in MeOH to afford the title compound as a medium solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.01 (d, 1H), 7.98 (s, 1H), 7.89 (m, 1H), 7.80 (m, 1H), 7.40 (d, 1H).
B. 2-chloroquinoline-6-sulfonyl chloride
The title compound is prepared using 2-chloro-6-bromoquinoline instead of thianaphthalene as described in D of Example 1. Crude product is triturated with hexanes to obtain a medium solid and of sufficient purity for use in subsequent steps.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.60 (s, 1H), 8.31 (d, 1H), 8.28 (m, 2H), 7.60 (d, 1H).
C. 2-Chloroquinoline-6-sulfonic acid [1- (3-cyanobenzyl) -2-oxopyrrolidine-3- (S) -amide
The title compound was prepared as 3- (3- (S) -amino using 2-chloroquinoline-6-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride as described in E of Example 1 Prepared from 2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride. The product is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.50 (s, 1H), 8.25 (d, 1H), 8.18 (m, 1H), 8.14 (m, 1H), 7.58 (m, 1H), 7.52 (d, 1H), 7.44 (m, 3H), 5.68 (bs, 1H), 4.45 (AB, 2H), 3.89 (m, 1H), 3.22 (m, 2H), 2.63 (m, 1H), 2.08 (m, 1H ).
D. 2-Chloroquinoline-6-sulfonic acid {1- [3- (aminoiminomethyl) -benzyl] -2-oxopyrrolidin-3- (S) -yl} amide trifluoroacetate
2-Chloroquinoline-6-sulfonic acid [1- (3-cyanobenzyl) -2-oxopyrrolidin-3- (S) -yl] -amide as described in F of Example 1 for the title compound Switch to The crude product is purified using RP-HPLC, eluting with a gradient of 10% to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.29 (bs, 2H), 9.13 (bs, 2H), 8.68 (d, 1H), 8.64 (s, 1H), 8.46 (d, 1H), 8.19 ( m, 1H), 8.13 (m, 1H), 7.75 (d, 1H), 7.66 (m, 1H), 7.55 (m, 3H), 4.42 (AB, 2H), 4.21 (m, 1H), 3.10 (m , 2H), 2.07 (m, 1 H), 1.62 (m, 1 H). IS MS, [M + H] ⁺ = 458, 460, Cl pattern.
Elemental analysis (contains 1.9 mol of H ₂ O)
Calculated Value: C 45.54%, H 4.13%, N 11.54%
Found: C 45.53%, H 3.49%, N 10.79%
Example 60
2-Aminoquinoline-6-sulfonic acid {1- [3- (aminoiminomethyl) -benzyl] -2-oxo-pyrrolidin-3- (S) -yl} -amide bistrifluoroacetate
2-Chloroquinoline-6-sulfonic acid {1- [3- (aminoiminomethyl) -benzyl] -2-oxo-pyrrolidin-3- (S) -yl] -amide trifluoroacetate (0.25 g, 0.50 mmol) and phenol (0.80 g, 8.25 mmol) are melted at 80 ° C. for 5 minutes and ammonium acetate (0.64 g, 8.25 mmol) is added to the mixture and heating is continued at 120 ° C. for 2.5 hours. This time add more NH ₄ OAc (s). After 1 hour the reaction mixture is cooled with Ceylon and partitioned between EtOAc and 0.5N HCl. The layers are separated and the aqueous phase is extracted with EtOAc. The aqueous layer is concentrated in vacuo to a small volume (5 ml). The crude product is purified using RP-HPLC, eluting with a gradient of 10% to 40% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.29 (bs, 2H), 9.21 (bs, 2H), 9.03 (bs, 2H), 8.46 (d, 1H), 8.44 (s, 1H), 8.37 ( d, 1H), 8.13 (d, 1H), 7.75 (d, 1H), 7.68 (m, 1H), 7.56 (m, 3H), 7.15 (d, 1H), 4.40 (s, 2H), 4.16 (m , 1H), 3.10 (m, 2H), 2.07 (m, 1H), 1.62 (m, 1H). IS MS, [M + H] ⁺ = 439.
Elemental analysis (contains 2.4 mol of H ₂ O)
Calculated Value: C 42.33%, H 4.09%, N 11.85%
Found: C 42.33%, H 3.69%, N 11.39%
Example 61
4-hydroxy-3- [3- (S)-(7-chloro-thieno [2,3-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate
A. 6H-thieno [2,3-c] pyridin-7-one
Triethylamine (12.0 g, 110.6 mmol) is added to a solution of 3-thiophen-3-yl-acrylic acid (15.5 g, 100.5 mmol) in 400 ml of acetone. The resulting solution is cooled to 0 ° C. and ethyl chloroformate (11.2 g, 110.6 mmol) is added dropwise. After 2 hours sodium azide (9.8 g, 150.8 mmol) is added to 100 mL of H ₂ O. The solution is stirred at 0 ° C. for 1.5 h. After this the solution is poured into 1000 ml of H ₂ O. The white precipitate is collected by filtration. The solid obtained is dried with P ₂ O ₂ under vacuum. The solid is suspended in 20 ml of diphenyl ether. The solution is added dropwise to a solution of tributylamine (18.6 g, 100.5 mmol) in 200 ml of diphenyl ether at 190 ° C. After 2 hours the solution is cooled to room temperature. The solution is diluted with 1000 ml of hexane and cooled to 0 ° C. The solid obtained is collected by filtration and the solid is washed with hexane. The title compound (10.9 g, 72.1 mmol) is obtained as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.4 (bs, 1H), 7.54 (d, 1H), 7.42 (d, 1H), 7.22 (d, 1H), 6.84 (d, 1H).
C. 7-chloro-thieno [2,3-c] pyridine
6H-thieno [2,3-c] pyridin-7-one (2.3 g, 15.22 mmol) is dissolved in 50 ml of phosphorus oxychloride. The solution is heated to 100 ° C. After 4 hours the solution is concentrated. The residue is dissolved in CH ₂ Cl ₂ . The resulting solution is washed with water and saturated NaClfh. The organic layer is dried over MgSO ₄ , filtered and concentrated. The crude product is purified by column chromatography eluting with a concentration gradient of 40% to 60% CH ₃ CN / H ₂ O (0.1% TFA). The title compound (2.0 g, 12.2 mmol) is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.26 (d, 1H), 7.76 (d, 1H), 7.62 (d, 1H), 7.41 (d, 1H). EI MS, [M] ⁺ = 169, 171, Cl pattern.
D. 7-Chloro-thieno [2,3-c] pyridine-2-sulfonyl chloride
The title compound is prepared using 7-chloro-thieno [2,3-c] pyridine in place of thianaphthalene as described in D of Example 1. The crude product is purified by column chromatography eluting with a concentration gradient of 40% to 60% CH ₃ CN / H ₂ O (0.1% TFA). The title compound is obtained as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.48 (d, 1H), 8.18 (s, 1H), 7.77 (d, 1H).
E. 4-hydroxy-3- [3- (S)-(7-chloro-thieno [2,3-c] pyridin-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl Methyl] -benzamidine trifluoroacetate
The title compound was substituted for 7-chloro-thieno [2,3-c] pyridine-2- in place of 4,6-dichlorobenzo [b] thienophen-2-sulfonyl chloride as described in G of Example 17. Prepared using sulfonyl chloride. The crude product was then taken as 7-chlorobenzo [b] thiophene-2-sulfonic acid [1- (3-cyano-benzyl) -2-oxo-pyrrolidine as starting material as described in F of Example 1 Treatment with 3- (S) -yl] -amide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 10.89 (bs, 1H), 9.03 (bs, 3H), 8.68 (bs, 2H), 8.40 (d, 1H), 8.18 (s, 1H), 8.00 ( d, 1H), 7.56 (d, 1H), 7.33 (s, 1H), 6.95 (d, 1H), 4.38 (m, 3H), 3.18 (m, 2H), 2.21 (m, 1H), 1.72 (m , 1H).
FAB MS, [M + H] ⁺ = 480, 482, Cl pattern.
Example 62
4-hydroxy-3- [3- (S)-(thieno [2,3-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Bistrifluoroacetate
A. 4-hydroxy-3- [3- (S)-(thieno [2,3-c] pyridin-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benz Amidine bistrifluoroacetate
4-hydroxy-3- [3- (S)-(thieno [2,3-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl]-in 15 ml of methanol To a solution of benzamidine trifluoroacetate (0.26 g, 0.54 mmol) is added KOH (0.07 g, 1.54 mmol) and 10 wt% Pd / C (0.05 g). The atmosphere of the reaction mixture is exchanged with hydrogen and the solution is heated to 50 ° C. After 24 hours the solution is cooled to room temperature and filtered through celite. Celite is washed with methanol. The collected solution is concentrated. Crude material is purified using RP-HPLC eluting with a concentration gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 40% CH ₃ CN. The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 10.89 (bs, 1H), 9.38 (bs, 2H), 8.96 (bs, 2H), 8.88 (d, 1H), 8.70 (m, 2H), 8.58 ( m, 1H), 8.12 (s, 1H), 7.98 (d, 1H), 7.58 (d, 1H), 7.38 (s, 1H), 6.95 (d, 1H), 4.28 (AB, 2H), 4.20 (m , 1H), 3.18 (m, 2H), 2.21 (m, 1H), 1.72 (m, 1H). FAB MS, [M + H] ⁺ = 446.
Example 63
4-hydroxy-3- [3- (S)-(thieno [3,2-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate
4-hydroxy-3- [3- (S)-(thieno [3,2-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate
The title compound was prepared as described in Example 62 A, 4-hydroxy-3- [3- (S)-(7-chloro-thieno [2,3-c] pyridine-2-sulfonylamino)- 4-hydroxy-3- [3- (S)-(4-chloro-thieno [3,2-c] instead of 2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate ] Pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 40% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.00 (bs, 1H), 9.35 (bs, 2H), 8.96 (m, 2H), 8.77 (d, 1H), 8.70 (bs, 2H), 8.28 ( s, 1H), 8.21 (s, 1H), 7.58 (d, 1H), 7.30 (s, 1H), 6.92 (d, 1H), 4.24 (AB, 2H), 4.16 (m, 1H), 3.12 (m , 2H), 2.18 (m, 1 H), 1.72 (m, 1 H). FAB MS, [M + H] ⁺ = 446.
Example 64
4- [3- (6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxamidine hydrochloride
A. 6-Fluorobenzo [b] thiophene-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl]- amides
The title compound was prepared as 4- (3- (instead of 3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride as described in E of Example 1). S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -thiophene-2-carbonitrile hydrochloride and 6-fluorobenzo [b] instead of benzo [b] thiophene sulfonyl chloride Prepared using thiophene sulfonyl chloride.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.58 (d, 1H), 8.02 (m, 3H), 7.82 (s, 1H), 7.78 (s, 1H), 7.38 (m, 1H), 4.36 ( s, 2H), 4.19 (m, 1H), 3.11 (m, 2H), 2.12 (m, 1H), 1.62 (m, 1H).
B. 4- [3- (6-Fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxamidine hydro Chloride
The title compound was 6-fluorobenzo [b] thiophene-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo as starting material as described in F of Example 1 -Pyrrolidin-3- (S) -yl] amide. The crude product is purified using RP-HPLC by eluting with a concentration gradient of 10% to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.34 (bs, 2H), 9.03 (bs, 2H), 8.68 (s, 1H), 8.03 (m, 3H), 7.88 (s, 1H), 7.36 ( m, 1H), 4.38 (AB, 2H), 4.17 (m, 1H), 3.16 (m, 2H), 2.17 (m, 1H), 1.71 (m, 1H). FAB MS, [M + H] ⁺ = 453.
Example 65
4- {3- (S)-[(3-aminopropyl)-(6-fluorobenzo [b] thiophene-2-sulfonylamino)]-2-oxo-pyrrolidin-1-ylmethyl} -Thiophene-2-carboxamidine bistrifluoroacetate
A. 4- {3- (s)-[(3-aminopropyl)-(6-fluorobenzo [b] thiophene-2-sulfonylamino)]-2-oxo-pyrrolidin-1-yl Methyl} -thiophene-2-carboxamidine bistrifluoroacetate
6-Pluorobenzo [b] thiophene-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo prepared as described in Example 62A in 6 ml of DMF. To a solution of -pyrrolidin-3- (S) -yl] -amide (0.50 g, 1.15 mmol) is added K ₂ CO ₃ (0.80 g, 5.75 mmol). The solution is cooled to 0 ° C. and 3-iodinepropyl azide (0.36 g, 1.173 mmol) is added. The solution is stirred for 16 hours. The solution is then diluted with EtOAc and the organic layer is washed with water and saturated NaCl. The organic layer is dried over MgSO ₄ , filtered and concentrated. The obtained residue is dissolved in ethanol. Saturate the solution with HCl. The solution is stirred for 16 hours. The solution is then concentrated. The residue is dissolved in MeOH. The solution is saturated with NH ₃ and heated to 50 ° C. for 3 h. The solution is then concentrated. Crude material is purified using RP-HPLC by eluting with a gradient of 10% to 80% of CH ₃ CN / H ₂ O (0.1% TFA). The product obtained is dissolved in 8 ml of MeOH. 10% by weight of Pd / C is added to the solution. The atmosphere of the reaction is exchanged with hydrogen. After 24 hours the solution is filtered through celite. Celite is washed with MeOH. The collected solution is concentrated. Crude material is purified using RP-HPLC by eluting with a gradient of 10% to 80% of CH ₃ CN / H ₂ O (0.1% TFA).
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.21 (bs, 2H), 9.07 (bs, 2H), 8.12 (s, 1H), 8.03 (m, 2H), 7.90 (s, 1H), 7.81 ( m, 1H), 7.68 (bs, 2H), 7.37 (m, 1H), 4.76 (m, 1H), 4.38 (AB, 2H), 3.17 (m, 2H), 2.79 (m, 2H), 2.09 (m , 1H), 1.86 (m, 3H). FAB MS, [M + H] ⁺ = 510.
Example 66
[[1- (5-carbamimidoyl-thiophen-3-ylmethyl-2-oxo-pyrrolidin-3-yl]-(6-fluorobenzo [b] thiophene-2-sulfonyl)- Amino] -acetic acid trifluoroacetate
A. [[1- (5-Cyano-thiophen-3-ylmethyl-2-oxo-pyrrolidin-3-yl]-(6-fluorobenzo [b] thiophene-2-sulfonyl) -Amino] -acetic acid tertiary butyl ester
6-fluorobenzo [b] thiophene-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidine prepared as described in Example 62A To a solution of -3- (S) -yl] -amide (0.58 g, 1.33 mmol) is added K ₂ CO ₃ (0.37 g, 2.68 mmol). Cool the solution to 0 ° C. and add tert butyl bromoacetate (0.4 g, 2.68 mmol). The solution is stirred for 4 hours. The solution is then diluted with EtOAc. The organic layer is washed with water and saturated NaCl. The organic layer is dried over MgSO ₄ , filtered and concentrated to give the product (0.71 g, 1.3 mmol) as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.02 (s, 1H), 7.83 (m, 1H), 7.54 (m, 1H), 7.48 (m, 1H), 7.20 (m, 2H), 4.57 (m, 1H), 4.40 (AB, 2H), 4.00 (AB, 2H), 3.27 (m, 2H), 2.59 (m, 1H), 2.44 (m, 2H), 1.42 (s, 9H).
B. [[1- (5-carbamimidoyl-thiophen-3-ylmethyl-2-oxo-pyridin-3-yl]-(6-fluorobenzo [b] thiophene-2-sulfonyl)- Amino] -acetic acid tert-butyl ester trifluoroacetate
[[1- (5-Cyano-thiophen-3-ylmethyl-2-oxo-pyrrolidin-3-yl]-(6-fluorobenzo [b] thiophene-2-sulfonyl) in 10 ml of pyridine To a solution of) -amino] -acetic acid tertiary butyl ester (0.7 g, 1.3 mmol) is added 1.0 ml of triethyl amine The resulting solution is saturated with H ₂ S. After 16 h the solution is concentrated The residue is acetone Dissolve in 30 ml Methyl iodine (1.7 ml, 26 mmol) is added to the solution The solution is heated to reflux for 3 hours After this time the solution is concentrated The residue is dissolved in 10 ml of MeOH and ammonium acetate (0.5 g, 6.5 mmol) are added, and the solution is heated to reflux After 3 hours the solution is concentrated to give a yellow solid.
FAB MS, [M + H] ⁺ = 557.
C. [[1- (5-carbamimidoyl-thiophen-3-ylmethyl-2-oxo-pyrrolidin-3-yl]-(6-fluorobenz [b] thiophene-2-sulfonyl ) -Amino] -acetic acid trifluoroacetate
[[1- (5-carbamimidoyl-thiophen-3-ylmethyl-2-oxo-pyrrolidin-3-yl]-(6-fluorobenzo [b] thiophene-2-sulfonyl)- Amino] -acetic acid tertiary bunyl ester trifluoroacetate is dissolved in CH ₂ Cl _{2. To} the solution is added 3 ml of trifluoroacetic acid After 3 hours the solution is concentrated The crude product is CH using RP-HPLC. ₃ CN / H ₂ O (0.1% TFA) Purify by eluting with a concentration gradient of 10% to 60%.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.21 (bs, 2H), 9.10 (bs, 2H), 8.14 (s, 1H), 8.01 (m, 2H), 7.88 (s, 1H), 7.78 ( s, 1H), 7.37 (m, 1H), 4.78 (m, 1H), 4.38 (AB, 2H), 3.98 (AB, 2H), 3.19 (m, 2H), 2.24 (m, 1H), 2.11 (m , 1H). FAB MS, [M + H] ⁺ = 511.
Example 67
[Imino- (4- {3- [7-methoxynaphthalene-2-sulfonyl) -pyridin-2-ylmethyl-amino] -2-oxo-pyrrolidin-1-ylmethyl} -thiophene- 2-yl) -methyl] -carbamic acid ethyl ester
A. 7-methoxy-naphthalene-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] amide
The title compound was prepared as 4- (3- (instead of 3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride as described in E of Example 1). S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -thiophene-2-carbonitrile hydrochloride and 7-methoxy-naphthalene sulfonyl instead of benzo [b] thiophene sulfonyl chloride Prepared using chloride.
FAB MS, [M + H] ⁺ = 442.
B. 7-methoxynaphthalene-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -pyridin-2-yl Methyl amide
7-methoxy-naphthalene-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide (0.5 in DMF 5 ml) g, 1.13 mmol) is added K ₂ CO ₃ (0.78 g, 5.65 mmol). To the solution is added 2-picoyl chloride (0.23 g, 1.41 mmol). After 16 hours the solution is diluted with EtOAc. The organic layer is washed with water and saturated NaCl. The organic layer is dried over MgSO ₄ , filtered and concentrated.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.44 (m, 2H), 7.98 (m, 2H), 7.76 (d, 1H), 7.69 (m, 2H), 7.48 (m, 2H), 7.21 (m, 2H), 4.72 (m, 1H), 4.50 (AB, 2H), 4.28 (AB, 2H), 3.16 (m, 2H), 2.24 (m, 1H), 2.00 (1H).
C. [Imino- (4- {3-[(7-methoxynaphthalene-2-sulfonyl) -pyridin-2-ylmethyl-amino] -2-oxo-pyrrolidin-1-ylmethyl}- Thiophen-2-yl) -methyl] -carbamic acid ethyl ester
The title compound was described as starting material in Example 1 F as 7-methoxynaphthalene-2-sulfonic acid [1- (5-cyanothiophen-3-ylmethyl) -2-oxo-pyrrolidine- Prepared using 3- (S) -yl] -pyridin-2-ylmethyl amide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 60% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid. The solid obtained (0.80 g, 1.04 mmol) is dissolved in 10 ml CH ₂ Cl ₂ : DMF (10: 1). To the solution is added N-methylpiperidine (0.46 g, 4.68 mmol) and ethyl chloroformate (0.11 g, 1.04 mmol). The reaction mixture is stirred for 16 hours. The solution is then diluted with CH ₂ Cl ₂ . The organic solution is washed with H ₂ O. The organic layer is dried over MgSO ₄ , filtered and concentrated. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 70% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.5 (bs, 4H), 9.03 (bs, 2H), 8.48 (d, 1H), 8.41 (s, 1H), 8.03 (d, 1H), 7.93 ( d, 1H), 7.86 (m, 1H), 7.77 (m, 4H), 7.66 (s, 1H), 7.52 (s, 1H), 7.32 (m, 1H), 4.90 (m, 1H), 4.42 (AB , 2H), 4.42 (AB, 2H), 4.10 (q, 2H), 3.90 (s, 3H), 3.12 (m, 2H), 2.12 (m, 1H), 1.78 (m, 1H), 1.18 (t, 3H). FAB MS, [M + H] ⁺ = 622.
Example 68
4-amino-3- {3- (S)-[(7-methoxy-naphthalene-2-sulfonyl) -pyridin-2-ylmethyl-amino] -2-oxo-pyrrolidin-1-ylmethyl } -Benzamidine trifluoroacetate
A. 4-amino-3-methylbenzonitrile
To a solution of 3-methyl-4-nitrobenzonitrile (2 g, 12.3 mmol) in 100 ml of EtOH is added SnCl ₂ (13.9 g, 61.7 mmol). The obtained solution is refluxed. After 2 hours the solution is cooled to room temperature. Pour the solution into 150 ml of ice water. The pH of the solution is adjusted to less than 7 with saturated NaHCO ₃ solution. The solution is diluted with EtOAc and the resulting mixture is filtered through celite roll. Separate the filtrate. The organic layer is dried over MgSO ₄ , filtered and concentrated to give the title compound (1.57 g, 8.7 mmol) as a gray solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.30 (m, 2H), 6.63 (d, 1H), 4.10 (bs, 2H), 2.15 (m, 2H). EI MS, [M] ⁺ = 132.
B. 4- (benzhydrylindenylamino) -3-methylbenzonitrile
To a solution of 4-amino-3-methylbenzonitrile (1.2 g, 9.08 mmol) in 75 ml of toluene is added benzophenone (1.74 g, 9.53 mmol) and p-toluenesulfonic acid (0.43 g, 2.1 mmol). The reaction vessel is equipped with a Dean Stark trap and the solution is heated to reflux. After 24 hours the solution is cooled to room temperature. The solution is concentrated. Crude material is purified by column chromatography eluting with a concentration gradient of 5% to 10% EtOAc / hexanes. The title compound (0.91 g, 2.43 mmol) is obtained as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.80 (m, 2H), 7.40 (m, 6H), 7.30 (s, 1H), 7.15 (d, 1H), 7.05 (bs, 2H), 6.50 (d, 1H), 2.20 (s, 3H). EI MS, [M] ⁺ = 296.
C. 4- (benzhydrylindenylamino) -3-bromomethylbenzonitrile
To a solution of 4- (benzhydrylindenylamino) -3-methylbenzonitrile (1.36 g, 4.27 mmol) in 40 ml of toluene, benzophenone (1.74 g, 9.53 mmol) and p-toluenesulfonic acid (0.43 g, 2.1 mmol) Add. The reaction vessel is equipped with a Dean Stark trap and the solution is heated to reflux. After 24 hours the solution is cooled to room temperature. The solution is concentrated. The unpurified product is purified by column chromatography eluting with a concentration gradient of 5% to 10% EtOAc / hexanes. The title compound (0.91 g, 2.43 mmol) is obtained as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.80 (m, 2H), 7.60 (d, 1H), 7.35 (m, 8H), 7.15 (dd, 1H), 6.35 (d, 1H), 4.55 (s, 2H). EI MS, [M] ⁺ = 374.
D. {1- [2- (Benzhydrylidenylamino) -5-cyano-benzyl] -2-oxopyrrolidin-3-yl} -carbamic acid tertiary butyl ester
The title compound is prepared using 4- (benzhydroylidenylamino) -3-bromomethylbenzonitrile instead of α-bromo-m-toluyl nitrile as described in Example 1. Crude material is purified by column chromatography eluting with a concentration gradient of 30% to 40% EtOAc / hexanes. The title compound is obtained as a yellow solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.70 (bs, 2H), 7.40 (s, 1H), 7.38 (bs, 6H), 7.30 (d, 1H), 7.15 (bs, 2H), 6.48 (d, 1H), 5.00 (d, 1H), 4.45 (AB, 2H), 4.15 (m, 1H), 3.30 (m, 2H), 2.61 (m, 1H), 1.90 (m, 1H), 1.45 (s, 9H ).
E. 7-methoxynaphthalene-2-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxopyrrolidin-3-yl] amide
Hydrogen chloride gas bubbles were blown for 5 min at 0 ° C. in 75 ml of EtOAc in {1- [2- (benzhydryldenylamino) -5-cyanobenzyl] -2-oxopyrrolidin-3-yl} carbamic acid 3 Inject into a solution of a tert-butyl ester (0.70 g, 1.42 mmol). After 1 hour the solution is concentrated. The obtained residue is dissolved in 50 ml of CH ₃ CN. To the solution is added triethyl amine (0.97 ml, 5.68 mmol) and 7-methoxynaphthalene sulfonyl chloride (0.38 g, 1.49 mmol). After 5 hours the reaction mixture is diluted with EtOAc. The resulting solution is washed with saturated NaHCO ₃ and saturated NaClfh. The organic layer is dried over MgSO ₄ , filtered and concentrated. Crude material is purified by column chromatography eluting with 5% CH ₃ OH / CH ₂ Cl ₂ . The title compound (0.60 g, 1.21 mmol) is obtained as a yellow solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.30 (s, 1H), 7.90 (d, 1H), 7.80 (d, 1H), 7.70 (d, 1H), 7.35 (m, 4H), 6.55 (d, 1H), 5.25 (d, 1H), 4.90 (s, 2H), 4.30 (AB, 2H), 3.95 (s, 3H), 3.75 (m, 1H), 3.20 (m, 2H), 2.55 (m, 1H ), 2.00 (m, 1 H).
F. 7-methoxynaphthalene-2-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxopyrrolidin-3-yl] -pyridin-2-ylmethyl-amide
2-Picolyl chloride hydrochloride (0.14 g, 0.84 mmol) was added to 7-methoxynaphthalene-2-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2 in DMF / acetone (5 ml / 20 ml). Oxopyrrolidin-3-yl] amide (0.33 g, 2.39 mmol), potassium carbonate (0.33 g, 2.39 mmol) and tetrabutylammonium iodine (0.07 g, 0.20 mmol) solution. The resulting solution is heated to reflux overnight and then cooled to room temperature. The reaction mixture is diluted with ethyl acetate and washed with brine. The organic layer is dried over MgSO ₄ , filtered and concentrated. Crude material is purified by column chromatography eluting with a concentration gradient of EtOAc / CH ₂ Cl ₂ 10%. The title compound (0.27 g, 0.50) is obtained as a foamy white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.4 (m, 2H), 7.95-7.8 (m, 3H), 7.65 (m, 2H), 7.35-7.23 (m, 4H), 7.15 (m, 1H), 6.55 (d, 1H), 4.9 (bs, 2H), 4.75 (t, 1H), 4.65 (d, 1H), 4.4-4.3 (m, 2H), 4.2-4.15 (m, 1H), 3.95 (s, 3H), 3.1 (m, 2H), 2.75 (m, 1H), 2.0-1.92 (m, 1H).
G. 4-Amino-3- {3- (S)-[(7-methoxy-naphthalene-2-sulfonyl) -pyridin-2-ylmethyl-amino] -2-oxo-pyrrolidine-1- Monomethyl} -benzamidine trifluoroacetate
The title compound was described as starting material in Example 1 F as 7-methoxynaphthalene-2-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxopyrrolidine-3- Prepared] ylpyridin-2-ylmethyl-amide.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.80 (s, 2H), 8.55 (s, 2H), 8.45 (d, 1H), 8.41 (s, 1H), 8.03 (d, 1H), 7.96 ( d, 1H), 7.84 (t, 1H), 7.78 (d, 1H), 7.69 (d, 1H), 7.47-7.54 (m, 2H), 7.41 (s, 1H), 7.30-7.38 (m, 2H) , 6.71 (d, 1H), 4.93 (t, 1H), 4.50 (AB, 2H), 4.30 (AB, 2H), 3.91 (s, 3H), 3.15 (m, 2H), 2.16 (m, 1H), 1.78 (m, 1 H). FAB MS, [M + H] ⁺ = 559.
Example 69
2-[[1- (2-amino-5-carbamididoyl-benzyl) -2-oxo-pyrrolidin-3- (S) -yl}-(7-methoxy-naphthalene-2-sulfonyl ) -Amino] -acetic acid tertiary butyl ester
The title compound was prepared as starting material 7-methoxynaphthalene-2-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxopyrrolidine-3 as described in Example 66A. -Yl] amide. The crude product is purified by column chromatography eluting with a concentration gradient of 10% to 20% EtOAc / CH ₂ Cl ₂ to afford the product as a yellow oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.40 (s, 1H), 7.90 (d, 1H), 7.77-7.83 (m, 2H), 7.37 (dd, 1H), 7.21-7.31 (m, 3H), 6.58 (d, 1H), 4.92 (s, 2H), 4.61 (m, 1H), 4.30 (AB, 2H), 3.98 (s, 3H), 3.20 (m, 2H), 2.49 (m, 1H), 2.30 (m, 1 H), 1.55 (s, 9 H).
B. 2-[[1- (2-Amino-5-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl}-(7-methoxy-naphthalene-2-sulfonyl) -Amino] -acetic acid
The title compound was described as starting material in Example 66 C as 2-[[1- (2-amino-5-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl} -(7-methoxy-naphthalene-2-sulfonyl) -amino] -acetic acid tertiary butyl ester. After workup the crude product is used in the next step without further purification.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.42 (s, 1H), 8.05-7.9 (m, 2H), 7.75 (d, 1H), 7.55 (s, 1H), 7.4-7.3 (m, 2H ), 7.25-7.15 (m, 2H), 6.65 (d, 1H), 4.85 (m, 2H), 4.2-4.18 (m, 2H), 3.95 (s, 3H), 3.65 (d, 1H), 3.2- 3.15 (m, 2 H), 2.3-2.2 (m, 1 H), 2.15-2.0 (m, 1 H).
C. 2-[[1- (2-amino-5-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl}-(7-methoxy-naphthalene-2-sulfonyl) -Amino] acetamide
Diisopropylethylamine (0.42 ml, 2.39 mmol) followed by TBTU90.27 g, 0.84 mmol) in 2-[[1- (2-amino-5-cyanobenzyl) -2-oxo pyrroli in DMF (8 ml). To din-3- (S) -yl}-(7-methoxy-naphthalene-2-sulfonyl) -amino] acetic acid solution. The mixture is stirred for 10 minutes, then concentrated ammonium hydroxide (0.12 ml) is added. After stirring for 2 hours the reaction mixture is diluted with EtOAc and washed with 1N HCl and brine. The organic layer is dried over MgSO ₄ , filtered and concentrated to dryness. The crude product is purified by column chromatography eluting with EtOAc: CH ₂ Cl ₂ : MeOH 5: 5: 1 to afford the title compound (0.38 g, 0.75 mmol) as a pale yellow foamy solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.35 (s, 1H), 8.0 (s, 1H), 7.9-7.85 (d, 1H), 7.8-7.65 (m, 3H), 7.4-7.2 (m, 3H ), 6.6 (d, 1H), 5.5 (bs, 1H), 4.95 (bs, 2H), 4.8-4.7 (t, 1H), 4.47 (d, 1H), 4.17 (d, 1H), 3.98 (s, 3H), 3.67 (s, 2H), 3.26 (m, 2H), 2.27 (m, 1H), 1.91 (m, 1H).
D. 2-[[1- (2-Amino-5-carbamimidoyl-benzyl) -2-oxo-pyrrolidin-3- (S) -yl}-(7-methoxy-naphthalen-2-sul Ponyyl) -amino] -acetamide trifluoroacetate
The title compound is 2-[[1- (2-amino-5-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl} as starting material as described in F of Example 1 -(7-methoxy-naphthalene-2-sulfonyl) -amino] -acetamide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 100% CH ₃ CN. The appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.8 (s, 2H), 8.47 (d, 2H), 8.05 (d, 1H), 7.97 (d, 1H), 7.77 (d, 1H), 7.6- 7.5 (m, 3H), 7.47 (s, 1H), 7.37 (m, 1H), 7.22 (s, 1H), 6.72 (d, 1H), 6.40-6.00 (b, 1H), 4.84 (t, 1H) , 4.27 (AB, 2H), 3.90 (s, 3H), 3.86 (d, 1H), 3.20 (m, 2H), 2.15 (m, 1H), 2.05 (m, 1H). FAB MS, [M + H] ⁺ = 525.
Example 70
[Imino- (3- {3-[(7-methoxy-naphthalene-2-sulfonyl) -methylamino] -2-oxo-3- (S) -pyrrolidin-1-ylmethyl} -4 -Amino-phenyl) -methyl] carbamic acid ethyl ester
A. {1- [2- (Benzhydrylidenylamino) -5-cyano-benzyl] -2-oxopyrrolidin-3-yl} -N-methylcarbamic acid tert-butyl ester
{1- [2- (Benzhydrylidenylamino) -5-cyano-benzyl] -2-oxopyrrolidin-3-yl} -N-methylcarbamic acid tert-butyl in 8 ml of DMF at 0 ° C. To the ester (3.94 g, 7.98 mmol) solution is added 60% of a mineral oil dispersion of NaH. After 20 minutes methyl iodine (0.99 ml, 15.9 mmol) is added. After 2 hours the solution is diluted with saturated NH ₄ Cl and EtOAc. Separate the layers. The organic layer is washed with H ₂ O and saturated NaCl. The organic layer is dried over MgSO ₄ , filtered and concentrated. Crude material is purified by column chromatography eluting with a concentration gradient of 30% to 50% EtOAc / hexanes. The title compound (3.72 g, 7.31 mmol) is obtained as a yellow solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.70 (bs, 2H), 7.45 (m, 8H), 7.10 (bs, 2H), 6.45 (dd, 1H), 4.70 (m, 1H), 4.49 (AB, 2H), 3.30 (m, 2H), 2.83 (s, 3H), 2.35 (m, 1H), 2.10 (m, 1H), 1.50 (s, 9H). FAB MS, [M + H] ⁺ = 509.
B. 7-methoxynaphthalene-2-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxopyrrolidin-3-yl] -N-methylamide
The title compound was prepared as described in E of Example 1 {1-[[2- (benzhydrylidenylamino) -5-cyanobenzyl] -2-oxopyrrolidin-3-yl} carbamic acid 3 {1- [2- (Benzhydrylidenylamino) -5-cyanobenzyl] -2-oxopyrrolidin-3-yl} -N-methylcarbamic acid tertiary butyl ester in place of the tertiary butyl ester To manufacture. The title compound is obtained as a yellow solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.38 (s, 1H), 7.87 (d, 1H), 7.78 (d, 1H), 7.72 (dd, 1H), 7.32 (dd, 1H), 7.30 (dd, 1H), 7.28 (d, 1H), 7.23 (dd, 1H), 6.55 (d, 1H), 4.98 (s, 2H), 4.25 (AB, 2H), 4.15 (m, 1H), 3.98 (s, 3H ), 3.20 (m, 2H), 2.70 (s, 3H), 1.95 (m, 1H).
C. 4-Amino-3- [3- (S)-(7-methoxynaphthalene-2-sulfonyl-N-methylamino) -2-oxopyrrolidin-1-ylmethyl] benzamidine trifluor Loacetate
7-methoxynaphthalene-2-sulfonic acid [1- (2-amino-5-cyano-benzyl) -2-oxopyrrolidin-3-yl] methylamide as described in Example F with the title compound Switch to The crude product is purified using RP-HPLC, eluting with a gradient of 10% to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.90 (bs, 2H), 8.75 (bs, 2H), 8.40 (s, H), 8.50 (d, 1H), 7.95 (d, 1H), 7.70 ( dd, 1H), 7.60 (d, 1H), 7.55 (dd, 1H), 7.48 (d, 1H), 7.39 (dd, 1H), 6.70 (d, 1H), 6.00 (bs, 1H), 4.98 (m , 1H), 4.20 (AB, 2H), 3.90 (s, 3H), 3.15 (m, 2H), 2.67 (s, 3H), 2.05 (m, 1H), 1.70 (m, 1H).
FAB MS, [M + H] ⁺ = 482.
Elemental Analysis (with 1.3 mmol of H ₂ O):
Calculation: C 50.49%, H 4.98%, N 11.32%
Found: C 50.50%, H 4.50%, N 10.99%
D. [Imino- (3- {3- [7-methoxy-naphthalene-2-sulfonyl) -methylamino] -2-oxo-3- (S) -pyrrolidin-1-ylmethyl]} 4-Amino-phenyl) -methyl] carbamic acid ethyl ester
The title compound was used as the starting material as described in Example 67 C as 4-amino-3- [3- (S)-(7-methoxynaphthalene-2-sulfonylmethylamino) -2-oxopyrrolidine 1-ylmethyl] benzamidine trifluoroacetate. The crude product is purified by column chromatography eluting with MeOH / CH ₂ Cl ₂ 3% to give a white solid as a product.
¹ H NMR (CDCl ₃ , 300 MHz) δ 9.60 (bs, 1H), 8.41 (s, 1H), 7.97 (d, 1H), 7.70-7.80 (m, 3H), 7.54 (d, 1H), 7.30 ( m, 2H), 6.50 (d, 1H), 4.90 (m, 1H), 4.85 (s, 2H), 4.40 (AB, 2H), 4.30 (q, 2H), 3.98 (s, 3H), 3.25 (m , 2H), 2.80 (s, 3H), 2.25 (m, 1H), 1.95 (m, 1H), 1.35 (t, 3H). FAB MS, [M + H] ⁺ = 554.
Example 71
4-hydroxy-3- {3- (S)-[5- (1-hydroxy-pyridin-4-yl) -thiophene-2-sulfonyl amino] -2 -oxo-pyrrolidine-1- Monomethyl} -benzamidine trifluoroacetate
A. 5-Pyridin-4-yl-thiophene-2-sulfonic acid [1- (5-cyano-2-hydroxybenzyl) -2-oxo-pyrrolidin-3- (S) -yl]- amides
The title compound was substituted with 5-pyridin-4-yl-thiophene-2-sulfonyl chloride in place of 4,6-dichlorobenzo [b] thiophene-2-sulfonylchloride as described in G of Example 17. To manufacture.
¹ H NMR (CDCl ₃ , 300 MHz) δ 9.30 (bs, 1H), 8.68 (m, 2H), 7.70 (d, 1H), 7.53 (dd, 1H), 7.40-7.45 (m, 3H), 7.39 ( d, 1H), 6.98 (d, 1H), 5.34 (d, 1H), 4.34 (AB, 2H), 4.05 (m, 1H), 2.70 (m, 2H), 2.10 (m, 1H), 0.98 (m , 1H).
FAB-MS, [M + H] ⁺ = 455.
B. 5-Pyridin-4-yl-thiophene-2-sulfonic acid [1- [2- (tert-butyl-dimethyl-silanyloxy) -5-cyanobenzyl] -2-oxo-pyrrolidine -3- (S) -yl] -amide
Tert-butyldimethylsilyl chloride (0.129 g, 0.856 mmol) was added 5-pyridin-4-yl-thiophene-2-sulfonic acid [1- (5-cyano-2-hydroxybenzyl) in DMF (14 ml). To a solution of 2-oxo-pyrrolidin-3- (S) -yl] -amide (0.325 g, 0.715 mmol) and imidazole (0.122 g, 1.79 mmol). The resulting mixture is stirred at rt overnight then diluted with EtOAc and washed with saturated sodium bicarbonate, water and brine. The organic layer is dried over MgSO ₄ , filtered and concentrated to dryness. The crude product is purified by column chromatography eluting with 5% MeOH / CH ₂ Cl ₂ to afford the title compound (0.330 g, 0.580 mmol) as a foamy yellow solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.70 (m, 2H), 7.70 (d, 1H), 7.45-7.50 (m, 4H), 7.30 (d, 1H), 6.88 (d, 1H), 5.45 ( d, 1H), 4.45 (AB, 2H), 3.98 (m, 1H), 3.20 (m, 2H), 2.61 (m, 1H), 2.13 (m, 1H), 0.98 (s, 9H), 0.25 (s , 6H).
FAB MS, [M + H] ⁺ = 569.
C. 5- (1-Hydroxy-pyridin-4-yl) -thiophene-2-sulfonic acid [1- [2- (tert-butyl-dimethyl-silanyloxy) -5-cyanobenzyl]- 2-oxo-pyrrolidin-3- (S) -yl] -amide
m-Chlorobenzoic acid (0.309 g of 65% grade m-CPBA) was converted to 5-pyridin-4-yl-thiophene-2-sulfonic acid [1- [2- (tert-butyl-) in CH ₂ Cl ₂ (19 ml). To dimethyl-silanyloxy) -5-cyanobenzyl] -2-oxopyrrolidin-3- (S) -yl] amide (0.330 g, 0.54 mmol) solution. The resulting solution is stirred at room temperature for 5 hours and then diluted with additional CH ₂ Cl ₂ and washed with saturated sodium bicarbonate and brine. The organic layer is dried over MgSO ₄ , filtered and concentrated. Crude material is used in the next step without further purification.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.23 (d, 2H), 7.68 (d, 1H), 7.50 (d, 2H), 7.38 (d, 1H), 7.30 (d, 1H), 6.90 (d, 1H), 5.45 (d, 1H), 4.45 (AB, 2H), 3.98 (m, 1H), 4.23 (m, 2H), 2.70 (m, 1H), 2.20 (m, 1H), 0.98 (s, 9H ), 0.20 (s, 6H).
FAB MS, [M + H] ⁺ = 585.
D. 4-hydroxy-3- [3- (S)-[5- (1-hydroxy-pyridin-4-yl) -thiophene-2-sulfonyl amino] -2-oxo-pyrrolidine- 1-ylmethyl] -benzamidine trifluoroacetate
The title compound is 5-pyridin-4-yl-thiophene-2-sulfonic acid [1- (5-cyano-2-hydroxybenzyl) -2-oxo as starting material as described in F of Example 1 -Pyrrolidin-3- (S) -yl] -amide. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% CH ₃ CN / H ₂ O (0.1% TFA) to 100% CH ₃ CN. The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.98 (bs, 1H), 9.10 (s, 2H), 8.80 (s, 2H), 8.50 (d, 1H), 8.30 (d, 2H), 7.68- 7.80 (m, 4H), 7.61 (d, 1H), 7.40 (d, 1H), 6.98 (d, 1H), 4.45 (AB, 2H), 4.20 (m, 1H), 3.20 (m, 2H), 2.14 (m, 1 H), 1.70 (m, 1 H). Ion spray MS, [M + H] ⁺ = 488.
Example 72
4-amino-3- [3- (S)-)-(5-chloro-thieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl ] -Hydroxybenzamidine trifluoroacetate
4-amino-3- [3- (S)-(5-chloro-thieno [3,2-b] pyridine-2-sulfonylamino) -2-oxopyrrolidin-3- (S) yl] The amide is converted to the title compound as described in Example 27. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 60% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.97 (bs, 1H), 8.94 (d, 1H), 8.68 (d, 1H), 8.66 (bs, 1H), 8.10 (s, 1H), 7.64 ( d, 1H), 7.37 (d, 1H), 7.28 (s, 1H), 6.71 (d, 1H), 6.07 (bs, 2H), 4.31 (m, 1H), 4.18 (AB, 2H), 3.21 (m , 2H), 2.21 (m, 1 H), 1.70 (m, 1 H). FAB MS, [M + H] ⁺ = 495, 497, Cl pattern.
Elemental analysis (containing 1.05 mol of H ₂ O);
Calculated Value: C 40.17%, H 3.55%, N 13.38% Cl 5.65%
Found: C 40.16%, H 2.99%, N 12.99% Cl 6.28%
Example 73
4-amino-3- [3- (s)-(5-methoxy-thieno [3,2-b] pyridin-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl]- Benzamidine Bistrifluoroacetate
4-amino-3- [3- (S)-(5-chlorothieno [3,2-b] pyridin-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] benzamidine Trifluoroacetate is converted to the title compound as described in Example 26. The reaction mixture is heated at 50 ° C. and hydrogenated at 50 psi for 3 days. The crude product was purified using RP-HPLC, eluting with a gradient of 10% to 80% of CH ₃ CN / H ₂ O (0.1% TFA), and the appropriate fractions were lyophilized to give 4-amino-3- [as the main product. 2-oxo-3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine bistrifluoroacetate and white solid A small amount of byproduct as a title compound is obtained.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.80 (bs, 2H), 8.77 (d, 1H), 8.48 (bs, 2H), 8.45 (d, 1H), 7.96 (s, 1H), 7.53 ( dd, 1H), 7.41 (d, 1H), 7.02 (d, 1H), 6.71 (d, 1H), 4.30 (m, 1H), 4.20 (AB, 2H), 3.95 (s, 3H), 3.20 (m , 2H), 2.20 (m, 1 H), 1.69 (m, 1 H). FAB MS, [M + H] ⁺ = 475.
Example 74
3- [3- (S)-(5-isoxazol-3-yl-thiophen-2-sulfonylamino) -2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] -benz Amidine trifluoroacetate
A. 5-isoxazol-3-yl-thiophen-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
The title compound was substituted with 5-isoxazol-3-yl-thiophene-2-sulfonyl chloride in place of benzo [b] thiophene-2-sulfonyl chloride as described in E of Example 1 Prepared from (3- (S) amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride. The crude product is used in later stages without further purification.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.36 (d, 1H), 7.70 (d, 1H), 7.61 (m, 1H), 7.49 (m, 4H), 6.57 (d, 1H), 5.55 (bs, 1H), 4.51 (s, 2H), 3.97 (m, 1H), 3.29 (m, 2H), 2.69 (m, 1H), 2.17 (m, 1H).
B. 3- [3- (S)-(5-isoxazol-3-yl-thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Loacetate
5-isoxazol-3-yl-thiophen-2-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide of Example 1 Convert to the title compound as described in F. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 40% CH ₃ CN / H ₂ O (0.1% TFA). The appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.31 (bs, 2H), 9.22 (bs, 2H), 8.74 (s, 1H), 8.70 (d, 1H), 7.75 (m, 3H), 7.57 ( m, 3H), 7.10 (d, 1H), 4.44 (AB, 2H), 4.26 (m, 1H), 3.15 (m, 2H), 2.20 (m, 1H), 1.71 (m, 1H). FAB MS, [M + H] ⁺ = 446.
Elemental analysis (contains 1.58 mol of H ₂ O)
Calculated Value: C 42.90%, H 3.97%, N 11.91%
Found: C 42.92%, H 3.39%, N 11.31%
Example 75
4-Amino-3- [3- (S)-(5-isoxazol-3-yl-thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate
A. 5-isoxazol-3-yl-thiophene-2-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] amide
The title compound was substituted for 4-isoxazol-3-yl-thiophen-2-sulfonyl chloride in place of 4,6-dichlorobenzo [b] thiophen-2-sulfonyl chloride as described in F of Example 17. Prepare from 4-amino-3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile dihydrochloride using The crude product is used in later stages without further purification.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.35 (d, 1H), 7.81 (d, 1H), 7.69 (d, 1H), 7.50 (d, 2H0, 7.39 (dd, 1H), 6.65 (d, 1H ), 6.59 (d, 1H), 4.32 (AB, 2H), 4.02 (m, 1H), 3.30 (m, 2H), 2.60 (m, 1H), 2.08 (m, 1H).
B. 4-Amino-3- [3- (S)-(5-isoxazol-3-yl-thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benz Amidine trifluoroacetate
5-isoxazol-3-yl-thiophene-2-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide Convert to the title compound as described in F of Example 1. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 70% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.80 (bs, 2H), 8.75 (d, 1H), 8.70 (d, 1H), 8.52 (bs, 2H), 7.75 (s, 2H), 7.52 ( dd, 1H), 7.45 (d, 1H), 7.10 (d, 1H), 6.71 (d, 1H), 6.20 (bs, 1H), 4.28 (m, 1H), 4.21 (AB, 2H), 3.20 (m , 2H), 2.20 (m, 1 H), 1.70 (m, 1 H). IS MS, [M + H] ⁺ = 461.
Example 76
4-hydroxy-3- [3- (S)-(5-isoxazol-3-yl-thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl} -benzami Dean trifluoroacetate
A. 5-isoxazol-3-yl-thiophene-2-sulfonic acid [1- (5-cyano-2-hydroxybenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amides
The title compound was substituted for 4-isoxazol-3-yl-thiophen-2-sulfonyl chloride in place of 4,6-dichlorobenzo [b] thiophen-2-sulfonyl chloride as described in F of Example 17. Prepared from 4-hydroxy-3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride. The crude product is purified by column chromatography eluting with 50% EtOAc / CH ₂ Cl ₂ to give a solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 9.37 (bs, 1H), 8.35 (d, 2H), 7.50 (m, 2H), 7.41 (d, 1H0, 7.00 (d, 1H), 6.57 (d, 1H ), 5.48 (bs, 1H), 4.35 (AB, 2H), 4.10 (m, 1H), 3.50 (m, 2H), 2.70 (m, 1H), 2.20 (m, 1H).
B. 4-hydroxy-3- [3- (S)-(5-isoxazol-3-yl-thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl}- Benzamidine trifluoroacetate
5-isoxazol-3-yl-thiophene-2-sulfonic acid [1- (5-cyano-2-hydroxybenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide Is converted to the title compound as described in F of Example 1. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to yield the title compound as a pale yellow solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.04 (bs, 2H), 8.87 (bs, 2H), 8.73 (d, 1H), 8.67 (d, 1H), 7.74 (m, 2H), 7.61 ( dd, 1H), 7.42 (d, 1H), 7.09 (d, 1H), 6.97 (d, 1H), 4.33 (AB, 2H), 4.23 (m, 1H), 3.21 (m, 2H), 2.21 (m , 1H), 1.75 (m. 1H).
IS MS, [M + H] ⁺ = 462.
Elemental Analysis (Contains 0.87mol of H ₂ O)
Calculated Value: C 42.65%, H 3.49%, N 11.41%
Found: C 42.65%, H 3.49%, N 11.41%
Example 77
3- (S)-[3-([2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
A. [2,2 '] bithiophenyl-5-sulfonyl chloride
The title compound was substituted with 3- (3- (S) -amino-2-oxo- using [2,2 '] bithiophenyl-5-sulfonyl chloride in place of thianaphthalene as described in D of Example 1 Prepared from pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride. The crude product is used in the next step without further purification.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.78 (d, 1H), 7.43 (d, 1H), 7.36 (d, 1H), 7.17 (d, 1H), 7.10 (t, 1H). EI MS, [M] ⁺ = 264, 266, Cl pattern.
B. [2,2 ']-Bithiophenyl-5-sulfonyl acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amino
The title compound was prepared in 3- (3- (3) using [2,2 '] bithiophenyl-5-sulfonyl chloride instead of benzo [b] thiophene-2-sulfonyl chloride as described in Example E. S) -Amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride. The crude product is used in the next step without further purification.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.60 (d, 2H), 7.50 (s, 1H), 7.46 (d, 2H), 7.34 (d, 1H), 7.28 (d, 1H), 7.13 (d, 1H), 7.06 (m, 1H), 5.46 (bs, 1H), 4.48 (s, 2H), 3.91 (m, 1H), 3.26 (m, 2H), 2.68 (m, 1H), 2.19 (m, 1H ).
C. 3- (S)-[3-([2,2 ']-bithiophenyl-5-sulfonylamino-2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate
[2,2 ']-bithiophenyl-5-sulfonic acid [1- (3-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide was obtained in F of Example 1. Convert to the title compound as described. The crude product is purified using RP-HPLC, eluting with a gradient of 10% to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.30 (bs, 2H), 9.10 (bs, 2H), 8.51 (d, 1H), 7.68 (m, 2H), 7.58 (m, 4H), 7.50 ( d, 1H), 7.35 (d, 1H), 7.15 (m, 1H), 4.47 (AB, 2H), 4.21 (m, 1H), 3.19 (m, 2H), 2.20 (m, 1H), 1.71 (m , 1H).
IS MS, [M + H] ⁺ = 461
Elemental analysis (contains 0.95 mol of H ₂ O)
Calculation: C 44.66%, H 3.90%, N 9.47%
Found: C 44.65%, H 3.20%, N 9.05%
Example 78
4-Amino-3- [3- (S)-([2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Loacetate
A. [2,2 ']-Bithiophenyl-5-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide
The title compound was prepared using [2,2 ′] bithiophenyl-5-sulfonyl chloride in place of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride as described in F of Example 17. Prepared from 4-amino-3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile dihydrochloride. The crude product is purified by column chromatography eluting with a concentration gradient of 10% to 25% EtOAc / CH ₂ Cl ₂ to give a solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 7.54 (d, 1H), 7.36 (m, 2H), 7.30 (m, 2H), 7.12 (d, 1H), 7.07 (dd, 1H), 6.60 (d, 1H), 5.39 (bs, 1H), 4.93 (bs, 2H), 4.31 (AB, 2H), 3.94 (m, 1H), 3.30 (m, 2H), 2.65 (m, 1H), 2.11 (m, 1H ).
B. 4-Amino-3- [3- (S)-[2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] benzamidine trifluor Loacetate
Example [2,2 ']-bithiophenyl-5-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -amide Convert to the title compound as described in F of 1. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 60% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.79 (bs, 2H), 8.50 (d, 1H), 8.48 (bs, 2H), 7.65 (dd, 1H), 7.59 (d, 1H), 7.51 ( dd, 1H), 7.47 (d, 1H), 7.43 (d, 1H), 7.34 (d, 1H), 7.14 (m, 1H), 6.72 (d, 1H), 6.20 (bs, 2H), 4.20 (m , 3H), 3.20 (m, 2H), 2.20 (m, 1H), 1.70 (m, 1H). FAB MS, [M + H] ⁺ = 476.
Elemental analysis (contains 1.2 mol of H ₂ O)
Calculated Value: C 43.23%, H 4.02%, N 11.46%
Found: C 43.17%, H 3.43%, N 10.87%
Example 79
4-Amino-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl]- Benzamidine trifluoroacetate
A. 5'-Chloro- [2,2 ']-bithiophenyl-5-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxo-pyrrolidine-3- (S)- General] -amide
The title compound was prepared using [2,2 ′] bithiophenyl-5-sulfonyl chloride in place of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride as described in F of Example 17. Prepared from 4-amino-3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile dihydrochloride. The crude product is purified by column chromatography eluting with a gradient of 10% to 30% EtOAc / CH ₂ Cl ₂ to give a medium solid.
¹ H NMR (CDCl ₃ + CD ₃ OD, 300 MHz) δ 7.59 (d, 1H), 7.39 (dd, 1H), 7.31 (dd, 1H), 7.08 (m, 2H), 6.90 (d, 1H), 6.65 (d, 1H), 4.30 (AB, 2H), 4.05 (m, 1H), 3.25 (m, 2H), 2.52 (m, 1H), 2.03 (m, 1H).
B. 4-Amino-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl ] -Benzamidine trifluoroacetate
5'-Chloro- [2,2 ']-bithiophenyl-5-sulfonic acid [1- (2-amino-5-cyanobenzyl) -2-oxo-pyrrolidin-3- (S) -yl] -Amide is converted to the title compound as described in F of Example 1. The crude product is purified using RP-HPLC, eluting with a gradient of 10% to 80% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.84 (bs, 2H), 8.74 (bs, 2H), 8.57 (d, 1H), 7.61 (d, 1H), 7.56 (dd, 1H), 7.49 ( dd, 1H), 7.39 (dd, 2H), 7.20 (d, 1H), 6.75 (d, 1H), 4.22 (m, 3H), 3.20 (m, 2H), 2.19 (m, 1H), 1.70 (m , 1H). FAB MS, [M + H] ⁺ = 510, 512, Cl pattern.
Elemental analysis (contains 1.1 mol of H ₂ O)
Calculated Value: C, 41.07%, H 3.63%, N 10.88% Cl 5.51%
Found: C, 41.08%, H 3.14%, N 10.44%, Cl 5.77%
Example 80
4-hydroxy-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl} Benzamidine hydrochloride
A. 5'-Chloro- [2,2 ']-bithiophenyl-5-sulfonic acid [1- (5-cyano-2-hydroxybenzyl) -2-oxo-pyrrolidine-3- (S) -Yl] -amide
The title compound was replaced with 5'-chloro- [2,2 ']-bithiophenyl-5-sulfur instead of 4,6-dichlorobenzo [b] thiophene-2-sulfonyl chloride as described in F of Example 17. Prepare from 4-hydroxy-3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride using polyvinyl chloride. The crude product is purified by column chromatography eluting with 25% EtOAc / CH ₂ Cl ₂ to give a solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 9.30 (s, 1H), 7.57 (d, 1H), 7.53 (s, 1H), 7.45 (s, 1H), 7.30 (s, 1H), 7.08 (m, 1H), 7.00 (d, 1H), 6.90 (d, 1H), 5.40 (bs, 1H), 4.36 (AB, 2H), 4.05 (m, 1H), 3.51 (m, 2H), 2.70 (m, 1H ), 2.20 (m, 1 H).
B. 4-hydroxy-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-yl Methyl} -benzamidine hydrochloride
5'-Chloro- [2,2 ']-bithiophenyl-5-sulfonic acid [1- (5-cyano-2-hydroxybenzyl) -2-oxo-pyrrolidin-3- (S) -yl ] -Amide is converted to the title compound as described in F of Example 1. The crude product is purified using RP-HPLC, eluting with a concentration gradient of 10% to 80% CH ₃ CN / H ₂ O (0.1% TFA) and the appropriate product fractions are lyophilized to afford the title compound as a pale yellow solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.56 (bs, 2H), 9.24 (bs, 2H), 8.74 (d, 1H), 8.71 (d, 1H), 8.07 (m, 2H), 7.98 ( s, 1H), 7.61 (d, 1H), 7.42 (m, 1H), 4.45 (AB, 2H), 4.31 (m, 1H), 3.20 (m, 2H), 2.20 (m, 1H), 1.79 (m , 1H).
IS MS, [M + H] ⁺ = 511, 513, Cl pattern.
Example 81
4-hydroxy-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Hydroxybenzamidine
5'-Chloro- [2,2 ']-bithiophenyl-5-sulfonic acid [1- (5-cyano-2-hydroxybenzyl) -2-oxo-pyrrolidin-3- (S) -yl ] -Amide is converted to the title compound as described in Example 27. The crude product is purified by column chromatography eluting with a concentration gradient of 5% to 10% MeOH / CH ₂ Cl ₂ to afford the title compound as a white solid.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.83 (s, 1H), 9.38 (s, 1H), 8.53 (d, 1H), 7.60 (d, 1H), 7.40 (dd, 1H), 7.39 ( d, 1H), 7.34 (d, 1H), 7.31 (s, 1H), 6.78 (d, 1H), 5.66 (bs, 2H), 4.29 (AB, 2H), 4.10 (m, 1H), 3.15 (m , 2H), 2.20 (m, 1 H), 1.67 (m, 1 H). FAB MS, [M + H] ⁺ = 527, 529 Cl pattern.
Elemental Analysis (Contains 0.70mol of H ₂ O)
Calculated Value: C, 44.52%, H 3.81%, N 9.67%, Cl 8.51%
Found: C, 44.52%, H 3.59%, N 9.67%, Cl 8.51%
Example 82
4- [3- (S)-(6-Fluoro-benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -pyridine-2-carboxami Dean hydrochloride
A. 2-cyano-4-[{tert-butyldimethylsilyl) oxy} methyl] pyridine
The title compound is described in J. Heterocyclic Chod. 1993, 30, 631. The crude residue obtained is purified by column chromatography eluting with a concentration gradient of 5% to 20% EtOAc / hexanes to afford the title compound as a yellow oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.66 (d, 1H), 7.69 (s, 1H), 7.48 (s, 2H), 1.00 (s, 9H), 0.19 (s, 6H).
B. 2-cyano-4- (hydroxymethyl) pyridine
A solution of 2-cyano-4-[{tert-butyldimethylsilyl) oxy} methyl] pyridine (10.1 g, 40.5 mmol) in 200 ml of anhydrous MeOH was mixed with 12 g of Dowex-50W-H ⁺ ion exchange resin (preliminary) for 18 hours. Stirred with MeOH). The mixture is then filtered and washed twice with MeOH. The combined filtrates are concentrated in vacuo. Crude residue is purified by column chromatography eluting with 50% EtOAc / hexanes to give the title compound (4.82 g, 35.9) as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.70 (m, 1H), 7.75 (s, 1H), 7.55 (d, 1H), 4.87 (d, 2H), 2.31 (bs, 1H).
C. 2-cyano-4- (bromomethyl) pyridine
Bromine (6.88 g, 43.1 mmol) is added dropwise to a solution of triphenylphosphine (11.3 g, 43.1 mmol) in 280 ml CH ₂ Cl ₂ at 0 ° C. The mixture is stirred at 0 ° C. for 30 minutes. At this time, 2-cyano-4- (hydroxymethyl) pyridine (4.82 g, 35.9 mmol) is added and the resulting mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with CH ₂ Cl ₂ and washed with water (2 ×) and saturated NaCl solution. The organic layer is dried over MgSO ₄ , filtered and concentrated. The crude product is purified by column chromatography eluting with a concentration gradient of 20% to 30% EtOAc / hexanes to afford the title compound (6.40 g, 32.5 mmol) as an oil.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.75 (d, 1H), 7.79 (s, 1H), 7.60 (d, 1H), 4.49 (s, 2H).
D. [1- (2-Cyano-pyridin-4-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tertiary butyl ester
The title compound was prepared using (2-oxo-pyrrolidine-) using 2-cyano-4- (bromomethyl) pyridine instead of a-bromo-m-toluyl nitrile as described in Example 1 B. Prepared from 3- (S) -yl) -carbamic acid tertiary butyl ester. The crude product is purified by column chromatography eluting with a concentration gradient of 25% to 50% EtOAc / CH ₂ Cl ₂ to afford the title compound as a solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.69 (d, 1H), 7.70 (s, 1H), 7.46 (d, 1H), 5.42 (bs, 1H), 4.57 (AB, 2H), 4.22 (m, 1H), 3.35 (m, 2H), 2.62 (m, 1H), 2.10 (m, 1H), 1.50 (s, 9H).
E. 4- (3- (S) -Amino-2-oxo-pyrrolidin-1-ylmethyl) pyridine-2-carbonitrile trifluoroacetate
[1- (2-Cyano-pyridin-4-ylmethyl) -2-oxo-pyrrolidin-3- (S) -yl] -carbamic acid tertiary butyl ester in 50 ml of CH ₂ Cl ₂ (3.34 g, 10.6 mmol) add 5 ml of TFA. The reaction mixture is stirred for 18 hours and then concentrated to afford the title compound (3.40 g, 10.3 mmol) as a white blowing agent.
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 7.90 (d, 1H), 7.70 (bs, 3H), 7.09 (s, 1H), 6.80 (m, 1H), 3.78 (AB, 2H), 3.35 ( m, 1H), 2.55 (m, 2H), 1.62 (m, 1H), 1.20 (m, 1H).
F. 6-Fluoro-benzo [b] thiophene-2-sulfonic acid- [1- (2-cyano-pyridin-4-ylmethyl) -2-oxo-pyrrolidine-3- (S)- General] -amide
The title compound was substituted for 6-fluorobenzo [3- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) -benzonitrile hydrochloride as described in E of Example 1]. b] thiophen-2-sulfonyl chloride and 4- (3- (S) -amino-2-oxo-pyrrolidin-1-ylmethyl) pyridine-2-carbonitrile trifluoroacetate . The crude product is purified by column chromatography eluting with a concentration gradient of 10% to 25% EtOAc / CH ₂ Cl ₂ to afford the title compound as a white solid.
¹ H NMR (CDCl ₃ , 300 MHz) δ 8.66 (d, 1H), 7.97 (s, 1H), 7.83 (dd, 1H), 7.58 (s, 1H), 7.50 (dd, 1H), 7.39 (d, 1H), 7.20 (m, 1H), 6.40 (bs, 1H), 4.56 (AB, 2H), 4.12 (m, 1H), 3.31 (m, 2H), 2.65 (m, 1H), 2.20 (m, 1H ). IS MS, [M + H] ⁺ = 431.
G. 4- [3- (S)-(6-Fluoro-benzo [b] thiophene-2-oxo-pyrrolidin-1-ylmethyl] -pyridine-2-carboxamidine hydrochloride
Hydrogen sulfide gas bubbles in 6 ml of 6-fluoro-benzo [b] thiophene-2-sulfonic acid- [1- (2-cyano-pyridin-4-ylmethyl)-in 10 ml of a mixture of pyridine / triethylamine 10: 1. Inject into a solution of 2-oxo-pyrrolidin-3- (S) -yl] -amide (0.67 g, 1.56 mmol). After stirring the pale green solution for 64 hours, the reaction mixture is concentrated in vacuo. The residue is diluted with acetone and concentrated to yield crude thioamide. To thioamide solution in 20 ml of acetone is added iodine methane (5.5 ml). The resulting mixture was heated to reflux for 2.5 hours, cooled to room temperature and concentrated in vacuo to afford crude thiimidate hydrochloride. To a solution of thiimidate hydroiodide in 20 ml of MeOH is added ammonium acetate (0.60 g, 7.60 mmol). The resulting mixture is heated to reflux for 2 hours, cooled to room temperature and stirred overnight. The resulting mixture is concentrated in vacuo to afford the crude amidine salt. The crude product was purified using RP-HPLC, eluting with a gradient of 10% to 80% of CH ₃ CN / H ₂ O (0.05% TFA) and the appropriate product fraction was lyophilized to give the title compound (0.27 g as an amorphous white solid). , 0.56 mmol).
¹ H NMR (DMSO-d ₆ , 300 MHz) δ 9.10 (bs, 2H), 8.77 (bs, 2H), 8.55 (d, 1H), 7.63 (dd, 1H), 7.61 (d, 1H), 7.43 ( d, 1H), 7.35 (dd, 2H), 7.19 (d, 1H), 7.01 (d, 1H), 4.33 (AB, 2H), 4.20 (m, 1H), 3.25 (m, 2H), 2.20 (m , 1H), 1.77 (m, 1H). FAB MS, [M + H] ⁺ = 448.
Elemental Analysis (Contains 0.70mol of H ₂ O)
Calculated Value: C, 42.96%, H 4.62%, N 13.18%
Found: C, 42.96%, H 3.58%, N 12.80%
The molecules described herein inhibit blood coagulation due to their ability to inhibit terminal second enzymes in the blood coagulation step by inhibiting the activity of factor Xa. Both the activity of the factor Xa bound in the free factor Xa and prothrombin complexes (factor Xa, factor Va, calcium and phospholipids) is inhibited by the compound of formula (I). Inhibition of factor Xa activity is obtained by direct complexation between inhibitors and enzymes and is therefore independent of plasma co-factor antithrombin III. Effective inhibition of Factor Xa activity is achieved by oral administration, continuous intravenous infusion, pill intravenous administration or other parenteral methods of administration of the compound, resulting in the desired effect of inhibiting Xa activity leading to thrombin formation from prothrombin. Will be done.
Anticoagulant therapy is for the treatment and prevention of various thrombotic states of veins and arteries. In the arterial system, abnormal thrombus formation is intrinsically related to arteries of coronary, brain and peripheral blood vessels. Diseases associated with thrombotic occlusion of these vessels are mainly acute myocardial infarction (AMI), unstable angina, thromboembolism, treatment of thrombotic collapse and coronary angioplasty (PTCA) through percutaneous caliber, transient anemia Symptoms, seizures, intermittent claudication and bypass transplantation of coronary (CABG) or peripheral arteries. Long-term anticoagulant therapy may also be beneficial in preventing vascular stenosis that frequently occurs after PTCA and CABG, or in maintaining vascular inlet opening in long-term hemodialysis patients. In venous vessels, pathogenic thrombus formation often occurs in the veins of the extremities of the lower body after abdominal, knee and hip surgery (deep vein thrombosis, DVT). In addition, DVT makes patients at higher risk for pulmonary thromboembolism. Systemic diffuse coagulopathy (DIC) usually occurs in both the vascular system when suffering from septic shock, certain viral infections, and cancer. This condition is characterized by the rapid depletion of the coagulation factor and its plasma inhibitor, resulting in the formation of life-threatening thrombin throughout the microvessels of some organ systems. The signs include some, but not all, possible clinical conditions for which anticoagulant therapy is justified. Those skilled in the art are well aware of situations that require acute or chronic prophylactic anticoagulant therapy.
These compounds may be used alone or in combination with other diagnostic, anticoagulant, antiplatelet or fibrin solubilizers. Additional administration of factor Xa inhibitors of activity using, for example, standard heparin, low molecular weight heparin, direct thrombin inhibitors (ie hirudin), aspirin, fibrinogen receptor antagonists, streptokinase, urokinase and / or tissue plasminogen activators Can result in stronger antithrombotic or thrombolytic effects and effects. The compounds described herein can be administered to treat thrombotic complications in various animals, such as primates, including humans. Inhibition of factor Xa is useful not only in anticoagulant treatment for thrombotic individuals, but also wherever inhibition of blood coagulation is needed, such as to prevent clotting of whole stored blood or to prevent coagulation of other test or storage biological samples. Thus, all inhibitors to the activity of Factor Xa can be added to or in contact with the medium containing or believed to contain Factor Xa, thereby inhibiting blood coagulation.
In addition to its use in anticoagulant therapy, inhibitors of factor Xa activity may be useful in the treatment and prophylaxis of other physiological conditions suggesting that the production of thrombin plays a pathogenic role. For example, thrombin is an acute degenerative disease, such as arthritis, cancer, arteriosclerosis, vascular stenosis and Alzheimer's disease, due to its ability to regulate many different cell types through specific division and activation of cell surface thrombin receptors. Are believed to contribute to morbidity and mortality. Inhibition of factor Xa activity will effectively block thrombin production and will negate the pathogenic action of thrombin in various cell types.
According to a further aspect of the invention there is provided a method of treating a human or animal patient suffering from or exposed to a physiological condition, eg, a physiological condition as described herein, which may be improved by administering an inhibitor of factor Xa activity. This includes administering to a patient a composition containing an effective amount of a compound of formula (I) or a compound of formula (I). An "effective amount" refers to an amount of a compound of the invention that is effective in inhibiting the activity of Factor Xa and thus results in a desired therapeutic effect.
The present invention also encompasses pharmaceutical formulations comprising, within its scope, one or more of the compounds of formula I in combination with a pharmaceutically acceptable carrier or coating.
In general, the compounds of the present invention may be administered parenterally, intravenously, subcutaneously, intramuscularly, colonically, nasal, intraperitoneally, rectally or orally.
The products according to the invention may exist in a form which can be administered in the most suitable manner and the invention also relates to pharmaceutical compositions containing one or more products according to the invention suitable for use in human or veterinary medicine. Such compositions may be prepared according to conventional methods using one or more pharmaceutically acceptable adjuvants or excipients. Adjuvants include, in particular, diluents, sterile aqueous media and various non-toxic organic solvents. The compositions may be present as tablets, pills, granules, powders, aqueous or suspensions, injectables, elixirs or syrups and contain one or more agents selected from the group consisting of sweeteners, spices, colorants or stabilizers, Acceptable medicaments can be obtained.
The choice of excipients and the amount of active substance in the excipients is generally determined by the solubility and chemical properties of the product, the particular dosage form and the provisions observed in pharmaceutical practice. Excipients such as laccose, sodium citrate, calcium carbonate, dicalcium phosphate in admixture with lubricants such as, for example, magnesium stearate, sodium lauryl sulfate and talc; And disintegrants such as starch, alginic acid, certain silicate complexes, can be used to make tablets. To prepare capsules, it is advantageous to use lactose and high molecular weight polyethylene glycols. If aqueous suspensions are used, they may contain emulsifiers or suspending accelerators. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.
For parenteral administration, as well as sterile aqueous solutions of pharmaceutically acceptable salts, as well as vegetable oils such as sesame oil, peanut oil or olive oil, or aqueous-oil solvents such as water and propylene glycol, organic esters such as ethyl oleate Among the emulsions, suspensions or solvents according to the present invention are used. Salt solutions of the products according to the invention are particularly useful for administration by intramuscular or subcutaneous injection. Aqueous solutions, including salt solutions in pure distilled water, can be used for intravenous administration, provided their pH is suitably adjusted, carefully buffered, isotonic with sufficient amounts of glucose or sodium chloride, and The condition is to be sterilized by microfiltration.
Suitable compositions containing the compounds of the present invention can be prepared by conventional methods. For example, the compounds of the present invention may be dissolved or suspended in suitable carriers used for nebulizers, suspensions or solution aerosols and may absorb or adsorb on a suitable solid carrier for dry powder inhalers.
Solid compositions for rectal administration include suppositories prepared according to known methods and containing one or more compounds of formula (I).
The percentage of active ingredient in the compositions of the present invention can vary and must be comprised in such a proportion that a suitable dosage form is obtained. Clearly, unit dosage number units may be administered at about the same time. The dosage used is determined by the physician and depends on the desired therapeutic effect, the method of administration and the duration of treatment and the condition of the patient. For adults, the dose is generally about 0.01 to about 100, preferably about 0.01 to about 10 mg / kg body weight / day for inhalation, about 0.01 to about 100, preferably 0.1 to 70, more particularly for oral administration About 0.5 to 10 mg / kg body weight / day, and about 0.01 to about 50, preferably 0.01 to 10 mg / kg body weight / day for intravenous administration. In each particular case, the dose is determined by factors such as age, weight, general condition of health, and other characteristics that may affect the efficacy of the medicament, which are distinct for each patient to be treated.
The product according to the invention can be administered as frequently as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to larger or smaller amounts and may find less suitable maintenance doses. In other patients, depending on the physiological needs of each individual patient, long-term treatment may be required at a rate of one to four dosage forms per day. In general, the active product may be administered orally 1 to 4 times a day. Of course, in other patients, only one or two dosage forms may be needed per day.
Compounds within the scope of the present invention exhibit significant pharmaceutical activity according to the tests described herein, wherein the test results are believed to be related to pharmaceutical activity in humans and other mammals. The following pharmaceutical test results are typical of the compounds of the present invention.
Enzyme Assay:
The ability of the compounds of the invention to act as inhibitors of factor Xa, thrombin, trypsin, tissue-plasminogen activator (t-PA), urokinase-plasminogen activator (u-PA), plasmin and activated protein C The purified enzyme is used to determine the concentration of the inhibitor (IC ₅₀ ) resulting in a 50% loss in enzyme activity.
All enzyme assays are performed at room temperature in 96-well microtiter plates with a final enzyme concentration of 1 nM. Factor Xa and thrombin concentrations are determined by active site titration and all other enzyme concentrations are based on protein concentration supplied by the manufacturer. The compounds according to the invention are dissolved in DMSO and diluted with their respective buffers and analyzed at a final maximum DMSO concentration of 1.25%. Compound dilutions are added to the wells containing buffer and enzyme and pre-equilibrated for 5-30 minutes. The enzymatic reaction is initiated by adding the substrate and the color expressed from the hydrolysis of the peptide-p-nitroanilide substrate is measured continuously for 5 minutes at 405 nm on a Vmax microplate reader (Molecular Devices). Under these conditions, less than 10% of the substrate is used in all assays. The measured initial rate is used to determine the amount of inhibitor (IC ₅₀ ) resulting in a 50% reduction in control rate. The apparent Ki is then determined according to the Cheng-Prusoff equation (IC ₅₀ = Ki [1+ [S] / Km], which represents competitive inhibition kinetics.
By way of example, 3- [3- (S)-(benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoro Acetate has a Ki value of 14 nM.
By way of example, 3- [2-oxo-3- (S)-(5-pyridin-4-yl-thiophen-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate has a Ki value of 55 nM.
Additional in vitro assays are used to assess the latent ability of the compounds according to the invention in normal human plasma. Activated partial thromboplastin time uses a plasma-based coagulation experiment, which produces factor Xa in situ, binds to its prothrombinase complex and subsequently, as the end of the assay, ultimately blood coagulation Leads to the formation of thrombin and fibrin, which will form a clot. This assay measures the ex vivo effects of commonly used anticoagulant heparin as well as directly acting antithrombin, which is currently being used clinically. Thus, activity in this in vitro assay is considered as a surrogate label for anticoagulant activity in vivo.
Human Plasma Basal Coagulation Assay
Activated partial thromboplastin coagulation time is determined in duplicate on the MLA Electra 800 device. 100 ul of citrated normal human plasma (George King Biomedical) is added to a cuvette containing 100 ul of the compound according to the invention in Tris / NaCl buffer (pH 7.5). After 3 minutes of warming the device adds 100ul of automatically activated cephaloplastin preparation (Actin, Dade) followed by 100ul of 0.035M CaCl ₂ to start the coagulation reaction. Solidification formation is determined by spectrophotometry and measured in seconds. Compound potency is quantified as the concentration required to double the control coagulation time as measured by human plasma in the absence of the compound according to the invention.
The compounds according to the invention can also be measured for in vivo antithrombotic efficacy in two well established animal experimental models of acute vascular thrombus. The rabbit model for jugular thrombi and the rat model for carotid thrombus are used to demonstrate antithrombotic activity of these compounds in a unique animal model example for human venous thrombus and arterial thrombus, respectively.
Experimental In vivo Rabbit Vein Thrombosis Model
This is a well-characterized model of fibrin-rich venous thrombosis demonstrated in the literature and shows sensitivity to some anticoagulant drugs, including heparin. Antithrombotic Effect of recombinant Truncated Tissue Factor Pathway Inhibitor (TFPI 1-161) in Experimental Venous Thrombosis-1 Comparison with Low Molecular Weight Heparin, J. Holst, B. Lindblad, D. Bergqvist, O. Nordfang, PB Ostergaard, JGL Petersen, G. Niesen and U. Hedner. Thrombosis and Haemostasis, 71 , 214-219 (1994)]. The purpose of using this model is to measure the ability of the compounds of the present invention to inhibit the formation of venous thrombus (coagulation mass) produced in vivo at wound and partial congestion sites in the jugular vein.
Female, male New Zealand white rabbits weighing 1.5 to 2 kg are anesthetized with ketamine 35 mg / kg and xylazine 5 mg / kg in a volume of 1 ml / kg (i.m.). The cannula is inserted into the right jugular vein for anesthetic injection and test substance injection (ketamine / xylazine 17 / 2.5 mg / kg / hr at a rate of about 0.5 ml / hr). The right carotid artery inserts a cannula to measure arterial blood pressure and collect blood samples. Body temperature is maintained at 39 ° C. with GAYMAR-T-PUMP. The left outer jugular vein is separated to bind all lateral vessels along the exposed 2-3 cm of the vessel. The internal jugular vein inserts the cannula into the branch just above the conventional jugular vein and the tip of the cannula is placed just near the conventional jugular vein. Associated stenosis is formed by separating a 1 cm segment of vein with a non-traumatic vascular clamp and ligation around the vein with an 18G needle just below the distal clamp. The separated segments are carefully washed with saline 2-3 times via cannula in the external jugular vein. The separated segments are then filled with 0.5 ml of 0.5% polyoxyethylene ether (W-1). W-1 is a detergent that destroys the endothelial cell layer of the segment and exposes the thrombogenic surface that initiates blood clot formation. After 5 minutes W-1 is removed from the segment and the segment is washed again with brine 2-3 times. The vascular clamp is removed and the blood flow back to the site of the vessel. Blood clot formation begins to form and forms for 30 minutes, then underneath the ligation site to examine blood flow (absence of blood flow is recorded as complete occlusion). The entire isolated vein segment is ligated again and the coagulation formation formed is removed and weighed (wet weight). The effect of the test agent on the weight of the final coagulation formation is used as the first end. Animals are kept on for additional 30 minutes to obtain final pharmacodynamic measurements of anticoagulant. Drug administration is initiated 15 minutes prior to vascular wound with W-1 and continues during clotting formation and maturation. Three blood samples (3 ml each) are obtained for hemostatic parameter measurements: one immediately before W-1 administration; The second 30 minutes after vascular clamp removal; And the third is obtained at the conclusion of the experiment. Antithrombotic efficacy is expressed as a reduction in the final coagulation formation weight in the experimental group treated with the compounds of the present invention compared to control animals treated with excipients.
Experimental In Vivo Rat Arterial Thrombus Model:
The antithrombotic efficacy of factor Xa inhibitors on platelet-rich arterial thrombi is assessed using a well-defined rat carotid artery FeCl ₂ -induced thrombus model. Thrombosis, WA Schumacher, CL Heran, TE Steinbacher, S. Youssef and ML Ogletree. Journal of Cardiovascular Pharmacology, 22, 526-533 (1993); Rat Model of Arterial Thrombosis Induced by Ferric Chloride, KD Kurtz, BW Main, and GE Sandusky. Thrombosis Research, 60, 269-280 (1990); The Effect of Thrombin Inhibition in a rat Arterial Thrombosis Model, RJ Broersma, LW Kutcher and EF Heminger. Thrombosis Research 64, 405-412 (1991). Such models are widely used to assess the antithrombotic potential of various agents including heparin and directly acting thrombin inhibitors.
Sprague Dawley rats weighing 375-450 g are anesthetized using sodium pentobarbitol (50 mg / kg ip). When the anesthetic reaches an acceptable level, the abdominal hair of the neck is shaved and a sterile surgery is prepared. Connect the ECG electrode and measure Lead II throughout the test. The compound of the invention is administered to the right femoral vein and artery, respectively, and a PE-50 tubing is inserted to obtain a blood sample and to measure blood pressure. Incision in the middle of the abdominal skin of the neck. The trachea is exposed and cultured using PE-240 tubing to ensure airway opening. Two 4-0 pongee sutures are placed around the vessel to separate the right carotid artery and to assist with device installation. An electromagnetic flow probe (internal diameter 0.95 to 1.0 mm) is placed around the vessel to measure blood flow. A 4 × 4 mm parafilm strip is placed around the vessel to surround the vessel to separate the vessel from the surrounding muscle layer. After completing the baseline flow measurement, a ₂ × 5 mm strip of filter paper saturated in 35% FeCl ₂ was placed at the top of the vessel downstream from the probe for 10 minutes and then removed. FeCl ₂ is believed to diffuse into underlying arterial sections and cause endothelial detachment resulting in acute thrombus formation. After applying FeCl ₂ -soaked filter paper, blood pressure, carotid blood flow and heart rate are measured for 60 minutes. After occlusion of the blood vessel (blood flow defined as 0), or 60 minutes after the application of the filter paper if the opening persists, the base of the wound and the distal end of the artery are ligated and the blood vessel is dissected. The thrombi is removed and weighed immediately and recorded as the first endpoint of the study.
After surgical measurement, a control blood sample (B1) is taken. All blood samples are collected from arterial catheter and mixed with sodium citrate to prevent coagulation. After each blood sample, the catheter is flushed with 0.5 ml of 0.9% saline. The compound according to the invention is administered (iv) by intravenous injection 5 minutes before FeCl ₂ application. The time between FeCl ₂ application and carotid blood flow reaching zero is recorded as occlusion time (TTO). For blood vessels that do not occlude within 60 minutes, the TTO assigns a value of 60 minutes. Five minutes after application of FeCl ₂ , a second blood sample is taken (B2). After 10 minutes of FeCl ₂ exposure, the filter paper is removed from the blood vessels and the animal is observed for the remainder of the experiment. When the blood flow reaches zero, a third blood sample is taken (B3) and the blood clot removed to weigh. Template bleeding time measurements are taken at the bottom of the front toe with the blood sample taken. In some cases, the compounds of the present invention are administered orally. Rats are administered upwards (dose of 5 ml / kg) using a standard 18 bent dosing needle by hand using standard techniques. After 10 minutes of administration, the animals are anesthetized and set up as described above. The experiment is then performed according to the protocol described above.
The invention may be embodied in other specific forms without departing from its spirit or gist.

权利要求:
Claims (57)
[1" claim-type="Currently amended] A compound of formula (I), a pharmaceutically acceptable salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof.
Formula I

In the above formula,
Is phenyl or monocyclic heteroaryl;
R is hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, R ₆ O (CH ₂ ) _x- , R ₆ O ₂ C (CH ₂ ) _x- , Y ¹ Y ² NC ( O) (CH ₂ ) _x -or Y ¹ Y ² N (CH ₂ ) _x- ;
R ₁ is hydrogen, alkyl, hydroxy, alkoxy, Y ¹ Y ² N-, halogen, -CO ₂ R ₆ , -C (O) NY ¹ Y ² ,-(CH ₂ ) _x OR ₆ ,-(CH ₂ ) _x NY ¹ Y ² or -CN;
R ₂ and R ₃ are independently hydrogen, hydroxy, alkoxy, Y ¹ Y ² N-, halogen, -CO ₂ R ₆ , -C (O) NY ¹ Y ² ,-(CH ₂ ) _x OR ₆ ,- (CH ₂ ) _x NY ¹ Y ² , -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 ₂ and R ₃ are optionally substituted with 5 to 7 membered fused cycloalkyl, together with the carbon atom to which they are linked, 5 To form a 7-membered fused heterocyclyl ring or an optionally substituted 6-membered fused aryl or an optionally substituted 5-7 membered fused heteroaryl ring;
R ₄ is hydrogen or optionally substituted lower alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl;
X ₁ and X _1a are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl or optionally substituted heteroaralkyl, or X ₁ and X _1a together form oxo To;
X ₂ and X _2a are hydrogen or together form oxo;
X ₃ is hydrogen, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or one of X ₃ and X ₁ and X _1a is Together with the carbon atom to which it is linked form a 4-7 membered cycloalkyl or heterocyclyl ring;
X ₄ is hydrogen, optionally substituted alkyl or optionally substituted aralkyl;
X ₅ and X _5a are hydrogen or together form = NR ₅ ;
R ₅ is hydrogen, R ₆ O ₂ C-, R ₆ O-, cyano, R ₆ CO-, optionally substituted lower alkyl, nitro or Y ¹ Y ² N-;
Y ¹ and Y ² are independently hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heteroaralkyl, or Y ¹ and Y ² together with N to which they are linked 4 to 7 membered hetero To form a cyclyl;
X ₆ and X _6a are independently hydrogen, R ₇ R ₈ N-, R ₉ O-, R ₇ R ₈ NCO-, R ₇ R ₈ NSO _2- , R ₇ R ₈ NSO ₂ N-, R ₇ R ₈ SO ₂ O-, R ₉ CO-, -CO ₂ R ₆ , -C (O) NY ¹ Y ² ,-(CH ₂ ) _x CO ₂ R ₆ ,-(CH ₂ ) _x C (O) NY ¹ Y ² ,-(CH ₂ ) _x OR ₆ ,-(CH ₂ ) _x NY ¹ Y ² , halo, cyano or nitro;
R ₆ is hydrogen, optionally substituted alkyl, optionally substituted aralkyl or optionally substituted heteroaralkyl;
R ₇ and R ₈ are independently hydrogen or optionally substituted lower alkyl, one of R ₇ and R ₈ is hydrogen and the other is R ₁₀ (O) CCH ₂ — or lower acyl;
R ₉ is hydrogen, optionally substituted lower alkyl, optionally substituted lower acyl or R ₁₀ (O) CCH ₂ —;
R ₁₀ 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;
x is 1, 2, 3, 4 or 5.
[2" claim-type="Currently amended] The compound of claim 1, wherein n is 1 and m is 1.
[3" claim-type="Currently amended] The compound of claim 1, wherein X ₂ and X _2a together are oxo.
[4" claim-type="Currently amended] The compound of claim ₁ , wherein X ₁ , X _1a and X ₄ are hydrogen and X ₃ is hydrogen or alkyl.
[5" claim-type="Currently amended] The compound of claim 1, wherein X ₅ and X _5a together are = NR _5, wherein R ₅ is R ₆ O ₂ C-.
[6" claim-type="Currently amended] The compound of claim 1, wherein X ₅ and X _5a together are = NR _5, wherein R ₅ is —OH.
[7" claim-type="Currently amended] The compound of claim 1, wherein X ₅ and X _5a together are = NR _5, wherein R ₅ is H. ₇ .
[8" claim-type="Currently amended] The method of claim 1, Is phenyl and carbon substituted with X ₅ , X _5a or R ₄ HN- is attached at the meta position for attachment of the-(CH) _n N- residue of phenyl.
[9" claim-type="Currently amended] The method of claim 1, Is thienyl, and carbon substituted with X ₅ , X _5a or R ₄ HN- is attached at position 2 relative to the sulfur of thienyl and the-(CH) _n N- residue is attached at position 4 of thienyl.
[10" claim-type="Currently amended] The compound of claim 1, wherein R is hydrogen, methyl, aralkyl, heteroaralkyl, HO ₂ CCH ₂ —, H ₂ NC (O) CH ₂ — or R ₆ HNC (O) CH ₂ —.
[11" claim-type="Currently amended] The compound of claim 1, wherein R ₁ is hydrogen, alkyl or halogen.
[12" claim-type="Currently amended] The compound of claim 1, wherein R ₂ and R ₃ are independently hydrogen, halogen, alkyloxy, amino, aryl or heteroaryl.
[13" claim-type="Currently amended] The compound of claim 1, wherein R ₂ and R ₃ form an optionally substituted fused aryl or optionally substituted fused heteroaryl ring, wherein the substituent is halogen, alkyl, amino, hydroxy or alkoxy.
[14" claim-type="Currently amended] The compound of claim 1, wherein R ₂ and R _{3 form an} optionally substituted fused cycloalkyl, or an optionally substituted fused heterocyclyl wherein the heteroatom is nitrogen, wherein the substituent is hydrogen, Y ¹ Y ² N or alkyl.
[15" claim-type="Currently amended] The method of claim 1, Is phenyl and X ₆ and X _6a are Compounds that are amino or hydroxy in the para position relative to the residue.
[16" claim-type="Currently amended] The compound of claim 1, wherein X ₆ and X _6a are hydrogen.
[17" claim-type="Currently amended] The compound of claim 1, wherein A is —CH═CH— and R ₂ and R ₃ together with the carbon atom to which they are linked form an optionally substituted 5 or 6 membered heteroaryl ring or an optionally substituted 6 membered aryl ring.
[18" claim-type="Currently amended] The compound of claim 1, wherein A is —CH═CH—, R ₂ is hydrogen, and R ₃ is an optionally substituted heteroaryl ring or an optionally substituted 6 membered aryl ring.
[19" claim-type="Currently amended] The compound of claim 1, wherein A is S. 7.
[20" claim-type="Currently amended] The compound of claim 1, wherein A is S and R ₂ and R ₃ together with the carbon atom to which they are linked form an optionally substituted 5 or 6 membered heteroaryl ring or an optionally substituted 6 membered aryl ring.
[21" claim-type="Currently amended] The compound of claim 1, wherein A is S, R ₂ is hydrogen, and R ₃ is an optionally substituted heteroaryl ring or an optionally substituted 6 membered aryl ring.
[22" claim-type="Currently amended] The method of claim 1,
3- [3- (S)-(benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(benzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
4- [3- (S)-(benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxamidine trifluoro acetate;
4- [3- (S)-[Benzo [b] thiophene-2-sulfonyl] -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxamidine Trifluoroacetate;
3- [3- (S)-(4-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-(6-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(4-chlorobenzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
3- [3- (S)-[(6-chlorobenzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
3- [3- (S)-[(5-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(5-chlorobenzo [b] thiophene-2-sulfonyl) -methyl-amino] -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
3- [3- (S)-[(4-methylbenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(6-methylbenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(5-methylbenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-[(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoro acetate;
([3- [3- (S)-(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -phenyl] -imino Methyl) -carbamic acid 2,2,2-trichloroethyl ester;
4-amino-3- [3- (S)-(4,6-dichlorobenzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4-hydroxy-3- [3- (S)-(4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dine trifluoroacetate;
3- [3- (S)-(6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
4-amino-3- [3- (S)-(6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
4-hydroxy-3- [3- (S)-(6-fluorobenzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4-amino-3- [3- (S)-(4-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
4-hydroxy-3- [3- (S)-(4-chlorobenzo [b] thiophen-2-sulfaminoamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
3- [3- (S)-(4-Chloro-thieno [3,2-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
4-hydroxy-3- [3- (S)-(4-chloro-thieno [3,2-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate;
3- [3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
3- [3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine bistrifluoroacetate ;
3- [3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -hydroxybenzamidine Trifluoroacetate;
3- {3- (S)-[(5-Chlorothieno [3,2-b] pyridine-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl} -benz Amidine trifluoroacetate;
3- [3- (S)-(6-chlorothieno [2,3-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
3- [3- (S)-(thieno [2,3-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine bistrifluoroacetate ;
3- {3- (S)-(6-Chlorothieno [2,3-b] pyridine-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl} -benzami Dine trifluoroacetate;
4-hydroxy-3- [2-oxo-3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl]- Benzamidine trifluoroacetate;
4-hydroxy-3- [2-oxo-3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine Bistrifluoroacetate;
4-hydroxy-3- [2-oxo-3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl]- Hydroxybenzamidine trifluoroacetate;
4-amino-3- [2-oxo-3- (S)-(5-chlorothieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benz Amidine trifluoroacetate;
4-Amino-3- [2-oxo-3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine bis Trifluoroacetate;
4- [3- (S)-(5-Chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2- Carboxamidine trifluoroacetate;
4- [3- (S)-(5-Chlorothieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2- Hydroxycarboxamidine trifluoroacetate;
4- {3- (S)-[(5-Chlorothieno [3,2-b] pyridine-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl} -thi Offen-2-carboxamidine trifluoroacetate;
3- {3- (S)-[5- (2-Methylsulfanyl-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl} Benzamidine trifluoroacetate;
3- {3- (S)-[5- (2-methoxy-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl}- Benzamidine trifluoroacetate;
3- {3- (S)-[5- (2-Amino-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-pyrrolidin-1-ylmethyl} -benz Amidine bistrifluoroacetate;
3- {3- (S)-(5- (2-Amino-pyrimidin-4-yl) -thiophene-2-sulfonyl] -methylamino) -2-oxo-pyrrolidin-1-ylmethyl } -Benzamidine bistrifluoroacetate;
3- [3- (S)-(5'-Chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
4-amino-3- [3- (S) -benzo [b] thiophene-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] benzamidine trifluoroacetate;
4-amino-3- [6-chlorobenzo [b] thiophen-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] benzamidine trifluoroacetate;
4-amino-3- [6-chlorobenzo [b] thiophen-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] hydroxybenzamidine trifluoroacetate;
3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophen-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
4-Amino-3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine tri Fluoroacetates;
4-hydroxy-3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4-hydroxy-3- [2-oxo-3- (S)-(5-pyridine-N-oxide-3-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate;
3- [2-oxo-3- (S)-(5-pyridin-4-yl-thiophene-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- [3- (S)-(4-Chloro-thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
3- {3- (S)-[5- (5-chloropyridin-3-yl) -thiophene-2-sulfonylamino] -2-oxopyrrolidin-1-ylmethyl} benzamidine trifluor Low acetate;
3- [3- (S)-(4-chloro-5-pyridin-3-ylthiophen-2-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate ;
4-hydroxy-3- [3- (S)-(6-chlorobenzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamide trifluor Low acetate;
3- [3- (S)-(1-aminoisoquinoline-6-sulfonylamino) -2-oxopyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
4-Fluoro-3- [3- (S)-(5-pyridin-3-yl-thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamide tri Fluoroacetates;
2-Chloroquinoline-6-sulfonic acid {1- [3- (aminoiminomethyl) -benzyl] -2-oxo-pyrrolidin-3- (S) -yl} -amide trifluoroacetate;
2-Aminoquinoline-6-sulfonic acid {1- [3- (aminoiminomethyl) -benzyl] -2-oxo-pyrrolidin-3- (S) -yl} -amide bistrifluoroacetate;
4-hydroxy-3- [3- (S)-(7-chloro-thieno [2,3-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate;
4-hydroxy-3- [3- (S)-(thieno [2,3-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Bistrifluoroacetate;
4-hydroxy-3- [3- (S)-(thieno [3,2-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4- [3- (6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxamidine hydrochloride;
4- {3- (S)-[(3-aminopropyl)-(6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl}- Thiophene-2-carboxamidine bistrifluoroacetate;
[[1- (5-carbamimidoyl-thiophen-3-ylmethyl-2-oxo-pyrrolidin-3-yl]-(6-fluorobenzo [b] thiophene-2-sulfonyl)- Amino] -acetic acid trifluoroacetate;
[Imino- (4- {3-[(7-methoxynaphthalene-2-sulfonyl) -pyridin-2-ylmethyl-amino] -2-oxo-pyrrolidin-1-ylmethyl} -thiophene -2-yl) -methyl] -carbamic acid ethyl ester;
4-amino-3- {3- (S)-[(7-methoxy-naphthalene-2-sulfonyl) -pyridin-2-ylmethyl-amino] -2-oxo-pyrrolidin-1-ylmethyl } -Benzamidine trifluoroacetate;
2-[[1- (2-Amino-5-carbamimidoyl-benzyl) -2-oxo-pyrrolidin-3- (S) -yl}-(7-methoxy-naphthalene-2-sulfonyl) -Amino] -acetamide trifluoroacetate;
[Imino (3- {3-[(7-methoxy-naphthalene-2-sulfonyl) -methylamino] -2-oxo-3- (S) -pyrrolidin-1-ylmethyl} -4- Amino-phenyl) -methyl] carbamic acid ethyl ester;
4-hydroxy-3- {3- (S)-[5- (1-hydroxy-pyridin-4-yl) -thiophene-2-sulfonyl amino] -2-oxo-pyrrolidine-1- Monomethyl} -benzamidine trifluoroacetate;
4-amino-3- [3- (S)-(5-chloro-thieno [3,2-b] pyridin-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl]- Hydroxybenzamidine trifluoroacetate;
4-amino-3- [3- (S)-(5-methoxy-thieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Benzamidine trifluoroacetate;
3- [3- (S)-(5-isoxazol-3-yl-thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate ;
4-Amino-3- [3- (S)-(5-isoxazol-3-yl-thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Trifluoroacetate;
4-hydroxy-3- [3- (S)-(5-isoxazol-3-yl-thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dine trifluoroacetate;
3- (S)-[3-([2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoroacetate;
4-Amino-3- [3- (S)-([2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor Low acetate;
4-Amino-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl]- Benzamidine trifluoroacetate;
4-hydroxy-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl} Benzamidine hydrochloride;
4-hydroxy-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] Hydroxybenzamidine; or
4- [3- (S)-(6-Fluoro-benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -pyridine-2-carboxami Dine hydrochloride.
[23" claim-type="Currently amended] The compound of claim 22, wherein 3- [3- (S)-[(benzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dine trifluoroacetate.
[24" claim-type="Currently amended] The compound of claim 22, wherein the 4- [3- (benzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -thiophene-2-carboxamidine tri Compound that is fluoroacetate.
[25" claim-type="Currently amended] 23. The compound of claim 22, wherein 3- [3- (S)-(6-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine Compound that is trifluoroacetate.
[26" claim-type="Currently amended] The compound of claim 22, wherein 3- [3- (S)-[(6-chlorobenzo [b] thiophene-2-sulfonyl) -methylamino] -2-oxo-pyrrolidin-1-ylmethyl] A compound that is benzamidine trifluoroacetate.
[27" claim-type="Currently amended] 23. The compound of claim 22, wherein 3- [3- (4,6-dichlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluor A compound that is a low acetate.
[28" claim-type="Currently amended] 23. The compound of claim 22, wherein ([3- [3- (S)-(4,6-dichlorobenzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -Phenyl] -iminomethyl) -carbamic acid 2,2,2-trichloroethyl ester.
[29" claim-type="Currently amended] 23. The compound of claim 22, wherein 3- [3- (6-fluorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoro Compounds that are acetate.
[30" claim-type="Currently amended] The method of claim 22, wherein 4-amino-3- [2-oxo-3- (S)-(6-fluorobenzo [b] thiophene-2-sulfylamino) -pyrrolidin-1-ylmethyl ] -Benzamidine trifluoroacetate.
[31" claim-type="Currently amended] 23. The compound of claim 22, wherein 4-hydroxy-3- [2-oxo-3- (S)-(6-fluorobenzo [b] thiophene-2-sulfylamino) -pyrrolidin-1-yl Methyl] -benzamidine trifluoroacetate.
[32" claim-type="Currently amended] The method of claim 22, wherein the 4-hydroxy-3- [2-oxo-3- (S)-(4-chloro-thieno [3,2-c] pyridine-2-sulfamilamino) -pyrrolidine -1-ylmethyl] -benzamidine trifluoroacetate.
[33" claim-type="Currently amended] 23. The compound of claim 22, wherein 3- [3- (S)-(thieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dine bistrifluoroacetate.
[34" claim-type="Currently amended] 23. The compound of claim 22, wherein 3- [3- (S)-(thieno [2,3-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzami Dine bistrifluoroacetate.
[35" claim-type="Currently amended] The method of claim 22, wherein 4-amino-3- [2-oxo-3- (S)-(thieno [3,2-b] pyridin-2-sulfonylamino) -pyrrolidin-1-ylmethyl ] -Benzamidine bistrifluoroacetate.
[36" claim-type="Currently amended] The compound of claim 22, wherein the 3- {3- (S)-[5- (2-methylsulfanyl-pyrimidin-4-yl) -thiophene-2-sulfonylamino] -2-oxo-pyrrolidine -1-ylmethyl} -benzamidine trifluoroacetate.
[37" claim-type="Currently amended] The method of claim 22, wherein 4-amino-3- [6-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -benzamidine trifluoro Compounds that are acetate.
[38" claim-type="Currently amended] The method of claim 22, wherein 4-amino-3- [6-chlorobenzo [b] thiophene-2-sulfonylamino) -2-oxo-pyrrolidin-1-ylmethyl] -hydroxybenzamidine tri Compound that is fluoroacetate.
[39" claim-type="Currently amended] The compound of claim 22, wherein 3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophen-2-sulfonylamino) -pyrrolidin-1-ylmethyl] -benzami Dine trifluoroacetate.
[40" claim-type="Currently amended] The compound of claim 22, wherein 4-hydroxy-3- [2-oxo-3- (S)-(5-pyridin-3-yl-thiophen-2-sulfonylamino) -pyrrolidin-1-yl Methyl] -benzamidine trifluoroacetate.
[41" claim-type="Currently amended] The compound of claim 22, wherein 4-hydroxy-3- [2-oxo-3- (S)-(5-pyridine-N-oxide-3-yl-thiophene-2-sulfonylamino) -pyrrolidine -1-ylmethyl] -benzamidine trifluoroacetate.
[42" claim-type="Currently amended] The compound of claim 22, wherein 4-hydroxy-3- [3- (S)-(6-chloro-benzo [b] thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl ] -Benzamide trifluoroacetate.
[43" claim-type="Currently amended] The method of claim 22, wherein 4-hydroxy-3- [3- (S)-(7-chloro-thieno [2,3-c] pyridine-2-sulfonylamino) -2-oxo-pyrrolidine -1-ylmethyl] -benzamidine trifluoroacetate.
[44" claim-type="Currently amended] The compound of claim 22, wherein 4-hydroxy-3- [3- (S)-(thieno [2,3-c] pyridin-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl Methyl] -benzamidine bistrifluoroacetate.
[45" claim-type="Currently amended] The compound of claim 22, wherein 4-hydroxy-3- [3- (S)-(thieno [3,2-c] pyridin-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl Methyl] -benzamidine trifluoroacetate.
[46" claim-type="Currently amended] The compound of claim 22, wherein 4-hydroxy-3- {3- (S)-[5- (1-hydroxy-pyridin-4-yl) -thiophene-2-sulfonylamino] -2-oxo- Pyrrolidin-1-ylmethyl} -benzamidine trifluoroacetate.
[47" claim-type="Currently amended] The method of claim 22, wherein 4-amino-3- [3- (S)-(5-methoxy-thieno [3,2-b] pyridine-2-sulfonylamino) -2-oxo-pyrrolidine -1-ylmethyl] -benzamidine bistrifluoroacetate.
[48" claim-type="Currently amended] The method of claim 22, wherein 4-amino-3- [3- (S)-(5-isoxazol-3-yl-thiophen-2-sulfonylamino) -2-oxo-pyrrolidin-1-yl Methyl] -benzamidine trifluoroacetate.
[49" claim-type="Currently amended] The compound of claim 22, wherein 4-hydroxy-3- [3- (S)-(5-isoxazol-3-yl-thiophen-2-sulfonylamino) -2-oxo-pyrrolidine-1- Ylmethyl] -benzamidine trifluoroacetate.
[50" claim-type="Currently amended] The method of claim 22, wherein 4-amino-3- [3- (S)-([2,2 ']-bithiophenyl-5-sulfonylamino) -2 -oxo-pyrrolidin-1-ylmethyl] A compound that is benzamidine trifluoroacetate.
[51" claim-type="Currently amended] 23. 4-Amino-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino) -2-oxo-pyrrolidine- 1-ylmethyl] -benzamidine trifluoroacetate.
[52" claim-type="Currently amended] The compound of claim 22, wherein 4-hydroxy-3- [3- (S)-(5'-chloro- [2,2 ']-bithiophenyl-5-sulfonylamino] -2-oxo-pyrrolidine -1-ylmethyl] -benzamidine hydrochloride.
[53" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
[54" claim-type="Currently amended] A method of treating a patient suffering from a physiological disease that can be controlled by inhibiting the activity of factor Xa, comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.
[55" claim-type="Currently amended] 55. The method of claim 54, wherein the physiological disease is venous vessels, arterial vessels, abnormal thrombus formation, acute myocardial infarction, unstable angina, thromboembolism, acute vessel occlusion associated with thromboembolic treatment, coronary angioplasty through percutaneous aperture, transient ischemic symptoms , Seizure, intermittent claudication and bypass transplantation of coronary or peripheral arteries, luminal stenosis, angina after coronary or venous angioplasty, maintenance of vessel opening in long-term hemodialysis patients, lower extremities of the lower body after abdominal, knee and hip surgery Pathogenic thrombus formation that occurs in the veins of (四,), the risk of pulmonary thromboembolism, or systemic diffuse coagulopathy that occurs in the vascular system during septic shock, certain viral infections, or cancer.
[56" claim-type="Currently amended] 55. The method according to claim 54, wherein the physiological disease is abnormal thrombus formation, acute myocardial infarction, unstable angina, thromboembolism, acute vascular obstruction associated with the treatment of thrombotic collapse, transient ischemic symptoms, intermittent claudication or bypass transplantation of coronary or peripheral arteries, A method that is at risk of developing pathogenic thrombus or pulmonary thromboembolism that occurs in the veins of the extremities of the lower body after coronary or venous angioplasty, angina, abdomen, knee, and hip surgery.
[57" claim-type="Currently amended] 55. The system of claim 54, wherein the physiological disease is systemic diffuse coagulopathy occurring in the vasculature during seizures, luminal stenosis, maintenance of vascular inlet opening in long-term hemodialysis patients, or septic shock, certain viral infections, or cancer Way.

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同族专利:

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公开号 | 公开日

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IL125677D0|1999-04-11|

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EP0894088A4|2001-12-05|

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WO1998024784A1|1998-06-11|

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BG102725A|1999-03-31|

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PL328618A1|1999-02-01|

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NO983603L|1998-10-05|

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US5731315A|1998-03-24|

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AU6012198A|1998-06-29|

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ZA9710968B|1998-07-22|

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OA10823A|2001-07-24|

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AU727810B2|2000-12-21|

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SI9720019A|1999-02-28|

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CN1418882A|2003-05-21|

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EA001739B1|2001-08-27|

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CN1093856C|2002-11-06|

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BR9707489A|1999-07-27|

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SK122398A3|1999-01-11|

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JP2000505815A|2000-05-16|

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CZ275798A3|1999-01-13|

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CA2245699A1|1998-06-11|

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HU9903336A2|2000-12-28|

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EP0894088A1|1999-02-03|

---

EA199800690A1|1999-02-25|

---

AP800A|2000-01-19|

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AP9801305A0|1998-09-30|

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CN1213370A|1999-04-07|

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NO983603D0|1998-08-05|

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HU9903336A3|2001-07-30|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1996-12-06|Priority to US08/761,414

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1996-12-06|Priority to US8/761,414

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1997-12-01|Application filed by 오흘러 로스 제이., 롱-프랑 로러 파마슈티칼즈 인코포레이티드

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1999-11-25|Publication of KR19990082323A

优先权:

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申请号 | 申请日 | 专利标题

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US08/761,414|US5731315A|1995-06-07|1996-12-06|Substituted sulfonic acid n- phenylalkyl!-azaheterocyclamide compounds|

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US8/761,414|1996-12-06|