AU2630000A - Lactam inhibitors of fxa and method - Google Patents
Lactam inhibitors of fxa and method Download PDFInfo
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- AU2630000A AU2630000A AU26300/00A AU2630000A AU2630000A AU 2630000 A AU2630000 A AU 2630000A AU 26300/00 A AU26300/00 A AU 26300/00A AU 2630000 A AU2630000 A AU 2630000A AU 2630000 A AU2630000 A AU 2630000A
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- C—CHEMISTRY; METALLURGY
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
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- A—HUMAN NECESSITIES
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Description
WO 00/47563 PCT/USOO/01859 LACTAM INHIBITORS OF FXa AND METHOD Field of the Invention The present invention relates to lactam inhibitors 5 of the enzyme Factor Xa which are useful as anticoagulants in the treatment of cardiovascular diseases associated with thromboses. Brief Description of the Invention 10 In accordance with the present invention, novel substituted lactam derivatives are provided which are inhibitors of the enzyme Factor Xa and have the structure I I. 0
R
1 H/ x N N R 2 0 15 including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrug esters thereof, wherein
R
1 and R 2 are the same or different and are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, 20 cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, or R 1 and R 2 can be taken with the nitrogen to which they are attached to form a cycloheteroalkyl ring; all optionally substituted 25 through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, 30 aryloxy, aryloxyalkyl, arylalkoxy. arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, - 1- WO 00/47563 PCT/USO0/01859 arylaminocarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, 5 alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl; X is R&-- or R 3
-S
1, - 02 Y 10
R
5 Y is O or S and R 4 is RN- or R 8
R
6
R
3 is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, 15 cycloalkenyl, cycloheteroalkyl, cycloalkenylalkyl, polycycloalkenyl, or polycycloalkenylalkyl; all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, 20 cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted 25 amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, 30 alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl; -2- WO 00/47563 PCT/US0O/01859
R
5 and R 6 are the same or different and are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, 5 cycloalkenyl, cycloheteroalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, arylcarbonyl, alkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or alkylsulfonyl, or R 5 and R 6 can be taken with the nitrogen to which they are attached to form a 10 cycloheteroalkyl ring; all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, 15 arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, 20 arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, 25 arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfony.anino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl;
R
7 and R 8 are independently selected from.alkyl, 30 alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, all optionally substituted through 35 available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, - 3- WO 00/47563 PCT/USOO/01859 cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, 5 nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, 10 alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, or 15 alkylsulfinyl; with the proviso that where in the formula I compounds X is ,N-C- or R 8
-C
R6 11 1| Y Y and (1) R 1 and R 2 are independently alkyl, cycloalkyl, 20 alkenyl, phenyl, benzyl, cyanoalkyl, alkoxycarbonylalkyl, or phenyl mono- or disubstituted with lower alkyl, cyano, hydroxy, dialkylamino, alkoxy, benzyloxy, alkylamino, alkoxycarbonyl, pyrrolidino, morpholino, halogen, alkyl substituted with one or more fluorines, then Y is S; 25 (2) where R1 and R 2 are alkyl, then Y is S; and (3) where one of R 1 and R 2 is alkyl and Y is 0, then the other is alkynyl, heteroaryl, heteroarylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl 30 or R 1 and R 2 can be taken with the nitrogen to which they are attached to form a cycloheteroalkyl ring, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 substituents as defined for R1 and R 2 . Thus, the compounds of formula I of the invention 35 can have the following structural formulae: -4- WO 00/47563 PCT/USOO/01859 IA 0 R H R02 N N
R
2 0 IB H 0 R RN N N R2 Y 0 5IC 0 RI H/ R7 N N
R
2 y 0 ID o
R
1 H/ Ra N N
R
2 Y0 It is preferred that Y in the above formulae is S. 10 Preferred are compounds of formula IB wherein R 1 and
R
2 together with the nitrogen to which they are attached form a cycloheteroalkyl ring, preferably a pyrrolidinyl ring, Y is S, one of R 5 and R 6 is hydrogen and the other of
R
5 and R 6 is aryl, alkylaryl or alkoxyaryl such as phenyl, 15 3-methylphenyl or 3-methoxyphenyl, 4-cyanophenyl, 3 fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4 methoxyphenyl, 3-chloro-4-methylphenyl, 3, 5-dichlorophenyl, 3-iodophenyl, 3, 5-dimethylphenyl or naphthyl. In addition, in accordance with the present 20 invention, a method for preventing, inhibiting or treating cardovascular diseases associated with thromboses is provided, wherein a compound of formula I is administered in a therapeutically effective amount which inhibits Factor Xa. 25 -5- WO 00/47563 PCT/USOO/01859 Detailed Description of the Invention The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances. 5 Unless otherwise indicated, the term "lower alkyl", "alkyl" or "alk" as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons (in the case of alkyl or alk), preferably 1 to 20 carbons, more preferably 10 1 to 12 carbons (in the case of lower alkyl), in the normal chain,such as methyl, ethyl, propyl, isopropyl, butyl, t butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4 dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various additional branched chain 15 isomers thereof, and the like as well as such groups including 1 to 4 substituents which may be any of the R 1 or the R 1 substituents set out herein. Unless otherwise indicated, the term "cycloalkyl" as employed herein alone or as part of another group includes 20 saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 4 to 12 carbons, forming the 25 ring and which may be fused to one aromatic ring as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, 30 any of which groups may be optionally substituted with 1 to 4 substituents which may be any of the R 1 groups, or the R 1 substituents set out herein. The term "cycloalkenyl" as employed herein alone or 35 as part of another group refers to cyclic hydrocarbons - 6 - WO 00/47563 PCT/USOO/01859 containing 5 to 20 carbons, preferably 6 to 12 carbons and 1 or 2 double bonds. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may be 5 optionally substituted as defined for cycloalkyl. The term "aryl" as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) 10 and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) and may be optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, 15 haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkyl alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, 20 heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, 25 alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkyl aminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfon 30 aminocarbonyl or any of the R 1 groups or the R 1 substituents set out herein. The term "aralkyl", "aryl-alkyl" or "aryllower alkyl" as used herein alone or as part of another group refers to alkyl groups as discussed above having an aryl 35 substituent, such as benzyl or phenethyl, or naphthylpropyl, or an aryl as defined above. - 7 - WO 00/47563 PCT/US0O/01859 The term "lower alkoxy", "alkoxy", "aryloxy" or "aralkoxy" as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom. 5 The term "amino" as employed herein alone or as part of another group may optionally be independently substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, 10 cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted with a carboxylic acid or any of the R 1 groups or R 1 substituents thereof as set out above. In addition, the amino substituents may be 15 taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-l-piperazinyl, 4-arylalkyl-l-piperazinyl, 4-diarylalkyl-l-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, 20 or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy. The term "lower alkylthio", alkylthio", "arylthio" or "aralkylthio" as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or 25 aryl groups linked to a sulfur atom. The term "lower alkylamino", "alkylamino", "arylamino", or "arylalkylamino" as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom. 30 The term "acyl" as employed herein by itself or part of another group, as defined herein, refers to an organic radical linked to a carbonyl C group; examples of acyl groups include any of -.. e R1 groups attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, 35 heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl and the like. -8- WO 00/47563 PCT/USOO/01859 The term "alkanoyl" as used herein alone or as part of another group refers to alkyl linked to a carbonyl group. Unless otherwise indicated, the term "lower alkenyl" 5 or "alkenyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 3 to 12 carbons, and more preferably 1 to 8 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2 10 propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2 hexenyl, 2-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3 octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, 15 halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonyl amino, nitro, cyano, thiol, alkylthio or any of the R 1 groups, or the R 1 substituents set out herein. 20 Unless otherwise indicated, the term "lower alkynyl" or "alkynyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one 25 triple bond in the normal chain, such as 2-propynyl, 3 butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3 hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3 nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with 1 to 4 30 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, or any of the R 1 groups, or the R1 substituents 35 set out herein. Where alkyl groups as defined above have single bonds for attachment to other groups at two different -9- WO 00/47563 PCT/USOO/01859 carbon atoms, they are termed "alkylene" groups and may optionally be substituted as defined above for "alkyl". Where alkenyl groups as defined above and alkynyl groups as defined above, respectively, have single bonds 5 for attachment at two different carbon atoms, they are termed "alkenylene groups" and "alkynylene groups", respectively, and may optionally be substituted as defined above for "alkenyl" and "alkynyl". Suitable alkylene, alkenylene or alkynylene groups 10 (CH 2 )p (where, p is 1 to 8, preferably 1 to 5) (which may include alkylene, alkenylene or alkynylene groups) as defined herein, may optionally include 1, 2, or 3 substituents which include any of the R 1 groups, or the R1 substituents set out herein. 15 Examples of alkylene, alkenylene and alkynylene include -CH CH-CH2- , -CH 2 CH=CH- , -C=C-CH 2 - 9
-CH
2 - C- - CH 2 - CH 2 - CH 2 -- C I I I I 0 0 20
CH
3
-CH
2 C =- CCH 2 - -C=CH -CH 2 ~' (CH22- ,-(CH 2
)
3 - -(CH 2
)
4 CH 3 - (CH 2 ) 2 -C- CH 2
CH
2 - - CH 2 CH- - CH 2
CHCH
2 I 1 25 CH 3
CH
3
C
2
H
5
-CHCH
2 - CHCH 2
CH
2 - -CHCHCH 2 CH 3
C
2
H
5
CH
3
CH
3
CH
3 F
-CH
2
-C-CH
2 - -(CH2) , -(CH 2
)
2
-C-CH
2 CH 3 30 - 10 - WO 00/47563 PCT/USOO/01859 Cl
CH
3 CH3 I I -- C 2
-CH-CH
2 - -(CH 2
)
2 -CH- 9 -CH 2 -CH-C- 9
CH
3
CR
3
-CH
2 - CH - CH -CH 2 - , -- CH 2 -H- CH2 -CH
CH
3
CH
3
CH
3
CH
3
CH
3 OCH3 5 -CH-CH 2
CH
2 - -CH-CH 2
CH
2 - - CH20CH2 - OCH 2
CH
2 - - CH2NHCH 2 - - NHCH 2 CH2
CH
3 -N- C 2
CH
2
-
-(CH
2
)
3
-CF
2 - , -CH 2
-N-CH
2 - or CH 3 10 The term "halogen" or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF 3 , with chlorine or fluorine being preferred. The term "metal ion" refers to alkali metal ions 15 such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum. The term "cycloheteroalkyl" as used herein alone or as part of another group refers to a 5-, 6- or 7-membered 20 saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH 2 )p (which is defined above), such as 25 0 N( N O CN - 11 - WO 00/47563 PCT/USOO/01859 N( 0 , and the like. The above groups may include 1 to 4 substituents such as alkyl, halo, oxo and/or any of of the RI groups, or the RI substituents set out herein. In 5 addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring. The term "heteroaryl" as used herein alone or as part of another group refers to a 5- or 6- membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such 10 as nitrogen, oxygen or sulfur,and such rings fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides. The heteroaryl group may optionally include 1 to 4 substituents such as any of the RI groups or the R1 15 substituents set out above. Examples of heteroaryl groups include the following: N S 0 0 NN N > N O N N N N 20 N H]Zz N-N N-N N-N N N=N -N N , 12- WO 00/47563 PCT/USOO/01859 C'1 --- C H 3 CH 3 O -_ C H 3 N N and the like. The term "cycloheteroalkylalkyl" as used herein alone or as part of another gorup refers to 5 cycloheteroalkyl groups as defined above linked through a C atom or heteroatom to a (CH 2 )p chain. The term "heteroarylalkyl" or "heteroarylalkenyl" as used herein alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom 10 or heteroatom to a -(CH 2 )p- chain, alkylene or alkenylene as defined above. The term "polyhaloalkyl" as used herein refers to an "alkyl" group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, 15 preferably F, such as CF 3
CH
2 , CF 3 or CF 3
CF
2
CH
2 The term "polyhaloalkyloxy" as used herein refers to an "alkoxy" or "alkyloxy" group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as 20 CF 3
CH
2 0, CF 3 0 or CF 3
CF
2
CH
2 0. The compounds of formula I can be present as salts, in particular pharmaceutically acceptable salts. If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts. These are 25 formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, 30 for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, +-"taric or citric acid, such as amino - 13 - WO 00/47563 PCT/USOO/01859 acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (Ci-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen, for 5 example methane- or p-toluene-sulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds of formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases 10 are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for 15 example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di or triethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for 20 pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included. Preferred salts of the compounds of formula I include monohydrochloride, hydrogensulfate, methanesulfonate, 25 phosphate or nitrate. All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon 30 atoms including any one of the R substituents. Consequently, compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures thereof. The processes for preparation can utilize racemates, enantiomers or diastereomers as starting 35 materials. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization. - 14 - WO 00/47563 PCT/USOO/01859 It should be understood that the present invention includes prodrug forms of the compounds of formula I such as alkylesters of acids or any known prodrugs for lactam derivatives. 5 The compounds of the instant invention may, for example, be in the free or hydrate form, and may be obtained by methods exemplified by the following descriptions. The compounds of formula I may be prepared by the 10 exemplary processes described in the following reaction schemes. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples. Compounds of formula I of the invention can be prepared from the corresponding amine 1 by using the 15 sequence of steps outlined in Scheme I set out below. Reaction Scheme I o
R
1 H2 N
R
2 + 2 or 3 or 4 or 5 0 1 0 0 R H/ Amidation
R
8 N S+ R8 ) C1 N R2 0 0 2 20 orID 0
R
1 O O H S+ R Sulfonylation R8 % N N \ I + R3-- Cl // s\0 N 0 R2 0 0 3 or IA - 15 - WO 00/47563 PCT/USOO/01859 0 H 1 + R7 ' K Condensation 7,0 N N 0 Cl 10 R N R 2 4 0 0 or IC 0 R 6 0R Rs5 N Condensation N N N 2 - ~ C Ni R 2 0 0 R6OO IB 5 Reaction of amine 1 in an inert organic solvent such as dichloromethane, chloroform or tetrahydrofuran with reactant acid chloride 2, sulfonyl chloride 3, chloroformate 4 or carbamoylchloride 5, employing a molar ratio of reactant:amine 1 within the range from about 5:1 10 to about 1:5, optionally in the presence of an acid scavenger such as triethylamine, diisopropylethylamine, pyridine, or polyvinylpyridine, forms compounds ID, IA, IC or IB of the invention. Starting compound 1 can be prepared by methods known 15 in the art as outlined in Reaction Scheme IA below. Reaction Scheme IA 0 Boc NH H 0 R'Ns R 2 + Cl Br 1314 15 Acylation 0 Et 3 N, CH 2 C1 2 , 0C-r.t.,36h. RIkN Br
R
2 ' 20 16 - 16 - WO 00/47563 PCT/USOO/01859 0 R1 1) Alkylation H 2 N 1 + 1 LiHMDS, THF 2 N r.t., 14h 2) Deprotection 1
TFA/CH
2 C1 2 Compound 1 is a novel compound provided that R 1 and R 2 are as defined herein, but excludes alkyl, alkenyl, aryl, 5 arylalkyl, cycloalkyl or polycycloalkyl. Compounds of formula I of the invention wherein Rs X is R 4 -C- Y is O and R 4 is IN y that is N-C R6 11 0 can be prepared from the corresponding acid 6 by using the 10 sequence of steps outlined in Scheme II (Procedures A and B) set out below. Reaction Scheme II Procedure A H 0 Amidation N H0 OH OR, N ,R 2 N 1) HNR5R6 (21) 6N R6- N oH DIC/HOAt/CH 2 Cl 2 /DMF N R2 r N O 2) SCX Purification Procedure B IB Amidation 1) HNR1R 2 (21)
EDAC/DMAP/CH
2 C1 2 15 2) SCX Purification Procedure A: For amines where R 1 and/or R 2 contain additional basic nitrogens. Procedure B: For amines where R- and/or R 2 contain no additional basic nitrogens. 20 In Procedure A (for amines where R 1 and/or R 2 contain additional basic nitrogens), a mixture of a solution of - 17 - WO 00/47563 PCT/USOO/01859 amine 21 in an inert organic solvent such as THF, methylenechloride or chloroform, a carbodiimide such as diisopropylcarbodiimide (DIC) and 7-aza-l-hydroxy benzotriazole (HOAt) is reacted with acid 20, employing a 5 molar ratio of amine 2l:acid 20 within the range from about 5:1 to about 1:5, preferably at about 1:1.1, to form a reaction mixture which is purified via an SCX column to separate out compound IB of the invention. The DIC will be employed in a molar ratio to acid 20 10 within the range from about 5:1 to about 1:5, preferably at about 1.6:1, and the HOAt will be employed in a molar ratio acid 20 within the range from about 5:1 to about 1:5, preferably at about 1.6:1. In Procedure B (for amines where R 1 and/or R 2 contain 15 no additional basic nitrogens) a mixture of a solution of amine 21 in an inert organic solvent such as THF methylenechloride or chloroform, ethyldimethylaminopropylcarbodiimide (EDAC) and dimethylaminopyridine (DMAP) with acid 20, employing a 20 molar ratio of amine 21:acid 20 within the range from about 5:1 to about 1:5, preferably at about 1.5:1, to form a reaction mixture which is purified via a SCX column to separate out compound IB of the invention. The EDAC will be employed in a molar ratio to acid 25 20 within the range from about 5:1 to about 1.5, preferably at about 1.5:1, and the DMAP will be employed in a molar ratio to acid 20 within the range from about 5:1 to about 1:5, preferably at about 1.5:1. Starting compound 20 can be prepared by methods 30 known in the art as outlined in Reaction Scheme IIA. - 18 - WO 00/47563 PCT/USOO/01859 Reaction Scheme IIA Alkylation O 0 ON Br >~ yNH OEt LHMDS THF 24 Deprotection OEt O N OEt 1M KHC1 N 0 0 Et 2 O0 RT 5 Condensation o NCO N OEt 0 0
ET
3 N THF RT Saponification 0 or Hydrolysis H H 2 M NaOH N N N OH _________0 60 THF EtOH 28 RT 10 Compounds of formula I of the invention wherein R5 X is R 4 -C- , Y is 0 or S, and R 4 is N that is ,N- C- or ,N- C R6' il R6' 11 0 S can be prepared from the corresponding amine 1 by using the 15 sequence of steps outlined in Scheme III set out below. - 19 - WO 00/47563 PCT/USOO/01859 Reaction Scheme III Condensation o R1 H H 0 ,R1 0- 1. R5NcO or R 5 NCS N N N H NCS N R 2 ( ) (30) N R 2 0 CH 2 Cl2,RT,6h. 0 0 2. aminomethyl- IB' polystyrene (3.2) or resin, 16h.,RT H H Y R1 R51N N N R 2 S 0 IB" 5 Reaction of amine 1 (in an inert organic solvent such as dichloromethane, chloroform or tetrahydrofuran) with reactant 30 or 31 employing a molar ratio of 30 or 31:amine 1 within the range of from about 5:1 to about 1:5, followed by treatment with aminomethylpolystyrene (32), 10 affords the compound of the invention IB' or IB". The compounds of the present invention are inhibitors of the activated coagulation serine protease known as Factor Xa and thus are useful for the treatment or prophylaxis of those processes which involve the production 15 and/or action of Factor Xa. Thus, the compounds of the invention are useful in the treatment or prevention of thrombotic events associated with coronary artery and cerebrovascular disease. This includes a number of thrombotic and prothrombotic states in which the 20 coagulation cascade is activated which include, but are not limited to, formation of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes, ischemia and angina (stable and unstable), deep vein thrombosis (DVT), disseminated intravascular coagulopathy, Kasabach-Merritt 25 syndrome, pulmonary embolism, myocardial infarction, cerebral infarction, cerebral thrombosis, atrial - 20 - WO 00/47563 PCT/USOO/01859 fibrillation, cerebral embolism, thromboembolic complications of surgery (such as hip replacement, introduction of artificial heart valves and endarterectomy) and peripheral arterial occlusion. The compounds of the 5 invention are also useful as inhibitors of blood coagulation such as during the preparation, storage and fractionation of whole blood. The present compounds may also be useful in maintaining whole and fractionated blood in the fluid phase 10 such as required for analytical and biological testing. Examples include, but are not limited to, ex vivo platelet and other cell function studies, bioanalytical procedures and quantitation of blood-containing components. In addition, the compounds of the present invention 15 may be useful to prevent restenosis following arterial injury induced by endogenous (rupture of an atherosclerotic plaque) or exogenous (invasive cardiological procedure such as vessel wall injury resulting from angioplasty) events. The compounds of the present invention may also be 20 used as an anticoagulant in extracorpeal blood circuits, such as those necessary in dialysis and surgery (such as coronary artery bypass surgery). In addition, the compounds of the present invention may be useful for maintaining blood vessel patency in 25 conjunction with vascular surgery including bypass grafting, arterial reconstruction, atherectomy, vascular graft and stent patency, organ, tissue and cell implantation and transplantation. The compounds of the present invention may be useful 30 for the treatment of heparin-intolerant patients, including those with congenital and acquired antithrcmbin III deficiencies, heparin-induced thrombocytopenia, and those with high levels of polymorphonuclear granulocyte elastase. The compounds of the present invention may also be 35 useful for the treatment of inflammatory diseases and the prevention of septic shock and vascular damage due to bacterial and/or riral infections. - 21 - WO 00/47563 PCT/USOO/01859 The compounds of the present invention may also be useful in the treatment of malignancies, prevention of metastases, prevention of prothrombotic complications of cancer, and as an adjunct to chemotherapy. 5 The compounds of the present invention may also be used in combination with prothrombolytic agents, such as tissue plasminogen activator (natural or recombinant), streptokinase, reteplase, activase, lanoteplase, urokinase, prourokinase, anisolated streptokinase plasminogen 10 activator complex (ASPAC), animal salivary gland plasminogen activators, and the like. The compounds of the present invention may act in a synergistic fashion with one or more of the above agents to prevent reocclusion following a successful thrombolytic therapy and/or reduce 15 the time to reperfusion. The compounds of the present invention may also allow for reduced doses of the thrombolytic agent to be used and therefore minimize potential hemorrhagic side-effects. The compounds of the present invention may also 20 inhibit other serine proteases, for example, thrombin, Factor VIIa, urokinase-type plasminogen activator (urokinase), tryptase and/or trypsin. As a result, these compounds may additionally be useful as angiogenesis inhibitors in the treatment of cancer, as antiinflammatory 25 agents particularly in the treatment of chronic asthma and in the treatment or prevention of allergic rhinitis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, and conjunctivitis and in the treatment or prevention of pancreatitis. 30 The compounds of the present invention may also be used in combination with other antithrombotic or anticoagulant drugs such as thrombin inhibitors, platelet aggregation inhibitors such as clopidogrel, ticlopidine, PAI-l inhibitors such as XR-330 and T-686, inhibitors of 35 a-2-antiplasmin such as anti-c-2-antiplasmin antibody and thromboxane receptor antagonists (such as ifetroban), prostacyclin mimetics, phosphodiesterase (PDE) inhibitors, - 22 - WO 00/47563 PCT/USOO/01859 such as dipyridamole or cilostazol, PDE inhibitors in combination with thromboxane receptor antagonists/thromboxane A synthetase inhibitors (such as picotamide), serotonin-2-receptor antagonists (such as 5 ketanserin), fibrinogen receptor antagonists, aspirin, hypolipidemic agents, (such as HMG-CoA reductase inhibitors for example pravastatin or simvastatin, or microsomal triglyceride transport protein inhibitors such as disclosed in U.S. Patent Nos. 5,739,135, 5,712,279 and 5,760,246), 10 antihypertensive agents, (such as angiotensin converting enzyme inhibitors, for example, captopril, lisinopril or fosinopril, angiotensin II receptor antagonists, for example, irbesartan, losartan or valsartan, and ACE/NEP inhibitors, for example omapatrilat), PDE inhibitors in 15 combination with aspirin, ifetroban, picotamide, ketanserin or clopidogrel and the like. The compounds of the invention can be administered orally or parenterally such as subcutaneously or intravenously, as well as by nasal application, rectally or 20 sublingually to various mammalian species known to be subject to such maladies, e.g., humans, cats, dogs and the like in an effective amount within the dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg 25 (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) on a regimen in single or 2 to 4 divided daily doses. The active substance can be utilized in a composition such as tablet, capsule, solution or suspension 30 or in other type carrier materials such as transdermal devices, iontophoretic devices, rectal. suppositories, inhalant devices and the like. The composition or carrier will contain about 5 to about 500 mg per unit of dosage of a compound or mixture of compounds of formulas I, IA., IB, 35 IC and ID. They may be compounded in conventional matter with a physiologically acceptable vehicle or carrier, - 23 - WO 00/47563 PCT/USOO/01859 excipient, binder, preservative, stabilizer, flavor, etc., as called for by accepted pharmaceutical practice. The following working Examples represent preferred embodiments of the present invention. 5 Example 1 0O /N H H N N Ni,/ 0 10 A. 0 H O N ',, N OEt 0 0 To a solution of 8.3 g (36 mmol, .1 eq) of 0 H N 0 N, ,6 0 compound in 40 mL of dry THF was added 15 dropwise 72 mL (72 mmol, 2 eq) of a 1 M solution of lithium hexamethyldisilazide (LHMDS) in THF over 1 h. After 10 min, a solution of 4.4 mL (40 mmol, 1.1 eq) of bromoethylacetate in 10 mL of dry THF was added dropwise over 10 min and the resulting reaction mixture was stirred 20 at RT for 17 h. The reaction mixture was diluted with diethyl ether (100 mL) and washed twice with 5% KHSO 4 (aq.), followed by saturated NaHCO 3 and brine. The organic solution was dried (MgSO 4 ) and concentrated to afford 11.3 g (99%) of title compound as a viscous yellow brown oil. 25 1H and 13C NMR spectra were consistent with the desired product and indicated the ma -rial was pure except for a small amount of hexamethyldisilazane. The material was used without further purification. - 24 - WO 00/47563 PCT/USOO/01859 B. 0 H2A ' N OEt 0 To a solution of 7.8 g (25 mmol, 1 eq) of Part A 5 compound in 10 mL of diethyl ether was added 50 mL (50 mmol, 2 eq) of a 1 M solution of hydrochloric acid in diethyl ether. The reaction mixture was stirred at RT for 18 h. The resulting heterogeneous reaction mixture was concentrated and the oily residue was triturated with 10 ether, dissolved in methanol and concentrated to afford 5.1 g (81%) of title compound as a yellow solid. .lH and 13C NMR spectra were consistent with the desired product. C. O OEt H HN 15 0 To a solution of 5.1 g (20 mmol, 1 eq) of Part B compound in 120 mL of dry THF was added 5.7 mL (41 mmol, 3 eq) of triethylamine and 3.9 mL (30 mmol, 1.5 eq) of m 20 tolylisocyanate. The reaction mixture was stirred at RT for 18 h. The reaction mixture was concentrated and the residue dissolved in methnol. An insoluble impurity was removed by filtration and the crude product was again concentrated. Flash chromatography (SiO 2 ) eluting with 9:1 25 CH 2 Cl 2 :ethyl acetate (EtOAc) afforded 3.3 g (48%) of title compound as a light brown solid. lH and 13C NMR spectra were consistent with the desired product. D. 0 OH H H N N/, 300 30 - 25 - WO 00/47563 PCT/USOO/01859 To a solution of 2.3 g (7 mmol, 1 eq) of Part C compound in 30 mL of THF and 30 mL of EtOH was added 8.3 mL (17 mmol, 2.5 eq) of 2 M sodium hydroxide in water. The reaction mixture was stirred at RT for 18 h. The reaction 5 mixture was concentrated, the residue was dissolved in 20 mL of water and the pH was adjusted to 3 with 1 M HCl. The resulting precipitate was collected by filtration, washed with water (10 mL), washed with hexane (10 mL) and dried to afford 1.7 g (82%) of title compound as a light yellow 10 solid. 1H and 13C NMR spectra were consistent with the desired product. E. Q \ /N H H N N N1/, 15 The title compound was prepared as part of an automated solution phase run using a liquid handler (Hamilton Microlab* 2200) for reagent and starting material addition using the following procedure. 20 To a 16 mm x 100 mm reaction tube was added via the liquid handler 100 IL (3.9 mg, 0.036 mmol, 1 eq) of a stock solution of 4-[2-(methylamino)ethyllpyriLdine in THF, 300 PL (7 mg, 0.057 mmol, 1.6 eq) of a stock solution of diisopropylcarbodiimide in CH2Cl2, 300 L (8 mg, 0.057 25 mmol, 1.6 eq) of a stock solution of 7-aza-l-hydroxybenzotriazole in DMF and 300 L (12 mg, 0.038 mmol, 1.05 eq) of a stock solution of Part D compound in CH2Cl2. The tube was removed and mixed on an orbital shaker for 72 h. The product was purified via solid phase extraction 30 using a Varian SCX cation exchange colunT (1 g of sorbent in 6 mL column, n.3 meq/g) by the procedure outlined below: -26 - WO 00/47563 PCT/USO0/01859 1) Column conditioned with 2 x 7.5 mL of MeOH (10 mL/min). 2) Reaction mixture (1 mL) loaded onto SCX column (3 mL/min) . 5 3) Column rinsed with 20 mL of MeOH (6 mL/min). 4) Column rinsed with 10 mL of 0.1 N ammonia in MeOH (6 mL/min). 5) Product eluted with 8 mL of 2 N ammonia in MeOH into a tared 16 x 100 tube (6 mL/min). 10 The product solution was concentrated using a speed vac for 14 h to afford 17 mg of title compound (109%) as an oil. Reverse phase analytical HPLC analysis indicated a purity of 96%. 15 MS (electrospray): m/z 438 (M+H). Examples 2 to 4 Following the procedure of Example 1, the following 20 compounds of the invention were prepared. Example Structure Mass Spec. No. m/z (M+H)+ 2 O O Chiral 424 -H NN O 3 Chiral 438 O H HO - H I N0 N~ f 4 Chiral 4g H N H NNN_ -27 - WO 00/47563 PCT/USOO/01859 Example 5 0 HH Chiral NO H N N Example 5 was prepared as part of an automated 5 solution phase run using a liquid handler (Hamilton MicrolabO 2200) for reagent and starting material addition using the following procedure. To a 16 mm x 100 mm reaction tube was added via the liquid handler 100 pL (0.057 mmol, 1.5 eq) of a stock 10 solution of 1,2,3,6-tetrahydropyridine in THF, 300 JIL of a stock solution containing both ethyldimethylaminopropyl carbodiimide hydrochloride (0.057 mmol, 1.5 eq) and dime thylaminopyridine (0.057 mmol, 1.5 eq) in CH 2 Cl 2 and 600 pL (0.038 mmol, 1.0 eq) of a stock solution of Example 15 1 Part D compound in CH 2 Cl 2 . The tube was removed and mixed on an orbital shaker for 72 h. The product was purified via solid phase extraction using a Varian SCX cation exchange column (1 g of sorbent in 6 mL column, 0.3 meq/g) by the procedure outlined below. 20 l) Column conditioned with 15 of MeOH (10 mL/min). 2) Reaction mixture (1 mL) was loaded onto SCX column (3 mL/min) and effluent was collected into a tared 16 mm x 100 mm tube. 25 3) Column rinsed with 6 mL of MeOH and collected into tared tube (6 mL/min). The product solution was concentrated using a speed vac for 14 h to afford 14 mg of Example 5 compound (94%) as 30 an oil. Reverse phase analytical HPLC analysis indicated a purity of 97%. MS (electrospray): m/z 385 (M + H). - 28 - WO 00/47563 PCT/USOO/01859 Examole 6 to 10 Following the procedure of Example 5, the following compounds of the invention were prepared. Example Structure Mass Spec. No. , m/z (M+H)+ 6 H N NChiral 403 N)HO H Nr NH38 HO y____ 7 0 HH0Chiral 389 _ _ ~ - /DNyN 7 OH_ _ 8 Chiral 387 H N-\N? 0 9 Chiral 427 -NN 10 0 H Chiral 373 /- H 0 5 Example 11 N N/ N NO S 0 - 29 - WO 00/47563 PCT/US0O/01859 A. 0 N .Br 0 11 To a solution of C1-c-CH 2 -Br (55 g, 0.35 mol) in 400 5 ML of CH 2 Cl 2 was added dropwise a solution of pyrrolidine (25 g, 0.35 mol) and triethylamine (42.4 g, 0.42 mol) in 100 mL of CH 2 Cl 2 at 0*C under argon over 5h. The reaction mixture was allowed to slowly warm to room temperature with stirring for an additional 14h. The reaction mixture was 10 washed with H 2 0 (250 mLx3), 0.5 N HCl (250 mL), saturated NaCl (300 mLx3), and dried (Na 2
SO
4 ) and concentrated. The resulting residue was purified by flash column chromatography (elute with 1% MeOH in CH 2 Cl 2 ) to yield title compound (46.1 g, 68.6%) as off-brown solid. 15 Found: MH+: 191.7. B. 0Q
H
2 2'' N 0 0 BocHIV,, 20 To a solution of (8.0 g, 35.1 mmol) in 600 mL of THF was added dropwise 70.2 mL of LHMDS (1.0 M in THF) at room temperature under argon over 3h, followed by adding dropwise a solution of Part B compound (7.4 g, 38.6 mmol) in 100 mL of THF over 2h. The reaction mixture was 25 stirred for an additional 14h at room temperature. The reaction mixture was poured into 5% KHSO 4 (300 mL), and added ethylacetate (AcOEt) (300 mL). The organic layer was washed with 5% KHSO 4 (300 mL), saturated NaHCO3 (300 mLx2), H20 (300 mLx3), and dried (Na 2
SO
4 ) and concentrated to 30 yield title compound (11.1 g, 93.2%) as yellow oil. Found: MH+: 340.1. - 30 - WO 00/47563 PCT/US0O/01859 C. 0 HC1 ' N 0 5 To a solution of Part B compound (4.1 g, 12.1 mmol) in 100 mL of CH 2 Cl 2 was added 100 mL of HCl in Et 2 0 (1.0 M) at room temperature. The mixture was stirred for 14h. The solvent was removed in vacuum and the resulting residue was purified by ion-exchange resin column chromatography (elute 10 with 2% ammonia in MeOH) to yield title compound (1.91 g, 66.0%) as yellow oil. Found: MH+: 240.2. D. H H N N ' N N S 0 15 To a solution of Part C compound (90.8 mg, 0.38 mmol) in 3 mL of CH 2 Cl 2 was added a solution of m-tolyl isothiocyanate (51.5 mg, 0.345 mmol) in 2 mL of CH 2 Cl2 at room temperature. The reaction mixture was stirred for 20 0.5h and concentrated in vacuum. The resulting residue was purified by flash column chromatography (eluted with 1% MeOH in CH 2 Cl 2 ) to yield title compound (130 mg, 97.0%) as white solid. Found: MH+: 389.1. 25 Examples 12 to 16 The following compounds of the invention were prepared employing procedures described in Example 11. - 31 - WO 00/47563 PCT/USOO/01859 Example Structure Mass Spec. No. m/z (M+H)* 12 chiral 375 H 0 H HNN 13 Chiral 403 0 N O H s S 0 14 O>Chiral 420 0 N+- O 0 N H O H N S H 15 / Chiral 405 H 0 N N 16 Chiral 400 0 H -32- WO 00/47563 PCT/USOO/01859 Example 17 /NN 9-0 0 To 13.9 mg of polyvinylpyridine (9.0 mmol/g) was 5 added 0.400 mL of solution of Example 13, Part C compound in dichloromethane (0.158 mmol/mL) and 0.400 mL of solution of o-toluoyl chloride in dichloromethane (0.173 mmol/mL). The mixture was shaken for 4h. at room temperature. The reaction mixture was then added to 31.4 mg of 10 aminomethylpolystyrene (1.0 mmol/g) and 0.200 mL of dichloromethane. The mixture was shaken for 14h at room temperature. The reaction solution was collected and the residue resins were washed with dichloromethane (0.400 mL). The combined reaction solutions were dried by speed vacuum 15 to yield title compound (17.1 mg, 69%). Found: MH+: 358.1. Examples 18, 19 The following compounds were prepared employing the procedure as described in Example 17. 20 Example Structure Mass Spec. No. 18 chiral 374 0 ; N 0 0 N 0 L 19 chiral 430 0 I HO N
N
- 330 -33 - WO 00/47563 PCT/USOO/01859 Examoles 20 to 57 The following compounds were prepared employing procedures as described in previous Examples. Example Structure Mass Spec. No. m/z (M+H)+ 20 S Chiral 409 N oy o Y C1 0 21 Chiral 405 o N< cE3- 1 CN N S 22 ci ci Chiral 443 0N N N S 23 Chiral 403 -33 N UN I, N S
CH
3 0 24 Chiral 425 /O\N IH S 0 -34- WO 00/47563 PCT/USOO/01859 25 chiral. 377 0 0 N4 N 26 .0Chiral 437 ___ 0 0_ 27 Chiral 409 0 0 HC 28 Chiral 393 0 H N 29 0Chiral. 409 0 NN -35 - WO 00/47563 PCT/USOO/01859 30 0 Chiral 443 s 0 N4 N F F 31 Chiral 393 S H N 32 Chiral 405
H
3 C-0 0 N N H S 33 Chiral 403 NcH3 O N CN N H S 34 Chiral 423
CH
3 cl 0 NO N N H - 36- WO 00/47563 PCT/USOO/01859 35 chiral 443 N N 0 Cl. C ci 36 Q Chiral 400 0 0 N SN NN Cf o N N C1 cH 3 sI C1\ N 38 Chiral 501 0 r NH s 0 N N 39 Chiral. 481
H
3 C-O0 0 N N CN N HS 0 - 37- WO 00/47563 PCT/USOO/01859 40 Chiral 433 0 N H< N______0 41- Chira 41 00
CH
3 0 42 Chiral 419
H
3 C- 0 43 Chiral 477 CiF F 0 ND S 44 Chiral. 403 - CH 3 0 N 0 -38- WO 00/47563 PCT/USOO/01859 45 Chiral 454 SN Cl N ON Y '>N0
NO
2 46 Chiral 420 0 N _NO 2 47 Chiral 434 HN N O NO 2 cH 3 48 Chiral 450
H
3 q\ O O NO 2 Y 39 2 -3 9 - WO 00/47563 PCT/USOO/01859 49 Chiral 450 N 0N N N O INO
H
3 0 50 Chiral 376 NP 0 N N NH 51 Chiral 393 N N H O 0 N 52 Chiral 415 Nc; 0 N- / CN N IIH S 0 __________ 53 Chiral 419 HcH - CH 3 ON0 CN N H S 0 54 chiral 481 0- 0 N 0 N N N S - 40 - WO 00/47563 PCT/USOO/01859 55 Chiral 437 0 N Br 56 Chiral 387 N 0 0 N 0 57 Chiral 427 ci Cl N N 0 0 58 Chiral 429 H H 0 NN NO 59 Chiral 413 H H 0 S6N- N -41 -
Claims (16)
1. A compound having the formula 0 R1 H/ N N R2 0 5 including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrug esters thereof, wherein R 1 and R 2 are the same or different and are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, 10 cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, cycloalkenylalkyl, polycycloalkenyl, or polycycloalkenylalkyl, or R 1 and R 2 can be taken with the nitrogen to which they are attached to form a cycloheteroalkyl ring; all optionally substituted 15 through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheterolkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, 20 aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, 25 arylaminocarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, 30 heteroarylsulfinyl, heteroarylthio, hete-oarylsulfonyl, or alkylsulfinyl; X is R4-- or 3 -S 11 02 Y - 42- WO 00/47563 PCT/US0O/01859 R 5 Y is o or S and R 4 is N- R 7 0- or RB R6 R 3 is selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, 5 cycloalkenyl, cycloheteroalkyl, cycloalkenylalkyl, polycycloalkenyl, or polycycloalkenylalkyl; all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, 10 cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted 15 amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, 20 alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl, 25 R 5 and R 6 are the same or different and are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, cycloalkenylalkyl, 30 polycycloalkenyl, polycycloalkenylalkyl, arylcarbonyl, alkylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, arylsulfonyl, or alkylsulfonyl, or R 5 and R 6 can be taken with the nitrogen to which they are attached to form a cycloheteroalkyl ring; all optionally substituted through 35 available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, - 43 - WO 00/47563 PCT/USOO/01859 alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, 5 heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, 10 alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, 15 heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl; R 7 and R 8 are independently selected from alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, 20 polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloheteroalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, 25 alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, 30 nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, 35 alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, - 44 - WO 00/47563 PCT/USOO/01859 arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, or alkylsulfinyl; with the proviso that where 5 R 5 X is ,N-C- R8- R6' 1t o1 Y Y and (1) R 1 and R 2 are independently cycloalkyl, alkenyl, phenyl, benzyl, cyanoalkyl, alkoxycarbonylalkyl, or phenyl mono- or disubstituted with lower alkyl, cyano, hydroxy, 10 dialkylamino, alkoxy, benzyloxy, alkylamino, alkoxycarbonyl, pyrrolidino, morpholino, halogen, alkyl substituted with one or more fluorines, then Y is S; (2) where R1 and R 2 are alkyl, then Y is S; and (3) where one of R 1 and R 2 is alkyl and Y is 0, 15 then the other is alkynyl, heteroaryl, heteroarylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl or R1 and R 2 can be taken with the nitrogen to which they are attached to form a cycloheteroalkyl ring, all 20 optionally substituted through available carbon atoms with 1, 2, 3 or 4 substituents as defined for R 1 and R 2 .
2. The compound as defined in Claim 1 having the formula O R1 H/ R3 0 N N S N , 0 25
3. The compound as defined in Claim 1 having the formula R 5 O R \ H/ N N N\ R6 N NN R2 Y 0 - 45 - WO 00/47563 PCT/USOO/01859
4. The compound as defined in Claim 1 having the formula H / R 7 o N N R2 y 0 5
5. The compound as defined in Claim 1 having the formula H / R 8 N N R2 10
6. The compound as defined in Claim 1 wherein X is R4-c II Y and Y is S.
7. The compound as defined in Claim 3 wherein Y is S.
8. The compound as defined in Claim 3 wherein R 1 and 15 R 2 together with the nitrogen to which they are attached form a cycloheteroalkyl ring, Y is S, one of R 5 and R 6 is hydrogen and the other of R 5 and R 6 is aryl, alkylaryl or alkoxyaryl.
9. The compound as defined in Claim 8 wherein R 1 and 20 R 2 together with the nitrogen to which they are attached form a pyrrolidinyl ring, Y is S, one of R 5 and R 6 is hydrogen and the other of R 5 and R 6 is phenyl, 3 methylphenyl, 3-methoxyphenyl, 4-cyanophenyl, 3 fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4 25 methoxyphenyl, 3-chloro-4-methylphenyl, 3, 5-dichlorophenyl, 3-iodophenyl, 3,5-dimethylphenyl or naphthyl.
10. The compound as defined in Claim 1 having the structure - 46 - WO 00/47563 PCT/USOO/01859 o N HH N N Chiral N H Chiral N N H N O HHCchira HN NH N NQ 5 O H Chiral chiral HH N N OH HO 0 Chirahiral SHChiral Chiral N N N -H --JN\__>H NN 0 H HChiral N >-NH00 HHCia N N N D NH N H, H -0 0 H Chiral hia 0- 0 HH H 0 0 0 0 Q 10 - 47 - WO 00/47563 PCT/USOO/01859 Chiral NH 0 0 N Chiral 0 -~ IIH Chiral 0 Chira2.chiral 0 o" - 0CHH 3 o N- NO IIH N s 0 (~N~/ S H Chiral Cia C3 N N 00 0N: 0 H 48 WO 00/47563 PCT/USOO/01859 Chiral 0 Chiral NN 0 0 Br Chiral 0 Chiral <j 0 H N N 0 Cl Chiral 0Chiral 0 0- N N ClF Chiral N N 0 0 -49- WO 00/47563 PCT/USOO/01859 Chiral Chiral H 3 C-0O o N\CE H sN N 00 Chiral Chirlral H3S 0 0o 0 N < N)K N H S YK N 0 0 l s / = Chiral Chiral 0 NN N H ~ ,CH 3 C Chral Chiral0 50 0r CN-k,- 50 0- WO 00/47563 PCT/USOO/01859 Chiral Chiral 0 CH 3 H 3 C- O C N CN NsH S N NS CE 3 O 0 Chiral C1 F Chiral F- CE, FF N 0 ND0 NYNH N N 0 Chiral Chiral 0 HN oNO2 NO 2 CH3 Chiral Chiral Chiral H3 N N NO NO 2 N NH 0N 2 0 S0 5 H 3 C - 51 - WO 00/47563 PCT/USOO/01859 Chiral Chiral N NI HD N O N N N iH S Chiral Chiral H 3 0 - CH 3 I O N CH3- O0 NO NH S N N 0 ~S0 chiral Chiral 0a Chiral 0 N 0 r N N N~~ Chiral Chiral H N H H 0 o N N w N 11 N 50
11. The compound as defined in Claim 1 having the structure 0 HN H HO N N N N0 y N,, N,,, S 0 - 52 - WO 00/47563 PCT/USOO/01859 Chiral N Cl s Chiral Chiral C: N O NCH3 Cl CN N H S Chiral CH3 ciC 1chiral Cl 0 C1 C1 No N N N N 0 Chiral 0ES Chiral Cl Cl NN N NN 1N N S(C -chiral 0 N-r CN rN 'lH S 5 53 - WO 00/47563 PCT/USOO/01859 Chiral Chiral H H NC> H H o N N YN N-" N YNN 0 14 S 0 0 0
12. A compound having the structure O 0 5 2 N wherein R 1 and R 2 are the same or different and are independently selected from alkynyl, heteroaryl, heteroarylalkyl, cycloalkenyl, cycloheteroalkyl, heteroaryloxy, cycloalkenylalkyl, polycycloalkenyl, 10 polycycloalkenylalkyl, or R 1 and R 2 can be taken with the nitrogen to which they are attached to form a cycloheteroalkyl ring; all optionally substituted through available carbon atoms with 1, 2, 3 or 4 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, 15 alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheterolkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, 20 nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, 25 alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, 30 alkylsulfinyl; or a pharmaceutically acceptable salt thereof. - 54 - WO 00/47563 PCT/USOO/01859
13. The compound as defined in Claim 11 having the formula H2Z5'/''N 0
14. A pharmaceutical composition comprising a 5 compound as defined in Claim 1 and a pharmaceutically acceptable carrier therefor.
15. A method for preventing or treating cardiovascular diseases associated with thromboses, which comprises administering to a mammalian species in need of 10 treatment a therapeutically effective amount of a compound as defined in Claim 1.
16. A method for preventing or treating thromboses, coronary artery disease or cerebrovascular disease, which comprises administering to a mammalian species in need of 15 treatment a therapeutically effective amount of a compound as defined in Claim 1. - 55 -
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US11937499P | 1999-02-09 | 1999-02-09 | |
US60/119374 | 1999-02-09 | ||
PCT/US2000/001859 WO2000047563A1 (en) | 1999-02-09 | 2000-01-27 | LACTAM INHIBITORS OF FXa AND METHOD |
Publications (2)
Publication Number | Publication Date |
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AU2630000A true AU2630000A (en) | 2000-08-29 |
AU756174B2 AU756174B2 (en) | 2003-01-09 |
Family
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Application Number | Title | Priority Date | Filing Date |
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AU26300/00A Ceased AU756174B2 (en) | 1999-02-09 | 2000-01-27 | Lactam inhibitors of FXa and method |
Country Status (5)
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EP (1) | EP1175405A4 (en) |
JP (1) | JP2002536437A (en) |
AU (1) | AU756174B2 (en) |
CA (1) | CA2361919A1 (en) |
WO (1) | WO2000047563A1 (en) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
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US6344450B1 (en) * | 1999-02-09 | 2002-02-05 | Bristol-Myers Squibb Company | Lactam compounds and their use as inhibitors of serine proteases and method |
CN1416346A (en) * | 2000-03-21 | 2003-05-07 | 史密丝克莱恩比彻姆公司 | Peotease inhibitors |
WO2001079261A1 (en) * | 2000-04-14 | 2001-10-25 | Corvas International, Inc. | Tetrahydro-azepinone derivatives as thrombin inhibitors |
US6544981B2 (en) | 2000-06-09 | 2003-04-08 | Bristol-Myers Squibb Company | Lactam inhibitors of factor Xa and method |
US6511973B2 (en) | 2000-08-02 | 2003-01-28 | Bristol-Myers Squibb Co. | Lactam inhibitors of FXa and method |
WO2002080853A2 (en) | 2001-04-09 | 2002-10-17 | Bristol-Myers Squibb Company | Fused heterocyclic inhibitors of factor xa |
GB0114005D0 (en) | 2001-06-08 | 2001-08-01 | Glaxo Group Ltd | Chemical compounds |
GB0114004D0 (en) * | 2001-06-08 | 2001-08-01 | Glaxo Group Ltd | Chemical compounds |
GB0127568D0 (en) | 2001-11-16 | 2002-01-09 | Glaxo Group Ltd | Chemical compounds |
CN100513398C (en) | 2002-12-03 | 2009-07-15 | Axys药物公司 | 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor VIIA inhibitors |
US7199149B2 (en) * | 2003-10-01 | 2007-04-03 | Bristol Myers Squibb Company | Monocyclic and bicyclic lactams as factor Xa inhibitors |
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Publication number | Priority date | Publication date | Assignee | Title |
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IT1247698B (en) * | 1990-06-21 | 1994-12-30 | Sigma Tau Ind Farmaceuti | 1-ALCHIL-3- (ACYLAMINE) -E-CAPROLATTAMI AS ACTIVATORS OF LEARNING PROCESSES AND MEMORY AND PHARMACEUTICAL COMPOSITIONS INCLUDING SUCH COMPOUNDS |
JPH10503176A (en) * | 1994-06-17 | 1998-03-24 | コーバス インターナショナル, インコーポレイテッド | 3-Amino-2-oxo-1-piperidineacetic acid derivatives as enzyme inhibitors |
GB9420763D0 (en) * | 1994-10-14 | 1994-11-30 | Glaxo Inc | Acetamide derivatives |
US5672598A (en) * | 1995-03-21 | 1997-09-30 | The Procter & Gamble Company | Lactam-containing hydroxamic acids |
CA2268281A1 (en) * | 1996-10-11 | 1998-04-23 | Cor Therapeutics, Inc. | Selective factor xa inhibitors |
US6326379B1 (en) * | 1998-09-16 | 2001-12-04 | Bristol-Myers Squibb Co. | Fused pyridine inhibitors of cGMP phosphodiesterase |
-
2000
- 2000-01-27 AU AU26300/00A patent/AU756174B2/en not_active Ceased
- 2000-01-27 CA CA002361919A patent/CA2361919A1/en not_active Abandoned
- 2000-01-27 JP JP2000598484A patent/JP2002536437A/en active Pending
- 2000-01-27 EP EP00904564A patent/EP1175405A4/en not_active Withdrawn
- 2000-01-27 WO PCT/US2000/001859 patent/WO2000047563A1/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
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CA2361919A1 (en) | 2000-08-17 |
WO2000047563A1 (en) | 2000-08-17 |
JP2002536437A (en) | 2002-10-29 |
EP1175405A4 (en) | 2002-05-15 |
EP1175405A1 (en) | 2002-01-30 |
AU756174B2 (en) | 2003-01-09 |
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