WO2002034711A1 - Composes biaryle utilises comme inhibiteurs de serine protease - Google Patents
Composes biaryle utilises comme inhibiteurs de serine protease Download PDFInfo
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- WO2002034711A1 WO2002034711A1 PCT/US2001/032582 US0132582W WO0234711A1 WO 2002034711 A1 WO2002034711 A1 WO 2002034711A1 US 0132582 W US0132582 W US 0132582W WO 0234711 A1 WO0234711 A1 WO 0234711A1
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- 0 COc1cccc(C=O)c1* Chemical compound COc1cccc(C=O)c1* 0.000 description 7
- LWPFHZMAQZTNHT-UHFFFAOYSA-N CC(c(cc1)cc(N)c1-c(c(C(C)=O)c1)ccc1O)=O Chemical compound CC(c(cc1)cc(N)c1-c(c(C(C)=O)c1)ccc1O)=O LWPFHZMAQZTNHT-UHFFFAOYSA-N 0.000 description 1
- PZGVOPPZHROXRK-UHFFFAOYSA-N CCOc(cc1)ccc1C(NC(OC(C)(C)C)=O)=N Chemical compound CCOc(cc1)ccc1C(NC(OC(C)(C)C)=O)=N PZGVOPPZHROXRK-UHFFFAOYSA-N 0.000 description 1
- WMPDAIZRQDCGFH-UHFFFAOYSA-N COc1cc(C=O)ccc1 Chemical compound COc1cc(C=O)ccc1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 1
- FTYOGLDPNBZSQC-UHFFFAOYSA-N Cc1c(CO)cc[o]1 Chemical compound Cc1c(CO)cc[o]1 FTYOGLDPNBZSQC-UHFFFAOYSA-N 0.000 description 1
- OXUZEENWOFWDJS-UHFFFAOYSA-N Cc1c(COc2ccccc2)[o]cc1CO Chemical compound Cc1c(COc2ccccc2)[o]cc1CO OXUZEENWOFWDJS-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Cc1ccccc1 Chemical compound Cc1ccccc1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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- C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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Definitions
- the present invention relates to the identification, through synthesis and testing, of heretofore unreported compounds which, in appropriate pharmaceutical compositions, exert a therapeutic effect through reversible inhibition of serine proteases.
- Serine proteases make up the largest and most extensively studied group of proteolytic enzymes. Their critical roles in physiological processes extend over such diverse areas as blood coagulation, fibrinolysis, complement activation, reproduction, digestion, and the release of physiologically active peptides. Many of these vital processes begin with cleavage of a single peptide bond or a few peptide bonds in precursor protein or peptides. Sequential limited proteolytic reactions or cascades are involved in blood clotting, fibrinolysis, and complement activation. The biological signals to start these cascades can be controlled and amplified as well. Similarly, controlled proteolysis can shut down or inactivate proteins or peptides through single bond cleavages.
- hile serine proteases are physiologically vital, they also can be hazardous. Their proteolytic action, if uncontrolled, can destroy cells and tissues through degradation of proteins. As a natural safeguard in normal plasma, 10% of the protein matter is composed of protease inhibitors.
- the major natural plasma inhibitors are specific for serine proteinases. Diseases (associated protease given in the parentheses) such as pulmonary emphysema (cathepsin G), adult respiratory distress syndrome (chymases), and pancreatitis (trypsin, chymotrypsin, and others) are characterized by uncontrolled serine proteases. Other proteases appear to be involved in tumor invasion (plasmin, plasminogen activator), viral transformation, and inflammation (kallikrein). Thus the design and synthesis of specific inhibitors for this class of proteinases could offer major therapeutic benefits.
- Thrombus formation that is blood coagulation, is normally initiated by tissue injury; its normal purpose is to slow or prevent blood loss and facilitate wound healing.
- tissue injury There are other conditions, however, not directly connected with tissue injury that may promote the coagulation process and lead instead to harmful consequences; examples of such conditions are atherosclerosis and inflammation.
- Blood coagulation or the coagulation cascade, is viewed mechanistically as two pathways, the extrinsic and the intrinsic (Fig. 1). Each pathway proceeds through a sequence of the Roman-numeral-designated factors until they converge at the activation of factor X after merger of the pathways.
- Thrombin generation proceeds stepwise through a common pathway. Thrombin then acts on the solution plasma protein, fibrinogen, to convert it to stable insoluble fibrin clots, thus completing the coagulation cascade.
- the extrinsic pathway is vital to the initiation phase of blood coagulation while the intrinsic pathway provides necessary factors in the maintenance and growth of fibrin.
- the initiation of the coagulation cascade involves the release of tissue factor (TF) from injured vessel endothelial cells and subendothelium. TF then acts upon factor VII to form the TF/FVIIa complex (where Vila designates the activated factor rather than the zymogen form).
- TF tissue factor
- TF tissue factor
- factor VII acts upon factor VII to form the TF/FVIIa complex (where Vila designates the activated factor rather than the zymogen form).
- This complex initiates coagulation by activating factors IX and X.
- the resulting factor Xa forms a prothrombinase complex that activates prothrombin to produce the thrombin that converts fibrinogen to insoluble fibrin.
- the intrinsic system is activated in vivo when certain coagulation proteins contact subendotheUal connective tissue.
- contact factors XII and XI are activated.
- the resulting factor XIa activates factor LX; then factor LXa activates factor X thereby intersecting with the extrinsic pathway.
- TFPI tissue factor pathway inhibitor
- Kunitz-type protease inhibitor protein which, when complexed with factor Xa, can inhibit the proteolytic activity of TF/FVIIa. If the extrinsic system is inhibited, additional factor Xa is produced through the thrombin-mediated action in the intrinsic pathway. Thrombin, therefore, exerts a dual catalytic role in (a) the conversion of fibrinogen to fibrin and (b) mediating its own production.
- the autocatalytic aspect of thrombin production affords an important safeguard against excessive blood loss, and, assuming presence of a threshold level of prothrombinase, ensures that the blood coagulation process will go to completion.
- Heparin and certain derivatives thereof are the most commonly used anti-clotting agents. These substances exert their effects mainly through inactivation of thrombin, which is inactivated 100 times faster than factor Xa. Two other thrombin-specific anticoagulants, hirudin and hirulog, are in clinical trials (as of September 1999). However, bleeding complications are associated with these agents.
- a specific inhibitor of factor Vila would provide clinicians with a valuable and needed agent that would be safe and effective in situations where the present drags of choice, heparin and related sulfated polysaccharides, are no better than marginally effective.
- An aspect of the present invention relates to compounds represented by the formula:
- Each E ! and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which maybe substituted with one or more hetero groups selected from N, O, S, S(O), and S(O 2 ) which may be saturated or unsaturated.
- the bicyclic rings typically contain 7-13 atoms in the ring.
- R 1 is H, -R, -NO 2 , -CN, -halo, -N 3 , -C ⁇ _ 8 alkyl, -(CH 2 ) complicatCO 2 R 2 , -C 2 . 8 alkenyl-CO 2 R 2 , -O(CH 2 ) n CO 2 R 2 , -C(O)NR 2 R 3 , -P(O)(OR 2 ) 2 , alkyl substituted tetrazol-5-yl, -(CH 2 ) n O(CH 2 ) n aryl, -NR 2 R 3 , -(CH 2 ) n OR 2 , -(CH 2 ) n SR 2 , -N(R 2 )C(O)R 3 , -S(O 2 )NR 2 R 3 , -N(R )S(O 2 )R 3 , -(CHR 2 ) n NR 2 R 3 , -C(
- m is 1 except that when E l is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring.
- R 2 is H, -halo, -alkyl, -haloalkyl, -(CH 2 ) n -phenyl, -(CH 2 ) ⁇ _ 3 -biphenyl, -(CH 2 ) -Ph- N(SO 2 -Ci. 2 -alkyl) 2 , -CO(CHR 1 ) n -OR 1 , -(CHR 5 ) n -heterocycle, -(CHR ⁇ -NH-CO-R 1 , -(CHR 1 )n-NH-SO 2 R 1 , -(CHR 1 ) n -Ph-N(SO -C,.
- R 3 is H, -OH, -CN, substituted alkyl, -C 2 . 8 alkenyl, substituted or unsubstituted cycloalkyl, -N(R ! )R 2 , or 5-6 membered saturated substituted or unsubstituted hetero ring.
- -NR 2 R 3 may form a ring system having 4 to 7 atoms or may be bicyclic ring.
- the ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted.
- E 2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, C ⁇ _ 8 alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino.
- each X individually is a direct bond, substituted or unsubstituted C ⁇ methylene chain; O, S, NR 2 , S(O), S(O 2 ), or N(O) containing one or two C M substituted or unsubstituted methylene chains.
- X at different places may be same or different.
- B 1 is selected from B; B 1 and B may be same or different.
- E there may be more than one similar or different R groups present on E , when E is a cyclic group of more than 5 atoms.
- p is 1 except that when E 2 is a cyclic ring of more than 5 atoms, p is 1 or higher depending upon the size of the ring.
- n 0-4
- A is selected from R . o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring.
- Each V and V 1 individually is selected from R 1 and N-alkyl substituted carboxamidyl (- CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic; N,N- disubstituted carboxamidyl (-CONR 1 R 2 where Ri and R 2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO 2 NHR or -SO 2 NR1R2); and methylene- or polymethylene chain- extended variants thereof.
- - CONHR N-alkyl substituted carboxamidyl
- -CONR 1 R 2 where Ri and R 2 may be substituted or unsubstituted alkyl or aryl and may be the same or different
- mono- or disubstituted sulfonamides SO 2 NHR or -SO 2 NR1R2
- Each R 4 and R 5 individually is H, -(CH 2 ) n OH, -C(O)OR 6 , -C(O)SR 6 , -(CH 2 ) objection C(O)NR 7 R 8 , -O-C(O)-O-R 7 , an amino acid or a dpeptide,
- Each R 6 is H, R 7 , -C(R 7 )(R 8 )-(CH 2 ) n -O-C(O)-R 9 , -(CH 2 ) n -C(R 7 )(R 8 )-O-C(O)R 9 , -(CH 2 ) n - C(R 7 )(R 8 )-O-C(O)-O-R 9 , or -C(R 7 )(R 8 )-(CH 2 ) n -O-C(O)-O-R 9 ,
- Each R 7 , R s and R 9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH 2 CO 2 alkyl.
- the present invention also relates to pharmaceutical compositions containing at least one of the above disclosed compounds and their prodrugs.
- a further aspect of the present invention relates to a method for inhibiting trypsin- like serine protease enzymes, such as thrombin, factor Xa, factor Vila, TF/VIIa, and trypsin in a patient which comprises administering to the patient an effective serine protease inhibiting amount of at least one of the above disclosed compounds.
- An aspect of the present invention relates to compounds represented by the formula: R B 1
- Each E 1 and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which may be substituted with one or more hetero groups selected from N, O, S, S(O), and S(O 2 ) which maybe saturated or unsaturated.
- these R, R 1 , R 2 , or R 3 do not include -(C 2 .
- R 1 is H, -R, -NO 2 , -CN, -halo, -N 3 , -C ⁇ . 8 alkyl, -(CH 2 ) n CO 2 R 2 , -C 2 . 8 alkenyl-CO 2 R 2 , -O(CH 2 ) n CO 2 R 2 , -C(O)NR 2 R 3 , -P(O)(OR 2 ) 2 , alkyl substituted tetrazol-5-yl,
- n is 1 except that when E 1 is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring. For instance if the ring is 6 atoms, m can be 1 or 2.
- R 2 is H, -halo, -alkyl, -haloalkyl, -(CH 2 ) réelle -phenyl, -(CH 2 ) ⁇ - 3 -biphenyl, -(CH ⁇ M -Ph- N(SO 2 -C ⁇ .
- R 3 is H, -OH, -CN, substituted alkyl, -C 2 . 8 alkenyl, substituted or unsubstituted cycloalkyl, -N R ⁇ R 2 , or 5-6 membered saturated substituted or unsubstituted hetero ring.
- -NR R may form a nng system having 4 to 7 atoms or may be bicyclic ring.
- the ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted.
- E 2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, Ci-g alkyl, C 2 - 8 alkenyl, C 2 . 8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino.
- each X individually is a direct bond, substituted or unsubstituted C methylene chain; O, S, NR 2 , S(O), S(O 2 ), orN(O) containing one or two C M substituted or unsubstituted methylene chains.
- X at different places may be same or different.
- B 1 is selected from B; B 1 and B may be same or different.
- There may be more than one similar or different R 2 groups present on E 2 when E 2 is a cyclic system of more than 5 atoms, p is 1 or higher if E 2 is a cyclic ring of more than 5 atoms. For example, if the ring is 6 atoms, p can be 1 or 2.
- n 0-4
- A is selected from R 1 .
- o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring. For instance, if the ring is 6 atoms, o can be 1 or 2.
- Each N and N ! individually is selected from R 1 and ⁇ -alkyl substituted carboxamidyl (- CO ⁇ HR) where the alkyl group may be straight, branched, cyclic, or bicyclic; ⁇ , ⁇ - disubstituted carboxamidyl (-CONR ⁇ R 2 where Ri and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO 2 NHR or -SO 2 NR1R 2 ); and methylene- or polymethylene chain- extended variants thereof.
- Each R 4 and R 5 individually is H, -(CH 2 ) n OH, -C(O)OR 6 , -C(O)SR 6 , -(CH 2 ) n C(O)NR 7 R 8 , -O-C(O)-O-R 7 , an amino acid or a dipeptide,
- Each R 6 is H, R 7 , -C(R 7 )(R 8 )-(CH 2 ) n -O-C(O)-R 9 , -(CH 2 ) n -C(R 7 )(R 8 )-O-C(O)R 9 , -(CH 2 ) n - C(R 7 )(R 8 )-O-C(O)-O-R 9 , or -C(R 7 )(R 8 )-(CH 2 ) n -O-C(O)-O-R 9 ,
- Each R 7 , R 8- and R 9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH 2 CO 2 alkyl.
- R substituent groups employed pursuant to the present invention contribute to significantly enhanced activity of the compounds of the present invention.
- alkyl refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms.
- lower alkyl refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
- alkenyl and alkynyl refer to straight or branched chain unsubstituted hydrocarbon groups typically having 2 to 8 carbon atoms.
- substituted alkyl refers to an alkyl, alkenyl or alkynyl group substituted by, for example, one to four substituents, such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamine, aroylamino, aralkanoylamino, substituted alkanolamino, substituted arylamino, substituted aralkanoylamino, thiol
- halogen refers to fluorine, chlorine, bromine and iodine.
- aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
- aralkyl or “alkylaryl” refers to an aryl group bonded directly through an alkyl group, such as benzyl or phenethyl.
- substituted aryl or “substituted alkylaryl” refers to an aryl group or alkylaryl group substituted by, for example, one to four substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, azido, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, hydroxyalkyl, aminoalkyl, azidoalkyl, alkenyl, alkynyl, allenyl, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl
- the substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
- substituted benzyl refers to a benzyl group substituted by, for example, any of the groups listed above for substituted aryl.
- cycloalkyl refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C -C carbocyclic ring.
- exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl.
- substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
- cycloalkenyl refers to optionally substituted, unsaturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3-7 carbons per ring.
- exemplary groups include cyclopentenyl and cyclohexenyl.
- heterocycle refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
- Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized.
- the heterocyclic group may be attached at any heteroatom or carbon atoms.
- Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazoUdinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, dihydropyrid
- bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, cournarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolapridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,l-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, diyhydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl,
- Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents.
- Preferred alkyl groups are lower alkyl groups containing 1 to about 8 carbon, and more preferably 1 to about 5 carbon atoms, and can be straight, branched-chain or cyclic saturated aliphatic hydrocarbon groups.
- suitable alkyl groups include methyl, ethyl and propyl.
- Examples of branched alkyl groups include isopropyl and t-butyl.
- An example of a suitable alkylaryl group is phenethyl.
- suitable cycloalkyl groups typically contain 3-8 carbon atoms and include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- the aromatic or aryl groups are preferably phenyl or alkyl substituted aromatic groups (aralkyl) such as phenyl C 1 - 3 alkyl such as benzyl.
- the N-heterocyclic rings preferably contain 3-7 atoms in the ring and a heteroatom such as N, S or O in the ring.
- suitable prefe ⁇ ed heterocyclic groups are pyrrolidino, azetidino, piperidino, 3,4-didehydropiperidino, 2- methylpiperidino and 2-ethylpiperidino.
- the above substitutions can include halo such as F, CI, Br, lower alkyl, lower alkoxy and halo substituted lower alkoxy.
- Prodrug forms of the compounds bearing various nitrogen functions may include the following types of derivatives where each R group individually may be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle, alkylaryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, or cycloalkenyl groups as defined beginning on page 7.
- prodrug derivatives are discussed in various literature sources (examples are: Alexander et al, J. Med. Chem. 1988, 31, 318; Aligas-Martin et al, PCT WO pp/41531, p. 30).
- the nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the invention.
- Prodrug forms of carboxyl-bearing compounds of the invention include esters (-CO 2 R) where the R group corresponds to any alcohol whose release in the body through enzymatic or hydrolytic processes would be at pharmaceutically acceptable levels.
- Another prodrug derived from a carboxylic acid form of the invention may be a quaternary salt type
- Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable, inorganic and organic acids and bases.
- suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycoUic, lactic, salicyclic, succinic, toluene-p- sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, trifluoroacetic and benzenesulphonic acids.
- Salts derived from appropriate bases include alkali such as sodium and ammonia.
- the reduction of the formyl group of 24ab, 24ae, 24ae, and 24ad was accomplished with NaBH 4 to give corresponding alcohols 24ab-i, 24ac-i, 24ae-i, and 24ad-i, respectively. Later, the MEM group was removed under acidic conditions to give 25ab, 25ac, 25ae, and 25af, respectively.
- the vinyl compound 24ah was oxidized with Os0 to give diol 24ah-i, followed by acidic hydrolysis of the MEM group to produce 25ah.
- the vinyl compound 24ah on dihydroxylation with Os0 gave diol 24ah-i.
- Oxidative cleavage of the diol with NaI0 4 produced aldehyde 24ah-ii.
- the aldehyde on reduction gave alcohol 24ah-iii, which on further reaction with methane sulfonyl chloride yielded mesylate 24ah-iv.
- the mesylate on further reaction with sodium azide gave the corresponding azide 24ah-v, which on acidic hydrolysis produced 25ai.
- Aldehyde 29g was converted to alcohol 29g-i by reduction with NaBH 4) followed by the reaction of methanesulfonyl chloride to give mesylate 29g-ii.
- the mesyl group was displaced with azide to give 29g- iii and finally, the MEM group was removed under acidic conditions to give 30g.
- DME 1,2-Dimethoxyethane
- DMAP 4-(Dimethylamino)pyridine Boc anhydride: Di-tert-butyl dicarbonate
- TIPS Triisopropylsilyl
- MEM Methoxyethoxyrnethyl
- Bn Phenylmethyl or Benzyl
- the organic extracts were dried over sodium sulfate or magnesium sulfate.
- reaction mixture was concentrated in vacuo to remove acetonitrile, diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, washed with water, brine, dried and concentrated in vacuo to furnish crude acid. Purification was achieved, if needed, by crystallization or using flash column chromatography to obtain pure acid.
- the reaction mixture was cooled to -40 °C and tributyl borate (5.6 mmol) in ether (20 mL) was added to the reaction and stirred at 4 °C for 12 h.
- the reaction mixture was allowed to warm to 0 °C and quenched with 2 M HCl (3 mmol) and heated at reflux for 2 h and added to ice water (25 mL).
- the aqueous layer was separated and the organic layer extracted twice with IN NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL).
- the basic layer was acidified to pH 3 using 6 N HCl and the solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid product was obtained, then the basic layer was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
- the basic extracts were combined and washed with ether (10 mL).
- the basic layer was acidified to pH 4 using 6 N HCl and the solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid ' product was obtained then the mixture was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
- pyridine hydrochloride (lOg) was heated in an oil bath at 180 °C. After the entire solid had melted, the corresponding aryl methyl ether (1 mmol) was added in small portions over a period of 20 min. The reaction mixture was heated at 180 °C for 4 h, cooled and quenched with water (100 mL). The reaction mixture was extracted with ethyl acetate (3 X lOmL). The combined organic layers were washed with brine, dried over MgSO , concentrated to give phenol. This can be further purified if needed by crystallization or column chromatography.
- a solution of methanolic HCl or ethanolic HCl was prepared by the addition of acetyl chloride (1 mL) to methanol/ethanol (9 mL) at 0 °C and stirred for 30 mins. To the solution of anhydrous methanolic HCl was added acid (1 mmol) and stirred at room temperature (or reflux if needed) overnight. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by column chromatography or crystallization to furnish the desired ester.
- the water layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO ) and evaporated to yield a solid.
- the solid was washed with hexane and dried in vacuo to furnish the desired amide.
- the mixture was diluted with water (15 mL) and washed with ether (2 x 10 mL).
- the aqueous layer was acidified to pH 2 using 6 N HCl and the solid that separated out was collected by filtration, washed with ether, dried in vacuo to furnish product, which was purified by flash column chromatography, if needed.
- the mixture was diluted with water (15 L) and washed with ether (2 X 10 mL).
- the aqueous layer was filtered and solid obtained was kept aside (mainly product).
- the aqueous layer was acidified to pH 2 using 6 N HCl and the solid that separated out was collected by filtration.
- the combined solid materials were purified, if needed, by flash column chromatography.
- the filtrate was concentrated in vacuo to give a second crop of the cmde desired aldehyde (60 g) as a dark brown solid.
- the above solids were combined and dissolved in glacial acetic acid (360 mL) by heating. Water (840 mL) was added and the solution was filtered hot. The solution was allowed to attain room temperature and kept in a refrigerator overnight. The crystals obtained were collected by filtration and washed with water, dried overnight in vacuo to furnish (60 g, 37%) of the desired product as a purplish brown crystalline solid, mp: 135 °C.
- AK Conversion of aryl triflates or halides to boronate ester
- the examples of the compounds prepared are given in the following tables.
- the tables describe the compounds, their method of preparation, the starting material, and the analytical data. In some cases, where analytical data have not been given, those compounds were characterized at the later step in the synthesis.
- TF/FNIIa an amidolytic assay based upon the absorbance of p- ⁇ itroanalide (p ⁇ A) at OD 405 was utilized.
- the IC 50 of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Nmax values.
- TF/FNIIa assay reactions were performed in a 200 ⁇ L mixture containing 4 nM FNIIa, 10 nM lipidated tissue factor, in an assay buffer containing 100 mM Tris, pH 7.2, 150 mM ⁇ aCl, 5 mM calcium chloride, 0.1 % bovine serum albumin (BSA), and 10% dimethyl sulfoxide (DMSO).
- TF and FVIIa were allowed to equilibrate at room temperature for 15 minutes.
- Test compounds dissolved in DMSO were incubated at varied concentrations with TF/FNIIa for 10 minutes, followed by addition of 500 DM substrate Spectrozyme-FNIIa. Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD 4 o 5 mn for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
- IC50 of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Nmax values.
- Thrombin assay reactions were performed in a 200 ⁇ L mixture containing human thrombin at (1 U/mL) in an assay buffer containing 100 mM HEPES, 10 mM calcium chloride, and 10 % DMSO, pH 7.5. Test compounds dissolved in DMSO were added to thrombin enzyme reactions at varied concentrations, followed by the addition of substrate N ⁇ -Benzoyl-Phe-Nal-Arg p- ⁇ itroanilide at a final concentration of 1 mM. Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD 05 nm for 10 minutes at 21 second intervals with a Powerwave (Bio-Tek Instruments) microplate reader.
- Powerwave Bio-Tek Instruments
- IC 5 o of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Nmax values.
- Trypsin assay reactions were performed in a 200 ⁇ L mixture containing human pancreatic trypsin at 1 ⁇ g/mL in an assay buffer containing 200 mM triethanolamine (TEA), 10 mM calcium chloride, 10 % DMSO, pH 7.8.
- Test compounds dissolved in DMSO were added to trypsin enzyme reactions at varied concentrations, followed by the addition of substrate ⁇ -Benzoyl-L-Arginine p- ⁇ itroanilide (L-BAP ⁇ A) at a final concentration of (0.25 mg/mL). Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD 4 os nm for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
- IC 50 values + means >1 ⁇ M; ++ means >100 nM; +++ means ⁇ 100 nM
- Compounds of the present invention are useful as inhibitors of trypsin-like serine protease enzymes such as thrombin, factor Vila, TF/FNIIa, and trypsin.
- These compounds may be employed to inhibit the coagulation cascade and prevent or limit coagulation.
- These compounds may be used to inhibit the formation of emboli or thromboli in blood vessels.
- These compounds may be used to treat thrombolymphangitis, thrombosinusitis, thromboendocarditis, thromboangitis, and thrornboarteritis.
- These compounds may be used to inhibit thrombus formation following angioplasty. These may be used in combination with other antithrombolytic agents such as tissue plasminogen activators and their derivatives, streptokinase and its derivatives, or urokinase and its derivatives to prevent arterial occlusion following thrombolytic therapy.
- tissue plasminogen activators and their derivatives such as tissue plasminogen activators and their derivatives, streptokinase and its derivatives, or urokinase and its derivatives to prevent arterial occlusion following thrombolytic therapy.
- These compounds may also be used in matastatic diseases, or for any disease where inhibition of coagulation is indicated.
- These compounds may be used as diagnostic reagents in vitro for inhibiting clotting of blood in the tubes.
- These compounds may be used alone or in combination with other compounds such as heparin, aspirin, or warfarin and any other anticoagulant agents. These compounds may be used as anti-inflammatory agents.
- compounds may be employed in preventing ex vivo coagulation such as that encountered in the extracorporeal perfusion of blood through for example artificial valves, prothesis, stents or catheters.
- the extracorporeal device may be coated with the compositions of the invention resulting in a lower risk of clot formation due to extrinsic pathway activation.
- the compounds of this invention can be administered by any means that produces contact of the active agent's site of action with factor Vila and other serine proteases in the body of a human, mammal, bird, or other animal. They can be administered by any conventional means, such as oral, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. Parenteral infusion includes intramuscular, intravenous, and intraarterial. They can be administered alone, but generally administered with a pharmaceutical carrier elected on the basis of the chosen route of administration and standard pharmaceutical practice.
- the dosage administered will, or course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms, the kind of concurrent treatment; the frequency of treatment; and the effect desired.
- a daily dosage of active ingredient can be expected to be about 0.0001 to 1000 milligram (mg) per kilogram (kg) of body weight, with the preferred dose being 0.1 to about 30 mg/kg.
- Dosage forms contain from about mg to about 500 mg of compound per unit. In these pharmaceutical compositions, the compound of the present invention will ordinarily be present in an amount of about 0.5- 95% by weight based on the total weight of the composition.
- the daily dose of the compounds of the invention that is to be administered can be a single daily dose or can be divided into several, for example, two, three or four, part administrations.
- the pharmaceutical compositions or medicaments of the invention can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures.
- Administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
- Gelatin capsules contain a compound of the present invention and powdered carriers, such as lactose, starch, cellulose derivatives, biocompatible polymers, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated to mask by unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
- powdered carriers such as lactose, starch, cellulose derivatives, biocompatible polymers, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated to mask by unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
- Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. They may also contain buffering agents, surfactants and preservatives. Liquid oral products can be developed to have sustained-release properties. They may also contain cyclodextrin derivatives to enhance the solubility of the active ingredient and to promote its oral uptake.
- parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
- Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffering agents.
- Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
- citric acid and its salts and sodium EDTA are also used.
- parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
- Suitable pharmaceutical carriers are described in Remington's Pharmaceutical
- Useful pharmaceutical dosage forms for administration of the compounds according to the present invention can be illustrated as follows:
- a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered 1500 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.
- Soft Gelatin Capsules 100 mg of powdered 1500 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.
- a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient.
- the capsules are washed and dried.
- the prodrug can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
- a large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcystalline cellulose, 11 mg of starch, and 9.98 mg of lactose.
- Appropriate aqueous and non-aqueous coatings may be applied to increase palatability improve elegance and stability or delay absorption.
- the drug is mixed containing ingredient such as sugar, gelatin, pectin, and sweeteners.
- ingredient such as sugar, gelatin, pectin, and sweeteners.
- These liquids are solidified into solid tablets or caplets by freeze drying and solid thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
- the compounds of the present invention can be administered in the form of nose drops, metered dose nasal or buccal inhalers.
- the drug is delivered from a nasal solution as a fine mist or from a powder as an aerosol.
- a compound of the invention can be used in an assay to identify the presence of factor Vila and other serine protease or to isolate , factor Vila and other serine protease in a substantially purified form.
- the compound of the invention can be labeled with, for example, a radioisotope, and the labeled compound is detected using a routine method useful for detecting the particular label.
- a compound the invention can be used advantageously as a probe to detect the location or amount of factor Vila and other serine protease activity in vivo, in vitro or ex vivo.
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MXPA03009130A MXPA03009130A (es) | 2000-10-20 | 2001-10-22 | Compuestos de biarilo que funcionan como inhibidores de proteasa serina. |
DK01981772T DK1383731T3 (da) | 2000-10-20 | 2001-10-22 | Biarylforbindelser som serinproteaseinhibitorer |
JP2002537705A JP4342178B2 (ja) | 2001-04-06 | 2001-10-22 | セリンプロテアーゼ阻害剤としてのビアリール化合物 |
EP01981772A EP1383731B1 (fr) | 2001-04-06 | 2001-10-22 | Composes biaryle utilises comme inhibiteurs de serine protease |
AT01981772T ATE438615T1 (de) | 2001-04-06 | 2001-10-22 | Biarylverbindungen als serinproteaseinhibitoren |
DE60139510T DE60139510D1 (de) | 2001-04-06 | 2001-10-22 | Biarylverbindungen als serinproteaseinhibitoren |
CA2426430A CA2426430C (fr) | 2000-10-20 | 2001-10-22 | Composes biaryle utilises comme inhibiteurs de serine protease |
AU2002213393A AU2002213393B2 (en) | 2000-10-20 | 2001-10-22 | Biaryl compounds as serine protease inhibitors |
AU1339302A AU1339302A (en) | 2000-10-20 | 2001-10-22 | Biaryl compounds as serine protease inhibitors |
IL15520201A IL155202A0 (en) | 2000-10-20 | 2001-10-22 | Biaryl compounds as serine protease inhibitors |
NZ526003A NZ526003A (en) | 2000-10-20 | 2001-10-22 | Biaryl compounds as serine protease inhibitors |
US10/127,460 US6699994B1 (en) | 2001-04-06 | 2002-04-23 | Biaryl compounds as serine protease inhibitors |
IL155202A IL155202A (en) | 2001-04-06 | 2003-04-02 | Baryl compounds as serine protease inhibitors |
US10/738,027 US6936719B2 (en) | 2001-04-06 | 2003-12-18 | Biaryl compounds as serine protease inhibitors |
HK04105585.6A HK1062676A1 (en) | 2000-10-20 | 2004-07-28 | Biaryl compounds as serine protease inhibitors |
IL222773A IL222773B (en) | 2001-04-06 | 2012-10-30 | Biaryl compounds, pharmaceutical preparations containing them, use of such compounds for the manufacture of drugs and in vitro methods and devices using such compounds |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US24184800P | 2000-10-20 | 2000-10-20 | |
US60/241,848 | 2000-10-20 | ||
US28173501P | 2001-04-06 | 2001-04-06 | |
US60/281,735 | 2001-04-06 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/127,460 Continuation-In-Part US6699994B1 (en) | 2001-04-06 | 2002-04-23 | Biaryl compounds as serine protease inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002034711A1 true WO2002034711A1 (fr) | 2002-05-02 |
Family
ID=26934639
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/032582 WO2002034711A1 (fr) | 2000-10-20 | 2001-10-22 | Composes biaryle utilises comme inhibiteurs de serine protease |
Country Status (8)
Country | Link |
---|---|
AU (2) | AU1339302A (fr) |
CA (1) | CA2426430C (fr) |
DK (1) | DK1383731T3 (fr) |
HK (1) | HK1062676A1 (fr) |
IL (1) | IL155202A0 (fr) |
MX (1) | MXPA03009130A (fr) |
NZ (1) | NZ526003A (fr) |
WO (1) | WO2002034711A1 (fr) |
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WO2002037937A2 (fr) * | 2000-11-07 | 2002-05-16 | Bristol-Myers Squibb Company | Derives d'acides utilises comme inhibiteurs de la serine protease |
WO2002042273A2 (fr) * | 2000-11-07 | 2002-05-30 | Bristol-Myers Squibb Company | Derives d'acide utiles comme inhibiteurs de serines proteases |
WO2003011858A1 (fr) * | 2001-07-30 | 2003-02-13 | Bayer Healthcare Ag | Isoindoles substitues et leur utilisation |
EP1388341A1 (fr) * | 2002-08-07 | 2004-02-11 | Aventis Pharma Deutschland GmbH | Dérivés héteroaromatiques acylamino substitués et leur utilisation en tant que medicaments |
EP1394147A1 (fr) * | 2001-06-04 | 2004-03-03 | Eisai Co., Ltd. | Derive de l'acide carboxylique et medicament comprenant un sel ou un ester dudit derive |
WO2004048335A2 (fr) * | 2002-11-25 | 2004-06-10 | F. Hoffmann-La Roche Ag | Derives d'acide mandelique |
US6818787B2 (en) | 2001-06-11 | 2004-11-16 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
US6833140B2 (en) * | 2001-06-11 | 2004-12-21 | Xenoport, Inc. | Orally administered dosage forms of GABA analog prodrugs having reduced toxicity |
US6906192B2 (en) | 2000-11-07 | 2005-06-14 | Bristol Myers Squibb Company | Processes for the preparation of acid derivatives useful as serine protease inhibitors |
FR2871157A1 (fr) * | 2004-06-04 | 2005-12-09 | Aventis Pharma Sa | Produits biaryl aromatiques, compositions les contenant et utilisation |
US7122559B2 (en) | 2003-02-11 | 2006-10-17 | Bristol-Myers Squibb Company | Phenylglycine derivatives useful as serine protease inhibitors |
US7144895B2 (en) | 2003-02-11 | 2006-12-05 | Bristol-Myers Squibb Co. | Benzene acetamide compounds useful as serine protease inhibitors |
US7148230B2 (en) | 2003-07-29 | 2006-12-12 | Astrazeneca Ab | Quinazoline derivatives |
US7163952B2 (en) | 2001-12-03 | 2007-01-16 | Japan Tobacco Inc. | Azole compound and medicinal use thereof |
JP2007523935A (ja) * | 2004-02-28 | 2007-08-23 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Xaインヒビターとして使用するための新規なカルボキサミド |
US7338956B2 (en) | 2002-08-07 | 2008-03-04 | Sanofi-Aventis Deutschland Gmbh | Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals |
US7348353B2 (en) | 2001-12-04 | 2008-03-25 | Novartis Ag | Acetylene derivatives having mGluR 5 antagonistic activity |
US7544835B2 (en) | 2001-04-20 | 2009-06-09 | Eisai R&D Management Co., Ltd. | Carboxylic acid derivative and salt thereof |
US7622585B2 (en) | 2005-01-10 | 2009-11-24 | Bristol-Myers Squibb Company | Phenylglycinamide derivatives useful as anticoagulants |
US7754717B2 (en) | 2005-08-15 | 2010-07-13 | Amgen Inc. | Bis-aryl amide compounds and methods of use |
US7790708B2 (en) | 2001-06-11 | 2010-09-07 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
US7816391B2 (en) | 2007-02-12 | 2010-10-19 | Astrazeneca Ab | Chemical compounds |
US7910731B2 (en) | 2002-03-30 | 2011-03-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
US7964618B2 (en) | 2006-11-03 | 2011-06-21 | Astrazeneca Ab | Chemical compounds |
US7998949B2 (en) | 2007-02-06 | 2011-08-16 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof |
US8048917B2 (en) | 2005-04-06 | 2011-11-01 | Xenoport, Inc. | Prodrugs of GABA analogs, compositions and uses thereof |
US8084614B2 (en) | 2007-04-06 | 2011-12-27 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
US8088782B2 (en) | 2008-05-13 | 2012-01-03 | Astrazeneca Ab | Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate form A |
US8263588B2 (en) | 2007-04-06 | 2012-09-11 | Neurocrine Biosciences, Inc. | Gonadotropin-releasing hormone receptor antagonists and methods relating thereto |
US8399461B2 (en) | 2006-11-10 | 2013-03-19 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for production of same |
US8497369B2 (en) | 2008-02-07 | 2013-07-30 | Boehringer Ingelheim International Gmbh | Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production |
US8623871B2 (en) | 2006-01-25 | 2014-01-07 | Synta Pharmaceuticals Corp. | Substituted biaryl compounds for inflammation and immune-related uses |
US8648191B2 (en) | 2008-08-08 | 2014-02-11 | Boehringer Ingelheim International Gmbh | Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them |
US8673974B2 (en) | 2010-11-16 | 2014-03-18 | Novartis Ag | Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors |
US8673889B2 (en) * | 2004-04-26 | 2014-03-18 | Ono Pharmaceutical Co., Ltd. | BLT2-mediated disease, BLT2 binding agent and the compound |
US8795725B2 (en) | 2004-11-04 | 2014-08-05 | Xenoport, Inc. | GABA analog prodrug sustained release oral dosage forms |
WO2016029214A1 (fr) * | 2014-08-22 | 2016-02-25 | Biocryst Pharmaceuticals, Inc. | Compositions et utilisations de dérivés d'amidine |
US9925174B2 (en) | 2002-03-07 | 2018-03-27 | Boehringer Ingelheim International Gmbh | Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof |
WO2018081513A1 (fr) * | 2016-10-31 | 2018-05-03 | Biocryst Pharmaceuticals, Inc. | Promédicaments d'inhibiteurs de la kallicréine |
US10647661B2 (en) | 2017-07-11 | 2020-05-12 | Vertex Pharmaceuticals Incorporated | Carboxamides as modulators of sodium channels |
US11697666B2 (en) | 2021-04-16 | 2023-07-11 | Gilead Sciences, Inc. | Methods of preparing carbanucleosides using amides |
US11767337B2 (en) | 2020-02-18 | 2023-09-26 | Gilead Sciences, Inc. | Antiviral compounds |
US12030903B2 (en) | 2021-02-17 | 2024-07-09 | Gilead Sciences, Inc. | Antiviral compounds |
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2001
- 2001-10-22 AU AU1339302A patent/AU1339302A/xx active Pending
- 2001-10-22 MX MXPA03009130A patent/MXPA03009130A/es active IP Right Grant
- 2001-10-22 DK DK01981772T patent/DK1383731T3/da active
- 2001-10-22 CA CA2426430A patent/CA2426430C/fr not_active Expired - Lifetime
- 2001-10-22 NZ NZ526003A patent/NZ526003A/en not_active IP Right Cessation
- 2001-10-22 WO PCT/US2001/032582 patent/WO2002034711A1/fr active IP Right Grant
- 2001-10-22 IL IL15520201A patent/IL155202A0/xx unknown
- 2001-10-22 AU AU2002213393A patent/AU2002213393B2/en not_active Expired
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2004
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US6713467B2 (en) | 2000-11-07 | 2004-03-30 | Bristol-Myers Squibb Company | Acid derivatives useful as serine protease inhibitors |
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US7189738B2 (en) | 2001-07-30 | 2007-03-13 | Bayer Healthcare Ag | Substituted isoindoles and their use thereof |
US7163952B2 (en) | 2001-12-03 | 2007-01-16 | Japan Tobacco Inc. | Azole compound and medicinal use thereof |
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US9925174B2 (en) | 2002-03-07 | 2018-03-27 | Boehringer Ingelheim International Gmbh | Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof |
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WO2004014369A1 (fr) * | 2002-08-07 | 2004-02-19 | Aventis Pharma Deutschland Gmbh | Composes heteroaromatiques acylamino-substitues et leur utilisation en tant que produits pharmaceutiques |
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WO2004048335A2 (fr) * | 2002-11-25 | 2004-06-10 | F. Hoffmann-La Roche Ag | Derives d'acide mandelique |
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US12030903B2 (en) | 2021-02-17 | 2024-07-09 | Gilead Sciences, Inc. | Antiviral compounds |
US11697666B2 (en) | 2021-04-16 | 2023-07-11 | Gilead Sciences, Inc. | Methods of preparing carbanucleosides using amides |
Also Published As
Publication number | Publication date |
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DK1383731T3 (da) | 2009-12-07 |
MXPA03009130A (es) | 2004-02-26 |
HK1062676A1 (en) | 2004-11-19 |
AU1339302A (en) | 2002-05-06 |
AU2002213393B2 (en) | 2007-02-15 |
NZ526003A (en) | 2005-09-30 |
CA2426430A1 (fr) | 2002-05-02 |
CA2426430C (fr) | 2014-10-07 |
IL155202A0 (en) | 2003-11-23 |
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