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WO1997019919A1 - Derives de sulfamides - Google Patents

Derives de sulfamides Download PDF

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Publication number
WO1997019919A1
WO1997019919A1 PCT/JP1996/003520 JP9603520W WO9719919A1 WO 1997019919 A1 WO1997019919 A1 WO 1997019919A1 JP 9603520 W JP9603520 W JP 9603520W WO 9719919 A1 WO9719919 A1 WO 9719919A1
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WIPO (PCT)
Prior art keywords
group
optionally substituted
acceptable salt
pharmaceutically acceptable
hydrate
Prior art date
Application number
PCT/JP1996/003520
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English (en)
Japanese (ja)
Inventor
Masayuki Haramura
Tsuyoshi Haneishi
Kiyonori Kuromaru
Original Assignee
C & C Research Laboratories
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Publication date
Application filed by C & C Research Laboratories filed Critical C & C Research Laboratories
Priority to AU76557/96A priority Critical patent/AU7655796A/en
Priority to KR1019980703942A priority patent/KR19990071666A/ko
Publication of WO1997019919A1 publication Critical patent/WO1997019919A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention has the general formula (1)
  • R t represents a hydrogen atom, a lower alkyl group or an amino protecting group
  • R 2 represents a nitrogen-containing heterocyclic ring which may have a substituent or may be condensed.
  • R 3 represents a group A— (CH 2 ) m —, a hydrogen atom or an optionally substituted lower alkyl group, wherein A represents an optionally substituted aryl group, an optionally substituted And m represents an integer of 0 to 6.
  • An optionally condensed heterocyclic ring or an optionally substituted lower cycloalkyl group, and m represents an integer of 0 to 6.
  • One (CH 2 ) ra — moiety is substituted with one or more substituents.
  • R 4 represents a hydrogen atom, a lower alkyl group or an amino protecting group
  • one (CH 2 ) n — represents one or more Which may be substituted with a substituent), more specifically, a sulfamide derivative having an antithrombin inhibitory activity, or a pharmaceutically acceptable salt or hydrate thereof;
  • the present invention relates to a pharmaceutical composition characterized by containing them as an active ingredient.
  • Thrombus is composed of aggregated platelets and fibrin, ischemic heart disease such as angina pectoris and myocardial infarction, cerebrovascular disorder such as cerebral infarction, venous thrombosis such as arterial thromboembolism, pulmonary embolism and generalized blood vessels It is involved in the occurrence and exacerbation of blood coagulation syndrome (DIC).
  • ischemic heart disease such as angina pectoris and myocardial infarction
  • cerebrovascular disorder such as cerebral infarction
  • venous thrombosis such as arterial thromboembolism
  • pulmonary embolism pulmonary embolism and generalized blood vessels It is involved in the occurrence and exacerbation of blood coagulation syndrome (DIC).
  • DIC blood coagulation syndrome
  • Antithrombotic drugs are classified into antiplatelet drugs such as aspirin, diviridamol, and abrostadil, and anticoagulants such as perfaline, heparin, and argatroban.Of these, most antiplatelet drugs are oral drugs, Has many questions.
  • anticoagulants which are oral drugs only, include pafarin, which inhibits the production of coagulation factors by antagonizing vitamin K, but has side effects such as skin necrosis and teratogenic effects. There are many. Therefore, the emergence of oral anticoagulants having a different mechanism of action from monophalin is desired in clinical settings.
  • Thrombin is the last step in blood coagulation and acts on fibrinogen to produce fibrin.
  • Thrombin inhibitors include argatroban, tripeptide (a synthetic derivative of D-Phe-Pro-Arg-II), and hirudin, all of which are injections and are used to treat or prevent thrombosis.
  • Oral drugs that can be administered for a long period of time are desirable.
  • platelet aggregation is considered to be important for thrombogenicity, and antiplatelet drugs have been widely used.
  • thrombin potently induces platelet aggregation via its receptor
  • antithrombin drugs have been reported to inhibit platelet aggregation by inhibiting thrombin receptor activation.
  • the inventors of the present invention have conducted intensive studies on an orally available anti-tombin drug with few side effects, and as a result, have found that a specific sulfamide derivative shows an excellent effect. Reached.
  • the present invention relates to the general formula (1)
  • R 2 represents a nitrogen-containing heterocyclic ring which may have a substituent and may be condensed
  • 3 represents a group A— (CH 2 ) m —, a hydrogen atom or an optionally substituted lower alkyl group, wherein A is an optionally substituted aryl group, an optionally substituted
  • m represents an integer of 0 to 6.
  • the heterocyclic ring which may be substituted or the lower cycloalkyl group which may be substituted is an integer of 0 to 6.
  • one (CH 2 ) m — moiety is substituted with one or more substituents.
  • R 4 represents a hydrogen atom, a lower alkyl group or an amino protecting group
  • the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, and an i-propyl group. , N-butyl group, tributyl group, s-butyl group, t-butyl group and the like.
  • the lower alkoxy group means a linear or branched alkyloxy group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methoxy group, an ethoxy group, an n-broboxine group, and an i-propoquine group.
  • the amino protecting group may be any group that can protect the amino group to which R i is bonded in the synthesis process of the general formula (1), and a commonly used amino protecting group is used.
  • Such amino protecting groups include, for example, formyl, acetyl, benzoyl, trifluoroacetyl, benzyloxycarbonyl, methoxycarbonyl, t-butoxycarbonyl, phthaloyl, benzyl, tosyl And a t-butoxycarbonyl group.
  • the optionally substituted amino group means, in addition to the above-mentioned amino protecting group, a hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted acryl group, for example, a substituted A lower alkoxycarbonyl group or an optionally substituted lower alkylaminocarbonyl group, an optionally substituted aryl group, an optionally substituted sulfonyl group, an optionally substituted or condensed An optionally substituted heterocyclic group, an optionally substituted lower alkoxy group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkyloxy group, an optionally substituted aryloxy group, 1 or more substituted or unsubstituted heterocyclic oxy group, optionally substituted silyl group, etc.
  • An amino group which may be substituted for example, a methylamino group, an ethylamino group, an acetylamino group, a dimethylaminocarbonylamino group, a phenylamino group, p-Toluenesulfonylamino group, methanesulfonylamino group, 4-piberidinylamino group, cyclohexylamino group, cyclopentylamino group, cyclobromoamino group, etc., preferably methylamino group, ethylamino group, acetylamino group , P-toluenesulfonylamino group, methanesulfonylamino group, cyclobutyrylamino group and the like.
  • the lower alkyl group which may be substituted means a halogen atom, a hydroxyl group, a thiol group, an amino group which may be substituted, an aryl group which may be substituted, for example, A lower alkoxycarbonyl group or an optionally substituted lower alkylaminocarbonyl group, a nitro group, a cyano group, an optionally substituted aryl group, an optionally substituted sulfonyl group, or an optionally substituted A heterocyclic group which may be fused, a carboxyl group which may be substituted, a lower alkoxy group which may be substituted, a cycloalkyl group which may be substituted, a cycloalkyl which may be substituted Alkyloxy group, optionally substituted aryloxy group, optionally substituted lower alkylthio group, substituted A heterocyclic oxy group which may be condensed, a cycloalkylthio group which may be substituted, a
  • the optionally substituted lower alkoxy group means a lower alkoxy group in which the same group as the above-mentioned lower alkyl group is substituted, for example, a fluoromethoxy group, a fluoroethoxy group. And a benzyloxy group.
  • An aryl group is a group in which one hydrogen atom has been removed from an aromatic hydrocarbon, and examples thereof include a phenyl group, a tolyl group, a naphthyl group, a xylyl group, a biphenyl group, an anthryl group, and a phenylamine group.
  • Preferable examples include a phenyl group and a naphthyl group.
  • the aryl group which may be substituted means that any hydrogen atom of the above aryl group is
  • optionally substituted lower alkyl groups optionally substituted lower alkoxy groups, halogen atoms, hydroxyl groups, thiol groups, optionally substituted amino groups, optionally substituted acyl groups
  • 2-ethoxyphenyl group 2-benzylphenyl group, 3-bromo-11-naphthyl group, 6-methoxy-11-naphthyl group, 1-1-naphthyl group, 2-naphthyl group, etc., and preferably 2-phenylethyl group Enyl group, 6-hydroquinone-naphthyl group,
  • the optionally substituted cycloalkyl group refers to a coal number of 3 to 4, preferably 4 to
  • any hydrogen atom of the cycloalkyl group 6 is substituted with one or more substituents
  • substituents include the same groups as the above aryl groups.
  • Such examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-fluorocyclopropyl, 2-benzylcyclohexyl, 2-aminocyclopentyl, 2-aminocyclopentyl and 2-aminocyclopentyl.
  • Examples thereof include a carboxycyclopentyl group and 2- (6-methoxy-1,4-benzoquinone), and preferably a cyclohexyl group.
  • a nitrogen-containing heterocyclic ring which may be substituted or condensed, contains at least one nitrogen atom as a hetero atom and further contains a hetero atom such as an oxygen atom or a zeo atom.
  • nitrogen-containing heterocyclic ring examples include, for example, an aziridine ring, an azetidine ring, a piar ring, a piar phosphorus ring, a piar lysine ring, an indole ring, an indoline ring, an isindole ring, an octahydroindole ring, Carbazole ring, pyridine ring, biperidine ring, quinoline ring, dihydroquinoline ring, tetrahydroquinoline ring, decahydroquinoline ring, isoquinoline ring, tetrahydroisoquinoline ring, decahydroisoquinoline ring, quinoline ring, acridine ring, phenanthridine ring Ring, benzoquinoline ring, pyrazole ring, imidazole ring, imidazoline ring, imidazolidine ring, benzimidazole ring,
  • the peridine ring, the perazine ring, and the Preferred are a soquinoline ring and a tetrahydroisoquinoline ring.
  • Preferred examples of the substituent include a N-acetylbiperazine ring, an N-p-toluenesulfonylbiberazine ring, a 4-methylbiveridine ring, and the like.
  • a heterocyclic ring which may be substituted or condensed is a saturated or unsaturated 3- to 7-membered ring containing one or more nitrogen, oxygen or iodo atoms as a hetero atom. It means a saturated heterocycle, and one or more aromatic rings, heterocycles and cycloalkyl rings other than a 3- to 7-membered ring may be condensed. Any hydrogen atom bonded to a carbon atom on the ring may be substituted with one or more substituents. Examples of such substituents are the same as those described above for the aryl group. No.
  • heterocyclic ring examples include, in addition to the aforementioned nitrogen-containing heterocyclic ring, for example, a pyran ring, a furan ring, a tetrahydrofuran ring, a tetrahydrofuran ring, a thiophene ring, a benzothiophene ring, a dihydrobenzothiophene ring, and a benzofuran.
  • An acryl group is a group obtained by removing OH of a carboxyl group of a carboxylic acid, for example, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, oxalyl group, malonyl group, succinyl group, benzoyl group, Examples include a toluolyl group, a naphthoyl group, a phthaloyl group, a pyrrolidinecarbonyl group, a pyridinecarbonyl group and the like, and preferably an acetyl group and a benzoyl group.
  • the optionally substituted acyl group means a lower alkyl group as a substituent, or an acyl group substituted with another group similar to the above-mentioned lower alkyl group.
  • Preferred examples include a lower alkylcarbonyl group, an optionally substituted lower alkylaminocarbonyl group, an optionally substituted lower alkyloxycarbonyl group, and an aminocarbonylcarbonyl group.
  • the acryloxy group means a group in which an oxygen atom is bonded to the acryl group, and examples thereof include an acetyloxy group and a benzoyloxy group.
  • the lower alkoxycarbonyl group means a group in which a carbonyl group is bonded to a lower alkoxy group, and represents a group having 1 to 6, preferably 1 to 4 carbon atoms in the alkoxy moiety.
  • methoxyquincarbonyl ethoxycarboxy, ⁇ -propoxycarbonyl, i-propoxycarbonyl, n-butynecarbonyl, ibutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl And the like, preferably a methoxycarbonyl group, an ethoxyquincarbonyl group and the like.
  • the lower alkoxycarbonyloxy group is a group in which an oxygen atom is bonded to a lower alkoxycarbonyl group, and represents an alkoxy moiety having 1 to 6, preferably 1 to 4 carbon atoms.
  • Examples include a carbonyloxy group and a t-butoxycarbonyloxy group, and preferably, a methoxycarbonyloxy group, an ethoxyquincarbonyloxy group, and the like.
  • the hydroxyalkylcarbonyloxy group is a group in which a carbonyloxy group (COO) is bonded to a group obtained by substituting one or more hydroxyl groups with the above-mentioned lower alkyl group, for example, a hydroxymethylcarbonyloxy group, Examples thereof include groups having 1 to 6, preferably 1 to 4 carbon atoms in the alkyl moiety such as a 2-hydroxyxylcarbonyloxy group and a 2,3-dihydroxypropylcarbonyloxy group.
  • the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom
  • the lower alkylsulfonyl group is a group in which a sulfonyl group is bonded to the lower alkyl group, and has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methylsulfonyl group, an ethylsulfonyl group, and a A propylsulfonyl group, an i-propylsulfonyl group and the like.
  • the arylsulfonyl group means a group in which a sulfonyl group is bonded to the above aryl group, and examples thereof include a phenylsulfonyl group and a naphthylsulfonyl group.
  • the lower alkylsulfonyl group which may be substituted and the arylsulfonyl group which may be substituted have one arbitrary hydrogen atom bonded to a carbon atom of the lower alkylsulfonyl group and the arylsulfonyl group.
  • T represents a group which may be substituted with the above substituents, and examples of the substituent include the same ones as those described as the substituent of the aryl group. Examples of such a group include a p-toluenesulfonyl group and a trifluoromethanesulfonyl group.
  • the optionally substituted aminosulfonyl group is a group in which a sulfonyl group is bonded to the above-mentioned optionally substituted amino group, and examples thereof include a methylaminosulfonyl group and a benzylaminosulfonyl group.
  • the optionally substituted lower alkoxysulfonyl group means a group in which a sulfonyl group is bonded to the above-mentioned optionally substituted lower alkoxy group, such as a methoxysulfonyl group or a benzyloxysulfonyl group.
  • the optionally substituted cycloalkyloxysulfonyl group means a group in which a sulfonyl group is bonded to an optionally substituted cycloalkyl group via an oxygen atom, for example, cyclohexyloxysulfonyl. And cyclopentyloxysulfonyl groups.
  • the optionally substituted cycloalkylsulfonyl group is a group in which a sulfonyl group is bonded to the optionally substituted cycloalkyl group, and examples thereof include a cyclohexylsulfonyl group and a cyclopentylsulfonyl group.
  • An optionally substituted or optionally fused heterocyclic sulfonyl group means a group in which a sulfonyl group is bonded to an optionally substituted heterocyclic group, for example, a 4-quinolylsulfonyl group, 8 —Tetrahydroquinolylsulfonyl group and the like are preferred.
  • the optionally substituted sulfonyl group includes an optionally substituted lower alkylsulfonyl group, an optionally substituted cycloalkylsulfonyl group, an optionally substituted cycloalkyloxysulfonyl group, a substituted An optionally substituted aminosulfonyl group, an optionally substituted or condensed heterocyclic sulfonyl group, an optionally substituted lower alkoxysulfonyl group or And represents an arylsulfonyl group which may be substituted.
  • the optionally substituted carboxyl group means a group in which an oxy group is bonded to the aforementioned optionally substituted acyl group, for example, a methylcarbonyloxy group, an ethylcarponyloxy group, an isopropyl group.
  • the lower alkoxyalkyl group means a group in which a lower alkyl group is bonded to the lower alkoxy group, for example, a methoxymethyl group, a methoxethyl group, a t-butoxymethyl group, a 1-ethoxyl group, or a 1- (isopropoxy) ethyl group. And the like. Further, the part of the alkoxy group or the alkyl group of the lower alkoxyalkyl group may be substituted with the same substituent as the above-mentioned alkyl group.
  • the lower hydroquinalkyl group means a group in which one or more hydroxyl groups are substituted on the lower alkyl group, for example, a hydroxymethyl group, a 2-hydroquinethyl group, a 1-hydroxyxethyl group, and a 3-hydroxy-1-n group.
  • a hydroxymethyl group for example, a 2-hydroquinethyl group, a 1-hydroxyxethyl group, and a 3-hydroxy-1-n group.
  • the alkyl group portion of the lower hydroxyalkyl group may be substituted with the same substituent as the above-mentioned alkyl group.
  • lower aminoalkyl group means a group in which the lower alkyl group is bonded to the above-mentioned optionally substituted amino group, for example, t-butylaminomethyl group, aminomethyl group, 2-aminoethyl group, benzyl group. Examples include a minomethyl group, a methylaminomethyl group, and a 2-methylaminoethyl group. Further, the alkyl group portion of the lower aminoalkyl group may be substituted with the same substituent as the above-mentioned alkyl group.
  • the lower-potential ruboxylalkyl group is a group in which the above-mentioned lower alkyl group is bonded to the above-mentioned optionally substituted carboxyl group, for example, acetyloquinmethyl group, 2-acetyloxetyl group, ethyl Examples include a carbonyloxymethyl group, a cyclohexylcarbonyloxymethyl group, a cyclopropylcarbonylcarbonylmethyl group, and an isobutyrylcarbonylcarbonylmethyl group.
  • the alkyl group portion of the lower carboxyl alkyl group is substituted with the same substituent as the above-mentioned alkyl group. It may be.
  • the lower carbonylaminoalkyl group means a group in which the lower aminoalkyl group is bonded to the optionally substituted sacyl group, for example, an acetylaminoamino group, a t-butyloxycarbonylaminomethyl group.
  • sacyl group for example, an acetylaminoamino group, a t-butyloxycarbonylaminomethyl group.
  • the amino group or the alkyl group of the lower carbonylaminoalkyl group may be substituted with the same substituent as the above-mentioned alkyl group.
  • the optionally substituted lower alkylthio group is a group in which a thio group is bonded to the aforementioned optionally substituted lower alkyl group, and examples thereof include a methylthio group, an ethylthio group, an isopropylpropyl group, and a t-butylthio group. .
  • the optionally substituted cycloalkylthio group means a group in which a thio group is bonded to the above-mentioned optionally substituted cycloalkyl group, for example, a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, Examples include a cyclohexylthio group.
  • the optionally substituted arylthio group is a group in which a thio group is bonded to the above-mentioned optionally substituted aryl group, for example, X-Xylthio, 11-naphthylthio,
  • the heterocyclic thio group which may be substituted or optionally condensed means a group in which a thio group is bonded to the above-mentioned optionally substituted or optionally condensed heterocyclic group,
  • a 4-quinolylthio group, an 8-tetrahydroquinolylthio group and the like can be mentioned.
  • the optionally substituted sulfonyloxy group is a group in which an oxy group is bonded to the above-mentioned optionally substituted sulfonyl group, and examples thereof include a p-toluenesulfonyloxy group and a methanesulfonyloxy group. .
  • the optionally substituted cycloalkyloxy group is a group in which the above-mentioned optionally substituted cycloalkyl group is bonded to an oxy group, for example, a cyclopropyloxy group, a cyclobenzyloxy group, a 4-amino group. Cyclohexyloxy group and the like. You.
  • the optionally substituted or optionally condensed heterocyclic oxy group means a group in which the above-mentioned optionally substituted or optionally condensed heterocyclic group is bonded to an oxy group, Examples thereof include a 4-quinolyloxy group and an 8-tetrahydroquinolyloxy group.
  • the optionally substituted silyl group means a silyl group in which the above-mentioned optionally substituted lower alkyl group or an optionally substituted aryl group is bonded to the same or different 1 to 3 silyl groups, for example, trimethylsilyl.
  • silyl group triethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triisopropylsilyl group and the like.
  • Examples of the substituents which may be substituted with one (CH 2 ) ra — moiety and one (CH 2 ) — moiety include those similar to the substituents described for the aryl group.
  • the compound of the present invention can form pharmaceutically acceptable salts.
  • such salts include hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate and the like.
  • Organic acids such as inorganic acid salt, succinate, oxalate, fumarate, maleate, lactate, tartrate, citrate, acetate, glycolate, methanesulfonate, toluenesulfonate Salts and the like can be mentioned.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof can also form a hydrate.
  • the compound of the present invention can have various steric structures.
  • the asymmetric carbon atom when considering the asymmetric carbon atom as its center, its absolute configuration may be any of D-form, L-form and DL-form. Included in the invention.
  • the absolute configuration of the asymmetric carbon atom in the substituted phenylalanine residue in the general formula (1) is desirably L-form.
  • Compounds that are a phenethylbenzyl group, a 3-bromonaphthyl group, a 1-isoquinolyl group, a 2,3-dimethoxybenzyl group, or a 6-hydroxynaphthyl group show particularly excellent effects as a medicament.
  • N In the general formula (1), R 2 represents a group (2) to (6)
  • R 7 is an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted low-valued alkoxy group, an optionally substituted or condensed Good heterocyclic ring, oxygen atom, hydroxyl group, optionally substituted acyl group, optionally substituted amino group, optionally substituted carboxyl group, optionally substituted acyloxy group, halogen atom, substituted Lower alkylsulfonyl group which may be substituted, arylsulfonyl group which may be substituted, low-handling alkoxyalkyl group, lower hydroxyalkyl group, lower aminoalkyl group, lower carboxyalkyl Group, a lower carbonyl ⁇ amino alkyl group.
  • B is TanShu atom, SansoHara child, a sulfur atom or NR 8, wherein R 8 is a hydrogen atom, a lower alkyl group but it may also be substituted, Amino protecting A, an optionally substituted aryl group, an optionally substituted acyl group, an optionally substituted sulfonyl group, an optionally substituted and optionally condensed heterocyclic ring, p and q is the same or different and represents an integer of 0 to 5, provided that + is any one of 1, 2.3, 4 or 5, and r and s are the same or different and represent an integer of 0 to 5 Where r + s Is any of 0, 1.
  • R 2 is particularly a group (2), particularly an optionally substituted piperazinyl group Or a compound which is a piperidinyl group which may be substituted, more preferably, R 2 is N-acetylbiperazinyl group, 4-methylbiperidinyl group, N- (N, N-dimethylaminocarbonyl)
  • R 2 is N-acetylbiperazinyl group, 4-methylbiperidinyl group, N- (N, N-dimethylaminocarbonyl)
  • Compounds that are a piperazinyl group, a methanesulfonylbiperazinyl group, a benzenesulfonylbiperazinyl group, or a p-toluenesulfonylbiverazinyl group also show excellent effects as pharmaceuticals and are included in the present invention.
  • the compounds having two or three preferable substituents of R 2 , R 3 and R 5 at the same time are particularly preferable compounds.
  • the compound of the present invention can be produced by a combination of reactions suitable for a target compound.
  • the following shows a typical reaction scheme, but the present invention is not limited to only the following method.
  • R 2 is a hydrogen atom or lower alkyl.
  • R 5 represents a lower alkyl group, and X represents a leaving group such as a halogen atom, a hydroxyl group, an alkanesulfonyl group, an arylsulfonyl group, etc.).
  • the compound of the general formula (10) is obtained by performing a condensation reaction of the compound of the general formula (9) and the compound of the general formula (19).
  • the condensation reaction used here includes, for example, the commonly used active ester method, acid anhydride method, azide method, acid chloride method, various condensing agents, etc., in basic and experimental peptide synthesis (1985, published by Maruzen, 1985). Examples include the methods shown.
  • the condensing agents used include N, N 'dicyclohexyl carbodiimide (DCC), water-soluble carbodiimide (WS CI), carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), Bop reagent, Py reagent Commonly used reagents such as the bop reagent are mentioned.
  • the compound of the general formula (19) is usually used in an amount of 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, relative to the compound of the general formula (9).
  • the compound of the general formula (11) can be prepared by reacting a compound of the general formula (9) with a suitable alcohol and an isocyanate such as chlorosulfonyl isocyanate in a suitable solvent in the presence or absence of a base.
  • a suitable solvent such as tetrahydrofuran, dioxane, dichloromethane, ethyl acetate and the like
  • examples of the base include organic bases such as triethylamine and pyridine.
  • alcohols, t-butyl alcohol, benzyl alcohol and the like are used, and the reaction can be carried out using phosgene or the like instead of chlorosulfonyl isocyanate.
  • This reaction can be usually carried out at -80 to 30 ° C for 0.1 to 24 hours.
  • the isocyanates used are usually of the general formula
  • the compound of (9) is used in an amount of 1.0 to 5.0 equivalents, preferably 1.0 to 1.2 equivalents, and the alcohol is used in an amount of 1.0 to 5.0 equivalents, 1.0 to 1.0 equivalent. Two equivalents are used.
  • the obtained carbamate compound can be converted to an amine compound by performing deprotection.
  • the compound of the general formula (12) can be obtained by performing the same reaction as in obtaining the compound of the general formula (11) from the compound of the general formula (10), or obtaining the compound of the general formula (10). Can be obtained by performing the same condensation reaction as described above from the compound of the general formula (11).
  • the compound of the general formula (13) can be obtained from the compound of the general formula (11) by a commonly used alkylation or arylation reaction. That is, in an appropriate solvent, an alcohol represented by the general formula (20) (when X is a hydroxyl group) activated by ethoxyazadicarboxylate (DEAD) -triphenylphosphine or the like, or a base Halide compound represented by the general formula (20) in the presence or absence of
  • Examples of compounds of the general formula (20), which are alcohols, include methanol, ethanol, phenol, benzyl alcohol, 2,3-dimethylbenzyl alcohol, 1-naphthalenemethanol, 3-bromo-1-naphthalenemethanol, and 2-phenylene.
  • 2,3-dimethoxybenzyl alcohol, 1-naphthalenemethanol, 2-phenethylbenzyl alcohol, etc. are exemplified.
  • Solvents used in this step include dichloromethane, chloroform, tetrahydrofuran, benzene and the like.
  • Bases that may be used in the reaction of halide compounds and the like include sodium hydride and lithium carbonate. And sodium hydrogencarbonate.
  • the reaction can be carried out at a temperature of 180 to 100 ° C and a reaction time of 1 to 240 hours.
  • the compound of the general formula (20) is usually
  • the compound of the general formula (14) is obtained by converting the compound of the general formula (11) into the general formula (13)
  • the same reaction as when the compound of the general formula (12) is obtained is performed from the compound of the general formula (12), or the same condensation as when the compound of the general formula (10) is obtained from the compound of the general formula (9).
  • the reaction can be produced by carrying out the reaction from the general formula (13).
  • the compound of the general formula (15) can be obtained by reacting a compound of the general formula (14) with hydrogen sulfide in a suitable solvent in the presence or absence of a base.
  • the solvent used here includes pyridine, methanol, ethanol, n-propanol, i-propanol, and the like.
  • the base includes pyridine, triethylamine, getylamine, and the like.
  • the reaction can be performed at a reaction temperature of 0 to 100 ° C and a reaction time of 1 to 2 hours.
  • the compound of the general formula (16) can be produced from the compound of the general formula (15) by reacting an alkyl halide in a suitable solvent in the presence or absence of a base.
  • the alkyl halides include, for example, methyl iodide, methyl iodide and the like, preferably methyl iodide and the like.
  • Solvents that can be used in this step include acetone, methanol, acetonitrile, tetrahydrofuran, and the like.
  • a base such as pyridine, triethylamine, or getylamine can be used.
  • the reaction can be performed at a temperature of 0 to 100 ° C for 0.1 to 10 hours.
  • the alkyl halides used here can be used in the range of 1.0 to 20.0 equivalents to the compound of the general formula (9).
  • the compound of the general formula (17) can be obtained by adding a strong acid to a compound of the general formula (14) in a lower alcohol solvent.
  • the lower alcohol solvent used here includes methanol, ethanol, n-propanol, i-propanol and the like.
  • As the strong acid hydrochloric acid, sulfuric acid, nitric acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like, or a mixed acid thereof can be used.
  • the strong acid can be used in an amount of 1 to 1000 equivalents, preferably 100 to 300 equivalents, relative to the compound of the general formula (14).
  • the reaction can be performed at a temperature of 30 to 30 ° (reaction time of 1 to 48 hours).
  • the compound of the general formula (1) can be prepared by reacting the compound of the general formula (16) with an ammonium salt or an alkylammonium salt in a suitable solvent, or by converting the compound of the general formula (17) It is obtained by reacting the compound with ammonia.
  • ammonium salts used herein include, for example, hydroxyammonium acetate and the like, which is usually used in an amount of 1.0 to 2.0 equivalents to the compound of the general formula (16).
  • Examples of the alkylammonium salts include methylammonium acetate and the like, which can be used usually in a range of 1.0 to 2.0 equivalents to the compound of the general formula (16).
  • the reaction temperature in this step can be in the range of 0 to 100 ° C., and the reaction time can be in the range of 1 to 72 hours.
  • the compound of the general formula (18) constituting a part of the compound of the present invention can be produced by subjecting the compound of the general formula (14) to a reduction reaction usually carried out.
  • the reduction reaction used here may be, for example, a method of adding hydrogen in the presence of a catalyst such as platinum, palladium, carbon-palladium, carbon-platinum, Raneynigel, or tin chloride, zinc, sodium sulfide, aluminum amalgam, chlorinated aluminum.
  • a reduction method using a commonly used reducing agent such as chromium, sodium thiosulfate, sodium borohydride, and lithium aluminum hydride may be mentioned.
  • the reaction temperature in this step is 180 to 100 ° C.
  • the reaction time can be 1 to 72 hours.
  • the compound of general formula (1) thus obtained can be purified in a simple manner by ordinary chemical operations such as extraction, crystallization, recrystallization and various types of chromatography.
  • the compounds of the present invention can be formulated together with suitable excipients, diluents, auxiliaries, wetting agents, lubricants, carriers, etc., and other flavors, coloring agents, sweetening agents, fragrances, preservatives, etc. .
  • suitable excipients diluents, auxiliaries, wetting agents, lubricants, carriers, etc., and other flavors, coloring agents, sweetening agents, fragrances, preservatives, etc.
  • suitable excipients diluents, auxiliaries, wetting agents, lubricants, carriers, etc., and other flavors, coloring agents, sweetening agents, fragrances, preservatives, etc.
  • suitable excipients diluents, auxiliaries, wetting agents, lubricants, carriers, etc., and other flavors,
  • liquid preparations for oral administration i.e., emulsions, syrups, suspensions, solutions, etc. should contain commonly used inert diluents, such as water or vegetable oils. Can be. In the case of liquid preparations, they may be contained in capsules of an absorbable substance such as gelatin.
  • preparations for parenteral administration that is, solvents or suspensions used in the production of injections, suppositories, etc.
  • the preparation method of the preparation may be a conventional method.
  • the dose may be administered in the range of 180 mg, preferably in the range of 1 to 60 mg, once or twice or three times at appropriate intervals, or may be administered intermittently.
  • Ncr- (benzyl (tert-butyloxycarbonyl) aminosulfonyl) -13-cyanophenylalanine-14-acetylbiperazide 0.8 g (1.4 mmo 1 ⁇ yield 50) %).
  • N- (tert-butyloxycarbonyl (3-phenyl-2-n-propyl) aminosulfonyl) -13-cyanophenylanilanine-14-acetylbiperazide 250 mg ( 0.42 mmo 1: 99% yield).
  • N- (tert-butyloxycarbonyl (2-methoxyethoxybenzyl) aminosulfonyl) 1-3-cyanophenylalanine 4-acetylbiperazide 39 Omg (0, 62 mmol) of pyridine 3 ml Bubble hydrogen gas at room temperature into a mixed solution of 6 ml of triethylamine for 30 minutes, and then leave for 3 days. 40 ml of water and 40 ml of ethyl acetate are added to the reaction solution, and 2N HCl is added to adjust the aqueous layer to pH 4, and then the layers are separated.
  • N- (tert-Butyloxycarbonyl (2-methoxymethoxybenzyl) aminosulfonyl) 1-3-Carbothioamidophenylalanine 1-4-Acetylbiperazide Add 353 mg of methyl and reflux under heating for 50 minutes. The reaction mixture was evaporated under reduced pressure, 2 ml of methanol and 29 mg of ammonium acetate were added to the obtained residue, and the mixture was heated and refluxed for 4 hours. After that, the reaction mixture was evaporated under reduced pressure, and the obtained residue was subjected to column chromatography (Fuji).
  • Plasma thrombin time is measured by an automatic blood coagulation analyzer KC-1OA (Ame
  • a single dose of 100 mg / kg S for test compound is orally administered to the rat.
  • Blood samples (0.45 ml) were collected from the left ventricle before and 0.5, 1, 2, and 4 hours after administration, and plasma TT was measured. From the measured TT values, the ratio of the TT values before and after the administration of the test compound (TT ratio) was calculated. Table 2 shows the results. Table 2
  • the sulfamide derivative of the present invention or a pharmaceutically acceptable salt thereof or a hydrate thereof exhibits excellent antithrombin activity and is orally administrable and has few side effects. It is valid.

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Abstract

L'invention porte sur des dérivés de sulfamides, de formule générale (1) ou leurs sels ou hydrates pharmacocompatibles, caractérisés par leur excellente activité antithrombique et qui peuvent servir de médicaments par exemple pour le traitement des thromboses et s'administrer par voie orale tout en présentant des effets secondaires réduits. Dans la formule (1), R1 représente H, alkyle inférieur, ou un groupe amino protecteur; R2 représente un hétérocycle azoté facultativement substitué et fusionné; R3 est un groupe représenté par A-(CH2)m-, H, ou alkyle inférieur facultativement substitué (dans lequel: A représente aryle facultativement substitué, un hétérocycle facultativement substitué et fusionné, ou cycloalkyle facultativement substitué; m est un entier de 0 à 6, et la partie représentée par -(CH2)m- peut comporter au moins un substituant); R4 représente H ou alkyle inférieur; et R5 est un groupe représenté par -C(=NR6)NH2, -NH-C(=NR6)NH2, ou -(CH2)n-NHR6 (dans lequel R6 représente H, alkyle inférieur, hydroxy, acyle, acyloxy, alcoxy inférieur, alcoxycarbonyle inférieur, alcoxycarbonyloxy inférieur, ou hydroxyalkylcarbonyloxy inférieur, n est un entier de 0 à 2 et le groupe représenté par -(CH2)n- peut comporter au moins un substituant).
PCT/JP1996/003520 1995-11-30 1996-12-02 Derives de sulfamides WO1997019919A1 (fr)

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AU76557/96A AU7655796A (en) 1995-11-30 1996-12-02 Sulfamide derivatives
KR1019980703942A KR19990071666A (ko) 1995-11-30 1996-12-02 술파미드 유도체

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054164A1 (fr) * 1997-05-30 1998-12-03 Takeda Chemical Industries, Ltd. Derives de la sulfonamide, leur production et leurs utilisations
US5998412A (en) * 1997-01-23 1999-12-07 Syntex (U.S.A.) Inc. Sulfamide-metalloprotease inhibitors
US6130220A (en) * 1997-10-16 2000-10-10 Syntex (Usa) Inc. Sulfamide-metalloprotease inhibitors
US6376506B1 (en) 1997-01-23 2002-04-23 Syntex (U.S.A.) Llc Sulfamide-metalloprotease inhibitors
US6538017B2 (en) 2001-03-09 2003-03-25 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
WO2003033024A1 (fr) * 2001-10-16 2003-04-24 Chugai Seiyaku Kabushiki Kaisha Inhibiteur de proliferation cellulaire
US6680312B2 (en) 1998-02-05 2004-01-20 Takeda Chemical Industries, Ltd. Sulfonamide derivatives, their production and use
US6710061B2 (en) 2001-03-09 2004-03-23 Ortho-Mcneil Pharamceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
ES2219177A1 (es) * 2003-05-05 2004-11-16 Almirall Prodesfarma, S.A. Derivados de n-(2-feniletil) sufalmida como antagonistas de la integrina alfa4.
US7115607B2 (en) 2001-07-25 2006-10-03 Amgen Inc. Substituted piperazinyl amides and methods of use
US7666610B2 (en) 2002-03-29 2010-02-23 Chugai Seiyaku Kabushiki Kaisha Expressing transporters on viral envelopes
US7666998B2 (en) 2001-12-04 2010-02-23 Chugai Seiyaku Kabushiki Kaisha Cell growth inhibitor containing anti-PepT antibody
US7731960B2 (en) 2003-03-28 2010-06-08 Chugai Seiyaku Kabushiki Kaisha Antibodies that inhibit transport activity of peptide transporters
US7750204B2 (en) 2002-06-05 2010-07-06 Chugai Seiyaku Kabushiki Kaisha Methods for producing antibody
US7964767B2 (en) 2004-03-31 2011-06-21 Chugai Seiyaku Kabushiki Kaisha Transgenic mice expressing baculovirus soluble GP64 and methods of using such mice to make antibodies
US8084490B2 (en) 2004-06-16 2011-12-27 Janssen Pharmaceutica N.V. Sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders
US8492431B2 (en) 2005-12-19 2013-07-23 Janssen Pharmaceutica, N.V. Use of benzo-fused heterocycle sulfamide derivatives for the treatment of obesity
US8497298B2 (en) 2005-12-19 2013-07-30 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels
US8691867B2 (en) 2005-12-19 2014-04-08 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction
US8716231B2 (en) 2005-12-19 2014-05-06 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain
US8853263B2 (en) 2006-05-19 2014-10-07 Janssen Pharmaceutica Nv Co-therapy for the treatment of epilepsy and related disorders
US8937096B2 (en) 2005-12-19 2015-01-20 Janssen Pharmaceutica Nv Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder

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JPS6056919A (ja) * 1983-08-10 1985-04-02 ソシエテ・デチユードウ・シヤンテイフイツク・エ・アンデユストリエル・ドウ・リールドウフランス Ｎ‐（１‐アリル‐２‐ピロリジニルメチル）‐２‐メトキシ‐４‐アミノ‐５‐メチルスルフアモイルベンズアミドを有効成分とする心臓血管障害および血小板機能不全等の治療剤
JPH06312973A (ja) * 1993-04-30 1994-11-08 Yamanouchi Pharmaceut Co Ltd 新規なフェニルスルファミド誘導体
JPH06340619A (ja) * 1993-05-03 1994-12-13 Bristol Myers Squibb Co グアニジニルまたはアミジニル置換メチルアミノ複素環トロンビン抑制剤
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JPH07278095A (ja) * 1994-03-04 1995-10-24 Eli Lilly & Co アルギニンアルデヒドの亜硫酸水素塩付加物

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5998412A (en) * 1997-01-23 1999-12-07 Syntex (U.S.A.) Inc. Sulfamide-metalloprotease inhibitors
US6143744A (en) * 1997-01-23 2000-11-07 Syntex (U.S.A.) Inc. Sulfamide-metalloprotease inhibitors
US6376506B1 (en) 1997-01-23 2002-04-23 Syntex (U.S.A.) Llc Sulfamide-metalloprotease inhibitors
WO1998054164A1 (fr) * 1997-05-30 1998-12-03 Takeda Chemical Industries, Ltd. Derives de la sulfonamide, leur production et leurs utilisations
US6359134B1 (en) 1997-05-30 2002-03-19 Takeda Chemical Industries, Ltd. Sulfonamide derivatives, their production and use
US6130220A (en) * 1997-10-16 2000-10-10 Syntex (Usa) Inc. Sulfamide-metalloprotease inhibitors
US6680312B2 (en) 1998-02-05 2004-01-20 Takeda Chemical Industries, Ltd. Sulfonamide derivatives, their production and use
US6538017B2 (en) 2001-03-09 2003-03-25 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6630505B2 (en) 2001-03-09 2003-10-07 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6710061B2 (en) 2001-03-09 2004-03-23 Ortho-Mcneil Pharamceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US6890939B2 (en) 2001-03-09 2005-05-10 Ortho-Mcneil Pharmaceutical, Inc. Aminopyrrolidine sulfonamides as serine protease inhibitors
US7115607B2 (en) 2001-07-25 2006-10-03 Amgen Inc. Substituted piperazinyl amides and methods of use
US7560460B2 (en) 2001-07-25 2009-07-14 Amgen Inc. Substituted piperazines and methods of use
WO2003033024A1 (fr) * 2001-10-16 2003-04-24 Chugai Seiyaku Kabushiki Kaisha Inhibiteur de proliferation cellulaire
EP1437142A4 (fr) * 2001-10-16 2006-09-20 Chugai Pharmaceutical Co Ltd Inhibiteur de proliferation cellulaire
US7666998B2 (en) 2001-12-04 2010-02-23 Chugai Seiyaku Kabushiki Kaisha Cell growth inhibitor containing anti-PepT antibody
US7666610B2 (en) 2002-03-29 2010-02-23 Chugai Seiyaku Kabushiki Kaisha Expressing transporters on viral envelopes
US8013208B2 (en) 2002-06-05 2011-09-06 Chugai Seiyaku Kabushiki Kaisha Methods for producing antibodies
US7750204B2 (en) 2002-06-05 2010-07-06 Chugai Seiyaku Kabushiki Kaisha Methods for producing antibody
US7731960B2 (en) 2003-03-28 2010-06-08 Chugai Seiyaku Kabushiki Kaisha Antibodies that inhibit transport activity of peptide transporters
ES2219177A1 (es) * 2003-05-05 2004-11-16 Almirall Prodesfarma, S.A. Derivados de n-(2-feniletil) sufalmida como antagonistas de la integrina alfa4.
US7964767B2 (en) 2004-03-31 2011-06-21 Chugai Seiyaku Kabushiki Kaisha Transgenic mice expressing baculovirus soluble GP64 and methods of using such mice to make antibodies
US8084490B2 (en) 2004-06-16 2011-12-27 Janssen Pharmaceutica N.V. Sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders
US8492431B2 (en) 2005-12-19 2013-07-23 Janssen Pharmaceutica, N.V. Use of benzo-fused heterocycle sulfamide derivatives for the treatment of obesity
US8497298B2 (en) 2005-12-19 2013-07-30 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels
US8691867B2 (en) 2005-12-19 2014-04-08 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction
US8716231B2 (en) 2005-12-19 2014-05-06 Janssen Pharmaceutica Nv Use of benzo-fused heterocycle sulfamide derivatives for the treatment of pain
US8937096B2 (en) 2005-12-19 2015-01-20 Janssen Pharmaceutica Nv Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder
US8853263B2 (en) 2006-05-19 2014-10-07 Janssen Pharmaceutica Nv Co-therapy for the treatment of epilepsy and related disorders

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