WO2016037592A1 - 一种氨基磺酰基类化合物、其制备方法及用途 - Google Patents

一种氨基磺酰基类化合物、其制备方法及用途 Download PDF

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WO2016037592A1
WO2016037592A1 PCT/CN2015/089471 CN2015089471W WO2016037592A1 WO 2016037592 A1 WO2016037592 A1 WO 2016037592A1 CN 2015089471 W CN2015089471 W CN 2015089471W WO 2016037592 A1 WO2016037592 A1 WO 2016037592A1
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group
compound
methyl
formula
alkyl
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PCT/CN2015/089471
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English (en)
French (fr)
Inventor
沈敬山
刘正
王震
田广辉
李剑峰
杨小军
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苏州旺山旺水生物医药有限公司
中国科学院上海药物研究所
上海特化医药科技有限公司
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Application filed by 苏州旺山旺水生物医药有限公司, 中国科学院上海药物研究所, 上海特化医药科技有限公司 filed Critical 苏州旺山旺水生物医药有限公司
Priority to CN201580042722.6A priority Critical patent/CN106687449B/zh
Priority to KR1020177007934A priority patent/KR101941794B1/ko
Priority to EP15840920.1A priority patent/EP3192792B1/en
Priority to JP2017514550A priority patent/JP6454413B2/ja
Priority to US15/509,796 priority patent/US10093679B2/en
Publication of WO2016037592A1 publication Critical patent/WO2016037592A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • 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
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/46—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom

Definitions

  • the invention belongs to the field of medicinal chemistry.
  • the present invention relates to a novel aminosulfonyl compound of the formula I or a tautomer thereof, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof, and a process for the preparation thereof, Pharmaceutical compositions and uses thereof.
  • Epilepsy is the second largest neurological disease after stroke, which is a serious threat to human health. It is a chronic disease in which sudden abnormal discharge of brain neurons leads to transient brain dysfunction.
  • the clinical manifestation of epilepsy is epileptic seizure, which is mainly divided into two categories: systemic seizures and partial seizures, of which partial seizures account for 60%. Sudden loss of consciousness in generalized seizures, including generalized tonic clonic seizure, abscess seizure, etc.; partial seizures generally do not produce disturbance of consciousness, including simple partial seizures (simple) Partial seizures), autonomic seizures and complex partial seizures.
  • epilepsy patients account for about 1% of the world's population, and 75%-80% of patients' symptoms can be effectively controlled by traditional drugs such as phenytoin, Zonisamide, Topiramate. Etc, but there are still about 20%-25% of patients with epilepsy drug treatment is invalid, so this prompted us to continue to develop new anti-epileptic drugs.
  • Another object of the invention is to provide a process for the preparation of the compounds of the invention.
  • Still another object of the present invention is to provide an aminosulfonyl compound of the formula I or a tautomer, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof as antiepileptic, anticonvulsant, and slimming Uses of agents, etc., and in the preparation of a medicament for treating diseases such as epilepsy, convulsions, obesity, and the like.
  • Still another object of the present invention is to provide one or more of the aminosulfonyl compound represented by Formula I or a tautomer, an enantiomer, a racemate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.
  • Pharmaceutical composition comprising
  • X is O, S, NH or CH 2 ,
  • Y is N or CH.
  • X is O or S, if Q is a benzene ring, Y is not CH;
  • Z is NR 5 , O or CHR 5 ; when X is O and Y is N, Z is not O or CH 2 ;
  • the Q ring is a 6- to 10-membered aromatic ring, or a 5- to 6-membered heterocyclic ring or a heteroaryl ring containing 1 to 4 hetero atoms selected from N, O, and S, or a Q ring is not present; preferably, a Q ring a benzene ring, a 5- to 6-membered heterocyclic ring or a heteroaryl ring containing 1 to 2 hetero atoms selected from N, O, S, or a Q ring is not present; more preferably, the Q ring is a benzene ring or a thiophene ring ;
  • n is an integer from 0 to 4, preferably m is 0, 1 or 2;
  • n is an integer from 0 to 2, preferably n is 0 or 1;
  • p is an integer of 1-2;
  • R 2 is each independently hydrogen, amino, halogen, trifluoromethyl, hydroxy, nitro, nitrile, fluorenyl, carboxy, aldehyde, C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 alkanoyl (ie -C(O)-C1-C10 alkyl), C1-C10 alkoxycarbonyl (ie -C(O)O-C1 ⁇ C10 alkyl), C1-C10 alkanoyloxy (ie, -OC(O)-C1-C10 alkyl), -NR 6 R 7 , -CONR 6 R 7 , -OCONR 6 R 7 , C1 to C10 sulfur
  • R 3 and R 4 are each independently H, amino, trifluoromethyl, hydroxy, carboxy, aldehyde, amino, C1 to C10 alkyl, C2 to C10 alkenyl, C2 to C10 alkynyl, C3 to C10 naphthenic a C1 to C10 alkoxy group, a C1 to C10 alkoxycarbonyl group (i.e., -C(O)O-C1 to C10 alkyl group), a C1 to C10 alkanoyl group (i.e., -C(O)-C1 to C10 alkyl group) , C1-C10 alkanoyloxy (ie, -OC(O)-C1-C10 alkyl), sulfonyl, C6-C10 aryl, 4 to 4 heteroatoms selected from N, O, S a 10- to 10-membered heterocyclic group or a 4 to 10 membered heteroaryl group having 1 to 4 hetero atoms selected
  • R 3 and R 4 together with the N atom to which they are attached form a 4 to 8 membered heterocyclic group having 1 to 4 hetero atoms selected from N, S, O or 4 to form a hetero atom having 1 to 4 ⁇ 8 yuan heteroaryl;
  • R 5 is H or a C1 to C10 alkyl group
  • R 6 and R 7 are each independently H or a C1 to C10 alkyl group, or R 6 and R 7 together with the N atom to which they are bonded form 4 to 8 which contain 1 to 4 hetero atoms selected from N, S, O.
  • the heterocyclic group may form a 4- to 8-membered heteroaryl group having 1 to 4 hetero atoms; preferably, R 6 and R 7 are each independently H or a methyl group.
  • the ring has the following structure:
  • the compound of formula I has the following structure IA:
  • Z is O or NR 5 ;
  • n 0, 1 or 2;
  • n 0 or 1
  • p 1;
  • R 1 is each independently hydrogen, halogen, trifluoromethyl, hydroxy, nitro, nitrile, fluorenyl, carboxy, aldehyde, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C3 to C8 cycloalkyl, C1-C8 alkoxy, C1-C8 alkanoyl (ie -C(O)-C1-C8 alkyl), C1-C8 alkoxycarbonyl (ie -C(O)O-C1 ⁇ C8 Alkyl), C1-C8 alkanoyloxy (ie, -OC(O)-C1-C8 alkyl), -NR 6 R 7 , -CONR 6 R 7 , -OCONR 6 R 7 , C1 to C8 sulfanyl a sulfonylamino group, a carbamoyl group (-CONH 2 ), a
  • R 2 is each independently hydrogen, halogen, trifluoromethyl, hydroxy, nitro, nitrile, amino, fluorenyl, carboxy, aldehyde, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 alkanoyl (ie, -C(O)-C1-C8 alkyl), C1-C8 alkoxycarbonyl (ie, -C(O)OC1 ⁇ C8 Alkyl), C1-C8 alkanoyloxy (ie, -OC(O)-C1-C8 alkyl), -NR 6 R 7 , CONR 6 R 7 , -OCONR 6 R 7 , C1 to C8 sulfanyl, Sulfonic acid group, sulfonylamino group, carbamoyl group (-CONH 2 ),
  • R 3 and R 4 are each independently H or a C 1 -C 8 alkyl group or a 5 to 6 membered heteroaryl group;
  • R 3 and R 4 together with the N atom to which they are attached form a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from N, S, O or form 1 to 3 selected from N, a 5- to 7-membered heteroaryl group of a hetero atom in S, O, for example, including but not limited to pyrrolidinyl, imidazolyl, piperazinyl, piperidinyl, morpholinyl;
  • R 5 is H or a C1 to C3 alkyl group
  • R 6 and R 7 are each independently H or a C1 to C8 alkyl group
  • R 6 and R 7 together with the N atom to which they are bonded form a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from N, S, O or form 1 to 3 selected from N, S, A 5- to 7-membered heteroaryl group of a hetero atom in O.
  • the compound of Formula I has the structure:
  • Y is N or CH, and when X is O or S, Y is not CH;
  • Z is O or NR 5 , and when X is O and Y is N, Z is not O or CH 2 ;
  • Q is a benzene ring
  • n 0, 1 or 2;
  • n 0 or 1
  • p 1;
  • R 1 is H, F, Cl, NO 2 , NH 2 , NHCOCH 3 or methoxy
  • R 2 is H or methyl
  • R 3 and R 4 are each independently H, methyl, ethyl or imidazolyl
  • R 5 is H
  • R 6 and R 7 are each independently H or methyl.
  • Halogen generally means fluorine, chlorine, bromine or iodine; preferably fluorine, chlorine or bromine; more preferably fluorine or chlorine;
  • the C1-C10 alkyl group means a straight or branched saturated hydrocarbon group having 1 to 10 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl.
  • C1-C8 alkyl refers to a straight or branched saturated hydrocarbon group having from 1 to 8 carbon atoms;
  • the C3-C10 cycloalkyl group means a saturated cycloalkyl group having 3 to 10 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group;
  • the aromatic ring is an aromatic ring, for example, a benzene ring;
  • the heteroaryl ring is a ring having at least one hetero atom selected from O, S or N and having an aromaticity, such as a thiazole ring, a pyrazole ring, Pyridine ring or imidazole ring.
  • the formula I of the present invention also includes tautomers, enantiomers, racemates or pharmaceutically acceptable salts thereof of the above preferred compounds.
  • the present invention provides a pharmaceutically acceptable salt of the compound of the formula I, for example, non-toxic with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, with an organic carboxylic acid or an organic sulfonic acid.
  • Acid addition salt preferably phosphoric acid, malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid, more preferably phosphate, methanesulfonate, hydrochloride Or trifluoroacetate.
  • the compounds of formula I can also be reacted with a base to provide pharmaceutically acceptable metal salts, especially non-toxic alkali metal salts (e.g., sodium and potassium).
  • the compounds of formula I may contain one or more chiral centers and thus may exist as stereoisomers, ie, enantiomers, diastereomers or mixtures thereof. If the compound of the formula I contains an alkenyl group or an alkenylene group, cis (E) and trans (Z) isomerism may also be present. Thus, the compounds of formula I of the present invention may be individual isomers or mixtures of individual isomers.
  • the compounds of the formula I can also be prepared by preparing from the corresponding optically pure intermediates or by resolution of the corresponding racemates using suitable chiral carriers, for example by HPLC or fractional crystallization from the corresponding racemic A diastereomeric salt formed by the reaction of a suitable optically active acid or base.
  • the compounds of formula I may exist in the form of tautomers, and the invention includes mixtures thereof and single tautomers.
  • the invention includes radiolabeled derivatives of the compounds of formula I which are suitable for use in biological research.
  • the invention includes any prodrug form of the compound of Formula I.
  • the invention also includes pharmaceutically acceptable oxides of the compounds of Formula I, or pharmaceutically acceptable solvates (including but not limited to hydrates).
  • the invention also includes various crystalline forms of the various forms of the compounds of Formula I, various salts of the compounds of Formula I, and various crystal forms.
  • Another object of the invention is to provide a process for the preparation of a compound of formula I, which process comprises:
  • the deprotection reaction can be selected according to the nature of the protecting group.
  • R8 can be a Boc, Cbz protecting group.
  • the protecting group can be removed under acidic conditions.
  • the acidic condition can be hydrochloric acid. , sulfuric acid or trifluoroacetic acid, etc.;
  • the amination reaction can be carried out by amination reaction of R 3 -A, R 4 -A or AR 3 -R 4 -B with compound 1-1 in the presence of a base to give compound I-2, wherein A and B are the same or Different, and independently of each other, Cl, Br or I;
  • the starting material brominated product II can be commercially available or prepared by a literature reporting method, a known conventional synthetic method, for example, by the following method:
  • Compound II can be prepared by bromination reaction of compound II-2.
  • the bromination reagent can be N-bromosuccinimide (NBS), Br 2, etc., and optionally benzoyl peroxide or azobisisobutylate.
  • a catalyst such as a nitrile;
  • Compound II can also be prepared from compound II-3 by bromination and decarboxylation;
  • the bromination reagent used in the bromination reaction may be NBS, liquid bromine (Br 2 ), etc., and a catalyst such as benzoyl peroxide or AIBN (azobisisobutyronitrile) may be added as the case may be;
  • Decarboxylation reaction can be prepared from compound II-4 under heating or other decarboxylation conditions;
  • compound III and compound VII (wherein R 8 is a protecting group, such as a Boc protecting group, a Cbz protecting group, etc.) can be subjected to sulfonylation reaction under base catalysis to obtain compound III-1, which may be an organic base or an inorganic base. , for example, triethylamine or potassium carbonate;
  • Compound III-1 is obtained by deprotection reaction under acid catalysis to obtain compound I-1, which may be an organic acid or a mineral acid such as trifluoroacetic acid, hydrochloric acid (HCl) or sulfuric acid;
  • the halogenated alkane R 3 -A, R 4 -A or AR 3 -R 4 -B is reacted with the compound I-1 in the presence of a base to give the compound I-2, wherein A and B are the same or different, and respectively Independently Cl, Br or I;
  • the starting material compound (III) can be commercially available or can be produced by a known method, for example, by the following method:
  • Compound III is prepared from the compound II by the Gabriel reaction, that is, the phthalimide is added to form the compound III-2, and then the amine is decomposed to obtain the compound III;
  • Compound IV-1 can be obtained by sulfonylation of compound IV with compound VII (wherein R8 is a protecting group such as a Boc protecting group, a Cbz protecting group, etc.) in the presence of a base;
  • Compound I-3 is further subjected to amination reaction in the presence of a base to obtain compound I-4;
  • the compound V can be purchased from the market or prepared by a known method.
  • the X, Y, Q rings, m, n, p, R 1 and R 2 are the same as defined in the formula I; except for not hydrogen, R 3 and R 4 is the same as defined above; R 5 is a C1-C10 alkyl group.
  • I, I-1, I-2, I-3, I-4, and I-5 are all target compounds of the present invention.
  • the present invention provides a pharmaceutical use of the aminosulfonyl compound of the formula I or a tautomer thereof, an enantiomer, a racemate thereof or a pharmaceutically acceptable salt thereof, It is used in the preparation of antiepileptic drugs, anti-obesity drugs, and in the preparation of drugs for the treatment of convulsions, epilepsy (including partial epilepsy, generalized epilepsy, seizures as complications of other diseases), obesity and the like. use.
  • the present invention provides a therapeutically effective amount of an aminosulfonyl compound selected from the formula I or a tautomer, an enantiomer thereof, a racemate thereof or A pharmaceutical composition of one or more of a pharmaceutically acceptable salts, which may be used as an anti-epileptic, anticonvulsant, anti-obesity agent, and the composition may optionally comprise a pharmaceutically acceptable carrier or excipient.
  • the composition consists of a therapeutically effective amount of one or more sulfamoyl compounds of the formula I (or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof) and at least one pharmaceutically acceptable excipient composition.
  • the choice of pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and is usually a filler, a diluent, a binder, a wetting agent, a disintegrant, a lubricant, an emulsifier, a suspending agent, and the like.
  • the proportion of the compound of the formula I of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof in the above composition is from 0.1% to 99.9%, preferably from 1% to 99%, based on the total amount.
  • the pharmaceutically acceptable carrier refers to a pharmaceutical carrier conventional in the pharmaceutical field, such as a diluent such as water; a filler such as starch, sucrose, etc.; a binder such as a cellulose derivative, an alginate, gelatin, Polyvinylpyrrolidone; wetting agent such as glycerin; disintegrants such as agar, calcium carbonate and sodium hydrogencarbonate; absorption enhancers such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and soap Clay; lubricants such as talc, calcium stearate and magnesium stearate, and polyethylene glycol.
  • a pharmaceutical carrier conventional in the pharmaceutical field, such as a diluent such as water; a filler such as starch, sucrose, etc.; a binder such as a cellulose derivative, an alginate, gelatin, Polyvinylpyrrolidone; wetting agent such as glycerin;
  • the present invention also provides a process for producing a pharmaceutically acceptable composition of the sulfamoyl compound represented by the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • the sulfamoyl compound represented by the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof is usually mixed with a pharmaceutically acceptable adjuvant, and is prepared in a form suitable for a certain route by a conventional preparation method (dosage form). .
  • Dosage forms include tablets, capsules, granules, pills, solutions, suspensions, emulsions, ointments, films, creams, aerosols, injections, suppositories, and the like. Preference is given to tablets and capsules.
  • the compound of the present invention is usually used in an amount of from 1 to 500 mg, preferably from 10 to 100 mg per day, in single or multiple doses. However, if necessary, the above dosage can be appropriately deviated. Professionals can determine the optimal dose based on specific circumstances and expertise. These conditions include the severity of the disease, individual differences in the patient, characteristics of the formulation, and route of administration.
  • the present invention provides the use of the sulfamoyl compound represented by the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof, or a pharmaceutically acceptable composition thereof as a medicament for human use.
  • the present invention also provides a method of treating seizures, epilepsy including partial epilepsy, generalized epilepsy, seizures as a complication of other diseases, obesity, the method comprising administering a therapeutically effective amount of a formula One or more of the aminosulfonyl compound represented by I or a tautomer thereof, an enantiomer, a racemate or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present invention is administered to a patient .
  • the compounds or compositions provided herein can be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, transurethral, vaginal, nasal, inhalation or topical routes.
  • the preferred route is oral.
  • it can be prepared into a conventional solid preparation such as a tablet, a powder, a granule, a capsule, etc., or as a liquid preparation, such as a water or oil suspension, or other liquid preparation, such as a syrup;
  • parenteral administration it may be prepared as a solution for injection, water or an oily suspension, or the like.
  • the present invention also provides the use of the sulfamoyl compound of the formula I, a pharmaceutically acceptable salt thereof or a solvate thereof for the preparation of a medicament for human use against epilepsy or related diseases.
  • the sulfamoyl compound represented by Formula I exhibits remarkable pharmacological effects in an animal model of anti-epilepsy, and has anti-epileptic, anticonvulsant or anti-epileptic-related diseases, in particular, can reduce the mortality of epileptic seizures, and has protection Role, and side effects are small.
  • the compound of the formula I of the present invention also has a weight-loss effect, which can reduce the body weight of the obese model rats and lower the total cholesterol and triglyceride levels.
  • Sulfonamide antiepileptic drugs such as thiazide, topiramate and zonisamide have strong inhibitory effects on renal carbonic anhydrase. Long-term application may lead to metabolic acidosis, causing kidney stones, osteoporosis and increased fracture risk. The growth of children is slow, affecting the fetal development of pregnant women (topiramate and zonisamide FDA label), limiting the use of the drug population and affecting the safety of the drug.
  • the compounds provided by the present invention are related to the marketed sulfonamide antiepileptic drugs. In comparison, the inhibition of carbonic anhydrase is significantly weakened, and it is expected to have a better clinical safety and a wider range of drug users.
  • the compounds provided by the present invention are expected to exhibit clinical safety and effectiveness.
  • the compound 1-3 (200 mg, 0.63 mmol) was added to methanol (10 ml), and hydrazine hydrate (70 mg, 1.3 mmol) was added thereto, and the mixture was heated to reflux for 1 hour. The reaction mixture was concentrated to dryness to dryness crystals crystals crystals 80mg).
  • the compound 1-5 (100 mg, 0.28 mmol) was added to dichloromethane (10 ml), then trifluoroacetic acid (1 ml) was added, and the mixture was warmed to 40 ° C for 1 hour, and the reaction was confirmed by TLC. Will react The solution was concentrated to dryness. EtOAc m.
  • the compound 2-2 (250 mg, 1.09 mmol) was used as a starting material, and the title compound 2-4 (120 mg) was obtained as a white solid.
  • the compound 2-4 (120 mg, 0.72 mmol) was used as a starting material, and the preparation of Compound 1 from Compound 1-4 in Example 1 was obtained to give Compound Compound 2 (80 mg) as a white solid.
  • the compound 4-2 250 mg, 0.7 mmol
  • methanol (10 ml) were added to the reaction flask, and hydrazine hydrate (70 mg, 1.4 mmol) was added thereto, and the mixture was heated to reflux for 1 hour, and detected by TLC. all.
  • the reaction mixture was concentrated to dryness to dryness crystals crystals crystals crystals ).
  • the compound 4-5 (160 mg, 0.38 mmol) was further added to dichloromethane (10 ml), then trifluoroacetic acid (1 ml) was added, and the mixture was warmed to 40 ° C for 1 hour, and then the reaction was confirmed by TLC. The reaction mixture was directly concentrated to dryness, and then evaporated, evaporated, evaporated, evaporated.
  • Example 1 The method of Example 1 was prepared by using 5-nitro-3-methylbenzisoxazole as a raw material.
  • the compound 6-3 (727 mg, 4.8 mmol) was dissolved in acetonitrile, potassium carbonate (1.35 g, 9.6 mmol), dimethyl sulfate (43 ⁇ l, 7.2 mmol) was added, and the mixture was heated at 50 ° C. It was extracted with ethyl acetate and water, and the ethyl acetate layer was washed with brine, dried,
  • step 6-5 200 mg was dissolved in DMF, and potassium salt of phthalimide was added thereto, and stirred at room temperature. After 30 min, the solvent was evaporated to give compound 6-6, which was directly used for the next step.
  • the compound 6-6 obtained in the above reaction is dissolved in methanol, added with hydrazine hydrate, and heated to reflux. After the reaction is completed by TLC, the mixture is concentrated, then dichloromethane, washed with water, washed with saturated brine, dried, concentrated, 7.
  • the compound 6-8 was dissolved in dichloromethane (2 ml), trifluoroacetic acid (0.3 ml) was added, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated, then a small amount of dichloromethane was added, stirred and filtered to give compound 6 (24 mg). Pure.
  • the product compound 11-2 (320 mg) obtained in the above step was dissolved in anhydrous methanol (3 ml), cooled to 0 ° C in an ice bath, and then, to the mixture was evaporated. The reaction mixture was concentrated to dryness. Collect the product, concentrate it, The residue was triturated with dichloromethane (3 mL).
  • reaction solution was cooled to room temperature, poured into about 50 ml of ice water, stirred for 20 minutes, filtered, and the filter cake was rinsed with water and dried to give the product as a pale yellow solid compound 12-2 (504 mg, yield 94%).
  • the next step is to react.
  • Lithium tetrahydroaluminum (474 mg, 12.48 mmol, 1.5 eq) was suspended in dry THF (5.0 mL) eluted with EtOAc EtOAc EtOAc. 1.65 g (8.32 mmol, 1.0 eq) was dissolved in THF (10 ml), and slowly added dropwise to the reaction mixture. After the completion of the dropwise addition, the mixture was slowly warmed to room temperature for 1 hour, and the TLC reaction was completed.
  • the mouse was evaluated for its anti-MES effect by the maximal electroshock seizure test of MES (maximal electroshock seizure test), and a preliminary evaluation was made on whether each compound has a therapeutic effect on treating epileptic seizures.
  • the YSD-4G type pharmacological and physiological experiment multi-purpose instrument was used, and the electroconvulsive mode was selected, and the stimulation condition of 115V stimulation voltage, 250ms stimulation time, and 50HZ AC voltage was used for the test.
  • the left and right ears of the mice moistened with physiological saline were clamped by positive and negative electrodes, respectively. After the agitation, whether the limb tonicity is straightened is the criterion for the judgment of epileptic seizures.
  • the mice were randomly divided into groups and administered by intragastric administration at a dose of 100 mg/kg. The compounds were observed to have an effect against MES at 0.5 h, 1.5 h, and 2 h after administration. The results are shown in Table 1.
  • mice Male Sprague-Dawley rats, 180-200 g, 40 rats, were randomly divided into 5 groups, 8 rats in each group.
  • the vehicle control was given by continuous gavage, topiramate (40 mg/kg), and the compound of Example 3 20 mg/kg, 40 mg/kg, 80 mg. /kg.
  • the serum and triglyceride levels in the serum of the rats were tested 5 weeks after administration, and the results are shown in Table 2. The results indicate that the compound of Example 3 can significantly reduce triglyceride and total cholesterol levels in rats.
  • Coloring buffer HEPES is dissolved in distilled water, prepared to a concentration of 10 mM solution, adjusted to pH 7.7 with 1 M Tris at 23 ° C; bromothymol blue soluble in HE ESS buffer at pH 7.7, concentration 50 mg / L;
  • Saturated CO2 ice water Prepare dry ice in ice distilled water
  • CA-II enzyme solution formulated into 2 ⁇ g / ml, stored at -20 ° C for use.
  • Test sample Different concentrations of solution were prepared using distilled water as a solvent.
  • the blank tube is recorded as t 0
  • the standard tube is marked as t mark
  • the test tube is recorded as t
  • (t 0 -t mark ) / t mark is normal enzyme activity
  • (t 0 - t)/t is the enzyme activity after being affected by the test compound.
  • the IC50 of the compound of Example 3 for carbonic anhydrase inhibitory activity was 154 ⁇ M
  • the IC50 of topiramate for carbonic anhydrase inhibitory activity was 0.89 ⁇ M
  • the IC50 of zonisamide for carbonic anhydrase inhibitory activity was 14.7 ⁇ M.
  • the inhibition of carbonic anhydrase by the compound of Example 3 was significantly weaker than that of topiramate and zonisamide.

Abstract

公开了一种通式（I）所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体或其药学上可接受的盐，其制备方法，药物组合物及其用途。所述化合物可以用于治疗癫痫、惊厥、肥胖症等。

Description

一种氨基磺酰基类化合物、其制备方法及用途 技术领域
本发明属于药物化学领域。具体而言，本发明涉及一种通式I所示的新的氨基磺酰基类化合物或其互变异构体、对映体、消旋体或其药学上可接受的盐，其制备方法，药物组合物及其用途。
背景技术
癫痫(epilepsy)是仅次于中风的神经内科第二大疾病，严重威胁着人类的健康，是大脑神经元突发性异常放电，导致短暂的大脑功能障碍的一种慢性疾病。癫痫的临床表现为癫痫发作(epileptic seizure)，主要分为全身性发作和部分性发作两大类，其中部分性发作占60％。全身性发作会出现意识丧失包括全身强直阵挛发作(generalized tonic clonic seizure，大发作)，失神发作(absence seizure，小发作)等；部分性发作一般不产生意识障碍,包括单纯部分性发作(simple partial seizures)，自主神经性发作和复杂部分性发作(complex partial seizures)等。
据统计，癫痫患者约占世界人口的1％，其中75％-80％的患者的症状能通过传统药物得到有效控制，所述药物例如苯妥英钠、唑尼沙胺(Zonisamide)、托吡酯(Topiramate)等，但是仍然有约20％-25％的癫痫患者药物治疗无效，因此，这促使我们继续开发新的抗癫痫药物。
发明内容
发明目的
本发明的一个目的是提供一种通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体或其药学上可接受的盐。
本发明的另一个目的是提供本发明所述的化合物的制备方法。
本发明的又一个目的是提供通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体或其药学上可接受的盐作为抗癫痫、抗惊厥、减肥剂等的用途，以及在制备治疗癫痫、惊厥、肥胖等疾病的药物中的应用。
本发明的再一个目的是提供包含通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体或其药学上可接受的盐中的一种或多种的药物组合物。
本发明的再一个目的是提供一种治疗癫痫、惊厥、肥胖症的方法。
技术方案
根据本发明的一个方面，提供了一种通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体，或其药学上可接受的盐：
Figure PCTCN2015089471-appb-000001
X为O、S、NH或CH2，
Y为N或CH，当X为O或S时，若Q为苯环，则Y不为CH；
Z为N-R5、O或CHR5；当X为O并且Y为N时，Z不为O或CH2；
Q环为6～10元芳环，或含1～4个选自N、O、S中的杂原子的5～6元杂环或杂芳环，或者Q环不存在；优选地，Q环为苯环、含1～2个选自N、O、S中的杂原子的5～6元杂环或杂芳环，或者Q环不存在；更优选地，Q环为苯环或噻吩环；
m为0～4的整数，优选m为0、1或2；
n为0至2的整数，优选n为0或1；
p为1～2的整数；
R1各自独立地为氢、氨基、卤素、三氟甲基、羟基、硝基、腈基、巯基、羧基、醛基、氧代(＝O)基团、硫代(＝S)基团、C1～C10烷基、C2～C10烯基、C2～C10炔基、C3～C10环烷基、C1～C10烷氧基、C1～C10烷酰基(即-C(O)-C1～C10烷基)、C1～C10烷氧羰基(即-C(O)O-C1～C10烷基)、C1～C10烷酰氧基(即-OC(O)-C1～C10烷基)、-NR6R7、-CONR6R7、-OCONR6R7、C1～C10 硫烷基、磺酸基、氨基甲酰基(-CONH2)、磺酰基、C6～C10芳基、含1～4个选自N、O、S中的杂原子的4～10元杂环基、或含1～4个选自N、O、S中的杂原子的4～10元杂芳基；上述氨基、C1～C10烷氧基、C1～C10烷基、C1～C10烷酰基、C1～C10烷氧羰基、C1～C10烷酰氧基、磺酰基、C6～C10芳基、含1～4个选自N、O、S中的杂原子的4～10元杂环基或含1～4个选自N、O、S中的杂原子的4～10元杂芳基可任选地被一个或多个选自卤素、三氟甲基、羟基、硝基、氨基、腈基、羧基、醛基、C1～C10烷基、C1～C10烷氧基、C1～C10烷酰氧基、C1～C10烷氧羰基、C1～C10烷酰基、磺酰基、C1～C10烷磺酰基、苯基和苯甲基中的取代基取代；
R2各自独立地为氢、氨基、卤素、三氟甲基、羟基、硝基、腈基、巯基、羧基、醛基、C1～C10烷基、C2～C10烯基、C2～C10炔基、C3～C10环烷基、C1～C10烷氧基、C1～C10烷酰基(即-C(O)-C1～C10烷基)、C1～C10烷氧羰基(即-C(O)O-C1～C10烷基)、C1～C10烷酰氧基(即-OC(O)-C1～C10烷基)、-NR6R7、-CONR6R7、-OCONR6R7、C1～C10硫烷基、磺酸基、氨基甲酰基(-CONH2)、磺酰基、C6～C10芳基、含1～4个选自N、O、S中的杂原子的4～10元杂环基、或含1～4个选自N、O、S中的杂原子的4～10元杂芳基；上述氨基、C1～C10烷氧基、C1～C10烷基、C1～C10烷酰基、C1～C10烷氧羰基、C1～C10烷酰氧基、磺酰基、C6～C10芳基、4～10元杂环基或4～10元杂芳基可任选地被一个或多个选自卤素、三氟甲基、羟基、硝基、氨基、腈基、羧基、醛基、C1～C10烷基、C1～C10烷氧基、C1～C10烷酰氧基、C1～C10烷氧羰基、C1～C10烷酰基、磺酰基、C1～C10烷磺酰基、苯基和苯甲基中的取代基取代；
R3和R4各自独立地为H、氨基、三氟甲基、羟基、羧基、醛基、氨基、C1～C10烷基、C2～C10烯基、C2～C10炔基、C3～C10环烷基、C1～C10烷氧基、C1～C10烷氧羰基(即-C(O)O-C1～C10烷基)、C1～C10烷酰基(即-C(O)-C1～C10烷基)、C1～C10烷酰氧基(即-OC(O)-C1～C10烷基)、磺酰基、C6～C10芳基、含1～4个选自N、O、S中的杂原子的4～10元杂环基、或含1～4个选自N、O、S中的杂原子的4～10元杂芳基；上述氨基、C1～C10烷基、C1～C10烷氧基、C1～C10烷氧羰基、C1～C10烷酰基、C1～C10烷酰氧基、磺酰基、C6～C10芳基、含1～4个选自N、O、S中的杂原子的4～10元杂环基或含1～4个选自N、O、S中的杂原子的4～10元杂芳基可任选地被一个或多 个选自卤素、三氟甲基、羟基、硝基、氨基、腈基、羧基、醛基、C1～C10烷基、C1～C10烷氧基、C1～C10烷酰氧基、C1～C10烷氧羰基、C1～C10烷酰基、磺酰基、C1～C10烷磺酰基、苯基和苯甲基中的取代基取代；
或R3与R4与跟其相连的N原子一起形成含1～4个选自N、S、O中的杂原子的4～8元杂环基或形成含1～4个杂原子的4～8元杂芳基；
R5为H或C1～C10烷基；
R6和R7各自独立地为H或C1～C10烷基，或R6与R7与其相连的N原子一起形成含1～4个选自N、S、O中的杂原子的4～8元杂环基或形成含1～4个杂原子的4～8元杂芳基；优选地，R6、R7各自独立地为H或甲基。
优选地，通式I所示的化合物中，
所述
Figure PCTCN2015089471-appb-000002
环具有如下结构：
Figure PCTCN2015089471-appb-000003
进一步优选地，通式I所示的化合物具有如下结构IA：
Figure PCTCN2015089471-appb-000004
其中，X为O、S或NH；
Z、m、n、p、R1、R2、R3和R4与前面的定义相同。
更进一步优选地，
Z为O或N-R5；
m为0、1或2；
n为0或1；
p为1；
R1各自独立地为氢、卤素、三氟甲基、羟基、硝基、腈基、巯基、羧基、醛基、C1～C8烷基、C2～C8烯基、C2～C8炔基、C3～C8环烷基、C1～C8烷氧基、C1～C8烷酰基(即-C(O)-C1～C8烷基)、C1～C8烷氧羰基(即-C(O)O-C1～C8烷基)、C1～C8烷酰氧基(即-OC(O)-C1～C8烷基)、-NR6R7、-CONR6R7、-OCONR6R7、C1～C8硫烷基、磺酰氨基、氨基甲酰基(-CONH2)、磺酰基、C1～C8烷基磺酰基、C6～C10芳基、含1～3个选自N、O、S中的杂原子的4～10元杂环基或4～10元杂芳基；
R2各自独立地为氢、卤素、三氟甲基、羟基、硝基、腈基、氨基、巯基、羧基、醛基、C1～C8烷基、C2～C8烯基、C2～C8炔基、C3～C8环烷基、C1～C8烷氧基、C1～C8烷酰基(即-C(O)-C1～C8烷基)、C1～C8烷氧羰基(即-C(O)OC1～C8烷基)、C1～C8烷酰氧基(即-OC(O)-C1～C8烷基)、-NR6R7、CONR6R7、-OCONR6R7、C1～C8硫烷基、磺酸基、磺酰氨基、氨基甲酰基(-CONH2)、磺酰基、C1～C8烷基磺酰基、C6～C10芳基、含1～3个选自N、O、S中的杂原子的4～10元杂环基、或含1～3个选自N、O、S中的杂原子的4～10元杂芳基；
R3和R4各自独立地为H或C1～C8烷基或5～6元杂芳基；
或R3与R4与跟其相连的N原子一起形成含1～3个选自N、S、O中的杂原子的5～7元杂环基或形成含1～3个选自N、S、O中的杂原子的5～7元杂芳基，例如，包括但不限于吡咯烷基、咪唑基、哌嗪基、哌啶基、吗啉基；
R5为H或C1～C3烷基；
R6和R7各自独立地为H或C1～C8烷基，
或R6与R7与其相连的N原子一起形成含1～3个选自N、S、O中的杂原子的5～7元杂环基或形成含1～3个选自N、S、O中的杂原子的5～7元杂芳基。
更进一步优选地，通式I所示的化合物具有如下结构：
其中，X为O、S或NH；
Y为N或CH，且当X为O或S时，Y不为CH；
Z为O或N-R5，且当X为O并且Y为N时，Z不为O或CH2；
Q为苯环；
m为0、1或2；
n为0或1；
p为1；
R1为H、F、Cl、NO2、NH2、NHCOCH3或甲氧基；
R2为H或甲基；
R3和R4各自独立地为H、甲基、乙基或咪唑基，
R5为H；
R6和R7各自独立地为H或甲基。
最优选地，通式I所示的化合物为如下化合物：
N-[(6-氯-苯并异噁唑-3-基)甲基]-氨基磺酰胺；
N-[(6-氟-苯并异噁唑-3-基)甲基]-氨基磺酰胺；
N-[(苯并异噁唑-3-基)甲基]-氨基磺酰胺；
N-[(苯并异噻唑-3-基)甲基]-氨基磺酰胺；
N-[(苯并异噁唑-3-基)甲基]-N’-甲基-氨基磺酰胺；
N-[(苯并异噁唑-3-基)甲基]-N’,N’-二甲基-氨基磺酰胺；
1-(苯并异噻唑-3-基)-甲氧基磺酰胺；
N-[(6-氟-苯并吡唑-3-基)甲基]-氨基磺酰胺；
N-[(5-甲氧基-苯并异噁唑-3-基)甲基]-氨基磺酰胺；
N-[(5-硝基-苯并异噁唑-3-基)甲基]-氨基磺酰胺；
N-[(5-氯-苯并异噁唑-3-基)甲基]-氨基磺酰胺；
N-[(噻吩-3-基)甲基]-氨基磺酰胺；
N-[(噻吩并[3,2-b]噻吩-3-基)甲基]-氨基磺酰胺；
N-[(2-氯-噻吩-3-基)甲基]-氨基磺酰胺。
在本发明中，各术语定义如下：
卤素通常是指氟、氯、溴或碘；优选为氟、氯或溴；更优选为氟或氯；
C1～C10烷基指含有1～10个碳原子的直链或支链的饱和烃基，例如，甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1-乙基丙基、异戊基、新戊基、异己基、3-甲基戊基或正己基等，优选为甲基、乙基、正丙基、异丙基、丁基、异丁基或叔丁基；类似地，C1～C8烷基指含有1～8个碳原子的直链或支链的饱和烃基；
C3～C10环烷基是指含有3～10个碳原子的饱和环烷基，如环丙基、环丁基、环戊基、环己基、环庚基或环辛基等；
芳环为具有芳香性的环，例如，苯环；所述杂芳环是至含有选自O、S或N中的至少一个杂原子且具有芳香性的环，例如噻唑环、吡唑环、吡啶环或咪唑环。
本发明的通式I还包括上述优选化合物的互变异构体、对映体、消旋体或其药学上可接受的盐。
其中，本发明提供了通式Ⅰ所示的化合物的药用盐，例如，与无机酸如盐酸、氢溴酸、氢碘酸、硫酸和磷酸，与有机羧酸或有机磺酸形成的无毒酸加成盐；优选磷酸、苹果酸、乳酸、马来酸、盐酸、甲磺酸、硫酸、柠檬酸、酒石酸、乙酸或三氟乙酸，更优选为磷酸盐、甲磺酸盐、盐酸盐或三氟乙酸盐。通式Ⅰ所示的化合物还可与碱反应提供药用金属盐，特别是无毒碱金属盐(例如钠盐和钾盐)。
通式Ⅰ所示的化合物可含有一个或多个手性中心，因此可存在立体异构体，即对映异构体、非对映异构体或其混合物。若通式Ⅰ所示的化合物中含有链烯基或亚烯基，则还可以存在顺式(E)和反式(Z)异构现象。因此，本发明式Ⅰ所示的化合物可以为单个异构体或各异构体的混合物。
利用常规工艺可以实现非对映异构体或顺式和反式异构体的分离，例如通式Ⅰ所示的化合物或其适合的盐或衍生物的立体异构体的混合物的分步结晶、色谱或HPLC。通式Ⅰ所示的化合物还可以这样制备：从对应的旋光纯中间体制备，或者利用适合的手性载体拆分对应的外消旋物，例如通过HPLC或者分步结晶由对应的外消旋物与适合的旋光活性酸或碱的反应所生成的非对映异构盐。
通式Ⅰ所示的化合物可存在互变异构体的形式，而本发明包括了其混合物和单一的互变异构体。
本发明包括通式Ⅰ所示的化合物的放射标记衍生物，这些衍生物适用于生物学研究。
本发明包括通式Ⅰ所示的化合物的任何前药形式。
本发明也包括通式Ⅰ所示的化合物的可药用氧化物，或可药用溶剂化物(包括但不限于水合物)。
本发明还包括通式Ⅰ所示的化合物的多种晶型、通式Ⅰ所示的化合物的各种盐的多种晶型。
本发明的另一个目的是提供通式I所示化合物的制备方法，所述方法包括：
(1)当Z为NH时
1)由溴代物II与N原子被保护基保护的氨基磺酰胺(化合物VI)经磺酰化、脱保护、胺化反应制备：
Figure PCTCN2015089471-appb-000005
其中，化合物II与化合物VI在碱存在下通过磺酰化反应得到化合物II-1，其中R8为保护基；
脱保护反应可以根据保护基性质选择相应的脱保护方法，例如，R8可以为Boc、Cbz保护基，当R8为Boc保护基时，该保护基可以在酸性条件下脱去，酸性条件可以是盐酸、硫酸或三氟甲乙酸等；
胺化反应可以由R3-A、R4-A或A-R3-R4-B，与化合物I-1在碱存在的条件下通过胺化反应得到化合物I-2，其中A和B相同或不同，并且分别独立地为Cl、Br或I；
其中，所述起始原料溴代物II可由市场购买或通过文献报道方法、已知常规合成方法制备，例如，按下述方法合成：
Figure PCTCN2015089471-appb-000006
由化合物II-2经溴代反应制备化合物II，溴代试剂可以是N-溴代丁二酰亚胺(NBS)、Br2等，并视情况加入过氧化苯甲酰或偶氮二异丁腈等催化剂；
Figure PCTCN2015089471-appb-000007
化合物II也可以由化合物II-3经溴代、脱羧反应制备；
其中，溴代反应采用的溴代试剂可以是NBS、液溴(Br2)等，并视情况加入过氧化苯甲酰或AIBN(偶氮二异丁腈)等催化剂；
脱羧反应可以由化合物II-4在加热条件或其他脱羧条件下制备化合物II；
或者
2)化合物III与保护基保护的氨基磺酰氯(VII)经磺酰化、脱保护、胺化反应制备化合物I-2：
Figure PCTCN2015089471-appb-000008
其中，化合物III与化合物VII(其中R8为保护基，例如Boc保护基、Cbz保护基等)在碱催化下通过磺酰化反应可以得到化合物III-1，所述碱可以是有机碱或无机碱，例如三乙胺或碳酸钾等；
化合物III-1在酸催化条件下通过脱保护反应得到化合物I-1，所述酸可以是有机酸或无机酸，例如三氟乙酸、盐酸(HCl)或硫酸等；
卤代烷R3-A、R4-A或A-R3-R4-B，在碱存在条件下与化合物I-1通过胺化反应得到化合物I-2，，其中A和B相同或不同，并且分别独立地为Cl、Br或I；
其中，起始原料化合物(III)可由市场购买或通过已知方法制备，例如按下述方法合成：
Figure PCTCN2015089471-appb-000009
由化合物II经盖布瑞尔反应制备化合物III，即，加入邻苯二甲酰亚胺生成化合物III-2，再胺解得到化合物III；
(2)当Z为O时
Figure PCTCN2015089471-appb-000010
化合物IV与化合物VII(其中R8为保护基，例如Boc保护基、Cbz保护基等)在碱的存在下通过磺酰化反应可以得到化合物IV-1；
或者
Figure PCTCN2015089471-appb-000011
在碱存在的条件下，化合物IV与氨基磺酰氯(化合物VIII)反应直接得到化合物I-3，所述反应条件与方法(1)中的相应反应类似，也可不加催化剂直接反应得到；
化合物I-3在碱的存在下再通过胺化反应得到化合物I-4；
其中，起始原料羟基化合物(IV)可由市场购买或通过已知方法制备；
(3)当Z为CH2时
Figure PCTCN2015089471-appb-000012
化合物V与相应的HNR3R4经胺化反应制备得到化合物I-5；
其中，化合物V可由市场购买或通过已知方法制备，
(4)当Z为N-R5或CH-R5时，可以由相应的通式I-2或通式I-5所示的化合物经烷基化反应制备得到。
上述制备方法中所涉及的通式中，X、Y、Q环、m、n、p、R1和R2、与通式I中的定义相同；除了不为氢之外，R3和R4与前述定义相同；R5为C1～C10烷基。
上述化合物中I，I-1，I-2，I-3，I-4，I-5均为本发明的目标化合物。
根据本发明的又一方面，本发明提供了通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体或其药学上可接受的盐的医药用途，其在制备作为抗癫痫药、抗肥胖药物的用途，和在制备用于治疗惊厥、癫痫(包括部分性癫痫、全面性癫痫、作为其他疾病并发症的癫痫发作)、肥胖等疾病的药物中的用途。
根据本发明的再一方面，本发明还提供了一种包含治疗有效量的选自通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体或其药学上可接受的盐中的一种或多种的药物组合物，其可以作为抗癫痫、抗惊厥剂、减肥药，以及该组合物可以任选包含药学上可接受的载体或赋形剂。
所述组合物由治疗有效量的一种或多种通式I所示的氨基磺酰基类化合物(或其可药用盐，或它们的可药用溶剂化物)与至少一种可药用辅料组成。药用辅料的选择因施用途径和作用特点而异，通常是填充剂、稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、乳化剂、助悬剂等。本发明的通式I所示的化合物、其药学上可接受的盐或其溶剂化物在上述组合物中的所占的比例为总重量的0.1％～99.9％，优选1％～99％。
所述药学上可接受的载体是指药学领域常规的药物载体，例如：稀释剂，如水等；填充剂，如淀粉、蔗糖等；粘合剂，如纤维素衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮；湿润剂，如甘油；崩解剂，如琼脂、碳酸钙和碳酸氢钠；吸收促进剂，如季铵化合物；表面活性剂，如十六烷醇；吸附载体，如高岭土和皂粘土；润滑剂，如滑石粉、硬脂酸钙和硬脂酸镁、和聚乙二醇等。另外，还可以在所述药物组合物中加入其它辅剂，如香味剂和甜味剂等。
本发明还提供了通式I所示的氨基磺酰基类化合物、其药学上可接受的盐或其溶剂化物的可药用的组合物的制备方法。通常将通式I所示的氨基磺酰基类化合物、其药学上可接受的盐或其溶剂化物与可药用辅料相混合，经常规的制备方法制成适于一定途径施用的形式(剂型)。剂型包括片剂、胶囊剂、颗粒剂、丸剂、溶液剂、混悬剂、乳剂、软膏、膜剂、霜剂、气雾剂、注射剂、栓剂等。优选片剂和胶囊剂。
本发明化合物的使用剂量一般为每天1～500mg，优选10～100mg，分单次或多次使用。但在必要时，可适当偏离上述剂量。专业人员可根据具体情况和专业知识，确定最佳剂量。这些情况包括疾病的严重程度、患者的个体差异、制剂的特性和给药途径等。
此外，本发明还提供了通式I所示的氨基磺酰基类化合物、其可药用盐或其溶剂化物，或其可药用的组合物作为人用药物的用途。
根据本发明的又一方面，本发明还提供了治疗惊厥、癫痫包括部分性癫痫、全面性癫痫、作为其他疾病并发症的癫痫发作、肥胖的方法，所述方法包括施用治疗有效量的通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体或其药学上可接受的盐中的一种或多种或者本发明的所述药物组合物给患者。
本发明提供的化合物或组合物可以口服、注射(静脉、肌肉、皮下和冠状动脉内)、舌下、经颊、经直肠、经尿道、经阴道、经鼻、吸入或局部途径施用。优选的途径是口服。用于口服时，可以将其制成常规的固体制剂，如片剂、粉剂、粒剂、胶囊等，或制成液体制剂，如水或油悬浮剂，或其它液体制剂，如糖浆等；用于肠外给药时，可将其制成注射用的溶液、水或油性悬浮剂等。
本发明还提供了通式I所示的氨基磺酰基类化合物、其可药用盐或其溶剂化物，在制备抗癫痫或相关疾病的人用药物中的用途。
通式I所示的氨基磺酰基类化合物在抗癫痫动物模型上表现了明显的药效，具有抗癫痫、抗惊厥或抗癫痫相关疾病的作用，尤其可减少癫痫大发作的死亡率，具有保护作用，且副作用小。
本发明通式I所示的化合物还具有减肥作用，可以降低肥胖模型大鼠的体重，降低总胆固醇和甘油三酯水平。
磺酰胺类抗癫痫药物如硫噻嗪、托吡酯及唑尼沙胺等对肾脏碳酸酐酶具有较强的抑制作用，长期应用易导致代谢性酸中毒，引起肾结石、骨质疏松、增加骨折风险，儿童生长发育缓慢，影响怀孕妇女的胎儿发育(托吡酯及唑尼沙胺FDA标签)，限制了用药人群并影响了用药的安全性，本发明提供的化合物与上市的磺酰胺类抗癫痫药物相比，对碳酸酐酶的抑制作用显著减弱，预计临床上具有更好的用药安全性及更广泛的用药人群。
因此本发明提供的化合物可望在临床上表现出更佳的安全性和有效性。
具体实施方式
下列实施例进一步解释了本发明的化合物及其中间体的合成方法，但并不限制本发明的范围。1H NMR在Mercury-400或Mercury-300核磁共振波谱仪(Varian公司)上完成。常规缩写如下：s，单峰；d，双峰；t，三重峰；q，四重峰；m，多重峰；br，宽峰。起始原料按文献方法制备或由市场购买。
实施例1：N-[(6-氯-苯并异噁唑-3-基)甲基]-氨基磺酰胺
Figure PCTCN2015089471-appb-000013
将化合物6-氯-3-甲基苯并异噁唑(化合物1-1)(300mg,1.8mmol)加入干燥四氯化碳(10ml)中，加入NBS(N-溴代丁二酰亚胺)(410mg,1.8mmol)，再加入过氧化苯甲酰(44mg,0.18mmol)，加入完毕后，在氮气保护条件下加热至回流反应12小时后，反应结束。将反应液冷却至常温后，过滤，滤液浓缩至干，柱层析，得到淡黄色固体产物1-2(150mg)。
Figure PCTCN2015089471-appb-000014
将化合物1-2(150mg,0.61mmol)加入乙腈(10ml)中，再加入邻苯二甲酰亚胺(130mg,0.61mol)，加热至回流反应2小时后，TLC检测，原料反应完全。将反应液直接浓缩干，再加入二氯甲烷，水洗，饱和盐水洗一次，无水硫酸钠干燥，滤除硫酸钠，滤液浓缩，得到淡红色固体产物1-3(200mg)，直接用于下一步反应。
将化合物1-3(200mg,0.63mmol)加入甲醇(10ml)中，再加入水合肼(70mg,1.3mmol)，再加热至回流反应1小时后，TLC检测，原料反应完全。将反应液直接浓缩干，得到油状产物(粗品)，再加入二氯甲烷，水洗，饱和食盐水洗一次，无水硫酸钠干燥，过滤，滤液浓缩，柱层析，得到白色固体产物1-4(80mg)。
Figure PCTCN2015089471-appb-000015
将叔丁醇(300mg,4mmol)、二氯甲烷(10ml)混合，再在冰水浴冷却条件下，慢慢滴加氯磺酸异氰酸酯(560mg,4mmol)，滴加完毕后，继续反应半小时后，得到产物N-Boc-氯磺酰胺溶液，可以直接用于下一步反应。
将化合物1-4(80mg,0.44mmol)加入二氯甲烷(10ml)中，再加入三乙胺(90mg,0.9mmol)，再在冰水浴冷却条件下，慢慢滴加上述N-Boc-氯磺酰胺的反应液，直至原料1-4反应完全。将反应液用水洗一次，稀盐酸洗一次，饱和食盐水洗一次，无水硫酸钠干燥，过滤，滤液浓缩，柱层析，得到白色固体产物1-5(100mg)。
将化合物1-5(100mg,0.28mmol)加入二氯甲烷(10ml)中，再加入三氟乙酸(1ml)，升温至40℃反应1小时后，TLC检测，原料反应完全。将反应 液直接浓缩干，再加入二氯甲烷，水洗，饱和盐水洗一次，无水硫酸钠干燥，过滤，滤液浓缩，柱层析，得到白色固体产物化合物1(10mg)。
1H NMR(DMSO-d6)δ:7.95(d,1H),7.76(d,1H),7.41(t,1H),7.30(s,1H),6.77(s,2H),4.39(d,2H)。
EI-MS m/z:261(M),263(M+2)。
实施例2：N-[(6-氟-苯并异噁唑-3-基)甲基]-氨基磺酰胺
Figure PCTCN2015089471-appb-000016
将6-氟-3-甲基苯并异噁唑(化合物2-1)(500mg,3.3mmol)加入干燥四氯化碳(10ml)中，加入NBS(750mg,3.3mmol)、过氧化苯甲酰(80mg,0.33mmol)，氮气保护条件下加热至回流反应12小时，TLC检测反应结束。将反应液冷却至常温后，过滤，除去亚胺，滤液浓缩干，过柱，得到淡黄色固体产物2-2(250mg)。
Figure PCTCN2015089471-appb-000017
以化合物2-2(250mg,1.09mmol)为原料，参照实施例1中由化合物1-2制备化合物1-4的制备方法，得到白色固体产物化合物2-4(120mg)。
Figure PCTCN2015089471-appb-000018
以化合物2-4(120mg,0.72mmol)为原料，参照实施例1中由化合物1-4制备化合物1的制备方法，得到白色固体产物化合物2(80mg)。
1H NMR(DMSO-d6)δ:7.75(d,1H)，7.41(t,1H),7.26(d,1H),6.91(s,1H),6.77(s,2H),4.36(d,2H)。
EI-MS m/z:245(M),165(基峰),137。
实施例3：N-[(苯并异噁唑-3-基)甲基]-氨基磺酰胺
Figure PCTCN2015089471-appb-000019
在反应瓶中加入1,2-苯并异噁唑-3-乙酸(化合物3-1)(5g,0.028mol)，再加入醋酸(20ml)，在常温条件下，慢慢滴加液溴(4.5g,0.028mol)，滴加完毕后，再加热至40℃反应2小时后，TLC检测，原料反应完全。将反应液倒入冰水中，有固体产物析出，搅拌半小时后，过滤，烘干，得到淡黄色固体产物(化合物3-2，6g)。
在反应瓶中加入上步所得淡黄色固体产物3-2(6g,0.024mol)，再加入甲苯(60ml)，加热至回流反应12小时后，TLC检测，原料反应完全。将反应液直接浓缩干，得到淡红色固体产物3-溴甲基-1,2-苯并异噁唑(化合物3-3，即通式II化合物)(4.5g)，可不经精制直接用于下一步。
Figure PCTCN2015089471-appb-000020
以3-溴甲基-1,2-苯并异噁唑(化合物3-3)(4.5g,0.021mol)为原料，参照实施例1中由化合物1-2制备化合物1-4的方法，制备得到白色固体产物3-5(3g)。
Figure PCTCN2015089471-appb-000021
以3-胺甲基-1,2-苯并异噁唑(化合物3-5)(3g,0.02mol)为原料，参照实施例1中由化合物1-4制备化合物1的制备方法，得到白色固体产物化合物3(1.3g)。
1H NMR(DMSO-d6)δ:8.03(dt,1H),7.74(d,1H),7.66(td,1H),7.47-7.38(m,2H),6.86(s,2H),4.47(d,2H)。
EI-MS m/z:227(M)。
实施例4N-[(6-氟-苯并吡唑-3-基)甲基]-氨基磺酰胺
Figure PCTCN2015089471-appb-000022
将6-氟-N-Boc-3-甲基苯并吡唑(化合物4-1)(500mg,2.15mmol)、干燥四氯化碳(10ml)加入反应瓶中，再加入NBS(490mg,2.15mmol)、过氧化苯甲酰(55mg,0.22mmol)，加入完毕后，在氮气保护条件下加热至回流反应12小时，反应结束后将反应液冷却至常温后，过滤，滤液浓缩干，柱层析，得到淡黄色固体产物4-2(250mg)。
Figure PCTCN2015089471-appb-000023
将化合物4-2(250mg,0.8mmol)、乙腈(10ml)加入反应瓶中，再加入邻苯二甲酰亚胺(170mg,0.8mol)，加热至回流反应2小时后，TLC检测，原料反应完全。将反应液直接浓缩干，再加入二氯甲烷，水洗，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩，得到淡红色固体产物4-3(250mg)，可不经纯化直接用于下一步。
将化合物4-2(250mg,0.7mmol)、甲醇(10ml)加入反应瓶中，再加入水合肼(70mg,1.4mmol)，加热至回流反应1小时后，TLC检测，原料反应完 全。将反应液直接浓缩干，得到油状产物(粗品)，再加入二氯甲烷，水洗，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩，过柱，共得到白色固体产物4-4(120mg)。
Figure PCTCN2015089471-appb-000024
将化合物4-4(120mg,0.48mmol)、二氯甲烷(10ml)加入反应瓶中，再加入三乙胺(100mg,1mmmol)，在冰水浴冷却条件下，慢慢滴加N-Boc-氯磺酰胺的溶液(化合物VII，参照实施例2制备)，直至原料反应完全。将反应液用水洗一次，稀盐酸洗一次，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩，过柱，共得到白色固体产物4-5(160mg)。
将化合物4-5(160mg,0.38mmol),再加入二氯甲烷(10ml)，再加入三氟乙酸(1ml)，再升温至40℃反应1小时后，TLC检测，原料反应完全。将反应液直接浓缩干，再加入二氯甲烷，水洗，饱和盐水洗一次，无水硫酸钠干燥，过滤，浓缩，过柱，共得到白色固体产物化合物4(40mg，收率)。
1H NMR(DMSO-d6)δ:12.81(s,1H),7.90(d,1H),7.49(d,1H),7.35(t,1H),7.02(t,1H),6.69(s,2H),4.40(d,2H)。
EI-MS m/z:244。
实施例5：N-[(5-硝基-苯并异噁唑-3-基)甲基]-磺酰胺
Figure PCTCN2015089471-appb-000025
参照实施例1的方法以5-硝基-3-甲基苯并异噁唑为原料制备得到。
EI-MS m/z:244。
实施例6：N-[(5-甲氧基-苯并异噁唑-3-基)甲基]-氨基磺酰胺
Figure PCTCN2015089471-appb-000026
将2,5-二羟基苯乙酮(化合物6-1)(4.5g，30mmol)溶于吡啶(17ml)，分批加入NH2OH·H2O(2.1g,30mmol)，室温搅拌过夜，TLC检测反应完全后，乙酸乙酯萃取，有机层依次用水，0.2M HCl溶液洗涤，减压浓缩至干，再加入甲苯，减压浓缩，干燥，得固体化合物6-2(4.63g)。
将PPh3(三苯基膦)(3.14g，13mmol)溶于干燥的二氯甲烷(50ml)，加入DDQ(2,3-二氯-5,6-二氰对苯醌)(2.72g，12mmol)，搅拌下缓慢加入上步所得化合物6-2，待TLC检测反应完全后，浓缩溶剂，残余物柱层析得化合物6-3。
Figure PCTCN2015089471-appb-000027
化合物6-3(727mg，4.8mmol)溶于乙腈，加入碳酸钾(1.35g，9.6mmol)、硫酸二甲酯(43μl，7.2mmol)，50℃下加热，TLC显示反应完全后，浓缩溶剂，用乙酸乙酯、水萃取，乙酸乙酯层用饱和食盐水洗涤，干燥，浓缩，柱层析，得化合物6-4。
将化合物6-4(390mg,2.4mmol)溶于CCl4，加入NBS，再加入AIBN(偶氮二异丁氰)，先60℃下加热半小时，后升至80℃反应，TLC检测反应完全后，冷却反应液，加入二氯甲烷稀释，再加入水，萃取，有机层用饱和食盐水洗涤，干燥，浓缩得化合物6-5，可不经精制进行下步反应。
Figure PCTCN2015089471-appb-000028
将上步产物6-5(200mg)溶于DMF中，加入邻苯二甲酰亚胺钾盐，室温搅拌，30min后，蒸干溶剂得化合物6-6，可直接用于下步反应。
上步反应所得化合物6-6溶于甲醇，加入水合肼，加热回流，TLC检测反应完全后，浓缩，加入二氯甲烷，水洗，饱和食盐水洗，干燥，浓缩，柱层析，得化合物6-7。
Figure PCTCN2015089471-appb-000029
化合物6-7溶于二氯甲烷(4ml)，加入三乙胺(0.42ml)，冰浴下缓慢加入现制的N-Boc-氯磺酰胺的溶液(化合物VII，参照实施例2制备)(1ml)，反应完全后，反应液用水，稀盐酸，饱和食盐水洗涤，有机层干燥，浓缩，得产物6-8(53mg)。
化合物6-8溶于二氯甲烷(2ml)，加入三氟醋酸(0.3ml)，室温下反应1h，反应完全后浓缩反应液，加入少量二氯甲烷，搅拌，过滤，得化合物6(24mg)纯品。
1H NMR(CD3OD-d4)δ:7.45(dd,1H)，7.38(d,1H)，7.17(dd,1H)，4.52(s,2H)，3.82(s 3H).
实施例7：N-[(苯并异噻唑-3-基)甲基]-氨基磺酰胺
Figure PCTCN2015089471-appb-000030
化合物7-1(870mg)、AIBN(10mg)加至CCl4中，加热回流后，加入NBS(1.14g)和AIBN(10mg)，加热回流，3小时后停止加热，冷却，加入CH2Cl2稀释，水洗一次，有机层用无水硫酸钠干燥，滤除硫酸钠，浓缩，得化合物7-2(1.3g)。
Figure PCTCN2015089471-appb-000031
将化合物VI(N-Boc-氨基磺酰胺)(3.5g,8eq)、K2CO3加入DMF中，加入化合物7-2(500mg)，室温搅拌，反应完全后减压浓缩溶剂至干，加入水，CH2Cl2萃取，洗涤有机层，干燥，浓缩，得化合物7-3(2.3g，粗品)。
将上步所得化合物7-3(500mg)溶于CH2Cl2，加入CF3COOH，室温搅拌，4小时后反应完全，浓缩溶剂至干，加入水、CH2Cl2萃取，洗涤有机层，有机层干燥，浓缩，所得产物经柱层析得实施例7的目标化合物7(41mg)。
1H NMR(DMSO-d6)δ:8.30(d,1H),8.19(d,1H),7.62(t,1H),7.52(t,1H),7.23(t,1H),6.76(s,2H),4.52(d,2H)。
EI-MS m/z:243(M+),163,135,91。
实施例8：N-[(苯并异噁唑-3-基)甲基]-N’-甲基-氨基磺酰胺
Figure PCTCN2015089471-appb-000032
取化合物8-1(400mg)，加入钠氢(88mg)，加入DMF(3ml)，碘甲烷(0.076ml,1eq)，室温下搅拌反应。1小时后停止反应，加入氯化铵溶液，浓缩DMF，加入二氯甲烷-水萃取，有机相干燥，浓缩，得到黄色油状物化合物8-2和9-2。再加入二氯甲烷(2ml)，三氟乙酸(2ml)，室温下搅拌1h。TLC检测反应完全。浓缩溶剂，加入饱和碳酸氢钠溶液调节pH至弱碱性，萃取，干燥，浓缩，采用硅胶制备板分离样品，得到终产物化合物8(60mg)和化合物9(100mg)。
化合物8：
1H NMR(DMSO-d6)δ:8.01(d,1H),7.75(t,2H),7.66(t,1H),7.42(t,1H),6.95(q,1H),4.43(d,2H),2.45(d,3H)。
EI-MS m/z：242,148,123,94。
实施例9：N-[(苯并异噁唑-3-基)甲基]-N’,N’-二甲基-氨基磺酰胺
使用与实施例8相同的步骤得到的产物进行薄层制备板分离得到终产物化合物9。
Figure PCTCN2015089471-appb-000033
1H NMR(DMSO-d6)δ:7.98-8.09(m,2H),7.75(d,1H),7.67(t,1H),7.43(t,1H),4.54(d,2H),2.64(s,6H)。
EI-MS m/z：256,161,108。
实施例10：N-[(5-氯-苯并异噁唑-3-基)甲基]-氨基磺酰胺
Figure PCTCN2015089471-appb-000034
将2-羟基-5-氯苯乙酮(化合物10-1)(1g)，NH2OH·HCl(820mg)溶于甲醇(10ml)，滴入吡啶(1ml)，待反应完全后，蒸干溶剂，用1M HCl溶液洗涤，加入水，乙酸乙酯萃取，有机层洗涤、干燥、浓缩，得化合物10-2(1.07g)。
PPh3(2.12g)溶于干燥CH2Cl2(5ml)，搅拌下加入DDQ(1.83g)，搅拌下加入化合物10-2(1g)，20分钟后反应完全，蒸干溶剂，柱层析，得化合物10-3(450mg)。
Figure PCTCN2015089471-appb-000035
将化合物10-3(383mg)，AIBN(8mg)溶于CCl4，80℃加热回流，加入NBS(490mg)与AIBN(8mg)，回流过夜，加入CH2Cl2稀释，加入水分层，洗涤有机层，干燥浓缩得化合物10-4(650mg)。
Figure PCTCN2015089471-appb-000036
将化合物VI(N-Boc-氨基磺酰胺)(2.4g)、K2CO3(1.68g)加入DMF(20ml)，再加入上步所得产物10-4(600mg)，30分钟后反应完全，减压浓缩溶剂至干，加入水，用CH2Cl2萃取，洗涤有机层，干燥，浓缩，得化合物10-5(650mg)。
化合物10-5(200mg)溶于CH2Cl2，加入CF3COOH(0.4ml)，室温搅拌，2小时后反应完全，蒸干溶剂，柱层析，得化合物10(40mg)。
1H NMR(DMSO-d6)δ:10.57(s,1H),10.02(s,1H),8.07(s,1H),7.03-7.15(m,2H),6.92(d,1H),4.25(d,2H)。
EI-MS m/z：261(M),263(M+2)。
实施例11：N-[(噻吩-3-基)甲基]-氨基磺酰胺
Figure PCTCN2015089471-appb-000037
3-溴甲基噻吩(化合物11-1)354mg(2.0mmol,1.0eq)溶于5.0mlDMF中，加入N-Boc磺酰胺(化合物VII，参照实施例2制备))(432mg,2.2mmol，1.1eq)，然后加入碳酸钾1.1g(8.0mmol，4.0eq)，室温搅拌反应过夜。反应液倒入50ml冰水中，析出粘稠油状物，加入乙酸乙酯萃取2次；合并有机相，水洗2次，盐水洗1次，硫酸钠干燥，过滤，滤液浓缩至干得粗品为粘稠油状物。柱层析，洗脱剂二氯甲烷/MeOH＝100/1～10/1，收集产品，浓缩干得化合物11-2(320mg，收率56％)。
上步所得产品化合物11-2(320mg)溶于无水甲醇3.0ml，冰浴冷却至0℃，加入氯化氢乙醇溶液3.0ml，升温至室温搅拌过夜。反应液浓缩至干，残余物柱层析纯化(洗脱剂DCM/MeOH＝100/1-10/1)。收集产品，浓缩干， 残余物用二氯甲烷(3.0ml)打浆，过滤，烘干得88mg纯品化合物11，白色固体，收率42％。
1H NMR(DMSO-d6)δ:7.48(dd,1H),7.34(m,1H),7.10(dd,1H),6.99(t,1H),6.60(s,2H),4.06(d,2H)。
ESI-MS m/z:191.01(M-1)。
实施例12：N-[(噻吩并[3,2-b]噻吩-3-基)甲基]-氨基磺酰胺
Figure PCTCN2015089471-appb-000038
噻吩并[3,2-B]噻吩-2-甲酸(化合物12-1)500mg(2.7mmol,1.0eq)加入甲醇5.0ml中，冷至0℃，滴加浓硫酸(265mg,2.7mmol,1.0eq)，加完后升温至室温反应，然后加热至回流过夜。TLC原料有剩余，将反应液冷至0℃，补加浓硫酸(530mg,5.4mmol,2.0eq)，然后加热至回流反应8小时，TLC反应完全。将反应液冷至室温，倒入约50ml冰水中，搅拌20分钟，过滤，滤饼用水淋洗，烘干得产品为土黄色固体化合物12-2(504mg，收率94％)，直接用于下一步反应。
四氢铝锂(474mg,12.48mmol,1.5eq)悬于干燥THF(5.0ml)中，氮气保护，冷至-30℃℃，将噻吩并[3,2-B]噻吩-2-甲酸甲酯1.65g(8.32mmol,1.0eq)溶于THF(10ml)中，缓慢滴加到反应液中，滴加完毕后缓慢升温至室温反应1小时，TLC反应完全。将反应体系冷却至-20℃后缓慢滴加EA至无明显气泡产生，然后滴加20％氢氧化钠水溶液，至形成松散沉淀；过滤，滤饼用EA充分淋洗；滤液用饱和氯化铵水溶液洗2次，水洗1次，盐水洗1次，无水硫酸钠干燥，过滤，滤液浓缩至干得粗品。粗品中加入正己烷15ml打浆30分钟，过滤，滤饼减压浓缩至干得化合物12-3，1.29g，收率90.8％。
Figure PCTCN2015089471-appb-000039
将噻吩并[3,2-B]噻吩-2-甲醇(化合物12-3)(366mg,2.15mmol,1.0eq)和BSA 422mg(2.15mmol,1.0eq)溶于7.5ml干燥THF中，加入三苯基膦(620mg, 2.37mmol,1.1eq)，氮气保护，冰盐浴冷至-10℃，滴加偶氮二甲酸二乙酯(DEAD)(412mg,2.37mmol,1.1eq)，滴加过程保持反应温℃低于0℃，滴加完全后缓慢升温至室温反应过夜。TLC原料有少量剩余。减压浓缩至干，残余物溶于二氯甲烷，柱层析纯化(洗脱剂石油醚/乙酸乙酯＝100/1-5/1)。收集产品，浓缩至干得类白色固体化合物12-4(331mg)，收率44.2％。
将上步所得化合物12-4(331mg)溶于甲醇(10ml)中，冰浴冷却至0℃，加入氯化氢乙醇溶液(3.2ml)，升温至室温搅拌过夜，TLC显示反应完全。减压浓缩至干，残余物柱层析纯化(洗脱剂石油醚/乙酸乙酯＝100/1-5/1)。收集产品，浓缩干，得纯品化合物12(176mg)，类白色固体，收率74.5％。
1H NMR(DMSO-d6)δ:7.60(d,1H),7.40(d,1H),7.35(s,1H),7.27(t,1H),6.71(s,2H),4.31(d,2H)。
ESI-MS m/z:248.91(M+1)。
实施例13：N-[(2-氯-噻吩-3-基)甲基]-氨基磺酰胺
Figure PCTCN2015089471-appb-000040
氨基磺酰胺(1.363g,14.18mmol，3.0eq)溶于DMF(15ml)中，加入碳酸钾(783mg,5.67mmol,1.2eq)，冰浴冷至0℃，滴加2-氯-3-溴甲基噻吩(化合物13-1)1.0g(4.73mmol,1.0eq)，反应室温搅拌过夜。TLC反应完全。反应液倒入100ml冰水中，加入乙酸乙酯萃取2次，合并有机相，水洗1次，饱和食盐水洗1次，无水硫酸钠干燥，过滤，滤液浓缩至干得粗品。柱层析纯化(洗脱剂石油醚/乙酸乙酯＝100/1-3/1)。收集产品，浓缩干，得化合物13(324mg)，浅黄色固体，收率32％。
1H NMR(DMSO-d6)δ:7.40(d,1H),7.08-7.03(m,2H),6.66(s,2H),3.98(d,2H)。
ESI-MS m/z:224.98(M-1),227.02(M+2-1)。
实施例14：1-(苯并异噻唑-3-基)甲氧基磺酰胺
Figure PCTCN2015089471-appb-000041
化合物14-1(3g)溶于甲醇(60ml)中，冷却到0度后，将氯化亚砜(6mL)滴加入反应液中。回流，待反应完全后冷却至室温。浓缩去除溶剂，剩余物溶于乙酸乙酯(60mL)中，水洗，有机层干燥、减压浓缩，得到产物化合物14-2(3g)。
将化合物14-2(1.2g)溶于THF(60ml)中，冷却到0度后，将LiBH4(0.23g)加入反应液中。搅拌反应1小时后，滴加饱和NaHCO3溶液，用乙酸乙酯(50mLx 2)萃取反应液，分出有机层，干燥、减压浓缩，得到化合物14-3(0.8g)。
Figure PCTCN2015089471-appb-000042
将化合物14-3(0.5g)溶于DMA(5mL)中，氨基磺酰氯(1g)加入反应体系中，室温搅拌10-12小时。TLC检测反应完全后，向反应体系中加入水(20mL)和乙酸乙酯(50mL)，分出有机层，有机层干燥、减压浓缩，经柱层析，得化合物14(0.2克)。
1H NMR(DMSO-d6)δ:8.28(d,1H),8.21(d,1H),7.84(s,2H),7.68(td,1H),7.59(td,1H),5.49(s,2H)。
ESI-MS m/z:243.0(M-1)。
小鼠最大电休克发作试验
通过小鼠最大电休克发作试验，即MES(maximal electroshock seizure test)，评价各化合物是否具有对抗MES的作用，对各化合物是否具有治疗癫痫大发作的药效做出初步的评价。通过YSD-4G型药理生理实验多用仪，选用电惊厥模式，使用115V刺激电压、250ms刺激时间、50HZ交流电压的刺激条件进行试验。以正负电极分别夹住生理盐水润湿的小鼠左右双耳，经刺 激后，以后肢强直性是否伸直为癫痫大发作判断标准。小鼠经初筛后随机分组，按照100mg/kg剂量灌胃给药后，观察化合物在给药后0.5h、1.5h、2h是否具有对抗MES的作用。结果见表1。
表1化合物抗癫痫作用
Figure PCTCN2015089471-appb-000043
*：抑制癫痫发作百分率：未发生全身强直性的小鼠数量/试验小鼠的总数量。
化合物对大鼠总胆固醇及甘油三酯的影响研究
雄性SD大鼠，180～200g，40只，随机分为5组，每组8只，连续灌胃给予溶媒对照，托吡酯(40mg/kg)，实施例3化合物20mg/kg、40mg/kg、80mg/kg。给药5周后测试大鼠血清中胆固醇及甘油三酯的水平，结果见表2。结果表明实施例3化合物可以显著降低大鼠的甘油三酯及总胆固醇水平。
表2大鼠血清胆固醇及甘油三酯测试结果
Figure PCTCN2015089471-appb-000044
注：*<0.05；**<0.01
化合物对碳酸酐酶的抑制作用 化合物对碳酸酐酶的抑制活性参考文献(Chem Biol Drug Des 2006；68:113–119)方法进行。人碳酸酐酶Ⅱ(CA-Ⅱ)，HEPES及Tri均购自Sigma。试剂的配制方法
显色缓冲液：HEPES溶于蒸馏水，配制成浓度为10mM溶液，23℃用1M Tris调PH值至7.7；溴百里酚蓝溶于PH 7.7的HEPES缓冲液，浓度为50mg/L；
饱和CO2冰水：将干冰放入冰蒸馏水中制备；
CA-Ⅱ酶溶液：配制成2μg/ml，置于-20℃保存备用。
受试样品：以蒸馏水为溶剂配制不同浓度的溶液。
测试步骤：
Figure PCTCN2015089471-appb-000045
记录各管变为黄色所需时间，空白管记为t0，标准管记为t标，测试管记为t，(t0-t标)/t标则为正常酶活，(t0-t)/t则为受测试化合物影响后的酶活。
测试结果：
实施例3化合物对碳酸酐酶抑制活性的IC50为154μM，托吡酯对碳酸酐酶抑制活性的IC50为0.89μM，唑尼沙胺对碳酸酐酶抑制活性的IC50为14.7μM。实施例3化合物对碳酸酐酶的抑制活显著弱于托吡酯及唑尼沙胺。

Claims (10)

  1. 一种通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体，或其药学上可接受的盐：
    Figure PCTCN2015089471-appb-100001
    X为O、S、NH或CH2，
    Y为N或CH，当X为O或S时，若Q为苯环，则Y不为CH；
    Z为N-R5、O或CHR5，当X为O并且Y为N时，Z不为O或CH2；
    Q环为6～10元芳环，或含1～4个选自N、O、S中的杂原子的5～6元杂环或杂芳环，或者Q环不存在；
    m为0～4的整数；
    n为0至2的整数；
    p为1～2的整数；
    R1各自独立地为氢、氨基、卤素、三氟甲基、羟基、硝基、腈基、巯基、羧基、醛基、氧代(＝O)基团、硫代(＝S)基团、C1～C10烷基、C2～C10烯基、C2～C10炔基、C3～C10环烷基、C1～C10烷氧基、C1～C10烷酰基、C1～C10烷氧羰基、C1～C10烷酰氧基、-NR6R7、-CONR6R7、-OCONR6R7、C1～C10硫烷基、磺酸基、氨基甲酰基、磺酰基、C6～C10芳基、含1～4个选自N、O、S中的杂原子的4～10元杂环基、或含1～4个选自N、O、S中的杂原子的4～10元杂芳基；上述氨基、C1～C10烷氧基、C1～C10烷基、C1～C10烷酰基、C1～C10烷氧羰基、C1～C10烷酰氧基、磺酰基、C6～C10芳基、含1～4个选自N、O、S中的杂原子的4～10元杂环基或含1～4个选自N、O、S中的杂原子的4～10元杂芳基可任选地被一个或多个选自卤素、三氟甲基、羟基、硝基、氨基、腈基、羧基、醛基、C1～C10烷基、C1～C10烷氧基、C1～C10烷酰氧基、C1～C10烷氧羰基、C1～C10烷酰基、磺酰基、C1～C10烷磺酰基、苯基和苯甲基中的取代基取代；
    R2各自独立地为氢、氨基、卤素、三氟甲基、羟基、硝基、腈基、巯基、羧基、醛基、C1～C10烷基、C2～C10烯基、C2～C10炔基、C3～C10环烷基、C1～C10烷氧基、C1～C10烷酰基、C1～C10烷氧羰基、C1～C10烷酰氧基、-NR6R7、-CONR6R7、-OCONR6R7、C1～C10硫烷基、磺酸基、氨基甲酰基、磺酰基、C6～C10芳基、含1～4个选自N、O、S中的杂原子的4～10元杂环基、或含1～4个选自N、O、S中的杂原子的4～10元杂芳基；上述氨基、C1～C10烷氧基、C1～C10烷基、C1～C10烷酰基、C1～C10烷氧羰基、C1～C10烷酰氧基、磺酰基、C6～C10芳基、4～10元杂环基或4～10元杂芳基可任选地被一个或多个选自卤素、三氟甲基、羟基、硝基、氨基、腈基、羧基、醛基、C1～C10烷基、C1～C10烷氧基、C1～C10烷酰氧基、C1～C10烷氧羰基、C1～C10烷酰基、磺酰基、C1～C10烷磺酰基、苯基和苯甲基中的取代基取代；
    R3和R4各自独立地为H、氨基、三氟甲基、羟基、羧基、醛基、氨基、C1～C10烷基、C2～C10烯基、C2～C10炔基、C3～C10环烷基、C1～C10烷氧基、C1～C10烷氧羰基、C1～C10烷酰基、C1～C10烷酰氧基、磺酰基、C6～C10芳基、含1～4个选自N、O、S中的杂原子的4～10元杂环基、或含1～4个选自N、O、S中的杂原子的4～10元杂芳基；上述氨基、C1～C10烷基、C1～C10烷氧基、C1～C10烷氧羰基、C1～C10烷酰基、C1～C10烷酰氧基、磺酰基、C6～C10芳基、含1～4个选自N、O、S中的杂原子的4～10元杂环基或含1～4个选自N、O、S中的杂原子的4～10元杂芳基可任选地被一个或多个选自卤素、三氟甲基、羟基、硝基、氨基、腈基、羧基、醛基、C1～C10烷基、C1～C10烷氧基、C1～C10烷酰氧基、C1～C10烷氧羰基、C1～C10烷酰基、磺酰基、C1～C10烷磺酰基、苯基和苯甲基中的取代基取代；
    或R3与R4与跟其相连的N原子一起形成含1～4个选自N、S、O中的杂原子的4～8元杂环基或形成含1～4个选自N、S、O中的杂原子的4～8元杂芳基；
    R5为H或C1～C10烷基；
    R6和R7各自独立地为H或C1～C10烷基，或R6与R7与其相连的N原子一起形成含1～4个选自N、S、O中的杂原子的4～8元杂环基或形成含1～4个选自N、S、O中的杂原子的4～8元杂芳基。
  2. 根据权利要求1所述的通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体，或其药学上可接受的盐，其中，
    Q环为苯环、含1～2个选自N、O、S中的杂原子的5～6元杂环或杂芳环，或者Q环不存在；
    m为0、1或2；
    n为0或1。
  3. 根据权利要求1所述的通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体，或其药学上可接受的盐，其中，
    所述
    Figure PCTCN2015089471-appb-100002
    环具有如下结构：
    Figure PCTCN2015089471-appb-100003
  4. 根据权利要求1所述的通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体，或其药学上可接受的盐，其中，
    所述通式I所示的氨基磺酰基类化合物具有如下结构IA：
    Figure PCTCN2015089471-appb-100004
    其中，X为O、S或NH；
    Z、m、n、p、R1、R2、R3和R4与权利要求1中的定义相同。
  5. 根据权利要求1所述的通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体，或其药学上可接受的盐，其中，
    Z为O或N-R5；
    m为0、1或2；
    n为0或1；
    p为1；
    R1各自独立地为氢、卤素、三氟甲基、羟基、硝基、腈基、巯基、羧基、醛基、C1～C8烷基、C2～C8烯基、C2～C8炔基、C3～C8环烷基、C1～C8烷氧基、C1～C8烷酰基、C1～C8烷氧羰基、C1～C8烷酰氧基、-NR6R7、-CONR6R7、-OCONR6R7、C1～C8硫烷基、磺酰氨基、氨基甲酰基、磺酰基、C1～C8烷基磺酰基、C6～C10芳基、含1～3个选自N、O、S中的杂原子的4～10元杂环基或4～10元杂芳基；
    R2各自独立地为氢、卤素、三氟甲基、羟基、硝基、腈基、氨基、巯基、羧基、醛基、C1～C8烷基、C2～C8烯基、C2～C8炔基、C3～C8环烷基、C1～C8烷氧基、C1～C8烷酰基、C1～C8烷氧羰基、C1～C8烷酰氧基、-NR6R7、CONR6R7、-OCONR6R7、C1～C8硫烷基、磺酸基、磺酰氨基、氨基甲酰基、磺酰基、C1～C8烷基磺酰基、C6～C10芳基、含1～3个选自N、O、S中的杂原子的4～10元杂环基、或含1～3个选自N、O、S中的杂原子的4～10元杂芳基；
    R3和R4各自独立地为H或C1～C8烷基或5～6元杂芳基；
    或R3与R4与跟其相连的N原子一起形成含1～3个选自N、S、O中的杂原子的5～7元杂环基或形成含1～3个选自N、S、O中的杂原子的5～7元杂芳基；
    R5为H或C1～C3烷基；
    R6和R7各自独立地为H或C1～C8烷基，
    或R6与R7与其相连的N原子一起形成含1～3个选自N、S、O中的杂原子的5～7元杂环基或形成含1～3个选自N、S、O中的杂原子的5～7元杂芳基。
  6. 根据权利要求1所述的通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体，或其药学上可接受的盐，其中，
    X为O、S或NH；
    Y为N或CH，且当X为O或S时，Y不为CH；
    Z为O或N-R5，且当X为O并且Y为N时，Z不为O或CH2；
    Q为苯环；
    m为0、1或2；
    n为0或1；
    p为1；
    R1为H、F、Cl、NO2、NH2、NHCOCH3或甲氧基；
    R2为H或甲基；
    R3和R4各自独立地为H、甲基、乙基或咪唑基；
    R5为H；
    R6和R7各自独立地为H或甲基。
  7. 根据权利要求1所述的通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体，或其药学上可接受的盐，其中，所述通式I所示的氨基磺酰基类化合物为如下化合物：
    N-[(6-氯-苯并异噁唑-3-基)甲基]-氨基磺酰胺；
    N-[(6-氟-苯并异噁唑-3-基)甲基]-氨基磺酰胺；
    N-[(苯并异噁唑-3-基)甲基]-氨基磺酰胺；
    N-[(苯并异噻唑-3-基)甲基]-氨基磺酰胺；
    N-[(苯并异噁唑-3-基)甲基]-N’-甲基-氨基磺酰胺；
    N-[(苯并异噁唑-3-基)甲基]-N’,N’-二甲基-氨基磺酰胺；
    1-(苯并异噻唑-3-基)-甲氧基磺酰胺；
    N-[(6-氟-苯并吡唑-3-基)甲基]-氨基磺酰胺；
    N-[(5-甲氧基-苯并异噁唑-3-基)甲基]-氨基磺酰胺；
    N-[(5-硝基-苯并异噁唑-3-基)甲基]-氨基磺酰胺；
    N-[(5-氯-苯并异噁唑-3-基)甲基]-氨基磺酰胺；
    N-[(噻吩-3-基)甲基]-氨基磺酰胺；
    N-[(噻吩并[3,2-b]噻吩-3-基)甲基]-氨基磺酰胺；或
    N-[(2-氯-噻吩-3-基)甲基]-氨基磺酰胺。
  8. 一种根据权利要求1所述的通式I所示的氨基磺酰基类化合物的制备方法，所述通式I所示的氨基磺酰基类化合物通过如下方法之一制备：
    (1)当Z为NH时
    1)由溴代物II与保护基保护的氨基磺酰胺化合物VI经磺酰化、脱保护、胺化反应制备：
    Figure PCTCN2015089471-appb-100005
    其中，化合物II与化合物VI在碱存在下通过磺酰化反应得到化合物II-1，其中R8为保护基；
    在酸性条件下脱去保护基R8；
    胺化反应由R3-A、R4-A或A-R3-R4-B，与化合物I-1在碱存在的条件下通过胺化反应得到化合物I-2，其中A和B相同或不同，并且分别独立地为Cl、Br或I；
    或者
    2)化合物III与保护基保护的氨基磺酰氯VII经磺酰化、脱保护、胺化反应制备化合物I-2：
    Figure PCTCN2015089471-appb-100006
    其中，化合物III与化合物VII在碱催化下通过磺酰化反应得到化合物III-1，其中R8为保护基；
    化合物III-1在酸催化条件下通过脱保护反应得到化合物I-1；
    卤代烷R3-A、R4-A或A-R3-R4-B，在碱存在条件下与化合物I-1通过胺化反应得到化合物I-2，其中A和B相同或不同，并且分别独立地为Cl、Br或I；
    (2)当Z为O时
    Figure PCTCN2015089471-appb-100007
    化合物IV与化合物VII在碱的存在下通过磺酰化反应得到化合物IV-1，其中R8为保护基；
    或者
    Figure PCTCN2015089471-appb-100008
    在碱存在的条件下，化合物IV与氨基磺酰氯化合物VIII反应直接得到化合物I-3；
    化合物I-3在碱的存在下再通过胺化反应得到化合物I-4；
    (3)当Z为CH2时
    Figure PCTCN2015089471-appb-100009
    化合物V与HNR3R4经胺化反应制备得到化合物I-5；
    (4)当Z为N-R5或CH-R5时，由相应的通式I-2或通式I-5所示的化合物经烷基化反应制备得到，
    其中，X、Y、Q环、m、n、p、R1和R2与权利要求1中的定义相同；R3和R4除不为氢外，与权利要求1中的定义相同；R5为C1～C10烷基。
  9. 一种药物组合物，其包含治疗有效量的选自根据权利要求1至7中任一项所述的通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体，或其药学上可接受的盐中的一种或多种以及药学上可接受的载体。
  10. 根据权利要求1至7中任一项所述的通式I所示的氨基磺酰基类化合物或其互变异构体、对映体、消旋体、或其药学上可接受的盐在制备用于治疗惊厥、癫痫、肥胖的疾病的药物中的用途。
PCT/CN2015/089471 2014-09-12 2015-09-11 一种氨基磺酰基类化合物、其制备方法及用途 WO2016037592A1 (zh)

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US15/509,796 US10093679B2 (en) 2014-09-12 2015-09-11 Amino sulfonyl-based compounds, the preparation method therefor and use thereof

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JP6454413B2 (ja) 2019-01-16
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CN106687449B (zh) 2019-04-09
KR20170067728A (ko) 2017-06-16
US20170298080A1 (en) 2017-10-19
CN105399697A (zh) 2016-03-16
EP3192792A4 (en) 2018-05-30
US10093679B2 (en) 2018-10-09
EP3192792A1 (en) 2017-07-19
JP2017530958A (ja) 2017-10-19

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