CN1533278A - Naphtothiazine positive allosteric AMPA receptor modulators (PAARM) - Google Patents
Naphtothiazine positive allosteric AMPA receptor modulators (PAARM) Download PDFInfo
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- CN1533278A CN1533278A CNA028100832A CN02810083A CN1533278A CN 1533278 A CN1533278 A CN 1533278A CN A028100832 A CNA028100832 A CN A028100832A CN 02810083 A CN02810083 A CN 02810083A CN 1533278 A CN1533278 A CN 1533278A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
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- 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
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- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The present invention relates to new positive allosteric AMPA-receptor modulators of general formula (I), wherein R1, R2, R3, R4 and R5 may have the meanings given in the specification and claims, processes for preparing them and the use thereof as pharmaceutical compositions.
Description
The invention relates to the ampa receptor instrumentality of novel positive allosteric, its preparation method and as the purposes of pharmaceutical composition.
Structurally be similar to the chemical compound according to The compounds of this invention, be described in the Ka Beipeinan with antibacterial activity (carbapenem) derivant among the WO 9967242, wherein naphtho-[1,8-de]-2,3-sodium catchol disulfonate, 1-dioxide-1,2-thiazines are as synthetic composition.
According to chemical compound of the present invention, be the chemical compound of general formula (I),
Wherein
R
1Represent one to be selected from following group: hydrogen, the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl ,-SO
2H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-CO-C
1-C
6-alkyl ,-O, phenyl-C
1-C
4-alkyl ,-C
1-C
4-alkyl-NR
6R
7, and-C
1-C
4-alkyl-O-C
1-C
4-alkyl and C
3-C
6-cycloalkyl,
R
2, R
3Can be identical or different, it represents one to be selected from following group: hydrogen, the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl, halogen ,-NO
2,-SO
2H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-CO-C
1-C
6-alkyl ,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl ,-C
1-C
4-alkyl-NR
6R
7And-C
1-C
4-alkyl-O-C
1-C
4-alkyl and C
3-C
6-cycloalkyl etc., or
R
1And R
2Can represent a C jointly
4-C
6-alkylidene bridge,
R
6, R
7Can be identical or different, represent hydrogen, C
1-C
4-alkyl or-CO-C
1-C
4-alkyl,
R
8, R
9Can be identical or different, represent hydrogen or C
1-C
4-alkyl,
R
4Can be identical or different, representative be selected from a following base: the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl, phenyl-C
1-C
4-alkyl, halogen ,-CN ,-NO
2,-SO
2H ,-SO
3H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-SO
2-NR
6R
7,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl ,-NR
6R
7, and can be randomly by halogen atom ,-NO
2,-SO
2H or C
1-C
4-alkyl list replaces or polysubstituted aromatic radical,
R
5Can be identical or different, representative is selected from a following base: the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl, phenyl-C
1-C
4-alkyl, halogen ,-CN ,-NO
2,-SO
2H ,-SO
3H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-SO
2-NR
6R
7,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl ,-NR
6R
7, and can be randomly by halogen atom ,-NO
2,-SO
2H or C
1-C
4-alkyl list replaces or polysubstituted aromatic radical, and
N, m can be identical or different, and are 0,1,2 or 3,
Its condition is a naphtho-[1,8-de] 2, the 3-sodium catchol disulfonate, in 1-dioxide-1,2-thiazines was not included in, it can randomly be multi-form enantiomer and diastereomer, and on the pharmacology acceptable salt.
Preferred chemical compound is the chemical compound in the general formula (I), wherein R
1Representative is selected from following base: hydrogen, the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl ,-SO
2H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-CO-C
1-C
6-alkyl ,-O ,-C
1-C
4-alkyl-NR
6R
7, and-C
1-C
4-alkyl-O-C
1-C
4-alkyl, benzyl,
R
2, R
3Can be identical or different, and represent one to be selected from following base: hydrogen, the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl, halogen ,-NO
2,-SO
2H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-CO-C
1-C
6-alkyl ,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl ,-C
1-C
4-alkyl-NR
6R
7And-C
1-C
4-alkyl-O-C
1-C
4-alkyl, or
R
1And R
2Can represent a C jointly
4-C
6-alkylidene bridge,
R
6, R
7Can be identical or different, and can represent hydrogen, C
1-C
4-alkyl or-CO-C
1-C
4-alkyl, and
R
4Can be identical or different, and represent one to be selected from following base: the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl, halogen ,-CN ,-NO
2,-SO
2H ,-SO
3H ,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl and-NR
6R
7,
R
5Can be identical or different, and represent one to be selected from following base: the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl, halogen ,-CN ,-NO
2,-SO
2H ,-SO
3H ,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl and-NR
6R
7, and
N, m can be identical or different, and represent 0,1 or 2,
Can be its enantiomer and diastereomer randomly, and on the pharmacology acceptable salt.
The chemical compound of particularly preferred general formula (I), wherein
R
1Represent hydrogen, C
1-C
4-alkyl or benzyl,
R
2, R
3Can be identical or different, and represent hydrogen or C
1-C
4-alkyl, or
R
1And R
2Represent a butylidene bridge jointly, and
R
4Can be identical or different, represent one to be selected from following base: the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl, halogen ,-CN ,-NO
2,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl and-NR
6R
7,
R
5Can be identical or different, represent one to be selected from following base: the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl, halogen ,-CN ,-NO
2,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl and-NR
6R
7, and
N, m can be identical or different, and represent 0,1 or 2,
It can be enantiomer and diastereomer randomly, and on the pharmacology acceptable salt multi-form.
The chemical compound of particularly preferred general formula (I), wherein
R
1, R
2, R
3Can be identical or different, represent hydrogen or C
1-C
4-alkyl,
R
4Can be identical or different, represent one to be selected from following base: the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl, halogen ,-NO
2,-O-CO-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-O-C
1-C
6-alkyl and-NR
6R
7,
R
5Can be identical or different, represent one to be selected from following base: the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl, halogen ,-NO
2,-O-CO-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-O-C
1-C
6-alkyl and-NR
6R
7, and
N, m can be identical or different, expression 0,1 or 2,
It can randomly be its enantiomer and diastereomer, with and on the pharmacology acceptable salt form.
The particularly importantly chemical compound in the general formula (I), wherein R according to the present invention
1Represent methylidene, ethyl, isopropyl, normal-butyl or benzyl,
Can randomly be its enantiomer and diastereomer, with and on the pharmacology acceptable salt multi-form.
The chemical compound of particularly preferred general formula (I), wherein
R
1Represent methylidene,
Can randomly go up the form of acceptable salt for its pharmacology.
Chemical compound in the also particularly preferred general formula (I), wherein
R
1Represent methylidene,
R
2, R
3Represent hydrogen,
R
4, R
5Can be identical or different, can represent halogen, be preferably fluorine, chlorine, bromine, the best then is a fluorine or chlorine, and
N, m can be identical or different, and represent 0,1 or 2, is preferably 0 or 1, can randomly go up acceptable salt for its pharmacology.
Unless otherwise specified, otherwise used alkyl, for having 1 to 6 carbon atom, be preferably the side chain and the straight chained alkyl of 1 to 4 carbon atom, example comprises: methyl, ethyl, propyl group, butyl, amyl group and hexyl, methyl, ethyl, propyl group or butyl also can randomly be represented with abbreviation Me, Et, Pr or Bu.Unless otherwise specified, otherwise definition propyl group, butyl, amyl group and hexyl also comprise its mentioned all possible isomeric forms.Therefore, for example, propyl group is just comprising-propyl group and isopropyl; Butyl comprises isobutyl group, sec-butyl and tert-butyl group or the like.
In abovementioned alkyl, one or more hydrogen atoms can randomly be replaced by halogen atoms such as fluorine, chlorine, bromine or iodines, and preferred substituents is fluorine and chlorine, substituent group fluorine the best.As needs, all hydrogen atoms in the alkyl can be substituted.
At phenyl-C
1-C
4Mentioned alkyl in the-alkyl can be side chain or linear form, and unless otherwise specified, benzyl and phenethyl are preferred phenyl-C
1-C
4-alkyl group, the benzyl spy is good.
-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-CO-C
1-C
6-alkyl ,-CO-C
1-C
4-alkyl ,-C
1-C
4-alkyl-NR
6R
7,-C
1-C
4-alkyl-O-C
1-C
4-alkyl ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl or-O-CO-O-C
1-C
4The alkyl of being mentioned in-the alkyl can be side chain or the straight chain with 1 to 6 carbon atom, and is preferred with 1 to 4 carbon atom, and 1 to 3 carbon atom is preferable, is preferably 1 to 2 carbon atom.
Unless otherwise specified, otherwise C
4-C
6-alkylidene bridge can be to have the side chain of 4 to 6 carbon atoms and an alkylidene group of straight chain, for example n-butylidene, 1-methyl propylidene, 2-methyl propylidene, 1, and 1-dimethyl ethylidene, 1,2-dimethyl ethylidene or the like, n-butylidene bridge are special good.Aromatic radical is an aromatic rings with 6 to 10 carbon atoms, is preferably phenyl.
In above-mentioned aromatic radical, one or more hydrogen atoms can be randomly by halogen atom ,-NO
2,-SO
2H or-C
1-C
4-alkyl replaces, be preferably fluorine, chlorine ,-NO
2, ethyl or methyl, bestly replaced by fluorine or methyl.
C
3-C
6The representative of-cycloalkyl has the saturated cyclic hydrocarbons carbon back of 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl.
Unless otherwise specified, halogen is meant fluorine, chlorine, bromine and iodine, is preferably fluorine, chlorine and bromine, is preferably fluorine and chlorine, and the best is a fluorine.
As described, the chemical compound of general formula (I) or its different enantiomer and diastereomer can change into its esters, particularly use on medicine, transform on the physiology and the pharmaceutically acceptable salt class.These salts be on the one hand the chemical compound of formula (I) and mineral acid or organic acid be formed on that the physiology goes up and materia medica on the form of acceptable acid-addition salts; On the other hand, R wherein
1Be chemical compound in the formula (I) of hydrogen, can by with the inorganic base reaction, and change on the physiology and pharmaceutically acceptable salt and with alkali metal or alkaline earth metal cation as counter ion counterionsl gegenions.These acid-addition salts classes can be for example, uses hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, pyrovinic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid and be prepared, and also can use the mixture of above-mentioned acid.Preparing wherein R
1When representing the alkali metal of formula (I) chemical compound of hydrogen and alkali salt, preferred hydroxide and the hydride that uses alkalies and alkaline earth, alkali-metal hydroxide and hydride, especially preferably sodium and potassium, and sodium hydroxide and potassium hydroxide are special good.
According to chemical compound of the present invention, can be prepared with known method itself, following general synthetic method 1 and 2 is shown in following diagram 1 and 2, is not to be subjected to its content constraints and method of the present invention is described.
Method 1
Diagram 1
Chemical compound by formula (II) begins, and by chlorination again after the sulfonation, the chemical compound of preparation formula (III) and obtains formula (IV) chemical compound after the derivant condensation of glycine, and adds the phosphoric acid cyclisation and obtain purpose chemical compound (I).
General preparation method according to chemical compound of the present invention is described in detail in following with diagram 1.
The sulfonation of naphthalene (II):
Get in 2 to 100 milliliters of the naphthalene derivativeses of about 10 mMs, be preferably 3 to 80 milliliters, in best about 4 milliliters acetic anhydride, and at 0 to 50 ℃, preferably at 5 to 20 ℃, under special good about 18 ℃, add 10 to 100 mMs, preferred 11 to 80 mMs, the concentrated sulphuric acid of special good 11 mMs, under 20 to 100 ℃, under preferred about 25 ℃, stir after 2 to 16 hours, preferred after about 5 hours, mixture is injected saturated NaCl solution, separate formed crystallization.
Acetic anhydride can be used dichloromethane, diisopropyl ether, ethyl acetate, chloroform, toluene, benzene or 1, the 4-dioxin substitutes, and can use oleum, sulfur trioxide, sulphuric acid chlorine (chlorine sulphate) or its compositions substitute as concentrated sulphuric acid simultaneously.
Naphthalene-1-sulfonic acid muriatic synthetic (III):
Naphthalene-1-sulfonic acid with about 10 mMs, with 10 to 500 mMs, the phosphorus oxychloride of preferred good about 90 mMs, and 8 to 50 mM, the chloritization phosphorus of preferred about 10 mMs, merge in succession, and under 20 to 100 ℃, preferably under refluxing, heated 2 to 16 hours, preferred about 5 hours, make up with the reactant mixture evaporation and with water then, after the organic diluent extraction, the dry organic extract that merges, and from solvent, deviate from, the raw product of gained can not purify, and is used for the step subsequently.
Can use the mixture or the light chloro of thionyl chloride, phosphorus pentachloride, phosphoric acid/chlorine to replace phosphorus oxychloride/phosphorus pentachloride mixture.Reaction also can be carried out in N-two-methyl ester acetamide, sulfolane, DMF, hexane or the dichloroethanes at diluent acetic acid ethyl ester, water, acetonitrile, N.
Synthesizing of naphthalene-1-sulfonyl-glycine:
With the chlorine sulfonyl-naphthalene of about 10 mMs, 10 to 100 mMs are preferably 11 to 30 mMs, the glycine of best about 12 mMs, and 10 to 100 mMs, preferred 11 to 30 mMs, the sodium hydroxide of best about 12 mMs, be dissolved in water and the toluene, at 0 to 110 ℃, preferred about 65 ℃ were stirred 2 to 16 hours down with reactant mixture, be separated then, with liquid phase acidify and extraction, the organic extract that merges is carried out drying and evaporation, can chromatography carry out purification.
Can use triethylamine, potassium carbonate, sodium bicarbonate or sodium hydride to replace sodium hydroxide, and can use oxolane, diethyl ether, dichloromethane, chloroform, dioxin, acetone, benzene, ethanol, methanol, ethyl acetate or acetonitrile, to replace toluene.
The cyclisation (IV) of naphthalene-1-sulphonyl-glycine
Naphthalene-1-sulphonyl-glycine with about 10 mMs, with 10 to 200 grams, the polyphosphoric acid of preferred about 40 grams combines, and at 20 to 110 ℃, preferably at 75 to 95 ℃, under best about 80 ℃, stirred 2 to 16 hours, and preferred about 5 hours, then reactant mixture was injected water and extraction, the organic extract that merges is carried out drying and evaporation, residue is carried out purification.
Method 2
Diagram 2
Formula (III) chemical compound that will obtain as the intermediate product of method 1 obtains the formula V chemical compound with primary amine reaction, add formula R then in the presence of strong acid
2R
3The chemical compound of C=O carries out cyclisation, and obtains purpose chemical compound (I).
In order to prepare wherein R
1And R
2Represent hydrogen formula (I) chemical compound, can use paraformaldehyde, trioxane or formalin, and can use methanesulfonic acid, trifluoroacetic acid, sulphuric acid, phosphoric acid or polyphosphoric acid as strong acid.
According to the general preparation method of The compounds of this invention, consult diagram 2 and be described in detail in down.
Synthetic (V) of naphthalene-sulfonamide:
With the chlorine sulphonyl-naphthalene (III) of about 10 mMs and the alcoholic solution of primary amine (in 5 to 200 milliliters of 10 to 1000 mMs, for example, 200 mMs are in 50 milliliters ethanol) merge, be heated to then 0 to 100 ℃ 2 to 16 hours, preferred about 5 hours, preferably reflux, then with reactant mixture evaporation and carry out purification.
Also can use toluene, benzene, chloroform, dichloromethane, Anaesthetie Ether, oxolane, water, acetonitrile, acetic anhydride, acetone, pyridine, dimethyl sulfoxide, dimethyl formamide, dioxin or hexane with the instead of ethanol solvent.
Cyclisation naphthalene-1-sulfonamide (V) is to form purpose chemical compound (I):
Naphthalene-1-the sulfonamide of about 10 mMs is joined 0 to 100 milliliter, preferred 20 to 80 milliliters, in best about 40 milliliters pyrovinic acid, and with 3 to 50 mMs, be preferably 4 to 30 mMs, the trioxane of best 5 mMs is at 0 to 100 milliliter, and the solution in preferred about 12 milliliters trifluoroacetic acid merges mutually.Reactant mixture is at 20 to 100 ℃, preferably at 30 to 80 ℃, bestly under 35 ℃, stirred 2 to 16 hours, and preferred 5 hours, inject frozen water then, the organic extract that merges is extracted also after the drying again with solution evaporation, raw product is carried out purification.
Can use paraformaldehyde or Formalin Qu Dai trioxane; And can use trifluoro diethyl ether boron, acetic acid, polyphosphoric acid, phosphoric acid or sulphuric acid to replace trifluoroacetic acid; Acetic anhydride or dichloromethane can be used as diluent.
The compounds of general formula (I) can synthesize to be similar to following synthetic embodiment, in any case these embodiment with explanation the present invention, do not limit its main method as just the method example.
2-methyl-2,3-dihydro-naphtho-[1,8-de] [1,3] thiazine-1, synthetic (embodiment 1) of 1-dioxide:
N-methyl isophthalic acid-LOMAR PWA EINECS 246-676-2 amide with 2.21 grams, under 35 ℃, be dissolved in 25 milliliters the pyrovinic acid, and merge with the solution of 0.30 gram De trioxane in 8 milliliters trifluoroacetic acid, after at room temperature stirring 2 hours, reactant mixture flow in 300 milliliters the frozen water, solid is told by filtering, with 100 milliliters water washings and dried overnight, from hexahydrotoluene, isolate white solid product after the crystallization, output: 2.20 grams, fusing point: 136 ℃.
6-chloro-2-methyl-2,3-dihydro-naphtho-[1,8-de] [1,3] thiazine-1, the synthetic (embodiment of 1-dioxide
2):
5-chloro-naphthalene-1-sulfonic acid-N-Methanamide with 0.45 gram, under 35 ℃, be dissolved in 6.8 milliliters the pyrovinic acid, and merge with the solution of 0.07 Ke trioxane in 2 milliliters of trifluoroacetic acids, after stirring 2 hours under 35 ℃, reactant mixture is injected 100 milliliters frozen water, and with the ethyl acetate extraction water, the organic extract of collecting is with dried over sodium sulfate, vaporising under vacuum carries out purification with chromatographic analysis then, output: 0.41 gram, fusing point: 150 ℃.
2,3-dihydro-naphtho-[1,8-de] [1,3] thiazine-1, synthetic (embodiment 3) of 1-dioxide:
Naphthalene-1-sulfonic acid t-butyl carboxamide:
8 milliliters tert-butylamine inserted in 50 milliliters the chloroform, be cooled to 0 ℃, and dropwise be added in the 1-naphthoic acid chloride of 5.75 in 45 milliliters of chloroforms grams, then mixture was at room temperature stirred 24 hours, after distillation concentrates under vacuum, the residue of gained is dissolved in the dichloromethane, and with 2N salt acid elution, with the organic extract collected with dried over sodium sulfate, vaporising under vacuum, output: 5.48 grams.2-tert-butyl-1,1-dioxo-1,2-dihydro-1 λ
6-naphtho-[1,8-de] [1,3] thiazine-3-ketone:
Naphthalene-1-sulfonic acid the tert-butylamides of 4.36 grams are inserted in 80 milliliters the oxolane, be cooled to-10 ℃, and drip 29 milliliters N-butyl lithium (1.6 moles of solution in hexane) carefully, mixture at first stirred 0.5 hour down at-10 ℃, at room temperature 3 hours then, be cooled to-5 ℃ then, and in 0.25 hour, import CO by the dry ice gained
2Reactant mixture at room temperature stir 2.5 hours then with hydration also.Solution injected 4N hydrochloric acid and, the organic extract of collecting is carried out drying with sodium sulfate, and carry out purification with chromatography behind the vaporising under vacuum, output: 0.42 gram with ethyl acetate extraction.2-tert-butyl-2,3-dihydro-naphtho-[1,8-de] [1,3] thiazine-1, the 1-dioxide:
With the 2-tert-butyl-1 of 0.17 gram, 1-dioxo-1,2-dihydro-1 λ
6-naphtho-[1,8-de] [1,3] thiazine-3-ketone at room temperature is suspended in 2 milliliters the oxolane, borine-oxolane the complex (1 molar solution) that adds 1.17 milliliters, then mixture is stirred down and refluxed 100 hours, 1M borine-oxolane the complex solution that with total amount is 8.2 milliliters again divides adding for several times, the 2N hydrochloric acid of reactant mixture and 2 milliliters and 2 ml methanol merge, stir then down and refluxed 12 hours, add 2 milliliters of ammonia and leach any crystal, with ethyl acetate extraction filtrate, with the organic extract collected with dried over sodium sulfate, behind the vaporising under vacuum, the residue that obtains carries out purification with chromatography, output: 0.06 gram.
2,3-dihydro-naphtho-[1,8-de] [1,3] thiazine-1, the 1-dioxide:
2-tert-butyl-2 with 0.06 gram, 3-dihydro-naphtho-[1,8-de] [1,3] thiazine-1, the 1-dioxide is dissolved in 1 milliliter the dichloromethane, and add 0.02 milliliter trifluoroacetic acid, under reflux temperature, mixture is stirred 22 hours altogether then, and at room temperature stirred 96 hours, 0.07 milliliter trifluoroacetic acid adding altogether during this period simultaneously, with the reactant mixture vaporising under vacuum and with the chromatography purification, output: 0.034 gram, fusing point: 206-207 ℃.
[2-(1,1-dioxo-1H-3H-1 λ
6
-naphtho-[1,8-de] thiazine-2-yl) ethyl] (implement synthesizing of dimethylamine
Example 4):
The sodium hydride of 0.028 gram is suspended in 0.5 milliliter the dimethyl formamide, and add 0.073 the gram 2,3-dihydro-naphtho-[1,8-de] [1,3] thiazine-1, the solution of 1-dioxide in 1 milliliter dimethyl formamide adds the 0.053 diethylamino ethyl chloride hydrogen chloride that restrains then in batches.Reactant mixture at room temperature stirs and injected frozen water in 18 hours then, and mixture is with dichloromethane extraction, and with the organic extract of collecting, with dried over sodium sulfate, the residue that obtains behind the vaporising under vacuum is with the chromatography purification, and output: 0.035 restrains fusing point: 97-98 ℃.
N-(2-methyl isophthalic acid, 1-dioxo-2,3-dihydro-1H-1 λ
6
-naphtho-[1,8-de] [1,3] thiazine-6-yl)-acetamide
Synthetic (embodiment 5):
5-acetylaminohydroxyphenylarsonic acid naphthalene-1-sulfonic acid chloride:
The 5-acetylaminohydroxyphenylarsonic acid naphthalene-1-sulfonic acid of 1.40 grams is merged mutually with the phosphorus pentachloride of 2.23 grams, and stirred 4 hours down at 60 ℃, then solution is injected frozen water and with dichloromethane extraction, with the organic extract collected with dried over sodium sulfate, and vaporising under vacuum, output: 1.10 grams.
N-(5-methyl sulfonamides-naphthalene-1-yl)-acetamide:
The 5-acetylaminohydroxyphenylarsonic acid naphthalene-1-sulfonic acid chlorides of 1.10 grams are dissolved in 8 milliliters the ethanol, and drip 8 milliliters the solution of methylamine in ethanol, then the gained mixture was stirred 3.5 hours under reflux temperature, and under vacuum, distill solvent, residue is with the chromatography purification, and output: 0.50 restrains.
N-(2-methyl isophthalic acid, 1-dioxo-2,3-dihydro-1H-1 λ
6-naphtho-[1,8-de] [1,3] thiazine-6-yl)-acetamide:
N-(5-methyl sulfonamides-naphthalene-1-the yl)-acetamide of 0.25 gram is dissolved under 35 ℃ in 3.4 milliliters the pyrovinic acid, and merge mutually with the 0.027 gram solution of trioxane in 1 milliliter of trifluoroacetic acid, after stirring 6 hours under 35 ℃, reactant mixture injected frozen water and with the ethyl acetate extraction water, with the organic extract collected with dried over sodium sulfate, vaporising under vacuum and with the chromatography purification, output: 0.136 gram, fusing point: 189-190 ℃.
2-(1,1-dioxo-1H, 3H-1 λ
6
-naphtho-[1,8-de] [1,3] thiazine-2-yl)-(implement synthesizing of acetamide
Example 6):
8-tert-butyl sulfonamides-naphthalene-1-carboxylic acid:
Naphthalene-1-sulfonic acid the t-butyl carboxamide of 4.36 grams is inserted in 80 milliliters of oxolanes, be cooled to-10 ℃, and drip 29 milliliters N-butyl lithium (1.6 moles hexane solutions) carefully, mixture at first stirred 0.5 hour down at-10 ℃, at room temperature 3 hours then, be cooled to-5 ℃ then, and in 0.25 hour, import CO by the dry ice gained
2, reactant mixture stirring at room 2.5 hours and with hydration also, solution injects 4N hydrochloric acid and with ethyl acetate extraction, with the organic extract collected with dried over sodium sulfate, and behind the vaporising under vacuum with the chromatography purification, output: 1.19 grams.
1,1-dioxo-1,1-dihydro-1 λ
6-naphtho-[1,8-de] [1,3] thiazine-3-ketone:
Get the polyphosphoric acid of 0.25 gram and add 0.15 gram 8-tert-butyl sulfonamides-naphthalene-1-carboxylic acid, mixture stirred 4 hours down at 150 ℃, then reactant mixture is injected frozen water and with the ethyl acetate extraction water, with the organic extract collected with dried over sodium sulfate, and vaporising under vacuum, output: 0.07 gram.2,3-dihydro-naphtho-[1,8-de] [1,3] thiazine-1, the 1-dioxide:
With 1 of 0.07 gram, 1-dioxo-1,1-dihydro-1 λ
6-naphtho-[1,8-de] [1,3] thiazine-3-ketone is dissolved in 2 milliliters the oxolane, the 1 mole of borine-oxolane complex that dropwise adds 1.2 milliliters then carefully, mixture stirred 18 hours under reflux temperature, reactant mixture merges mutually with 1.5 milliliters of 2N hydrochloric acid and 2 ml methanol, under reflux temperature, stirred 2 hours then, add 2 milliliters of ammonia, and filter the crystal of any formation, with ethyl acetate extraction filtrate, with the organic extract collected with dried over sodium sulfate, behind the vaporising under vacuum, output: 0.06 gram.
2-(1,1-dioxo-1H, 3H-1 λ
6-naphtho-[1,8-de] [1,3] thiazine-2-yl)-acetamide:
The sodium hydride of 0.011 gram is suspended in 0.5 milliliter the dimethyl formamide, and add 0.06 the gram 2,3-dihydro-naphtho-[1,8-de] [1,3] thiazine-1, the solution of 1-dioxide in 1 milliliter of dimethyl formamide, mixture at room temperature stirs the 2-acetbromamide that in batches added 0.042 gram in 1 hour then, mixture at room temperature stirred 18 hours then, reactant mixture was injected frozen water and with dichloromethane extraction, with the organic extract of collecting, with dried over sodium sulfate, and behind the vaporising under vacuum with the chromatography purification, output: 0.043 the gram, fusing point: 195-196 ℃.
7-hydroxy-2-methyl-2,3-dihydro-naphtho-[1,8-de] [1,3] thiazine-1, the synthetic (embodiment of 1-dioxide
7):
With 0.6 gram 7-methoxyl group-2-methyl-2,3-dihydro-naphtho-[1,8-de] [1,3] thiazine-1, the 1-dioxide is dissolved in 23 milliliters the dichloride methane, and solution is cooled to-78 ℃, drip 2.3 milliliters of Boron tribromides (1 mole of solution in dichloride methane), then mixture at room temperature stirred 24 hours, vaporising under vacuum and with residue with the chromatography purification, output: 0.36 gram, fusing point: 245-246 ℃.
The 2-methyl isophthalic acid, 1-dioxo-2,3-dihydro-1H-1 λ
6
-naphtho-[1,8-de] [1,3] thiazine-7-yl carboxylic acid methyl ester
Synthetic (embodiment 8):
With the 7-hydroxy-2-methyl-2 of 0.11 gram, 3-dihydro-naphtho-[1,8-de] [1,3] thiazine-1, the triethylamine of 1-dioxide and 0.061 milliliter places 2 milliliters of toluene and is cooled to 0 ℃, drips 0.037 milliliter methylchloroformate, then mixture is at room temperature stirred 5 hours, then suspension is injected frozen water and with ethyl acetate extraction, with the organic extract of collecting, with dried over sodium sulfate, behind the vaporising under vacuum with the chromatography purification, output: 0.065 gram, fusing point: 161-162 ℃.
Particularly be similar to said procedure and obtain chemical compound with following formula IA.
Table 1
Embodiment R
1R
2R
3R
4R
5R
6Fusing point [℃]
9???????????CH
3????????H??????????H????????H????????H???????Br???????226-227
10??????????CH
3????????NO
2???????H????????H????????H???????H????????264-265
11??????????CH
3????????H??????????H????????OCH
3????H???????H????????174-175
12??????????CH
3????????H??????????H????????F????????H???????H????????129-130
13??????????CH
3????????H??????????H????????Br???????H???????H????????163-164
14??????????CH
3????????H??????????H????????CH
3?????H???????H????????142-143
15??????????CH
3????????H??????????H????????I????????H???????H????????192-193
16??????????CH
3????????H??????????I????????H????????H???????H????????160-161
17??????????CH
3????????H??????????NO
2?????H????????H???????H????????169-170
18??????????CH
3????????H??????????OH???????H????????H???????H????????160-161
19??????????CH
3????????N(CH
3)
2??H????????H????????H???????H
20??????????CH
3????????H??????????H????????H????????H???????N(CH
3)
2
21??????????CH
3????????i-Pr???????H????????H????????iso-Pr??H
22??????????CH
3????????H??????????OCOMe????H????????H???????H
23??????????CH
3????????H??????????F????????H????????H???????H
The chemical compound of having found general formula (I) has widely used characteristic on the treatment field, will should be mentioned that especially, in these are used, plays the positive control of ampa receptor.
According to the effect of The compounds of this invention as the ampa receptor regulator, can on cell, record with electrophysiology by performance ampa receptor function, the research of carrying out is whether to look test substances to inducing the agonist electric current that positive allosteric influence is arranged.
Test is to carry out under the concentration between 0.3 micromole and 300 micromoles.
Table 2: the reinforcement (+active good, ++ active splendid) of inducing the agonist electric current
| Embodiment | Active |
| ????1 | ????+ |
| ????2 | ????++ |
This compounds also can be used for treating wherein the nerve network, and impaired or its function limitation needs under the disease condition of ampa receptor because of function.
Therefore the chemical compound of general formula (I) can be used in dementia, neurodegenerative or psychotic disorder, and is used for the brain locality ischemia of nerve degeneration disorder and Different Origin, preferably is used for schizophrenia or learning and memory disorder.
In below being also included within: epilepsy, hypoglycemia, anoxia, anoxia, big brain trauma, cerebral edema, amyotrophic lateral sclerosis, prosperous front yard Dun Shi disease, senile dementia, sexual dysfunction, the disorder of sensation/motor function, memory constitutes, hyperkinesis (particularly child), hypotension, heart defect, cerebral (intracranial pressure increase), ischemic and hemorrhagic apoplexy, the globality cerebral ischemia of cardiac block, acute and chronic neuralgia, diabetic polyneural disease, tinnitus, suffocate term, psychosis, Parkinson's disease and melancholia, and relevant anxiety neurosis.
This compounds also can be combined with other active substances that are used in identical indication, or for example class psychosis, cerebral metabolism, psychoanaleptics or the like, they can be topical, oral, percutaneous dosing, nose administration, parenteral or inhalation, in addition, the compound or its salt class of general formula (I) also can be combined with the active substance of other kinds.
The chemical compound of general formula (I) can be individually dosed or combined with other active substances of the thing according to the present invention, also can be combined with other active substances on the pharmacology, appropriate formulations comprises, for example particular solution of tablet, capsule, suppository, solution, injection (subcutaneous injection, intravenous injection, intramuscular injection) and infusion solution, elixir, Emulsion or diffusing shape powder.The content range of the active substance on the pharmacology (s) must account for total composition 0.1 to 90wt.-% between, excellent is between 0.5 to 50wt.-%, that is, its total amount must be enough to reach the measuring range of following explanation.Suitable tablet can by, for example active substance (s) is mixed mutually with known adjuvant and obtains, adjuvant is the inert diluent of calcium carbonate, calcium sulfate or lactose for example; Disintegrating agent such as beautiful another name for Sichuan Province starch or alginic acid; Binding agent such as starch or gelatin; Such as magnesium stearate or steatitic lubricant and/or the preparation in order to postpone to discharge, as methylcellulose, phthalic acid ester acid, cellulose or polyethylene acetate, tablet also can include multilamellar.
Coated tablet can use the material that generally is used for the tablet coating by the core that will be similar to preparation tablets, for example can found fourth or Lac, arabic gum, Pulvis Talci, titanium dioxide or steamed bun stuffed with sugar covers and prepares, reach postpone to discharge or prevent incompatibility then core can coat multilamellar, similarly, the coating of tablet can comprise multilamellar and postpone to discharge the auxiliary agent that can use above-mentioned tablet to use to reach.
The syrup or the elixir that contain active substance or compositions of the present invention can contain sweeting agent and flavour enhancer just like glucide, cyclamate, glycerol or sugar in addition; The for example vanillin or the flavoring agent of orange extract.They also can comprise suspension aids or such as the thickening agent of sodium carboxymethyl cellulose; Wetting agent such as the condensation product of fatty acid and oxirane; Or as the antiseptic of right-hydroxy benzoate.
Injection solution and transfusion prepare in a general way with solution, for example add isotonic agent, as the antiseptic of p-hydroxy benzoate or as the stabilizing agent of the alkali metal group salt of ethylenediaminetetraacetic acid, also can select to use emulsifying agent and/or dispersant, when making water as dilution, for example organic solvent also can randomly be used as solvate or dissolving helps thing, and is transferred to injection vials or ampoule or injection bottle.
Comprise one or more active substances or the capsule of the compositions of active substance, can be by mixed active material for example with such as the inert carrier of lactose or Sorbitol, and it is packaged in the gelatine capsule and prepares.
The suppository that is fit to then can be for example by with the carrier that is used for this purpose, mix and make as neutral fat or Polyethylene Glycol or derivatives thereof, operable adjuvant comprises, for example, water, the last acceptable organic solvent of pharmacology is as paraffin (for example petroleum distillate), vegetable oil (for example Oleum Arachidis hypogaeae semen or Oleum sesami), unit alcohol or polyhydric alcohol (as ethanol or glycerol), natural mineral powder (Kaolin for example for example, clay, Pulvis Talci, Chalk) carrier, synthetic mineral powder (for example silicic acid of polymolecularity and silicate), sugar (sucrose for example, lactose and glucose), emulsifying agent (lignin for example, useless sulfurous acid saline solution, methylcellulose, starch and polyethylene pyrrole alkane ketone) and lubricant (magnesium stearate for example, Talcum, stearic acid and sodium laurylsulfate).
Preparation can pass through the general fashion administration, is preferably oral or the percutaneous approach, and special good is oral.Tablet for oral use certainly can contain the additive just like sodium citrate, calcium carbonate and dicalcium phosphate except above-mentioned carrier, and with different additive such as starch, be preferably mealy potato, gelatin and analog thereof together.In addition, in film-making agent operation, can use simultaneously as magnesium stearate, sodium laurylsulfate and steatitic lubricant, if be under the situation of watery suspending agent, then except above-mentioned auxiliary agent active substance also can with different flavour enhancer or dye combinations.
Through the gastrointestinal approach, then can use the solution of active substance for non-with suitable liquid carrier.
The dosage that vein is used, is preferably per hour between 5 and 500 milligrams by 1 to 1000 milligram for per hour.
In any case, sometimes must be according to body weight, route of administration, individual time or at interval during to the characteristic of the reaction of medicine, preparation and administration, and depart from specified dose, therefore, in some cases, it is just enough that use is lower than the above minimum dose of giving, yet in the next necessary on the contrary upper limit that surpasses of other situations.When a large amount of administration, dose can be divided into for several times less dosage and be distributed in one day comparatively suitable.
Following example of formulations is explanation the present invention, and does not limit its scope.
The embodiment of pharmaceutical preparation
A)
Tablet Every content
100 milligrams of active substances
140 milligrams of lactose
240 milligrams of corn starchs
15 milligrams of polyvinylpyrrolidones
Magnesium stearate
5 milligrams
500 milligrams
The active substance of fine grinding is mixed mutually with lactose and some corn starchs, mixture is sieved, with polyvinylpyrrolidonesolution solution moistening soluble in water, knead then, make become to wet granular and dry, with sieve back and mixing of coarse grain, remaining corn starch and magnesium stearate.Mixture is suppressed to produce the tablet of suitable profile and size.
B)
Tablet Every content
80 milligrams of active substances
55 milligrams of lactose
190 milligrams of corn starchs
35 milligrams of microcrystalline Cellulose
15 milligrams of polyvinylpyrrolidones
23 milligrams of sodium carboxymethyl starch
Magnesium stearate
2 milligrams
400 milligrams
Active substance, some corn starchs, lactose, microcrystalline Cellulose and the polyvinylpyrrolidone of fine grinding are mixed, mixture sieved and handle with remaining corn starch and water, make it to form granular, and it is dry and sieve, add sodium carboxymethyl starch and magnesium stearate and mixing, mixture is suppressed to form the tablet of suitable size.
C)
Ampoule solution
50 milligrams of active substances
50 milligrams in sodium chloride
5 milliliters of waters for injection
Active substance is dissolved in self pH value, or choose wantonly in the water under pH value 5.5 to 6.5, and adding sodium chloride makes it etc. to ooze, with gained solution elimination depyrogenation, and under aseptic condition, filtrate is transferred in the ampoule, sterilize then and merge sealing, ampoule contains the active substance of 5 milligrams, 25 milligrams and 50 milligrams.
Claims (16)
1. the chemical compound of a general formula (I),
Wherein
R
1Represent one to be selected from following group: hydrogen, can be randomly by the alternate C of one or more halogen atoms
1-C
6-alkyl ,-SO
2H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-CO-C
1-C
6-alkyl ,-O, phenyl-C
1-C
4-alkyl ,-C
1-C
4-alkyl-NR
6R
7With-C
1-C
4-alkyl-O-C
1-C
4-alkyl, and C
3-C
6-cycloalkyl,
R
2, R
3Can be identical or different, represent one to be selected from following base: hydrogen, can be randomly by the alternate C of one or more halogen atoms
1-C
6-alkyl, halogen ,-NO
2,-SO
2H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-CO-C
1-C
6-alkyl ,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl ,-C
1-C
4-alkyl-NR
6R
7With-C
1-C
4-alkyl-O-C
1-C
4-alkyl, and C
3-C
6-cycloalkyl, or
R
1And R
2Can represent a C jointly
4-C
6-alkylidene bridge,
R
6, R
7Can be identical or different, represent hydrogen, C
1-C
4-alkyl or-CO-C
1-C
4-alkyl, R
4Can be identical or different, represent one to be selected from following base: the C that can randomly replace by one or more halogen atoms
1-C
6-alkyl, phenyl-C
1-C
4-alkyl, halogen ,-CN ,-NO
2,-SO
2H ,-SO
3H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-SO
2-NR
6R
7,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl ,-NR
6R
7, and can be randomly by halogen atom ,-NO
2,-SO
2H or C
1-C
4-alkyl list or polysubstituted aryl,
R
5Can be identical or different, representative is selected from a following base: randomly can be by the C of one or more halogen atoms replacements
1-C
6-alkyl, phenyl-C
1-C
4-alkyl, halogen ,-CN ,-NO
2,-SO
2H ,-SO
3H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-SO
2-NR
6R
7,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl ,-NR
6R
7In, and can be randomly by halogen atom ,-NO
2,-SO
2H or C
1-C
4-alkyl etc. are made monomer or polysubstituted aryl, and
N, m can be identical or different, and can represent 0,1,2 or 3,
Its condition is except naphtho-[1,8-de]-2,3-dihydro-1, and 1-dioxo-1,2-thiazines,
Also can be the enantiomer and the diastereomer of its different types, and on the pharmacology acceptable salt.
2. according to the chemical compound of the general formula (I) of claim 1, wherein
R
1Representative is selected from a following base: the C that can randomly be replaced by one or more halogen atoms
1-C
6-alkyl ,-SO
2H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-CO-C
1-C
6-alkyl ,-O ,-C
1-C
4-alkyl-NR
6R
7, and-C
1-C
4-alkyl-O-C
1-C
4-alkyl, benzyl,
R
2, R
3Can be identical or different, it represents one to be selected from following group: hydrogen, randomly can be by the C of one or more halogen atoms replacements
1-C
6-alkyl, halogen ,-NO
2,-SO
2H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-CO-C
1-C
6-alkyl ,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl ,-C
1-C
4-alkyl-NR
6R
7And-C
1-C
4-alkyl-O-C
1-C
4-alkyl, or
R
1And R
2Can represent a C jointly
4-C
6-alkylidene bridge,
R
6, R
7Can be identical or different, can represent hydrogen, C
1-C
4-alkyl or-CO-C
1-C
4-alkyl, and
R
4Can be identical or different, represent one to be selected from following group: the C that can randomly replace by one or more halogen atoms
1-C
6-alkyl, halogen ,-CN ,-NO
2,-SO
2H ,-SO
3H ,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl and-NR
6R
7, R
5Can be identical or different, represent one to be selected from following base: the C that can randomly replace by one or more halogen atoms
1-C
6-alkyl, halogen ,-CN ,-NO
2,-SO
2H ,-SO
3H ,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl, and-NR
6R
7, and
N, m can be identical or different, expression 0,1 or 2,
Randomly can be the enantiomer and the diastereomer of different types, and in the pharmaceutically acceptable salt class.
3. according to the chemical compound of the general formula (I) of claim 1 or 2, wherein
R
1Represent hydrogen, C
1-C
4-alkyl or benzyl,
R
2, R
3Can be identical or different, and represent hydrogen or C
1-C
4-alkyl, or
R
1And R
2Represent a butylidene bridge jointly, and
R
4Can be identical or different, represent one to be selected from a following base: the C that can randomly replace by one or more halogen atoms
1-C
6-alkyl, halogen ,-CN ,-NO
2,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl and-NR
6R
7,
R
5Can be identical or different, represent one to be selected from following base: the C that can randomly replace by one or more halogen atoms
1-C
6-alkyl, halogen ,-CN ,-NO
2,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl and-NR
6R
7, and
N, m can be identical or different, and represent 0,1 or 2,
Randomly can be the enantiomer and the diastereomer of different types, and in the pharmaceutically acceptable salt class.
4. according to the chemical compound of the general formula (I) of claim 1 to 3, wherein
R
1, R
2, R
3Can be identical or different, and represent hydrogen or C
1-C
4-alkyl,
R
4Can be identical or different, represent one to be selected from following base: the C that can randomly replace by one or more halogen atoms
1-C
6-alkyl, halogen ,-NO
2,-O-CO-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-O-C
1-C
6-alkyl, and-NR
6R
7,
R
5Can be identical or different, represent one to be selected from following base: the C that can randomly replace by one or more halogen atoms
1-C
6-alkyl, halogen ,-NO
2,-O-CO-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-O-C
1-C
6-alkyl, and-NR
6R
7, and
N, m can be identical or different, its expression 0,1 or 2,
Can randomly be the enantiomer and the diastereomer of different types, and in the pharmaceutically acceptable salt class.
5. according to the chemical compound of each general formula (I) in the claim 1 to 4, R wherein
1Represent methylidene, ethyl, isopropyl, butyl or benzyl,
It can randomly be the enantiomer and the diastereomer of different types, and in the pharmaceutically acceptable salt class.
6. according to the chemical compound of each general formula (I) in the claim 1 to 5,
Wherein
R
1Represent methylidene,
And can randomly be the form of pharmaceutically acceptable salt class.
7. according to the chemical compound in the general formula (I) of claim 1, wherein
R
1Represent methylidene,
R
2, R
3Represent hydrogen,
R
4, R
5Can be identical or different, can represent halogen,
And
N, m can be identical or different, its expression 0,1 or 2,
And randomly be the form of pharmaceutically acceptable salt class.
8. the chemical compound of general formula (I)
Wherein
R
1Represent one to be selected from following group: hydrogen, can be randomly by the alternate C of one or more halogen atoms
1-C
6-alkyl ,-SO
2H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-CO-C
1-C
6-alkyl ,-O, phenyl-C
1-C
4-alkyl ,-C
1-C
4-alkyl-NR
6R
7, and-C
1-C
4-alkyl-O-C
1-C
4-alkyl and C
3-C
6-cycloalkyl,
R
2, R
3Can be identical or different, represent one to be selected from following group: hydrogen, the C that can randomly replace by one or more halogen atoms
1-C
6-alkyl, halogen ,-NO
2,-SO
2H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-CO-C
1-C
6-alkyl ,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl ,-C
1-C
4-alkyl-NR
6R
7And-C
1-C
4-alkyl-O-C
1-C
4-alkyl and C
3-C
6-cycloalkyl, or
R
1And R
2Can represent a C jointly
4-C
6-alkylidene bridge,
R
6, R
7Can be identical or different, represent hydrogen, C
1-C
4-alkyl or-CO-C
1-C
4-alkyl,
R
4Can be identical or different, represent one to be selected from following group: the C that can randomly replace by one or more halogen atoms
1-C
6-alkyl, phenyl-C
1-C
4-alkyl, halogen ,-CN ,-NO
2,-SO
2H ,-SO
3H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-SO
2-NR
6R
7,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl ,-NR
6R
7, and can be randomly by halogen atom ,-NO
2,-SO
2H or C
1-C
4-alkyl list replaces or polysubstituted benzyl,
R
5Can be identical or different, represent one to be selected from following group: the C that can randomly replace by one or more halogen atoms
1-C
6-alkyl, phenyl-C
1-C
4-alkyl, halogen ,-CN ,-NO
2,-SO
2H ,-SO
3H ,-SO
2-C
1-C
6-alkyl ,-SO-C
1-C
6-alkyl ,-SO
2-NR
6R
7,-COOH ,-CO-C
1-C
6-alkyl ,-O-CO-C
1-C
4-alkyl ,-CO-O-C
1-C
4-alkyl ,-O-CO-O-C
1-C
4-alkyl ,-CO-NR
6R
7,-OH ,-O-C
1-C
6-alkyl ,-S-C
1-C
6-alkyl ,-NR
6R
7, and can be randomly by halogen atom ,-NO
2,-SO
2H or C
1-C
4-alkyl list replaces or polysubstituted aryl, and
N, m can be identical or different, expression 0,1,2 or 3,
Can randomly be the enantiomer and the diastereomer of different types, and in the pharmaceutically acceptable salt class, it be as pharmaceutical composition.
9. the chemical compound of general formula according to Claim 8 (I), it is as the pharmaceutical composition with neuroprotective effect.
10. according to the purposes of the chemical compound of each general formula (I) in the claim 1 to 7, be used for preparation and be used for the treatment of and/or prevent neurodegenerative disease, and/or the pharmaceutical composition of the brain locality ischemia of different positions.
11. according to the purposes of the chemical compound of each general formula (I) in the claim 1 to 7, it is used for preparation and is used for the treatment of schizoid pharmaceutical composition.
12. according to the purposes of each general formula (I) chemical compound in the claim 1 to 7, it is used to prepare the pharmaceutical composition that is used for the treatment of and/or prevents disturbance of memory.
13. according to the purposes of each general formula (I) chemical compound in the claim 1 to 7, it is used to prepare the pharmaceutical composition that is used for the treatment of dementia.
14. one kind treats and/or prevents neurodegenerative disease, and/or the method for the brain locality ischemia of different positions, it is characterized in that giving the patient with the formula I chemical compound in the claim 1 to 7 of effective dose.
15. a method that treats and/or prevents disturbance of memory and/or dementia is characterized in that, gives the patient with the formula I chemical compound in the claim 1 to 7 of effective dose.
16. a pharmaceutical preparation, its chemical compound or its physiology who comprises one or more general formulas (I) in the claim 1 to 7 goes up acceptable salt as active substance, and according to circumstances can be combined with common adjuvant and/or carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10123952.1 | 2001-05-17 | ||
| DE10123952A DE10123952A1 (en) | 2001-05-17 | 2001-05-17 | New naphtho-1,2-thiazine compounds, useful as neuroprotectants for treating e.g. epilepsy or Alzheimer's disease, are allosteric modulators of AMPA receptors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1533278A true CN1533278A (en) | 2004-09-29 |
Family
ID=7685080
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA028100832A Pending CN1533278A (en) | 2001-05-17 | 2002-05-15 | Naphtothiazine positive allosteric AMPA receptor modulators (PAARM) |
Country Status (26)
| Country | Link |
|---|---|
| EP (1) | EP1404340A1 (en) |
| JP (1) | JP2004529980A (en) |
| KR (1) | KR20040007572A (en) |
| CN (1) | CN1533278A (en) |
| AR (1) | AR036332A1 (en) |
| BG (1) | BG108324A (en) |
| BR (1) | BR0209796A (en) |
| CA (1) | CA2449189A1 (en) |
| CO (1) | CO5550460A2 (en) |
| CZ (1) | CZ20033112A3 (en) |
| DE (1) | DE10123952A1 (en) |
| EA (1) | EA006608B1 (en) |
| EC (1) | ECSP034852A (en) |
| EE (1) | EE200300566A (en) |
| HR (1) | HRP20030933A2 (en) |
| HU (1) | HUP0401273A3 (en) |
| IL (1) | IL158642A0 (en) |
| MX (1) | MXPA03010373A (en) |
| NO (1) | NO20035088D0 (en) |
| NZ (1) | NZ530154A (en) |
| PL (1) | PL364053A1 (en) |
| SK (1) | SK14222003A3 (en) |
| UY (1) | UY27290A1 (en) |
| WO (1) | WO2002100411A1 (en) |
| YU (1) | YU90403A (en) |
| ZA (1) | ZA200308466B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111518058A (en) * | 2020-05-29 | 2020-08-11 | 四川大学华西医院 | Oxathiazine compound and application thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8039468B2 (en) * | 2006-08-31 | 2011-10-18 | The Governors Of The University Of Alberta | Method of inhibition of respiratory depression using positive allosteric AMPA receptor modulators |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998012185A1 (en) * | 1996-09-17 | 1998-03-26 | The Regents Of The University Of California | Benzothiadiazide derivatives and their use as allosteric up-modulators of the ampa receptor |
| AU4711899A (en) * | 1998-06-25 | 2000-01-10 | Merck & Co., Inc. | Naphtho(1,8-de)thiasin-2-yl methyl carbapenem antibacterials |
| DE10004572A1 (en) * | 2000-02-02 | 2001-08-09 | Boehringer Ingelheim Pharma | New positive allosteric AMPA receptor modulators (PAARM), processes for their production and their use as medicines |
-
2001
- 2001-05-17 DE DE10123952A patent/DE10123952A1/en not_active Withdrawn
-
2002
- 2002-05-15 BR BR0209796-6A patent/BR0209796A/en not_active Expired - Fee Related
- 2002-05-15 PL PL02364053A patent/PL364053A1/en not_active Application Discontinuation
- 2002-05-15 SK SK1422-2003A patent/SK14222003A3/en unknown
- 2002-05-15 YU YU90403A patent/YU90403A/en unknown
- 2002-05-15 KR KR10-2003-7014965A patent/KR20040007572A/en not_active Application Discontinuation
- 2002-05-15 UY UY27290A patent/UY27290A1/en not_active Application Discontinuation
- 2002-05-15 CN CNA028100832A patent/CN1533278A/en active Pending
- 2002-05-15 HU HU0401273A patent/HUP0401273A3/en unknown
- 2002-05-15 WO PCT/EP2002/005338 patent/WO2002100411A1/en not_active Application Discontinuation
- 2002-05-15 CA CA002449189A patent/CA2449189A1/en not_active Abandoned
- 2002-05-15 MX MXPA03010373A patent/MXPA03010373A/en unknown
- 2002-05-15 NZ NZ530154A patent/NZ530154A/en unknown
- 2002-05-15 EA EA200301167A patent/EA006608B1/en not_active IP Right Cessation
- 2002-05-15 EP EP02750931A patent/EP1404340A1/en not_active Withdrawn
- 2002-05-15 EE EEP200300566A patent/EE200300566A/en unknown
- 2002-05-15 IL IL15864202A patent/IL158642A0/en unknown
- 2002-05-15 CZ CZ20033112A patent/CZ20033112A3/en unknown
- 2002-05-15 JP JP2003503232A patent/JP2004529980A/en not_active Abandoned
- 2002-05-17 AR ARP020101827A patent/AR036332A1/en not_active Suspension/Interruption
-
2003
- 2003-10-30 ZA ZA200308466A patent/ZA200308466B/en unknown
- 2003-11-07 BG BG108324A patent/BG108324A/en active Pending
- 2003-11-14 HR HR20030933A patent/HRP20030933A2/en not_active Application Discontinuation
- 2003-11-14 NO NO20035088A patent/NO20035088D0/en not_active Application Discontinuation
- 2003-11-17 EC EC2003004852A patent/ECSP034852A/en unknown
- 2003-12-01 CO CO03105591A patent/CO5550460A2/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111518058A (en) * | 2020-05-29 | 2020-08-11 | 四川大学华西医院 | Oxathiazine compound and application thereof |
| CN111518058B (en) * | 2020-05-29 | 2021-03-09 | 四川大学华西医院 | Oxathiazine compound and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EA200301167A1 (en) | 2004-06-24 |
| NO20035088L (en) | 2003-11-14 |
| WO2002100411A1 (en) | 2002-12-19 |
| UY27290A1 (en) | 2002-12-31 |
| EE200300566A (en) | 2004-02-16 |
| EP1404340A1 (en) | 2004-04-07 |
| SK14222003A3 (en) | 2004-05-04 |
| PL364053A1 (en) | 2004-12-13 |
| KR20040007572A (en) | 2004-01-24 |
| IL158642A0 (en) | 2004-05-12 |
| NZ530154A (en) | 2005-09-30 |
| CZ20033112A3 (en) | 2004-03-17 |
| DE10123952A1 (en) | 2002-11-21 |
| BG108324A (en) | 2004-12-30 |
| NO20035088D0 (en) | 2003-11-14 |
| HUP0401273A3 (en) | 2006-11-28 |
| EA006608B1 (en) | 2006-02-24 |
| YU90403A (en) | 2006-05-25 |
| HRP20030933A2 (en) | 2004-04-30 |
| ZA200308466B (en) | 2004-05-24 |
| HUP0401273A2 (en) | 2004-10-28 |
| ECSP034852A (en) | 2003-12-24 |
| MXPA03010373A (en) | 2004-03-16 |
| BR0209796A (en) | 2004-06-01 |
| AR036332A1 (en) | 2004-09-01 |
| CA2449189A1 (en) | 2002-12-19 |
| CO5550460A2 (en) | 2005-08-31 |
| JP2004529980A (en) | 2004-09-30 |
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