CN101838269B - 1,3,8-triaza-spiro[4.5]decane-4-ketone compounds and pharmaceutical application thereof - Google Patents
1,3,8-triaza-spiro[4.5]decane-4-ketone compounds and pharmaceutical application thereof Download PDFInfo
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Abstract
The invention relates to 1,3,8-triaza-spiro[4.5]decane-4-ketone compounds shown by a general formula I. Isomers, optical isomers, racemates or medicine salts of the 1,3,8-triaza-spiro[4.5]decane-4-ketone compounds contain the medical combinations thereof. The compounds are used for preparing, or preventing or treating various pains such as postoperative pain, migraine, visceral pain, neuropathic pain and the like and such diseases as addition and tolerance caused by analgesic drugs.
Description
Technical field
The present invention relates to 1; 3; 8-three azepines-spiral shell [4.5] decane-4-ketone compounds, its optical antipode, raceme or pharmacologically acceptable salt, their preparation method; The pharmaceutical composition that contains them, and this compounds is used to prepare the purposes of the medicine of illnesss such as the habituation property that prevents and/or treats pain and caused by analgesics such as opiatess and tolerance.
Background technology
Pain is the common sympton of numerous disease; Present result of study shows; N type calcium channel is an important step in pain generation and the pain sensation conductive process; Because the blocker to N type calcium channel directly acts on N type calcium channel, does not relate to second messenger or G albumen, therefore be difficult for producing habituation property.(ω-conotoxin) MVIIA
is come into the market to sell by drugs approved by FDA in December, 2004 the N type calcium ion channel blockor omega-conotoxin of highly selective; Its clinical practice shows; N type calcium ion channel blockor has been proved to be a novel target of treatment pain, has a good application prospect.
Developed to N type calcium channel and a plurality of series of small molecules compound (CoxB.; Current Review of Pain; 2000; 4:488-498), wherein, the disclosed 4-piperidyl of WO99/43658 phenyl amines micromolecular compound shows tangible analgesic activities as the optionally N type calcium ion channel blockor of taking orally; Seko T. etc. from the screening of compound library, also obtained one type have the active compound of N type calcium ion channel blockor (BioorganicMedicinal Chemistry, 2003,11:1901-1913).People's such as Elisabetta T. research also obtained preferably the result (Journal of Medicinal Chemistry, 2004,47:6070-6081).But there is certain defective in general, present research.On the one hand, these compounds are structurally too similar with opium kind analgesics things such as fentanyls, possibly have potential habituation property; On the other hand, the pharmacokinetic property of these compounds is relatively poor, need could to produce analgesic activities through non-clinically simple route of administration such as outer ventricles of the brain administrations, thereby, still there is demand in the N type calcium ion channel blockor of development of new.
Summary of the invention
The objective of the invention is to seek and develop the new medicine that prevents and/or treats with the pain diseases related.The inventor passes through 1; 3,8-three azepines-spiral shell [4.5] decane-4-ketone compounds carries out structure of modification, has now found that to have 1 of following general formula I; 3,8-three azepines-spiral shell [4.5] decane-4-ketone compounds shows tangible analgesic activities and has good pharmacokinetic property.
Therefore, first aspect of the present invention relates to 1,3 of general formula I, 8-three azepines-spiral shell [4.5] decane-4-ketone compounds, and its optical antipode, raceme or pharmacologically acceptable salt:
Wherein:
R
1, R
2And R
3Represent Wasserstoffatoms, C independently of one another
1-8Alkyl, substituted C
1-8Alkyl, C
3-8Alkenyl, C
3-8Naphthenic base, substituted C
3-8Naphthenic base, C
1-8Alkoxyl group, C
5-20Aryl, C
5-20Aryloxy, substituted C
5-20Aryl, C
3-20Heteroaryl, C
5-20Heteroaryloxy, substituted C
3-20Heteroaryl, C
3-20Heterocyclic radical, substituted C
3-20Heterocyclic radical or C
3-20The heterocyclyloxy base;
Said substituting group is selected from halogen, C
1-8Alkyl, C
1-8Alkoxyl group, C
3-10Naphthenic base, cyanic acid, nitro, sulfydryl, trifluoromethyl, amino, single C
1-8Alkylamino, two C
1-8Alkylamino, C
1-8Alkyl sulphonyl, hydroxyl, phenoxy, C
5-20Heteroaryloxy, C
5-20Aryl, C
3-20Heterocyclic radical, C
3-20Heteroaryl; These substituting groups itself can also randomly be replaced by other substituting group list or be polysubstituted, and said other substituting group is selected from the tertiary butyl, methyl, trifluoromethyl, chlorine, fluorine, bromine, methoxyl group, oxyethyl group, hydroxyl, dimethylamino, diethylin and methylene-dioxy;
Condition is R
1, R
2And R
3Be not hydrogen simultaneously.
Second aspect present invention relates to 1,3 of general formula I, the preparation method of 8-three azepines-spiral shell [4.5] decane-4-ketone compounds, its optical antipode, raceme or pharmacologically acceptable salt.
Third aspect of the present invention relates to pharmaceutical composition; Said pharmaceutical composition comprises 1 of at least a general formula I; 3,8-three azepines-spiral shell [4.5] decane-4-ketone compounds, its optical antipode, raceme or pharmacologically acceptable salt and one or more pharmaceutically acceptable carrier or vehicle.
The compound that the 4th aspect of the present invention relates to general formula I is used to prepare the purposes of the medicine of illnesss such as the habituation property that prevents and/or treats pain and caused by analgesics such as opiatess and tolerance.
The 5th aspect of the present invention relates to the compounds for treating pain that adopts general formula I and the method for illness such as the habituation property that caused by analgesics such as opiatess and tolerance, and said method comprises that the patient that these needs are arranged prevents and/or treats the compound of at least a general formula I of significant quantity, its optical antipode, raceme or pharmacologically acceptable salt.
According to the present invention, term " halogen " is fluorine, chlorine, bromine or iodine.
According to the present invention, the hydrocarbon chain of the straight or branched that term " alkyl " expression is saturated.Said alkyl preferably comprises 1-8 carbon atom, more preferably 1-6 carbon atom, and most preferably 1-4 carbon is former.The example of said alkyl comprises for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec.-butyl, the tertiary butyl, amyl group, 2-ethyl-butyl, hexyl, heptyl, octyl group etc.
According to the present invention, term " alkoxyl group " expression " alkyl-O-", wherein alkyl as above defines.
According to the present invention, term " alkenyl " expression comprises the carbochain of one or more pairs of keys.Said alkenyl preferably comprises 2-8 carbon atom, more preferably 3-8 carbon atom, more preferably 3-6 carbon atom, most preferably 2-4 carbon atom.The example of said alkenyl comprises vinyl, 1-or 2-propenyl, allyl group, 1-, 2-or 3-crotonyl, 3-methyl-but-2-ene base, 4-methyl-3-alkene-1-amyl group etc.
According to the present invention, term " naphthenic base " expression cyclic alkyl.Said naphthenic base preferably comprises 3-10 carbon atom, more preferably 3-8 carbon atom, most preferably 3-6 carbon atom.The example of said naphthenic base comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group etc.
According to the present invention, term " aryl " preferably comprises 5-20 carbon atom, more preferably 6-18 carbon atom, most preferably 6-12 carbon atom.The example of said aryl comprises phenyl, naphthyl, anthryl etc.
According to the present invention, term " aryloxy " expression " aryl-O-", wherein aryl as above defines.
According to the present invention, term " heterocyclic radical " preferably comprises 3-20 carbon atom, more preferably 4-18 carbon atom, more preferably 5-16 carbon atom, and 1-3 are selected from the heteroatoms of oxygen, nitrogen and sulphur.The example of said heterocyclic radical comprises tetrahydrofuran base, pyrrolidyl, piperidyl, morpholinyl etc., thiazolidyl etc.
According to the present invention, term " heterocyclyloxy base " expression " heterocyclic radical-O-", wherein heterocyclic radical as above defines.
According to the present invention, term " heteroaryl " preferably comprises 3-20 carbon atom, more preferably 4-18 carbon atom, more preferably 5-16 carbon atom, and most preferably 6-12 carbon atom, and 1-3 is selected from the heteroatoms of oxygen, nitrogen and sulphur.The example of said heteroaryl comprises pyrryl, pyridyl, imidazolyl, furyl, pyranyl, thienyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, quinolyl, pyridopyridine base etc.
According to the present invention, term " heteroaryloxy " expression " heteroaryl-O-", wherein heteroaryl as above defines.
According to the present invention, contain one or more substituting groups on the said group of term " substituted " expression, said substituent example is including, but not limited to halogen, C
1-8Alkyl, C
1-8Alkoxyl group, C
3-10Naphthenic base, cyanic acid, nitro, sulfydryl, trifluoromethyl, amino, single C
1-8Alkylamino, two C
1-8Alkylamino, C
1-8Alkyl sulphonyl, hydroxyl, phenoxy, C
5-20Heteroaryloxy, C
5-20Aryl, C
3-20Heterocyclic radical and C
3-20Heteroaryl.These substituting groups itself can also randomly be replaced by one or more other substituting groups, and said other substituting group is selected from the tertiary butyl, methyl, trifluoromethyl, chlorine, fluorine, bromine, methoxyl group, oxyethyl group, hydroxyl, dimethylamino, diethylin and methylene-dioxy.
In one embodiment of the invention, the present invention relates to compound, its optical antipode, raceme, its pharmacologically acceptable salt of general formula I:
Wherein:
R
1, R
2And R
3Represent Wasserstoffatoms, C independently of one another
1-8Alkyl, substituted C
1-8Alkyl, C
3-8Alkenyl, C
3-8Naphthenic base, substituted C
3-8Naphthenic base, C
1-8Alkoxyl group, C
5-20Aryl, C
5-20Aryloxy, substituted C
5-20Aryl, C
3-20Heteroaryl, C
5-20Heteroaryloxy, substituted C
3-20Heteroaryl, C
3-20Heterocyclic radical, substituted C
3-20Heterocyclic radical or C
3-20The heterocyclyloxy base;
Said substituting group is selected from halogen, C
1-8Alkyl, C
1-8Alkoxyl group, C
3-10Naphthenic base, cyanic acid, nitro, sulfydryl, trifluoromethyl, amino, single C
1-8Alkylamino, two C
1-8Alkylamino, C
1-8Alkyl sulphonyl, hydroxyl, phenoxy, C
5-20Heteroaryloxy, C
5-20Aryl, C
3-20Heterocyclic radical and C
3-20Heteroaryl; These substituting groups itself can also randomly be replaced by other substituting group list or be polysubstituted, and said other substituting group is selected from the tertiary butyl, methyl, trifluoromethyl, chlorine, fluorine, bromine, methoxyl group, oxyethyl group, hydroxyl, dimethylamino, diethylin and methylene-dioxy;
Condition is R
1, R
2And R
3Be not hydrogen simultaneously.
According to a preferred implementation of the present invention, the compound of general formula I is following compound, its optical antipode, raceme or pharmacologically acceptable salt:
Wherein:
R
1Be hydrogen, phenyl, 4-dimethylamino phenyl, 2-methoxyl group-4-dimethylamino phenyl, 4-diethylin phenyl, 5-methyl furan-2-base, 5-bromine furans-2-base, 3; 5-dimethyl--4-hydroxyl-phenyl, 3; 5-di-t-butyl-4-hydroxyl-phenyl, 4-p-methoxy-phenyl, 4-isopropyl phenyl, 4-butoxy phenyl, 4-hexyloxy phenyl, 4-cyano-phenyl, 4-benzyloxy phenyl, 3-benzyloxy phenyl, 2-benzyloxy phenyl, 3; 4-methylene-dioxy-phenyl, 4; 5-methylene-dioxy-2-chloro-phenyl, 4; 5-methylene-dioxy-2-bromo-phenyl, 4-fluorophenyl, 4-nitrophenyl, 4-ethylphenyl, 4-tert-butyl-phenyl, 2-fluoro-4-p-methoxy-phenyl, 3; 5-two (trifluoromethyl)-phenyl, 4-(piperidino)-3-nitro-phenyl, 4-(1-pyrryl)-3-nitro-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethyl--4-benzyloxy-phenyl, tert.-butoxy or 3-bromo-4-fluoro-phenyl;
R
2Be hydrogen, 3-methylbutyl, 3-methyl-2-alkene-1-butyl, 2-methoxy ethyl, 2-ethyl-butyl, hexyl, octyl group, 2-dimethylaminoethyl, 3-dimethylamino-propyl, ring third methyl, 2-cyclopropyl ethyl, 2-pyrroles's ethyl, 2-(N-N-ethyl pyrrole N--2-yl)-ethyl, cyclopentyl, cyclohexyl or 3,4-dimethoxy styroyl;
R
3Be hydrogen, phenyl, fluorenyl, 4-dimethylamino phenyl, 2-methoxyl group-4-dimethylamino phenyl, 4-diethylin phenyl, 5-methyl furan-2-base, 5-methyl-thiophene-2-base, 5-bromine furans-2-base, 3; 5-dimethyl--4-hydroxyl-phenyl, 3; 5-two bromo-4-hydroxyl-phenyl, 3; 5-dimethoxy-4 '-hydroxyl-phenyl, 3; 5-di-t-butyl-4-hydroxyl-phenyl, 4-p-methoxy-phenyl, 4-isopropyl phenyl, 4-butoxy phenyl, 4-hexyloxy phenyl, 4-cyano-phenyl, 4-benzyloxy phenyl, 3-benzyloxy phenyl, 2-benzyloxy phenyl, 3; 4-methylene-dioxy-phenyl, 2-chloro-4; 5-methylene-dioxy-phenyl, 4; 5-methylene-dioxy-2-bromo-phenyl, 4-fluorophenyl, 4-nitrophenyl, 4-ethylphenyl, 4-tert-butyl-phenyl, 2-fluoro-4-p-methoxy-phenyl, 3,5-two (trifluoromethyl)-phenyl, 4-(piperidino)-3-nitro-phenyl, 4-(1-pyrryl)-3-nitro-phenyl, 3,4-dimethoxy-phenyl, 3; 5-dimethyl--4-benzyloxy-phenyl, tert.-butoxy, 3-bromo-4-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 2-fluoro-4-trifluoromethyl-phenyl, 3; 4-Dimethoxyphenyl, 2,3-Dimethoxyphenyl, 2-hydroxyl-4,5-two chloro-phenyl, 2-methoxyl group-4-bromo-phenyl, 2-fluoro-4-methoxyl group-phenyl, 3-bromo-5-methoxyl group-phenyl, 2-chloro-5-nitro-phenyl, 4-(4-fluoro-benzyloxy)-phenyl, 5-phenyl-furans-2-base, 3-methoxyl group-4-hydroxyl-phenyl, 3; 4,5-trimethoxy-phenyl, 2-hydroxyl-4-bromo-phenyl, 4-[(2-cyano ethyl) methylamino]-phenyl or 2-(4-chloro-phenyl-sulfydryl)-phenyl;
According to the present invention, the compound of general formula I is preferably following compounds, its optical antipode, raceme or pharmacologically acceptable salt:
(±) 8-(3-methoxyl group-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(3-methyl-butyryl radicals)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone),
(±) (1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl)-ketone-methyl acetate,
(±) 8-(4-methoxyl group-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-encircles penta formyl radical-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(3,3-dimethyl--butyryl radicals)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) (1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl)-ketone-ETHYLE ACETATE,
(±) 8-(4-chloro-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(3-phenyl-propionyl group)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(3-methyl-butyryl radicals)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) [1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl]-ketone-methyl acetate,
(±) 8-[2-(4-methoxyl group-phenyl-ethanoyl)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(4-chloro-benzoyl-)-1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(2-fluoro-benzoyl-)-1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(3-methoxyl group-benzoyl-)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(4-methoxyl group-benzoyl-)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-phenylbenzene ethanoyl-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-encircles penta formyl radical-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) [1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl]-ketone-ETHYLE ACETATE,
(±) 8-(3,3-dimethyl--butyryl radicals)-1-(3,5-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(3-methyl-2-phenyl-butyryl radicals)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(2-methyl-butyryl radicals)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) (2-chloro-4-nitro-benzoyl-)-1-(4-fluoro-phenyl-)-8-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(4-fluoro-benzoyl-)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) [1-(3,5-dimethyl--phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl]-ketone-ETHYLE ACETATE,
(±) [1-(3,5-dimethyl--phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl]-ketone-methyl acetate,
(±) 8-(2-ethyl-butyryl radicals)-1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(4-fluorine-based-benzoyl-)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 1-(3,3-dimethyl--phenyl)-4-ketone-1,3,8-three azepines-spiral shell [4.5] decane-8-benzyl formate,
(±) 8-(2-ethyl-butyryl radicals)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-[2-(3-methoxyl group-phenylacetyl)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-two phenylacetyl-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(4-fluoro-benzoyl-)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(3,4-dimethoxy-benzoyl-)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-encircles penta formyl radical-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(2-chloro-4-nitro-benzoyl-)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(4-fluoro-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(2-ethyl-butyryl radicals)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(4-methoxyl group-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(phenylbenzene ethanoyl)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(3-methoxyl group-benzoyl-)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-benzyl formate,
(±) 8-[2-(3-methoxy-phenyl)-ethanoyl]-1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 1-(3,5-two fluoro-phenyl)-4-[1-(4 fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl]-1, the 4-dimethyl diketone,
(±) 8-(4-chloro-benzoyl-)-1-(3,5-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±)-8-benzoyl--1-(3,5-dimethyl--phenyl) 1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(2-fluoro-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone), or
(±) 8-[2-(3-methoxyl group-phenyl)-ethanoyl]-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone.
Can adopt the compound of the synthetic general formula I of the present invention of the synthetic route shown in the following reaction scheme, in addition, also can be referring to the detailed description in the embodiment of the invention.As required, can also make the compound of general formula I of the present invention and acid-respons be converted into its pharmacologically acceptable salt.
Reaction scheme
For synthesizing of volution parent nucleus, the first step reaction adopts Glacial acetic acid min. 99.5 to make solvent, makes benzyl piepridine ketone, arylamine and Potssium Cyanide reaction, and stirring at room 6 hours to 72 hours is because of the substituent steric hindrance difference of arylamine is decided.Directly pour in ice/ammonia water mixture after reaction finishes, can separate out solid, can remove all dirt with the ether washing behind the suction filtration.The second step reaction is to generate acid amides with 90% sulfuric acid catalysis hydrolysis cyanic acid, and temperature of reaction is 50-150 ℃, and the reaction times is 10 minutes to 2 hours, pours in the frozen water after reaction finishes, and machinery stirs fast, and it is 10 can separate out solid that use ammoniacal liquor alkalizes to pH.Three-step reaction is made solvent simultaneously as reaction raw materials with methane amide, closes ring and forms volution.This step was reflected under 150-180 ℃ of condition of conventional heating stirring reaction 12 hours, also can adopt microwave catalysis.Reaction finishes, and cooling solution can be separated out title product.Four-step reaction is that benzyl is taken off in hydrogenation, and the catalysis of palladium carbon is used in this step reaction, the normal pressure hydrogenation reaction, and temperature is 25-80 ℃, suction filtration is removed palladium carbon, revolves can obtain various R after doing
1Substituted mother nucleus structure.And then with suitable reaction reagent such as acyl chlorides or halohydrocarbon in the presence of alkali such as organic bases or salt of wormwood in appropriate solvent such as acetone reaction can obtain having various substituent R
2, R
3The compound of general formula I.
As required, the compound of general formula I can also be converted into its pharmacologically acceptable salt with suitable acid-respons.
According to the present invention; The pharmacologically acceptable salt of the compound of general formula I comprises its inorganic acid salt or organic acid salt, comprising but be not limited to: hydrochloride, hydrobromate, hydriodate, nitrate salt, vitriol, hydrosulfate, phosphoric acid salt, hydrophosphate, acetate, oxyacetate, propionic salt, butyrates, oxalate, trifluoroacetate, adipate, alginate, lactic acid salt, Citrate trianion, tartrate, SUMATRIPTAN SUCCINATE, PHENRAMINE MALEATE, fumarate, picrate, aspartate, glyconate, benzoate, mesylate, esilate, benzene sulfonate, tosilate, embonate, pyruvate salt, glycollate, malonate, trifluoroacetate, malate, salicylate, para-aminosalicylic acid salt, pamoate and ascorbate salt etc.; The hydrochloride of the compound of preferred formula I.
The compound or pharmaceutically acceptable salt thereof of general formula I of the present invention can also form solvolyte, for example hydrate, alcohol adduct etc.Above-claimed cpd can also be prodrug or the form that discharges said activeconstituents in vivo after the metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.
According to the present invention, the compound of general formula I is as existing with stereoisomer form, and asymmetric center wherein can be R-configuration or S-configuration.The present invention includes all possible steric isomer such as enantiomer or diastereomer, and the mixture of two or more steric isomers, the for example mixture of any required ratio of enantiomer and/or diastereomer.If there is suitable/trans isomer, the present invention relates to its cis form or trans forms or the mixture of the two.If desired, the preparation of single stereoisomers can split mixture according to conventional methods, or through the synthetic preparation of stereoselectivity.If there is the mobile Wasserstoffatoms, the present invention also relates to its tautomeric form.
Experimental result shows; The compounds of this invention is in mouse acetic acid twisting model and hot plate model; Under the gastric infusion condition, promptly can show tangible analgesic activities; Show that its pharmacokinetic property and analgesic activities are better, can the administered through oral route of administration be used for preventing and/or treating various antalgesics such as postoperative pain, migraine, Encelialgia, neuropathic pain; On the other hand; The compounds of this invention not only has and 4-piperidyl amino benzenes compounds such as fentanyl various structure characteristic; The result of study of analgesic experiment also shows; The analgesic activity of this compounds and the effect of opiate receptor do not have dependency, so it can not cause addicted generation when producing analgesic activity.Further experimental result is also pointed out, and this compounds can strengthen the analgesic activity of morphine, and has the purposes of illnesss such as treating and/or preventing the habituation property that caused by the opium kind analgesics thing and tolerance.Therefore, The compounds of this invention can be used to prevent and/or treat various pain such as postoperative pain, migraine, Encelialgia, neuropathic pain and illness such as the habituation property that caused by analgesics such as opiatess and tolerance.
Active compound of the present invention can form administration own, perhaps with the pharmaceutical compositions administration, and wherein active compound and one or more pharmaceutically acceptable carriers, vehicle or mixing diluents.Pharmaceutical composition of the present invention is normally pressed the usual manner preparation, uses acceptable carrier or vehicle on one or more physiology, and they help active compound is processed into can be at the preparation that pharmaceutically uses.Appropriate formulations depends on selected route of administration, can prepare according to general knowledge well known in the art.
The pharmaceutical carrier or the vehicle that can be used for pharmaceutical composition of the present invention include but not limited to: ionite, aluminum oxide, StAl, Yelkin TTS, serum proteins such as human serum protein, buffer substance such as phosphoric acid salt; Glycerine, Sorbic Acid, POTASSIUM SORBATE GRANULAR WHITE, the partial glycerol ester mixture of saturated vegetable fatty acid, water; Salt or ionogen, like protamine sulfate, Sodium phosphate, dibasic, potassium hydrogen phosphate, sodium-chlor; Zinc salt, colloidal silica, Magnesium Trisilicate, Vinylpyrrolidone polymer, cellulosic material; Polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, beeswax, Vilaterm-polyoxypropylene block polymer and yolk.
The compound of general formula I of the present invention or the route of administration that contains its pharmaceutical composition can be enteron aisle or non-enteron aisle, like oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.Form of administration is for example tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized injectable powder etc.Can also be prepared into sustained release preparation, controlled release preparation and various particulate delivery system.
Term used herein " administration " comprises that all directly arrive the means at its predictive role position with indirect release compound.
Compound as herein described or its pharmaceutically acceptable derivates can be individually dosed or with other The compounds of this invention administation of combination, and/or with other known treatment agent administation of combination.
The compounds of this invention is decided by many factors to different patients' specific using dosage and method of use, comprises patient's age, body weight; Sex, natural health situation, nutritional status; The activity intensity of compound; Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's subjective judgement.Usually, the dosage of The compounds of this invention will be in the 0.01mg/kg body weight to the scope of 100mg/kg body weight, and more preferably the 0.1mg/kg body weight is to the 10mg/kg body weight, and particularly the 1mg/kg body weight is to the 5mg/kg body weight.
The unit dosage of The compounds of this invention will contain 0.1 to 99 weight % active substance usually, be more typically 5 to 75 weight % active substances.For instance, unit dosage can contain 1mg to 1g compound, is more typically 10mg to 500mg compound, and for example between 50mg and 400mg compound, dosage is generally 100mg to 200mg compound.
Embodiment
Following embodiment is used for explaining the present invention, but the present invention is not constituted any limitation.
Embodiment 1: (±) 8-(3-methoxyl group-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (401)
Get 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) places the ground triangular flask of 50ml; Add Anhydrous potassium carbonate 0.5g, acetone 30ml, excessive slightly 3-methoxybenzoyl chlorine (0.15ml; About 0.0012mol), stirring at room 12 hours, TLC (Cl
2CH
2: CH
3OH 5: 1) monitoring reaction to the disappearance of raw material point, revolves and does back adding 30ml water and 30ml methylene dichloride; After the separation, anhydrous sodium sulfate drying revolves dried after the filtration; Add the small amount of acetone dissolving, the ether that adds logical hydrogenchloride is separated out solid, suction filtration; Solid gets product 0.12g, productive rate 66.7% with acetone/anhydrous diethyl ether recrystallization after the drying.m.p.216-218℃。M
++1(m/z)：365。
1HNMR(DMSO-d
6，ppm)δ：7.35-7.39(t，1H，J＝8Hz)，7.25-7.29(t，2H，J＝8Hz)，6.96-7.03(m，3H)，6.77-6.80(m，3H)，4.61(s，2H)，4.41(s，1H)，3.77(s，3H)，3.6(m，1H)，3.32(s，2H)，2.50(m，2H)，2.35(s，1H)，1.74(d，2H，J＝8Hz)。
Embodiment 2: (±) 8-(3-methyl-butyryl radicals)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (402)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly isoveryl chloride (0.15ml, about 0.001mol).Obtain target compound 0.12g, productive rate is 76.4%.m.p.80-82℃。M
++1(m/z)：345。
Embodiment 3: (±) (1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl)-ketone-methyl acetate (403)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4,5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly methyl oxalyl chloride (0.15ml, about 0.0013mol).Obtain target compound 0.10g, productive rate is 69.2%.m.p.178-180℃。M
++1(m/z)：318。
Embodiment 4: (±) 8-(4-methoxyl group-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (404)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 4-methoxy benzoyl chloride (0.15ml, about 0.001mol).Obtain target compound 0.13g, productive rate is 68.7%.Survey 148-150 ℃ of fusing point.M
++1(m/z)：379。
1HNMR(DMSO-d
6，ppm)δ：7.24-7.26(d，2H，J＝8.4Hz)，7.12-7.14(t，2H，J＝8.4Hz)，6.86-6.93(m，2H)，6.70-6.73(t，1H，J＝8.0Hz)，6.45-6.47(d，2H，J＝8Hz)，4.54(s，2H)，4.36(dd，1H，J＝4.8，7.6Hz)，3.83(s，1H)，3.79(s，1H)，3.69(s，3H)，3.39(t，1H，J＝7.2Hz)，3.32(s，2H)，3.24(m，1H)，2.24(m，1H)，2.01(m，1H)，1.48-1.58(q，2H，J＝14Hz)。
Embodiment 5: (±) 8-encircles penta formyl radical-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (405)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly ring penta formyl chloride (0.15ml, about 0.0012mol).Obtain target compound 0.15g, productive rate is 75%.m.p.120-122℃。M
++1(m/z)：327。
1HNMR(DMSO-d
6，ppm)δ：6.76-7.23(m，5H)，4.62(d，2H，J＝6.0Hz)，3.48-3.57(dd，4H，J＝12Hz)，3.28(d，4H，J＝10Hz)，2.80-2.87(m，4H)，1.77-1.80(m，6H)。
Embodiment 6: (±) 8-(3,3-dimethyl--butyryl radicals)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (406)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly uncle's butyryl chloride (0.15ml, about 0.0012mol).Obtain target compound 0.09g, productive rate is 56.2%.m.p.238-240℃。M
++1(m/z)：329。
1HNMR(DMSO-d
6，ppm)δ：6.76-7.21(m，5H)，4.62(s，2H)，4.36(dd，1H，J＝4.8，10Hz)，3.94(s，1H)，3.51(m，2H)，3.28(m，2H)，2.82(t，2H，J＝8.4)，2.25(m，1H)，1.78(d，2H，J＝14Hz)，1.01(s，6H)，0.90(s，3H)。
Embodiment 7: (±) (1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl)-ketone-ETHYLE ACETATE (407)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4,5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly ethyl oxalyl chloride (0.15ml, about 0.0012mol).Obtain target compound 0.1g, productive rate is 66.7%.m.p.156-158℃。M
++1(m/z)：331。
Embodiment 8: (±) 8-(4-chloro-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (408)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4,5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 4-chloro-Benzoyl chloride 99min. (0.15ml, about 0.0012mol).Obtain target compound 0.12g, productive rate is 65%.m.p.90-92℃。M
++1(m/z)：365。
Embodiment 9: (±) 8-(3-phenyl-propionyl group)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (409)
Compound method preparation according to compound 401.Raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4,5] decane-4-ketone 0.12g (about 0.0005mol) and excessive slightly phenylpropyl alcohol acyl chlorides (0.15ml, about 0.0011mol).Obtain target compound 0.08g, productive rate is 42%.m.p.120-122℃。M
++1(m/z)：381。
Embodiment 10: (±) 8-(3-methyl-butyryl radicals)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (410)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.12g (about 0.0005mol) and excessive slightly isoveryl chloride (0.15ml, about 0.0012mol).Obtain target compound 0.13g, productive rate is 78%.m.p.158-160℃。M
++1(m/z)：333。
Embodiment 11: (±) [1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl]-ketone-methyl acetate (411)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.12g (about 0.0005mol) and excessive slightly methyl oxalyl chloride (0.15ml, about 0.0012mol).Obtain target compound 0.11g, productive rate is 71.7%.m.p.180-182℃。M
++1(m/z)：335。
Embodiment 12: (±) 8-[2-(4-methoxyl group-phenyl-ethanoyl)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (412)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.12g (about 0.0005mol) and excessive slightly 4-methoxyl group-phenyllacetyl chloride (0.15ml, about 0.001mol).Obtain target compound 0.13g, productive rate is 65.6%.m.p.188-190℃。M
++1(m/z)：397。
1HNMR(DMSO-d
6，ppm)δ：6.89-7.23(m，6H)，6.53-6.54(m，2H)，4.32(m，4H)，3.70-3.72(m，6H)，3.57(m，1H)，3.24(t，1H，J＝3.2Hz)，2.02(m，1H)，1.81(m，1H)，1.49(m，2H)。
Embodiment 13: (±) 8-(4-chloro-benzoyl-)-1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (413)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.12g (about 0.0005mol) and excessive slightly 4-chloro-Benzoyl chloride 99min. (0.15ml, about 0.0012mol).Obtain target compound 0.09g, productive rate is 46.1%.m.p.218-220℃。M
++1(m/z)：387。
Embodiment 14: (±) 8-(2-fluoro-benzoyl-)-1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (414)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.12g (about 0.0005mol) and excessive slightly 2-fluoro-Benzoyl chloride 99min. (0.15ml, about 0.0012mol).Obtain target compound 0.12g, productive rate is 64.7%.m.p.105-107℃。M
++1(m/z)：371。
1HNMR(DMSO-d
6，ppm)δ：7.11-7.60(m，6H)，6.84-6.85(m，2H)，4.57(m，2H)，3.35-3.39(m，4H)，2.28(m，1H)，2.06(m，1H)，1.79(d，1H，J＝10Hz)，1.67(d，1H，J＝10Hz)，1.09(t，1H，J＝6.8Hz)。
Embodiment 15: (±) 8-(3-methoxyl group-benzoyl-)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (415)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.12g (about 0.0005mol) and excessive slightly 3-methoxyl methyl-Benzoyl chloride 99min. (0.15ml, about 0.001mol).Obtain target compound 0.11g, productive rate is 57.9%.m.p.146-148℃。M
++1(m/z)：383。
1HNMR(DMSO-d
6，ppm)δ：7.11-7.37(m，6H)，6.90-6.93(m，2H)，4.54(d，2H)，3.70-3.76(m，5H)2.28(m，1H)，2.07(m，1H)，1.75(m，3H)，1.06(t，1H，J＝6.8Hz)。
Embodiment 16: (±) 8-(4-methoxyl group-benzoyl-)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (416)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.12g (about 0.0005mol) and excessive slightly 4-methoxyl group-Benzoyl chloride 99min. (0.15ml, about 0.001mol).Obtain target compound 0.13g, productive rate is 68.4%.m.p.226-227℃。M
++1(m/z)：383。
1HNMR(DMSO-d
6，ppm)δ：7.73-7.75(d，2H，J＝8.4Hz)，7.39-7.4(d，2H，J＝8.4Hz)，6.85(d，2H，J＝8.4Hz)，6.75(d，2H，J＝4.4Hz)，4.57(s，2H)，3.72-3.78(m，5H)，2.08-2.21(m，2H)，1.73(m，3H)，1.06(t，1H，J＝6.8Hz)。
Embodiment 17: (±) 8-phenylbenzene ethanoyl-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (417)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.12g (about 0.0005mol) and excessive slightly two phenyllacetyl chlorides (0.25ml).Obtain target compound 0.15g, productive rate is 68.2%.m.p.208-210℃。M
++1(m/z)：443。
1HNMR(DMSO-d
6，ppm)δ：7.21-7.38(m，10H)，7.04(m，2H)，6.54(m，2H)，5.59(s，1H)，4.50(s，2H)，4.01(d，1H，J＝10Hz)，4.05(d，1H，J＝12Hz)，3.71(m，1H)，3.31(m，1H)，2.08(m，2H)，1.63(m，2H)，1.45(t，1H，J＝6.8Hz)。
Embodiment 18: (±) 8-encircles penta formyl radical-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (418)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3, and 8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly ring penta formyl chloride (0.15ml, 0.0012mol).Obtain target compound 0.13g, productive rate is 74.9%.m.p.141-142℃。M
++1(m/z)：345。
Embodiment 19: (±) [1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl]-ketone-ETHYLE ACETATE (419)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly ethyl oxalyl chloride (0.15ml, about 0.0013mol).Obtain target compound 0.12g, productive rate is 75%.m.p.160-162℃。M
++1(m/z)：349。
Embodiment 20: (±) 8-(3,3-dimethyl--butyryl radicals)-1-(3,5-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (420)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly uncle's butyryl chloride (0.15ml, about 0.0012mol).Obtain target compound 0.13g, productive rate is 74.9%.m.p.172-173℃。M
++1(m/z)：347。
Embodiment 21: (±) 8-(3-methyl-2-phenyl-butyryl radicals)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (421)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 3-methyl-2-phenyl-butyryl chloride (0.25ml).Obtain target compound 0.15g, productive rate is 73.3%.m.p.168-170℃。M
++1(m/z)：421。
Embodiment 22: (±) 8-(2-methyl-butyryl radicals)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (422)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 2-methylbutyryl chlorine (0.15ml, about 0.0012mol).Obtain target compound 0.08g, productive rate is 48.2%.m.p.286-288℃。M
++1(m/z)：427。
Embodiment 23: (±) (2-chloro-4-nitro-benzoyl-)-1-(4-fluoro-phenyl-)-8-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (423)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 2-chloro-4 nitrobenzoyl chlorides (0.25ml).Obtain target compound 0.13g, productive rate is 60.2%.m.p.140-141℃。M
++1(m/z)：432。
Embodiment 24: (±) 8-(4-fluoro-benzoyl-)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (424)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 4-fluorobenzoyl chloride (0.15ml, about 0.0012mol).Obtain target compound 0.09g, productive rate is 48.5%.m.p.150-152℃。M
++1(m/z)：369。
Embodiment 25: (±) [1-(3,5-dimethyl--phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl]-ketone-ETHYLE ACETATE (425)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3, and 8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly ethyl oxalyl chloride (0.15ml, 0.0013mol).Obtain target compound 0.10g, productive rate is 60.4%.m.p.91-93℃。M
++1(m/z)：359。
Embodiment 26: (±) [1-(3,5-dimethyl--phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl]-ketone-methyl acetate (426)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly methyl oxalyl chloride (0.15ml, about 0.0012mol).Obtain target compound 0.11g, productive rate is 69.4%.m.p.210-212℃。M
++1(m/z)：345。
Embodiment 27: (±) 8-(2-ethyl-butyryl radicals)-1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (427)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3, and 8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 2-ethyl butyryl chloride (0.15ml, 0.0012mol).Obtain target compound 0.07g, productive rate is 40.3%.m.p.181-183℃。M
++1(m/z)：347。
Embodiment 28: (±) 8-(4-fluorine-based-benzoyl-)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (428)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 4-fluoro-Benzoyl chloride 99min. (0.15ml, about 0.0012mol).Obtain target compound 0.12g, productive rate is 63.1%.M
++1(m/z)：381。
1HNMR(DMSO-d
6，ppm)δ：7.31-7.40(m，4H)，6.39-6.44(m，3H)，4.59(m，2H)，4.57(d，1H，J＝4.8Hz)，3.74(d，1H，J＝3.2Hz)，3.47(d，1H，J＝3.2Hz)，3.39(m，1H)，2.49(s，1H)，2.27(s，6H)，2.08-2.21(m，2H)，1.75(d，1H，J＝12Hz)，1.62(d，1H，J＝12Hz)。
Embodiment 29: (±) 1-(3,3-dimethyl--phenyl)-4-ketone-1,3,8-three azepines-spiral shell [4.5] decane-8-benzyl formate (429)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly carbobenzoxy chloride (0.15ml, about 0.0012mol).Obtain target compound 0.14g, productive rate is 71.2%.m.p.164-166℃。M
+(m/z)：393。
1HNMR(DMSO-d
6，ppm)δ：7.33-7.37(m，5H)，6.33-6.43(m，3H)，4.57(m，2H)，3.94(m，2H)，3.42(s，1H)，3.39(m，1H)，2.50(s，2H)，2.15(s，6H)，2.08-2.21(m，2H)，1.63(d，2H，J＝14Hz)。
Embodiment 30: (±) 8-(2-ethyl-butyryl radicals)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (430)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 2-ethyl-butyryl chloride (0.15ml, about 0.0012mol).Obtain target compound 0.06g, productive rate is 33.6%.M
++1(m/z)：357。
Embodiment 31: (±) 8-[2-(3-methoxyl group-phenylacetyl)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (431)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 3-anisole Acetyl Chloride 98Min. (0.15ml, about 0.001mol).Obtain target compound 0.16g, productive rate is 80%.m.p.215-217℃。M
++1(m/z)：407。
Embodiment 32: (±) 8-two phenylacetyl-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (432)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly two phenyllacetyl chlorides (0.25ml).Obtain target compound 0.14g, productive rate is 61.8%.m.p.228-230℃。M
++1(m/z)：453。
Embodiment 33: (±) 8-(4-fluoro-benzoyl-)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (433)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.12g (about 0.0005mol) and excessive slightly 4-be fluorine-based-and Benzoyl chloride 99min. (0.15ml, about 0.0012mol).Obtain target compound 0.11g, productive rate is 57.9%.m.p.201-203℃。M
++1(m/z)：381。
Embodiment 34: (±) 8-(3,4-dimethoxy-benzoyl-)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (434)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 3,4-dimethoxy-Benzoyl chloride 99min. (0.25ml).Obtain target compound 0.15g, productive rate is 71.4%.m.p.148-150℃。M
++1(m/z)：423。
Embodiment 35: (±) 8-encircles penta formyl radical-1-(3,3-dimethyl--phenyl)-1,3, synthetic (435) of 8-three azepines-spiral shell [4.5] decane-4-ketone
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly ring penta formyl chloride (0.15ml, about 0.0012mol).Obtain target compound 0.13g, productive rate is 73.4%.m.p.218-220℃。M
++1(m/z)：355。
Embodiment 36: (±) 8-(2-chloro-4-nitro-benzoyl-)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (436)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--aniline)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 2-chloro-4-nitro-Benzoyl chloride 99min. (0.25ml).Obtain target compound 0.17g, productive rate is 77.3%.m.p.138-140℃。M
++1(m/z)：442。
Embodiment 37: (±) 8-(4-fluoro-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (437)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3, and 8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 4-fluoro-Benzoyl chloride 99min. (0.15ml, 0.0012mol).Obtain target compound 0.12g, productive rate is 67.9%.m.p.178-180℃。M
++1(m/z)：352。
Embodiment 38: (±) 8-(2-ethyl-butyryl radicals)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (438)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 2-ethyl-butyryl acyl chlorides (0.15ml, about 0.0012mol).Obtain target compound 0.07g, productive rate is 42.5%.m.p.218-220℃。M
++1(m/z)：329。
Embodiment 39: (±) 8-(4-methoxyl group-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (439)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 4-methoxyl group-Benzoyl chloride 99min. (0.15ml, about 0.001mol).Obtain target compound 0.13g, productive rate is 71.2%.m.p.102-103℃。M
++1(m/z)：364
Embodiment 40: (±) 8-(phenylbenzene ethanoyl)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (440)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly two phenyllacetyl chlorides (0.25ml).Obtain target compound 0.18g, productive rate is 84.7%.m.p.118-120℃。M
++1(m/z)：425。
Embodiment 41: (±) 8-(3-methoxyl group-benzoyl-)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (441)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.12g (about 0.0005mol) and excessive slightly 3-methoxy benzoyl chloride (0.15ml, about 0.001mol).Obtain target compound 0.16g, productive rate is 81.4%.m.p.138-140℃。M
++1(m/z)：393。
Embodiment 42: (±) 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-benzyl formate (442)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly carbobenzoxy chloride (0.15ml, about 0.0012mol).Obtain target compound 0.11g, productive rate is 60.3%.m.p.125-128℃。M
++1(m/z)：365。
Embodiment 43: (±) 8-[2-(3-methoxy-phenyl)-ethanoyl]-1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (443)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 3-methoxyl group-Benzoyl chloride 99min. (0.15ml, about 0.001mol).Obtain target compound 0.15g, productive rate is 75.6%.m.p.140-142℃。M
++1(m/z)：397
Embodiment 44: (±) 1-(3,5-two fluoro-phenyl)-4-[1-(4 fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl]-1,4-dimethyl diketone (444)
Compound method preparation according to compound 401.Wherein raw material is 1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 4-(3-fluoro-5-methyl-phenyl)-4-butyryl chloride (0.25ml).Obtain target compound 0.17g, productive rate is 76.4%.m.p.109-111℃。M
++1(m/z)：445。
Embodiment 45: (±) 8-(4-chloro-benzoyl-)-1-(3,5-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (445)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 4-chloro-Benzoyl chloride 99min. (0.15ml, about 0.0012mol).Obtain target compound 0.13g, productive rate is 62.9%.m.p.136-138℃。M
++1(m/z)：397。
Embodiment 46: (±)-8-benzoyl--1-(3,5-dimethyl--phenyl) 1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (446)
Compound method preparation according to compound 401.Wherein raw material is 1-(3,5-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.12g (about 0.0005mol) and excessive slightly Benzoyl chloride 99min. (0.15ml, about 0.0012mol).Obtain target compound 0.13g, productive rate is 71.6%.m.p.125-127℃。M
++1(m/z)：364。
Embodiment 47: (±) 8-(2-fluoro-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (447)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 2-fluoro-Benzoyl chloride 99min. (0.15ml, about 0.0012mol).Obtain target compound 0.10g, productive rate is 56.6%.m.p.163-165℃。M
++1(m/z)：397。
Embodiment 48: (±) 8-[2-(3-methoxyl group-phenyl)-ethanoyl]-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone (448)
Compound method preparation according to compound 401.Wherein raw material is a 1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone 0.11g (about 0.0005mol) and excessive slightly 3-methoxyl group-phenyllacetyl chloride (0.15ml, about 0.0012mol).Obtain target compound 0.14g, productive rate is 73.8%.m.p.121-123℃。M
++1(m/z)：380。
Following biological test is used for further specifying the present invention.
Embodiment 49: the analgesic activity of embodiment compound
Experiment purpose: measure the analgesic activities of compound on mouse acetic acid twisting model
Experiment material: Kunming mouse (18-22g), male and female half and half are provided by Military Medical Science Institute's Experimental Animal Center.
Experimental technique:
Mouse is weighed, and mark divides into groups, and 10 every group, gastric infusion (40mg/kg).After 40 minutes, abdominal injection 0.6% acetic acid 0.4ml is recorded in the number of times of mouse writhing in 15 minutes subsequently after 5 minutes, be calculated as follows the inhibiting rate of medicine to the mouse acetic acid twisting, thereby estimates the analgesic effect of medicine, and the result sees table 1.
Table 1: mouse acetic acid twisting experimental result
| Implement compound number | Turn round body inhibiting rate % | Every treated animal quantity (only) |
| ZC1 (positive control) | 54.4 | 10 |
| 401 | 68.8 | 10 |
| 402 | 34.0 | 10 |
| 403 | 23.2 | 10 |
| 404 | 44.2 | 10 |
| 405 | 7.9 | 10 |
| 406 | 41.4 | 10 |
| 413 | 27.3 | 10 |
| 414 | 2.73 | 10 |
| 418 | 5.8 | 10 |
| 423 | 35.5 | 10 |
| 424 | 0 | 10 |
| 425 | 0 | 10 |
| 434 | 58.6 | 10 |
| 435 | 28.8 | 10 |
| 436 | 0 | 10 |
| 439 | 0 | 10 |
| 443 | 16 | 10 |
| 445 | 40.4 | 10 |
| 447 | 7.3 | 10 |
| 448 | 0 | 10 |
Above embodiment compound analgesic activity evaluation result shows that The compounds of this invention shows significant analgesia role on mouse acetic acid twisting model.
Embodiment 50: the N-type Calcium Current of embodiment compound suppresses active
Experiment purpose: measure the N type calcium channel (α of compound to the xenopus leavis oocytes transient expression
1B/ β
1b/ α 2
δ) the electric current restraining effect.
Experiment material: xenopus leavis oocytes.
Experimental technique:
(1) microbial culture
100LB solution, 100 μ L penbritins, 1ml express alpha
1BIntestinal bacteria under 37 ℃, with 200 rev/mins rotating speed joltings 12-17 hour, subsequent use.
(2) extract plasmid
Get the 4ml bacterial cultures centrifugal 5 minutes, abandon or adopt light liquid, and test tube is inverted in to inhale on the paper handkerchief removes remaining nutrient solution with desk centrifuge (13000g).
Add 250 μ L cell suspending liquids, vortex concussion or piping and druming is with abundant suspension cell (cell fully suspends very crucial), with the cell transfer that suspends to the sterilization centrifuge tube of 5ml (note: later on not again the vortex concussion in order to avoid cut off chromosomal DNA).Add 250 μ L cell pyrolysis liquids and put upside down 4 times, with thorough mixing.The about 1-5 of incubation time minute, surpass 5 minutes, otherwise breach (note: the preceding observation of adding alkaline protease solution lysate is partly clarified very necessary, but incubation time is not above 5 minutes) can appear in DNA.
Add 10 μ L alkaline protease solutions and put upside down centrifuge tube 4 times, in incubated at room 5 minutes with thorough mixing.The albumen that can influence the separation quality grain quality that discharges in basic protein endonuclease capable deactivation nucleicacidase and other bacterium cracking process.
Add 350 μ L neutralizers and put upside down 4 times rapidly with thorough mixing, in room temperature with cell pyrolysis liquid centrifugal 10 minutes with top speed (14000g).
About 850 μ L transfer in the ready centrifugal post with clarifying lysate, do not stir or any white precipitate and supernatant are together shifted.
, take off centrifuge tube and discard the liquid the collection tube with top speed centrifugal 1 minute with whizzer, centrifugal post is inserted on the collection tube again from collection tube in room temperature.
Add the post scavenging solution that 750 μ L had before crossed with 95% alcohol dilution.
, take off centrifuge tube and discard the liquid the collection tube with top speed centrifugal 1 minute with whizzer, centrifugal post is inserted on the collection tube again from collection tube in room temperature.
Add 250 μ L posts and clean, repeated washing once.
With whizzer with top speed centrifugal 2 minutes in room temperature.
Centrifugal post is transferred in the new 1.5ml disinfectant centrifuge tube, needs during operation carefully scavenging solution and centrifugal post together not to be shifted.
Centrifugal post is transferred in the new 1.5ml disinfectant centrifuge tube, adds the water that enzyme is calculated in 100 μ L stonings, with wash-out DNA (can wait 2 minutes, be convenient to dissolve fully), in room temperature with whizzer with maximum velocity centrifugation 1 minute.
Behind the wash-out centrifugal post is taken out, and abandon it.Merging centrifugate preserves subsequent use under-20 ℃ of conditions.
(3) separation of xenopus leavis oocytes and cultivation
Instruments was soaked 30 minutes in 75% ethanol, take out airing.No. 5 silk thread was sterilized in boiling water 10 minutes.
Xenopus laevis is buried in the trash ice about 40 minutes, makes its anesthesia.Take out the Xenopus laevis of having anaesthetized, belly upwards places on the trash ice of tiling, and buries its head and four limbs with trash ice.With cotton ball soaked in alcohol sterilization abdomen skin, provoke (taking back or be right in the center) with syringe needle then, cut off the osculum about 1cm with eye scissors.Use the same method and cut off muscle layer (note not damaging any internal organs, cut off muscle layer then can see ovocyte).Take out 1cm with tweezers and scissors
3The leaflet of size is put into the nutrient solution ware of the preprepared OR-2 of containing (containing penicillium mould), respectively suture muscles layer and skin layer.
Ovocyte transferred to repeat in the aseptic Glass tubing to clean, till cleaning residual blood with OR-2 solution.Add the collagenase solution jolting and digested about 1 hour, change new collagenase solution and continue about 1 hour of jolting (can see that great majority have separated or individual cells this moment).
Remove Digestive system, clean 5-6 time, change over to and select sophisticated cell of V phase in the petridish that fills ND-96 solution and place ND-96 solution with OR-2 solution, subsequent use with biochemical incubator preservation under 1 ℃ of condition, change liquid every day once.
(4) inject plasmid
With plasmid α
1B, α
2δ, β
1bInject xenopus leavis oocytes according to 1: 1: 1 ratio, each cell injects 50nM approximately.Cell after the injection places the ND-96 nutrient solution, and temperature is placed for 18 ℃ and cultivated record current after 48 hours.
(5) electric current record
The administration of perfusion method, flow velocity are 3ml/min, and drug level is 50 μ mol/L.Adopting two electrodes voltage clamp technology, built in-100mV, is step with 10mV with cell clamp, and depolarize is to+60mV, record current.
N-type Calcium Current suppresses experimental result and sees table 2.
Table 2:N-type Calcium Current suppresses experimental result
| Compound number | Electric current inhibiting rate % | Number of cells |
| 402 | 59±1.8 | 3 |
| 405 | 78±3.7 | 3 |
| 406 | 85±2.7 | 3 |
Claims (5)
1. compound, its optical antipode, raceme or pharmacologically acceptable salt, said compound is selected from:
(±) 8-(3-methoxyl group-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(3-methyl-butyryl radicals)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone),
(±) (1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl)-ketone-methyl acetate,
(±) 8-encircles penta formyl radical-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(3,3-dimethyl--butyryl radicals)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) (1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone-8-yl)-ketone-ETHYLE ACETATE,
(±) 8-[2-(4-methoxyl group-phenyl-ethanoyl)-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(4-chloro-benzoyl-)-1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(2-fluoro-benzoyl-)-1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-encircles penta formyl radical-1-(4-fluoro-phenyl-)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) (2-chloro-4-nitro-benzoyl-)-1-(4-fluoro-phenyl-)-8-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(3,4-dimethoxy-benzoyl-)-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-encircles penta formyl radical-1-(3,3-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-[2-(3-methoxy-phenyl)-ethanoyl]-1-(4-fluoro-phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone,
(±) 8-(4-chloro-benzoyl-)-1-(3,5-dimethyl--phenyl)-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone and
(±) 8-(2-fluoro-benzoyl-)-1-phenyl-1,3,8-three azepines-spiral shell [4.5] decane-4-ketone).
2. pharmaceutical composition, said pharmaceutical composition comprises at least a compound as claimed in claim 1, its optical antipode, raceme or pharmacologically acceptable salt and one or more pharmaceutically acceptable carrier or vehicle.
3. compound as claimed in claim 1 is used to prepare the purposes of the medicine that prevents and/or treats illness, habituation property and tolerance that said illness is selected from pain and is caused by analgesic.
4. purposes as claimed in claim 3, wherein said analgesic are the opium kind analgesics thing.
5. purposes as claimed in claim 3, wherein said pain are postoperative pain, migraine, Encelialgia or neuropathic pain.
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