CN101065355A - N- [ (3s)- pyrrolidin-3-yl]- benzamide derivatives as monoamine re-uptake inhibitors - Google Patents

N- [ (3s)- pyrrolidin-3-yl]- benzamide derivatives as monoamine re-uptake inhibitors Download PDF

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CN101065355A
CN101065355A CNA2005800401025A CN200580040102A CN101065355A CN 101065355 A CN101065355 A CN 101065355A CN A2005800401025 A CNA2005800401025 A CN A2005800401025A CN 200580040102 A CN200580040102 A CN 200580040102A CN 101065355 A CN101065355 A CN 101065355A
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tetramethyleneimine
compound
benzamide
chloro
methyl
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保罗·文森特·菲什
托马斯·瑞克曼斯
艾伦·斯多比
弗罗云·瓦肯呼特
盖文·阿里斯戴尔·惠特洛克
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Pfizer Inc
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
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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
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical

Abstract

A compound of Formula (I) and pharmaceutically and/or veterinarily acceptable derivatives thereof, wherein: R<1>, R<2>, R<3> and R<20 >are each independently H, CI, Br, F, I, CF3, OCF3, Me or Et; R<4> is het or C3-7 cycloalkyl optionally substituted by C1-4 alkyl, C1-4 alkoxy, alkoxyalkyl containing 2 to 4 carbon atoms or -S-(C1-4 alkyl); a is 0 or 1; and het is a non-aromatic 4-, 5- or 6- membered heterocycle which contains at least one N, O or S heteroatom, optionally fused to a 5- or 6- membered carbocyclic group or a second 4-, 5- or 6-membered heterocycle which contains at least one N, O or S heteroatom, wherein the het group is optionally substituted by at least one substituent independently selected from C1-8alkyl, C1-8alkoxy, OH, halo, CF3, OCF3, SCF3, hydroxy-C1-6alkyl, C1-4 alkoxy-C1-6alkyl and C1-4 alkyl-S-C1-4alkyl; provided that at least one of R<1>, R<2> and R<3> are other than H. The compounds of the invention exhibit activity as both serotonin and noradrenaline re-uptake inhibitors and therefore have utility in a variety of therapeutic areas, for example urinary incontinence.

Description

N-[(3s as the monoamine reuptake inhibithors)-tetramethyleneimine-3-yl]-benzamide derivatives
The present invention relates to suppress the resorbent novel amidation compound of monoamine, its preparation method comprises its pharmaceutical composition, and relates to its purposes in medicine.
Compound of the present invention shows the activity as serotonin and/or noradrenaline reuptake inhibitor, and thereby has practicality in various treatments field.For example, compound of the present invention can be used for treating the illness that the wherein regulation and control of monoamine translocator function are affected, and more specifically, treats the illness that serotonin wherein or the resorbent inhibition of norepinephrine are affected.In addition, compound of the present invention can be used for the illness that the wherein inhibition of serotonin and norepinephrine all is affected, such as the urinary incontinence.In addition, compound of the present invention can be used for wherein may wishing that one of them preferentially suppresses alternative resorbent illness with respect to norepinephrine or serotonin, such as pain pain, and fibromyalgia, attention-deficit hyperactivity disease and depression.
According to first aspect, the invention provides the compound of formula (I),
Figure A20058004010200061
With and pharmaceutically and/or veterinarily acceptable derivative, wherein:
R 1, R 2, R 3And R 20Be H independently of one another, Cl, Br, F, I, CF 3, OCF 3, Me or Et;
R 4Be het or C 3-7Cycloalkyl is randomly by C 1-4Alkyl, C 1-4Alkoxyl group contains the alkoxyalkyl of 2 to 4 carbon atoms, or-S-(C 1-4Alkyl) replaces;
A is 0 or 1; And
Het is the 4-of non-fragrance, 5-or 6-unit heterocycle, it comprises at least one N, O or S heteroatoms, randomly be fused to 5-or 6-unit's carbon ring group or comprise at least one N, heteroatomic the 2nd 4-of O or S, 5-or 6-unit heterocycle, wherein this het group is randomly replaced by at least one substituting group, and described at least one substituting group is independently selected from C 1-8Alkyl, C 1-8Alkoxyl group, OH, halogen, CF 3, OCF 3, SCF 3, hydroxyl-C 1-6Alkyl, C 1-4Alkoxy-C 1-6Alkyl and C 1-4Alkyl-S-C 1-4Alkyl;
Condition is R 1, R 2And R 3In at least one be not H.
In embodiments of the present invention, R 1Be Cl, Br, F, I, CF 3, Me or Et; R 2And R 3Be H independently of one another, Cl, Br, F, I, CF 3, Me or Et.In another embodiment, R 1And R 2Be Cl independently of one another, Br, F, I, CF 3, Me or Et, and R 3Be H, Cl, Br, F, I, CF 3, Me or Et.In another embodiment, R 1Be Cl, Me or CF 3R 2Be H, Cl or F; And R 3Be H, Cl or F.
According to another embodiment of the present invention, R 2And R 20Not H.In such embodiment, R 2And R 20Can be Cl independently of one another, F, CF 3, Me or Et.
According to another embodiment of the present invention, R 1, R 2And R 20Not hydrogen.In such embodiment, R 1, R 2And R 20Can be Cl independently of one another, F, CF 3, Me or Et.
According to another embodiment of the present invention, R 1, R 3And R 20Not hydrogen.In such embodiment, R 1, R 3And R 20Can be Cl independently of one another, F, CF 3, Me or Et.
According to above-mentioned any embodiment of the present invention, R 4Can be C 3-7Cycloalkyl is randomly by C 1-4Alkyl, C 1-4Alkoxyl group, comprise 2 to 4 carbon atoms alkoxyalkyl or-S-(C 1-4Alkyl) replaces.According to another embodiment, R 4Can be C 3-7Cycloalkyl is randomly replaced by Me or Et.
According to above-mentioned any embodiment of the present invention, a can be 0.
According to above-mentioned any embodiment of the present invention, described het group can be by one, two or three substituting groups replacements, and described substituting group is independently selected from halogen, OH, C 1-4Alkyl and CF 3In another embodiment, with reference to a first aspect of the present invention and any embodiment in the above the het group of defined compound can be unsubstituted.
In another embodiment, the invention provides and be selected from following compound:
2,3-two chloro-N-cyclopentyl-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
2,3-two chloro-N-cyclopentyl-4-fluoro-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
3-chloro-N-cyclopentyl-2-methyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
N-cyclopentyl-3-fluoro-2-methyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
2-chloro-N-cyclopentyl-3-fluoro-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
2,3-two chloro-N-cyclohexyl-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
2-chloro-N-cyclohexyl-3-fluoro-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
N-cyclohexyl-3-fluoro-2-methyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
2,3-two chloro-N-cyclobutyl-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
N-cyclobutylmethyl-2,3-two chloro-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
2,3-two chloro-N-(cyclopropyl methyl)-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
2,3-two chloro-N-[(3S)-tetramethyleneimine-3-yl]-N-tetrahydrochysene-2H-pyrans-4-yl-benzamide,
2-chloro-N-cyclopentyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
2-chloro-N-cyclohexyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
2-chloro-N-suberyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
The N-suberyl-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide,
The N-cyclohexyl-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide,
The N-cyclopentyl-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide,
2,3-two chloro-N-[(1-methyl cyclopropyl) methyl]-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
3-chloro-2-methyl-N-[(1-methyl cyclopropyl) methyl]-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
N-(cyclobutylmethyl)-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide,
Or it pharmaceutically and/or veterinarily acceptable derivative.
Pharmaceutically and/or the implication of veterinarily acceptable derivative be, pharmaceutically any or veterinarily acceptable salt, solvate, ester or the acid amides of formula (I) compound, or the salt of above-mentioned ester or acid amides or solvate, perhaps any other can (or directly) when being administered into the recipient provides the compound of formula (I) compound or its active metabolite or resistates indirectly.
For pharmacy or veterinary science purposes, above-mentioned salt will be for pharmaceutically or veterinarily acceptable salt, and still, other salt for example can be used for preparation formula (I) compound and pharmaceutically or veterinarily acceptable salt.
Above-mentioned pharmaceutically or veterinarily acceptable salt comprise its acid-adducting salt and its alkali salt.
Suitable acid-adducting salt is formed by the acid that forms non-toxic salt.The example comprises acetate, aspartate, benzoate, benzene sulfonate, bicarbonate/carbonate, hydrosulfate/vitriol, d-camphorsulfonic acid salt, Citrate trianion, half Citrate trianion, ethanedisulphonate, half ethanedisulphonate, esilate, fumarate, gluceptate, gluconate, glucosiduronate, hibenzate, hydrogen chlorate/muriate, hydrobromate/bromide, hydriodate/iodide, hydroxyethylsulfonic acid, lactic acid salt, malate, maleate, malonate, mesylate, Methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, Orotate, embonate, phosphate/phosphor acid hydrogen salt/dihydrogen phosphate, sugar lime, stearate, succinate, tartrate and tosylate.
Suitable alkali salt is formed by the alkali that forms non-toxic salt.The example comprises aluminium salt, arginic acid salt, benzyl star salt, calcium salt, choline salt, diethyl amine salt, diethanolamine salt, glycinate, lysine salt, magnesium salts, meglumine salt, ethanolamine salt, sylvite, sodium salt, trimethanolamine salt and zinc salt.
For the summary of suitable salt, referring to " Handbook ofPharmaceutical Salts:Properties, Selection, and Use " (Wiley-VCH, Weinheim, Germany, 2002) of Stahl and Wermuth.
The pharmacy acceptable salt of formula (I) compound can easily be prepared as required by the solution of compound and the acid or the alkali of expectation are mixed.Salt can be precipitated out from solution, and collects by filtering, and perhaps reclaims by evaporating solvent.The degree of ionization of salt can change in the scope from complete ionization to nonionicization almost.
Pharmaceutically acceptable solvate according to the present invention comprises the hydrate and the solvate of formula (I) compound.
Being included in equally in the scope of the present invention is following complex compound, such as inclusion compound, and medicine-main body inclusion complex (wherein different with aforesaid solvate is that medicine and main body exist with stoichiometry or nonstoichiometry).Being included in equally in the scope of the present invention is the complex compound of described medicine, and it comprises two or more a plurality of organic and/or inorganic component, described organic and/or inorganic component can be stoichiometry or the nonstoichiometry amount.The complex compound of gained can be Ionized, partial ionization or nonionicization.For the summary of such complex compound, referring to the J Pharm Sci of Haleblian, 64 (8), 1269-1288 (August 1975).
Formula (I) compound can be in compound any functional group place modified, to provide it pharmaceutically or veterinarily acceptable derivative.The example of such derivative exists: Drugs of Today, and Volume 19, and Number 9,1983, pp 499-538; Topics in Chemistry, Chapter 31, pp 306-316; With " the Design of Prodrugs " of H.Bundgaard, Elsevier, 1985, among the Chapter 1 (disclosure in the above-mentioned file is contained in this by reference) description is arranged, and comprise: ester, carbonic ether, half-ester, phosphoric acid ester, nitro ester, sulfuric ester, sulfoxide, acid amides, sulfanilamide (SN), carbaminate/ester, azo-compound, phosphamide, glycoside, ether, acetal and ketal.
Those skilled in the art also will understand, some group (being called as " preceding group (pro-moieties) " in the art), for example as H.Bundgaard described in " Design of Prodrugs " (the same), can be disposed in the suitable functional group, and such functional group is present in the compound of the present invention.
Because the unsymmetrical carbon of tetramethyleneimine-3-base group, and as can be by R 4The more unsymmetrical carbon that some implication limited, formula (I) compound comprises one or more chiral centres.Though the stereochemistry at the 3rd place is a fixed, any other chiral centre can exist with any possible stereoisomeric forms in any ratio.
Should be appreciated that, the present invention has covered all isomer of compound of the present invention, comprise all rotamerisms, tautomerism and optical siomerism form (except the chiral centre at the 3rd place of pyrrolidyl), and composition thereof (for example tautomerism or racemic mixture).
Compound of the present invention exists with one or more tautomeric forms.All tautomers and composition thereof are included in the scope of the present invention.For example, the claim of claimed 2 hydroxy pyrimidine base also will cover its tautomeric form α-pyriconyl.
Should be appreciated that, the present invention includes through radiolabeled formula (I) compound.
Pharmaceutically also possibility can be to exist more than a kind of crystalline form with veterinarily acceptable derivative for formula (I) compound and its, and this is the characteristic that is called as polymorphism.All such polycrystalline forms (" polymorphic ") are included in the scope of the present invention.Polymorphism generally may take place owing to temperature or pressure or both variations, and can be caused by the variation of crystallisation process.Polymorphic form can be distinguished by multiple physical property, and usually, X-ray diffraction pattern, solubility property and the fusing point of compound are used to distinguish polymorphic form.
Except as otherwise noted, any alkyl can be straight chain or branching, and has 1 to 8 carbon atom, such as 1 to 6 carbon atom or 1 to 4 carbon atom, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl or the tertiary butyl.If alkyl comprises the carbon atom more than, it can be undersaturated.Therefore, term C 1-6Alkyl comprises C 2-6Thiazolinyl and C 2-6Alkynyl.Similarly, term C 1-8Alkyl comprises C 2-8Thiazolinyl and C 2-8Alkynyl, and term C 1-4Alkyl comprises C 2-4Thiazolinyl and C 2-4Alkynyl.
Term halogen is used to represent fluorine, chlorine, bromine or iodine.
Except as otherwise noted, term het comprises any non-fragrance, saturated or unsaturated 4-, and 5-or 6-unit heterocycle, it comprises at the most 4 and is selected from N, the heteroatoms of O and S.The example of such heterocyclic radical comprises furyl, thienyl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, dioxolanyl oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidyl, pyrazolyl, pyrazolinyl, pyrazolidyl isoxazolyl, isothiazolyl oxadiazole base, triazolyl, thiadiazolyl group, pyranyl, THP trtrahydropyranyl, pyridyl, piperidyl alkyl dioxin, morpholino, the dithiane base, thiomorpholine generation, pyridazinyl, pyrimidyl, pyrazinyl, piperazinyl, the thia cyclopentyl, tetrazyl, triazinyl, the azatropylidene base, oxygen azatropylidene base, sulphur azatropylidene base, diazepine base and thiazolinyl.In addition, the term heterocycle comprises the annelated heterocycles base, for example benzimidazolyl-, benzoxazolyl, imidazopyridyl, benzoxazinyl, benzothiazine Ji, oxazole and pyridyl, benzofuryl, quinolyl, quinazolyl, quinoxalinyl, dihydroquinazoline base, benzothiazolyl, benzene imide base, benzodiazepine base, indyl and pseudoindoyl.Term " het ", " heterocyclic radical " has similar explanation with " heterocyclic ".
For fear of query, except as otherwise noted, term " substituted " means by one or more and limits the group replacement.Can be selected from group under the situation of a plurality of optional groups, selected group can be identical or different.In addition, term " independently " is if mean from a plurality of possible substituting groups and select substituting group more than one, and then these selected substituting groups can be identical or different.
After this, formula (I) compound and its pharmaceutically with veterinarily acceptable derivative, aforementioned substances through radiolabeled analogue, the isomer of aforementioned substances and the polymorphic form of aforementioned substances are called as " compound of the present invention ".
In an embodiment of the invention, compound of the present invention be formula (I) compound pharmaceutically with veterinarily acceptable derivative, all suc as formula (I) compound pharmaceutically or veterinarily acceptable salt or solvate (for example formula (I) compound pharmaceutically or veterinarily acceptable salt).
In another embodiment of the present invention, a kind of compound of the present invention is provided, it is serotonin and/or the resorbent inhibitor of norepinephrine monoamine, has 200nM or littler SRI or NRI K iValue.In another embodiment, this compound has 100nM or littler SRI and/or NRI K iValue.In another embodiment, this compound has 50nM or littler SRI and/or NRI K iValue.In another embodiment, this compound has 50nM or littler SRI and/or NRI K iValue.In also having an embodiment, this compound has 25nM or littler SRI and/or NRI K iValue.
According to scheme 1, formula V compound (promptly wherein a is 1 formula (I) compound) can be by formula (VI) compound, by with aldehyde R 4CHO reaction, then with shown in acid or carboxylic acid halides (promptly wherein X is OH or halogen) reaction and deprotection, prepare.
Scheme 1
In the superincumbent scheme, R 1, R 2, R 3, R 4And R 20As defined above, a be 1 and PG be suitable blocking group.
(a)-reduction amination
It is reductive amination process that 1 ° of amine (VI) generates 2 ° of amine (VII) with aldehyde reaction, and wherein, after the dehydration of amine and aldehyde, the imines that is generated at room temperature, reduces by metal hydride reagent or by hydrogenation in suitable solvent.
In this reaction, use or triacetyl oxygen sodium borohydride (STAB) NaCN (BH) usually 3Perhaps NaBH 4, (DCM for example at room temperature handled the amine of equimolar amount and aldehyde in THF) 1 to 24 hour at suitable solvent.Perhaps, at amine with after the mixed 1-18 of aldehyde hour, add and to be in suitable solvent (THF for example, MeOH, EtOH) excessive reductant in (NaBH for example 4, LiAlH 4, STAB), randomly, add siccative (for example molecular sieve) or utilize the Dean-Stark device to adopt suitable solvent (for example toluene, dimethylbenzene) to remove water.Another kind of alternative is included under the existence of palladium or nickel catalyzator (for example Pd/C, Raney  Ni), at H 2In the atmosphere, randomly under the temperature and pressure that raises, in suitable solvent (for example EtOH), carry out catalytic hydrogenation.
The example more specifically of reduction amination comprises or in the presence of 10%Pd/C, randomly in the presence of triethylamine, in ethanol, under the hydrogen of about 415kPa (about 60psi), handled aldehyde 18 hours in room temperature with amine, perhaps the excessive sodium borohydride in being in methyl alcohol in the presence of, at room temperature handled aldehyde 6 hours with amine.
To be clear that for those skilled in the art, in the reduction amination step, under appropriate condition, can use ketone or other suitable contain carbonyl reagent, replace aldehyde.
(b)-acid amides formation
The formation of the peptide bond between acid or carboxylic acid halides and the amine (VII) can be undertaken by using following scheme:
(i) carboxylic acid halides and amine (VII) adopt excessive acid acceptor, in suitable solvent, perhaps
(ii) acid (randomly comprising conventional coupling agent) and amine (VII) randomly in the presence of catalyzer, adopt excessive acid acceptor, in suitable solvent.
The example of such reaction is as follows:
(i) with acyl chlorides (randomly, original position generates) and excessive amine (VII) reaction, randomly, use 3 ° of excessive amine, such as Et 3N, H ü nig ' s alkali or NMM, at DCM, in the toluene Huo diox, randomly at elevated temperatures, reaction was carried out 1 to 24 hour;
(ii) with acid, WSCDI/DCCI/TBTU and HOBT/HOAT and excessive amine (VII) and excessive N MM, Et 3N, H ü nig ' s alkali, at room temperature, reacted 4 to 48 hours among DCM or the EtOAc at THF; Perhaps
(iii) with acid and PYBOP /PyBrOP /Mukaiyama ' s reagent and excessive amine (VII) and excessive N MM, Et 3N, H ü nig ' s alkali are at THF, and toluene among DCM or the EtOAc, at room temperature reacted 4 to 24 hours.
If carboxylic acid halides is acyl chlorides (being X=Cl), then it can generate by the standard method original position, reacts 90 minutes down at 70 ℃ in methylene dichloride with amine (VII) and triethylamine then.
(c)-deprotection
If PG is suitable amine-blocking group, preferred BOC, trifluoro-acetate or phenmethyl, then come to remove PG from (VIII) by this blocking group being had optionally method, to form amine (V) without protection, described method is at TW Greene and PGM Wuts " Protective Groups inOrganic Synthesis ", the third edition, John Wiley ﹠amp; Sons, Inc. has a detailed description in 1999, and it is contained in this by reference.
The example of such deprotection reaction is as follows:
When PG was BOC, deprotection comprised that (HCl for example TFA) at room temperature handles (VIII) in suitable solvent (for example DCM, EtOAc ， diox) with excessive strong acid.
When PG was trifluoro-acetate, deprotection comprised with alkali (K for example 2CO 3, Na 2CO 3, NH 3, Ba (OH) 2) alcoholic solvent (MeOH for example, EtOH) in, randomly make water and randomly at elevated temperatures, handle (VIII).
When PG was Bz, deprotection comprised and utilizes transition metal or transition metal salt hydrogenation catalyst (Pd/C for example, Pd (OH) 2), at hydrogen donor (NH for example 4 +HCO 2 -) existence under polar solvent (for example tetrahydrofuran (THF), ethanol, methyl alcohol), randomly under temperature that raises and/or pressure, carry out transfer hydrogenation, perhaps under the existence of palladium or nickel catalyzator (for example Pd/C, Raney  Ni), at H 2Under the atmosphere, randomly under the temperature and pressure that raises, in suitable solvent, carry out catalytic hydrogenation.
More specifically:
When PG was BOC, deprotection comprised that the excessive 4M spirit of salt that is used in the diox at room temperature handled 18 hours, or at room temperature handles 4.5 hours with the TFA among the DCM.
When PG was trifluoro-acetate, deprotection comprises used K 2CO 3At methyl alcohol: water mixture was at room temperature handled 18 hours in (5: 1 to 10: 1).
When PG was Bz, deprotection comprises used NH 4 +HCO 2 -With 10%Pd/C in ethanol under the gentle reflux condition, handled 6 to 20 hours.
By the alternative method of primary amine (VI) preparation secondary amine compound (VII) below scheme 1a and scheme 1b in be described.
Scheme 1a
Figure A20058004010200151
Wherein PG is suitable blocking group, R 4As defined above.
According to scheme 1a, formula VII compound can by reacting with SULPHURYL CHLORIDE, then with the alkylation of gained sulfanilamide (SN), be removed sulfonyl group then by formula VI compound, prepares.
(aa) preparation of sulfanilamide (SN) with the primary amine (VI) of equimolar amount and SULPHURYL CHLORIDE (such as 2, the 4-dinitrophenyl chloride) at suitable solvent (such as DCM, THF or toluene) in, at organic bases (such as pyridine or 2, the 6-lutidine) or under the existence of mineral alkali (such as carbonate), reaction 24 hours at the most obtains sulfanilamide (SN) (XAA).
(bb) alkylation of sulfanilamide (SN) XAA utilizes activatory alkylating agent XBB (wherein X is the cancellation group, such as halogen (such as iodine, bromine or chlorine) or sulphonate (such as methanesulfonates)), in the presence of organic bases or mineral alkali, in suitable solvent (such as DMF or THF), with the sulfanilamide (SN) alkylation of formula XAA.Perhaps, the alkylation of the sulfanilamide (SN) of formula XAA can realize by the following method: utilize pure XBB (wherein X is OH), phosphine (such as triphenylphosphine) and azo-2-carboxylic acid's ester cpds (such as DIAD), at suitable solvent, in THF, under the temperature of 45C, handled 24 hours at the most at-20C.
(cc) removal of alkylsulfonyl is adopted at suitable solvent (such as DCM; THF or lower alcohol) in organic bases (such as triethylamine) or mineral alkali (such as carbonate or oxyhydroxide); and with mercaptan (such as Thiovanic acid); randomly at elevated temperatures, with formula XCC compound treatment 24 hours at the most.
Scheme 1b
In the superincumbent scheme, R 4As defined above, and PG be blocking group.
Acidylate-reduction
According to scheme 1b, formula (VII) compound can be by the amine of 1 ° of formula (VI), by with carboxylic acid or carboxylic acid halides AAA (randomly, in-situ preparing) R 4COX (wherein X is OH or halogen) with reductive agent (such as borine) reaction, prepares then.
(x)-acid amides formation
The formation of the peptide bond between acid or carboxylic acid halides and the amine (VI) can be undertaken by following scheme:
(i) carboxylic acid halides and amine (VI) adopt excessive acid acceptor, in suitable solvent, perhaps
(ii) acid (randomly comprising conventional coupling agent) and amine (VI) randomly in the presence of catalyzer, adopt excessive acid acceptor, in suitable solvent.
The example of such reaction is as follows:
(iv), randomly, use 3 ° of excessive amine, such as Et with acyl chlorides (randomly, original position generates) and excessive amine (VI) reaction 3N, H ü nig ' s alkali or NMM, in DCM Huo diox, randomly at elevated temperatures, reaction was carried out 1 to 24 hour;
(v) with acid, WSCDI/DCCI/TBTU and HOBT/HOAT and excessive amine (VI) and excessive N MM, Et 3N, H ü nig ' s alkali, at room temperature, reacted 4 to 48 hours among DCM or the EtOAc at THF; Perhaps
(iii) with acid and 1-propyl phosphate cyclic acid anhydride/PYBOP /PyBrOP /Mukaiyama ' s reagent and excessive amine (VI) and excessive N MM, Et 3N, H ü nig ' s alkali, at room temperature reacted 4 to 24 hours among DCM or the EtOAc at THF.
The example more specifically that acid amides forms comprises, in the presence of 1-propyl phosphate cyclic acid anhydride, and in the presence of triethylamine, in DCM, at room temperature, handles acid 1 hour with amine.
If carboxylic acid halides is acyl chlorides (being X=Cl), then it can generate by the standard method original position, reacts 90 minutes down at 70 ℃ in methylene dichloride with amine (VI) and triethylamine then.
(y)-reduction
Reaction (y) is that acid amides is for example by the reduction of hydride reducer under appropriate condition.
Easily, the reduction of acid amides is performed as follows: in the presence of borine, refluxed 2 hours in THF, add methyl alcohol and aqueous ammonium chloride then, refluxed 4 hours.
According to scheme 2, formula (IX) compound can be by formula (VI) compound, by with R 4-(CH 2) a-L (wherein a as defined above, L is the cancellation group) reacts under appropriate condition, prepares.Then, the formula of gained (IX) compound can transform an accepted way of doing sth (I) compound by to carry out acid amides formation and deprotection with top at scheme 1 described similar mode.
Scheme 2
Figure A20058004010200181
In the superincumbent scheme, R 1, R 2, R 3, R 4, R 20With a as defined above, PG is suitable blocking group, and L is the cancellation group, its implication will depend on reaction property and used concrete reaction conditions etc.Suitable cancellation group will be clearly for those skilled in the art, and in the organic chemistry teaching material of many standards, description is arranged, for example: " Advanced Organic Chemistry ", Jerry March, Third Edition, Wiley (1985), page 587, and it is contained in this by reference; The cancellation group comprises halogen (for example Br) and sulphonate (for example methane sulfonate or trifluoromethayl sulfonic acid ester).
According to scheme 3, formula (IX) compound can be by the ketone of formula (XII), by with primary amine R 4-(CH 2) a-NH 2Under appropriate condition, react, prepare.Then, the formula of gained (IX) compound can transform an accepted way of doing sth (I) compound by to carry out acid amides formation and deprotection with top at scheme 1 described similar mode.
Scheme 3
In the superincumbent scheme, R 1, R 2, R 3, R 4, R 20With a as defined above, PG is suitable blocking group.
Primary amine R 4-(CH 2) a-NH 2With the reaction (e) of ketone (XII) can be reductive amination process expediently, wherein, after the dehydration of amine and ketone, for example by metal hydride reagent or by hydrogenation, the imines to gained under appropriate condition reduces.
Easily, the reaction of amine and ketone is performed as follows: in the presence of the four different third oxygen titaniums (IV), at room temperature carried out 18 hours in THF, at room temperature reduced in methyl alcohol 5 hours by excessive sodium borohydride then.
Those skilled in the art can select the only synthetic route for desired compound according to formula (I).Certainly, top scheme can be made amendment on demand according to those skilled in the art's known technology.
It will be understood by those skilled in the art that in the building-up process of formula (I) compound, one or more responsive functional groups may need protected and deprotection.This can realize by routine techniques, for example as " Protective Groups in Organic Synthesis " at TW Greene and PGM Wuts, 3rdedition, John Wiley ﹠amp; Sons, Inc., the technology described in 1999 (they are contained in this by reference), the document has also been described the method that is used to remove these groups.
Those skilled in the art are with clear; some of compound of the present invention may itself not have pharmaceutical active through the derivative (it can be to be produced before the stage at final deprotection) of protection; but in some cases; can be by oral or administered parenterally; metabolism in vivo afterwards forms the compound of the present invention with pharmaceutical active.Therefore such derivative can be called as prodrug.In addition, some compound of the present invention can serve as the prodrug of other compound of the present invention.
Therefore, according to a further aspect in the invention, provide the method that is used for preparation formula (I) compound, described method comprises: with formula (IX) compound:
Figure A20058004010200201
R wherein 4With a as defined above, PG is a blocking group, and the acid of formula (II) or carboxylic acid halides formula (II) reaction:
Wherein X is OH or halogen,
And, deprotection.
If a is 1, then formula (IX) compound can pass through formula (VI) compound and aldehyde R 4CHO reacts and prepares.
Figure A20058004010200211
Perhaps, formula (IX) compound can pass through formula (VI) compound and compound R 4-(CH 2) a-L (wherein L is the cancellation group, randomly is selected from halogen, methane sulfonate and trifluoromethayl sulfonic acid ester) reaction prepares.
In addition, formula (IX) compound can pass through formula (XII) compound and compound R 4-(CH 2) a-NH 2Reaction prepares.
Figure A20058004010200212
Some intermediate recited above is novel compound, should be appreciated that all novel intermediates have constituted others of the present invention here.
Racemic compound can utilize preparation HPLC to separate with the post with chiral stationary phase, perhaps uses method known to those skilled in the art to split, to obtain each enantioner.In addition, the chiral intermediate compound can be split, and is used to prepare the compound of the present invention of chirality.
The metabolite that forms in vivo of one or more compounds of the present invention is provided according to a further aspect in the invention.
Compound of the present invention can have following advantage, and it is more effective, has longer acting duration, have the more activity of wide region, more stable, have side effect still less, have more selectivity, have better film-making performance, perhaps have the performance more useful than the compound of prior art.
Compound of the present invention is useful, because it has pharmaceutical active in comprising people's Mammals.Therefore, it can be used for the illness for the treatment of or preventing the wherein regulation and control of monoamine translocator function to be affected, more specifically, treat the illness that serotonin wherein or the resorbent inhibition of norepinephrine are affected, but especially wherein serotonin and the resorbent illness that all is affected of putting of norepinephrine.
Therefore, compound of the present invention can be used for treating following illness: the urinary incontinence, and such as true stress incontinence (GSI), the stress incontinence (SUI) or the senile urinary incontinence; Overactive bladder (OAB), comprise the IDI, sacred disease (Parkinson's disease for example, multiple sclerosis, Spinal injury and apoplexy) secondary detrusor over-activity disease and bladder outlet obstruction (BOO) (for example benign prostate hyperplasia (BPH), ureterostenosis) secondary detrusor over-activity disease; Nocturnal enuresis; Because the urinary incontinence (for example relevant stress incontinence) that the combination of above-mentioned symptom causes with overactive bladder; And lower urinary tract symptom, such as frequent micturition and urgent urination.Term OAB is intended to comprise dryness (OABwet) and moist (OAB dry).
Consider the aforementioned pharmaceutical active of compound of the present invention, it is depressed that it also can be used for treatment, such as major depression, the recurrent depression, the single outbreak is depressed, inferior syndrome depression, cancer patients's depression, the disturbances in patients with Parkinson disease depression, myocardial infarction retarded depression, children's depression, the Childhood maltreat the depression that causes, infertile women's depression, postpartum depression, premenstrual tension syndrome and the old man syndrome of being sullen in nature.
Consider the aforementioned pharmaceutical active of compound of the present invention, it can also be used for the treatment of following illness: cognitive disorder, such as dementia, particularly the degeneration dementia (comprises senile dementia, alzheimer's disease, Pick's disease, Huntington Chorea, Parkinson's disease and creutzfeldt-jakob disease) and vascular dementia (comprising multiple infarct dementia), and with intracranial spaceoccupying lesion, damage, infection and related symptoms (comprising that HIV infects), metabolism, toxin, dementia that anoxia is relevant with vitamin deficiency; The mild cognitive impairment relevant with age ageing, particularly relevant dysmnesia (AAMI), amnesia and the cognition decline (ARCD) relevant with the age with the age; Psychotic disorders, such as] schizophrenia and manic disorder; Anxiety disorder, such as generalized anxiety disorder, phobia (for example agoraphobe, social phobia and simple phobias), panic disorder, obsession, posttraumatic stress disorder, mixed type anxiety and depression; Personality disorder is such as avoidant personality disorder and attention-deficit hyperactivity disease (ADHD); Sexual dysfunction, such as premature ejaculation, male erectile dysfunction (MED) and Female sexual dysfunction (FSD) (for example female sexual arousal disorder (FSAD)); Premenstrual tension syndrome; Seasonal emotional maladjustment (SAD); Eating disorder is such as anorexia nervosa and disease of eating too much at one meal; Fat; Poor appetite; The chemical that drug habit or substance abuse cause relies on, such as nicotine addiction, alcohol addiction, ***e habituation, heroin addiction, phenylethyl barbituric acid habituation and benzodiazepine habituation; Drug withdrawal syndrome is such as relying on those that are caused by above-mentioned chemical; Headache, such as migraine, cluster headache, chronic paroxysmal hemicrania, the headache relevant with vascular disease relies on the relevant headache of drug withdrawal syndrome that causes with the chemical dependence or by chemical, and tension headache; Pain; Parkinson's disease, such as the Parkinson's disease dementia, parkinson's syndrome and tardive dyskinesia are induced in Antipsychotic drug; Endocrinopathy is such as hyperprolactinemia; Vasospasm is such as cerebrovascular vasospasm; Cerebellar ataxia; Tourette syndrome; Trichotillomania; Kleptomania; Emotional lability; Pathologic is cried; Somnopathy (dampinging off); And shock.
In above-mentioned illness, interested especially is attention-deficit hyperactivity disease (ADHD).The diagnosis of attention-deficit hyperactivity disease is based on clinical evaluation (M.Dulcan, et al.J Am Acad ChildAdolesc Psychaitry, Oct.1997,36 (10 Suppl), 85S-121S; National Institutes ofHealth, 1998). " essential characteristic of ADHD is; the persistent mode of attention deficit and/or many moving impulsions is observed more frequent and serious usually than institute in the individuality of control level development " (Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), AmericanPsychiatric Association, Washington, D.C., 1994).In order to make a definite diagnosis patient with attention-deficit hyperactivity disease, patient must show the attention-deficit hyperactivity disease syndrome that caused obstacle before 7 years old, and at least two kinds of environment (for example, school's [or work] and be in) development syndrome always above 6 months.(seeing DSM-IV).
Consider the aforementioned pharmaceutical active of The compounds of this invention, it also can be used for treating multiple other illness and disease, comprising: ypotension; Gastrointestinal tract disease (comprising that reactivity and secretion change) is such as irritable bowel syndrome (IBS), intestinal obstruction (for example intestinal obstruction during postoperative ileus and the septicemia), gastroparesis (for example diabetic gastroparesis), stomach ulcer, gastroesophageal reflux disease (GORD, or its synonym GERD), flatulence and other functional bowel disorder are such as maldigestion (for example non-ucler dyspepsia (NUD)) and NCCP (NCCP); And fibromyalgia syndrome.
Compound of the present invention may be used for the treatment of various diseases as serotonin and/or noradrenaline reuptake inhibitor, comprises pain.
Physiology pain is a kind of important protection mechanism that is designed to warn from the potential noxious stimulation of outside atmosphere.This system is by one group of specific main Sensory neurone running, and activated (detailed content can referring to Millan 1999 Prog.Neurobio.57:1-164) by destructive stimulus through peripheral sensing mechanism specially.These Sensory fibres are called as nociceptor, show as the low minor diameter aixs cylinder of conduction of velocity.Nociceptor is encoded to intensity, time length and the character of destructive stimulus, and arrives the epispinal position that stimulates through the projection coding of topology tissue by it.Nociceptor is present on the nerve fiber that pain reaction is arranged, and described nerve fiber has two types: A-δ fiber (myelinated fibre) and C fiber (unmyelinated nerve fiber).After the complex process in the dorsal horn, the activity that the nociceptor input is produced directly or via the brain stem relay nucleus is passed to ventral thalamus, is passed to cortex then, produces the pain sensation on cortex.
Pain generally can be divided into acute pain or chronic pain.The acute pain outbreak is unexpected and the time length is short (being generally for 12 weeks or shorter).Its concrete reason common and such as concrete damage is relevant, and usually violent and serious.It is a kind of may be in the pain that takes place by operation, dental work, after pulling or sprain the concrete damage that causes.Acute pain generally can not cause any lasting physiological response.On the contrary, chronic pain is long-term pain, and general continuing surpasses 3 months and cause tangible physiology and emotional problem.Chronic pain be neuropathic pain (for example the diabetic neuropathy of pain, postherpetic neuralgia) referring to example, carpal tunnel syndrome, backache, headache, cancer pain, arthritis ache and chronic post-operative pain.
When body tissue being produced substantive damage (because disease or wound), nociceptor activates characteristic and is changed, near damage is peripheral, local and be formed centrally the sensitizing range in the nociceptor terminated.These effects cause pain perception to strengthen.For acute pain, these mechanism help promoting the protection behavior, and this can make repair process to carry out better.And in case damage is fully recovered, it is normal that susceptibility is expected to recover usually.Yet for many chronic pain states, hypersensitive time length is much larger than agglutination, and normally since nervous system injury cause.This damage usually causes unusual (the Woolf ﹠amp of the sensing nerve fiber relevant with maladjustment and abnormal movement; Salter2000 Science 288:1765-1768).
Do not accommodate unusual susceptibility if exist in patient's symptom, clinical pain then occurs.The patient often originates and mixes and have various pain syndromes.Such syndrome comprises: 1) spontaneous pain can be numbness, cusalgia or shouting pain; 2) pain (hyperpathia) that excites of Kua Da destructive stimulus; 3) pain of normal non-noxious stimulation generation (unusual pain-M eyer etc., 1994Textbook of Pain 13-44).Can have similar symptom although suffer from various forms of acute and patients chronic pain, implicit mechanism is discrepant, thereby the different treatment plan of needs.Therefore, according to the difference on the physiopathology, pain can be divided into many different subtypes, comprises nociceptive pain, inflammatory pain, neuropathic pain.
Nociceptive pain is to cause by tissue injury or by the severe irritation that may cause damage.Pain is imported into and is to be activated in the stimulation transduction of damage position by the injury transmitter, and on its terminal horizontal the neurone in the spinal cord is activated.This is passed to the brain (Meyer etc., 1994 Textbook of Pain 13-44) of perception pain by the backbone passage then.The activation of nociceptor has activated two class afferent neurofibers.The fast transmission and to violent and pierce through pain and make and replying of marrow A-δ fiber is arranged, and do not have marrow C fiber with than the jogging speed transmission and pass on secret anguish.Moderate to violent acute injury susceptibility pain is the principal character by the following pain that causes: central nervous system injury, pull/sprain, pain, renal colic, cancer pain and backache after burn, myocardial infarction and acute critical pancreatitis, postoperative pain (pain after the surgical operation of any kind), the wound.Cancer pain can be a chronic pain, such as with tumour ache related (for example ostalgia, headache and face ache, visceral pain), perhaps relevant (for example pain syndrome after syndrome, the chronic surgical operation, radiation back syndrome after the chemotherapy) with cancer therapy.Cancer pain can also be replied chemotherapy, immunotherapy, hormonotherapy or radiotherapy and be produced.Backache can be eliminated naturally, but in some patients, if backache continued more than 12 weeks, then it becomes the chronic disease that can especially make people's weakness.
Neuropathic pain is defined as the pain that caused or caused by neural main infringement or dysfunction at present.Nerve injury can be caused by wound and disease, so term " neuropathic pain " comprises the numerous disease with Different Kinds of Pathogens.These diseases include but not limited to, pain and pain, thyroprivia, uremia, multiple sclerosis, Spinal injury, Parkinson's disease, epilepsy or the vitamin deficiency relevant with chronic alcoholism after peripheral neurophaty, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, backache, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, the maincenter apoplexy.Neuropathic pain is not owing to have a provide protection, thereby is ill.It occurs after initial reason has just disappeared usually, generally lasts for several years, and has greatly reduced patient's quality of life (Woolf and Mannion 1999 Lancet 353:1959-1964).Neuropathic pain syndrome is difficult to treatment, and reason is that they are of a great variety, even also there are differences (Woolf ﹠amp suffering between the patient of same disease; Decosterd 1999 Pain Supp.6:S141-S147; Woolf and Mannion 1999Lancet 353:1959-1964).Neuropathic pain comprises spontaneous pain, can be continuity or pain sudden and that excite unusually, for example hyperpathia (susceptibility to destructive stimulus improves) and allodynia (to normal non-noxious stimulation sensitivity).
Inflammatory process is that the existence to tissue injury or foreign matter responds and the biochemistry and the cell incident of a series of complexity of exciting can cause swelling and pain (Levine and Taiwo 1994:Textbookof Pain 45-56).Arthritis pain is modal inflammatory pain.Similar rheumatism is a kind of chronic inflammatory diseases common in the developed country, and rheumatoid arthritis is to cause disabled common cause.The accurate cause of disease of rheumatoid arthritis is unknown, and the two all is important (Grennan ﹠amp but present hypothesis is thought inherited genetic factors and microbiological factor; Jayson 1994 Textbook of Pain 397-407).Existing estimation, have 1,600 ten thousand Americans to suffer from symptomatic osteoarthritis (OA) or degenerative joint disease approximately, wherein the Most patients age surpasses 60 years old, and along with aging population, this digital expectation will increase to 4,000 ten thousand, make it to become serious public health problem (Houge ﹠amp; Mersfelder 2002 AnnPharmacother.36:679-686; McCarthy etc., 1994 Textbook of Pain 387-395).Most of osteoarthritis patient is owing to the pain of being followed is sought medicine help.Sacroiliitis has remarkably influenced to social mentality and body function, and is to cause disabled first cause in living from now on.Ankylosing spondylitis also is the arthritic rheumatosis that causes backbone and sacrum joint.It can be from the backache of the intermittent attack of lifelong generation to the severe chronic disease of attacking backbone, peripheral joint and other body member.
The inflammatory pain of another kind of type is the visceral pain that comprises the pain relevant with inflammatory bowel disease (IBD).Visceral pain is the pain relevant with internal organ, and wherein internal organ comprise the organ in abdominal cavity.These organs comprise sexual organ, spleen and part Digestive tract.The pain relevant with internal organ can be divided into digestive viscera pain and non-digestive viscera pain.The common stomach that causes pain (GI) disease comprises functional type intestinal disease (FBD) and inflammatory bowel disease (IBD).These GI diseases comprise a large amount of morbid states that only are subjected to appropriateness control at present, for FBD, comprise gastroesophageal reflux disease, maldigestion, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS); For IBD, comprise Crohn disease, ileitis and ulcerative colitis, these all cause visceral pain regularly.The visceral pain of other type comprises pain and the pelycalgia relevant with dysmenorrhoea, urocystitis and pancreatitis.
The pain that should be noted that some types comprises multiple cause of disease, therefore can be classified into a more than field, and for example backache and cancer pain have nociceptive pain and these two kinds of compositions of neuropathic pain.
The pain of other type comprises:
The pain that-flesh-skeletal diseases causes comprises, myalgia, fibromyalgia, spondylitis, seronegativity (non-rheumatic) joint disease, non-rheumatic arthritis, dystrophin disease, glycogenolysis, polymyositis, pyomyositis;
-heart and blood vessel pain comprise the pain that is caused by stenocardia, myocardial infarction, mitral stenosis, pericarditis, Raynaud phenomenon, scleredoma, skeletal muscle ischemic;
-headache is such as migraine (comprising migraine without aura, absence of aura migraine), cluster headache, tension headache, mixed type headache, the headache relevant with vascular disease; And
-actinal surface pain comprises toothache, bright mouthful syndrome and temporomandibular joint sarolemma pain.
Interested especially disease comprises the urinary incontinence, such as the mixed type urinary incontinence, and GSI and USI; Pain; Depressed; Anxiety disorder is such as obsession and posttraumatic stress disorder; Personality disorder is such as attention-deficit hyperactivity disease; Sexual dysfunction; Rely on the drug withdrawal syndrome that causes with the chemical dependence with by chemical.
Therefore, according to others, the invention provides:
I) compound of the present invention is used for physianthropy or animal doctor;
Compound ii) of the present invention is used for the treatment of the illness that the wherein regulation and control of monoamine translocator function are affected, such as the urinary incontinence;
Compound iii) of the present invention is used for the treatment of purposes in the medicine of the illness that the wherein regulation and control of monoamine translocator function are affected in preparation;
Compound iv) of the present invention is used for the treatment of the illness that the regulation and control of serotonin wherein or norepinephrine are affected;
Compound v) of the present invention is used for the treatment of purposes in the medicine of the illness that the regulation and control of serotonin wherein or norepinephrine are affected in preparation;
Compound vi) of the present invention is used for the treatment of the illness that the wherein regulation and control of serotonin and norepinephrine are affected;
Compound vii) of the present invention is used for the treatment of purposes in the medicine of the illness that the wherein regulation and control of serotonin and norepinephrine are affected in preparation;
Compound viii) of the present invention is used for the treatment of the urinary incontinence, such as GSI or USI;
Ix) compound of the present invention is used for the treatment of purposes in the medicine of the urinary incontinence (such as GSI or USI) in preparation;
X) treat the method for the illness that the wherein regulation and control of monoamine translocator function are affected, comprise will the treatment significant quantity compound administration of the present invention give the patient of the such treatment of needs;
Xi) treat the method for the illness that the regulation and control of serotonin wherein or norepinephrine are affected, comprise will the treatment significant quantity compound administration of the present invention give the patient of the such treatment of needs;
Xii) treat the method for the illness that the wherein regulation and control of serotonin and norepinephrine are affected, comprise will the treatment significant quantity compound administration of the present invention give the patient of the such treatment of needs; And
Xiii) the treatment urinary incontinence (such as GSI or USI) comprises and gives the patient of the such treatment of needs with the compound administration of the present invention of treatment significant quantity.
Should be appreciated that unless expressly stated otherwise,, Zhi Liao implication comprises healing, alleviates and prophylactic treatment herein.
Compound of the present invention can be by independent administration, perhaps as the part of combined therapy agent by administration.If the combination of multiple therapeutical agent is by administration, then activeconstituents can be by order or administration simultaneously individually, or with the pharmaceutical preparation administration of combination.
The example that is used for the suitable medicament of additional treatment comprises:
Opium class anodyne, for example morphine, heroine, hydromorphone, oxymorphone, levorphan, Lorfan, methadone, Pethidine, fentanyl, Cocaine, morphine monomethyl ether, paracodin, oxycodone, hydrocodone, the third oxygen sweet smell, Nalmefene, nalorphine, naloxone, TREXUPONT, buprenorphine, Bu Tuonuo coffee, nalbuphine or pentazocine;
On-steroidal anti-inflammatory drug (NSAID), for example acetylsalicylic acid, diclofenac, diflusinal, R-ETODOLAC (etodolac), benzophenone acid, fenoprofen, flufenisal, flurbiprofen, Ibuprofen BP/EP, indomethacin, Ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, Naproxen Base (naproxen), nimesulide, nitroflurbiprofen, Olsalazine Evil promazine, BUTE, piroxicam (piroxicam), sulfasalazine, sulindac (sulindac), tolmetin (tolmetin) or zomepirac;
Barbiturate(s) tranquilizer, for example Amobarbital, somnifen, Secbutabarbital, Butobarbital, Mephogarbital, metharbital, Methohexitone, Sodital, phenylethyl barbituric acid, secobarbital, talbutal, theamylal or Thiothal;
Benzodiazepines medicine with sedative effect, for example zeisin (chlordiazepoxide), the tall and erect hydrochlorate of chlorine, stable (diazepam), flurazepam, Wypax, oxazepam, stable, the ALprazolanic of first hydroxyl;
H with sedative effect 1Antagonistic, for example diphenhydramine (diphenhydramine), pyrilamine, promethazine, chlorphenamine or chloreyclizine;
Tranquilizer, for example glutethimide, meprobamate, methaqualone or Dichloralphenazone;
Skeletal muscular relaxant, for example baclofen, flesh are stable, solaxin, cyclobenzaprine, methocarbamol or orphrenadine;
Nmda receptor antagonist; for example dromethan ((+)-3-hydroxy-n-methylmorphinan) and meta-bolites Dextrorphan ((+)-3-hydroxy-n-methylmorphinan), ketamine, Memantine hydrochloride (memantine), pyrroloquinoline quinone and suitable-4-((phosphonomethyl))-2 piperidine carboxylic acid, 1-tert-butyl-4,4-diphenylpiperidine, EN-3231 (MorphiDex ; the combination preparation of morphine and Dextromethorphane Hbr), topiramate, neramexane or perzinfotel, comprise NR 2The B antagonist, ifenprodil for example, traxoprodil or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxyl-piperidino]-1-hydroxyethyl-3,4-dihydro-2 (1H)-quinolinone;
α-suprarenin active compound, for example Doxazosin (doxazosin), Tamsulosin (tamsulosin), clonidine catapresan, guanfacine, dexmetatomidine, modafinil, phentolamine, terazosin, Prazosin or 4-amino-6,7-dimethoxy-2-(5-sulfonyl methane amido-1,2,3,4-tetrahydroisoquinoline-2-yl)-5-(2-pyridyl) quinazoline;
Tricyclics, for example desmethylimipramine, imipramine, amytriptiline or nortriptiline;
Anticonvulsive drug, for example carbamazepine, lamotrigine, topiramate (topiratmate) or Valproic acid salt sodium;
Tachykinin (Tachykinin) is antagonist (NK), NK-3 particularly, NK-2 and NK-1 antagonist, (aR for example, 9R)-7-[3,5-two (trifluoromethyl) phenmethyl]-8,9,10,11-tetrahydrochysene-9-methyl-5-(4-aminomethyl phenyl)-7H-[1,4] two azocines also [2,1-g] [1,7] naphthyridine-6,13-diketone (TAK-637), 5-[[(2R, 3S)-2-[(1R)-1-[3,5-two (trifluoromethyl) phenyl] oxyethyl group-3-(4-fluorophenyl)-4-morpholinyl] methyl]-1,2-dihydro-3H-1,2,4-triazole-3-ketone (MK-869), aprepitant, lanepitant, dazidamine (dapitant) or 3-[[2-methoxyl group-5-(trifluoromethoxy) phenyl] methylamino]-2-phenyl-piperidines (2S, 3S);
Muscarine antagonist, for example Oxybutynin (oxybutin), tolterodine (tolterodine), propiverine (propiverine), tropsium chloride and darifenacin (darifenacin), solifenacin, temiverine and Ipratropium Bromured;
Cox 2 inhibitor, for example celecoxib (celecoxib), rofecoxib (rofecoxib), Parecoxib, cut down ground former times cloth (valdecoxib), SC 59046, support is examined former times or lumiracoxib;
Coal tar analgesic agent, particularly Paracetamol (paracetamol);
Antipsychotic drug, such as droperidol, chlorpromazine, haloaperidol, trilafon, thioridazine, mesoridazine, trifluoperazine, Fluphenazine, leoponex, olanzapine, risperidone, Ziprasidone, Quetiapine, Sertindole, Aripiprazole, sonepiprazole, blonanserin, iloperidone, Perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, handkerchief woods Dorr, eplivanserin, Osanetant, Rimonabant, meclinertant, Miraxion  or sarizotan;
Capsaicin receptor agonists (for example resinferatoxin) or antagonist (for example capsazepine);
Beta-adrenaline compound, for example Proprasylyte (propranolol);
Local anesthetic, for example mexiletine (mexiletine);
Steroid, for example dexamethasone (dexamethasone);
5-HT receptor agonists or antagonist, particularly 5-HT 1B/1DAgonist, such as Eletriptan, sumatriptan, Nola for smooth, zolmitriptan or Rizatriptan;
5-HT 2AReceptor antagonist is such as R (+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenyl ethyl)]-4-piperidine carbinols (MDL-100907);
Cholinergic (nicotine) analgesic agent is such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridyl)-3-butene-1-amine (RJR-2403), (R)-5-(2-azetidinyl methoxy)-2-chloropyridine (ABT-594) or Nicotine;
·Tramadol；
The PDEV inhibitor, such as 5-[2-oxyethyl group-5-(4-methyl isophthalic acid-piperazinyl-alkylsulfonyl) phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (Virga), (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3, the 4-methylenedioxyphenyl)-pyrazolo [2 ', 1 ': 6,1]-pyrido [3,4-b] indoles-1,4-diketone (IC-351 or Tadalafil (Cialis)), 2-[2-oxyethyl group-5-(4-ethyl-piperazine-1-base-1-alkylsulfonyl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazole-4-ketone (Vardenafil), 5-(5-ethanoyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 5-(5-ethanoyl-2-propoxy--3-pyridyl)-3-ethyl-2-(1-sec.-propyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 5-[2-oxyethyl group-5-(4-ethyl piperazidine-1-base alkylsulfonyl) pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, 4-[(3-chloro-4-methoxybenzyl) amino]-2-[(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl]-N-(pyrimidine-2-base methyl) pyrimidine-5-Carboxylamide, 3-(1-methyl-7-oxo-3-propyl group-6, the 7-dihydro-1 h-pyrazole is [4,3-d] pyrimidine-5-yl also)-N-[2-(1-methylpyrrolidin-2-yl) ethyl]-4-propoxy-benzsulfamide;
Alpha-2-delta ligand, such as gabapentin (gabapentin), pregabalin, 3-methyl gabapentin, (1a, 3a, 5a) (3-amino-methyl-dicyclo [3.2.0] heptan-3-yl)-acetate, (3S, 5R)-3-amino methyl-5-methyl-enanthic acid, (3S, 5R)-3-amino-5-methyl-enanthic acid, (3S, 5R)-and 3-amino-5-methyl-sad, (2S, 4S)-4-(3-chlorobenzene oxygen) proline(Pro), (2S, 4S)-4-(3-fluorobenzene methyl)-proline(Pro), [(1R, 5R, 6S)-and 6-(amino methyl) dicyclo [3.2.0] heptan-6-yl] acetate, 3-(1-amino methyl-cyclohexyl methyl)-4H-[1,2,4] oxadiazole-5-ketone, C-[1-(1H-tetrazolium-5-ylmethyl)-suberyl]-methylamine, (3S, 4S)-(1-amino methyl-3,4-dimethyl-cyclopentyl)-acetate, (3S, 5R)-and 3-amino methyl-5-methyl-sad, (3S, 5R)-3-amino-5-methyl-n-nonanoic acid, (3S, 5R)-and 3-amino-5-methyl-sad, (3R, 4R, 5R)-3-amino-4,5-dimethyl-enanthic acid and (3R, 4R, 5R)-3-amino-4,5-dimethyl-sad;
Cannaboid;
Metabotropic glutamate hypotype 1 acceptor (mGluR 1) antagonist;
The serotonin reuptake inhibithors, such as Sertraline, Sertraline metabolite demethyl Sertraline, fluoxetine, Norfluoxetine (fluoxetine demethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite demethyl citalopram, escitalopram, d, l-Phenfluoramine, femoxetine, ifoxetine, cyanodothiepin, Litoxetine, dapoxetine, nefazodone, chloramines (cericlamine) and trazodone;
Norepinephrine (norepinephrine) reuptake inhibithors, such as maprotiline, labor good fortune miaow piperazine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, Bupropion, bupropion metabolites hydroxyl Bupropion, nomefensine and viloxazine (Vivalan ), especially selectivity noradrenaline reuptake inhibitor, such as Reboxetine (reboxetine), particularly (S, S)-Reboxetine;
Serotonin-norepinephrine absorbs double inhibitor again, such as venlafaxin (venlafaxine), venlafaxin metabolite O-demethyl venlafaxin, clomipramine, clomipramine metabolite demethyl clomipramine, duloxetine, Midalcipran and imipramine;
Inducible nitric oxide synthase (iNOS) inhibitor, such as S-[2-[(1-imido ethyl) amino] ethyl]-L-homocysteine, S-[2-[(1-imido ethyl)-amino] ethyl]-4,4-dioxo-L-halfcystine, S-[2-[(1-imido ethyl) amino] ethyl]-2-methyl-L-halfcystine, (2S, 5Z)-and 2-amino-2-methyl-7-[(1-imido ethyl) amino]-5-enanthic acid, 2-[[(1R, 3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl] sulfo-]-5-chloro-3-pyridine nitrile; 2-[[(1R, 3S)-and 3-amino-4-hydroxy-1-(5-thiazolyl) butyl] sulfo-]-4-benzyl chloride nitrile, (2S, 4R)-and 2-amino-4-[[2-chloro-5-(trifluoromethyl) phenyl] sulfo-]-5-thiazole butanols, 2-[[(1R, 3S)-and 3-amino-4-hydroxy-1-(5-thiazolyl) butyl] sulfo-]-6-(trifluoromethyl)-3 pyridine nitrile, 2-[[(1R, 3S)-and 3-amino-4-hydroxy-1-(5-thiazolyl) butyl] sulfo-]-5-benzyl chloride nitrile, N-[4-[2-(3-chlorophenylmethyl amino) ethyl] phenyl] thiophene-2-carbonamidine, or guanidine ethyl disulphide;
The acetyl cholinesterase enzyme inhibitors is such as E2020;
PGE 2Hypotype 4 (EP4) antagonist, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridine-1-yl) phenyl] ethyl } amino)-carbonyl]-4-methylbenzene Toluidrin or 4-[(1S)-1-({ [5-chloro-2-(3-fluorophenoxy) pyridin-3-yl] carbonyl } amino) ethyl] phenylformic acid;
The serum leukotriene B 4 antagonists; Such as 1-(3-xenyl-4-ylmethyl-4-hydroxyl-chroman-7-yl)-Cyclopentane carboxylic acid (CP-105696), 5-[2-(2-carboxy ethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl] the phenoxy base]-valeric acid (ONO-4057) or DPC-11870;
The 5-lipoxidase inhibitor is such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydrochysene-2H-pyrans-4-yl]) phenoxy group-methyl]-1-methyl-2-quinolone (ZD-2138) or 2,3,5-trimethylammonium-6-(3-picolyl), 1,4-benzo quinone (CV-6504);
Sodium channel blockers is such as lignocaine;
The 5-HT3 antagonist is such as ondansetron, granisetron, tropisetron, azasetron, dolasetron or Lotronex;
Oestrogenic hormon agonist or selective estrogen receptor adjusting control agent (for example HRT therapeutical agent or Lasofoxifene);
The alpha-adrenergic receptor agonist is such as Super Odrinex or R-450;
Dopamine Receptors agonist (for example apomorphine, its instruction as pharmaceutical use can be found in US-A-5945117) comprises d2 dopamine receptor agonist (premiprixal for example, Pharmacia Upjohn compound number PNU95666; Or Ropinirole);
PGE1 agonist (for example Prostaglandin E1);
And pharmacy acceptable salt and solvate.
Therefore, the present invention provides the combination that comprises compound of the present invention and other therapeutical agent on the other hand.
For human purposes, compound of the present invention can be by independent administration, but in the human treatment, with generally with at the form of mixtures of the selected suitable drug excipient of the route of administration of hope and standard pharmacy convention, thinner, supporting agent by administration.
For example, compound of the present invention can be with the form of tablet, capsule (comprising the flexible glue body capsule), ovule agent (ovules), elixir, solution or suspension, by oral administration, cheek administration, sublingual administration, these formulations can comprise seasonings or tinting material, are used for fast, postpone, slow down, continue, dual, sustained release or pulsatile administration application.Compound of the present invention can also be via the cavernous body inner injecting and administering.Compound of the present invention can also be by quick dispersion or rapid-dissolve dosage form administration.
Such tablet can comprise vehicle, such as Microcrystalline Cellulose, and lactose, Trisodium Citrate, lime carbonate, secondary calcium phosphate, glycine, and starch (preferred corn, potato or tapioca (flour)), disintegrant, such as Explotab, croscarmellose sodium and some composition silicate, and granule agglomerant, such as Polyvinylpyrolidone (PVP), HYDROXY PROPYL METHYLCELLULOSE (HPMC), hydroxy propyl cellulose (HPC), sucrose, gelatin and Sudan Gum-arabic.In addition, can also comprise lubricant, such as Magnesium Stearate, stearic acid, docosoic glyceryl ester and talcum.
The solid ingredient of similar type can also be used as the filler in the gelatine capsule.Thus, preferred vehicle comprises lactose, starch, Mierocrystalline cellulose, lactose or high molecular weight polyethylene glycol.For waterborne suspension and/or elixir, compound of the present invention and pharmacy acceptable salt thereof, can with various sweeting agents or seasonings, coloring material or dye combinations, with the combination of emulsifying agent and/or suspension agent and with such as water, ethanol, the thinner combination of propylene glycol and glycerol and so on, and combined with the combination of above-mentioned substance.
Slow down and discharge and pulsed release dosage form can comprise those vehicle and the additional excipients that is described in detail such as at the snap-out release formulation, described additional excipients is served as rate of release and is slowed down agent, its by dressing on installing and/or be included in the device main body.Rate of release is slowed down agent and is included, but not limited to HYDROXY PROPYL METHYLCELLULOSE, methylcellulose gum, carboxylic acid methyl sodium cellulosate, ethyl cellulose, cellulose ethanoate, polyethylene oxide, xanthan gum, carbomer, ammonium alkylmethacrylate polymer, hydrogenated castor oil, palm wax, paraffin, cellulose ethanoate phthalate, HYDROXY PROPYL METHYLCELLULOSE phthalandione or ester, Sipacril 2739OF and composition thereof.Slow down and discharge and pulsed release dosage form can comprise a kind of rate of release and slows down the combination that vehicle or rate of release are slowed down vehicle.Rate of release is slowed down vehicle and can be among the formulation, promptly is among the matrix, and/or is on the formulation, promptly is on surface or the dressing.
Disperse or dissolve formulation (FDDFs) fast and can comprise following composition: aspartame (aspartame), acesulfame potassium, citric acid, croscarmellose sodium; polyvinylpolypyrrolidone, two xitix, ethyl propenoate, ethyl cellulose; gelatin, HYDROXY PROPYL METHYLCELLULOSE, Magnesium Stearate, N.F,USP MANNITOL; methyl methacrylate, peppermint seasonings, polyoxyethylene glycol; thermal silica, silicon-dioxide, primojel; sodium stearyl fumarate, Sorbitol Powder, Xylitol.Be used herein to the term of describing FDDFs, disperse or dissolve, depend on the solvability of used drug substance, promptly under the insoluble situation of medicine, can prepare the fast-dispersing type, under the soluble situation of drug substance, can prepare rapid-dissolve dosage form.
Compound of the present invention also can pass through parenteral admin, administration in for example administration in administration in intravenous administration, intra-arterial administration, intraperitoneal administration, intrathecal drug delivery, the ventricle, the urethra, the interior administration of breastbone, the skull, intramuscular administration and subcutaneous administration, or it can be by infusion techniques by administration.For such parenteral admin, it preferably is used with the form of aseptic aqueous solution, and described aseptic aqueous solution can comprise other material, and for example enough salt or glucose are so that solution and blood etc. ooze.If necessary, the aqueous solution should suitably be cushioned (preferably, pH from 3 to 9).The preparation of the suitable parenteral formulation under aseptic condition is finished by sign pharmaceutical technology well known by persons skilled in the art easily.
For oral and administered parenterally to human patients, the dosage level of compound or its salt of the present invention or solvate will be usually from 10 to 500mg (single or be divided into multi-agent).
Therefore, for example, the tablet of compound or its salt of the present invention or solvate or capsule can comprise from 5mg to the 250mg active compound, are used for as required single, two or more of single administrations.Under any circumstance, the doctor will determine actual dose, and this actual dose will be best suited in individual patient, and it will change with concrete patient's age, body weight and reaction.Above-mentioned dosage is the exemplary dose of generalized case.Certainly, may have the discrete example, wherein, higher or lower dosage range is favourable, and these also fall into scope of the present invention.Those skilled in the art also will understand, and when (comprising PE), compound of the present invention can use as single dose on the basis of " as required " (promptly as required) in some illness of treatment.
The exemplary tablet formulation
In general, tablet reagent can comprise the of the present invention compound (or its salt) of about 0.01mg to 500mg usually, and tablet weighting material weight can be from 50mg to 1000mg.The 10mg tablet formulation of exemplary is as follows:
Composition %w/w
The free alkali of compound or salt 10.000 *
Lactose 64.125
Starch 21.375
Croscarmellose sodium 3.000
Magnesium Stearate 1.500
*This amount is regulated according to pharmaceutical activity and based on the weight of free alkali usually.
But compound of the present invention is intranasal administration or pass through inhalation also, and usually the dry powdered form of self-desiccation powder inhalator by administration, perhaps as (using suitable propelling agent from pressurizing vessel, pump, atomizer, spraying gun, Refrigerant 12 for example, trichlorofluoromethane, dichloro tetrafluoro ethane is such as 1,1,1, the 2-Tetrafluoroethane (HFA 134A[trade mark]) or 1,1,1,2,3,3, the 3-HFC-236fa) hydro fluoroalkanes of (HFA 227EA[trade mark]), carbonic acid gas or other suitable gas) aerosol spray by administration.In the situation of pressurized aerosol, can by be provided with valve carry by the metering amount, determine dose unit.Pressurizing vessel, pump, atomizer or spraying gun can comprise the solution or the suspension of active compound, and described solution or suspension for example utilize the mixture of ethanol and propelling agent as solvent, can also comprise lubricant, for example sorbitan trioleate.Being used for the capsule of sucker or insufflator and medicine box (for example being made by gelatin) can be formulated into and comprise The compounds of this invention and such as the powdered mixture of the suitable powder matrix of lactose or starch.
Aerosol or dry powder formulations preferably are designed to each dosing or each " spraying " comprises 1 to 50mg compound of the present invention, is used to flow to the patient.Utilize aerocolloidal total per daily dose to arrive in the scope of 50mg 1, this dosage can be to measure by administration with single, perhaps more usually, is divided into multidose by administration in one day.
Compound of the present invention can also be formulated into by spraying gun and carry.The preparation that is used for atomizer arrangement can comprise following composition as solubilizing agent, emulsifying agent or suspension agent: water, ethanol, glycerol, propylene glycol, low molecular poly, sodium-chlor, fluorocarbon, polyglycol ether, sorbitan trioleate, oleic acid.
Perhaps, compound of the present invention can be with the form of suppository or vaginal suppository by administration, and perhaps it can be with the form of gel, hydrogel, lotion, solution, emulsion, ointment or conspergative by topical application.Compound of the present invention can also be by skin or transdermal administration, for example by using skin patch.They can also pass through eyes, lung or rectum approach by administration.
For the eyes purposes, compound can be formulated into and be in isoosmotic, the micronization suspension of pH in that regulate, aseptic salt solution, perhaps preferably, be formulated into isoosmotic, the solution of pH in that regulate, aseptic salt solution, randomly comprise sanitas, phenmethyl alkyl positively charged ion muriate.Perhaps, it can pass through ointment, prepares such as paraffin oil.
For topical application, compound of the present invention can be formulated into suitable ointment, described ointment comprises suspension or is dissolved in for example active compound of following mixture, and described mixture has one or more in the following composition: mineral oil, Witco 70, white paraffin oil, propylene glycol, polyoxyethylene oxypropylene compound, emulsifying wax and water.Perhaps, it can be formulated into suitable lotion or emulsion, suspend or be dissolved in one or more the mixture in the following composition: mineral oil, the sorbitol monostearate that anhydrates, polyoxyethylene glycol, whiteruss, poly-polysorbate60, hexadecyl ester type waxes, hexadecyl alcohol, 2-octyl dodecanol, phenylcarbinol and water.
Compound of the present invention can also be used in combination with cyclodextrin.Cyclodextrin is known to form envelope complex compound and non-envelope complex compound with drug molecule.The formation of drug-cyclodextrin complex compound can improve solvability, dissolution rate, biological effectiveness and/or the stability of drug molecule.The drug-cyclodextrin complex compound generally can be used for most of formulations and route of administration.As with the replacement scheme of the direct complexing of medicine, cyclodextrin can be used as supplementary additive, for example as supporting agent, thinner or solubilizing agent.The most frequently used is alpha-cylodextrin, beta-cyclodextrin and γ-Huan Hujing, and suitable example has description at International Patent Application WO-A-91/11172 among WO-A-94/02518 and the WO-A-98/55148.
For the oral or parenteral admin to human patients, the dosage level of formula (I) compound and pharmacy acceptable salt thereof will be in 0.01 to 30mg/kg scope (single or be divided into repeatedly), and preferably 0.01 in the scope of 5mg/kg.Therefore, tablet will comprise the compound of 1mg to 0.4g, be used for as required single, two or more of single administrations.Under any circumstance, the doctor will determine actual dose, and this actual dose will be best suited in individual patient, and it will change with concrete patient's age, body weight and reaction.Above-mentioned dosage only is the exemplary dose of generalized case certainly, and may to have wherein higher or lower dosage range be favourable example, and these also fall into scope of the present invention.
Oral administration is preferred.
Use for the animal doctor, compound of the present invention according to common veterinary science convention with suitable acceptable preparation by administration, and animal doctor doctor will determine that for concrete animal be only dose therapies and route of administration.
Therefore, according to another aspect, the invention provides the pharmaceutical preparation that comprises compound of the present invention and pharmaceutically acceptable adjuvant, thinner or supporting agent.
Combination recited above can also be used by the form with pharmaceutical preparation easily, therefore, comprises the pharmaceutical preparation of combination as defined above together with pharmaceutically acceptable adjuvant, thinner or supporting agent, has constituted another aspect of the present invention.The single component of such combination can be separately order or simultaneously by administration, perhaps with the pharmaceutical preparation of combination by administration.
When compound of the present invention and second therapeutical agent are used in combination, the dosage the when dosage of each compound can be different from this compound and is used alone.Those skilled in the art will easily know proper dosage.
By following non-limiting example the present invention is described, wherein can uses following abbreviation and definition:
The APCI atmospheric pressure chemical ionization
Arbacel  filtering medium
The br broad peak
The BOC tertbutyloxycarbonyl
The CDI carbonyl dimidazoles
The δ chemical shift
D is bimodal
The Δ heating
The DCCI dicyclohexylcarbodiimide
The DCM methylene dichloride
DMF N, dinethylformamide
The DMSO dimethyl sulfoxide (DMSO)
ES +The scanning of electron spray ionisation positive ion
ES -The scanning of electron spray ionisation negative ion
H hour
HOAT 1-hydroxyl-7-azepine benzotriazole
The HOBT I-hydroxybenzotriazole
The HPLC high pressure liquid chromatography
The m/z mass spectra peak
Min minute
The MS mass spectrum
The NMM N-methylmorpholine
The NMR nucleus magnetic resonance
The q quartet
S is unimodal
The t triplet
TBTU Tetrafluoroboric acid 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea salt
The Tf trifluoromethane sulfonyl group
The TFA trifluoroacetic acid
The THF tetrahydrofuran (THF)
The TLC thin-layer chromatography
TS +The scanning of thermospray ionization positive ion
WSCDI hydrochloric acid 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide
Following preparation and embodiment illustrate the present invention, but are not restriction the present invention.All temperature adopt ℃.Adopt Merck silica gel 60 (9385) to carry out the flash column chromatography analysis.Adopt Varian MegaBond Elut (Si) box (Anachem) under the 15mmHg vacuum, to carry out Solid-Phase Extraction (Solid PhaseExtraction (SPE)) stratographic analysis.Thin-layer chromatographic analysis (TLC) carries out on Merck silica gel 60 plates (5729).Fusing point adopts Gallenkamp MPD350 device to measure, and not calibrated.Utilize Varian-Unity Inova 400MHz nmr spectrometer or Varian Mercury 400MHz nmr spectrometer to carry out NMR.Adopt single four utmost point electrospray mass spectrometers of Finnigan Navigator or Finnigan aQa APCI mass spectrograph to carry out mass spectroscopy.
Usually, compound of the present invention form with free alkali after aftertreatment is separated, but also can utilize conventional means to prepare the pharmaceutically acceptable acid-adducting salt of compound of the present invention.The solvate of compound of the present invention (for example hydrate) can form in the last handling process of one of previous process steps.
If to prepare compound at the described mode of front embodiment, then it will be appreciated by those skilled in the art that, the equivalents of reaction times, reagent and temperature of reaction can be made amendment at each reaction, but may need or it is desirable to, and use different aftertreatment or purification condition.
Preparation 1
(3S)-3-(cyclopentyl amino) tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200391
With cyclopentanone (12.7ml, 143mmol) add methyl alcohol to: 3: 1 (600ml: (the 3S)-3-amino-pyrrolidine in mixture 200ml)-1-carboxylic acid tert-butyl ester (26.6g of toluene, 143mmol), and reaction mixture at room temperature stirred under nitrogen atmosphere 1.5 hours.Then mixture is evaporated to 50ml, and methyl alcohol: (600ml: 200ml) azeotropic was 3 times, and concentrated under vacuum in 3: 1 for toluene.Reaction mixture is dropped in the methyl alcohol (250ml), is cooled to 0 ℃, and by part add a sodium borohydride (7.5g, 200.2mmol).After reaction is finished, add water (50ml), and evaporating solvent.Resistates is diluted with more water (150ml), and extract 3 times with methylene dichloride (250ml).Organic phase is merged, use dried over mgso, and under vacuum, concentrate, to provide gelationus title compound, 36.1g (99.4%).
1HNMR(CDCl 3，400MHz)δ：1.18(brs，1H)，1.28(m，2H)，1.44(s，9H)，1.52(m，2H)，1.67(m，3H)，1.83(m，2H)，2.05(m，1H)，2.98(m，1H)，3.08(m，1H)，3.30(m，2H)，3.45(m，1H)，3.58(m，1H)
MS?APCI +?m/z?255[MH] +
Preparation 2
(3S)-and 3-[cyclopentyl (2, the 3-dichloro-benzoyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200401
Under nitrogen atmosphere, (24ml, (36.1g is 142mmol) in the solution of methylene dichloride (350ml) 170mmol) to add preparation 1 amine to triethylamine.Reaction mixture is cooled to 0 ℃, and drips and to be in 2 in the methylene dichloride, (29.8g 142mmol), remains on temperature below 5 ℃ 3-two chloro-Benzoyl chlorides simultaneously.Then reaction mixture was stirred 6 hours.Add water (200ml), and collect organic phase.With methylene dichloride (250ml) extraction waterbearing stratum.The organic phase that merges is washed with 2M water-soluble sodium hydroxide and 10% citric acid solution, concentrate with dried over mgso and under vacuum.By column chromatography, use ethyl acetate on silica gel: hexanaphthene (1: 6 by volume to 1: 4 to 1: 2 to 1: 1) wash-out comes purifying crude product, obtains the title product, 50g (82.4%).
1HNMR (CDCl 3, 400MHz, rotational isomer) and δ: 1.43-1.47 (d, 9H), 1.56-1.66 (m, 5H), 1.79 (m, 0.5H), 1.98 (m, 3H), 2.37 (m, 1H), 2.92 (m, 0.5H), 3.15 (m, 0.5H), 3.40 (m, 1H), 3.58 (m, 1.5H), 3.74 (m, 2H), 3.97 (m, 1H), 7.10 (m, 1H), 7.24 (m, 1H), 7.46 (d, 1H)
MS?APCI +?m/z?427[MH] +and?m/z?327[MH-Boc] +
Preparation 3
(3S)-and 3-[cyclopentyl (2,3-two chloro-4-fluoro-benzoyls) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200411
At room temperature in nitrogen atmosphere, (2.13ml 24.4mmol) adds 2 to, and (4.25g is 20.33mmol) in (referring to EP0600317, embodiment 15) suspension in anhydrous methylene chloride (41ml) for 3-two chloro-4-fluorobenzoic acids with oxalyl chloride.Add N, dinethylformamide (80 μ l, 1mmol), and with reaction mixture stirring 1 hour.By the evaporation under reduced pressure removed solvent, obtain yellow solid, this yellow solid is dissolved in the methylene dichloride (20ml), and under nitrogen atmosphere, be added drop-wise to triethylamine (4.72ml, 33.9mmol) and preparation 1 amine (4.31g is 16.95mmol) in the solution in methylene dichloride (36ml).After at room temperature stirring 18 hours, with the mixture of gained methylene dichloride (100ml) and water-soluble salt of wormwood (90ml) dilution of 1M.The organic phase dried over mgso is filtered, and by the evaporation under reduced pressure removed solvent.Resistates is dissolved in the methylene dichloride of minimum, and by chromatogram, change to ethyl acetate with pentane on silica gel: the solvent gradient elution of pentane (20: 80 by volume) carries out purifying, obtains the title compound of white foam shape, 6.6 (73%).
1HNMR (CD 3OD, 400MHz, rotational isomer) δ: 1.43-1.47 (d, 9H), 1.62 (m, 1.5H), 1.72 (m, 3H), 1.88 (m, 1.5H), 1.97 (m, 0.5H), 2.13 (m, 1.5H), 2.32 (m, 0.5H), 2.74 (m, 1H), 3.40 (m, 1H), 3.51-3.59 (m, 1.5H), 3.76 (m, 2H), 3.88 (m, 1H), 4.05 (m, 1H), 7.33 (m, 2H)
Preparation 4
(3S)-3-(cyclohexyl amino) tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200421
(3S)-and 3-(cyclohexyl amino) tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method described in the preparation 1, and utilization (3S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester and pimelinketone prepare, and obtain desirable product, 5.9g (82%).
1HNMR(CDCl 3，400MHz)δ：1.09(m，2H)，1.24(m，3H)，1.45(s，9H)，1.62(m，2H)，1.72(m，2H)，1.88(m，2H)，2.06(m，1H)，2.48(m，1H)，3.01(m，1H)，3.30(m，1H)，3.45(m，2H)，3.55-3.62(m，1H)
MS?APCI +?m/z?269[MH] +
Preparation 5
(3S)-and 3-[cyclohexyl (2,3-two chloro-benzoyls) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
(3S)-and 3-[cyclohexyl (2, the 3-dichloro-benzoyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method described in the preparation 2, and the amine and the 2,3 dichloro benzoyl chloride of utilization preparation 4 prepare, and obtain desirable product, 5.14g (83%).
1HNMR (CDCl 3, 400MHz, rotational isomer) δ: 1.00-1.09 (m, 2H), 1.26 (m, 1H), 1.43-1.47 (d, 9H), 1.58 (m, 3H), 1.73 (m, 2H), 1.89 (m, 2H), 2.68 (m, 1H), 2.89 (m, 1H), 3.10 (m, 1H), 3.39 (m, 1H), 3.52 (m, 1H), 3.69 (m, 1H), 3.92 (m, 2H), 7.10 (m, 1H), 7.23 (m, 1H), 7.47 (d, 1H)
LCMS?ELSD/APCI +?m/z?441[MH] +
Preparation 6
(3S)-and 3-[cyclohexyl (2-chloro-3-fluorobenzoyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200431
(3S)-and 3-[cyclohexyl (2-chloro-3-fluorobenzoyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method described in the preparation 3, and the amine and the 2-chloro-3-fluorobenzoic acid of utilization preparation 4 prepare, and obtain desirable product, 158mg (29%).
1HNMR (CDCl 3, 400MHz, rotational isomer) δ: 0.98-1.06 (m, 2.5H), 1.29 (m, 1.5H), 1.47 (d, 9H), 1.57 (m, 3H), 1.73 (m, 2H), 1.87 (m, 2H), 2.66 (m, 0.5H), 2.89 (m, 1H), 3.11 (m, 1H), 3.38 (m, 1H), 3.53 (m, 1H), 3.69 (m, 0.5H), 3.91 (m, 2H), 6.99 (m, 1H), 7.15 (t, 1H), 7.28 (m, 1H)
MS?APCI +?m/z?425[MH] +and?m/z?325[MH-Boc] +
Preparation 7
(3S)-and 3-[cyclohexyl (3-fluoro-2-toluyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
(3S)-and 3-[cyclohexyl (3-fluoro-2-toluyl) amino] tetramethyleneimine-1-carboxylic acid is by being similar in the method described in the preparation 3, and the amine and the 3-fluoro-2-tolyl acid of utilization preparation 4 prepare, and obtain desirable product, 63mg (12%).
1HNMR (CDCl 3, 400MHz, rotational isomer) and δ: 1.02 (m, 2.5H), 1.30 (m, 2.5H), 1.47 (d, 9H), 1.57 (m, 1H), 1.62 (m, 4H), 1.73 (m, 1H), 1.91 (m, 1H), 2.20 (s, 3H), 2.71 (m, 0.5H), 2.91 (m, 1H), 3.18 (m, 1H), 3.39 (m, 1H), 3.49 (m, 0.5H), 3.68 (m, 0.5H), 3.85-3.93 (m, 1.5H), 6.87 (d, 1H), 7.01 (t, 1H), 7.17 (q, 1H)
MS?APCI +?m/z?405[MH] +and?m/z?305[MH-Boc] +
Preparation 8
(3S)-3-(cyclobutyl amino) tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200442
(3S)-3-(cyclobutyl amino) tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method for preparation described in 1, (15 equivalents: 10eq. at first adds to utilize (3S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester and cyclobutanone, 5eq. before the second time, azeotropic anhydrated, add) prepare, difference is that thick product is by column chromatography purifying on silica gel, obtain title compound, 542mg (28%).
1HNMR(CD 3OD，400MHz)δ：1.45(s，9H)，1.70(m，3H)，1.81(m，3H)，2.05(m，1H)，2.21(m，2H)，3.03(m，1H)，3.26(m，2H)，3.47(m，2H)
MS?APCI +?m/z?241[MH] +
Preparation 9
(3S)-and 3-[cyclobutyl (2,3-two chloro-benzoyls) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200451
(3S)-and 3-[cyclobutyl (2, the 3-dichloro-benzoyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method described in the preparation 2, and the amine and the 2,3 dichloro benzoyl chloride of utilization preparation 8 prepare, and obtain desirable product, 370mg (79%).
1HNMR(CD 3OD，400MHz)δ：1.43(m，1H)，1.48(s，9H)，1.66(m，1H)，1.95(m，1H)，2.12-2.27(m，4H)，2.72(m，1H)，3.42(m，1H)，3.61(m，1H)，3.69(m，1H)，3.86(m，1H)，3.98(m，1H)，4.45(m，1H)，7.24(dd，1H)，7.40(t，1H)，7.62(d，1H)
MS?APCI +?m/z?313[MH-Boc] +
Preparation 10
(3S)-and 3-{[(2, the 4-dinitrophenyl) alkylsulfonyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200461
Under nitrogen atmosphere, (5g 27mmol) adds 2 to, and (6.2mL is 54mmol) in the solution in methylene dichloride (150ml) for the 6-lutidine with (3S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester.Reaction mixture is cooled to 0 ℃, and in 15 minutes under 0 ℃, slowly add 2,4-dinitrophenyl chloride (7.15g, 27mmol) solution in methylene dichloride (100ml).Under nitrogen atmosphere, reaction mixture was at room temperature stirred 48 hours then.Add water (100ml), then add the 2N hydrochloride aqueous solution, reach pH 2 up to the waterbearing stratum.Then each layer separated, the waterbearing stratum is extracted with more methylene dichloride (100ml).Organic phase is merged, and water (100ml) washing 2 times concentrates with dried over mgso and under vacuum, obtains gelationus title compound, 10g (89%).
1HNMR(CDCl 3，400MHz)δ：1.42(s，9H)，1.88(m，1H)，2.15(m，1H)，3.18(m，1H)，3.37-3.44(m，2H)，4.07(m，1H)，5.58(d，1H)，8.40(d，1H)，8.57(d，1H)，8.68(s，1H)，
Preparation 11
(3S)-3-(cyclobutylmethyl amino) tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200462
Under nitrogen atmosphere, (0.2ml 2.11mmol), then is that (465mg, (0.8g is 1.92mmol) in the solution of tetrahydrofuran (THF) (40ml) 2.3mmol) to add preparation 10 compound to for triphenylphosphine with tetramethylene methyl alcohol.Reaction mixture is cooled to 0 ℃, and (0.45ml, 2.3mmol) solution in tetrahydrofuran (THF) (15ml) remains on temperature below 3 ℃ simultaneously to drip the diisopropyl azo-2-carboxylic acid.Reaction mixture was stirred 0.5 hour down at 0 ℃, at room temperature stirred then 18 hours.The evaporation tetrahydrofuran (THF) drops into resistates in the methylene dichloride (20ml).Add triethylamine (0.53ml, 3.84mmol) and Thiovanic acid (0.16ml 2.3mmol), and at room temperature stirred reaction mixture 2 hours.Then, with the washing of 2N hydrochloride aqueous solution.With 2M sodium hydroxide the waterbearing stratum is basified to pH11, and strips 3 times with ethyl acetate.The vacuum concentration organic phase obtains title compound (151mg, 31%) then.
1HNMR(CDCl 3，400MHz)δ：1.44(s，9H)，1.65(m，3H)，1.87(m，2H)，2.05(m，3H)，2.45(m，1H)，2.62(d，1H)，3.05(m，1H)，3.28-3.51(m，5H)
Alternative method
Under nitrogen atmosphere, with borine tetrahydrochysene furan complex compound (1M in tetrahydrofuran (THF), 100ml, (9g is in the solution of compound 33.54mmol) in anhydrous tetrahydro furan (100ml) 100mmol) to add preparation 27 to.With reaction mixture refluxed 2 hours.With the reaction mixture cool to room temperature, use the methyl alcohol quencher, and under vacuum, concentrate.With resistates and methanol azeotropic, and then be dissolved in the methyl alcohol (200ml) reflux 18 hours, vacuum concentration then.Use methylene dichloride by chromatogram on silica gel: methyl alcohol: 0.88 ammoniacal liquor (by volume, 95: 5: 0.5) wash-out comes resistates is carried out purifying, obtains gluey title compound, (7.67g, 90%).
1HNMR(400MHz，CD 3OD)δ：1.44(s，9H)，1.70(m，3H)，1.90(m，2H)，2.08(m，3H)，2.47(m，1H)，2.62(m，2H)，3.06(m，1H)，3.27(m，2H)，3.45(m，1H)，3.54(m，1H)
MS?APCI?m/z?255[MH] +
Preparation 12
(3S)-and 3-[cyclobutylmethyl (2,3-two chloro-benzoyls) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200481
(3S)-and 3-[cyclobutylmethyl (2, the 3-dichloro-benzoyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method described in the preparation 2, and the amine and the 2,3 dichloro benzoyl chloride of utilization preparation 1 prepare, and obtain desirable product, 94mg (37%).
LCMS?ELSD/APCI +?m/z?427[MH] +
Preparation 13
(3S)-3-(cyclopropyl methylamino) tetramethyleneimine-1-carboxylic acid tert-butyl ester
(3S)-3-(cyclopropyl methylamino) tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method for preparation described in 1, utilize (3S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester and cyclopanecarboxaldehyde to prepare, difference is, thick product is used from methylene dichloride on silica gel by chromatogram and changed to methylene dichloride: methyl alcohol: 0.88 ammoniacal liquor (by volume, 90: 10: 1) solvent gradient elution carry out purifying, obtain title compound, 5.2g (81%).
1HNMR(CDCl 3，400MHz)δ：0.15(m，2H)，0.48(m，2H)，0.97(m，1H)，1.43(s，9H)，1.75(m，1H)，2.05(m，1H)，2.50(d，2H)，3.10(m，1H)，3.47(m，2H)，3.50(m，2H)
MS?APCI +m/z?241[MH] +
Preparation 14
(3S)-3-(tetrahydrochysene-2H-pyrans-4-base is amino) tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200491
(3S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester is added in tetrahydrochysene-4H-pyrans-4-ketone and the solution of 10%Pd/C (300mg) in ethanol, and reaction mixture was placed 18 hours under the hydrogen of about 415kPa (about 60psi).Reaction mixture is filtered by Arbocel , thoroughly clean with ethyl acetate.With the filtrate vacuum concentration, thick product carries out purifying by column chromatography on silica gel, obtain desirable product, 6.7g (61%).
1HNMR(CDCl 3，400MHz)δ：1.39(m，2H)，1.46(s，9H)，1.67(m，1H)，1.82(m，2H)，2.07(m，1H)，2.72(m，1H)，3.02(brm，1H)，3.31-3.39(m，5H)，3.59(brm，1H)，3.96(m，2H)
MS?ES+m/z?271[MH] +
Preparation 15
(3S)-and 3-[(2, the 3-dichloro-benzoyl) (tetrahydrochysene-2H-pyrans-4-yl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200501
(3S)-3-[(2, the 3-dichloro-benzoyl) (tetrahydrochysene-2H-pyrans-4-yl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method (utilize N-methylmorpholine as alkali) of preparation described in 2, utilize the amine and 2 of preparation 14, the 3-dichlorobenzoyl chloride prepares, obtain desirable product, 200mg (31%).
1HNMR (CD 3OD, 400MHz) δ: 1.43-1.47 (d, 9H), 1.58 (m, 1.5H), 1.76 (m, 0.5H), 1.94 (m, 2H), 2.11 (m, 1H), 2.76 (m, 0.5H), 2.98 (m, 0.5H), 3.13 (m, 2H), 3.4-3.58 (m, 4H), 3.69 (m, 0.5H), 3.9 (m, 2.5H), 4.04 (m, 0.5H), 4.2 (m, 0.5H), 7.29 (d, 1H), 7.43 (t, 1H), 7.62 (d, 1H) rotational isomers
MS APCI +M/z 443[MH] +And 343[MH-Boc] +
Preparation 16
(3S)-and the 3-[(2-chlorobenzoyl) (cyclopentyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200502
(3S)-and the 3-[(2-chlorobenzoyl) (cyclopentyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester (utilizes toluene as solvent by being similar in the method for preparation described in 2, N-methylmorpholine is as alkali, reaction mixture was heated 18 hours down at 60 ℃), utilize the amine and the 2-chloro-benzoyl chloride of preparation 1 to prepare, obtain desirable product, 1.16g (75%).
1HNMR (CD 3OD, 400MHz, rotational isomer) δ: 1.42-1.47 (d, 11H), 1.62 (m, 1H), 1.71 (m, 3H), 1.89 (m, 1H), 1.99 (m, 1H), 2.13 (m, 1H), 2.33 (m, 0.5H), 2.77 (m, 1H), 3.07 (m, 0.5H), 3.46 (m, 1H), 3.60 (m, 0.5H), 3.70 (m, 1H), 3.78 (m, 1H), 3.90 (m, 0.5H), 4.04 (m, 1H), 7.30 (m, 1H), 7.41 (m, 2H), 7.48 (m, 1H)
MS?APCI +?m/z?393[MH] +and?m/z?293[MH-Boc] +
Preparation 17
(3S)-and the 3-[(2-chlorobenzoyl) (cyclohexyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
(3S)-and the 3-[(2-chlorobenzoyl) (cyclohexyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester (utilizes toluene as solvent by being similar in the method for preparation described in 2, N-methylmorpholine is as alkali, reaction mixture was heated 18 hours down at 60 ℃), utilize the amine and the 2-chloro-benzoyl chloride of preparation 4 to prepare, obtain desirable product, 1.09g (72%).
1HNMR (CD 3OD, 400MHz, rotational isomer) δ: 0.97 (m, 1H), 1.09 (m, 1H), 1.43-1.47 (d, 9H), 1.55-1.87 (m, 8H), 2.07 (m, 1H), 2.76 (m, 1H), 3.16 (m, 1H), 3.39 (m, 1H), 3.54 (m, 1H), 3.68 (m, 1H), 3.88 (m, 1H), 4.146 (m, 1H), 7.30 (d, 1H), 7.41 (m, 2H), 7.48 (m, 1H)
LCMS APCI +M/z 407[MH] +With m/z 307[MH-Boc] +
Preparation 18
(3S)-3-(suberyl amino) tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200521
(3S)-and 3-(suberyl amino) tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method described in the preparation 14, and utilization (3S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester and suberone prepare, and obtain desirable product, 4.54g (100%).
1HNMR(CD 3OD，400MHz)δ：1.45(s，1?2H)，1.57(m，5H)，1.69(m，3H)，1.89(m，2H)，2.12(m，1H)，2.71(m，1H)，3.02(m，1H)，3.26(m，1H)，3.45(m，2H)，3.59(m，1H)
MS?APCI +?m/z?283[MH] +
Preparation 19
(3S)-and the 3-[(2-chlorobenzoyl) (suberyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200522
(3S)-and the 3-[(2-chlorobenzoyl) (suberyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester (utilizes toluene as solvent by being similar in the method for preparation described in 2, N-methylmorpholine is as alkali, reaction mixture was heated 18 hours down at 60 ℃), utilize the amine and the 2-chloro-benzoyl chloride of preparation 18 to prepare, obtain desirable product, 1.27g (90%).
MS APCI +M/z 421[MH] +With m/z 321[MH-Boc] +
Preparation 20
(3S)-and 3-{ suberyl [2-(trifluoromethyl) benzoyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200531
(3S)-and 3-{ suberyl [2-(trifluoromethyl) benzoyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester (utilizes toluene as solvent by being similar in the method for preparation described in 2, N-methylmorpholine is as alkali, reaction mixture was heated 18 hours down at 60 ℃), utilize the amine and 2-(trifluoromethyl) Benzoyl chloride of preparation 18 to prepare, obtain desirable product, 910mg (57%).
MS APCI +M/z 455[MH] +With m/z 355[MH-Boc] +
Preparation 21
(3S)-and 3-{ cyclohexyl [2-(trifluoromethyl) benzoyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200532
(3S)-and 3-{ cyclohexyl [2-(trifluoromethyl) benzoyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester (utilizes toluene as solvent by being similar in the method for preparation described in 2, N-methylmorpholine is as alkali, reaction mixture was heated 18 hours down at 60 ℃), utilize the amine and 2-(trifluoromethyl) Benzoyl chloride of preparation 4 to prepare, obtain desirable product, 860mg (52%).
MS APCI +M/z 441[MH] +With m/z 341[MH-Boc] +
Preparation 22
(3S)-and 3-{ cyclopentyl [2-(trifluoromethyl) benzoyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200541
(3S)-and 3-{ cyclopentyl [2-(trifluoromethyl) benzoyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester (utilizes toluene as solvent by being similar in the method for preparation described in 2, N-methylmorpholine is as alkali, reaction mixture was heated 18 hours down at 60 ℃), utilize the amine and 2-(trifluoromethyl) Benzoyl chloride of preparation 1 to prepare, obtain desirable product, 910mg (54%).
1HNMR (CDCl 3, 400MHz, rotational isomer) δ: 1.43-1.47 (brd, 11H), 1.55 (m, 2H), 1.65 (m, 1H), 1.76 (m, 2H), 1.99 (m, 2H), 2.35 (m, 0.5H), 2.89 (m, 0.5H), 3.05 (m, 0.5H), 3.19 (m, 0.5H), 3.39 (m, 1H), 3.57 (m, 1H), 3.69 (m, 2H), 3.96 (m, 1H), 7.24 (m, 1H), 7.50 (m, 1H), 7.57 (m, 1H), 7.69 (d, 1H)
MS APCI +M/z 427[MH] +With m/z 327[MH-Boc] +
Preparation 23
(3S)-and 3-{[(1-methyl cyclopropyl) carbonyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200551
At room temperature, (2.96g, (5g is 26.85mmol) in the solution in methylene dichloride (135ml) 29.54mmol) to add (3S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester to 1-methyl cyclopropane carboxylic acid.Add then triethylamine (9.4ml, 67.13mmol).Reaction is cooled to 0 ℃, and adds 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4, the 6-trioxide (50%, in ethyl acetate, 17.4ml, 29.54mmol).Mixture was at room temperature stirred 1 hour, then concentrating under reduced pressure.Resistates is diluted in the methylene dichloride (100ml), and adds 20% wet chemical (80ml).Mixture is at room temperature stirred 18 hours, and separate each layer.With 20% solution of potassium carbonate (50ml), dried over mgso is used in hydrochloric acid (80ml) washing with organic layer, vacuum concentration, and with the Anaesthetie Ether azeotropic, obtain the title compound (6.815g, 95%) of white solid.
1HNMR(CDCl 3，400MHz)δ：0.52-0.54(m，2H)，1.16-1.19(m，2H)，1.29(s，3H)，1.45(s，9H)，1.81(brs，1H)，2.14(m，1H)，3.14(brs，1H)，3.42(brs，2H)，3.64(m，1H)，4.44(m，1H)，5.73(brs，1H)。
MS?APCI +?m/z?269[MH] +。
Preparation 24
(3S)-and 3-{[(1-methyl cyclopropyl) methyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200552
Under nitrogen atmosphere, with borine (1M, in tetrahydrofuran (THF), 75ml, (6.815g is 25.39mmol) in the solution of tetrahydrofuran (THF) (75ml) 75mmol) slowly to add preparation 23 compound to.Mixture heating up was refluxed 2 hours, at room temperature stirred then 18 hours.Add methyl alcohol carefully, with the quencher reaction mixture, then with the mixture vacuum concentration.Resistates is dropped in the methyl alcohol (120ml), and reflux 3 hours.Add water-soluble ammonium chloride then, with reaction mixture reflux 4 hours.Then with the reaction mixture vacuum concentration, resistates is distributed in the water-soluble NaOH of ethyl acetate and 1N, contain water with ethyl acetate extraction 1 time, and, filter also concentrating under reduced pressure the organic phase dried over mgso that merges.Thick product is used ethyl acetate by column chromatography on silica gel: pentane (20: 80 to 30: 70) wash-out carries out purifying, obtains the title product (3.85g, 60%) of white solid.
1HNMR(CD 3OD，400MHz)δ：0.55-0.58(m，2H)，0.62-0.64(m，2H)，1.22(s，3H)，1.46(s，9H)，2.08(m，1H)，2.36(m，1H)，2.94(q，2H)，3.36-3.41(m，2H)，3.56(m，1H)，3.74-3.86(m，2H)。
MS?APCI +?m/z?255[MH] +。
Preparation 25
(3S)-and 3-{ (2, the 3-dichloro-benzoyl) [(1-methyl cyclopropyl) methyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200561
(3S)-3-{ (2, the 3-dichloro-benzoyl) [(1-methyl cyclopropyl) methyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method described in the preparation 2, and the amine and the 2,3 dichloro benzoyl chloride of utilization preparation 24 prepare, obtain desirable product (448mg, 85%).
1HNMR (DMSO-D 6, 400MHz, rotational isomer) and δ: 0.15-0.18 (m, 1.5H), 0.26-0.31 (m, 1.5H), 0.42 (m, 0.5H), 0.53 (m, 1H), 0.88 (d, 2H), 1.07 (s, 1.5H), 1.33 (s, 4H), 1.39 (s, 5H), 2.05 (m, 1H), 2.55 (m, 0.5H), 2.82 (m, 0.5H), 2.96 (m, 0.5H), 3.10-3.22 (m, 2H), 3.31 (m, 1H), 3.49-3.56 (m, 1.5H), 3.65 (m, 0.5H), 4.23 (m, 0.5H), 7.35 (m, 1H), 7.42 (m, 1H), 7.66 (m, 1H).
MS?APCI +?m/z?427[MH] +。
Preparation 26
(3S)-and 3-{ (3-chloro-2-toluyl) [(1-methyl cyclopropyl) methyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200571
(3S)-and 3-{ (3-chloro-2-toluyl) [(1-methyl cyclopropyl) methyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method for preparation described in 3, utilize the amine and the 3-chloro-2-tolyl acid of preparation 24 to prepare, obtain desirable product (300mg, 60%).
1HNMR (DMSO-D 6, 400MHz, rotational isomer) and δ: 0.18 (m, 1H), 0.24-0.32 (m, 2H), 0.51 (m, 1H), 0.83 (s, 2H), 1.06 (s, 1H), 1.32 (s, 4H), 1.39 (s, 5H), 1.85 (m, 0.5H), 2.04 (m, 1H), 2.18 (s, 2H), 2.22 (s, 1H), 2.56 (m, 1H), 2.95 (m, 1H), 3.09 (m, 1H), 3.18-3.22 (m, 2H), 3.48-3.55 (m, 1.5H), 3.66 (m, 0.5H), 4.22 (m, 0.5H), 7.15 (m, 1H), 7.26 (t, 1H), 7.45 (d, 1H).
MS?APCI +?m/z?407[MH] +
Preparation 27
(3S)-and the 3-[(cyclobutyl carbonyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200581
At room temperature, under nitrogen atmosphere, with tetramethylene carbonyl chlorine (9g, 76mmol) add to triethylamine (12.5ml, 89.7mmol) and (3S)-(12.87g is 69mmol) in the solution in methylene dichloride (385ml) for 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester.After at room temperature stirring 18 hours, reaction mixture is washed with water, concentrate, obtain the glass title product of light brown, (17.4g, 94%) with dried over mgso and under vacuum
1HNMR(400MHz，CDCl 3)δ：1.45(s，9H)，1.75-2.00(m，3H)，2.07-2.30(m，5H)，2.95(m，1H)，3.15(m，1H)，3.40(m，2H)，3.60(m，1H)，4.44(m，1H)，5.40(brs，1H)
Preparation 28
(3S)-and 3-{ (cyclobutylmethyl) [2-(trifluoromethyl) benzoyl] amino } tetramethyleneimine-1-carboxylic acid tert-butyl ester
Figure A20058004010200582
To be in (the 3S)-3-[(cyclobutylmethyl in the toluene (10ml)) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester (and 0.80g, 3.15mmol) with 2-(trifluoromethyl) Benzoyl chloride (0.55ml, 3.78mmol) and triethylamine (0.88ml, 6.3mmol) processing.Solution was at room temperature stirred 18 hours, and solvent is removed in decompression.Thick product uses on silica gel from pentane by column chromatography: ethyl acetate (4: 1 by volume) changes to pentane: the gradient of ethyl acetate (1: 1 by volume) is carried out purifying, obtain the title compound (1.40g of colorless oil, thick product), it is directly used in following step.
MS APCI +M/z 427[MH] +, the 371[MH-iso-butylene] +, 327[MH-Boc] +
Embodiment 1
Half ethionic acid 2,3-two chloro-N-cyclopentyl-N-[(3S)-and tetramethyleneimine-3-yl] benzamide
Figure A20058004010200591
Under nitrogen atmosphere, (46g 107mmol) is dissolved in the methylene dichloride (85ml), and reaction mixture is used in 0 ℃ of trifluoroacetic acid that drips down, and (85ml 1mol) handles with preparation 2 the product of being protected by Boc.Then, reaction mixture was at room temperature stirred 4 hours, reduction vaporization with methylbenzene azeotropic 2 times, and concentrates under vacuum.Resistates is dropped in the methylene dichloride (400ml), and wash with the water-soluble sodium hydroxide of 1M (200ml).Separate organic phase, concentrate with dried over mgso and under vacuum.With resistates and ethyl acetate (10x) azeotropic, vacuum-drying then obtains the free alkali of gelationus title product, 34g (97%).(24g 70mmol) places Virahol (400ml), with ethionic acid hydrate (6.65g, 35mmol) solution-treated in Virahol (70ml) with the part of this product.Vacuum is removed solvent, and with resistates and ethyl acetate azeotropic, obtains cream-coloured foam, and it from Virahol/Di Iso Propyl Ether crystallization, is obtained pale solid (23.3g).This solid is from Virahol/methyl alcohol (700ml Virahol and realize the methyl alcohol of the needed minimum of dissolving) recrystallization, dry under high vacuum, obtain the title compound (13.94g) of white solid.
1HNMR(CD 3OD，400MHz)δ：1.40-1.74(m，7H)，1.92(m，1H)，2.52(m，2H)，3.24(s，2H)，3.30(m，1H)，3.56(m，1H)，3.78(m，3H)，4.33(m，1H)，7.35(dd，1H)，7.42(t，1H)，7.63(d，1H)
MS?APCI +?m/z?327[MH +]LC-MS?ELSD?m/z?327?100％
Trace analysis: obtain: C, 47.37; H, 5.59; N, 6.47.
C 16H 20Cl 2N 2O0.5C 2H 6O 6S 20.5H 2O requires C, 47.34; H, 5.61; N, 6.49%.
Embodiment 2
Hydrochloric acid 2,3-two chloro-N-cyclopentyl-4-fluoro-N-[(3S)-tetramethyleneimine-3-yl] benzamide
Figure A20058004010200601
With hydrogenchloride (4M, 1, in the 4-diox, 37ml, (6.65g is 14.93mmol) in the solution of methylene dichloride (40ml) 148mmol) to add preparation 3 product to.After at room temperature stirring 18 hours, solvent obtains solid by evaporation under reduced pressure removed, and solid and ether are ground, and obtains the title product (5.5g) of white solid.
1HNMR(CD 3OD，400MHz)δ：1.54(m，4H)，1.73(m，3H)，1.92(m，1H)，2.52(m，2H)，3.25(m，1H)，3.52(m，1H)，3.78(m，3H)，4.32(m，1H)，7.37(m，2H)
MS?APCI +?m/z?345[M] +
Embodiment 3
Hydrochloric acid 3-chloro-N-cyclopentyl-2-methyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide
Figure A20058004010200602
(3S)-and 3-[cyclopentyl (3-chloro-2-toluyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method for preparation described in 3, utilize the amine and the 3-chloro-2-tolyl acid of preparation 1 to prepare, obtain desirable product, 606mg (thick product).
MS?APCI +?m/z?407[MH] +。
Hydrochloric acid 3-chloro-N-cyclopentyl-2-methyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 2, utilizes above-claimed cpd to prepare, and obtains the title product of solid state, 199mg (47%).
1HNMR(CD 3OD，400MHz)δ：1.44-1.60(m，4H)，1.79(m，4H)，2.33(d，3H)，2.44-2.54(m，2H)，3.24(m，1H)，3.54(m，1H)，3.72(m，1H)，3.80(m，2H)，4.3?1(m，1H)，7.1?6(dd，1H)，7.28(t，1H)，7.47(d，1H)
LCMS?ELSD/APCI +?m/z?307[MH] +100％。
Trace analysis: obtain: C, 58.25; H, 7.20; N, 7.92%.
For C 17H 23ClN 2OHCl0.4H 2The calculated value of O: C, 58.26; H, 7.13; N, 7.99%.
Embodiment 4
Hydrochloric acid N-cyclopentyl-3-fluoro-2-methyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide
Figure A20058004010200611
(3S)-and 3-[(3-fluoro-2-toluyl) (cyclopentyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method for preparation described in 3, utilize the amine and the 3-fluoro-2-tolyl acid of preparation 1 to prepare, obtain desirable product, 639mg (thick product).
MS?APCI +?m/z?391[MH] +。
Hydrochloric acid N-cyclopentyl-3-fluoro-2-methyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 2, utilizes above-claimed cpd to prepare, and obtains the title product of solid state, 182mg (46%).
1HNMR(CD 3OD，400MHz)δ：1.49-1.63(m，4H)，1.78(m，4H)，2.22(d，3H)，2.49(m，2H)，3.25(m，1H)，3.55(m，1H)，3.74(m，1H)，3.87(m，2H)，4.31(m，1H)，7.03(dd，1H)，7.14(t，1H)，7.31(q，1H)
MS?APCI +?m/z?291[MH] +
LCMS?ELSD/APCI +?m/z?291[MH] +100％。
Trace analysis: obtain: C, 61.18; H, 7.51; N, 8.25%.
For C 17H 23FN 2OHCl0.39H 2The calculated value of O: C, 61.16; H, 7.48; N, 8.39%.
Embodiment 5
Hydrochloric acid 2-chloro-N-cyclopentyl-3-fluoro-N-[(3S)-and tetramethyleneimine-3-yl] benzamide
(3S)-and 3-[(2-chloro-3-fluorobenzoyl) (cyclopentyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method described in the preparation 3, and the amine and the 2-chloro-3-fluorobenzoic acid of utilization preparation 1 prepare, and obtain desirable product.
Hydrochloric acid 2-chloro-N-cyclopentyl-3-fluoro-N-[(3S)-and tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 2, utilizes above-claimed cpd to prepare, and obtains the title product of solid state, 62mg (15%).
1HNMR(CD 3OD，400MHz)δ：1.44-1.63(m，4H)，1.73(m，3H)，1.92(m，1H)，2.52(m，2H)，3.24(m，1H)，3.58(m，1H)，3.80(m，3H)，4.32(m，1H)，7.19(dd，1H)，7.35(t，1H)，7.45(m，1H)。
LCMS?ELSD/APCI +?m/z?311[MH] +100％。
Trace analysis: obtain: C, 53.68; H, 6.30; N, 7.71%.
For C 16H 20ClFN 2OHCl0.6H 2The calculated value of O: C, 53.67; H, 6.25; N, 7.82%.
Embodiment 6
Hydrochloric acid 2,3-two chloro-N-cyclohexyl-N-[(3S)-and tetramethyleneimine-3-yl] benzamide
Figure A20058004010200631
Hydrochloric acid 2,3-two chloro-N-cyclohexyl-N-[(3S)-and tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 2, and the compound of utilization preparation 5 prepares, and obtains the title product of solid state, 3.95g (89%).
1HNMR(CD 3OD，400MHz)δ：1.02-1.10(m，3H)，1.56-1.81(m，7H)，2.46(m，2H)，3.13(m，1H)，3.25(m，1H)，3.48(m，1H)，3.73(m，1H)，3.81(m，1H)，4.45(m，1H)，7.32(dd，1H)，7.43(t，1H)，7.66(d，1H)。
MS?APCI +?m/z?341[MH] +。
Embodiment 7
Hydrochloric acid 2-chloro-N-cyclohexyl-3-fluoro-N-[(3S)-and tetramethyleneimine-3-yl] benzamide
Figure A20058004010200641
Hydrochloric acid 2-chloro-N-cyclohexyl-3-fluoro-N-[(3S)-and tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 2, and the compound of utilization preparation 6 prepares, and obtains the title product of solid state, 118mg (88%).
1HNMR(CD 3OD，400MHz)δ：0.99-1.12(m，3H)，1.56-1.91(m，7H)，2.47(m，2H)，3.16-3.22(m，2H)，3.50(m，1H)，3.71(m，1H)，3.81(m，1H)，4.45(m，1H)，7.21(dd，1H)，7.37(t，1H)，7.46(m，1H)。
MS?APCI +?m/z?325[MH] +。
Trace analysis: obtain: C, 54.87; H, 6.55; N, 7.30%.
For C 17H 22ClFN 2OHCl0.6H 2The calculated value of O: C, 54.88; H, 6.56; N, 7.53%.
Embodiment 8
Hydrochloric acid N-cyclohexyl-3-fluoro-2-methyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide
Figure A20058004010200642
Hydrochloric acid N-cyclohexyl-3-fluoro-2-methyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 2, and the compound of utilization preparation 7 prepares, and obtains the title product of solid state, 45mg (85%).
1HNMR(CD 3OD，400MHz)δ：0.99-1.17(m，3H)，1.54-1.77(m，7H)，2.20(d，3H)，2.47(m，2H)，3.23(m，2H)，3.48(m，1H)，3.70(m，1H)，3.81(m，1H)，4.43(m，1H)，7.03(dd，1H)，7.16(t，1H)，7.3?1(q，1H)。
MS?APCI +?m/z?305[MH] +?LCMS?ELSD?m/z?305[MH] +100％。
Trace analysis: obtain: C, 60.87; H, 7.80; N, 7.59%.
For C 18H 25FN 2OHCl0.79H 2The calculated value of O: C, 60.88; H, 7.83; N, 7.89%.
Embodiment 9
Hydrochloric acid 2,3-two chloro-N-cyclobutyl-N-[(3S)-and tetramethyleneimine-3-yl] benzamide
Figure A20058004010200651
Hydrochloric acid 2,3-two chloro-N-cyclobutyl-N-[(3S)-and tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 2, and the compound of utilization preparation 9 prepares, and obtains the title product of solid state, 311mg (99%).
1HNMR(CD 3OD，400MHz)δ：1.56(m，1H)，1.70(m，1H)，2.00(m，1H)，2.13(m，1H)，2.23-2.30(m，2H)，2.46(m，1H)，2.54(m，1H)，3.26(m，1H)，3.54(m，1H)，3.73-3.81(m，2H)，4.00(m，1H)，4.71(m，1H)，7.31(m，1H)，7.43(t，1H)，7.66(d，1H)。
MS?APCI +?m/z?313[MH] +。
Embodiment 10
Hydrochloric acid N-cyclobutylmethyl-2,3-two chloro-N-[(3S)-tetramethyleneimine-3-yl] benzamide
Hydrochloric acid N-cyclobutylmethyl-2,3-two chloro-N-[(3S)-tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 1, and the compound of utilization preparation 12 prepares, and obtains gelationus title product, 55mg (68%).
1HNMR(CD 3OD，400MHz)δ：1.55-1.70(m，3H)，1.85-2.03(m，3H)，2.54(m，3H)，3.15(m，1H)，3.26(m，2H)，3.50(m，1H)，3.76(m，2H)，4.30(m，1H)，7.38(m，1H)，7.43(t，1H)，7.66(d，1H)。
LCMS?UV/ESI +?m/z?327[MH] +。
Trace analysis: obtain: C, 50.83; H, 5.90; N, 7.42%.
For C 16H 20Cl 2N 2OHCl0.75H 2The calculated value of O: C, 50.94; H, 6.01; N, 7.43%.
Embodiment 11
Hydrochloric acid 2,3-two chloro-N-(cyclopropyl methyl)-N-[(3S)-tetramethyleneimine-3-yl] benzamide
Figure A20058004010200662
(3S)-and 3-[cyclopropyl methyl (2, the 3-dichloro-benzoyl) amino] tetramethyleneimine-1-carboxylic acid tert-butyl ester is by being similar in the method described in the preparation 1, and the amine and the 2,3 dichloro benzoyl chloride of utilization preparation 13 prepare, and obtain desirable product (thick product).
MS APCI +M/z 413[MH] +With m/z 313[MH-Boc] +
Hydrochloric acid 2,3-two chloro-N-(cyclopropyl methyl)-N-[(3S)-tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 1, utilizes above-mentioned compound to prepare, by chromatogram purification and form hydrochloride, obtain gelationus title product, 393mg (77%).
1HNMR(CD 3OD，400MHz)δ：0.09(m，2H)，0.502(m，2H)，0.88(m，1H)，2.47-2.54(m，2H)，3.01(m，2H)，3.21(m，1H)，3.50(m，1H)，3.76(m，2H)，4.42(m，1H)，7.36(m，2H)，7.59(d，1H)。
LCMS?ELSD/APCI +?m/z?313[MH] +100％。
Trace analysis: obtain: C, 49.52; H, 5.65; N, 7.45%.
For C 15H 18Cl 2N 2OHCl0.78H 2The calculated value of O: C, 49.53; H, 5.70; N, 7.70%.
Embodiment 12
2,3-two chloro-N-[(3S)-tetramethyleneimine-3-yl]-N-tetrahydrochysene-2H-pyrans-4-yl-benzamide
Figure A20058004010200671
2,3-two chloro-N-[(3S)-tetramethyleneimine-3-yl]-(utilize on silica gel from methylene dichloride by column chromatography: methyl alcohol: ammoniacal liquor (100: 0: 0 by volume) changes to methylene dichloride to N-tetrahydrochysene-2H-pyrans-4-yl-benzamide: methyl alcohol: the gradient acquisition free alkali of ammoniacal liquor (100: 10: 1 by volume)) in the method described in the embodiment 2 by being similar to, utilize the compound of preparation 15 to prepare, obtain the colorless oil title compound, obtain gelationus title product with it, 120mg (77%).
1HNMR(CD 3OD，400MHz)δ：1.58(m，1H)，1.74(m，1H)，1.89-1.97(m，2H)，2.28(m，2H)，2.96(m，1.5H)，3.11-3.20(m，3H)，3.45-3.53(m，3H)，3.92(m，1.5H)，4.03(m，0.5H)，4.20(m，0.5H)，7.32(dd，1H)，7.42(t，1H)，7.64(d，1H)
MS?APCI +?m/z?343[MH] +
Embodiment 13
2-chloro-N-cyclopentyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide
2-chloro-N-cyclopentyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 1, and the compound of utilization preparation 16 prepares, and obtains the title product, 640mg (74%).
1HNMR(CD 3OD，400MHz)δ：1.43(m，2H)，1.61(m，2H)，1.72(m，3H)，1.92(m，2H)，2.38(m，2H)，3.09(q，1H)，3.57-3.65(m，2H)，3.79(m，1H)，4.15(m，1H)，7.33(m，1H)，7.43(m，2H)，7.49(m，1H)MS?APCI +?m/z?293[MH +]
Embodiment 14
2-chloro-N-cyclohexyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide
2-chloro-N-cyclohexyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 1, and the compound of utilization preparation 17 prepares, and obtains the title product, 685mg (83%).
1HNMR(CD 3OD，400MHz)δ：0.98-1.13(brm，3H)，1.54-1.88(brm，7H)，2.44(m，2H)，3.19(m，2H)，3.44(q，1H)，3.66(m，1H)，3.78(m，1H)，4.41(m，1H)，7.34-7.52(brm，4H)。
MS?APCI +?m/z?307[MH] +。
Embodiment 15
2-chloro-N-suberyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide
Figure A20058004010200691
2-chloro-N-suberyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 1, and the compound of utilization preparation 19 prepares, and obtains title product 785mg (81%).
1HNMR(CD 3OD，400MHz)δ：1.27(m，3H)，1.44(m，3H)，1.62(m，1H)，1.75-1.92(m，5H)，2.49(m，2H)，3.22(m，2H)，3.49(q，1H)，3.70(m，1H)，3.81(m，1H)，4.36(m，1H)，7.35-7.52(brm，4H)。
MS?APCI +?m/z?321[MH] +。
Embodiment 16
The N-suberyl-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide
Figure A20058004010200692
The N-suberyl-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide is by being similar in the method described in the embodiment 1, and the compound of utilization preparation 20 prepares, and obtains the title product, 502mg (72%).
1HNMR(CD 3OD，400MHz)δ：1.19(m，2H)，1.32(m，1H)，1.42(m，3H)，1.65-1.81(m，6H)，2.45(m，2H)，3.24(m，2H)，3.48(t，1H)，3.56(m，0.5H)，3.76(m，1.5H)，4.35(m，1H)，7.49(dd，1H)，7.69(m，1H)，7.75(m，1H)，7.81(m，1H)。
MS?APCI +?m/z?355[MH] +。
Embodiment 17
The N-cyclohexyl-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide
Figure A20058004010200701
The N-cyclohexyl-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide is by being similar in the method described in the embodiment 1, and the compound of utilization preparation 21 prepares, and obtains title product 460mg (69%).
1HNMR(CD 3OD，400MHz)δ：0.95-1.08(m，3H)，1.52-1.73(m，7H)，2.08(m，1H)，2.20(m，1H)，2.79(m，1H)，2.96(m，1H)，3.06(m，1H)，3.21(dd，0.5H)，3.37(m，1.5H)，4.06(m，1H)，7.42(dd，1H)，7.65(m，1H)，7.72(m，1H)，7.79(m，1H)。
MS?APCI +?m/z?341[MH] +。
Embodiment 18
The N-cyclopentyl-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide
Figure A20058004010200711
The N-cyclopentyl-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide is by being similar in the method described in the embodiment 1, and the compound of utilization preparation 22 prepares, and obtains title product 690mg (99%).
1HNMR(CD 3OD，400MHz)δ：1.44(m，2H)，1.59(m，2H)，1.73(m，4H)，2.47(m，2H)，3.24(m，1H)，3.53(m，1.5H)，3.76(m，2.5H)，4.29(m，1H)，7.46(dd，1H)，7.66(m，1H)，7.74(m，1H)，7.80(m，1H)。
MS?APCI +?m/z?327[MH] +。
Embodiment 19
Hydrochloric acid 2,3-two chloro-N-[(1-methyl cyclopropyl) methyl]-N-[(3S)-and tetramethyleneimine-3-yl] benzamide
Figure A20058004010200712
Hydrochloric acid 2,3-two chloro-N-[(1-methyl cyclopropyl) methyl]-N-[(3S)-and tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 2, and the compound of utilization preparation 25 prepares, and obtains the title product (269mg, 100%) of solid state.
1HNMR(CD 3OD，400MHz)δ：0.25-0.32(m，2H)，0.44(m，1H)，0.50(m，0.5H)，0.60(m，0.5H)，0.98(s，3H)，2.50-2.61(m，2H)，2.95(dd，1H)，3.24-3.36(m，2H)，3.57(m，1H)，3.75-3.87(m，2H)，4.52(m，1H)，7.36-7.45(m，2H)，7.63(d，1H)。
MS?APCI +?m/z?327[MH] +。
Embodiment 20
Hydrochloric acid 3-chloro-2-methyl-N-[(1-methyl cyclopropyl) methyl]-N-[(3S)-and tetramethyleneimine-3-yl] benzamide
Figure A20058004010200721
Hydrochloric acid 3-chloro-2-methyl-N-[(1-methyl cyclopropyl) methyl]-N-[(3S)-and tetramethyleneimine-3-yl] benzamide is by being similar in the method described in the embodiment 2, utilize the compound of preparation 26 to prepare, obtain the title product (310mg, 90%) of solid state.
1HNMR(CD 3OD，400MHz).δ：0.29-0.42(m，3.5H)，0.51(m，0.5H)，0.96(s，3H)，2.31(d，3H)，2.50(m，1H)，2.59(m，1H)，3.02(d，0.5H)，3.15(q，1H)，3.25-3.32(m，1.5H)，3.59(m，1H)，3.78-3.83(m，2H)，4.51(brs，1H)，7.21(m，1H)，7.29(t，1H)，7.47(d，1H)。
MS?APCI +?m/z?307[MH] +。
Embodiment 21
Hydrochloric acid N-(cyclobutylmethyl)-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide
Will be from preparation (3S)-3-{ (cyclobutylmethyl) [2-(trifluoromethyl) benzoyl] amino of 28 } (1.40g 3.3mmol) is dissolved in the 4N hydrogenchloride that is in the diox tetramethyleneimine-1-carboxylic acid tert-butyl ester.With solution stirring 1 hour, solvent was removed in decompression.Resistates is dissolved in the water, and solution is washed with ether.Water alkalizes by adding the NaOH aqueous solution, and extracts with ether.Ether is used dried over mgso mutually, filter, and decompression removal solvent, obtain jelly, this jelly is handled with the 2N hydrogenchloride that is in the ether, obtain the title compound of 0.99 g (86%) white foam shape.
1HNMR(400MHz，CD 3OD)δ：1.61-1.72(m，3H)，1.92-2.03(m，3H)，2.45(m，1H)，2.59(m，2H)，3.14(m，1H)，3.26(m，2H)，3.55(m，1H)，3.68-3.82(m，2H)，4.34(m，1H)，7.54(m，1H)，7.72(m，1H)，7.80(m，1H)，7.85(m，1H)。
LCMS?APCI +?m/z?327[MH] +
Embodiment 22
The NRI K of the compound of embodiment 1 to 21 iWith SRI K iBy following mensuration.The result is selected to list in the following table 1.All embodiment compounds show the NRI K less than 100nM iWith SRI K i
Biological activity
Flicker detection (SPA) technology is got close in utilization, suppresses the bonded ability of the selective emission part that human serotonin and norepinephrine transporter (being respectively SERT and NET) locate, the biological activity of test compounds by compound.Adopt radioligand 3The H-citalopram ( 3H-citalopram) and 3The H-nisoxetine ( 3H-nisoxetine), utilize cell membrane preparation to carry out the SPA combination, described cell membrane preparation is by the human cDNA that expresses coding SERT or NET (hSERT, clone preparation hNET).
I) cell culture processes
Utilize the standard cell lines culture technique, the human embryos nephrocyte (HEK-293) of expressing each translocator as continuous culture, is remained on 225cm 250mL growth medium in the flask (composition is seen substratum and buffer section), temperature is 37 ℃, is in to have 5%CO 2Humid atmosphere in.Cell is with 1: 3-1: 4 ratio goes down to posterity from 90% confluent monolayer.
Be harvested cell, growth medium is removed from individual layer, and with cell cell dissociation solution (Sigma) incubation, up to showing dissociated sign.Then, cell is knocked the bottom of leaving flask, and become spherolite, before further using, to store (freezing down) at-80 ℃ by centrifugation.
Ii) cytolemma preparation
The cell spherolite is thawed on ice, and it is suspended in the damping fluid again, utilize vortex mixer cell dispersion spherolite by every 1mL close-packed cell volume 3mL membrane prepare damping fluid (composition is seen substratum and buffer section).
After incubation on ice 10 minutes, use hand-held homogenizer, with suspension homogenizing 4 times, each 10 seconds.Then with homogenate 1075xg, 4 ℃ centrifugal 20 minutes down.
Then, collection and reservation supernatant.Then, use above-mentioned condition, initial cell and nuclear are precipitated spherolite homogenizing and centrifugal again, collect supernatant, and with itself and centrifugal those merging that obtain for the first time.
To merge supernatant liquor 35000xg, 4 ℃ centrifugal 30 minutes down, and supernatant liquor will be abandoned.Then, will precipitate spherolite (P2) is suspended in the damping fluid again with the original close-packed cell volume of every 1mL 1mL membrane prepare damping fluid.Then, measure protein concn, and film suspension finally is frozen into a plurality of equal portions of fixed volume, and before being used for detecting, be stored under-80 ℃.
Iii) detection method
A. determine the optimal detection condition of each film batch
For each translocator, special SPA bead type difference, the yttrium silicate of wheat cdna lectin coating (YSi WGA) SPA bead is used to hSERT and detects, and the polyvinyl toluene of WGA-coating (PVT WGA) SPA bead is used to hNET and detects.For used each batch film, determine the optimum concn of bead and film.
The radioligand that use is specific to the tritiate of each translocator (for hSERT is 3The H-citalopram for hNET is 3The H-nisoxetine).Each free radioligand concentration that detects is represented as a percentage ratio of total free radioligand concentration, so that the estimation for the radioligand degree of exhaustion to be provided.For the radioligand degree of exhaustion in the detection of two kinds of translocators less than 30%, to guarantee existing enough radioligands can supply combination.When using the film of new lot, part exhausts value also can be used to select optimal detection condition.
Under selected protein and bead concentration, batch determine affinity for the specificity radioligand of each translocator for each film.This is by determining K DObtain K DThe concentration of free radioligand when promptly 50% translocator binding site is occupied.
Under a collection of film for the average K of radioligand DDetermine by the data that obtain from least three independent detection.Then, this average K DBe used to the detection that all use this film batch, make and to utilize by Cheng and Prussoff (Cheng YC and Prusoff WH.Relationship betweenthe inhibition constant (K i) and the concentration of inhibitor which causes 50%inhibition of an enzymatic reaction.Biochem Pharmacol 1973; 22:2099-3108.) definite method, the K of definite compound of being studied iValue
B. detection scheme
Bead/film compound formulation
The film of aequum is thawed on ice, and add in the suspension of bead in detecting damping fluid of pre-determined volume.Then by on bottle swingging machine at 4 ℃ of following incubations by the protein of mg bead predetermined amount 2 hours, with the pre-coupling of bead.
Then, bead/membrane complex was rotated precipitation 5 minutes under 865xg.The precipitation spherolite of gained is suspended in again and detects in the damping fluid, repeats this rotation/washing step then.Then, final precipitation spherolite with the required specific concentrations of final detection, is suspended in again and detects in the damping fluid.
The part preparation
With portion [ 3H]-the radioligand mother liquor is diluted in and detects in the damping fluid, and so that predetermined final detectable level to be provided, this concentration is less than equilibrium dissociation constant (K D) value.
The preparation of compound plate
All test compounds are prepared by the concentration of dry-eye disease with 4mM in 100% dimethyl sulfoxide (DMSO) (DMSO).In 384 orifice plates, with diluted chemical compound 0.75% at ddH 2Among the DMSO among the O,, provide the final volume of 20 μ L so that suitable test concentrations to be provided.
The detection damping fluid of equal volume is added in the specific hole of plate, makes to finish total radioligand bonded is measured subsequently.In addition, the compound that is specific to each translocator detection of 20 μ L high densitys is added in the predetermined hole subsequently, to measure non-specific binding (NSB).Fluoxetine (the final detectable levels of 10 μ M) is used to hSERT, and Desipramine (the final detectable levels of 40 μ M) is used to hNET.
Detect for each translocator, the specificity radioligand of the preparation of 20 μ L is added in each hole of final check-out console (inclusion compound solution).Then, corresponding bead/membrane complex of 20 μ L is added in each hole of final check-out console, guarantee that suspension is mixed well.Then, with plate sealing and incubation 1 hour under vibration at room temperature.Then, before reading,, adopt dark adatpation again with plate incubation 6 hours.
C. data analysis
By total mean value in conjunction with reading being deducted average N SB reading (in the counting or the cpm of per minute), calculate the detection window (specificity combination) of each plate.The cpm reading in every hole (having deducted average N SB) is represented as the per-cent of plate window then, to determine to be attached to the amount of the radioligand on the translocator.
With of the compound concentrations mapping of these values, and use four constant logarithmic equations and free fitting parameter, make Sigmoidal inhibitor concentration effect curve come fitting data, obtain IC being tested 50Value (50% the specificity that suppresses neurotransmitters translocator place is in conjunction with required compound concentration).
Then, utilize the Cheng-Prusoff equation, by IC 50Value is calculated inhibitor dissociation constant (K i) value.
K at each compound of measuring test iAfter the value, adopt 95% fiducial interval and n value, calculate total geometrical mean, wherein, n is each K iTotal number of value.The K of the embodiment 1-18 compound of gained iData can be referring to table 1.
Iv) substratum and damping fluid
The hSERT cell growth medium
DMEM, 10% (w/v) is through the FCS of dialysis
2mM L-glutamine (by the mother liquor dilution of 200mM)
25mM HEPES (by the mother liquor dilution of 1M)
250μg/mL?genetecin
The hNET cell growth medium
DMEM，10％(w/v)FCS
2mM L-glutamine (by the mother liquor dilution of 200mM)
25mM HEPES (by the mother liquor dilution of 1M)
250μg/mL?genetecin
The membrane prepare damping fluid
20mM HEPES is (by 1M mother liquor ddH 2The O dilution), at room temperature pH is 7.4, is stored in 4 ℃.Before using, complete proteinase inhibitor tablet of dissolving in the damping fluid of every 50mL.
Detect damping fluid (the final detectable level of 1.5x)
30mM HEPES is (by 1M mother liquor ddH 2O dilution) and 180mM NaCl (by 5M mother liquor ddH 2The O dilution), at room temperature pH is 7.4, is stored in 4 ℃.
Table 1
Compound SRI?Ki(nM) NRI?Ki(nM)
1 5 15
6 9 11
14 11 9
20 3 14
Can also in specific disease model (such as following pain model), test compound:
Neuropathic pain
The activity of compounds for treating neuropathic pain can be measured according to following testing scheme.
Animal: male Sprague Dawley rat is raised in cages with the group of suitable size.All animals were maintained at for 12 little time/under the dark cycle (brightening) at 07: 00, and the ad lib water inlet.All experiments are by carrying out for the unwitting viewer of processing and according to Home Office Animals (ScientificProcedures) Act 1986.
Chronic constriction damage (CCI) rat model of neuropathic pain
Sciatic CCI is according to before by Bennett and Xie (Bennett GJ, Xie YK.Aperipheral mononeuropathy in rat that produces disorders of pain sensation likethose seen in man.Pain:33:87-107,1988) described carrying out.With animal with 2% isofluranum (isofluorane)/O 2Mixture anesthesia.Right back thigh is scraped hair, and 1% tincture of iodine is cleaned.Then, process the duration, animal is transferred on the constant temperature blanket, and in surgical procedure, is kept anesthesia via nose cone.Skin is cut along the femur line.Open biceps muscle of thigh by blunt dissection, total sciatic nerve is exposed to the center of thigh.By below nerve, inserting tweezers, make that about 7mm nerve of next-door neighbour's sciatic nerve trident is unfettered, and nerve is gently drawn out thigh.Use tweezers below nerve, to draw suture line, and beat unijunction,, beat binode then up to feeling slight resistance.Repeat this process, bind around neural loosely up to the spacing of 4 root knot bindings (4-0 silk thread) with about 1mm.With otch layering closure, and wound is handled with local antibiotic.
In rat by the diabetes psychosis of U-9889 (STZ)-bring out
By a fresh intraperitoneal injection that is dissolved in the U-9889 (50mg/kg) in 0.9% Sterile Saline, bring out diabetes.U-9889 is injected at and causes reproducible mechanical allodynia in 3 weeks, continued at least 7 weeks (Chen and Pan, Hypersensitivity of Spinothalamic TractNeurons Associated With Diabetic Neuropathic Pain in Rats.J?Neurophysiol87：2726-2733，2002)。
The assessment of static state and dynamic abnormal pain
Static allodni
Before the assessment allodynia, make animal adapt to metal wire bottom test-cage (wire bottomtest cage).By (Illinois USA.) is applied to the foot bottom surface of rear solid end for Stoelting, Wood Dale, estimates Static allodni and is with von Frey hair with the order (0.6,1,1.4,2,4,6,8,10,15 and 26 gram) of the power that edges up.Von Frey fleece was applied to pawl lasting 6 seconds at most each time, perhaps up to the withdrawal reaction takes place.In case the withdrawal reaction for von Frey hair is set up, and then this pawl is tested again, begin to test with the order of gradually little power with remaining silk then, up to not withdrawing with the silk that is lower than the silk that produces withdrawal.The power of the maximum of 26g is lifted pawl, and induces reaction, and has therefore represented cut-out point.Test two rear solid ends of each animal by this way.The Schwellenwert of the required power that induces reaction is registered as pawl withdrawal threshold value (PWT), and unit is gram.Static allodni is defined as, if animal responds to 4g or littler stimulation (is not have influence for the rat that is used to first test), then there is allodynia (Field MJ, Bramwell S, Hughes J, Singh L.Detection of static and dynamic componentsof mechanical allodynia in rat models ofneurapathic pain:are they signalled bydistinct primary sensory neurones? Pain, 1999; 83:303-11).
Dynamic abnormal pain
Dynamic abnormal pain is by assessing for the sole plane of knocking rear solid end lightly with cotton rod.For fear of the common motor activity of record, in the sluggish rat that adapts to fully, carry out this process carefully.Carry out at least twice test at each time point, its mean value is represented pawl withdrawal latent period (PWL).If not reaction in 15 seconds, then this process is terminated, and this withdrawal time is assigned to animal.Pain withdrawal reaction is attended by the pawl or lick the pawl behavior of contracting repeatedly usually.If animal is reacted beginning to knock in back 8 seconds cotton rod stimulated, then be considered to exist dynamic abnormal pain (Field et al, 1999).
Nociceptive pain
The activity of compounds for treating nociceptive pain can be measured according to following testing scheme.
Hot plate
Experimentation: with male Sprague Dawley rat place the hot plate that remains under 55 ± 5 ℃ (Ugo Basile, Italy) on.Measurement is placed on animal on the hot plate and licks fore paw or rear solid end, shake or jump out of the time between the surface.Carry out base measurement, and after medicine gives, animal is reevaluated.Hot plate is hidden and is set as 20 seconds dead line, to prevent tissue injury.
Ovariohysterectomy (OVX)
Experimentation: female Sprague Dawley rat is placed anaesthetic room, and with 2% isofluranum O 2Mixture is anaesthetized.At intra-operative, keep anesthesia via nose cone.OVX carries out via the midline incision in the white line (linea alba) (length is 2cm), and animal is on the hot blanket simultaneously.Use single tongs technology, with 5-0 silk thread ligation ovary frenulum and uterine cervix.Then, remove ovary and uterus.Use 4 simple interrupted suture sealing stomach walls, and seal skins with 4 wound clamps.After operation, immediately animal is placed on respectively in the one synthetic glass chamber.In case animal recovers from anesthesia, just at each time point, with 30 minutes intervals, record belly figure.The attitude that is counted is that contraction, the health of bow-backed posture, the abdominal muscles relevant with the inside motion of hind leg stretches and abdomen is squatted by the floor.In these behaviors each is counted as an attitude.
Brennan
Experimentation: male Sprague Dawley rat is placed anaesthetic room, and with 2% isofluranum O 2Mixture anesthesia.At intra-operative, keep anesthesia via nose cone.The sole outside surface of right back pawl is cleaned with 50% ethanol.With No. 11 blades, see through the skin and the manadesma of the sole outside surface of foot, extend from the near side (ns) 0.5cm beginning of the sufficient heel of distance and towards toe, form the long longitudinal cut of 1cm.Utilize tweezers to raise sole of the foot flesh, and vertically cutting, flesh starting point and flesh adhere to and are kept perfectly.After with soft pressure hemostasis, with 2 simple sewn closed skins of braided silk.
The OA model of one iodo acetic ester (MIA)-bring out
With big Sprague-Dawley (SD, Japan SLC or Charles River Japan) rat of male 6 weeks of Sodital (pentobarbital) anesthesia.Injection position is scraped Mao Bingyong 70% ethanol cleaning.Use the 29G syringe needle, with 25 μ l MIA solution or saline injection in right knee joint.After MIA injection 7,14,19 and 20 days, trained rat does not have its weight under stress situation to tolerate (WB) with measurement.After MIA injection 21 days, the WB on two in each rear solid end is measured, and WB shortage value is calculated.WB is lacked value defined be " preceding value (pre value) ".Based on the consideration of preceding value and pre-preceding value, experiment arrangement grouping equably.After administration test compounds and carrier, measure the WB on two in each rear solid end.
The cancer pain model
These experiment use bulls C3H/HeN mouse (Nihon SLC, Shizuoka, Japan).According to National Institutes of Health guidelines, mouse is raised in cages in the ecological rearing-box that remains under 22 ℃, adopt 12-hour alternately cycle light and dark, and the ad lib water inlet.Employed sarcoma infusion protocol is described.After causing general anesthesia, use in the skin of Mora scissors on Patella and form surface cuts by suction isofluranum (2%).Then, cut the Patella ligament, the femoral joint of exposed distal end.The 30-gauge syringe needle is inserted at the fossa intercondylaris femoris place, and be inserted into medullary space, to create initial Nei Sheng district path (core pathway).After forming initial Nei Sheng district, use 29-gauge syringe needle is formed into the final path in the bone.With pneumatic tooth high speed handpiece (pneumatic dental high speed handpiece), use the cup head file, form the 0.5-mm depression, to serve as the mechanical fixing that is used for dentistry resin connector.Then, utilize 29-gauge syringe needle and .25cc injector to inject 20 μ l α-minimum minimum medium (Sigma; False injection) or comprise 1 * 10 520 μ l substratum (American Type CultureCollection, Rockville, Maryland of 2472 molten bone sarcoma cells; The sarcoma injection).In order to prevent that cell from leaking into outside the bone, injection position is resin-blocked with dentistry, uses the filtered water over flow rinse then.(Becton Dickinson, San Jose California) realize the wound sealing to utilize two automatic wound clamps.Took off wound clamp at the 5th day, to prevent interference to performance testing.
The assessment of static state and dynamic abnormal pain
Static allodni
Before the assessment allodynia, make animal adapt to metal wire bottom test-cage (wire bottomtest cage).By (Illinois USA.) is applied to the foot bottom surface of rear solid end for Stoelting, Wood Dale, estimates Static allodni and is with von Frey hair with the order (0.6,1,1.4,2,4,6,8,10,15 and 26 gram) of the power that edges up.Von Frey fleece was applied to pawl lasting 6 seconds at most each time, perhaps up to the withdrawal reaction takes place.In case the withdrawal reaction for von Frey hair is set up, and then this pawl is tested again, begin to test with the order of gradually little power with remaining silk then, up to not withdrawing with the silk that is lower than the silk that produces withdrawal.The power of the maximum of 26g is lifted pawl, and induces reaction, and has therefore represented cut-out point.Test two rear solid ends of each animal by this way.The Schwellenwert of the required power that induces reaction is registered as pawl withdrawal threshold value (PWT), and unit is gram.Static allodni is defined as, if animal responds to 4g or littler stimulation (is not have influence for the rat that is used to first test), then there is allodynia (Field MJ, Bramwell S, Hughes J, Singh L.Detection of static and dynamic componentsof mechanical allodynia in rat models ofneurapathic pain:are they signalled bydistinct primary sensory neurones? Pain, 1999; 83:303-11).
Dynamic abnormal pain
Dynamic abnormal pain is by assessing for the sole plane of knocking rear solid end lightly with cotton rod.For fear of the common motor activity of record, in the sluggish rat that adapts to fully, carry out this process carefully.Carry out at least twice test at each time point, its mean value is represented pawl withdrawal latent period (PWL).If not reaction in 15 seconds, then this process is terminated, and this withdrawal time is assigned to animal.Pain withdrawal reaction is attended by the pawl or lick the pawl behavior of contracting repeatedly usually.If animal is reacted beginning to knock in back 8 seconds cotton rod stimulated, then be considered to exist dynamic abnormal pain (Field et al, 1999).
The withdrawal of radiant heat pawl
Experimentation: utilize and adopt Hargreaves et al., 1988 the rat sole of improving one's methods test (Ugo Basile, Italy) the hot pawl withdrawal of assessment.Make rat adapt to the device of forming by three on the glass table that is in rising independent synthetic glass boxes.Movably radiant heat source is arranged in the table below, and converges on the rear solid end, and the record pawl is withdrawn latent period (PWL).The automatic cut-out point is 22.5 seconds, to prevent tissue injury.Two rear solid ends for each animal are got PWL 2-3 time, and its mean value is represented the baseline of right back pawl and left back pawl.Device is demarcated, so that about 10 seconds PWL to be provided.
The weight tolerance
Experimentation: (Norfolk U.K.), carries out hypersensitivity to animal and detects in weight tolerance test for LintonInstruments, Diss to use " anergy tester (incapacitance tester) ".Rat is located in the mode that its forelimb upwards is placed on the synthetic glass inclined-plane, and by the force sensor measuring hind leg weight distribution under each rear solid end.Each animal is placed in the described device, and writes down the weight load that is applied by rear solid end.By offside pawl (normally) being deducted homonymy (injured) pawl, calculated weight tolerates difference, and this constitutes raw data.
Inflammatory pain
The activity of compounds for treating inflammatory pain can be measured according to following testing scheme.
CFA-brings out weight tolerance shortage in the rat
Male 7 all big SD rat fasting whole night.CFA (300 μ g Mycobacterium Tuberculosis H37 RA (Difco Laboratories) in 100 μ L whiterusss (Wako)) is expelled in the right back palmula of rat.Behind administration CFA two days, (Linton Instrumentation UK) measured rear solid end weight distribution variation between a left side (homonymy) and right (offside) limb, as the pain index to use Linton anergy tester.Be suspended in test compounds among the 0.1%MC (Wako) with 1mL/100g body weight oral administration.Each animal is placed in the described device, and before medicine gives, medicine give after 1,2 and 4 hour, measure the weight load that applies by rear solid end.
The mechanical hyperalgesia of carrageenin in the rat-bring out
With the big SD rat fasting of male 4-week whole night.Hyperpathia by the hypodermic λ in vola ~-(solution of the 1%w/v of 0.1ml in salt solution Zushikagaku) brings out carrageenin.Test compounds (0.1% methylcellulose gum of 1ml/100g body weight) is given when carrageenin is injected back 5.5 hours.By analgesimeter (Ugo Basile) 3.5,4.5,6.5 and 7.5 hours measuring claw withdrawal threshold values (gram) after the carrageenin injection.(Randall?L.O.&?Selitto?I.J.，Arch.Int.Pharmacodyn.111，409-419，1957)
The thermal hyperalgesia (CITH) of carrageenan in the rat-bring out
According to by improved methods (1988) such as Hargreaves, utilize the test of rat vola (UgoBasile, Comerio, Italy), the assessment thermal hyperalgesia.In brief, rat is adapted to by three devices that independent synthetic glass box constitutes that are on the glass table.Removable radiant heat source is disposed in the table below, and converges on the desirable pawl.For two rear solid ends of each animal, write down three pawls and withdraw latent period (PWLs), its mean value is represented the baseline of left back pawl and right back pawl.Device is demarcated to making that the PWL that is used to the rat of testing first is about 10 seconds.In order to prevent the tissue injury of plantar region, adopt and ended in 22.5 seconds.Go into-(100ml 20mg/ml) to right back pawl, and carried out PWT baseline record in 2 hours to carrageenan after administration by the vola subcutaneous injection.
Visceral pain
The activity of compounds for treating visceral pain can be measured according to following testing scheme.
Some models can be used for determining whether compound is effective to treatment internal organ illness.These models comprise LPS model (Eutamene H et al, J Pharmacol Exp Ther 2,000 295 (1): 162-7), TNBS model (Diop L.et al, Gastroenterology 1999,116,4 (2): A986), IBD model (Clemett D, Markham A, Drugs 2000 Apr; 59 (4): 929-56), pancreatic gland pain model (Isla AM, Hosp Med 2000 Jun; 61 (6): 386-9) with the non-digestion pain model of internal organ (Boucher M et al, J Urol 2000 Jul; 164 (1): 203-8).
The chronic internal organ allodynia that TNBS-brings out in the rat
In the colon expansible experimental model in awake rat, in advance trinitro-benzene-sulfonic acid (TNBS) is expelled in the near section colon, to reduce the visceral pain threshold value.
Material and method: use male Sprague-Dawley rat.With animal with 3 in every cage raise in cages under modulated environment (20 ± 1 ℃, 50 ± 5% humidity, 8:00am illuminates to 8:00pm).At the 0th day, under anesthesia, (restrain his life (ketamine) 80 mg/kg i.p.; Vetrnquil 12mg/kg i.p.), with TNBS (50mg/kg is in ethanol 30%), or salt solution (1.5ml/kg) (for control rats), be expelled in the near section colon wall (apart from caecum 1cm).After operation, animal is raised in cages separately in the polypropylene cage, and remain under the modulated environment (20 ± 1 ℃, 50 ± 5% humidity, 8:00a.m. is to 8:00p.m.), lasting 7 days.After the TNBS administration the 7th day, insert balloon (5-6cm is long) by anus, and by conduit being tied to the bottom of tail, with balloon location (top of balloon is apart from anus 5cm).The oral administration test compounds, after 1 hour, carry out the colon expansion cycles: with 5mm Hg (0.667kPa) step-length, from 0 to 75mm Hg, inflation balloon gradually, each step inflation continues 30 seconds.By each circulation of standard pressurestat control colon expansible.Threshold value (mm Hg) stops expansion cycles then corresponding to the pressure that produces belly contraction for the first time.On same animal, carry out determining the colon threshold value after four expansion cycles.
The rectum allergy that LPS-brings out in the rat
In awake rat, the peritoneal injection of bacteria lipopolysaccharide (LPS) has shown and has brought out rectum hyperpathia.
Material and method: the operation preparation is used for the animal of EMG: by injection in the abdominal cavity film of vetrnquil (0.6mg/kg) and his life (120mg/kg) of gram, anesthetized rat.3 electrodes of three groups are implanted in the external oblique muscle of abdomen, near the inguinal ligament top.Electrode exposes at the place, back of neck, and by the Glass tubing protection that is attached on the skin.Animal is raised in cages individually in the polypropylene cage, and remains in the room of controlled temperature (21 ℃).Ad lib (the UAR sheet, Epinay, France) and the water inlet.
The 5th day opening entry electromyogram(EMG) after operation.Utilize short-time constant (0.03 second) eliminate low frequency signal (＜3Hz) and use the chart drive speed of 3.6cm/min, utilize electroencephalograph (electroencephalograph machine) (Mini VIII Alvar, Paris, France), the record belly is striate electroactive.Spike is recorded the indication of shrinking as belly.
Expansion process: rat is placed plastic conduit (6cm diameter * 25cm length), and at this, it can not move, runs away or turn round, to prevent the damage to balloon.Before rectum expands, make animal carry out 4 days adaptation, so that stress reaction minimizes in experimentation to this process.Being used for the expansible balloon is arterial embolectomy conduit (Fogarty, Edwards Laboratories Inc.).By balloon (2mm diameter * 2cm length) is inserted rectum from anus 1cm place, carry out rectum and expand, and conduit is fixed on the bottom of tail.Utilize warm water, with the step-length of 0.4ml, from 0 to 1.2ml expanding baloon gradually, each step expands and continues 5 minutes.In order to detect possible leakage, by when the expansion time finishes, utilize syringe to take out water fully, check the volume that is incorporated into the water in the balloon.

Claims (21)

1. the compound of formula (I)
Figure A2005800401020002C1
With and pharmaceutically and/or veterinarily acceptable derivative, wherein:
R 1, R 2, R 3And R 20Be H independently of one another, Cl, Br, F, I, CF 3, OCF 3, Me or Et;
R 4Be het or C 3-7Cycloalkyl is randomly by C 1-4Alkyl, C 1-4Alkoxyl group contains the alkoxyalkyl of 2 to 4 carbon atoms, or-S-(C 1-4Alkyl) replaces;
A is 0 or 1; And
Het is the 4-of non-fragrance, 5-or 6-unit heterocycle, it comprises at least one N, O or S heteroatoms, randomly be fused to 5-or 6-unit's carbon ring group or comprise at least one N, heteroatomic the 2nd 4-of O or S, 5-or 6-unit heterocycle, wherein this het group is randomly replaced by at least one substituting group, and described at least one substituting group is independently selected from C 1-8Alkyl, C 1-8Alkoxyl group, OH, halogen, CF 3, OCF 3, SCF 3, hydroxyl-C 1-6Alkyl, C 1-4Alkoxy-C 1-6Alkyl and C 1-4Alkyl-S-C 1-4Alkyl;
Condition is R 1, R 2And R 3In at least one be not H.
2. compound as claimed in claim 1, wherein:
R 1Be Cl, Br, F, I, CF 3, Me or Et;
R 2And R 3Be H independently of one another, Cl, Br, F, I, CF 3, Me or Et.
3. compound as claimed in claim 2, wherein:
R 1And R 2Be Cl independently of one another, Br, F, I, Me or Et;
R 3Be H, Cl, Br, F, I, Me or Et.
4. compound as claimed in claim 1 or 2, wherein:, wherein:
R 1Be Cl, Me or CF 3
R 2Be H, Cl or F;
R 3Be H, Cl or F.
5. as claim 1 to 4 any one described compound, wherein R 4Be C 3-7Cycloalkyl.
6. as any one described compound of claim 1 to 5, wherein a is 0.
7. compound as claimed in claim 1, described compound is:
2,3-two chloro-N-cyclopentyl-N-[(3S)-tetramethyleneimine-3-yl],
2,3-two chloro-N-cyclopentyl-4-fluoro-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
3-chloro-N-cyclopentyl-2-methyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
N-cyclopentyl-3-fluoro-2-methyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
2-chloro-N-cyclopentyl-3-fluoro-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
2,3-two chloro-N-cyclohexyl-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
2-chloro-N-cyclohexyl-3-fluoro-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
N-cyclohexyl-3-fluoro-2-methyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
2,3-two chloro-N-cyclobutyl-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
N-cyclobutylmethyl-2,3-two chloro-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
2,3-two chloro-N-(cyclopropyl methyl)-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
2,3-two chloro-N-[(3S)-tetramethyleneimine-3-yl]-N-tetrahydrochysene-2H-pyrans-4-yl-benzamide,
2-chloro-N-cyclopentyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
2-chloro-N-cyclohexyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
2-chloro-N-suberyl-N-[(3S)-tetramethyleneimine-3-yl] benzamide,
The N-suberyl-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide,
The N-cyclohexyl-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide,
The N-cyclopentyl-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide,
2,3-two chloro-N-[(1-methyl cyclopropyl) methyl]-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
3-chloro-2-methyl-N-[(1-methyl cyclopropyl) methyl]-N-[(3S)-and tetramethyleneimine-3-yl] benzamide,
N-(cyclobutylmethyl)-N-[(3S)-tetramethyleneimine-3-yl]-2-(trifluoromethyl) benzamide, or
It pharmaceutically and/or veterinarily acceptable derivative.
8. compound as claimed in claim 7, described compound are 2,3-two chloro-N-cyclopentyl-N-[(3S)-tetramethyleneimine-3-yl], or pharmaceutically and/or veterinarily acceptable derivative.
9. a pharmaceutical composition comprises as any one described compound of claim 1 to 8 and pharmaceutically acceptable adjuvant, thinner or supporting agent.
10. as any one described compound of claim 1 to 8, described compound is as medicine.
11. as the purposes of any one described compound of claim 1 to 8 in the preparation medicine, described medicine is used for the treatment of the wherein affected illness of regulation and control of the monoamine translocator function in Mammals.
12. in the purposes of preparation in the medicine, described medicine is used for the treatment of the affected illness of regulation and control of serotonin in Mammals wherein or norepinephrine as any one described compound of claim 1 to 8.
13. the purposes of compound as claimed in claim 12, wherein the regulation and control of serotonin and norepinephrine all are affected.
14. as the purposes of any one described compound of claim 1 to 8 in the preparation medicine, described medicine is used for the treatment of the uropoiesis obstacle in the Mammals, depression, pain, premature ejaculation, attention-deficit hyperactivity disease or fibromyalgia.
15. the purposes of compound as claimed in claim 14 is used for the treatment of the mammiferous urinary incontinence, such as GSI or USI.
16. treat the wherein method of the affected illness of regulation and control of monoamine translocator function for one kind, described method comprise to patient's drug treatment significant quantity of the such treatment of needs as any one described compound of claim 1 to 8.
17. a method for the treatment of the affected illness of regulation and control of serotonin wherein or norepinephrine, described method comprise to patient's drug treatment significant quantity of the such treatment of needs as any one described compound of claim 1 to 8.
18. method according to claim 17, wherein the regulation and control of serotonin and norepinephrine all are affected.
19. a treatment uropoiesis obstacle, depression, pain, premature ejaculation, the method for attention-deficit hyperactivity disease or fibromyalgia, described method comprise to patient's drug treatment significant quantity of the such treatment of needs as any one described compound of claim 1 to 8.
20. method as claimed in claim 19, wherein said uropoiesis obstacle is the urinary incontinence, such as GSI or USI.
21. be used to prepare the method as any one described compound of claim 1 to 8, described method comprises makes formula (IX) compound:
Figure A2005800401020005C1
R wherein 4Any one defines with a such as claim 1 to 8, and PG is a blocking group, and the acid or the carboxylic acid halides reaction of formula (II):
Figure A2005800401020005C2
Wherein, X is OH or halogen,
And deprotection.
CNA2005800401025A 2004-11-23 2005-11-18 N- [ (3s)- pyrrolidin-3-yl]- benzamide derivatives as monoamine re-uptake inhibitors Pending CN101065355A (en)

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