CN100551924C

CN100551924C - 8-aza-bicyclo [3.2.1] octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors

Info

Publication number: CN100551924C
Application number: CNB200480002868XA
Authority: CN
Inventors: D·彼得斯; E·O·尼尔森; G·M·奥尔森; J·谢尔-克鲁格尔
Original assignee: Neurosearch AS
Current assignee: NTG Nordic Transport Group AS
Priority date: 2003-02-12
Filing date: 2004-02-10
Publication date: 2009-10-21
Anticipated expiration: 2024-02-10
Also published as: CN1742011A

Abstract

The present invention relates to novel 8-aza-bicyclo [3.2.1] octane derivatives useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects, the invention relates to the use of these compounds in methods of treatment and pharmaceutical compositions comprising the compounds of the invention.

Description

8-aza-bicyclo [3.2.1] Octane derivatives and they purposes as monoamine neurotransmitter re-uptake

Technical field

The present invention relates to new 8-aza-bicyclo [3.2.1] Octane derivatives as monoamine neurotransmitter re-uptake.

In others, the present invention relates to these compounds in methods of treatment application and comprise the pharmaceutical composition of compound of the present invention.

Background technology

WO 97/30997 (NeuroSearch A/S) describes active tropane (tropane) derivative that has as neurotransmitter re-uptake.

But, exist lasting intensive need find that for example serotonin reuptake transporter is to the compound of norepinephrine and Dopamine HCL activity ratio at the biological chemical performance that has optimization aspect the re-uptake activity of monoamine neurotransmitter serotonin, Dopamine HCL and norepinephrine.

Summary of the invention

In first aspect, the invention provides 8-aza-bicyclo [3.2.1] Octane derivatives of a kind of formula I

Any mixture of perhaps any its isomer or its isomer, perhaps its pharmacy acceptable salt, wherein R, R ²And R ³As to give a definition.

In second aspect, the invention provides a kind of pharmaceutical composition, described pharmaceutical composition comprises treatment significant quantity compound of the present invention, any mixture of perhaps any its isomer or its isomer, perhaps its pharmacy acceptable salt, and at least a pharmaceutically acceptable carrier, vehicle or thinner.

On the other hand, the any mixture or its pharmacy acceptable salt that the invention provides compound of the present invention or any its isomer or its isomer are used to prepare treatment, prevention or releasing mammal, comprise the application of the pharmaceutical composition of people's disease or obstacle or illness, described disease, obstacle or illness are replied the inhibition of the monoamine neurotransmitter re-uptake in the central nervous system.

On the other hand, the present invention relates to a kind of treatment, prevention or alleviate the animal body of living, comprise the people, comprise people's the disease or the method for obstacle or illness, the method of described obstacle, disease or illness, described obstacle, disease or illness are replied the inhibition of the monoamine neurotransmitter re-uptake in the central nervous system, described method comprises to the compound of the present invention of the animal body administering therapeutic significant quantity of the work that needs this method or any mixture of any its isomer or its isomer, the perhaps step of its pharmacy acceptable salt.

Those skilled in the art can obviously find out other purpose of the present invention according to the description and the embodiment of following detailed description.

Detailed Description Of The Invention

Tropane derivatives

In first aspect, the invention provides 8-aza-bicyclo [3.2.1] Octane derivatives of a kind of formula I:

Any mixture of perhaps any its isomer or its isomer, perhaps its pharmacy acceptable salt,

Wherein

R represents hydrogen or alkyl;

R representative-CH ₂-X-R ^a

Wherein X representative-O-or-S-;

R ^aRepresent phenyl or naphthyl,

Described phenyl or naphthyl is optional to be selected from following substituting group and to replace by one or more: halogen, hydroxyl, amino, cyano group, nitro, trifluoromethyl, trifluoromethoxy, alkoxyl group, cycloalkyloxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl;

R ³Represent heteroaryl;

Described heteroaryl is optional to be selected from following substituting group and to replace by one or more: halogen, hydroxyl, amino, cyano group, nitro, trifluoromethyl, trifluoromethoxy, alkoxyl group, cycloalkyloxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl.

In one embodiment, R represents hydrogen.In another embodiment, R represents alkyl, for example methyl.In another embodiment, R represents hydrogen or methyl.

In another embodiment, X representative-O-.In another embodiment, X representative-S-.

In another embodiment, R ^aThe optional phenyl that replaces of representative.In a specific embodiment, R ^aRepresentative is optional by the phenyl of one or more halogens or the replacement of one or more alkoxyl group.In another embodiment, R ^aRepresentative is optional by 2 halogens, for example 2 phenyl that chlorine replaces.In another embodiment, R ^aThe optional phenyl that is replaced by 2 fluorine of representative.In another embodiment, R ^aRepresentative is optional by 2 alkoxyl groups, for example 2 phenyl that methoxyl group replaces.In another embodiment, R ^aRepresent 2,3-dichlorophenyl or 3,4-dichlorophenyl.In another embodiment, R ^aRepresent 2, the 3-difluorophenyl.In another embodiment, R ^aRepresent 2, the 3-Dimethoxyphenyl.

In another embodiment, R ^aThe optional naphthyl that replaces of representative.In a specific embodiment, R ^aRepresent naphthyl, for example naphthalene-1-base or naphthalene-2-base.

In a specific embodiment, R ²Represent 2,3-Dichlorophenoxy ylmethyl, 2,3-difluoro phenoxymethyl, 2,3-dimethoxy phenoxymethyl, naphthalene-1-yloxymethyl or naphthalene-2-yloxymethyl.In another specific embodiment, R ²Represent 2,3-Dichlorophenoxy ylmethyl or naphthalene-1-yloxymethyl.

In another embodiment, R ³Representative is optional by the thienyl of one or more halogens or alkoxyl group replacement.In a specific embodiment, R ³Represent the chlorothiophene base, for example 5-chloro-thiophene-2-base.In another specific embodiment, R ³Representation methoxy thienyl, for example 5-methoxyl group-thiophene-2-base.In another embodiment, R ³Represent thienyl, for example thiophene-2-base or thiene-3-yl-.In another embodiment, R ³Represent furyl, optional by one or more halogens, for example one or more chlorine replace.In a specific embodiment, R ³Represent the chlorine furyl, for example 5-chloro-furans-2-base.In another embodiment, R ³Represent furyl, for example furans-2-base or furans-3-base.

In another embodiment of the compound of formula I,

R represents hydrogen or methyl;

X representative-O-;

R ^aRepresent 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-Dimethoxyphenyl or naphthyl; With

R ³Represent thienyl or furyl, optional by one or more halogens or alkoxyl group replacement.

In another embodiment of the compound of formula I,

R represents hydrogen or methyl;

X representative-O-;

R ^aRepresent 2,3-dichlorophenyl or naphthyl; And

R ³Represent thiophene or furyl.

In a specific embodiment, compound of the present invention is

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-thienyl-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(1-naphthyloxy methyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(1-naphthyloxy methyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(1-naphthyloxy methyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(1-naphthyloxy methyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(1-naphthyloxy methyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(1-naphthyloxy methyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(1-naphthyloxy methyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(1-naphthyloxy methyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(5-chloro-thiophene-2-yl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(1-naphthyl)-8-methyl-3-(5-chloro-thiophene-2-yl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-difluoro phenoxymethyl)-8-methyl-3-(5-chloro-furans-2-yl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-difluoro phenoxymethyl)-8-methyl-3-(5-methoxyl group-thiophene-2-yl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-dimethoxy phenoxymethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(5-methoxyl group-thiophene-2-yl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2-naphthyl)-8-methyl-3-(5-chloro-thiophene-2-yl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-difluoro phenoxymethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(1-naphthyloxy methyl)-8-H-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(1-naphthyloxy methyl)-8-H-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(1-naphthyloxy methyl)-8-H-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane;

(2R, 3S)-2-(1-naphthyloxy methyl)-8-H-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(1-naphthyloxy methyl)-8-H-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(1-naphthyloxy methyl)-8-H-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(1-naphthyloxy methyl)-8-H-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane;

(2S, 3R)-2-(1-naphthyloxy methyl)-8-H-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane;

Any mixture of perhaps any its isomer or its isomer, perhaps its pharmacy acceptable salt.

The arbitrary combination of two or more above-mentioned embodiments is deemed to be within the scope of the present invention.

The substituting group definition

Within the scope of the present invention, halogen is represented fluorine, chlorine, bromine or iodine.

Within the scope of the present invention, alkyl refers to that monovalence is saturated, the straight or branched hydrocarbon chain.This hydrocarbon chain preferably comprises 1-6 carbon atom (C _1-6-alkyl), comprise amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl and isohexyl.In a preferred embodiment, alkyl represent C _1-4-alkyl comprises butyl, isobutyl-, sec-butyl and the tertiary butyl.In another embodiment preferred of the present invention, alkyl represent C _1-3-alkyl, described group can be specially methyl, ethyl, propyl group or sec.-propyl.

Within the scope of the invention, alkenyl refers to comprise the carbochain of one or more pairs of keys, comprises diene, triolefin and polyenoid.In a preferred embodiment, alkenyl of the present invention comprises 2-6 carbon atom (C _2-6-alkenyl), comprise at least one two key.In a most preferred embodiment, alkenyl of the present invention is a vinyl; 1-or 2-propenyl; 1-, 2-or 3-butenyl, or 1,3-butadiene base; 1-, 2-, 3-, 4-or 5-hexenyl, or 1, the 3-hexadienyl, or 1,3,5-hexatriene base.

Within the scope of the invention, alkynyl refers to comprise the carbochain of one or more three keys, comprises diine, three alkynes and polyyne.In a preferred embodiment, alkynyl of the present invention comprises 2-6 carbon atom (C _2-6-alkynyl), comprise at least one three key.In its most preferred embodiment, alkynyl of the present invention is an ethynyl; 1-or 2-propynyl; 1-, 2-or 3-butynyl, or 1,3-diacetylene base; 1-, 2-, 3-, 4-pentynyl, or 1,3-pentadiine base; 1-, 2-, 3-, 4-or 5-hexin base, or 1,3-hexadiyne base or 1,3, oneself three alkynyls of 5-.

Within the scope of the invention, cycloalkyl finger ring type alkyl preferably comprises 3-7 carbon atom (C _3-7-cycloalkyl), comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.

Alkoxyl group is the O-alkyl, wherein alkyl such as above definition.

Cycloalkyloxy means the O-cycloalkyl, wherein cycloalkyl such as above definition.

Cycloalkylalkyl means above-mentioned cycloalkyl and above-mentioned alkyl, for example means the cyclopropyl methyl.

Amino is NH ₂Or NH-alkyl or N-(alkyl) ₂, wherein alkyl such as above definition.

Heteroaryl is the single, double or many heterocyclic groups of fragrance, and this group has one or more heteroatomss in its ring structure.Preferred heteroatoms comprises nitrogen (N), oxygen (O) and sulphur (S).

Preferred bicyclic heteroaryl of the present invention comprises fragrant 5-and 6 yuan of heterocycle one cyclic groups, for example Bao draws together but Bu Xian Yu oxazole-2-base oxazole-4-base oxazole-5-base isoxazole-3-base isoxazole-4-base isoxazole-5-base, thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazole-3-base, isothiazole-4-base, isothiazole-5-base, 1,2,4-oxadiazole-3-base, 1,2,4-oxadiazole-5-base, 1,2,4-thiadiazoles-3-base, 1,2,4-thiadiazoles-5-base, 1,2,5-oxadiazole-3-base, 1,2,5-oxadiazole-4-base, 1,2,5-thiadiazoles-3-base, 1,2,5-thiadiazoles-4-base, the 2-imidazolyl, the 4-imidazolyl, the 5-imidazolyl, the 2-pyrryl, the 3-pyrryl, the 2-furyl, the 3-furyl, the 2-thienyl, the 3-thienyl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrimidyl, the 4-pyrimidyl, 5-pyrimidyl or 6-pyrimidyl.

Preferred bicyclic heteroaryl of the present invention comprises indolizine base, particularly 2-, 5-or 6-indolizine base; Indyl, particularly 2-, 5-or 6-indyl; Pseudoindoyl, particularly 2-, 5-or 6-pseudoindoyl; Benzo [b] furyl, particularly 2-, 5-or 6-benzofuryl; Benzo [b] thienyl, particularly 2-, 5-or 6-benzothienyl; Benzimidazolyl-, particularly 2-, 5-or 6-benzimidazolyl-; Benzothiazolyl, particularly 5-or 6-benzothiazolyl; Purine radicals, particularly 2-or 8-purine radicals; Quinolyl, particularly 2-, 3-, 6-or 7-quinolyl; Isoquinolyl, particularly 3-, 6-or 7-isoquinolyl; Cinnolines base, particularly 6-or 7-cinnolines base; Phthalazinyl, particularly 6-or 7-phthalazinyl; Quinazolyl, particularly 2-, 6-or 7 quinazolyls; Quinoxalinyl, particularly 2-or 6-quinoxalinyl; 1,8-naphthyridinyl, particularly 1,8-naphthyridines-2-, 3-, 6-or 7-base; Pteridyl, particularly 2-, 6-or 7 pteridyls; And indenyl, particularly 1-, 2-, 3-, 5-or 5-indenyl.

Pharmacy acceptable salt

The form that compound of the present invention can anyly be suitable for the target administration provides.Suitable form comprises pharmaceutically the salt and the prodrug forms of (being on the physiology) acceptable The compounds of this invention.

The example of pharmaceutically acceptable addition salt includes but not limited to nontoxic inorganic and organic acid addition salt, for example by hydrochloric acid deutero-hydrochloride, by Hydrogen bromide deutero-hydrobromate, by nitric acid deutero-nitrate, by perchloric acid deutero-perchlorate, by phosphoric acid deutero-phosphoric acid salt, by sulfuric acid deutero-vitriol, by formic acid deutero-formate, by acetate deutero-acetate, by equisetic acid deutero-aconitate, by xitix deutero-ascorbate salt, by Phenylsulfonic acid deutero-benzene sulfonate, by phenylformic acid deutero-benzoate, by styracin deutero-cinnamate, by citric acid deutero-Citrate trianion, by pamoic acid deutero-embonate, by enanthic acid deutero-enanthate, fumarate by fumarate derivative, by gluconic acid deutero-gluconate, by oxyacetic acid deutero-hydroxyl acetate, by lactic acid deutero-lactic acid salt, by toxilic acid deutero-maleate, by propanedioic acid deutero-malonate, by amygdalic acid deutero-mandelate, by methylsulfonic acid deutero-mesylate, by naphthalene-2-sulfonic acid deutero-naphthalene-2-sulfonic acid salt, by phthalic acid deutero-phthalate, by Whitfield's ointment deutero-salicylate, by Sorbic Acid deutero-sorbate, the stearate of deriving by stearic acid, by succsinic acid deutero-succinate, the tartrate of deriving by tartrate, by tosic acid deutero-tosilate etc.These salt can be by method preparation known in the present technique and that described.Be considered to pharmaceutically unacceptable other acid and can be used to prepare the intermediate product that is used as acquisition compound of the present invention and pharmaceutically-acceptable acid addition thereof as oxalic acid.

The metal-salt of compound of the present invention comprises an alkali metal salt, for example comprises the sodium salt of the compound of the present invention of carboxyl.

Within the scope of the invention, " salt " of nitrogenous compound also is considered to pharmacy acceptable salt.Preferably " salt " comprises alkyl-salt, cycloalkyl-salt and cycloalkylalkyl-salt.

The example of the prodrug forms of compound of the present invention comprises the example of the prodrug of suitable material of the present invention, is included in the adorned compound of one or more reactions or deriveding group place of parent compound.Useful especially compound is an adorned compound on carboxyl, hydroxyl or amino.The example of suitable deutero-is ester or acid amides.

Compound of the present invention can solvable or insoluble form provide with pharmaceutically acceptable solvent such as water, ethanol etc.Soluble form can also comprise hydrated form, for example monohydrate, dihydrate, semihydrate, trihydrate, tetrahydrate etc.Usually, think that soluble form is equal to insoluble form for the object of the invention.

Steric isomer

Those skilled in the art will recognize that compound of the present invention can comprise one or more chiral centres, and this compound is with isomer, promptly the form of 1R/S, 2R/S, 3R/S and 5R/S exists.

And, at substituting group-CH of 2 of the 8-of formula I aza-bicyclo [3.2.1] octane skeleton ₂-X-R ^aSubstituent R with 3 ³Can be specially cis respect to one another or transconfiguration.In an embodiment preferred of the present invention, 2 and 3 substituting group is a transconfiguration.In another embodiment preferred of the present invention, 2 and 3 substituting group is a cis-configuration.

The present invention includes all these isomer and any its mixture, comprise racemic mixture.

Racemic form can split into optical antipode with known method and technology.A kind of method of separating isomerism salt is to use optical activity acid, and by discharge the optical activity amine compound with alkaline purification.

The another kind of method that racemic modification is split into optical antipode is handled based on the enterprising circumstances in which people get things ready for a trip spectrum of optical activity matrix.Therefore for example can split into their optical antipode by fractional crystallization d-or l-(tartrate, mandelate or camsilate) and with racemic compound of the present invention.

Compound of the present invention can also split by the following method: make compound of the present invention and optical activity activatory carboxylic acid as forming the diastereomer acid amides by (+) or (-) phenylalanine, (+) or (-) phenylglycocoll, (+) or (-) dextrocamphoric acid deutero-carboxylic acid reaction, perhaps make reactions such as compound of the present invention and optical activity chloro-formic ester form the diastereomer carbamate.

Other method that is used for splitting optical isomer is known in present technique.These methods comprise Jaques J, ColletA ， ﹠amp; Wilen Sin " Enantiomers.Racemates, andResolutions ", JohnWiley and Sons, the described method of New York (1981).

Optically active compound can also be by the optical activity feedstock production.

Tagged compound

Compound of the present invention can their mark or unlabelled form use.Within the scope of the present invention, " mark " representative is bonded to compound of interest with marker, thereby makes the detection by quantitative of this compound easy.

The compound of mark of the present invention can be used as diagnostic tool, radiotracer or the monitoring agent in the multiple diagnostic method, and is used for the imaging of body inner recipient.

The isomer of mark of the present invention preferably comprises at least one radionuclide and serves as a mark.The radionuclide of emission positron is all purposes material standed fors.Within the scope of the invention, radionuclide is preferably selected from ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C, ¹³¹I, ¹²⁵I, ¹²³I and ¹⁸F.

The physical method that is used to detect the isomer of mark of the present invention can be selected from PET (positron emission tomography) (PET), single photon tomography computer fault imaging (SPECT), nuclear magnetic resonance spectroscopy (MRS), nuclear magnetic resonance (MRI) and axial X-ray topography of area of computer aided (CAT) or their combination.

The preparation method

Compound of the present invention can be by being used for the ordinary method of chemosynthesis, for example described in an embodiment method preparation.The raw material that is used for the described method of the application is known, perhaps can easily be prepared by the chemical substance that is available commercially by ordinary method.

Can also change into another kind of compound of the present invention with ordinary method a kind of compound of the present invention.

The end product of reaction as herein described can pass through routine techniques, for example waits by extraction, crystallization, distillation, chromatography and separates.

Biological activity

Can test compound of the present invention and suppress the ability of the re-uptake of monoamine Dopamine HCL, norepinephrine and serotonin in the synaptosome, as described in the WO97/30997.According to observed equilibrium activity in these tests, consideration with compound of the present invention be used for the treatment of, prevention or releasing mammal, comprise people's disease or obstacle or illness, described disease, obstacle or illness are replied the inhibition of the monoamine neurotransmitter re-uptake in the central nervous system.

In a specific embodiment, consider compound of the present invention is used for the treatment of, prevention or alleviation: emotional handicap, depressed, the atypia depression, major depressive disorder, evil mood, the bipolarity obstacle, I type bipolarity obstacle, II type bipolarity obstacle, the cyclothymia obstacle, the emotional handicap that causes by the general medicine illness, the emotional handicap that material causes, pseudodementia, Ganser's syndrome, obsessional idea and behavior disorder, Phobias, the Phobias of no agoraphobia, the Phobias that agoraphobia is arranged, the agoraphobia of no Phobias medical history, panic attack, memory impairment, the loss of memory, attention deficit hyperactivity disease, fat, anxiety, generalized anxiety disorder, eating disorder, Parkinson's disease, Parkinson, dull-witted, the aging dementia, senile dementia, Alzheimer, acquired immune deficiency syndrome (AIDS), chronic brain syndrome, aging memory machine dysfunction, specific phobias, social phobia, nervous obstacle after the wound, acute nervous obstacle, drug habit, drug abuse, cocaine abuse, the nicotine abuse, tobacco abuse, alcohol addiction, alcoholism, pain, inflammatory pain, neuropathic pain, migraine, tension-type headache, chronic tension-type headache, the pain relevant with depression, fibromyalgia, sacroiliitis, osteoarthritis, rheumatoid arthritis, back pain, pain caused by cancer, intestines easily swash property pain, irritable bowel syndrome, post-operative pain, pain after the apoplexy, drug induced neuropathy, diabetic neuropathy, sympathetic nerve maintenance pain, trigeminal neuralgia, toothache, muscular fascia pain, phantom limb pain, exessive appetite, syndrome before the menstruation, the evening luteal phase syndrome, posttraumatic syndrome, chronic fatigue syndrome, the urinary incontinence, stress incontinence, urge incontinence, night the urinary incontinence, premature ejaculation, it is difficult to erect, anorexia nervosa, somnopathy, autism, mutism, trichotillomania, hypnolepsy, the apoplexy retarded depression, apoplexy inductive cerebral lesion, infringement of apoplexy inductive neurone or Du Leite disease.In a preferred embodiment, consideration with this compound be used for the treatment of, prevention or alleviate depression.

The suitable dosage range of considering active pharmaceutical ingredient (API) at present is about 0.1 to about 1000mg API/ day, more preferably about 10 to about 500mg API/ days, most preferably about 30 to about 100mg API/ days, but it get in definite administering mode, its form of medication, the indication of consideration, experimenter, particularly related experimenter's body weight and preference and the experience of further being responsible for physician or animal doctor.

Preferred compound of the present invention shows the biological activity of sub-micro mole and micro-molar range, and promptly activity is to about 100 μ M less than 1.

Pharmaceutical composition

On the other hand, the invention provides the new pharmaceutical composition that comprises the compound of the present invention for the treatment of significant quantity.

Though the form administration that the compound of the present invention that is used for the treatment of can original chemical, preferred activeconstituents and one or more auxiliary agents, vehicle, carrier, buffer reagent, thinner and/or other conventional medicine auxiliary agent of in pharmaceutical composition, introducing optional for acceptable salt form on the physiology.

Therefore in a preferred embodiment, the invention provides and comprise The compounds of this invention or its pharmaceutically acceptable derivates, with one or more pharmaceutically acceptable carriers, and in the optional present technique known and use other treat and/or prevent composition pharmaceutical composition.This carrier must be that the implication of " acceptable " is compatible with other composition of preparation, and harmless to its receptor.

Pharmaceutical composition of the present invention can be the pharmaceutical composition that is suitable for mouth, rectum, segmental bronchus, nose, lung, part (comprising cheek and hypogloeeis), transdermal, vagina or parenteral (comprise in skin, subcutaneous, intramuscular, intraperitoneal, intravenously, intra-arterial, the brain, intraocular injection or infusion) administration, or be suitable for by sucking or be blown into administration, comprise powder or liquid aersol administration, or pass through the form of sustained release system administration.The example of suitable sustained release system comprises the semipermeability matrix of the solid hydrophobic polymkeric substance that comprises The compounds of this invention, and described matrix can be the form of shaped particles, for example film or micro-capsule.

Compound of the present invention can be put into the formulation of pharmaceutical composition or its dosage unit with auxiliary agent, carrier or the thinner of routine.These formulations comprise solid, particularly tablet, filled capsules, powder and pill, and the capsule (they all are used for oral) of liquid, the particularly aqueous solution or non-aqueous solution, suspension, emulsion, elixir and this compound of filling, be used for the suppository of rectal administration and be used for the aseptic injectable solution of parenteral applications.This pharmaceutical composition and unit dosage form thereof can comprise the conventional ingredient of conventional ratio, and contain or do not contain additional active compound or composition, and this unit dosage form can comprise any suitable suitable effective amount of actives of using with expectation of per daily dose scope.

Compound of the present invention can multiple oral and parenteral dosage forms administration.Those skilled in the art obviously following as can be seen formulation can comprise the pharmacy acceptable salt of compound of the present invention or The compounds of this invention as activeconstituents.

For by compound pharmaceutical composition of the present invention, pharmaceutically acceptable carrier can be solid or liquid.But solid preparation comprises powder, tablet, pill, capsule, lozenge, suppository or discrete particles.Solid carrier can be one or more materials that can also be used as thinner, seasonings, stablizer, lubricant, suspending agent, tackiness agent, sanitas, tablet disintegrant or encapsulated materials.

In powder, carrier can be the solid of segmentation, and it mixes with the activeconstituents that segments.

In tablet, activeconstituents mixes with an amount of carrier with necessary adhesive capacity, and is pressed into target shape and size.

Powder and tablet preferably comprise 5 or 10% to about 70% active compound.Suitable carrier is magnesiumcarbonate, Magnesium Stearate, talcum, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose gum, Xylo-Mucine, low melt wax, cocoa wet goods.Terms " formulation " means and comprises and contain encapsulated materials as the preparation of the active compound of capsular carrier is provided, and wherein surrounds with carrier and contains or not carrier-containing described activeconstituents, thereby make its combination.Similarly, the present invention includes lozenge and sugar shallow lake.Tablet, powder, capsule, pill, lozenge and sugared shallow lake can be as being suitable for oral solid dosage.

For preparation suppository, at first with low melt wax, the mixture melt of fatty acid glycerine or theobroma oil for example, and by stirring active ingredient is scattered in wherein equably.With the conventional big or small mould of the uniform mixture impouring of fusing, make its cooling, thereby it is solidified then.

The composition that is suitable for vagina administration can be used as the hysterophore, cotton balls, emulsifiable paste, gel, paste, foam or the sprays that comprise known appropriate carrier in activeconstituents and the present technique and provides.

Liquid preparation comprises solution, suspension and emulsion, for example not or water-propylene glycol solution.For example, the parenteral injection liquid preparation can be formed in the solution in the polyoxyethylene glycol aqueous solution.

Therefore, compound of the present invention be used for administered parenterally (for example by injection, as bolus injection or connect inculcate), and can inculcate or the unit dosage form of multi-dose container provides at ampoule, pre-injection of filling, the small volume that contains the sanitas of adding.Said composition can be the form of suppository, solution or the emulsion in oil or vehicle, and can comprise preparation reagent such as suspending agent, stablizer and/or divide powder.As alternative selection, activeconstituents can powder, obtains by aseptic separation sterile solid or by freeze-drying solution, is used for before use and suitable vehicle such as aseptic, as not contain pyrogen water combination.

If desired, the aqueous solution that is suitable for mouthful usefulness can be by water-soluble with activeconstituents, and add suitable tinting material, seasonings, stablizer and thickening material and prepare.

The aqeous suspension that is suitable for mouthful usefulness can be dissolved in the water that contains viscous substance by the active ingredient with segmentation, and for example natural or synthetic gum, resin, methylcellulose gum, Xylo-Mucine or other known suspending agent prepare.

The present invention also comprises and changes into the solid dosage that is used for oral liquid preparation in the short period of time before being intended to use.These liquid dosage forms comprise solution, suspension and emulsion.Except active ingredient, these preparations can comprise tinting material, seasonings, stablizer, buffer reagent, artificial and synthetic sweetener, divide powder, thickening material, solubility promoter etc.

For epidermis is carried out topical, compound of the present invention can be made ointment, emulsifiable paste or washing lotion, perhaps make transdermal patch.For example, ointment and emulsifiable paste can use or oleaginous bases, and add suitable thickening and/or gelling reagent and prepare.Washing lotion can use or the oleaginous base preparation, and generally also comprises one or more emulsifying agents, stablizer, dispersion agent, suspending agent, thickening material or tinting material.

Be suitable in mouth, carrying out topical drug delivery composition and comprise and containing, be generally the lozenge of the active agent in sucrose and gum arabic or the tragacanth at flavoured base; Be included in the lozenge (pastilles) of the activeconstituents in inert base such as gel and glycerine or sucrose and the gum arabic; With the mouthwash that is included in the activeconstituents in the appropriate liquid carrier.

By ordinary method, for example solution or suspension are directly applied to nasal cavity with dropper, suction pipe or spraying.Described composition can be single or the multiple doses form provide.

Respiratory tract administration can also be finished by the gaseous solvents preparation, wherein containing suitable propellent, for example providing in the pressure packing of Chlorofluorocarbons (CFC) as Refrigerant 12, trichlorofluoromethane or dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas.

Described aerosol can also comprise tensio-active agent, for example Yelkin TTS expediently.The dosage of medicine can be controlled by metering valve is provided.

As alternative selection, activeconstituents can anhydrous powder, and for example the form at the powdered mixture of suitable powder matrix such as the compound in lactose, starch, starch derivative such as Vltra tears and the polyvinylpyrrolidone (PVP) provides.Conventional powder carrier will form gel in nasal cavity.This powder composition can provide by unit dosage form, for example in gelatine capsule or cartridge case, perhaps can use in the Blister Package of powder by sucker.

Composition desiring to be used for to respiratory tract administration comprises in the intranasal compositions that this compound generally has small particle size, and for example particle diameter progression is 5 microns or littler.This particle diameter can obtain by known method in the present technique, for example obtains by micronization.

If necessary, can use the composition that is suitable for continuing release of active ingredients.

This pharmaceutical preparation is preferably unit dosage form.In this formulation, preparation is subdivided into the dosage unit that comprises an amount of active ingredient.Unit dosage form can packaged preparation, comprises the packing of the preparation that separates quantity, for example Bao Zhuan tablet, capsule and the powder in bottle or ampoule.And unit dosage form can be capsule, tablet, cachet or a lozenge itself, and perhaps it can be any of these packaged form of suitable number.

Be used for oral tablet or capsule and be used for intravenous administration and the liquid of continuous infusion is preferred compositions.

Further details about preparation and medicine-feeding technology can see Remington ' s Pharmaceutical Sciences(Maack Publishing Co., Easton, latest edition PA).

The treatment effective dose refers to alleviate the quantity of the activeconstituents of illness or situation.Treatment is renderd a service and poison, for example ED ₅₀And LD ₅₀Can determine by the cell culture or the laboratory animal pharmacological method of standard.Dosage ratio between treatment and the toxic action is a therapeutic index, and it can use ratio LD ₅₀/ ED ₅₀Expression.The big treatment of preferred performance exponential pharmaceutical composition.

Dosage certainly must be individual according to treatment age, weight and illness and route of administration, formulation and scheme, and the result of expectation and adjusting carefully, and definite dosage should be determined by practitioner.

Actual dosage depends on the character and the severity of the disease of being treated, and in physician's judgement scope, and can change by particular case titration dosage according to the present invention, to produce the goal treatment effect.But, to think at present to comprise about activeconstituents of 0.1 to about 500mg/individually dosed, preferably approximately 1 is to about 100mg, and most preferably about pharmaceutical composition of 1 to about 10mg is suitable for treating.

Activeconstituents can every day one or several dosed administration.In some cases, can under the dosage that is low to moderate 0.1 μ g/kg i.v. and 1 μ g/kg p.o, obtain satisfied result.Be limited to about 10mg/kg i.v. and 100mg/kg p.o on the current dose scope.Preferred range is extremely approximately 10mg/kg/ days i.v. of about 0.1 μ g/kg, and about 1 μ g/kg is to about 100mg/kg/ days p.o.

Methods of treatment

On the other hand, the invention provides and a kind ofly be used for the treatment of, prevent or alleviate moving object, comprise people's the disease or the method for obstacle or illness, described disease, obstacle or illness are replied the inhibition of the monoamine neurotransmitter re-uptake in the central nervous system, and described method comprises to the moving object that these needs are arranged, comprises that the people uses the compound of the present invention of significant quantity.

Think at present, the appropriate dosage scope is the 0.1-1000 mg/day, the 10-500 mg/day, 30-100 mg/day particularly, usually depend on definite administering mode, form of administration, administration at indication, the experimenter who relates to, the experimenter's that relates to body weight, and preference and the experience of further being responsible for physician or animal doctor.

Embodiment

Further with reference to the present invention of following examples illustration, described embodiment is not intended to the scope of the present invention that requires patent protection that limits by any way.

Raw material

(+)-2-methoxycarbonyl tropinone

Prepare by known method (J.F.Casale, Forensic Science International, 33 (1987) 275-298).

(-)-2-methoxycarbonyl tropinone

Synthetic similarly.

Method A

(-)-tropine carboxylic acid ethyl ester

In the solution of the stirring of (+)-2-methoxycarbonyl tropinone (37.4g) in methyl alcohol (1.5L) under-45 ℃, divide small portion to add sodium borohydride (37g), thereby make internal temperature remain on-45 ℃ to-35 ℃.Reaction mixture was stirred 2 hours down in-45 ℃, and by dripping spirit of salt (120mL) termination reaction, keeping temperature simultaneously is-45 ℃.Reaction mixture is heated to room temperature, and stirs and spend the night.Reaction mixture is concentrated into the volume of about 120mL, adds entry (500mL), and with ether (3 * 100mL) washings.Add 25% ammonia (aqueous solution) until pH 10-11 to water, and (4 * 200mL) extract with methylene dichloride.The organic phase that dry (sodium sulfate) merges, and be evaporated to oil.This oil is dissolved in ethyl acetate (370mL), and adds sodium ethylate (from 7g sodium) solution.With the vlil of gained 3 hours, be cooled to room temperature, and be evaporated to oil.Add toluene (0.5L) and be evaporated to oil to residuum, repeat this step.Product 30g (79%) is a kind of oil.

(+)-tropine carboxylic acid ethyl ester

Synthetic similarly (-)-2-methoxycarbonyl tropinone.

Method B

(2R, 3S)-8-methyl-3-(2-thienyl)-8-azabicyclo [3.2.1] octane-2-carboxylic acid, ethyl ester

Will be at (-)-tropine carboxylic acid ethyl ester (4.9g in the dry toluene (60mL); Solution 25mmol) be added under-40 ℃ at anhydrous Et ₂The solution of the stirring of the 2-thienyl magnesium bromide (48mmol) among the O (100mL), thus make internal temperature remain on-20 ℃ to-40 ℃.Reaction mixture was stirred 90 minutes down in-20 ℃ to-40 ℃, perhaps show that until TLC raw material transforms fully.With the mixture of dense HCl of reaction mixture impouring (20mL) and ice (200mL), and stirred 20 minutes.Use Et ₂O (2x30mL) washs water, and down to make its alkalescence with 4M NaOH at 20 ℃ be pH10-11.Use CH ₂Cl ₂(4x100mL) aqueous phase extracted, and dry (MgSO ₄) organic fraction that merges, filter and evaporation as for, obtain the oil of 5.36g (80%).Slightly (4ml, 2M) mixture with anhydrous MeOH (100mL) refluxed 40 hours, was evaporated to dried then for oil, NaOMe.Add entry (50mL), and use CH ₂Cl ₂(3x50mL) extraction.Dry (MgSO ₄) organic fraction that merges, filter and be evaporated to dried, obtain 4.2g (63%), be a kind of oil.

(2S, 3R)-8-methyl-3-(2-thienyl)-8-azabicyclo [3.2.1] octane-2-carboxylic acid, ethyl ester

Prepare by (+)-tropine carboxylic acid ethyl ester similarly.

Method C

(2R, 3S)-(8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol

Under 0 ℃ to (2R, 3S)-8-methyl-3-(2-thienyl)-8-azabicyclo [3.2.1] octane-2-carboxylic acid, ethyl ester (3.65g, 13.75mmol) and add in the mixture of toluene (75ml) Red-Al (6ml, 65%, 20mmol).Mixture was stirred 1 hour down in 0 ℃.The dropping sodium aqueous solution (20ml, 4M), add then warm water (50 ℃, 150ml).With toluene (2x100ml) extraction mixture.With mixture drying (MgSO ₄) and evaporation.Separated product is a kind of crystallization.Mp 153.7-157.5℃。Output 2.04g (63%).

(2S, 3R)-(8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol

Similarly by (2S, 3R)-8-methyl-3-(2-thienyl)-8-azabicyclo [3.2.1] octane-2-carboxylic acid, ethyl ester is synthetic.

Use above-mentioned method preparation like the following compounds:

(2R, 3S)-(8-methyl-3-(5-chloro-thiophene-2-yl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol.Mp172-176℃。

(2R, 3S)-(8-methyl-3-(5-chloro-furans-2-yl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol.Mp88-145℃。

(2R, 3S)-(8-methyl-3-(5-methoxyl group-thiophene-2-yl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol.Mp 164.5-167℃。

Method D

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane fumarate

Will be at anhydrous CH ₂Cl ₂(15mL) (2R, 3S)-(8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol (1.74g; 7.36mmol), Tosyl chloride (1.75mg; 9.2mmol) and the mixture of pyridine (10ml) stirred 1 hour down in 0 ℃.Add H to reaction mixture ₂O (50mL) and aqueous sodium hydroxide solution (5ml, 4M).By filtering separation crystallization O-toluenesulphonic acids intermediate product.Mp：115.4-120.3℃。Output 2.42g (84%).To in DMF (15mL) 2,3-chlorophenesic acid (820mg; 5.0mmol) and O-toluenesulphonic acids intermediate product (1.17g, and stirred solution adding NaH 3.0mmol) (200mg, 60%, 5.2mmol).Reaction mixture was heated 2.5 hours down in 100 ℃.Reaction mixture is cooled to room temperature, and adds entry (50ml).Use Et ₂O (2x50mL) extracts mixture.Dry (MgSO ₄) organic fraction that merges, filter, and be evaporated to dried.Column chromatography is handled (acetone: MeOH: NH ₃(1% aqueous solution)=9: 1: 1) obtain 940mg (82%) product.Free alkali is changed into the horse hydrochlorate.Mp：151.5℃。

(2R, 3S)-2-(1-naphthyloxy methyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane fumarate

According to method D by (2R, 3S)-(8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol preparation.Mp 203.1℃。

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2R, 3S)-(8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol is synthetic.

(2R, 3S)-2-(1-naphthyloxy methyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane fumarate

According to method D by (2R, 3S)-(8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol preparation.Mp 156.4-205.9℃。

(2R, 3S)-2-(1-naphthyloxy methyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane fumarate

According to method D by (2R, 3S)-(8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol preparation.Mp 189.7-214.1℃。

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2R, 3S)-(8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol is synthetic.

(2R, 3S)-2-(1-naphthyloxy methyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2S, 3R)-(8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol is synthetic.

(2S, 3R)-2-(1-naphthyloxy methyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2S, 3R)-(8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol is synthetic.

(2S, 3R)-2-(1-naphthyloxy methyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2S, 3R)-(8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol is synthetic.

(2S, 3R)-2-(1-naphthyloxy methyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2S, 3R)-(8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol is synthetic.

(2S, 3R)-2-(1-naphthyloxy methyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(5-chloro-thiophene-2-yl)-8-aza-bicyclo [3.2.1] octane fumarate

According to method D by (2R, 3S)-(8-methyl-3-(5-chloro-thiophene-2-yl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol preparation.Mp125.9-128.0℃。

(2R, 3S)-2-(1-naphthyl)-8-methyl-3-(5-chloro-thiophene-2-yl)-8-aza-bicyclo [3.2.1] octane fumarate

According to method D by (2R, 3S)-(8-methyl-3-(5-chloro-thiophene-2-yl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol preparation.Mp154-155℃。

(2R, 3S)-2-(2,3-difluoro phenoxymethyl)-8-methyl-3-(5-chloro-furans-2-yl)-8-aza-bicyclo [3.2.1] octane Citrate trianion

According to method D by (2R, 3S)-(8-methyl-3-(5-chloro-furans-2-yl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol preparation.Mp145℃。

(2R, 3S)-2-(2,3-difluoro phenoxymethyl)-8-methyl-3-(5-methoxyl group-thiophene-2-yl)-8-aza-bicyclo [3.2.1] octane free alkali

According to method D by (2R, 3S)-(8-methyl-3-(5-methoxyl group-thiophene-2-yl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol preparation.Mp oil.

(2R, 3S)-2-(2,3-dimethoxy phenoxymethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane fumarate

According to method D by (2R, 3S)-(8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol preparation.Mp 151.4-156.3℃。

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(5-methoxyl group-thiophene-2-yl)-8-aza-bicyclo [3.2.1] octane free alkali

According to method D by (2R, 3S)-(8-methyl-3-(5-chloro-thiophene-2-yl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol preparation.Mp61-67℃。

(2R, 3S)-2-(2-naphthyl)-8-methyl-3-(5-chloro-thiophene-2-yl)-8-aza-bicyclo [3.2.1] octane fumarate

According to method D by (2R, 3S)-(8-methyl-3-(5-chloro-thiophene-2-yl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol preparation.Mp215-217℃。

(2R, 3S)-2-(2,3-difluoro phenoxymethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane Citrate trianion

According to method D by (2R, 3S)-(8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] suffering-2-yl)-methyl alcohol preparation.Mp 94.8-129℃。

Method E

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane fumarate

With (2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-and 8-methyl-3-(2-thienyl-8-aza-bicyclo [3.2.1] octane fumarate (0.69g, 1.8mmol), the mixture of 1-chloroethyl chloro-formic ester (1ml) and toluene (25ml) at room temperature stirred 0.5 hour.This mixture was stirred 70 hours down in 100 ℃.Add entry (20ml), and with mixture stirring and refluxing 5 hours.Make mixture reach room temperature, and (50ml 1M), use ether (3x50ml) extraction then to add ammonia.Use column chromatography, use silica gel and methylene dichloride: methyl alcohol: the mixture of ammoniacal liquor (90: 9: 1) is as liquid phase purifying crude product.By (175mg stirs that (0.49g 1.33mmol) changes into fumarate, cools off then and filters with the oil of gained in 1.5mmol) at ethanol (25ml) and fumaric acid.Mp：201.2℃。

(2R, 3S)-2-(1-naphthyloxy methyl)-8-H-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane fumarate

According to method E by (2R, 3S)-2-(1-naphthyloxy methyl)-8-methyl-3-(2-thienyl)-preparation of 8-aza-bicyclo [3.2.1] octane.Mp 199.1℃。

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2R, 3S)-2-(1-naphthyloxy methyl)-8-H-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2R, 3S)-2-(1-naphthyloxy methyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2R, 3S)-2-(1-naphthyloxy methyl)-8-H-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2R, 3S)-2-(1-naphthyloxy methyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2R, 3S)-2-(1-naphthyloxy methyl)-8-H-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2R, 3S)-2-(1-naphthyloxy methyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2S, 3R)-2-(1-naphthyloxy methyl)-8-H-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2S, 3R)-2-(1-naphthyloxy methyl)-8-H-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2S, 3R)-2-(1-naphthyloxy methyl)-8-H-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2S, 3R)-2-(1-naphthyloxy methyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2S, 3R)-2-(1-naphthyloxy methyl)-8-H-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2S, 3R)-2-(1-naphthyloxy methyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2S, 3R)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

(2S, 3R)-2-(1-naphthyloxy methyl)-8-H-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane

Similarly by (2S, 3R)-2-(1-naphthyloxy methyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo [3.2.1] octane is synthetic.

Experimental example

The vitro inhibition activity

The test chemical compound lot suppresses the ability of monoamine neurotransmitter dopamine (DA), norepinephrine (NA) and serotonin (5-HT) re-uptake in the synaptosome, as described in WO 97/16451.

Trial value is with IC ₅₀Provide (50% inhibition ³H-DA, ³H-NA or ³The concentration (μ M) of H-5-HT specificity bonded test-compound).

By testing during test-results that selected compound of the present invention obtains is listed in the table below:

Table 1

Test-compound	DA-absorbs IC ₅₀(μM)	NA-absorbs IC ₅₀(μM)	5-HT-absorbs IC ₅₀(μM)
Test-compound	DA-absorbs IC ₅₀(μM)	NA-absorbs IC ₅₀(μM)	5-HT-absorbs IC ₅₀(μM)	The-compound of method D; (2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane fumarate	0.30	0.0019	0.00052
Second compound of method D; (2R, 3S)-2-(1-naphthyloxy methyl-8-methyl-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane fumarate	0.36	0.0036	0.00042		0.30	0.0019	0.00052
	0.36	0.0036	0.00042	The 5th compound of method D; (2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane fumarate	0.31	0.00090	0.00036
The 6th compound of method D; (2R, 3S)-2-(1-naphthyloxy methyl-8-methyl-3-(2-furyl)-8-aza-bicyclo [3.2.1] octane fumarate	0.92	0.0030	0.00053		0.31	0.00090	0.00036
	0.92	0.0030	0.00053	First compound of method E; (2R, 3S)-2-(2,3-Dichlorophenoxy ylmethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane fumarate	0.074	0.0018	0.00074
Second compound of method E; (2R, 3S)-2-(1-naphthyloxy methyl)-8-H-3-(2-thienyl)-8-aza-bicyclo [3.2.1] octane fumarate	0.19	0.0016	0.00054		0.074	0.0018	0.00074

Claims

1. 8-aza-bicyclo[3.2.1]octane derivatives of formula I

Or any stereoisomer thereof or any mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, wherein

R represents hydrogen or alkyl;

R ² represents -CH ₂ -XR ^a ;

Where X stands for -O- or -S-;

R ^a represents phenyl or naphthyl,

The phenyl or naphthyl is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkoxy, ring Alkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl;

R ³ represents thienyl or furyl;

The thienyl or furyl is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, alkoxy, ring Alkoxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl.

2. The compound of claim 1, wherein

R represents hydrogen or methyl.

3. A compound according to claim 1 or 2,

wherein R ^a represents phenyl optionally substituted by one or more halogens or one or more alkoxy groups.

4. The compound of claim 1 or 2, wherein

R ^a represents naphthyl.

5. The compound of claim 1 or 2, wherein

R ³ represents thienyl optionally substituted by one or more halogen or alkoxy.

6. The compound of claim 1 or 2, wherein ^R3 represents furyl optionally substituted by one or more halogen.

7. The compound of claim 1, wherein

R represents hydrogen or methyl;

X stands for -O-;

R ^represents 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,3-dimethoxyphenyl or naphthyl; and

R ³ represents thienyl or furyl, optionally substituted by one or more halogen or alkoxy.

8. The compound of claim 1, which is

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(1-naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(1-naphthyloxymethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(1-naphthyloxymethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(1-naphthyloxymethyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(1-naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(1-naphthyloxymethyl)-8-methyl-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(1-naphthyloxymethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(1-naphthyloxymethyl)-8-methyl-3-(3-furyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(5-chloro-thiophen-2-yl)-8-aza-bicyclo[3.2. 1] octane;

(2R,3S)-2-(1-naphthyl)-8-methyl-3-(5-chloro-thiophen-2-yl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-difluorophenoxymethyl)-8-methyl-3-(5-chloro-furan-2-yl)-8-aza-bicyclo[3.2. 1] octane;

(2R,3S)-2-(2,3-difluorophenoxymethyl)-8-methyl-3-(5-methoxy-thiophen-2-yl)-8-aza-bicyclo[ 3.2.1] octane;

(2R,3S)-2-(2,3-dimethoxyphenoxymethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo[3.2.1 octane ;

(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(5-methoxy-thiophen-2-yl)-8-aza-bicyclo[ 3.2.1] octane;

(2R,3S)-2-(2-naphthyl)-8-methyl-3-(5-chloro-thiophen-2-yl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-difluorophenoxymethyl)-8-methyl-3-(2-furyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(1-naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(1-naphthyloxymethyl)-8-H-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-furyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(1-naphthyloxymethyl)-8-H-3-(2-furyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-furyl)-8-aza-bicyclo[3.2.1]octane;

(2R,3S)-2-(1-naphthyloxymethyl)-8-H-3-(3-furyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(1-naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(1-naphthyloxymethyl)-8-H-3-(3-thienyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-furyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(1-naphthyloxymethyl)-8-H-3-(2-furyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(3-furyl)-8-aza-bicyclo[3.2.1]octane;

(2S,3R)-2-(1-naphthyloxymethyl)-8-H-3-(3-furyl)-8-aza-bicyclo[3.2.1]octane;

Or any stereoisomer thereof or any mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-8, or any stereoisomer thereof or any mixture of stereoisomers thereof, or a pharmaceutically acceptable acceptable salts, and at least one pharmaceutically acceptable carrier, excipient or diluent.

10. Use of the compound according to any one of claims 1-8, or any stereoisomer thereof or any mixture of stereoisomers thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament.

11. The use according to claim 10, for the preparation of a pharmaceutical composition for the treatment, prevention or alleviation of a disease or disorder or condition in a mammal which reuptakes monoamine neurotransmitters in the central nervous system Response to inhibition.

12. Use according to claim 11, wherein the mammal is a human.

13. Use according to claim 11 or 12, wherein the disease, disorder or condition is a mood disorder, depression, dysthymia, bipolar disorder, cyclothymic temperament disorder, pseudodementia, Gansel's syndrome, obsessive-compulsive Associated with conduct disorder, panic disorder, agoraphobia without history of panic disorder, panic attacks, memory deficits, memory loss, ADHD, obesity, anxiety, eating disorders, Parkinson's disease, Parkinson's syndrome , dementia, Alzheimer's disease, acquired immunodeficiency syndrome dementia syndrome, aging memory dysfunction, specific phobias, social phobias, post-traumatic stress disorder, acute stress disorder, drug addiction, drug Abuse, tobacco abuse, alcohol addiction, alcoholism, pain, fibromyalgia, arthritis, irritable bowel syndrome, drug-induced neuropathy, diabetic neuropathy, bulimia, premenstrual syndrome, late luteal phase syndrome , posttraumatic syndrome, chronic fatigue syndrome, urinary incontinence, premature ejaculation, erectile dysfunction, anorexia nervosa, sleep disturbance, autism, muteness, trichotillomania, narcolepsy, post-stroke depression, stroke-induced brain damage, Stroke-induced neuronal damage or Durett's syndrome.