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CN101072774A - Enantiomers of 3-heteroaryl-8h-8-azabicyclo(3.2.1)oct-2-ene and their use as monoamine neurotransmitter re-uptake inhibitors - Google Patents

Enantiomers of 3-heteroaryl-8h-8-azabicyclo(3.2.1)oct-2-ene and their use as monoamine neurotransmitter re-uptake inhibitors Download PDF

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Publication number
CN101072774A
CN101072774A CNA2005800417536A CN200580041753A CN101072774A CN 101072774 A CN101072774 A CN 101072774A CN A2005800417536 A CNA2005800417536 A CN A2005800417536A CN 200580041753 A CN200580041753 A CN 200580041753A CN 101072774 A CN101072774 A CN 101072774A
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ene
oct
azabicyclo
compound
pain
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Inventor
D·彼得斯
D·T·布朗
S·M·陶里奥
E·达姆
D·S·琼斯
B·弗勒斯特鲁普
E·O·尼尔森
G·M·奥尔森
J·P·雷德罗布
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NTG Nordic Transport Group AS
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Neurosearch AS
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Abstract

This invention relates to novel enantiomers of 3-heteroaryl-8H-8azabicyclo- [3.2.1] oct-2-ene useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these compounds in a method for therapy and to pharmaceutical compositions comprising the compounds of the invention.

Description

The enantiomorph of 3-heterocyclic aryl-8H-8-azabicyclo [3.2.1] oct-2-ene and as the purposes of monoamine neurotransmitter re-uptake
Technical field
The present invention relates to can be used for novel enantiomer as monoamine neurotransmitter re-uptake.
On the other hand, the present invention relates to these compounds in therapy purposes and relate to the pharmaceutical composition that comprises The compounds of this invention.
Background technology
WO02/30405 (NeuroSearch A/S) has described one group of 8-azabicyclo [3.2.1] oct-2-ene derivatives with double activity of nicotine reuptake inhibitor and monoamine agonist or antagonist or monoamine re-uptake inhibitor.One in the disclosed compound is racemoid (±)-3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] oct-2-ene (compound 1D1, method D, the 16th page).
We have found except having double activity at present, 8-azabicyclo [3.2.1] oct-2-ene derivatives, as (±)-3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] hot-2, alkene shows the interesting pharmacological characteristic as monoamine re-uptake inhibitor, especially with regard to regard to the active level of the re-uptake of monoamine neurotransmitter serotonin, Dopamine HCL and norepinephrine, as serotonin reuptake transporter with respect to the active ratio of the re-uptake of norepinephrine and Dopamine HCL.
Further, ideal and be subjected to the regulation and control needs sometimes normally is to specific enantiomer but not racemic drugs is carried out medicament research and development.This theory is based on following discovery: the desired character of chipal compounds is one of its enantiomer usually, and its another enantiomer in fact may make the potential toxicology effect of medicine increase.
Simultaneously, thoroughly be studied for making each enantiomer, the method that mapping pure compound and being used to obtains the pure this compound of chipal compounds mapping has remarkable importance for medicament research and development.
Summary of the invention
Aspect its first, the invention provides the mapping pure compound of formula I:
Or its pharmacy acceptable salt; Wherein R and Q are as giving a definition.
Aspect its second, the invention provides the mapping pure compound of 3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] oct-2-ene, or its pharmacy acceptable salt.
Aspect its 3rd, the invention provides pharmaceutical composition, it comprises the The compounds of this invention that significant quantity is gone up in treatment, or its pharmacy acceptable salt, and at least a pharmaceutically acceptable supporting agent, vehicle or thinner.
In yet another aspect, the invention provides the purposes that compound of the present invention or its pharmacy acceptable salt are used to prepare treatment, prevent or alleviate the pharmaceutical composition of disease, obstacle or illness that Mammals comprises the people, this disease, obstacle or illness are replied the inhibition of monoamine neurotransmitter re-uptake in the central nervous system.
Aspect further, the method of disease, obstacle or the illness that the present invention relates to treat, prevent or alleviate animal body alive to comprise the people, this disease, obstacle or illness are replied the inhibition of monoamine neurotransmitter re-uptake in the central nervous system, this method comprises the The compounds of this invention of the last significant quantity of animal body treatment of the work that these needs are arranged, or its pharmacy acceptable salt.
To those skilled in the art, other purpose of the present invention is conspicuous from following detailed description and embodiment.
Detailed description of the present invention
The mapping pure compound
Aspect its first, the invention provides the mapping pure compound of formula I:
Figure A20058004175300081
Or its pharmacy acceptable salt; Wherein
R represents hydrogen or alkyl:
This alkyl is optional independently to be selected from following substituting group replacement by one or more:
Halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, nitro, alkoxyl group, cycloalkyloxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl; And
Q represents heteroaryl;
This heteroaryl is optional independently to be selected from following substituting group replacement by one or more:
Halogen, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, alkoxyl group, cycloalkyloxy, alkoxyalkyl, cycloalkyloxy alkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl ,-NR ' R " ,-(C=O) NR ' R " or (C=O) R of NR ' "
Wherein R ' and R " be hydrogen or alkyl independently of one another.
In one embodiment, R represents hydrogen or alkyl.In a concrete embodiment, R represents hydrogen.In another embodiment, R represents alkyl, as methyl.
In second embodiment, the optional benzothienyl that replaces of Q representative.
In the 3rd embodiment, Q represents benzothienyl, as the 2-benzothienyl.
In another embodiment, the Q representative is by the benzothienyl of halogen such as chlorine or fluorine replacement.In a concrete embodiment, Q represents 7-fluoro-benzo [b] thiophene-2-base or 7-chloro-benzo [b] thiophene-2-base.
In embodiment further, the invention provides the mapping pure compound of 3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] oct-2-ene, or its pharmacy acceptable salt.
In embodiment further, the invention provides 3-(7-fluoro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1] oct-2-ene; 3-(7-fluoro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1] oct-2-ene; 3-(2-benzothienyl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene; The mapping pure compound of 3-(7-fluoro-benzo [b] thiophene-2-yl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene, or its pharmacy acceptable salt.
In embodiment further, compound of the present invention is mapping pure (+)-3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] oct-2-ene; Or its pharmacy acceptable salt.
In further embodiment, compound of the present invention is mapping pure (-)-3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] oct-2-ene; Or its pharmacy acceptable salt.
In further embodiment, compound of the present invention is:
(+)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1] oct-2-ene that mapping is pure;
(-)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1] oct-2-ene that mapping is pure;
(-)-3-(7-chloro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1] oct-2-ene that mapping is pure;
(-)-3-(2-benzothienyl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene that mapping is pure;
(+)-3-(2-benzothienyl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene that mapping is pure;
(+)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene that mapping is pure:
(-)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene that mapping is pure;
Or its pharmacy acceptable salt.
Two of embodiment described above or more multinomial any combination are considered within the scope of the invention.
The substituting group definition
In the context of the invention, halogen is represented fluorine, chlorine, bromine or iodine.
In the context of the invention, alkyl is represented unit price hydrocarbon chain saturated, straight or branched.This hydrocarbon chain preferably contains one to six carbon atom (C 1-6-alkyl), comprises amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl and isohexyl.In a preferred embodiment, alkyl is represented C 1-4-alkyl comprises butyl, isobutyl-, sec-butyl and the tertiary butyl.In another embodiment preferred of the present invention, alkyl is represented C 1-3-alkyl, it can be methyl, ethyl, propyl group or sec.-propyl especially.
In the context of the invention, alkenyl represents to contain the carbochain of one or more pair key, comprises two-alkene, three-alkene and many-alkene.In a preferred embodiment, alkenyl of the present invention contains two to six carbon atom (C 2-6-alkenyl), it comprises at least one two key.In a most preferred embodiment, alkenyl of the present invention is a vinyl; 1-propenyl or 2-propenyl; 1-butylene base, crotyl or 3-butenyl, or 1,3-butadiene base: 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl, or 1, the 3-hexadienyl, or 1,3,5-hexatriene base.
In the context of the invention, alkynyl represents to contain one or more triple-linked carbochain, comprises two-alkynes, three-alkynes and many-alkynes.In a preferred embodiment, alkynyl of the present invention contains two to six carbon atom (C 2-6-alkynyl), comprise at least one triple bond.In its most preferred embodiment, alkynyl of the present invention is an ethynyl; 1-proyl or 2-propynyl: ethyl acetylene base, 2-butyne base or 3-butynyl, or 1,3-diacetylene base; 1-pentynyl, valerylene base, 3-pentynyl, 4-pentynyl, or 1,3-pentadiine base; 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base or 5-hexin base, or 1,3-hexadiyne base, or 1,3, oneself three alkynyls of 5-.
In the context of the invention, cycloalkyl is represented a kind of cyclic alkyl, preferably contains three to seven carbon atom (C 3-7-cycloalkyl), comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.
Alkoxyl group is the O-alkyl, and alkyl wherein as defined above.
Cycloalkyloxy is the O-cycloalkyl, and cycloalkyl wherein as defined above.
Cycloalkylalkyl means aforesaid cycloalkyl and aforesaid alkyl, for example cyclopropyl methyl of anticipating promptly.
Amino is NH 2Or NH-alkyl or N-(alkyl) 2, alkyl wherein as defined above.
In the context of the invention, heteroaryl is represented aromatic monocyclic or bicyclic heterocyclic radical, and it contains one or more heteroatoms in its ring structure.Preferred heteroatoms comprises nitrogen (N), oxygen (O) and sulphur (S).
Preferred bicyclic heteroaryl of the present invention comprises aromatics 5-and 6-element heterocycle monocyclic groups, for example includes but not limited to  azoles base ( azoles-2-base,-4-base or-the 5-yl), different  azoles base (different  azoles-3-base,-4-base or-the 5-yl), thiazolyl (thiazol-2-yl,-4-base or-the 5-yl), isothiazolyl (isothiazole-3-base,-4-base or-the 5-yl), 1,2,4- di azoly (1,2,4- diazole-3-base or-the 5-yl), 1,2,4-thiadiazolyl group (1,2,4-thiadiazoles-3-base or-the 5-yl), 1,2,5- di azoly (1,2,5- diazole-3-base or-the 4-yl), 1,2,5-thiadiazolyl group (1,2,5-thiadiazoles-3-base or-the 4-yl), imidazolyl (2-, 4-or 5-imidazolyl), pyrryl (2-or 3-pyrryl), furyl (2-or 3-furyl), thienyl (2-or 3-thienyl), pyridyl (2-, 3-or 4-pyridyl), pyrimidyl (2-, 4-, 5-or 6-pyrimidyl), or pyridazinyl (3-or 4-pyridazinyl).
Preferred bicyclic heteroaryl of the present invention for example includes but not limited to, indolizine base (2-, 5-or 6-indolizine base), indyl (2-, 5-or 6-indyl), pseudoindoyl (2-, 5-or 6-pseudoindoyl), indazolyl (1-or 3-indazolyl), benzofuryl (2-, 5-or 6-benzofuryl), benzo [b] thienyl (2-, 5-or 6-benzothienyl), benzimidazolyl-(2-, 5-or 6-benzimidazolyl-), benzoxazol base (2-, 5-or 6-benzoxazol base), benzothiazolyl (2-, 5-or 6-benzothiazolyl), benzo [d] isothiazolyl (1,2-benzo [d] isothiazole-3-yl), purine radicals (2-or 8-purine radicals), quinolyl (2-, 3-, 6-, 7-or 8-quinolyl), isoquinolyl (1-, 3-, 5-, 6-or 7-isoquinolyl), cinnolines base (6-or 7-cinnolines base), phthalazinyl (6-or 7-phthalazinyl), quinazolyl (2-, 6-or 7-quinazolyl), quinoxalinyl (2-or 6-quinoxalinyl), 1,8-naphthyridinyl (1,8-naphthyridines-2-, 3-, 6-or 7-yl), pteridyl (2-, 6-or 7-pteridyl), and indenyl (1-, 2-, 3-, 5-or 5-indenyl).
Enantiomeric purity
In the context of the present invention, compound is that the pure compound that means of mapping surpasses its opposite enantiomer with the enantiomeric excess of at least 95.0% (w/w).In one embodiment, this mapping pure compound surpasses its opposite enantiomer with at least 97.0%, 98.0% or 99.0% enantiomeric excess.In another embodiment, this mapping pure compound surpasses its opposite enantiomer with at least 99.2%, 99.5% or 99.7% enantiomeric excess.In embodiment further, this mapping pure compound surpasses its opposite enantiomer with at least 99.90% or 99.95% enantiomeric excess.
The pharmacy acceptable salt class
The compounds of this invention can any suitable expection administration form provide.The form that is fit to comprises that the pharmacy (being physiology) of The compounds of this invention goes up acceptable salt and prodrug (predrug) or prodrug (prodrug) form.
The example of pharmaceutically acceptable addition salt class includes but not limited to: non-toxic inorganic and organic acid addition salt class, for example hydrochloride, hydrobromate, nitrate, perchlorate, phosphoric acid salt, vitriol, formate, acetate, aconate, ascorbate salt, benzene sulfonate, benzoate, cinnamate, Citrate trianion, embonate (embonate), enanthate (enantate), fumarate, glutaminate, oxyacetate, lactic acid salt, maleate, malonate, mandelate, mesylate, the naphthalene-2-sulfonic acid salt derivative, phthalate, salicylate, sorbate, stearate, succinate, tartrate, right-tosylate etc.Such salt can form by the method for knowing in this area and describing.
Other acids is oxalic acid for example, and it may not be considered to be pharmaceutically acceptable, but can be used in the preparation of salt, and described salt can be used as intermediate product in obtaining The compounds of this invention and pharmaceutically-acceptable acid addition thereof.
The example of the pharmaceutically acceptable positively charged ion salt of The compounds of this invention includes but not limited to: contain the sodium salt of the The compounds of this invention of anionic group, sylvite, calcium salt, magnesium salts, zinc salt, aluminium salt, lithium salts, choline salt, lysine salt and ammonium salt etc.Such positively charged ion salt can form by the method for knowing in this area and describing.
In the context of the invention, " the  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 of The compounds of this invention or prodrug form comprises the example of material appropriate drug precursor of the present invention, is included in adorned compound on one or more reactions of parent compound or the deriveding group.Making us compound of interest especially is adorned compound on carboxyl, hydroxyl or amino.The appropriate derivative example is ester or acid amides.
The compounds of this 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, with regard to the object of the invention, think that soluble form is equal to insoluble form.
Tagged compound
The compounds of this invention can its mark or the use of unlabelled form.In the context of the invention, this tagged compound has one or more atom, and described atom is had to be different from the atomic mass usually found at occurring in nature or the atomic mass of total mass number or the atom of total mass number and to replace.Described mark can make the easy detection by quantitative of this compound.
Tagged compound of the present invention can be used as diagnostic tool, radiotracer or the monitoring agent in the multiple diagnostic method, and can be used for the imaging of body inner recipient.
Labelled isomer of the present invention preferably comprises at least a radionuclide and serves as a mark.The radionuclide of emission positron is the use material standed for.In the context 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 labelled isomer of the present invention can be selected from positron emission tomography art (PET), single photon tomography computer tomography (SPECT), nuclear magnetic resonance spectroscopy method (MRS), nuclear magnetic resonance (MRI) and the axial x-ray tomography imaging of area of computer aided art (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 be easily by ordinary method by the chemical production that is available commercially.
Can also a kind of compound of the present invention be changed into another kind of compound of the present invention with ordinary method.
The end product of reaction described herein can pass through routine techniques, for example separates by extraction, crystallization, distillation, chromatogram etc.
Biological activity
Can test The compounds of this invention and suppress the ability of monoamine Dopamine HCL, norepinephrine and serotonin reuptake transporter in the synaptosome, as described in the WO97/30997.Based on observed equilibrium activity in these tests, consideration is used for the treatment of The compounds of this invention, prevent or alleviates Mammals, comprise people's disease, 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, the prevention or alleviate: mood disorder, depressed, the atypia depression, be secondary to the depression of pain, major depressive disorder, dysthymic disorder, bipolar disorder, I type bipolar disorder, II type bipolar disorder, the cyclicity emotional handicap, the mood disorder that causes by the general medicine illness, material inductive emotional handicap, 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, the distractibility hyperkinetic syndrome, fat, anxiety, generalized anxiety disorder, eating disorder, Parkinson's disease, Parkinson, dull-witted, old and feeble dementia, senile dementia, Alzheimer, the dull-witted complex of acquired immune deficiency syndrome (AIDS), aging memory machine dysfunction, specific phobias, social phobia, social anxiety disorder, nervous obstacle after the wound, acute nervous obstacle, drug habit, drug abuse, cocaine abuse, the nicotine abuse, tobacco abuse, alcohol addiction, alcoholism, the kleptomania, pain, chronic 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, mastectomy postoperative pain syndrome (PMPS), 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, irritated disease before the menstruation, the evening luteal phase syndrome, posttraumatic syndrome, chronic fatigue syndrome, the urinary incontinence, the pressure incontinence, urge incontinence, the incontinence at night, sexual dysfunction, premature ejaculation, it is difficult to erect, erective dysfunction, too early female orgasm, restless legs syndrome, Periodic limb movement disorder, eating disorder, anorexia nervosa, somnopathy, PDD, autism, the A Sibogeer obstacle, the special obstacle of thunder, childhood disintegrative disorder, the learning capacity forfeiture, motor skill disorder, mutism, trichotillomania, hypnolepsy, the apoplexy retarded depression, apoplexy inductive cerebral lesion, infringement of apoplexy inductive neurone or Ji Ledelatulei syndrome.In a preferred embodiment, consideration is used for the treatment of this compound, prevent or alleviates depression.
The suitable dosage range of expection active pharmaceutical ingredient (API) is about 0.1 to about 1000mg API/ day at present, more preferably about 10 to about 500mg API/ days, most preferably about 30 to about 100mg API/ days, but depend on the indication, patient of definite administering mode, its form of medication, consideration and particularly related patient's body weight, and further, attending doctor or animal doctor's preference and experience.
Preferred The compounds of this invention shows the biological activity of sub-micro mole and micro-molar range, promptly less than 1 to about 100 μ M.
Pharmaceutical composition
In one aspect of the method, the invention provides the novel pharmaceutical combination thing, it comprises the The compounds of this invention for the treatment of significant quantity.
Although the form administration that the The compounds of this invention that is used for the treatment of can starting compound, but preferably with activeconstituents, randomly with the form of physiologically acceptable salt, introducing with one or more assistant agents, vehicle, carrier, buffer reagent, thinner and/or other conventional excipient substance becomes pharmaceutical composition.
In preferred embodiments, the invention provides pharmaceutical composition, it comprises The compounds of this invention or its pharmacy acceptable salt or derivative and one or more pharmaceutically acceptable carriers and therapeutic and/or preventative composition randomly known in the art with other and that use and mixes.This carrier must be " acceptable ", promptly with preparation in other composition compatible and can be harmful to its recipient.
Pharmaceutical composition of the present invention can be those pharmaceutical compositions that are suitable for oral, rectum, segmental bronchus, nose, lung, part (comprising in the cheek and the hypogloeeis), transdermal, vagina or parenteral (comprise in skin, subcutaneous, intramuscular, intraperitoneal, intravenously, intra-arterial, the brain, intraocular injection or infusion) administration, or those are adapted to pass through the forms that suck or be blown into administration, comprise powder and liquid aerosol drug delivery or the pharmaceutical composition by the slow-released system administration.The example of suitable slow-released system comprises the semi-permeable matrix of the solid hydrophobic polymkeric substance that contains The compounds of this invention, and this matrix can be the formed article form, for example film or micro-capsule.
Therefore compound of the present invention can be made the form of pharmaceutical composition and unitary dose thereof with assistant agent, carrier or the thinner of routine.Such form comprises solid, and the especially form and the liquid of tablet, filled capsules, powder and pill, especially the capsule of the aqueous solution or non-aqueous solution, suspension, emulsion, elixir and the above-mentioned form of filling, the suppository that all these forms all is used for is oral, be used for rectal administration and be used for parenteral sterile injectable solution.Such pharmaceutical composition and unit dosage form thereof can comprise conventional ratio conventional ingredient, contain or do not conform to other active compound or composition, and such unit dosage form can contain the activeconstituents with the suitable any suitable effective amount of expection application dose scope every day.
The compounds of this invention can various oral and parenteral dosage form administrations.For a person skilled in the art, it is evident that following formulation can comprise The compounds of this invention or the The compounds of this invention pharmacy acceptable salt as activeconstituents.
For from the The compounds of this invention pharmaceutical compositions, pharmaceutically acceptable carrier can be solid or liquid.The preparation of solid form comprises powder, tablet, pill, capsule, cachet, suppository and dispersible granules agent.Solid carrier can be one or more materials that can also play thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, sanitas, tablet disintegrant or coating material effect.
In powder agent, carrier is a fine-grained solids, and it mixes with the particulate active ingredient.
In tablet, activeconstituents mixes in the proper ratio with the carrier with necessary binding capacity and is compressed into required shape and size.
Powder agent and tablet preferably contain 5% or 10% to about 70% active compound.Suitable carriers is magnesiumcarbonate, Magnesium Stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Active compound and formulation as the coating material of carrier desired to comprise in term " preparation ", and described coating material provides capsule, wherein contains or carrier-free activeconstituents suppressed by vector surrounds, and carrier combines with active compound thus.Similarly, also comprise cachet and lozenge.Tablet, powder agent, capsule, pill, cachet and lozenge can be as the solid forms that is suitable for oral administration.
In order to prepare suppository, at first with low-melting wax, as the mixture melt of glycerin fatty acid ester or theobroma oil, by stirring activeconstituents is evenly dispersed in wherein then.In the suitable big or small mould of the uniform mixture impouring that will melt then, make its cooling and curing thus.
The composition that is suitable for vagina administration can vaginal suppository, the form of tampon, ointment, gelifying agent, paste, foam or sprays exists, and described composition also contains suitable carriers known in the art except that containing activeconstituents.
Liquid preparation comprises solution, suspension and emulsion, for example, and the aqueous solution or water-propylene glycol solution.For example, the parenteral injection liquid preparation can be mixed with the solution of moisture polyoxyethylene glycol.
Therefore, The compounds of this invention can be mixed with and be used for administered parenterally (for example injection, as inject or continuous infusion) preparation, and can provide with the unit dosage form of ampoule, pre-filled syringe, small volume transfusion or with multi-dose container with the sanitas that adds.Said composition can be taked the form of suspension, solution or the emulsion of oiliness or aqueous carrier, and can contain the preparation composition, as suspension agent, stablizer and/or dispersion agent.In addition, activeconstituents can be a powder type, and the aseptic separation by sterile solid or obtain by the solution freeze-drying is used for before use preparing with suitable carriers such as aseptic, pyrogen-free water.
The aqueous solution that is suitable for orally using can prepare by solubilization of active ingredient is also added suitable tinting material, seasonings, stablizer and thickening material as required in water.
The aqeous suspension that is suitable for orally using can contain viscous substance by the particulate active ingredient is dispersed in, as natural or synthetic is gummy, prepare in the water of resin, methylcellulose gum, Xylo-Mucine or other known suspension agent.
Also comprise the solid form preparation of desiring before facing usefulness, to be converted into the liquid form preparation that is used for oral administration.Such liquid form comprises solution, suspension and emulsion.Except that active ingredient, such preparation can comprise tinting material, seasonings, stablizer, buffer reagent, artificial and natural sweeting agent, dispersion agent, thickening material, solubilizing agent etc.
In order to locally apply to epidermis, The compounds of this invention can be mixed with ointment, creme, or lotion, or transdermal patch.For example, ointment and creme can add suitable thickening and/or jelling agent is formulated with water-based or oleaginous base.Lotion can be formulated with water-based or oleaginous base, and also contain one or more emulsifying agents, stablizer, dispersion agent, suspension agent, thickening material or tinting material usually.
Be suitable for that topical drug delivery composition is included in flavoured base in the oral cavity, be generally the lozenge that comprises activeconstituents in sucrose and kordofan gum or the tragacanth gum; The pastille (pastilles) that comprises activeconstituents at inert base, as gelatin and glycerine or sucrose and kordofan gum; And the mouth wash shua that in suitable liquid vehicle, comprises activeconstituents.
Solution or suspension for example can be applied directly to nasal cavity with dropper, suction pipe or atomizer with ordinary method.Said composition can single dose or the form of multiple doses provide.
Respiratory tract administration also can be realized by aerosol, wherein activeconstituents provides in pressurized package with suitable propelling agent, suitable propelling agent comprises chlorofluorocarbon (CFC) for example Refrigerant 12, trichlorofluoromethane or dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas.Aerosol also can suitably contain tensio-active agent such as Yelkin TTS.The dosage of medicine can be by being equipped with metering valve control.
Perhaps, activeconstituents can provide by dry powder form, for example the powdered mixture of compound in suitable powder matrix such as lactose, starch, starch derivative such as Vltra tears and polyvinylpyrrolidone (PVP).Easily, powder carrier will form gel at nasal cavity.Powder composition can present by unit dosage form, for example with capsule or cartridge case (as the capsule or the cartridge case of gelatin) form, or can be by the sucker Blister Package form of administration therefrom with powder.
Comprise intranasal compositions at the composition of desiring to be used for respiratory tract administration, compound has little particle diameter usually, for example is 5 microns or the littler order of magnitude.Such particle diameter can be by methods known in the art, for example obtain by micronization.
When needing, can use the composition that is fit to provide the activeconstituents slowly-releasing.
Pharmaceutical preparation is preferably unit dosage form.In this class form, preparation is subdivided into the unitary dose that contains an amount of active ingredient.Unit dosage form can be the preparation of packing, and this packing contains the preparation of discrete amount, as tablet, the capsule of packing, and the powder in bottle or the ampoule.In addition, unit dosage form can be capsule, tablet, cachet or a lozenge itself, maybe can be the packaged form that is fit to any of these formulation of quantity.
The tablet or the capsule that are used for oral administration are preferred compositions with the liquid and the continuous infusion liquid that are used for intravenously administrable.
About the more detailed data of preparation and medicine-feeding technology can (Maack PublishingCo.Easton finds on PA) at the Reminaton ' of latest edition s Pharmaceutical Sciences.
The treatment effective dose refers to the amount of activeconstituents, and it can improve symptom or symptom.Treatment effectiveness and toxicity, for example ED 50And LD 50Can in cell culture or laboratory animal, be measured by standard pharmacology program.But the dosage between result of treatment and the toxic action is than being therapeutic index and passing ratio LD 50/ ED 50Expression.Preferably show the pharmaceutical composition of big therapeutic index.
The dosage that gives certainly must be at age, body weight and the illness of the individuality of being treated, and route of administration, dosage form and dosage regimen, and the result of expectation and adjusting carefully, and definite dosage should be determined by the doctor certainly.
Actual dosage depends on the character and the severity of the disease for the treatment of, and within doctor's determination range, can be according to the present invention particular case the reaction of dosage is changed, to produce required result of treatment.Yet expection at present contains from about 0.1 to about 500mg, preferably from about 1 to about 100mg, more preferably the pharmaceutical composition from about activeconstituents of 1 to about 10mg/single dosage is suitable for therapeutic treatment.
Activeconstituents can every day one or several doses give.In some cases, can obtain gratifying result with the dosage that is low to moderate 0.1 μ g/ kilogram (intravenously) and 1 μ g/ kilogram (oral).Think that at present the upper limit of dosage range is about 10mg/ kilogram (intravenously) and 100mg/ kilogram (oral).Preferable range is from about 0.1 μ g/ kilogram to about 10mg/ kilogram/day (intravenously), and from about 1 μ g/ kilogram to about 100mg/ kilogram/day (oral).
Methods of treatment
In one aspect of the method, the invention provides treatment, prevent or alleviate the disease that animal body alive comprises the people, the method of obstacle or illness, this disease wherein, obstacle or illness are replied for the inhibition of monoamine neurotransmitter re-uptake in the central nervous system, and this method comprise the work that these needs are arranged animal body, comprise the The compounds of this invention of human significant quantity.
Expection at present, suitable dosage range is that every day 0.1 is to 1000mg, every day 10 is to 500mg, and particularly every day 30-100mg, depend on definite administering mode usually, form of medication, administration at indication, related patient and related patient's body weight, and further, doctor or animal doctor's preference and experience.
Brief Description Of Drawings
The present invention is further by explaining with reference to the diagram of enclosing, wherein:
Fig. 1 shows the separating of two kinds of enantiomers of 3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] oct-2-ene will be labeled as A and B.
Fraction A that Fig. 2 a and 2b explanation obtains through chromatogram and the purity of B.
Embodiment
Further specify the present invention with reference to the following example, but these embodiment have no intention to limit by any way the desired scope of the invention.
Embodiment 1
Synthesizing of (±)-3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] oct-2-ene
This racemoid is according to WO02/30405 (NeuroSearch A/S), the step synthetic of method D.
Embodiment 2
The separation of two kinds of enantiomers of 3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] oct-2-ene
Analysis HPLC
With HPLC two kinds of enantiomers (A of mark and B) are separated under the following conditions:
Post: CHIRALCEL ROD-H, 4.6cm * 250mm
Temperature: normal temperature
Flow velocity: 0.5ml/min
Volume injected: 20 microlitres
UV detects: 290nm
Moving phase: ethanol: normal hexane (10: 90, v/v)
Representational tomographic map as shown in Figure 1.
Preparation HPLC
Utilize chromatographiccondition described above isolating enantiomer to be collected in the Erlenmeyer flask with manual mode.
The racemoid stock solution of 250 microlitres (0.45 mg/ml) is expelled on the post.During six continuous injections, collect fraction A and B, obtain every kind of enantiomer of 0.34 milligram of theoretical amount.
The purity of fraction A and B illustrates in the chromatogram mode in Fig. 2.
Embodiment 3
Synthesizing of (+) and (-)-3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] oct-2-ene and derivative thereof
General method:
The reaction that all relates to airsensitive reagent or intermediate all is to carry out in nitrogen and non-aqueous solvent.In post-processing step, use sal epsom as siccative, then solvent removed by evaporation at reduced pressure.
The chiral purity of product is to analyze with following HPLC method:
Post: ChromTech Chiral-AGP, 100 * 4.6mm, 5 microns.Temperature: 25 ℃.Flow velocity: 0.9 ml/min.Volume injected: 10 microlitres.Detect: UV290nm.Moving phase: contain the 5mM sodium acetate buffer of 3%v/v acetonitrile, pH5.0.
Method A
(+)-3-(2-benzothienyl)-8-H-8-azabicyclo [3.2.1] oct-2-ene hydrochloride
At room temperature with (-)-3-(2-benzothienyl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene (1.72 grams, 6.7 mmoles), chloroformic acid 2,2,2-trifluoro ethyl ester (2.8 milliliters, 20.1 mmoles) and toluene (50 milliliters) stirred 30 minutes.Mixture was stirred 15 hours at 90 ℃.Add water (50 milliliters) and with mixture stirring at room 30 minutes.Separate organic phase and wash (2 * 20 milliliters) with water.With ether (50 milliliters) water is extracted.The organic phase that evaporation merges.Add zinc powder (2.5 grams, 38.2 mmoles), acetate (60 milliliters) and water (20 milliliters), then stirred 15 hours.Make mixture become alkalescence by adding ice (50 gram) and strong aqua (60 milliliters), follow with methylene dichloride (2 * 30 milliliters) and extract and evaporate.(1ml 4M) precipitates hydrochloride from ether (10 milliliters) to be dissolved in alcoholic acid hydrochloric acid by interpolation.(0.5 milliliter, mixture 4M) makes crystalline product recrystallization, productive rate 0.50 gram (2 7%) from water (100 milliliters) and hydrochloric acid.Specific rotation (free alkali): [α] D 25=(+)-24.9 °.Chirality HPLC:(+) 97.76% and (-) 2.2%.Mp＞300℃。
(-)-3-(2-benzothienyl)-8-H-8-azabicyclo [3.2.1] oct-2-ene free alkali
Prepare productive rate 39% from (+)-3-(2-benzothienyl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene according to method A.Mp88.9-91.6℃。Chirality HPLC:(-) 98.1% and (+) 1.9%.Specific rotation (free alkali): [α] D 25=(-)-22.1 °.Mp90℃。
(-)-3-(2-benzothienyl)-8-H-8-azabicyclo [3,2.11 oct-2-ene hydrochlorides
Prepare productive rate 39% from (+)-3-(2-benzothienyl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene according to method A.Mp＞300 ℃, chirality HPIC:(-) 98.1% and (+) 1.9%.
(-)-3-(2-benzothienyl)-8-H-8-azabicyclo [3.2.1] oct-2-ene vitriol
The sulfuric acid (0.12 gram, 1.25 mmoles) that will be dissolved in ethanol (5 milliliters) adds in the mixture of (-)-3-(2-benzothienyl)-8-H-8-azabicyclo [3.2.1] oct-2-ene (0.30 gram, 1.25 mmoles) and ethanol (20 milliliters).Sedimentary mixture refluxed stir, the clarification that becomes of this mixture.At 5 ℃, make this mixture precipitation during 15 hours.Filtering precipitate and with the flushing of ethanol and ether.Productive rate 0.30 gram (71%).Mp220-290℃。
(-)-3-(2-benzothienyl)-8-H-8-azabicyclo [3.2.1] oct-2-ene Citrate trianion
The mixture of (-)-3-(2-benzothienyl)-8-H-8-azabicyclo [3.2.1] oct-2-ene (0.30 gram, 1.25 mmoles) and citric acid (0.24 gram, 1.25 mmoles) and water (15 milliliters) stirring and this mixture under backflow are become clarification.Make mixture during 15 hours in the precipitation.Filtering precipitate and washing with water.Productive rate 0.20 gram (37%), Mp60-100 ℃.
(-)-3-(2-benzothienyl)-8-H-8-azabicyclo [3.2.1] oct-2-ene L-(+)-tartrate
With (-)-3-(2-benzothienyl)-8-H-8-azabicyclo [3.2.1] oct-2-ene (0.30 gram, 1.25 mmole) and L-(+)-tartrate (0.19 the gram, 1.25 mmole) and the mixture of ethanol (20 milliliters, 96%) under refluxing, stir, this mixture becomes clarification.Make under 5 ℃ mixture during 15 hours in the precipitation.Filtering precipitate and with the washing of ethanol and ether.Productive rate 0.44 gram (90%), Mp219 ℃.
(-)-3-(2-benzothienyl)-8-H-8-azabicyclo [3.2.1] oct-2-ene fumarate
With (-)-3-(2-benzothienyl)-8-H-8-azabicyclo [3.2.1] oct-2-ene (0.30 gram, 1.25 mmole) and fumaric acid (0.14 the gram, 1.25 mmole) and the mixture of ethanol (20 milliliters, 96%) under refluxing, stir, this mixture becomes clarification.Make under 5 ℃ mixture during 15 hours in the precipitation.Filtering precipitate and with the washing of ethanol and ether.Productive rate 0.36 gram (81%), Mp208 ℃.
(-)-3-(2-benzothienyl)-8-H-8-azabicyclo [3.2.1] oct-2-ene acetate
With the mixture of (-)-3-(2-benzothienyl)-8-H-8-azabicyclo [3.2.1] oct-2-ene (0.30 gram, 1.25 mmoles) and acetate (0.14 restrains 1.25 mmoles) and ethanol (10 milliliters, 96%) through being mixed into clear soln.Make mixture slowly be evaporated to 1 milliliter.Filtering precipitate and with the washing of ethanol and ether.Productive rate 0.31 gram (82%), Mp177 ℃.
(+)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1) oct-2-ene D-tartrate
Prepare from (-)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-methyl-8-azepine two dicyclos [3.2.1] oct-2-ene according to method A.Mp186-195℃。
(-)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1] oct-2-ene L-tartrate
Prepare from (+)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene according to method A.Mp192.7-195.8℃。
(-)-3-(7-chloro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1] oct-2-ene L-tartrate
Prepare from (+)-3-(7-chloro-benzo [b] thiophene-2-yl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene according to method A.Mp200.1-207.2℃。
Method B
(-)-3-(2-benzothienyl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene D-tartrate
With (-)-8-methyl-3-(trifluoromethyl sulfonyloxy)-8-azabicyclo [3.2.1] oct-2-ene (4.64 grams, 17.1 mmole), 1,2-glycol dimethyl ether (100 milliliters), boric acid 2-benzothiophene ester (4.5 grams, 25 mmoles), salt of wormwood (9.2 grams, 66.6 mmole), fed argon gas bubbles 10 minutes in the mixture of lithium chloride (2.0 grams, 47.2 mmoles) and water (50 milliliters).Add Pd (PPh 3) 4 (0.17 gram, 0.13 mmoles), then refluxed 45 minutes.Make the mixture cool to room temperature.Adding water (100 milliliters) then extracts with ether (2 * 50 milliliters).Water (2 * 50 milliliters) washing organic phase.Make the dry and evaporation of organic phase.The hydrochloric acid (4M) that is dissolved in ethanol (5 milliliters, 96%) by interpolation makes the hydrochloride precipitation.Add water (50 milliliters) and strong aqua (50 milliliters) and then extract generation free alkali (4.09 grams, 100% derives from this salt) [α] with methylene dichloride (2 * 50 milliliters) D 25=(-)-46.3 °.Prepare tartrate by adding the free alkali and ethanol (96%) mixture of D-tartrate (2.4 grams, 16 mmoles) under refluxing.Make mixture cool overnight and filtering separation.Productive rate 5.06 grams (12.47 mmole), chirality HPLC (-) 94.9% and (+) 5.1%.4.85 gram (11.9 mmole) recrystallization from ethanol (150 milliliters, 96%) obtains 3.26 grams (8.0 mmole), chirality HPLC (-) 97.9% and (+) 2.1%.Mp67.6-76.0℃。
(+)-3-(2-benzothienyl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene L-tartrate
Prepare from (+)-8-methyl-3-(trifluoromethyl sulfonyloxy)-8-azabicyclo [3.2.1] oct-2-ene according to method B.Be transformed into free alkali, [α] behind the recrystallization for the first time D 25=(+)-53.3 °.Chirality HPLC (+) 98.3% and (-) 1.7%.Mp66.2-73.6℃。
(+)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene hydrochloride
Prepare from (+)-8-methyl-3-(trifluoromethyl sulfonyloxy)-8-azabicyclo [3.2.1] oct-2-ene according to method B.Be transformed into free alkali, [α] behind the recrystallization for the first time D 25=(+)-45.3 °.Mp＞300℃。
(-)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene hydrochloride
Prepare from (-)-8-methyl-3-(trifluoromethyl sulfonyloxy)-8-azabicyclo [3.2.1] oct-2-ene according to method B.Be transformed into free alkali, [α] behind the recrystallization for the first time D 25=(-)-46.0 °.Mp287℃。
Method C
(-)-8-methyl-3-(trifluoromethyl sulfonyloxy)-8-azabicyclo [3.2.1] oct-2-ene
Under＜5 ℃, to [S-(R*, R*)] (-)-two-Alpha-Methyl benzylamine hydrochloride ([α] that is stirring D 25=(-)-73.2 °) the mixture interpolation butyllithium of (86.5 grams, 0.33 mole) and tetrahydrofuran (THF) (1000 milliliters) (264 milliliters, 2.5M).Under 0 ℃, mixture was stirred 1 hour.Mixture is cooled to-70 ℃ and during 90 minutes in the tropinone (41.8 grams, 0.3 mole) that adds to be dissolved in the tetrahydrofuran (THF) (200 milliliters), stirred these mixtures three hours at-70 ℃.During 2 hours, will be dissolved in N-phenyl in the tetrahydrofuran (THF) (200 milliliters) two-fluoroform sulfimide (114.3 grams, 0.32 mole) adds in the mixture under＜70 ℃.Make this mixture through reaching ambient temperature overnight.Add water (3L) then with ether (2 * 1L) extractions.Water (2 * 1L) washing organic phases.Title product is separated with silica gel (1 kilogram) column chromatography with the crude mixture of Chiral Amine, used ethyl acetate at first so that the Chiral Amine wash-out is come out, and then with mixture (2: the 8) wash-out of methyl alcohol and methylene dichloride.This product is with 78% productive rate be separated (0.233 mole).
(+)-8-methyl-3-(trifluoromethyl sulfonyloxy)-8-azabicyclo [3.2.1] oct-2-ene
Utilize another kind of asymmetric amine [R-(R*, R*)] (+)-two-Alpha-Methyl benzylamine hydrochloride preparation, [α] according to method C D 25=(+)-73.8 °.

Claims (14)

1. the pure compound of the mapping of formula I:
Figure A2005800417530002C1
Or its pharmacy acceptable salt;
Wherein
R represents hydrogen or alkyl;
This alkyl is optional independently to be selected from following substituting group and to replace by one or more:
Halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, amino, nitro, alkoxyl group, cycloalkyloxy, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl and alkynyl; And
Q represents heteroaryl;
This heteroaryl is optional independently to be selected from following substituting group replacement by one or more:
Halogen, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, alkoxyl group, cycloalkyloxy, alkoxyalkyl, cycloalkyloxy alkyl, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl ,-NR ' R " ,-(C=O) NR ' R " or-(C=O) R of NR ' "
Wherein R ' and R " be hydrogen or alkyl independently of one another.
2. according to the compound of claim 1, wherein R represents hydrogen or alkyl.
3. according to the compound of claim 1 or 2, wherein Q represents benzothienyl.
4. according to the compound of claim 1 or 2, wherein Q represents the benzothienyl that halogen replaces.
5. according to the compound of claim 1, it is the mapping pure compound of 3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] oct-2-ene; Or its pharmacy acceptable salt.
6. according to the compound of claim 1, it is
3-(7-fluoro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1] oct-2-ene;
3-(7-chloro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1] oct-2-ene;
3-(2-benzothienyl)-8 methyl-8-azabicyclo [3.2.1] oct-2-ene;
3-(7-fluoro-benzo [b] thiophene-2-yl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene
The mapping pure compound;
Or its pharmacy acceptable salt.
7. according to the compound of claim 1, it is pure (+)-3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] oct-2-ene of mapping; Or its pharmacy acceptable salt.
8. according to the compound of claim 1, it is pure (-)-3-(2-benzothienyl)-8H-8-azabicyclo [3.2.1] oct-2-ene of mapping: or its pharmacy acceptable salt.
9. according to the compound of claim 1, it is
(+)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1] oct-2-ene that mapping is pure;
(-)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1] oct-2-ene that mapping is pure;
(-)-3-(7-chloro-benzo [b] thiophene-2-yl)-8-azabicyclo [3.2.1] oct-2-ene that mapping is pure:
(-)-3-(2-benzothienyl)-8 methyl-8-azabicyclo [3.2.1]-oct-2-ene that mapping is pure;
(+)-3-(2-benzothienyl)-8 methyl-8-azabicyclo [3.2.1]-oct-2-ene that mapping is pure;
(+)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene that mapping is pure;
(-)-3-(7-fluoro-benzo [b] thiophene-2-yl)-8-methyl-8-azabicyclo [3.2.1] oct-2-ene that mapping is pure;
Or its pharmacy acceptable salt.
10. pharmaceutical composition, it comprises each compound or its pharmacy acceptable salt of claim 1-9 for the treatment of significant quantity, and at least a pharmaceutically acceptable carrier, vehicle or thinner.
11. each compound or its pharmacy acceptable salt purposes of being used to prepare medicine of claim 1-9.
12. the purposes of claim 11 is used to prepare treatment, prevent or alleviate the mammiferous disease that comprises the people or the pharmaceutical composition of obstacle or illness, this disease, obstacle or illness are replied the inhibition of monoamine neurotransmitter re-uptake in the central nervous system.
13. according to the purposes of claim 11, this disease wherein, obstacle or illness are mood disorders, depressed, the atypia depression, be secondary to the depression of pain, major depressive disorder, dysthymic disorder, bipolar disorder, I type bipolar disorder, II type bipolar disorder, the cyclicity emotional handicap, the mood disorder that causes by the general medicine illness, material inductive emotional handicap, 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, the distractibility hyperkinetic syndrome, fat, anxiety, generalized anxiety disorder, eating disorder, Parkinson's disease, Parkinson, dull-witted, old and feeble dementia, senile dementia, Alzheimer, the dull-witted complex of acquired immune deficiency syndrome (AIDS), aging memory machine dysfunction, specific phobias, social phobia, social anxiety disorder, nervous obstacle after the wound, acute nervous obstacle, drug habit, drug abuse, cocaine abuse, the nicotine abuse, tobacco abuse, alcohol addiction, alcoholism, the kleptomania, pain, chronic 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, mastectomy postoperative pain syndrome (PMPS), 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, irritated disease before the menstruation, the evening luteal phase syndrome, posttraumatic syndrome, chronic fatigue syndrome, the urinary incontinence, the pressure incontinence, urge incontinence, the incontinence at night, sexual dysfunction, premature ejaculation, it is difficult to erect, erective dysfunction, too early female orgasm, restless legs syndrome, Periodic limb movement disorder, eating disorder, anorexia nervosa, somnopathy, PDD, autism, the A Sibogeer obstacle, the special obstacle of thunder, childhood disintegrative disorder, the learning capacity forfeiture, motor skill disorder, mutism, trichotillomania, hypnolepsy, the apoplexy retarded depression, apoplexy inductive cerebral lesion, infringement of apoplexy inductive neurone or Ji Ledelatulei syndrome.
14. treatment, prevent or alleviate the disease of animal body of the work that comprises the people or the method for obstacle or illness, this disease, obstacle or illness are replied for the inhibition of monoamine neurotransmitter re-uptake in the central nervous system, this method comprise the work that these needs are arranged animal body treatment significant quantity claim 1-9 each compound or the step of its pharmacy acceptable salt.
CNA2005800417536A 2004-12-17 2005-12-15 Enantiomers of 3-heteroaryl-8h-8-azabicyclo(3.2.1)oct-2-ene and their use as monoamine neurotransmitter re-uptake inhibitors Pending CN101072774A (en)

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