CN1705644A - Novel piperidine derivatives as monoamine neurotransmitter reuptake inhibitors and their use - Google Patents
Novel piperidine derivatives as monoamine neurotransmitter reuptake inhibitors and their use Download PDFInfo
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- CN1705644A CN1705644A CNA2003801013422A CN200380101342A CN1705644A CN 1705644 A CN1705644 A CN 1705644A CN A2003801013422 A CNA2003801013422 A CN A2003801013422A CN 200380101342 A CN200380101342 A CN 200380101342A CN 1705644 A CN1705644 A CN 1705644A
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Abstract
The present invention relates to novel piperidine derivatives which act as monoamine neurotransmitter re-uptake inhibitors. Other aspects of the invention relate to the use of these compounds in a method of treatment and to pharmaceutical compositions comprising the compounds of the invention.
Description
Technical field
The present invention relates to novel piperidine derivative as monoamine neurotransmitter re-uptake.
On the other hand, the present invention relates to the purposes of these compounds in a kind of methods of treatment and the pharmaceutical composition that comprises The compounds of this invention.
Background technology
People such as Petukhov [Petukhov PA, Zhang J, Kozikowski A P, Wang C Z, Ye Y P, Johnson K Mt Tella S R]; J.Med.Chem., 2002, the 45th phase, the 3161-3170 page or leaf was described the SAR research based on the piperidines analogs thing of Cocaine.
WO 00/20390 (Georgetown University) has described the purposes in monomer and dimer heterocycle and the treatment thereof.
WO 98/51668 (NeuroSearch A/S) has described the 3-alkoxyl group imido grpup methyl piperidine derivative as neurotransmitter re-uptake.Embodiment 1 and embodiment 2 have described two kinds of intermediate mixture (±)-suitable/anti--1-methyl-3-methoxycarbonyl-4-(3, the 4-dichlorophenyl)-piperidines and (±)-suitable/anti--1-methyl-3-hydroxymethyl-4-(3, the 4-dichlorophenyl)-piperidines.The pharmacology purposes of these two kinds of intermediate mixture is all not revealed.
Yet, with regard to monoamine neurotransmitter serotonin, Dopamine HCL, suprarenin re-uptake are active, find to have the optimizing biochemical characteristic compound of (as serotonin reuptake transporter with respect to suprarenin and the active ratio of Dopamine HCL) still had continue the intensive demand.
Further, for find structure and synthetic aspect with the irrelevant active compound of Cocaine the intensive demand is arranged.
The invention summary
In its first aspect, the invention provides the piperidine derivative of formula (I):
Or any mixture of any its isomer or its isomer or its pharmacy acceptable salt class,
R wherein
1, R
3And R
4Be defined as follows.
In its second aspect, the invention provides a kind of pharmaceutical composition, it comprises the The compounds of this invention for the treatment of significant quantity or any mixture or its pharmacy acceptable salt and at least a pharmaceutically acceptable carrier, vehicle or the thinner of any its isomer or its isomer.
Further, the invention provides the purposes that any mixture of The compounds of this invention or any its isomer or its isomer or its pharmacy acceptable salt are used to prepare treatment, prevent or alleviate the pharmaceutical composition of disease that Mammals comprises the people or obstacle or illness, this disease or obstacle or illness are replied monoamine neurotransmitter re-uptake restraining effect in the central nervous system.
Further on the one hand, the present invention relates to treat, prevent or alleviate moving object comprise people's the disease or the method for obstacle or illness, the monoamine neurotransmitter re-uptake restraining effect is replied in this disease or obstacle or the sick neural system, and this method comprises the The compounds of this invention of the moving object administering therapeutic significant quantity that these needs are arranged or any mixture or its pharmacy acceptable salt of any its isomer or its isomer.
Other purpose of the present invention to those skilled in the art will be more obvious from following detailed description and embodiment.
Detailed Description Of The Invention
Piperidine derivative
In its first aspect, the invention provides the piperidine derivative of formula (I):
Or any mixture of any its isomer or its isomer or its pharmacy acceptable salt class,
Wherein
R
1Represent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl; R
3Representative-C (=O)-O-R
cOr-CH
2-O-R
C
R wherein
cRepresent hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl;
R
4Representative
R wherein
aAnd R
bHalogen or the trifluoromethyl represented independently of one another;
Condition is that mixture of isomers is not
(±)-suitable/anti--1-methyl-3-methoxycarbonyl-4-(3, the 4-dichlorophenyl)-piperidines or
(±)-suitable/anti--1-methyl-3-hydroxymethyl-4-(3, the 4-dichlorophenyl)-piperidines.
In one embodiment, R
1Represent hydrogen or alkyl.
In second embodiment, R
aAnd R
bThe halogen of representing independently of one another.In a specific embodiment, R
aRepresent chlorine.In further embodiment, R
bRepresent chlorine.In embodiment further, R
aRepresent chlorine and R
bRepresent chlorine.
In further embodiment, R
3Representative-C (=O)-O-R
cIn further embodiment, R
3Representative-CH
2-O-R
c
In embodiment further, R
cRepresent hydrogen, alkyl or cycloalkyl alkyl.In further embodiment, R
cRepresent hydrogen or alkyl.In embodiment further, R
cRepresent the alkyl or cycloalkyl alkyl.In specific embodiment, R
cRepresent hydrogen.In further embodiment, R
cRepresent alkyl, as methyl or ethyl.In embodiment further, R
cThe representation ring alkyl alkyl is as the cyclopropyl methyl.
In the further embodiment of formula (I) compound,
R
1Represent hydrogen, alkyl or cycloalkyl;
R
cRepresent hydrogen or alkyl; And
R
aAnd R
bThe halogen of representing independently of one another.
In the further embodiment of formula (I) compound,
R
1Represent hydrogen or alkyl;
R
cRepresent hydrogen or alkyl; And
R
aAnd R
bThe halogen of representing independently of one another.
In the further embodiment of formula (I) compound,
R
1Represent hydrogen or alkyl;
R
3Representative-CH
2-O-R
c
R
cRepresent alkyl or cycloalkyl; And
R
aAnd R
bThe halogen of representing independently of one another.
In specific embodiment, compound of the present invention is
1-methyl-4-(3, the 4-dichlorophenyl)-piperidines-3-carboxylate methyl ester;
1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines;
1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines;
1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines;
1-methyl-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
1-methyl-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines;
3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines;
3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
Or any mixture of any its isomer or its isomer or its pharmacy acceptable salt.
In further specific examples, compound of the present invention is
(±)-suitable-1-methyl-4-(3, the 4-dichlorophenyl)-piperidines-3-carboxylate methyl ester;
(±)-anti--1-methyl-4-(3, the 4-dichlorophenyl)-piperidines-3-carboxylate methyl ester;
(±)-suitable-1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines;
(±)-anti--1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-suitable-1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-suitable-1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-anti--1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-anti--1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines;
(±)-suitable-1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(±)-suitable-1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines;
(±)-anti--1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(±)-anti--1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-suitable-1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-suitable-1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-suitable-1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-suitable-1-methyl-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-suitable-1-methyl-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-suitable-1-methyl-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-anti--1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-anti--1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-anti--1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-anti--1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-anti--1-methyl-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-anti--1-methyl-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-suitable-1-methyl-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-anti--1-methyl-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-anti--1-methyl-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-suitable-1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-suitable-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-suitable-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-suitable-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-suitable-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-suitable-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-suitable-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-anti--3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-anti--3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-anti--3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-anti--3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-anti--3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-anti--3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-suitable-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-suitable-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(+)-anti--3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
(-)-anti--3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines;
Or its pharmacy acceptable salt.
The combination of any two or more above-mentioned specific embodiments is considered among scope of the present invention.
Substituent definition
Hereinafter of the present invention, halogen is represented fluorine, chlorine, bromine or iodine.
In the context of the present invention, alkyl is meant the hydrocarbon chain of a monovalent saturated straight chain or side chain.This hydrocarbon chain preferably comprises from 1 to 6 carbon atom (C
1-6-alkyl), comprise amyl group, isopentyl, neo-pentyl, table amyl group, hexyl and isohexyl.In a preferred embodiment, alkyl represent C
1-4-alkyl comprises butyl, isobutyl-, sec-butyl and the tertiary butyl.In another preferred embodiment, alkyl represent C of the present invention
1-3-alkyl, it especially can be methyl, ethyl, propyl group or sec.-propyl.
In the context of the present invention, alkenyl is meant the carbochain that comprises one or more pairs of keys, and it comprises dienes, trienes or polyenoid class.In a preferred embodiment, alkenyl of the present invention comprises 2 to 6 carbon atom (C
2-6-alkenyl), comprise at least one two key.In the 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 1,3-hexadienyl or 1,3,5-hexatriene base.
In the context of the present invention, alkynyl is meant the carbochain that comprises one or more ginseng keys, and it comprises diine class, three alkynes classes or polyyne class.In a preferred embodiment, alkynyl of the present invention comprises 2 to 6 carbon atom (C
2-6-alkynyl), comprise at least one ginseng key.In the 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-.
In the context of the present invention, cycloalkyl means the cyclic alkyl, preferably comprises 3 to 7 carbon atom (C
3-7-cycloalkyl), comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.
Pharmacy acceptable salt
Any form that The compounds of this invention can be suitable for planning to use provides.Suitable form comprises pharmaceutically (that is on physiology) acceptable salt, and the prodrug forms of The compounds of this invention.
The example of pharmacy acceptable addition salt includes but not limited to nontoxic mineral acid and organic acid addition salt, as hydrochloride derived from hydrochloric acid, derived from hydrobromic hydrobromate, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphoric acid salt derived from phosphoric acid, derived from vitriolic vitriol, formate derived from formic acid, acetate derived from acetate, aconitate derived from equisetic acid, ascorbate salt derived from xitix, benzene sulfonate derived from Phenylsulfonic acid, derived from benzoic benzoate, cinnamate derived from styracin, Citrate trianion derived from citric acid, two hydrogen naphthoates derived from two hydrogen naphthoic acids, enanthate derived from enanthic acid, fumarate derived from fumaric acid, glutaminate derived from L-glutamic acid, glycollate derived from oxyacetic acid, derived from the lactic acid salt of lactic acid, derived from the maleate of toxilic acid, derived from the malonate of propanedioic acid, mandelate derived from amygdalic acid, derived from the mesylate of methylsulfonic acid, derived from the naphthalene-2-sulfonic acid salt of naphthalene-2-sulfonic acid, derived from the phthalate of phthalic acid, derived from salicylic salicylate, derived from the sorbate of Sorbic Acid, derived from stearic stearate, derived from the succinate of succsinic acid, derived from tartaric tartrate, derived from tosilate of tosic acid etc.This salt can form by method known in the art and that described.
Other acid are as oxalic acid, and it is acceptable not to be considered to pharmacy, but also can be used for preparing salt, and described salt can be used as the intermediate in acquisition The compounds of this invention and the acceptable acid salt process of pharmacy thereof.
The example of the pharmaceutically acceptable cationic salts of The compounds of this invention includes but not limited to comprise sodium salt, sylvite, calcium salt, magnesium salts, zinc salt, aluminium salt, lithium salts, choline salt, lysine salt and the ammonium salt etc. of the The compounds of this invention of anionic group.This kind cationic salts can borrow the method for having known in this area and having illustrated to form.
In about of the present invention, " salt " of nitrogenous compound estimates also to can be used as pharmacy acceptable salt.Preferably " salt " comprises alkyl salt, cycloalkyl salt and cycloalkylalkyl salt.
The example of the prodrug form of The compounds of this invention comprises the suitable prodrug of the material according to the present invention, but it is included in the compound of modifying on one or more activity of parent compound or the deriveding group.Making us interested especially is the compound of modifying on carboxyl, hydroxyl or amido.The example of suitable derivatives is ester class or amides.
The compounds of this invention can solubilized or undissolved form provide with a kind of pharmaceutically acceptable solvent such as water, ethanol etc.Soluble form also comprises hydrated form such as monohydrate, dihydrate, semihydrate, trihydrate, tetrahydrate etc.Usually, for the purposes of the present disclosure, soluble form is regarded as being equal to undissolved form.
Steric isomer
The compounds of this invention can (+) and (-) form and racemic form (±) existence.The racemoid of these isomer and each isomer itself are all within the scope of the invention.
Racemic form can be split as optically active enantiomorph by currently known methods and technology.A kind of method of separating diastereoisomeric salt is, by using the acid of optically active, and discharges the amine compound of optically active with alkaline purification.Another kind of is that the method for optically active enantiomorph is based on carry out chromatography on the matrix of optically active with racemate resolution.Racemic compound of the present invention like this can be split as its optically active enantiomorph, for example, and by fractional crystallization d-or 1-(tartrate, amygdalic acid or camphorsulfonic acid) salt.
Also can by with compound of the present invention with as by (+) or (-) phenylalanine, (+) or (-) phenylglycocoll, the activating carboxy acid of (+) or (-) dextrocamphoric acid deutero-optically active reacts and forms diastereomeric acid amides, and perhaps the diastereomeric carbamate of reactions such as chloro-formic ester formation with compound of the present invention and optically active splits compound of the present invention.
The additive method that splits optically active isomer is well known in the art.These methods comprise the J by Jaques, and Collet A and Wilen S be at " Enantiomers, Racemates, andResolutions ", John Wiley and Sons, the method described in New York (1981).The compound that also can prepare optically active by the initiator of optically active.
And configuration that The compounds of this invention can be suitable or anti-and composition thereof exists.The R of the piperidines skeleton of formula (I)
3Substituting group and R
4Substituting group especially with cis or transconfiguration toward each other.In one embodiment of the invention, R
3And R
4Substituting group is transconfiguration.In another embodiment of the invention, R
3And R
4Substituting group is cis-configuration.The present invention includes all this isomer and any its mixture, comprise racemic mixture.
The compound of mark
Compound of the present invention can it use through form mark or un-marked.In the context of the present invention, " mark " representative is attached to marker on the compound of interest, thereby detection by quantitative goes out this compound easily.
The compounds of this invention through mark can be used as diagnostic tool, radiotracer or monitor agent among many diagnostic methods, and is used for the imaging of body inner recipient.
The present invention preferably comprises at least a radionuclide thing that serves as a mark through the isomer of mark.The radionuclide of emission positron is the candidate of use.In the context of the present invention, radionuclide is preferably selected from
2H (deuterium),
3H (deuterium),
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: the photography of positron emitter layer (PET), single photon emission tomography computer layer radiography (SPECT), NMR (Nuclear Magnetic Resonance) spectrum (MRS), Magnetic resonance imaging (MRI) and axial as calculated X-tomography X (CAT) or its combination.
The preparation method
The compounds of this invention can prepare by conventional chemical synthesis process, and is for example illustrated in operational instances.In this application the starting raw material of described method be known maybe can be by ordinary method from the preparation of the chemical substance that can buy.
Simultaneously, The compounds of this invention can utilize ordinary method to be converted into another kind of compound of the present invention.
Reacting final product described herein can be separated by the technology of routine, for example: extraction, crystallization, distillation, chromatography etc.
Biological activity
Compound of the present invention can be tested it suppresses monoamine Dopamine HCL, suprarenin, serotonin reuptake transporter in synaptosome ability according to the method for the description among the WO97/30997 for example.
Therefore further, test viewed equilibrium activity according to these, The compounds of this invention is considered to can be used for treatment, prevents or alleviate Mammals to comprise Human diseases or obstacle or illness that described disease or obstacle or illness suppress to reply to monoamine neurotransmitter re-uptake in the central nervous system.
In embodiment, compound of the present invention is considered to can be used for treatment, prevention or alleviate emotional handicap, dysthymia disorders, the atypia dysthymia disorders, major depressive disorder, depression, the bipolarity obstacle, I type bipolarity obstacle, II type bipolarity obstacle, hot-tempered strongly fragrant cyclothymia obstacle, because the emotional handicap that the general medicine situation is caused, the emotional handicap that material brings out, pseudodementia, Ganser's syndrome, obsessional idea and behavior disorder, Phobias, do not have a Phobias of agoraphobia, Phobias with agoraphobia, do not have an agoraphobia of Phobias medical history, panic attack, hypomnesis, the loss of memory, the attention-deficient Attention Deficit Hyperactivity Disorder, fat, anxiety disorder, general anxiety disease, eating disorder, Parkinsonism, the Ba Jinsen Cotard, dementia, aging dementia, senile dementia, alzheimer's disease, the dull-witted complication of acquired immune deficiency syndrome (AIDS), aging memory dysfunction, social phobia, posttraumatic stress disorder, acute stress disorder, 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 related with dysthymia disorders, fibromyalgia, sacroiliitis, osteoarthritis, rheumatoid arthritis, back pain, cancer pain, irritable bowel pain, irritable intestine syndrome, postoperative pain, pain after the apoplexy, drug-induced DPN, the DPN of diabetes-induced, sympathetic nerve is kept pain, trigeminal neuralgia, toothache, muscular fascia pain, phantom limb pain, disease of eating too much at one meal, premenstrual tension syndrome, 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, epilation disease, narcolepsy, apoplexy retarded depression disease, the brain injury that apoplexy is brought out, neuronal damage that apoplexy is brought out or Tu Leiteshi disease (Gilles de la Tourettes disease).In preferred embodiment, this compound is considered to can be used for treatment, prevents or alleviates dysthymia disorders.
At present the suitable dosage of the active medical components (API) of expection about 0.1 to the scope of about 1000 milligrams of API/ every days, be more preferably about 10 to about 500 milligrams of API/ every days, most preferably be about 30 to about 100 milligrams of API/ every days, yet depend on definite method of application, this API form of administration, at the body weight of symptom, subject and especially related object, also have the doctor that is responsible for or animal doctor's preference and experience.
The preferred compound of the present invention shows its biological activity in the scope of inferior micro-molar concentration and micro-molar concentration (μ M), promptly from being lower than 1 to about 100 μ M.
Pharmaceutical composition
On the other hand, the invention provides the novel pharmaceutical combination thing, comprise the The compounds of this invention for the treatment of significant quantity.
Although the The compounds of this invention that is used for the treatment of can be given birth to the form administration of product with compound, preferably activeconstituents (being chosen as the form of acceptable salt on the physiology) is made pharmaceutical composition with one or more auxiliarys, vehicle, carrier, buffer reagent, thinner and/or other habitual pharmaceutical auxiliary agents.
In preferred embodiment, 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 optional other treatment and/or preventative composition, these all are known in the art and used.Carrier with preparation in other compositions compatible and to the harmless meaning of its recipient on must be " acceptable ".
Pharmaceutical composition of the present invention can be to be suitable for those of oral, rectum, segmental bronchus, nose, lung, part (comprising oral cavity and hypogloeeis), transdermal, vagina or parenteral (comprise in skin, subcutaneous, intramuscular, intraperitoneal, intravenously, intra-arterial, the brain, intraocular injection or infusion) administration, perhaps be suitable for sucking or be blown into those of administration, comprise pulvis and liquid aersol, perhaps by the sustained release system administration.The suitable example of sustained release system comprises the semipermeability matrix of the solid hydrophobic polymkeric substance that contains The compounds of this invention, and this matrix can be the form of molding, for example film or micro-capsule.
The compounds of this invention and conventional auxiliary agent, carrier or thinner thereby can be made into the form of pharmaceutical composition and dosage unit thereof.This class form comprises solid, and particularly tablet, filled capsules, powder and particle form, and liquid, particularly water-based or non-aqueous solution, suspension, emulsion, elixir and be filled with their capsule all are to orally use; Rectal administration suppository; With the parenteral sterile injectable solution.This class pharmaceutical composition and unit dosage form thereof can comprise the conventional ingredient of conventional ratio, and or do not have other active compounds or a composition, this class unit dosage form can contain the effective amount of actives that is fit to arbitrarily, matches with dosage range every day that is adopted.
The compounds of this invention can be in administration in the oral and parenteral dosage forms widely.It is evident that to those skilled in the art following dosage forms can comprise the pharmacy acceptable salt of The compounds of this invention or The compounds of this invention as active ingredient.
With regard to regard to the The compounds of this invention pharmaceutical compositions, pharmaceutically acceptable carrier can be solid or liquid.But the solid form prepared product comprises pulvis, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one or more materials, and it also can serve as thinner, correctives, solubilizing agent, lubricant, suspension agent, tackiness agent, sanitas, tablet disintegrant or encapsulating material.
In pulvis, carrier is the solid of fine pulverizing, and it is the mixture with the active ingredient of fine pulverizing.
In tablet, active ingredient and carrier with necessary adhesive capacity by suitable mixed, are pressed into desired shape and size again.
Pulvis and tablet preferably contain 5 percent or ten to about 70 active compound.The carrier that is fit to is magnesiumcarbonate, Magnesium Stearate, talcum, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Active compound and preparation as the encapsulating material of carrier planned to comprise in term " prepared product ", obtains a kind of capsule, wherein active ingredient and or do not have carrier to be surrounded by a kind of carrier, thereby associate with it.Similarly, comprise cachet and lozenge.Tablet, pulvis, capsule, pill, cachet and lozenge can be as the solid dosages that is suitable for oral administration.
With regard to preparation suppository, at first melt low melt wax, for example fatty glyceride mixt or theobroma oil are again along with stirring with the active ingredient homodisperse wherein.The uniform mixture that will melt is then poured in the mould of suitable size, cooling, thus solidify.
The pharmaceutical composition that is suitable for vagina administration can be vaginal suppository, tampon, creme, gel, paste, foam or sprays, takes the circumstances into consideration to contain carrier known in the art except activeconstituents.
The liquid prepared product comprises solution, suspension and emulsion, for example water or water-propylene glycol solution.For example, parenteral solution for injection body prepared product can be formulated into the solution in moisture polyglycol solution.
According to compound of the present invention thereby can be formulated into administered parenterally (for example the injection, for example bolus is injected or continuous infusion), can be the presented in unit dosage form in ampoule, pre-filled syringe, small volume infusion device or multi-dose container, wherein adding has sanitas.Composition can be taked suspension, solution or the emulsion form in oiliness or aqueous carrier, can contain preparaton, for example suspension agent, stablizer and/or dispersion agent.Select as an alternative, activeconstituents can be a form of powder, gets by the degerming separation of sterile solid or the lyophilize of solution, before use with the carrier regeneration that is fit to, for example aseptic pyrogen-free water.
The aqueous solution that is suitable for orally using can prepare like this, and active ingredient is water-soluble, adds tinting material, correctives, stablizer and the thickening material that is fit to as required.
The aqueous suspensions that is suitable for orally using can prepare like this, and the active ingredient of fine pulverizing is dispersed in the water, wherein contains cohesive material, for example natural or synthetic gum, resin, methylcellulose gum, Xylo-Mucine or other suspension agents of knowing.
The prepared product that also comprises solid form is used for being converted into soon before use oral administration liquid form prepared product.This class I liquid I form comprises solution, suspension and emulsion.Except active ingredient, this class prepared product can also comprise tinting material, correctives, stablizer, buffer reagent, artificial and natural sweeteners, dispersion agent, thickening material, solubilizing agent etc.
With regard to the epidermis topical, The compounds of this invention can be formulated into ointment, creme or lotion, perhaps transdermal patch.Ointment and creme for example can use or oleaginous base preparation, wherein suitable thickening material and/or the jelling agents of adding.Lotion can use or the oleaginous base preparation, generally also will contain one or more emulsifying agents, stablizer, dispersion agent, suspension agent, thickening material or tinting material.
Be suitable for a mouthful interior topical drug delivery composition and comprise lozenge, comprising activeconstituents through in the matrix of flavoring, matrix is generally sucrose and gum arabic or tragacanth gum; Pastille comprises activeconstituents in inert base, matrix is gelatin and glycerine or sucrose and gum arabic for example; And mouth wash shua, in the liquid vehicle that is fit to, comprise activeconstituents.
By conventional equipment solution or suspension directly are applied to nasal cavity, for example use dropper, volumetric pipette or atomizer.Composition may be provided as single or multiple dosage form.
Can realize also that to respiratory tract administration wherein activeconstituents is provided in the pressurized package by aerosol, wherein contain suitable propelling agent, for example Chlorofluorocarbons (CFCs) (CFC), for example Refrigerant 12, trichlorine methyl fuoride or dichloro tetrafluoro ethane; Carbonic acid gas; Perhaps other gases that are fit to.Aerosol also can suit to contain tensio-active agent, for example Yelkin TTS.The dosage of medicine can be controlled by metering valve.
Select as an alternative, activeconstituents may be provided as the form of dried powder, the powdered mixture of compound in being fit to powder matrix for example, matrix is lactose, starch, starch derivative (for example Vltra tears) and polyvinylpyrrolidone (PVP) for example.Aptly, powder carrier will form gel in nasal cavity.Powder composition can be a presented in unit dosage form, and for example in gelatine capsule or cartridge case or in blister pack, therefrom powder can be by the sucker administration.
In composition to respiratory tract administration, comprise intranasal compositions, compound generally will have smaller particle size, for example 5 microns or the following order of magnitude.A kind of like this particle diameter can obtain by means known in the art, for example micronization.
When needed, can adopt composition, to produce the lasting release of activeconstituents through adjusting.
Pharmaceutical preparations is unit dosage form preferably.In this class formulation, prepared product is subdivided into the dosage unit that contains an amount of active ingredient.Unit dosage form can be the prepared product of band packing, and packing contains the prepared product of discrete magnitude, for example is packaged in tablet, capsule and pulvis in bottle or the ampoule.Unit dosage form also can be capsule, tablet, cachet or a lozenge itself, perhaps can be proper amt these band packaged form arbitrarily.
Oral administration is a preferred compositions with tablet or capsule and intravenous administration and continuous infusion liquid.
About the further details of preparation and medicine-feeding technology, can referring to the Remington ' s Pharmaceutical Sciences of latest edition (Maack Publishing Co., Easton, PA).
Effective dose on the therapeutics represents that activeconstituents improves the amount of symptom or obstacle.Therapeutic efficiency and toxicity, for example ED
50And LD
50, can in cell culture or laboratory animal, be measured by standard pharmacology technology.Dosage ratio between result of treatment and the toxic effect is a therapeutic index, can be expressed as LD
50/ ED
50The ratio.The pharmaceutical composition that therapeutic index is big is preferred.
Dosage must be adjusted according to treating individual age, body weight and situation and route of administration, formulation, system and required result certainly modestly, and accurate dose should depend on the professional certainly.
Actual dose depends on the attribute and the seriousness of the disease for the treatment of, and is decided by the doctor, can specific environment adjust dosage according to the present invention, to produce required result of treatment.But, present what pay close attention to is to be suitable for pharmaceutical composition that therapeutic disposes to contain and have an appointment 0.1 to the every single agent of about 500mg activeconstituents, and preferably about 1 to about 100mg, and most preferably from about 1 to about 10mg.
Activeconstituents can divide potion or multi-agent administration every day.In some cases, under the low dosage that reaches 0.1 μ g/kg i.v. and 1 μ g/kg p.o., can obtain gratifying result.The upper limit of dosage range is regarded as about 10mg/kg i.v. and 100mg/kg p.o. at present.Preferred range is about 0.1 μ g/kg to about 10mg/kg/ days i.v. and about 1 μ g/kg about 100mg/kg/ days p.o. extremely.
Methods of treatment
On the other hand, the invention provides treatment, prevent or alleviate moving object and comprise people's the disease or the method for obstacle or illness, described disease or obstacle or illness suppress to reply for monoamine neurotransmitter re-uptake in the central nervous system, and this method comprises such moving object to this treatment of needs, comprises that the people imposes the The compounds of this invention of significant quantity.
The suitable dosage range of expection is 0.1 to 1000 milligram/every day at present, 10 to 500 milligrams/every day, be in particular 30 to 100 milligrams/every day, usually depend on definite method of application, the formulation of using, use at the body weight of illness, referent and object, also have the doctor that is responsible for and animal doctor's preference and experience.
Embodiment
The present invention is described further with following embodiment, and described embodiment is intended to limit the scope of the invention by any way.
Embodiment 1
(±)-suitable-1-methyl-4-(3, the 4-dichlorophenyl)-piperidines-3-carboxylate methyl ester (1)
With
(±)-anti--1-methyl-4-(3, the 4-dichlorophenyl)-piperidines-3-carboxylate methyl ester (1)
With 1-bromo-3, the solution that 4-dichlorobenzene (29 gram, 130 mmoles) is dissolved in ether (150 milliliters) adds in the suspension of stirring that magnesium chips (3.4 grams, 142 mmoles) is dissolved in ether (20 milliliters).Mixture heating up was refluxed 20 minutes, then-40 ℃ of coolings.Slowly adding arecoline (10 grams, 65 mmoles) is dissolved in the solution of toluene (100 milliliters) and keeps internal temperature between-40 ℃ and-30 ℃.Reaction mixture was added 4N HCl (50 milliliters) in 6 hours then-20 ℃ of stirrings.Then two-phase separately and at water is added ammoniacal liquor up to becoming alkaline pH, and extract, make its dry and evaporation become oil with sal epsom with methylene dichloride (4 * 100 milliliters).With the isomer separation of (1) and (2), (1) (fusing point 70-75 ℃) and 2.0 that obtain 5.0 grams (25%) restrain (2) (oil) of (10%) with column chromatography (sherwood oil, ether, triethylamine 70: 25: 5).
Embodiment 2
Method A1
(±)-suitable-1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines (3)
Under-50 ℃, be dissolved in to (1) (5.0 gram, 17 mmoles) in the solution of tetrahydrofuran (THF) (50 milliliters) and add LiAlH
4(0.50 gram, 13 mmoles).Stirred three hours at-30 ℃, add water then and make reaction terminating and be evaporated to solid.Residue is dissolved in the methylene dichloride, with dried over mgso and be evaporated to dried, obtain 4.6 the gram (3) (100%).Fusing point 127-129 ℃.
(±)-anti--1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-hexafluoro pyridine (4)
The solution reduction of (2) (2.0 grams, 6.6 mmoles) is produced the product (4) of 1.9 grams (100%) according to method (A1).Molten some 109-111 ℃.
Step (a)
By the mandelate precipitation racemic modification is separated into one enantiomorph.
(+)-suitable-1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines (5)
The mixture (6.6 grams, 43.3 mmoles) of (3) (23.8 grams, 86.8 mmoles) and (-) amygdalic acid is dissolved in the mixture heating up of dehydrated alcohol (60 milliliters) up to becoming clear soln.With reaction mixture be evaporated to dry doubling from toluene (100 milliliters) recrystallization once, and recrystallization is once from toluene (100 milliliters) and dehydrated alcohol (12 milliliters).In throw out separation and impouring water (75 milliliters).Adding strong aqua extracts with ethyl acetate (3 * 75 milliliters) up to the pH that becomes alkalescence and with mixture.The organic phase that merges with dried over sodium sulfate and be evaporated to driedly, is obtained (5) of 8.2 grams (69%), fusing point 94.5-96.5 ℃, [α]
D 25=+67 °.
(+)-suitable-1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines fumarate, fusing point 147-149 ℃, [α]
D 25=+68 °.
Step (b)
(-)-suitable-1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines (6)
In the resulting toluene of recrystallization that step (a) is mentioned, add water (75 milliliters) and strong aqua up to being alkaline pH.With ethyl acetate (2 * 75 milliliters) mixture is extracted.With the organic phase that merges with dried over sodium sulfate and be evaporated to dried.Be dissolved in residue in the dehydrated alcohol (60 milliliters) and interpolation (+) amygdalic acid (6.6 grams, 43.3 mmoles).
Step (b) is abideed by the step that step (a) is mentioned then, obtains (6) of 7.4 grams (62%), and fusing point 95-97 ℃, [α]
D 25=-65 °.
(-)-suitable-1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines fumarate, fusing point 148-150 ℃, [α]
D 25=-67 °.
Method A2
Anti--1-methyl-3-methylol-4-(3, the 4-the dichlorophenyl)-piperidines of pure enantiomorph (+) and (-) can prepare by the isomerization of (5) and (6).
(+)-anti--1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines (7)
(5) (10.0 grams, 36 mmoles) and the solution stirring that potassium tert.-butoxide (12.0 grams, 1.08 mmoles) is dissolved in dimethyl formamide (75 milliliters) are spent the night.Add CaCl
2(75 milliliters 3M) and with reaction mixture extract with ethyl acetate (2 * 200 milliliters).With the organic phase that merges with dried over sodium sulfate and be evaporated to dried.With residue ethyl acetate (7 milliliters) recrystallization, obtain (7) of 6.3 grams (63%), fusing point 137-139 ℃, [α]
D 25=+39 °.
(-)-anti--1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines (8)
(8) be according to method (A2) from (6) (2.0 gram, 7.3 mmoles) synthetic, obtain (8) of 1.4 grams (70%), fusing point 137-139 ℃, [α]
D 25=-38 °.
(-)-anti--1-methyl-3-methylol-4-(3, the 4-dichlorophenyl)-piperidines fumarate, fusing point 138-140 ℃, [α]
D 25=-25 °.
Embodiment 3
Method B1
(±)-suitable-1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines (9)
In tetrahydrofuran (THF) (40 milliliters) solution of (3) (2.4 grams, 8.6 mmoles), add 60%NaH (0.69 gram, 17 mmoles), and at room temperature stirred one hour.Add ethyl sulfate (1.4 milliliters, 11 mmoles) and reaction mixture stirred and spend the night.Add water and use ether (3 * 40 milliliters) to extract reaction mixture.Make the organic phase drying of merging and be evaporated to dried with sal epsom.Use the mixture of methylene dichloride, methyl alcohol and ammoniacal liquor (9: 1: 1%) to carry out column chromatography, obtain the product (9) (oil) of 1.5 grams (56%).
Prepare following material with similar method:
By (3) being carried out methylation preparation (±)-suitable-1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines (10) (oil) with methyl-sulfate
(±)-anti--1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines (11)
Method according to (B1) is synthesized (11) from (4) (1.8 grams, 6.6 mmoles), obtains the product (11) (oil) of 0.83 gram (43%).
Prepare following material with similar method:
By (4) being carried out methylation preparation (±)-anti--1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines (12) (oil) with methyl-sulfate
Method B2
(+)-suitable-1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (13)
Be dissolved in to (5) (11.0 gram, 40 mmoles) in the solution of tetrahydrofuran (THF) (150 milliliters) and add potassium tert.-butoxide (13.3 grams, 120 mmoles).Reaction mixture was stirred one hour and be cooled to 5 ℃.Add methyl-sulfate (5.7 milliliters, 44 mmoles) and water (50 milliliters), and with reaction mixture with ethyl acetate (2 * 80 milliliters) extraction, with dried over sodium sulfate and be evaporated to driedly, obtain 12 (13) that restrain (99%).Fusing point 72.5-74 ℃, [α]
D 25=+65 °.
Prepare following material with similar method:
With methyl-sulfate (5) are carried out alkylating preparation (+)-suitable-1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines (14) (oil).
With methyl-sulfate (6) are carried out alkylating preparation (-)-suitable-1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines (15) (oil).
With (brooethyl) cyclopropane (5) are carried out alkylating preparation (+)-suitable-1-methyl-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (16).Fusing point 187-188.5 ℃, [α]
D 25=+63 °.
With (brooethyl) cyclopropane (6) are carried out alkylating preparation (-)-suitable-1-methyl-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (17).Fusing point 184.5-187.6 ℃, [α]
D 25=-66 °.
With 1-bromo-2-methylpropane (6) are carried out alkylating preparation (-)-suitable-1-methyl-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (18).Fusing point 181-183 ℃, [α]
D 25=-64 °.
With ethyl sulfate (7) are carried out alkylating preparation (+)-anti--1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines (19), (oil).
With ethyl sulfate (8) are carried out alkylating preparation (-)-anti--1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines (20), (oil).
With methyl-sulfate (7) are carried out alkylating preparation (+)-anti--1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines (21), (oil).[α]
D 25＝+44°。
With methyl-sulfate (8) are carried out alkylating preparation (-)-anti--1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (22).Fusing point 50-70 ℃ (hygroscopic), [α]
D 25=-23 °.
With (brooethyl) cyclopropane (8) are carried out alkylating preparation (-)-anti--1-methyl-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (23).Fusing point 180-182 ℃, [α]
D 25=-31 °.
With 1-bromo-2-methylpropane (8) are carried out alkylating preparation (-)-anti--1-methyl-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (24).Fusing point 162-164 ℃, [α]
D 25=-29 °.
Prepare following material with similar method:
(+)-suitable-1-methyl-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate;
(+)-anti--1-methyl-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate;
(+)-anti--1-methyl-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate;
Embodiment 4
Method C
The racemic modification of (±)-suitable-1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines (9) can split into one enantiomorph by dibenzoyl tartaric acid salt.
Step (a)
(+)-suitable-1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines hydrobromate (13)
(±)-suitable-1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines (9) (1.1 gram, 3.7 mmoles) and (-)-dibenzoyl tartaric acid (0.48 restrains 1.3 mmoles) be dissolved in 99% the ethanol (10 milliliters) and be evaporated to dried.Residue crystallization from toluene (3 milliliters) with evaporation.Recrystallization from the mixture of toluene (10 milliliters) and ethanol (10 milliliters).Isolate throw out and be dissolved in 4N NaOH (5 milliliters) and the mixture of ether (10 milliliters) in.Ether is separated and use dried over mgso, produce 0.25 product that restrains (45%), be free alkali.Add Hydrogen bromide (0.20 milliliter, 1.7 mmoles) and mixture is evaporated to dried.Residue recrystallization from ethanol (2 milliliters) and ether (10 milliliters), obtain (13) of 0.20 gram (28%), molten some 183-185 ℃, [α]
D 25=+62.8 °.(the c=14 mg/ml is in 99% ethanol).
Step (b)
(-)-suitable-1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines hydrobromate (25)
To step (a) mentioned from the toluene of recrystallization in add 4N NaOH (5 milliliters) and extract with ether (3 * 25 milliliters), with dried over mgso and be evaporated to dried.Residue is dissolved in 99% the ethanol (10 milliliters), and adds (+)-dibenzoyl tartaric acid (0.67 gram, 1.8 mmoles).According to the step of mentioning in the step (a), obtain (25) of 0.14 gram (20%) then, fusing point 183-185 ℃, [α]
D 25=-66.1 °.(the c=14 mg/ml is in 99% ethanol).
(+)-anti--1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines hydrobromate (19) and
(-)-anti--1-methyl-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines hydrobromate (20)
Parse (19) and (20), (19) that produce 0.16 gram (30%), fusing point 222-224 ℃ ℃, [α] according to the employed step of method C from (11) (0.83 gram, 2.8 mmoles)
D 25=+34.9 °.(the c=10 mg/ml is in 99% ethanol); With (20) of 0.14 gram (26%), fusing point 219-221 ℃, [α]
D 25=-32.7 °.(the c=10 mg/ml is in 99% ethanol).
(+)-suitable-1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines hydrobromate (14) and
(-)-suitable-1-methyl-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines hydrobromate (15)
Parse (14) and (15) according to the employed step of method C from (10).(14) [α]
D 25=+6.5 °, fusing point 212-215 ℃, [α] of (15)
D 25=-65 °, fusing point 212-215 ℃.
Embodiment 5
(+)-suitable-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines (26)
The mixture of (13) 0.7 grams and chloroformic acid 1-chloroethene ester (2.5 milliliters) was stirred 2 days down in 100 ℃, add 4N NaOH (25 milliliters) then.This mixture backflow stirring is spent the night.After the cooling, mixture is extracted with toluene.Make the dry and evaporation generation fluid of organic phase, fluid is handled (SiO with column chromatography
2, methylene dichloride, MeOH, ammoniacal liquor 9: 1: 1%), obtain linen crystalline product.Fusing point 68-70 ℃.
(+)-suitable-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate, fusing point 149-151 ℃, [α]
D 25=+68 °.
Prepare following material with similar method:
(-)-suitable-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines hydrobromate (27), fusing point 181-184 ℃, [α]
D 25=-75 °.
(+)-suitable-3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (28), fusing point 154.5-156 ℃, [α]
D 25=+66 °.
(-)-suitable-3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (29), fusing point 147-149 ℃, [α]
D 25=-68 °.
(+)-suitable-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (30), fusing point 172-173.5 ℃, [α]
D 25=+63 °.
(-)-suitable-3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (31), fusing point 175-176.5 ℃, [α]
D 25=-65 °.
(+)-anti--3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines (32), (oil), [α]
D 25=+46 °.
(-)-anti--3-ethoxyl methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (33), fusing point 140-142 ℃, [α]
D 25=-37 °.
(+)-anti--3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines (34), (oil), [α]
D 25=+44 °.
(+)-anti--3-methoxymethyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (35), fusing point 140-142 ℃, [α]
D 25=-31 °.
(-)-anti--3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate (36), fusing point 153.5-155.5 ℃, [α]
D 25=-37 °.
Prepare following material with similar method:
(+)-anti--3-cyclo propyl methoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate
(-)-suitable-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate
(-)-suitable-3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate
(+)-anti--3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate
(-)-anti--3-isobutoxy methyl-4-(3, the 4-dichlorophenyl)-piperidines fumarate
Claims (15)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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| DKPA200201689 | 2002-11-01 | ||
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|---|---|
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| CNA2003801013422A Pending CN1705644A (en) | 2002-11-01 | 2003-10-30 | Novel piperidine derivatives as monoamine neurotransmitter reuptake inhibitors and their use |
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| Country | Link |
|---|---|
| CN (1) | CN1705644A (en) |
| IS (1) | IS7866A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101939297B (en) * | 2008-02-05 | 2012-10-17 | 大日本住友制药株式会社 | Benzylpiperizine compound |
-
2003
- 2003-10-30 UA UAA200501948A patent/UA79484C2/en unknown
- 2003-10-30 CN CNA2003801013422A patent/CN1705644A/en active Pending
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2005
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101939297B (en) * | 2008-02-05 | 2012-10-17 | 大日本住友制药株式会社 | Benzylpiperizine compound |
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| ZA200502498B (en) | 2006-06-28 |
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| UA79484C2 (en) | 2007-06-25 |
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