CN101137654A - Novel salt of quinuclidine derivative - Google Patents
Novel salt of quinuclidine derivative Download PDFInfo
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- CN101137654A CN101137654A CNA2006800073523A CN200680007352A CN101137654A CN 101137654 A CN101137654 A CN 101137654A CN A2006800073523 A CNA2006800073523 A CN A2006800073523A CN 200680007352 A CN200680007352 A CN 200680007352A CN 101137654 A CN101137654 A CN 101137654A
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- tetrahydroisoquinoline
- phenyl
- rubane
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Abstract
There is provided an acid addition salt of (-)-(3R)-quinuclidin-3-yl (1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate with an acid selected from the group consisting of (-)-(2S,3S)-tartaric acid, (+)-(2S,3S)-di-O-benzoyltartaric acid, (+)-(2S,3S)-di-O-(4-methylbenzoyl)tartaric acid, (-)-L-phenylalanine, benzenesulfonic acid, cyclohexanesulfamic acid, hydrobromic acid, naphthalene-2-sulfonic acid, sebacic acid, (+)-camphor-10-sulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, methanesulfonic acid and methyl phosphate, which has little hygroscopicity that affects the use as a drug or its drug substance, and is very useful as a drug or its drug substance.
Description
Technical field
The present invention relates to as medicine, particularly as muscarine M
3(-)-(1R)-1-phenyl-1,2,3 that receptor antagonist is useful, the novel acid addition salt of 4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (below be called compd A).
Background technology
Known compound A has following chemical structure, to muscarine M
3Acceptor has affinity and selectivity, and it is as M
3Receptor antagonist is to prevention or treatment and M
3Urinary systems such as the urinary incontinence in the relevant various diseases, particularly nervosa frequent micturition, neurogenic bladder, nycturia, unstable bladder, cystospasm, chronic cystitis etc. and frequent micturition; Respiratory system diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis; Digestive system (patent documentation 1) such as irritable colon syndrome, spastic colitis and diverticulitis are useful.
Compd A
As the acid salt of compd A, the hydrochloride of compd A is only disclosed in the embodiment 10 of above-mentioned patent documentation 1, about other acid salt, in above-mentioned patent documentation 1, the hydrochloride of record, also there is not concrete known acid salt.
Patent documentation 1: No. 3014457 communique of Japanese Patent
Summary of the invention
Invent problem to be solved
Can be used as the crystallinity anhydride and obtain as the unique compound known A hydrochloride of the acid salt of compd A, but confirmed that hydrochloride has following character: the moisture absorption deliquescence takes place in about 70% (room temperature) of relative humidity under general environment, and impurity increases during prolonged preservation.
Therefore, thirst for finding that water absorbability is lower, particularly humidity is had the more acid salt of the desalination hydrochlorate compd A in addition of high stability, so that safer medicine or effective ingredient is provided.
Solve the method for problem
When the acid salt of all cpds A was studied, the inventor etc. are unexpected to be found: the specific acid salt of compd A, it compared the water absorbability excellence with the known compound hydrochloride, and humidity is had high stability, thereby has finished the present invention.That is,, provide the acid salt of a kind of compd A with the acid that is selected from group S according to the present invention.Wherein, group S comprises: (-)-(2S, 3S)-tartrate, (+)-(2S, 3S)-two o-benzoyl tartrate, (+)-(2S, 3S)-two neighbour's (4-toluyl) tartrate, (-)-L-phenylalanine, Phenylsulfonic acid, cyclohexane sulfamic acid, Hydrogen bromide, naphthalene-2-sulfonic acid, sebacic acid, (+)-camphor-10-sulfonic acid, tosic acid, ethyl sulfonic acid, methylsulfonic acid and methyl orthophosphoric acid.
Particularly, by the invention provides a kind of (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester, it is the acid salt of compd A, it is selected from: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (-)-(2S, 3S)-tartrate, (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (+)-(2S, 3S)-two o-benzoyl tartrate, (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (+)-(2S, 3S)-two neighbour-(4-toluyl) tartrate, (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (-)-L-phenylalanine salt, (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester benzene sulfonate, (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester cyclamate, (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester hydrobromate, (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester naphthalene-2-sulfonic acid salt, (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester sebacate, (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (+)-camphor-10-sulfonate, (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester tosilate, (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester esilate, (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester mesylate and (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester methyl orthophosphoric acid salt.
In the above-mentioned salt, be preferably: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (-)-(2S, 3S)-tartrate; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (+)-(2S, 3S)-two o-benzoyl tartrate; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (+)-(2S, 3S)-two neighbour's (4-toluyl) tartrate; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (-)-L-phenylalanine salt; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester benzene sulfonate; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester cyclamate; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester hydrobromate; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester naphthalene-2-sulfonic acid salt; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester sebacate; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (+)-camphor-10-sulfonate; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester tosilate; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester esilate; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester mesylate; Other scheme optimizations are: (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester methyl orthophosphoric acid salt.
It should be noted that cyclohexane sulfamic acid is also referred to as the thionamic acid cyclohexyl; Sebacic acid is also referred to as decane dicarboxylic acid; (+)-camphor-10-sulfonic acid is also referred to as (+)-[(1S, 4R)-7,7-dimethyl-2-oxo two ring [2.2.1] heptane-1-yls] methylsulfonic acid; Tosic acid is also referred to as the 4-toluene sulfonic acide.
According to the present invention, provide more than one to state (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester, be that the acid salt of compd A is the pharmaceutical composition of effective constituent, particularly as the pharmaceutical composition of muscarine M3 receptor antagonist.The invention effect
Compd A of the present invention and the acid salt that is selected from the acid of above-mentioned group of S, with known compound is that the compd A hydrochloride is compared, water absorbability improves, and particularly the stability to humidity is improved, and is very useful compound as medicine or effective ingredient.
Particularly as is generally known, improved medicine of known water absorbability or effective ingredient, under its keeping state, the preservation of humidity aspect and the problem in the qualitative control are alleviated, when making solid preparation such as tablet or capsule, the problem on the preparation that is caused by the changes in weight of effective constituent is alleviated.Promptly, the acid salt of compd A of the present invention, therefore water absorbability improves, and can expect stable preservation, carry out qualitative control easily, even on preparation, also can be described as the easy to handle compound, therefore help the medicine that provides quality higher, more excellent.
The accompanying drawing summary
Fig. 1 is that the expression known compound is the figure of suction dehydration isothermal curve of the hydrochloride of compd A.
Fig. 2 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 1.
Fig. 3 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 2.
Fig. 4 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 3.
Fig. 5 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 4.
Fig. 6 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 5.
Fig. 7 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 5-1.
Fig. 8 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 6.
Fig. 9 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 7.
Figure 10 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 8.
Figure 11 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 9.
Figure 12 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 10.
Figure 13 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 11.
Figure 14 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 12.
Figure 15 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 13.
Figure 16 is the figure of suction dehydration isothermal curve of the compound of expression embodiment 14.
Figure 17 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 1.
Figure 18 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 2.
Figure 19 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 3.
Figure 20 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 4.
Figure 21 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 5.
Figure 22 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 5-1.
Figure 23 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 6.
Figure 24 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 7.
Figure 25 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 8.
Figure 26 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 9.
Figure 27 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 10.
Figure 28 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 11.
Figure 29 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 12.
Figure 30 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 13.
Figure 31 is the compound powder X-ray diffraction spectrographic figure of expression embodiment 14.
The best mode that carries out an invention
The acid salt of compd A of the present invention is to moisture stable, having reached can be as the degree of medicine or effective ingredient, during in particular as medicine or effective ingredient, its water absorbability can not have problems, even can expect chemically stable or stable when preserving yet.Therefore, any acid salt of the present invention all is suitable as medicine or effective ingredient, is especially suitable for use as the effective ingredient of solid preparation.
(preparation method)
The acid salt of compd A of the present invention can be prepared by following preparation method.
That is, with respect to the weight of the free state of compd A, add 1mL/g to 100mL/g solvent after, at room temperature add as the acid of salt or contain the solution of acid by the scope that with respect to compd A is 0.5 to 2.0 equivalent.When residual insolubles, add identical or different solvent or make it dissolving forming solution, afterwards under agitation or under the static condition, under room temperature or cooling, place by heating.Even when exist adding solvent or heat also undissolved insolubles, can before separating out crystallization, filter, remove insolubles.The crystallization that leaching generates through aforesaid operations is washed with appropriate solvent, can obtain the acid salt of target compound A.It should be noted that when being cooled to room temperature be not only and put coldly, slow cooling sometimes or quenching also are effective to obtaining good crystallization.
Operable solvent can list in the operation of above-mentioned preparation salt: water, acetic acid, acetone, methyl-phenoxide, the 1-butanols, the 2-butanols, n-butyl acetate, t-butyl methyl ether, cumene, dimethyl formamide, ethanol (EtOH), ethyl acetate (EtOAc), diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isopropyl acetate (iPrOAc), methyl acetate, 3-methyl isophthalic acid-butanols, butanone (2-butanone), mibk, 2-methyl isophthalic acid-propyl alcohol, pentane, the 1-amylalcohol, the 1-propyl alcohol, 2-propyl alcohol (2-PrOH), propyl acetate, acetonitrile, chlorobenzene, chloroform, hexanaphthene, 1, the 2-Ethylene Dichloride, methylene dichloride, 1, the 2-glycol dimethyl ether, DMF, DMA, 1, the 4-diox, cellosolvo, ethylene glycol, methane amide, hexane, methyl alcohol, 2-methyl cellosolve, espeleton, methylcyclohexane, N-Methyl pyrrolidone, Nitromethane 99Min., pyridine, tetramethylene sulfone, THF, tetralin, toluene, 1,1, the 2-trieline, dimethylbenzene, benzene, tetracol phenixin, 1, the 2-ethylene dichloride, 1, the 1-Ethylene Dichloride, 1,1, the 1-trichloroethane, diisopropyl ether etc.
The crystallization of so operating and obtaining is carried out recrystallization by the method for utilizing common those skilled in the art to adopt, can obtain the higher crystallization of purity.
It should be noted that, above-mentioned preparation method's starting compound is the free state of compd A, can pass through above-mentioned patent documentation 1, that is, and the method for putting down in writing in No. 3014457 communique of Japanese Patent or be that the method or the self-evident method of those skilled in the art of benchmark is prepared with it.
The acid salt of compd A of the present invention, as the preparation raw material of medicine, can with its more than one and this field in normally used medicament with combinations such as carrier, vehicle, be used to prepare medicine.The preparation of medicine can be undertaken by method usually used in this field.
The medicine that contains the acid salt of The compounds of this invention A can be following any form: gastrointestinal administration preparations such as tablet, pill, capsule, granule, powder, liquid preparation; Or the injection of intraarticular, intravenously, intramuscular etc., suppository, through skin with liquid preparation, ointment, through skin with patch, through the mucous membrane liquid preparation, through parenteral administration preparations such as mucous membrane patch, inhalations.Particularly with the crystallization of the acid salt of compd A as the gastrointestinal administration of preparation raw material with tablet, pill, capsule, granule, powder, be favourable as stable solid preparation.
Be used for the solids composition of gastrointestinal administration, with more than one active substance and for example mixing such as lactose, N.F,USP MANNITOL, glucose, hydroxypropylcellulose, Microcrystalline Cellulose, starch, polyvinylpyrrolidone, silicoaluminate magnesium of at least a inert diluent.Composition can contain additive except that inert diluent, for example disintegrating agent, stablizer, solubilizing agent etc. such as lubricant, Mierocrystalline cellulose Calcium Glycolate such as Magnesium Stearate according to ordinary method.As required, tablet or pill can be coated with sugar-coat such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or gastric solubility or enteric film.
The liquid composition that is used for gastrointestinal administration comprises acceptable emulsion, solution, suspension agent, syrup, elixir etc. on the medicament, comprises normally used inert diluent, for example purified water, ethanol.Except inert diluent, above-mentioned composition can also comprise: auxiliarys such as wetting agent, suspension agent; Sweeting agent, flavour agent, perfume compound, sanitas.
The injection that is used for parenteral administration comprises: sterile aqueous solutions or non-aqueous solution agent, suspension agent, emulsion.Aqueous pharmaceutical, suspension agent comprise for example distilled water for injection and physiological saline.Non-aqueous solution agent, suspension agent for example have: propylene glycol, polyoxyethylene glycol, olive wet goods vegetables oil; Alcohols such as EtOH; Tween 80 etc.Above-mentioned composition may further include: auxiliarys such as sanitas, wetting agent, emulsifying agent, dispersion agent, stablizer, solubilizing agent.Above-mentioned substance can filter by for example strainer with not saturating bacterium, mixed bactericide or irradiation are sterilized.Above-mentioned substance can also manufacture aseptic solids composition, is dissolved in sterilized water or aseptic injection before use with using in the solvent.
Pharmaceutical composition of the present invention, its effective constituent contain the acid salt as the compd A of the present invention of muscarine M3 receptor antagonist, therefore can be used for the treatment of or prevention or inspection and the relevant various diseases of muscarine M3 acceptor.That is, particularly, pharmaceutical composition of the present invention is as for example crossing urine meaning sense of urgency, frequent micturition, the urinary incontinence, the nycturia in the urinary systems such as movable bladder, unstable bladder, neurogenic bladder, urocystitis or crossing the curative that reflects bladder; The curative or the prophylactic agent of the cystospasm that causes by surgical intervention or conduit; The curative of respiratory system diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, rhinitis; The curative of digestive system such as irritable colon syndrome; Relaxant during digestive tract examining; Myopia medicine or mydriatic; The curative of hyperhidrosis or prophylactic agent are useful.
Embodiment
Below, specify the present invention by embodiment, but the present invention not being subjected to any restriction of these embodiment, these embodiment not delimit the scope of the invention.
It should be noted that heat is analyzed and powder x-ray diffraction carries out by the following method.
(1) heat is analyzed
(DSC)
About 3mg sample is filled in the special-purpose aluminum sample disc, under nitrogen atmosphere (50mL/ minute), measurement range is room temperature～300 ℃, and heat-up rate is 10 ℃/minute, METHOD FOR CONTINUOUS DETERMINATION, record sample and with reference to the thermal change that produces between (empty aluminum sample disc).The operation that it should be noted that the device that comprises data processing is carried out according to each device indicated method and order.(device: TA Instrument system Hi-Res DSC2910)
(TGA)
About 3mg sample is filled in the special-purpose platinum system sample disc, and under nitrogen atmosphere (100mL/ minute), measurement range is room temperature～300 ℃, and heat-up rate is 10 ℃/minute, METHOD FOR CONTINUOUS DETERMINATION, writes down sample weight.The operation that it should be noted that the device that comprises data processing is carried out according to each device indicated method and order.(device: (2) powder x-ray diffraction TA Instrument system Hi-Res TGA2950)
About 10mg sample is filled in the special-purpose sample basin (wide 5mm, long 18mm, dark 0.2mm), measures, write down the powder x-ray diffraction of sample under the following conditions.The operation that it should be noted that the device that comprises data processing is carried out according to each device indicated method and order.(device: MAC Science (existing Bruker) system MXP18TAHF22)
(condition)
Radioactive source: Cu; Wavelength: 1.54056 ; Measurement range: 3.00～40.00 °; Sampling interval: 0.02 °; Sweep velocity: 3.00 °/minute; Tube voltage: 40kV; Tube current: 200mA; Divergent slit: 1.00 °; Scatter slit: 1.00 °; Receive slit: 0.15mm.
It should be noted that the numerical value that obtained by various spectrum is sometimes because of more or less changes such as the direction of crystal growth, particle size, condition determinations.Therefore, should not tightly resolve these numerical value.
The preparation of the free state of reference example 1 compd A
Be prepared according to the method for putting down in writing in No. 3014457 communique of Japanese Patent.
Reference example 2 is the preparation of the compd A hydrochloride of compound as a comparison
Be prepared according to the method for putting down in writing in No. 3014457 communique of Japanese Patent.
The free state of 26.0g compd A is dissolved among the 260mL EtOH, add 10.8g (-)-(2S, 3S)-tartrate after, by heating with its dissolving.Put be chilled to room temperature after, stirred 20 hours.The crystallization of leaching gained obtains the 30.6g white crystals.The crystallization of 1.00g gained is suspended among the 10mL EtOH, adds 0.4mL water, heating for dissolving.Put to be chilled to after the room temperature and stirred 6 hours, the crystallization of leaching gained obtains the title compound that 871mg is a white crystals.
1H-NMR(DMSO-d
6，25.9℃)：
1.40-1.98(4H，m)，2.00-2.25(1H，m)，2.70-3.20(7H，m)，3.33-3.53(2H，m)，3.83-3.94(1H，m)，3.99(2H，s)，4.85(1H，brs)，6.25(1H，brs)，7.08-7.37(9H，m).
Heat absorption summit among the DSC (peak top) temperature: 194 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 1 as shown in figure 17.
Embodiment 2 compd As (+)-(2S, 3S)-two preparation of o-benzoyl tartrate
The free state of 180mg compd A is dissolved among the 1.8mL EtOH, and 180mg (+)-(2S, 3S)-two o-benzoyl tartrate at room temperature stirred 12 hours in adding.The crystallization that leaching generates after the EtOH washing, by drying under reduced pressure, obtains the title compound that 284mg is a white crystals.
1H-NMR(DMSO-d
6：70℃)：
1.52-1.90(4H，m)，2.16(1H，brs)，2.76-3.16(7H，m)，3.37-3.56(2H，m)，3.89(1H，dt，J=13.2，5.4Hz)，4.85-4.92(1H，m)，5.68(2H，s)，6.23(1H，s)，7.11-7.33(9H，m)，7.43-7.55(4H，m)，7.57-7.63(2H，m)，7.90-7.96(4H，m).
Heat absorption summit temperature among the DSC: 159 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 2 as shown in figure 18.
The preparation of embodiment 3 compd A (+)-(2S3S)-two neighbours (4-toluyl) tartrate
The free state of 1.00g compd A is dissolved among the 20mL EtOH, and 1.12g (+)-(2S, 3S)-two neighbour's (4-toluyl) tartrate at room temperature stirred 22 hours in adding.Leaching gained throw out obtains the title compound that 1.60g is a white crystals.
1H-NMR(DMSO-d
6：70℃)：
1.53-1.88(4H，m)，2.15(1H，brs)，2.32-2.38(6H，m)，2.76-3.16(7H，m)，3.42(1H，ddd，J=13.6，8.8，5.2Hz)，3.50(1H，dd，J=14.4，8.8Hz)，3.90(1H，dt，J=13.2，5.2Hz)，4.88(1H，dt，J=8.8，4.4Hz)，5.64(2H，s)，6.23(1H，s)，7.11-7.34(13H，m)，7.77-7.84(4H，m).
Heat absorption summit temperature among the DSC: 160 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 3 as shown in figure 19.
The preparation of embodiment 4 compd As (-)-L-phenylalanine salt
The free state of 1.13g compd A is dissolved among the 11.25mL EtOH, adds 515mg (-)-L-phenylalanine and 4.5mL water, after the heating for dissolving, at room temperature stirred 10 hours.The crystallization of leaching gained after water-EtOH mixed solvent washing, by drying under reduced pressure, obtains the title compound that 1.12g is a white crystals.
1H-NMR(DMSO-d
6：70.0℃)：
1.20-1.36(1H，m)，1.41-1.70(3H，m)，1.86-1.95(1H，m)，2.50-2.95(8H，m)，3.03-3.17(2H，m)，3.33-3.47(2H，m)，3.84-3.95(1H，m)，4.60-4.71(1H，m)，6.23(1H，s)，7.11-7.33(14H，m)。
Heat absorption summit temperature among the DSC: 118 ℃ and 235 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 4 as shown in figure 20.
The preparation (1) of embodiment 5 compd A benzene sulfonates
The free state of 2.69g compd A is dissolved among the 40mL EtOAc, adds 1.31g Phenylsulfonic acid monohydrate, at room temperature stirred 1 hour.Behind the leaching gained throw out, it is suspended in the 30mL2-butanone, adds 0.35mL water, heating for dissolving.Put to be chilled to after the room temperature and stirred 60 hours, leaching gained throw out obtains the title compound that 2.49g is a white crystals.
1H-NMR(DMSO-d
6：70℃)：
1.65-1.99(4H，m)，2.23(1H，brs)，2.77-2.96(2H，m)，3.06-3.32(5H，m)，3.44(1H，ddd，J=13.6，8.4，5.2Hz)，3.66(1H，dd，J=13.6，8.4Hz)，3.91(1H，dt，J=12.8，5.6Hz)，4.97(1H，dt，J=8.4，4.4Hz)，6.25(1H，s)，7.11-7.35(12H，m)，7.59-7.64(2H，m)，9.39(1H，brs).
Heat absorption summit temperature among the DSC: 178 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 5 as shown in figure 21.
The preparation (2) of embodiment 5-1 compd A benzene sulfonate
The free state of 7.00g compd A is dissolved in the 70mL acetone, adds 3.40g Phenylsulfonic acid monohydrate and 70mL t-butyl methyl ether, at room temperature stirred 9 hours with mechanical stirrer.Leaching gained throw out obtains the title compound that 8.10g is a white crystals.
1H-NMR and embodiment's 5
1H-NMR is in full accord, is polymorphic but DSC and powder x-ray diffraction show the title compound of embodiment 5 and embodiment 5-1.
Heat absorption summit temperature among the DSC: 170 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 5-1 as shown in figure 22.
The preparation of embodiment 6 compd A cyclamates
The free state of 500mg compd A is dissolved among the 5mL2-PrOH, adds the 494mg cyclohexane sulfamic acid, at room temperature stirred 13 hours.Leaching gained throw out obtains the title compound that 550mg is a white crystals.
1H-NMR(DMSO-d
6：70℃)：
1.00-1.35(10H，m)，1.46-2.08(14H，m)，2.23(1H，brs)，2.77-3.30(11H，m)，3.44(1H，ddd，J=13.6，8.8，5.2Hz)，3.64(1H，dd，J=13.8，8.8Hz)，3.91(1H，dt，J=12.8，5.6Hz)，4.96(1H，dt，J=8.4，4.4Hz)，6.25(1H，s)，7.10-7.36(9H，m).
Heat absorption summit temperature among the DSC: 127 ℃ and 170 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 6 as shown in figure 23.
The preparation of embodiment 7 compd A hydrobromates
The free state of 200mg compd A is dissolved among the 1.0mL EtOH, adds the 95mg47% Hydrogen bromide.Stir adding 1.1mL diisopropyl ether down, stirred 18 hours down at 5 ℃.Leaching gained throw out obtains the title compound that 165mg is a white crystals.
1H-NMR(DMSO-d
6：70℃)：
1.65-1.98(4H，m)，2.24(1H，brs)，2.77-2.97(2H，m)，3.05-3.35(5H，m)，3.45(1H，ddd，J=13.6，8.8，5.2Hz)，3.65(1H?dd，J=13.2，8.4Hz)，3.91(1H，dt，J=12.8，5.6Hz)，4.97(1H，dt，J=8.8，4.4Hz)，6.26(1H，s)，7.11-7.35(9H，m)，9.68(1H，brs).
Ultimate analysis (theoretical value: with C
23H
26N
2O
2The HBr meter):
C，62.31，H，6.14，N，6.32，Br，18.02。(measured value) C, 62.04, H, 6.10, N, 6.09, Br, 17.73.
Heat absorption summit temperature among the DSC: 199 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 7 as shown in figure 24.
The preparation of embodiment 8 compd A naphthalene-2-sulfonic acid salt
The free state of 100mg compd A is dissolved among the 1.0mL EtOH, adds 65mg2-naphthene sulfonic acid hydrate, stirred 26 hours.The crystallization of leaching gained, obtaining 79mg is light grey crystalline title compound.
1H-NMR(DMSO-d
6：70℃)：
1.65-2.00(4H，m)，2.24(1H，brs)，2.77-2.97(2H，m)，3.05-3.32(5H，m)，3.45(1H，ddd，J=14.0，9.2，5.2Hz)，3.65(1H，dd，J=14.0，8.8Hz)，3.90(1H，dt，J=12.8，5.6Hz)，4.97(1H，dt，J=8.0，4.4Hz)，6.25(1H，s)，7.12-7.34(9H，m)，7.49(2H，dt，J=10.4，4.0Hz)，7.74(1H，dd，J=8.4，1.6Hz)，7.82(1H，d，J=8.0Hz)，7.85-7.95(2H，m)，8.14(1H，s)，9.35(1H，brs).
Heat absorption summit temperature among the DSC: 178 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 8 as shown in figure 25.
The preparation of embodiment 9 compd A sebacates
The free state of 300mg compd A is dissolved among the 1.0mL EtOH, adds the 171mg sebacic acid, stirred 3 hours.Washing with alcohol is used in the crystallization of leaching gained, obtains the title compound that 165mg is a white crystals.
1H-NMR(DMSO-d
6：26.1℃)：
1.16-2.00(17H，m)，2.17(4H，t，J=7.2)，2.50-2.97(7H，m)，3.02-3.08(1H，m)，3.28-3.50(1H，m)，3.78-3.98(1H，m)，4.65(1H，brs)，6.24(1H，brs)，7.12-7.26(10H，m).
Heat absorption summit temperature among the DSC: 127 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 9 as shown in figure 26.
The preparation of embodiment 10 compd As (+)-camphor-10-sulfonate
The free state of 200mg compd A is dissolved in the 2mL acetone, adds 138mg (+)-camphor-10-sulfonic acid, at room temperature stirred 5 hours.Leaching gained throw out obtains the title compound that 191mg is a white crystals.
1H-NMR(DMSO-d
6?70℃)：
0.76(3H，s)，1.08(3H，s)，1.20-1.33(2H，m)，1.65-1.98(7H，m)，2.18-2.28(2H，m)，2.37-2.42(1H，m)，2.65-2.97(4H，m)，3.05-3.31(5H，m)，3.44(1H，ddd，J=13.6，8.8，4.8Hz)，3.65(1H，dd，J=13.6，8.4Hz)，3.91(1H，dt，J=13.2，5.6Hz)，4.97(1H，dt，J=8.8，4.4Hz)，6.25(1H，s)，7.11-7.35(9H，m)，9.44(1H，brs).
Heat absorption summit temperature among the DSC: 198 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 10 as shown in figure 27.
The preparation of embodiment 11 compd A tosilate
The free state of 200mg compd A is dissolved in the mixing solutions of 1.5mL acetone and 0.5mL t-butyl methyl ether, adds 105mg tosic acid monohydrate, at room temperature stirred 17 hours.Leaching gained throw out obtains the title compound that 83mg is a white crystals.
1H-NMR(DMSO-d
6：70℃)：
1.65-2.00(4H，m)，2.24(1H，brs)，2.28(3H，s)，2.76-2.96(2H，m)，3.05-3.30(5H，m)，3.44(1H，ddd，J=13.6，8.0，5.0Hz)，3.65(1H，dd，J=13.6，8.0Hz)，3.91(1H，dt，J=12.8，5.6Hz)，4.97(1H，dt，J=8.4，4.4Hz)，625(1H，s)，7.09(2H，d，J=7.6Hz)，7.11-7.35(9H，m)，7.47-7.52(2H，m)，9.38(1H，brs).
Heat absorption summit temperature among the DSC: 150 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 11 as shown in figure 28.
The preparation of embodiment 12 compd A esilates
The free state of 100mg compd A is dissolved in the 1.0mL2-butanone, adds the 31mg ethyl sulfonic acid, at room temperature stirred 6.5 hours.Leaching gained throw out obtains the title compound that 95mg is a white crystals.
1H-NMR(DMSO-d：70℃)：
1.07(3H，t，J=7.6Hz)，162-2.10(4H，m)，2.24(1H，brs)，2.39(2H，q，J=7.6Hz)，2.76-2.96(2H，m)，3.08-3.32(5H，m)，3.44(1H，ddd，J=13.6，8.8，4.8Hz)，3.65(1H，dd，J=13.6，8.8Hz)，3.91(1H，dt，J=12.4，5.2Hz)，4.92-5.02(1H，m)，6.25(1H，s)，7.10-7.35(9H，m)，9.51(1H，brs).
Heat absorption summit temperature among the DSC: 233 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 12 as shown in figure 29.
The preparation of embodiment 13 compd A mesylates
The free state of 200mg compd A is dissolved in the 1.0mL2-butanone, adds the iPrOAc solution that 1.0mL contains the 53mg methylsulfonic acid, at room temperature stirred 0.5 hour.Leaching gained throw out obtains the title compound that 187mg is a white crystals.
1H-NHR(DMSO-d
6：70℃)：
1.62-2.02(4H，m)，2.24(1H，brs)，2.30(3H，s)，2.76-2.96(2H，m)，3.00-3.34(5H，m)，3.44(1H，ddd，J=13.6，8.8，4.8Hz)，3.65(1H，dd，J=13.6，8.6Hz)，3.91(1H，dt，J=13.2，5.2Hz)，4.90-5.40(1H，m)，6.25(1H，s)，7.08-7.36(9H，m)，9.37(1H，brs).
Heat absorption summit temperature among the DSC: 178 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 13 as shown in figure 30.
The preparation of embodiment 14 compd A methyl orthophosphoric acid salt
The free state of 200mg compd A is dissolved in the mixed solvent of 2.0mL EtOAc and 0.5mL2-butanone, adds the 98mg methyl orthophosphoric acid, at room temperature stirred 22 hours.Leaching gained throw out obtains the title compound that 124mg is a white crystals.
1H-NHR(DMSO-d
6：70℃)：
1.43-1.54(1H，m)，1.57-1.81(3H，m)，2.01-2.10(1H，m)，2.77-2.99(7H，m)，3.29-3.46(2H，m)，3.42(3H，d，J=10.8Hz)，3.90(1H，dt，J=13.2，5.6Hz)，4.76-4.84(1H，m)，6.24(1H，s)，7.12-7.33(9H，m).
Heat absorption summit temperature among the DSC: 195 ℃
The powder x-ray diffraction spectrum of the compound of embodiment 14 as shown in figure 31.
The effect of the acid salt of compd A of the present invention obtains confirming by following test example.
The 1 water absorbability evaluation of test example
About 5mg sample is filled in the special-purpose quartz system basin, under the following conditions METHOD FOR CONTINUOUS DETERMINATION, the weight of record sample under each humidity.The operation that it should be noted that the device that comprises data processing is carried out according to each device indicated method and order.(device: SMS system, dynamically water vapor adsorption determinator DVS Advantage)
(condition)
Measure temperature: 25 ℃; Dry before measuring: not dry; Initial humidity: 5%RH; Maximal humidity: 95%RH; End of a period humidity: 5%RH; Ladder: 5%RH; Balance benchmark: 0.03%wt in 5 minutes; Maximum starting time: 180 minutes; Sampling interval: 20 seconds; Data logging interval: 1 minute;
The chart that above-mentioned test obtains such as Fig. 1～shown in Figure 16.Changes in weight in the condition determination scope is as shown in table 1.
[table 1]
| Test-compound | Changes in weight (%) | Test-compound | Changes in weight (%) |
| |
<1 | Embodiment 8 | <4 |
| Embodiment 2 | <1 | Embodiment 9 | <1 |
| |
<1 | |
<2 |
| |
<2 | Embodiment 11 | <6 |
| |
<1 | Embodiment 12 | <5 |
| Embodiment 5-1 | <1 | Embodiment 13 | <25 |
| Embodiment 6 | <3 | Embodiment 14 | <11 |
| Embodiment 7 | <4 | Reference example 2 | 35 (with deliquescence) |
Shown in Fig. 1 and table 1, the affirmation known compound is that the hydrochloride of compd A begins rapid moisture absorption from relative humidity about 65%, the changes in weight that is caused by moisture absorption more than 75% in relative humidity is more than 15%, 5～95% times changes in weight of relative humidity in the condition determination scope surpass 35%, and this changes with deliquescence.On the other hand, shown in Fig. 2～Figure 16 and table 1, the acid salt of compd A of the present invention and known compound are that the hydrochloride of compd A is compared, and confirm that its water absorbability improves, and have more excellent character as medicine or effective ingredient.
Test example 2 estimation of stabilitys (1)
In the glass bottle, measure about 0.5mg sample, under following preservation condition, force decomposition run.
Condition 1:120 ℃-sealing-24 hours
Open-5 days of condition 2:25 ℃-relative humidity 93%-
Condition 3:25 ℃-NUV (near-ultraviolet light) irradiation-sealing-5 day
With the sample dissolution after preserving in 1mL MeOH as sample solution, this sample solution is diluted to 100 times as standardized solution with MeOH, use the impurity in the standardized solution quantitative sample solution.The operation that it should be noted that the device that comprises data processing is carried out according to each device indicated method and order.(device: Agilent system LC-MSD1100 series)
Above-mentioned test-results is as shown in table 2.
[table 2]
| Impurity level (%) before preserving | From preserving the variation (%) of preceding | |||
| Condition | ||||
| 1 | Condition 2 | |
||
| |
1.5 | 0.2 | -0.1 | -0.3 |
| Embodiment 2 | 0.0 | 0.2 | 0.1 | 0.0 |
| |
0.0 | 2.3 | 0.1 | 0.0 |
| |
1.9 | 508 | -0.3 | -0.3 |
| |
1.6 | 0.3 | 0.1 | -0.1 |
| Embodiment 5-1 | 1.8 | -0.1 | 0.0 | -0.2 |
| Embodiment 6 | 1.4 | 8.1 | 0.0 | 0.1 |
| Embodiment 7 | 0.5 | -0.2 | 0.2 | 0.3 |
| Embodiment 8 | 2.0 | 1.3 | 0.2 | 26 |
| Embodiment 9 | 37 | -0.3 | 0.2 | -0.8 |
| |
0.9 | 0.0 | 0.0 | 0.0 |
| Embodiment 11 | 0.5 | -0.1 | 0.1 | 0.0 |
| Embodiment 12 | 1.4 | -0.2 | -0.1 | -0.1 |
| Reference example 2 | 0.1 | 0.2 | 38 | 2.0 |
Test example 3 estimation of stabilitys (2)
In 10mL glass measuring bottle, measure about 5mg sample, under following preservation condition, carry out load test.
Condition 1:5 ℃-shading-sealing
Condition 2:40 ℃-relative humidity 75%-is open
Condition 3:60 ℃-shading-sealing
Condition 4:80 ℃-shading-sealing
Condition 5:25 ℃-D65 (1000lux)-sealing
Chemical stability: pack MeOH into until scale marks in the measuring bottle of the sample after preservation is housed, with the sample dissolution after preserving as sample solution, this sample solution is diluted 100 times as standardized solution with MeOH, with the impurity in the standardized solution quantitative sample solution.The detection that it should be noted that impurity is carried out under the UV of 210nm, comprises that the operation of the device of data processing is carried out according to each device indicated method and order.(device: Agilent system LC-MSD1100 series)
Above-mentioned test-results is as shown in table 3.
[table 3]
| Test conditions | During this time | Impurity level (%) | |
| |
Reference example 2 | ||
| |
Two weeks | 0.00 | 0.25 |
| 1 month | 0.00 | 0.21 | |
| 2 months | 0.00 | 0.18 | |
| Condition 2 | Two weeks | 0.00 | 872 |
| 1 month | 0.00 | 8.19 | |
| 2 months | 0.00 | 9.20 | |
| |
Two weeks | 0.00 | 0.34 |
| 1 month | 0.00 | 0.22 | |
| 2 months | 0.00 | 0.24 | |
| |
Two weeks | 0.00 | 0.43 |
| 1 month | 0.00 | 0.39 | |
| 2 months | 0.00 | 0.47 | |
| |
Two weeks | 0.00 | 1.73 |
| 1 month | 0.00 | 238 | |
| 2 months | 0.00 | 3.68 | |
Shown in table 2 and table 3 as can be known: known compound is that the hydrochloride of compd A increases because of preservation impurity.Particularly, the stability to humidity (condition 2 of the condition 2 of test example 2 and test example 3) and light (condition 5 of the condition 3 of test example 2 and test example 3) is not high.On the other hand, shown in table 2 and table 3, the acid salt of compd A of the present invention and known compound are that the hydrochloride of compd A is compared, and do not find that almost the impurity that causes because of preservation increases.Physicochemical property are highly stable, have more excellent character as medicine or effective ingredient.It should be noted that and think that the melting point compound of embodiment 4 and embodiment 6 is low slightly, in the condition 1 of the test relevant-test example 2, melt with thermostability or preservation condition near fusing point, so confirm the increase of impurity.
Test example 4: to the functional affinity of bladder muscarine M3 acceptor
According to Ikeda etc., Naunyn-Schmiedeberg ' s Archives ofPharmacology, the method for the 366th volume 97-103 page or leaf (2002) is with Ca in the cell
2+Be changed to index, measure the functional affinity of test-compound to bladder muscarine M3 acceptor.Below, sketch this method.
Separate smooth muscle cell from the cavy bladder of having removed epithelium, additional thereon calcium susceptibility fluorochrome Fura2 is suspended in it and is added with in not containing of 20mM HEPES (pH7.4) and 0.1% bovine serum albumin of the phenol red Hanks damping fluid.The limit continues to stir this 490 μ L cell suspending liquid limit insulation at 28 ℃, observes the ratio of the fluorescence of the 500nm when 340nm excites with respect to the fluorescence of the 500nm when 380nm excites.In each cell suspending liquid, to continue to add test-compound and the carbachol solution of 5 μ L in 2 minutes at interval, will be from being about to be used for data parsing to peaked increase part before the stimulation.It is EC that 50% stimulation or 50% suppresses necessary concentration
50Or IC
50Try to achieve by applying mechanically S type curve, afterwards according to the EC of carbachol
50Value is used the IC of Cheng-Prusoff equation with test-compound
50Value transform is the Ki value.
Its result is as shown in table 4.
[table 4]
| Test-compound | IC 50(ng/mL) | Ki(nM) |
| |
24±0.75 | 0.68±0.21 |
| Embodiment 2 | 32±0.97 | 0.62±0.16 |
| |
38±1.2 | 0.69±0.19 |
| |
2.5±0.044 | 0.66±0.046 |
| |
1.8±0.79 | 0.47±0.12 |
| Embodiment 6 | 4.3±1.2 | 0.84±0.10 |
| Embodiment 7 | 1.8±0.49 | 0.66±0.28 |
| Embodiment 8 | 2.3±0.87 | 0.55±0.12 |
| Embodiment 9 | 2.2±0.33 | 0.56±0.048 |
| |
2.6±0.42 | 0.65±0.12 |
| Embodiment 11 | 22±0.87 | 0.52±0.13 |
| Embodiment 12 | 1.9±0.30 | 0.54±0.055 |
As implied above, as can be known: the acid salt of compd A of the present invention has sufficient affinity as drug use for muscarine M3 acceptor.
The carbachol of test example 5 anesthetized mices brings out the bladder contracts restraining effect
Test-compound is as follows to the inhibiting evaluation method of bladder contracts.
Use the vetanarcol (75mg/kg intravenous injection) of the consumption low slightly than lethal quantity to anaesthetize the female mice of body weight 30-35g, dorsal position is placed on the hot-plate to keep body temperature.(PE10) is inserted into intravesical from urethra with polyethylene catheter, adopts purse-string suture to be fixed on the urethra peristome.Insert the conduit that is used for injecting soup with the capacity of 3mL to the thigh intravenously.Bladder catheter is connected on the pressure transmitter by T-valve.To urinate discharge by conduit, make intravesical urine emptying, make expansion of the bladder, measure intravesical pressure with the physiological saline of about 100 μ L.
After intravesical pressure is stable, give the muscarine stimulant carbachol of 10 μ g/kg with the interval more than 15 minutes or 15 minutes.Utilize aforesaid method, tool circulation ratio ground produces bladder contracts during 2 hours, and without the deterioration of general body state.After obtaining three carbachol reactions, give test-compound after 10 minutes, increase consumption and inject carbachol repeatedly.Every kind of test-compound uses 4 to 5 mouse, obtains the preceding reaction inhibiting rate of compound administration, obtains the consumption (ID of the necessary test-compound of 50% inhibition by linear regression analysis
50).It should be noted that the mouse that demonstrates rhythmic bladder contracts is not used in data parsing.
Its result is: the ID of the compound of embodiment 1
50Value is 0.079mg/kg; The ID of the compound of embodiment 4
50Value is 0.090mg/kg; The ID of the compound of embodiment 5
50Value is 0.059mg/kg; The ID of the compound of embodiment 7
50Value is 0.050mg/kg; The ID of the compound of embodiment 8
50Value is 0.057mg/kg.
By above result as can be known: the acid salt of compd A of the present invention, it is inhibited to the bladder contracts of being brought out by muscarine stimulant carbachol.
Claims (17)
1. one kind (-)-(1R)-1-phenyl-1,2,3, the acid salt of 4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester and the acid that is selected from group S, wherein organizing S comprises: (-)-(2S, 3S)-tartrate, (+)-(2S, 3S)-two o-benzoyl tartrate, (+)-(2S, 3S)-two neighbour's (4-toluyl) tartrate, (-)-L-phenylalanine, Phenylsulfonic acid, cyclohexane sulfamic acid, Hydrogen bromide, naphthalene-2-sulfonic acid, sebacic acid, (+)-camphor-10-sulfonic acid, tosic acid, ethyl sulfonic acid, methylsulfonic acid and methyl orthophosphoric acid.
2. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (-)-(2S, 3S)-tartrate.
3. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (+)-(2S, 3S)-two o-benzoyl tartrate.
4. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (+)-(2S, 3S)-two neighbour's (4-toluyl) tartrate.
5. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (-)-L-phenylalanine salt.
6. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester benzene sulfonate.
7. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester cyclamate.
8. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester hydrobromate.
9. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester naphthalene-2-sulfonic acid salt.
10. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester sebacate.
11. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester (+)-camphor-10-sulfonate.
12. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester tosilate.
13. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester esilate.
14. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester mesylate.
15. the acid salt of claim 1, it is (-)-(1R)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-formic acid (3R)-rubane-3-base ester methyl orthophosphoric acid salt.
16. one kind with the acid salt of claim 1 pharmaceutical composition as effective constituent.
17. the pharmaceutical composition of claim 16, it is muscarine M
3Receptor antagonist.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005063405 | 2005-03-08 | ||
| JP063405/2005 | 2005-03-08 | ||
| JP088872/2005 | 2005-03-25 |
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| Publication Number | Publication Date |
|---|---|
| CN101137654A true CN101137654A (en) | 2008-03-05 |
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ID=39161075
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|---|---|---|---|
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