CN100390165C - Medicinal composition containing alkyl acyl ramosqiong and its application - Google Patents
Medicinal composition containing alkyl acyl ramosqiong and its application Download PDFInfo
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- CN100390165C CN100390165C CNB2005100139034A CN200510013903A CN100390165C CN 100390165 C CN100390165 C CN 100390165C CN B2005100139034 A CNB2005100139034 A CN B2005100139034A CN 200510013903 A CN200510013903 A CN 200510013903A CN 100390165 C CN100390165 C CN 100390165C
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- Prior art keywords
- ramosqiong
- alkyl acyl
- ranimustine
- pharmaceutical composition
- vomiting
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- 125000005257 alkyl acyl group Chemical group 0.000 title claims description 20
- 239000000203 mixture Substances 0.000 title abstract description 7
- 206010047700 Vomiting Diseases 0.000 claims abstract description 22
- 230000008673 vomiting Effects 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 6
- 239000003981 vehicle Substances 0.000 claims description 6
- 238000002512 chemotherapy Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000003405 delayed action preparation Substances 0.000 claims description 2
- 206010025482 malaise Diseases 0.000 claims description 2
- -1 alkanoyl ramosetron Chemical compound 0.000 abstract description 23
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 8
- 229950001588 ramosetron Drugs 0.000 abstract description 6
- 208000024891 symptom Diseases 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 2
- 206010028813 Nausea Diseases 0.000 abstract 1
- 230000000973 chemotherapeutic effect Effects 0.000 abstract 1
- 230000008693 nausea Effects 0.000 abstract 1
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- NTHPAPBPFQJABD-LLVKDONJSA-N ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 description 4
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- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 2
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
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- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
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Images
Abstract
The present invention discloses the medicinal value and the new purpose of alkanoyl ramosetron represented by the structural formula I, namely the application of the compound (of the formula I) for preventing digestive tract symptoms such as nausea, vomiting, etc. caused by chemotherapeutic medicines, or for preparing medicines treating the symptoms. The present invention also discloses a medical composition using alkanoyl ramosetron as an active ingredient.
Description
Technical field
The invention belongs to medical technical field, or rather, relate to the application of alkyl acyl ramosqiong in preparation prevention or treatment emesis medicine.The present invention also discloses simultaneously and has comprised the pharmaceutical composition of forming as the alkyl acyl ramosqiong of the treatment significant quantity of activeconstituents.
Background technology
Ramosetron hydrochloride (Ramosetron hydrochloride) is after listing in 96 years, as the powerful highly selective 5-HT of a new generation
3Receptor antagonist is subjected to international generally attention, and many scholars have carried out a large amount of research to its pharmacological action, toxicity.It is to be present in the 5-HT that imports the vagus nerve tip in the gastrointestinal mucosal into by blocking-up
3Acceptor, suppress that chemotherapeutics, operation etc. cause feel sick, gastrointestinal side effect such as vomiting.Proved, be mainly used in symptoms of digestive tract such as prevention or treatment chemotherapy, radiotherapy are drug-inducedly felt sick, vomiting by a large amount of clinical trials.
Alkyl acyl ramosqiong is the intermediate in the ranimustine building-up process, has the compound of following formula structure
Its chemical name is: carbonyl 1-alkyloyl-5-[(1-skatole-3-yl)]-4,5,6, the 7-Tetrahydrobenzimidazderivative.
Alkyl acyl ramosqiong is that the inventor at first develops discovery; on November 2nd, 2004; applied for " a kind of novel method of synthetic hydrochloric acid ranimustine " patent of invention; application number is 2000410072595.8; in this application; be described in detail with the Tetrahydrobenzimidazderivative is starting raw material; adopt the protection of imidazole ring acyl group; prepare the Tetrahydrobenzimidazderivative derivative of acidylate; with after the aromatic carbon acidylate; make alkyl acyl ramosqiong (I), again through acid hydrolysis, the novel method of preparation DL ranimustine.
Unexpectedly, have now found that the rat vomiting model that disclosed alkyl acyl ramosqiong is adopting cis-platinum to cause; observation is to the validity aspect of antiemetic; demonstrate higher pharmacologically active, and compare with ranimustine, the result shows to have tangible antiemetic effect.
Summary of the invention
One object of the present invention is, discloses the alkyl acyl ramosqiong compound.
Another object of the present invention is, discloses the purposes of alkyl acyl ramosqiong as emesis medicine aspect.
A further object of the present invention is that disclosing with the alkyl acyl ramosqiong is the pharmaceutical composition of main active ingredient.
Content of the present invention is achieved by the following technical programs:
A kind of alkyl acyl ramosqiong of representing by following structural formula I
Wherein, R is C
1～C
3Straight-chain paraffin, comprising:
1-ethanoyl-5-[(1-skatole-3-yl) carbonyl]-4,5,6, the 7-Tetrahydrobenzimidazderivative.
1-propionyl-5-[(1-skatole-3-yl) carbonyl]-4,5,6, the 7-Tetrahydrobenzimidazderivative.
1-butyryl radicals-5-[(1-skatole-3-yl) carbonyl]-4,5,6, the 7-Tetrahydrobenzimidazderivative.
The present invention further discloses alkyl acyl ramosqiong,, particularly, be used to prepare prevention or treatment because of the application aspect feeling sick of causing of chemotherapy, the vomiting medicine in the purposes that is used to prepare aspect prevention or the treatment emesis medicine with said structure formula I.
Learn experiment below by pharmacodynamics and general pharmacology and further specify the vomiting restraining effect of alkyl acyl ramosqiong of the present invention rat.
One, general pharmacology is learned experiment
1, central nervous system
At mouse body internal jugular vein injection acetyl ranimustine, when dosage reaches 1000ug/kg, do not influence the common behavioral activity of mouse.When dosage is 100ug/kg, do not influence the behavior of mouse autonomic movement.Mouse mainline acetyl ranimustine does not influence owing to symptoms such as the anesthesia of using barbiturate or reasons such as electricity irritation, medicine irritation to cause or spasm.
2, respiratory circulatory system
Anesthesia dog body internal jugular vein injection acetyl ranimustine, when dosage reached 1000ug/kg, transience appears in blood pressure, left ventricular pressure slightly to be reduced, and carotid artery and femoral artery blood flow transience slightly increase.During dosage 0-1000ug/kg, electrocardiogram(ECG does not have considerable change.
3, gi system
In the guinea pig ileum experiment of exsomatizing, concentration is 10
-4The acetyl ranimustine solution of M can suppress the ileum contraction that Acetyl Chloride 98Min., histamine, bariumchloride etc. cause.
Intravenous injection acetyl ranimustine when dosage reaches 100ug/kg, does not influence the GI transmission of mouse or rat and arranges effects such as routed; This dosage does not cause that ferret produces emetic action.
Two, pharmacodynamic experiment
1 test objective
Multiple nauseant inductive rat vomiting such as copper sulfate, apomorphine and cis-platinum model, its animal shows as pica, and promptly animal is had a liking for the no nutritive substance of food, as kaolin.The rat vomiting model that this research adopts cis-platinum to cause is observed the validity of acetyl ranimustine to antiemetic, and compares with ranimustine.
2 test materialss
Medicine: the acetyl ranimustine, Kanghong Medicine Tech Development Co., Ltd., Tianjin provides, and molecular weight is 321.Face with the preceding solution of desired concn that is mixed with physiological saline for the animal used for intravenous injection.
Positive control drug: ramosetron hydrochloride, Kanghong Medicine Tech Development Co., Ltd., Tianjin provides, and molecular weight is 315.5.Face with the preceding solution of desired concn that is mixed with physiological saline for the animal used for intravenous injection.
Nauseant: cisplatin for inj, Jiutai Pharmaceutical Co Ltd, Jinzhou City's product, lot number 041101.The 20mg/ bottle.Face with preceding and dissolve, and be diluted to desired concn with physiological saline with water for injection.
Kaolin: Tianjin reagent two factory's products, lot number 20010828.
Gum arabic powder: the special chemical in Rui Jin, Tianjin company limited product, lot number 20041013.
Kaolin pellet preparation: 50g kaolin mixes with 1% gum arabic, and adds an amount of distilled water, be twisted into spherical, drying at room temperature, stand-by.
The preparation of normal diet pellet: the rat conventional feed adds an amount of distilled water, is twisted into onesize pellet, and drying at room temperature is stand-by.
Animal: male Wistar rat, Tianjin Inst. of Materia Medica laboratory animal room provides, animal conformity certification number: No. the 001st, Tianjin kinoplaszm word.
3 test methods
70 of male Wistar rats, the about 150g of body weight is divided into 7 groups at random by body weight, 10 every group.The single cage of animal is raised, and every cage adds 1 kaolin pellet and normal diet pellet, first acclimatization training 3 days.With the different food kaolin of last 24h amount as moulding before basic value.After acclimatization training is finished, the model group tail vein injection gives physiological saline, 3 are subjected to reagent group tail vein injection to give the acetyl ranimustine, dosage is respectively 1,3,10 μ g/kg, 3 positive drug group tail vein injections give ramosetron hydrochloride, dosage is respectively 1,3,10 μ g/kg, and the administration volume is 10ml/kg.Behind the 10min, the equal abdominal injection nauseant of animal (cis-platinum 10mg/kg) causes the vomiting model, and the rat vomiting shows as in behavior has a liking for food kaolin pica.Each treated animal administration every day 1 time, successive administration 4 days.Measure the kaolinic amount of the different food of 24h of respectively organizing every day, with to the inhibition of pica effect as suppressing vomiting reaction.Carry out statistical procedures with the t-check, observe the antiemetic effect of medicine.
4 test-results
Normal rat 24h kaolin intake is less, is 0.06 ± 0.09g.Behind the abdominal injection cis-platinum, the kaolin intake obviously increases, and is 0.70 ± 0.26g, and tangible significant difference (P＜0.01) is arranged before the moulding, shows that the vomiting model forms success.After reduce gradually, recovered to approach to normal level to 3-4 days.
4.1 acetyl ranimustine validity
The rat vomiting model that intravenous injection acetyl ranimustine 1-10 μ g/kg causes cis-platinum has the antiemetic effect of dose- dependently.Acetyl ranimustine 1,3,10 μ g/kg antiemetic effects have suppressed 9.8%, 33.7%, 45.8% respectively; ED
50Be 9.9 μ g/kg.
4.2 compare with ranimustine
Ranimustine is dose-dependent inhibition to the rat vomiting effect that cis-platinum causes, 1,3,10 μ g/kg antiemetic effects have suppressed 25.6%, 39.2%, 51.3% respectively; ED
50Be 8.4 μ g/kg.Compare with the ranimustine equimolecular, press ED
50Conversion acetyl ranimustine suppresses the vomiting effect and is about 86% of ranimustine.
5 conclusions
1) the acetyl ranimustine can obviously suppress the different food kaolin of rat that cis-platinum causes, shows the effect with obvious antiemetic.
2) compare with ranimustine, the antiemetic effect of acetyl ranimustine is about 86% of its antiemetic effect.
The present invention further discloses the pharmaceutical composition of treatment vomiting, it comprises compound and one or more pharmaceutically acceptable carrier, vehicle or the thinner of 0.1%～90% (weight) as the claim 1 of activeconstituents.
Further preferred 0.5%～70% (weight) is as compound and one or more pharmaceutically acceptable carriers, vehicle or the thinner of the claim 1 of activeconstituents.
Described pharmaceutical composition comprises: oral preparations, liquid preparation or sustained release preparation a kind of.Be preferably liquid preparation, as small-volume injection, powder pin, intravenous infusion or the like.These compositions prepare with well-known method in the medicine specialty, and contain a kind of active compound at least.
Be prepared as follows: use standard and conventional technology make on The compounds of this invention and the technology of pharmaceutics acceptable solid or liquid vehicle combine, and make it at random to combine with acceptable auxiliary and vehicle on the technology of pharmaceutics and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.Solid carrier can be at least a material, and it can serve as thinner, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.
Liquid dosage form comprises solvent, suspension for example injection, pulvis, large and small transfusion, intravenous drip liquid or the like.Liquid vehicle comprises: isotonic agent such as glucose, sodium-chlor, sorbyl alcohol.The mixed solvent of one or more in non-aqueous solvent such as ethanol, propylene glycol, glycerine, polyoxyethylene glycol-400 solvent.Solubility promoter such as N.F,USP MANNITOL, Sodium.alpha.-hydroxypropionate, nucite or the like.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (alkyl acyl ramosqiong) can be according to patient's the state of an illness, specific being applied of situation of diagnosis; the amount of used compound or concentration are regulated in the scope of a broad; therefore, this composition contains the claimed compound of the present invention of have an appointment 0.1%～90% (weight).Another preferred range is 0.5%-70%.
Description of drawings
The rat that Fig. 1 causes cis-platinum for the acetyl ranimustine vomits the influence of the different appetite of model.
The rat that Fig. 2 causes cis-platinum for ranimustine vomits the influence of the different appetite of model.
Embodiment
The present invention is further illustrated below in conjunction with embodiment,
For the preparation method of alkyl acyl ramosqiong of the present invention more clearly is described, provide following synthetic route.
The preparation of raw material 5-carboxylate methyl ester benzoglyoxaline vitriol of the present invention makes with reference to benzimidazoles derivative synthesis preparation method in meticulous organic chemical industry's handbook (P482-496).
4,5,6, the preparation of 7-Tetrahydrobenzimidazderivative-5-carboxylic acid vitriol (II) is to adopt the method for Chinese patent ZL90100544.4 to obtain (embodiment 1-2 specifically sees reference).
Reference example 1
The preparation of 5-carboxylate methyl ester benzoglyoxaline vitriol
Add 3200ml methyl alcohol in the reaction flask of 5L, the 5-carboxylic acid benzoglyoxaline vitriol of 304g stirs the vitriol oil of Dropwise 35 2ml down, reflux 7 hours, cooling, the activated carbon of adding 20g, reflux 0.5 hour, heat filtering, filtrate concentrates, cooling, get white crystals, filtration, dry 240g, fusing point: 169-171 ℃, the yield 74% of getting.
Reference example 2
4,5,6, the preparation (II) of 7-Tetrahydrobenzimidazderivative-5-carboxylic acid vitriol
In the autoclave of 2L, add the acetate of 1200ml, the 5-carboxylic acid benzoglyoxaline methyl esters vitriol of 80g, the 10%Pd/C of 40g (dry weight), 80 ℃, 60kg/cm
2Pressure condition under about 16 hours of hydrogenation (no longer change to pressure till), cooling, discharging, filtering catalyst, concentrating under reduced pressure gets light yellow oil, the 6N hydrochloric acid that adds 300ml, reflux 4 hours is evaporated to driedly, adds the acetone of 30ml, filter, dry, as to get 53.6g white crystals, fusing point 145-148 ℃, yield 70%.
1-ethanoyl-5-carboxylic acid-4,5,6, the preparation of 7-benzoglyoxaline (III)
With 4,5,6 of 66g, 7-Tetrahydrobenzimidazderivative-5-carboxylic acid vitriol, the triethylamine of 62.0g, the acetonitrile of 300ml add in the reaction flask, drip the 36.2g Acetyl Chloride 98Min., reflux stirred 4 hours, acetonitrile layer was evaporated to dried, cooling, the water of dropping 300ml is used ethyl acetate extraction, drying is filtered, and filtrate decompression is concentrated into dried, get brown oil 70g, can directly drop into next step and react.
1-ethanoyl-5-[(1-skatole-3-yl) carbonyl]-4,5,6, the preparation of 7-Tetrahydrobenzimidazderivative (I)
With acetyl Tetrahydrobenzimidazderivative 70g, the acetonitrile of 200ml, the sulfur oxychloride of 40ml adds in the reaction flask, is heated to backflow, stirs 2 hours, and underpressure distillation goes out partial solvent and takes excessive sulfur oxychloride out of.Cool off, the Pyrrolidine of slow Dropwise 5 3g and the acetonitrile solution of 100ml under 2 ℃ condition drip and finish, and are warming up to room temperature, stir 2 hours, and 40 ℃ were stirred 1 hour, and concentrating under reduced pressure gets brown oil 132g.
With the brown oil of 132g, the N-skatole of 100g adds in the acetonitrile of 300ml, adds the phosphoryl chloride of 132g, stirs 7 hours under heating, vigorous reflux, is chilled to room temperature.Under the cooling conditions, slowly drip the water of 660ml, the ethyl acetate of 500ml stirs, layering, organic layer is used anhydrous magnesium sulfate drying after washing 2 times with water, filters, and is evaporated to dried light brown solid 87.7g, fusing point: 176-178 ℃, yield 81.2%, the HPLC detection level is greater than 98%.
Carry out structural identification by nuclear-magnetism, concrete test result as follows:
1H?NMR(400MHz，CDCl
3)δ：2.03-2.04(1H，d)，2.21(1H，s)，2.66(3H，s)，2.79-3.23(4H，m)，3.47(1H，s)，3.855(3H，s)，7.258-7.34(3H，m)，7.79(1H，s)，8.36-8.51(2H，q).
1-propyl group-5-[(1-skatole-3-yl) carbonyl]-4,5,6, the preparation of 7-Tetrahydrobenzimidazderivative (I)
With propionyl Tetrahydrobenzimidazderivative 700g, the acetonitrile of 3300ml, the sulfur oxychloride of 400ml adds in the reaction flask, is heated to backflow, stirs 6 hours, and underpressure distillation goes out partial solvent and takes excessive sulfur oxychloride out of.Cool off, the Pyrrolidine of slow Dropwise 5 30g and the acetonitrile solution of 1650ml under 10 ℃ condition drip and finish, and are warming up to room temperature, stir 2 hours, and 40 ℃ were stirred 1 hour, and concentrating under reduced pressure gets brown oil 1320g.
With the brown oil of 1320g, the N-skatole of 530g adds in the acetonitrile of 6600ml, adds the phosphoryl chloride of 1320g, stirs 10 hours under heating, vigorous reflux, is chilled to room temperature.Under the cooling conditions, slowly drip the water of 6600ml, the ethyl acetate of 1000ml stirs, layering, and organic layer use anhydrous magnesium sulfate drying after washing 2 times with water, and filtration is evaporated to dried light brown solid 580g, and fusing point: 165-168 ℃, yield 78%.
For explanation more fully, the pharmaceutical composition that contains alkane acyl acyl ranimustine of the present invention provides example of formulations below, and described embodiment only is used for explanation, rather than is used to limit the scope of the invention.Described preparation can use any active compound in the The compounds of this invention.
Prepare hard gelatin capsule with following compositions
Consumption/capsule weight concentration (%)
Acetyl ranimustine 20mg 10.0
Dry starch 200mg 43.0
Magnesium Stearate 10mg 2.0
After the mentioned component mixing, be packed in the hard gelatin capsule with 460mg.
Consumption/sheet weight concentration (%)
Propionyl ranimustine 10mg 10.0
Starch 45mg 45.0
Carboxymethyl starch sodium salt 4.5mg 4.5
Magnesium Stearate 0.5mg 0.5
Talcum powder 1mg 1.0
Supplementary material is dry in advance, and it is standby to cross 100 mesh sieves.Earlier with the abundant mixing of the auxiliary material of recipe quantity.Bulk drug is added in the auxiliary material to increase progressively dilution method, and each abundant mixing of added-time 2-3 time guarantees medicine and the abundant mixing of auxiliary material, cross 20 mesh sieves, dry 2h in 55 ℃ of ventilated drying ovens, dried particle cross the arrangement of 16 mesh sieves, measure intermediate content, mix compressing tablet on tabletting machine.
The preparation of injection liquid (little pin)
Acetyl ranimustine 20mg
Lactic acid 100mg
Polysorbate 80 10mg
Sodium-chlor is an amount of
Water for injection 300ml
Get activeconstituents and join in the water for injection that dissolves sorbyl alcohol and lactic acid, add medicinal basic and regulate pH value and make its dissolving to 4-8.Add gac, whip attachment 30 minutes, carbon removal, smart filter, embedding, sterilization.
The preparation of injection lyophilized powder
Acetyl ranimustine 100mg
Medicinal basic 0.1-7%
N.F,USP MANNITOL 55-85%
Get activeconstituents and add water for injection, regulate pH value with medicinal basic and make its dissolving to 4-8.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, seals promptly.
Claims (6)
1. alkyl acyl ramosqiong of representing by following structural formula I
Wherein, R is C
1～C
3Alkyl.
2. the alkyl acyl ramosqiong of claim 1 is in the purposes that is used to prepare aspect prevention or the treatment emesis medicine.
3. the alkyl acyl ramosqiong of claim 1 is being used to prepare prevention or treatment because of the application aspect feeling sick of causing of chemotherapy, the vomiting medicine.
4. pharmaceutical composition that is used for the treatment of vomiting, it comprises alkyl acyl ramosqiong and one or more pharmaceutically acceptable carriers, vehicle or the thinner that weight percent is 0.1%～90% claim 1.
5. pharmaceutical composition as claimed in claim 4 is characterized in that the pharmaceutical composition for preparing is a kind of of oral preparations, liquid preparation or sustained release preparation.
6. pharmaceutical composition as claimed in claim 5 is characterized in that the pharmaceutical composition for preparing is a liquid preparation.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1045583A (en) * | 1989-02-02 | 1990-09-26 | 山之内制药株式会社 | Tetrahydrobenzimidazderivative derivative |
| CN1315823C (en) * | 2004-11-02 | 2007-05-16 | 天津康鸿医药科技发展有限公司 | New method for synthesizing Ramosetron Hydrochloride |
-
2005
- 2005-06-24 CN CNB2005100139034A patent/CN100390165C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1045583A (en) * | 1989-02-02 | 1990-09-26 | 山之内制药株式会社 | Tetrahydrobenzimidazderivative derivative |
| CN1315823C (en) * | 2004-11-02 | 2007-05-16 | 天津康鸿医药科技发展有限公司 | New method for synthesizing Ramosetron Hydrochloride |
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