CN109369523A - A kind of preparation method and use of tetrahydroisoquinoline derivatives - Google Patents
A kind of preparation method and use of tetrahydroisoquinoline derivatives Download PDFInfo
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
本发明公开了一种四氢异喹啉类衍生物的制备方法，采用1‑(四氢吡咯‑1‑甲基)‑1，2，3，4‑四氢异喹啉和2，3‑二氢‑茚‑3‑酮‑1‑羧酸进行缩合制得，通过优化工艺条件，简化了制备步骤，并且制备过程中采用的试剂无污染，制得的四氢异喹啉类衍生物1‑(四氢吡咯‑1‑甲基)‑2‑(2，3‑二氢‑茚‑3‑酮‑1‑羰基)‑1，2，3，4‑四氢异喹啉对神经性疼痛具有良好的镇静作用，将其用于治疗疼痛的药物组合，替代吗啡等具有依赖性的镇痛药物，具有很高的医用价值。The invention discloses a preparation method of tetrahydroisoquinoline derivatives, which adopts 1-(tetrahydropyrrole-1-methyl)-1,2,3,4-tetrahydroisoquinoline and 2,3- Dihydro-indene-3-keto-1-carboxylic acid is prepared by condensation. By optimizing the process conditions, the preparation steps are simplified, and the reagents used in the preparation process are pollution-free, and the prepared tetrahydroisoquinoline derivatives 1 -(Tetrahydropyrrole-1-methyl)-2-(2,3-dihydro-indene-3-keto-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline for neuropathic pain It has a good sedative effect, and it is used as a drug combination for the treatment of pain, replacing the dependent analgesic drugs such as morphine, and has high medical value.
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to the preparation method of tetrahydroisoquinoliderivatives derivatives and contains
The Pharmaceutical composition of these compounds and their medical usage.
Background technique
Neuropathic pain is a kind of chronic pain disorders as caused by nervous system primary lesion or dysfunction, it is a variety of not
Same damage, such as wound, neurotrosis or infection disease can all cause neuropathic pain.The most common neuropathic pain type
Including diabetic neuralgia (DNP), post-herpetic neuralgia (PHN and the relevant neuropathic pain of AIDS.With it is secondary
Property (injury pain) on the contrary, neuropathic pain may occur after a couple of days or even several months after wound generation, usually from chronic pain
Bitterly, it is characterized in that hyperalgia, sense organ is sensitive to stimulation oversaturation, allodynia and spontaneous burning pain.Neuropathic pain at present
Therapeutic agent mainly include anticonvulsive drug, antidepressants, narcotic analgeiscs and local anesthetic.These drugs can be effective
Nociceptive pain is treated, but it is very limited to the treatment of neuropathic pain, and it is accompanied by serious side effect, including
Cognitive change, sedation, nausea and generation drug resistance and dependence.Accordingly, it is desirable to provide one kind can effectively treat and
Prevent neuropathic pain and the lesser drug of side effect.
Inventor have found in the course of the research a kind of tetrahydro isoquinoline derivative with structure of the invention have treat,
Activity in terms of prevention or alleviation neuropathy or neuropathic pain, can be applied to primary neuropathy, secondary neuropathy, surrounding
Neuropathy damages caused neuropathy, painful diabetic neuropathy (PDN) or phase by mechanical nerve injury or biochemical nerve
The exploitation for closing neurogenic disease drug, has broad application prospects.
Summary of the invention
In view of this, being moved the present invention provides a kind of preparation method of tetrahydro isoquinoline derivative and purposes through preliminary
Analgesic test is shown in object, and the compounds of this invention shows stronger neuropathic pain analgesic activities, specific using as follows
Technological means:
A kind of preparation method of tetrahydroisoquinoliderivs derivs, comprising the following steps:
1- (nafoxidine -1- methyl) -1,2,3,4- tetrahydroisoquinolines and 2,3- dihydro-indenes -3- are added in three-necked bottle
Then catalysts and solvents are added in ketone -1- carboxylic acid, condensing agent is added in ice bath stirring 0.5-1h later, react at room temperature 8-12h, mistake
Filter, filtrate cross chromatographic column, and obtaining white solid is tetrahydroisoquinoliderivs derivs 1- (nafoxidine -1- methyl) -2- (2,3- bis-
Hydrogen-indenes -3- ketone -1- carbonyl) -1,2,3,4- tetrahydroisoquinolines.
Further, by the mass ratio of the material, the 1- (nafoxidine -1- methyl) -1,2,3,4- tetrahydroisoquinolines: 2,3-
Dihydro-carboxylic acid=5 indenes -3- ketone -1-: 6.
Preferably, the solvent is methylene chloride, 1,2- dichloroethanes, acetonitrile, n,N-Dimethylformamide, N, N- diformazan
Yl acetamide or dimethyl sulfoxide；The catalyst is 4-dimethylaminopyridine or I-hydroxybenzotriazole；The condensing agent is two
Carbodicyclo hexylimide or 1- ethyl -3- (3- dimethylamino-propyl) carbodiimide hydrochloride.
Preferably, by the mass ratio of the material, the catalyst: carboxylic acid=10 2,3- dihydros-indenes -3- ketone -1-: 9.According to right
It is required that a kind of preparation method of tetrahydroisoquinoliderivs derivs described in 1, which is characterized in that the chromatographic column is petroleum ether: second
Acetoacetic ester: triethylamine=4: 1: 0.1 chromatographic column.
Specific reaction equation is as follows:
Wherein a represents reaction condition: i.e. addition condensing agent, catalyst and solvent, wherein condensing agent is dicyclohexyl carbon two
Imines or 1- ethyl -3- (3- dimethylamino-propyl) carbodiimide hydrochloride；Catalyst is 4-dimethylaminopyridine or 1- hydroxyl
Benzotriazole；Solvent be methylene chloride, 1,2- dichloroethanes, acetonitrile, n,N-Dimethylformamide, n,N-dimethylacetamide or
Dimethyl sulfoxide.
Preferably, the 1- (nafoxidine -1- methyl) -1,2,3,4- tetrahydroisoquinolines are prepared using following methods:
(1) β-phenyl ethylamine, sodium carbonate and dichloromethane solvent are added in three-necked bottle, ice bath slowly drips under stirring condition
Chlorination chloroacetic chloride, by the mass ratio of the material, β-phenyl ethylamine: sodium carbonate: chloracetyl chloride=1: 1: 1.2, it is warming up to 5-10 DEG C of reaction 2-
Ice water is added in 4h later, isolates organic layer and is successively washed with dilute hydrochloric acid and saturated sodium-chloride, and solvent is removed in drying, then ties again
Crystalline substance, filtration drying obtain white needle-like crystals one；
(2) xylene solvent and phosphorus pentoxide are added in three-necked bottle, stirring is warming up to 140-150 DEG C, nitrogen protection
It is lower be added step (1) white needle-like crystals, press the mass ratio of the material, phosphorus pentoxide: white needle-like crystals=25: 6, reflux instead
2-3h is answered, it is cooling later to pour out dimethylbenzene, ice water is added in remaining solid object and stirs 0.5-1h, sodium hydroxide adjusts pH, ether
It extracting, is filtered after the dry 8-12h of anhydrous sodium sulfate, filtrate is passed through HCl gas under the conditions of ice-water bath, solvent is poured out later,
Solids is dried to obtain, is dissolved in methanol later；
(3) methanol solvate and nafoxidine, ice bath and under nitrogen protection agitation and dropping step (2) are added in three-necked bottle
The methanol solution of solids, by the mass ratio of the material, nafoxidine: solids=4: 1, it is warming up to 25-30 DEG C of reaction 8-12h, ice
Bath, be added sodium borohydride, press the mass ratio of the material, nafoxidine: solids: sodium borohydride=2: 0.5: 0.1, reaction 2-3h, so
After be warming up to 25-30 DEG C of removing solvent, residue extraction goes out solvent up to 1- (nafoxidine -1- methyl)-after drying, filtering
1,2,3,4- tetrahydroisoquinoline.
Specific reaction equation is as follows:
Preferably, 2, the 3- dihydro-indenes -3- ketone -1- carboxylic acid is prepared with the following method:
(1) addition aniline, fluoborate solution are mixed evenly in three-necked bottle, and sodium nitrite is added dropwise under the conditions of ice-water bath
Solution, by the mass ratio of the material, aniline: fluoboric acid: sodium nitrite=1: 2: 1,0-5 DEG C of reaction 0.5-1h, filtering are successively adopted later
It is washed with dehydrated alcohol and ether, the diazobenzene borofluoride after natural drying；
(2) catalyst solution is added in three-necked bottle, maleic anhydride is added under ice bath stirring and the mixing of sodium hydroxide is molten
Acetone solvent is added in liquid, 0-5 DEG C of reaction 0.5-1h, and the diazobenzene fluoboric acid in step (1) is added under agitation later
Salt, by the mass ratio of the material, titanium trichloride: maleic anhydride: sodium hydroxide: diazobenzene borofluoride=6: 0.1: 0.2: 0.1, heating
To 25-30 DEG C of removing acetone, residue refrigerates crystallization, and filtering ice water is washed, recrystallizes, obtain phenylsuccinic acid；
(3) phenylsuccinic acid and chlorinating agent are added in three-necked bottle, by the mass ratio of the material, phenylsuccinic acid: chlorinating agent=1
: 3.5, flow back 1-2h, is added dropwise in the solvent A solution of alchlor later, and flow back 2-3h, and dilute salt is added in reaction solution
It is filtered after acid, obtained solid is dissolved with ethyl acetate, and saturated sodium carbonate extracts combining water layer, ether washing, water layer hydrochloric acid tune
PH is saved, solid filtering is generated, is drying to obtain 2,3- dihydro-indenes -3- ketone -1- carboxylic acid after ice water washing；
Wherein catalyst is titanium trichloride, and chlorinating agent is thionyl chloride, and solvent A is anhydrous methylene chloride.
Specific reaction equation is as follows:
The present invention also provides a kind of its pharmaceutically acceptable salts of tetrahydroisoquinoliderivs derivs, which is characterized in that is
Tetrahydroisoquinoliderivs derivs and it is following acid formed acid-addition salts: hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, tartaric acid,
One of phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or arginine.
The present invention also provides a kind of pharmaceutical compositions, which is characterized in that claim 1 preparation containing therapeutically effective amount
Tetrahydroisoquinoliderivs derivs and pharmaceutically acceptable carrier.
The present invention also provides a kind of purposes of tetrahydroisoquinoliderivs derivs, are mainly used in preparation for preventing or controlling
Treat the drug of neuropathic pain.
Specific embodiment
The following is a clear and complete description of the technical scheme in the embodiments of the invention, it is clear that described embodiment
Only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, the common skill in this field
Art personnel every other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
Embodiment 1
1- (nafoxidine -1- methyl) -1, the preparation of 2,3,4- tetrahydroisoquinolines:
(1) β-phenyl ethylamine 0.4mol (48.4g), sodium carbonate 0.4mol (4.24g) and dichloro are added in 500ml three-necked bottle
0 DEG C of ice bath temperature control, chloracetyl chloride 0.48mol (54.24g), time for adding is slowly added dropwise under stirring condition in methane solvent 300ml
1h is warming up to 5-10 DEG C of reaction 2-4h, and ice water 150ml is added later, isolates organic layer and successively uses 10% dilute hydrochloric acid and saturation
NaCl, solvent is removed in vacuum distillation after anhydrous sodium sulfate is dry, is then recrystallized, filtration drying, is obtained white with methanol-water
One 48g of acicular crystal；
(2) xylene solvent 300ml and phosphorus pentoxide 0.2mol (28.4g) is added in 500ml three-necked bottle, stirring rises
The white needle-like crystals 0.048mol (9.48g), back flow reaction 2- of step (1) is added to 140-150 DEG C in temperature under nitrogen protection
3h, it is cooling later to pour out dimethylbenzene, ice water 450ml is added in remaining solid object, stirs 0.5-1h, 50% sodium hydroxide adjusts pH
=11, ether extracts, and filters after the dry 8-12h of anhydrous sodium sulfate, and filtrate is passed through dry HCl gas under the conditions of ice-water bath, it
After solvent is poured out, dry to obtain solids 5.3g, be dissolved in methanol later；
(3) methanol solvate 40ml and nafoxidine 0.05mol (3.55g), ice bath and in nitrogen are added in 100ml three-necked bottle
The methanol solution of agitation and dropping step (2) solids 0.125mol (2.71g) under gas shielded is warming up to 25-30 DEG C of reaction 8-
12h, ice bath are added sodium borohydride 0.025mol (1.68g), react 2-3h, then heat to 25-30 DEG C of removing solvent, remaining
Object extracted by ether, vacuum distillation goes out solvent up to 1- (nafoxidine -1- methyl) -1,2 after anhydrous sodium sulfate dries, filters,
3,4- tetrahydroisoquinolines.
Embodiment 2
The preparation of 2,3- dihydros-indenes -3- ketone -1- carboxylic acid:
(1) addition aniline 0.5mol (63.8g), fluoborate solution 1mol (220ml) are mixed evenly in three-necked bottle,
Sodium nitrite 0.5mol (34.5g) solution is added dropwise under the conditions of ice-water bath, later 0-5 DEG C of reaction 0.5-1h, filtering successively uses nothing
Water-ethanol and ether wash each washing three times, the diazobenzene borofluoride after natural drying；
(2) titanium trichloride solution 12mol (323ml) is added in three-necked bottle, maleic anhydride is added under ice bath stirring
Acetone solvent is added in the mixed solution of 0.2mol (19.6g) and sodium hydroxide 0.4mol (16g), 0-5 DEG C of reaction 0.5-1h
500ml is added the diazobenzene borofluoride 0.2mol (45g) in step (1) under agitation later, is warming up to 25-30 DEG C
Acetone is removed, residue refrigerates crystallization, and filtering ice water is washed, and water recrystallization obtains phenylsuccinic acid；
(3) phenylsuccinic acid 0.2mol (22.8g) and thionyl chloride 0.35mol (25ml), reflux are added in three-necked bottle
1-2h is added dropwise to later in the anhydrous methylene chloride solution of alchlor 0.5mol (26.7g), and flow back 2-3h, is being reacted
It is filtered after 10% hydrochloric acid 375ml stirring 0.5h is added in liquid, obtained solid 550ml ethyl acetate dissolves, saturated sodium carbonate
Combining water layer after 300ml is extracted in three times, the washing of 40ml ether, water layer hydrochloric acid adjust pH=2, the solid filtering of generation, ice
Water washing is drying to obtain 2,3- dihydro-indenes -3- ketone -1- carboxylic acid afterwards twice.
Embodiment 3
The preparation of tetrahydroisoquinoliderivs derivs:
In three-necked bottle be added 1- (nafoxidine -1- methyl) -1,2,3,4- tetrahydroisoquinoline 4.5mmol (0.97g) and
Catalyst DMAP and methylene chloride, ice bath control is then added in 2,3- dihydros-indenes -3- ketone -1- carboxylic acid 5.4mmol (0.95g)
Condensing agent DCC6.3mmol (1.3g) is added later in 0 DEG C of stirring 0.5-1h of temperature, reacts at room temperature 8-12h under nitrogen protection, filters off
Except DCU, filtrate crosses petroleum ether: ethyl acetate: triethylamine=4: 1: 0.1 chromatographic column, obtaining white solid is tetrahydroisoquinoline
Analog derivative 1- (nafoxidine -1- methyl) -2- (2,3- dihydros-indenes -3- ketone -1- carbonyl) -1,2,3,4- tetrahydroisoquinolines.
Embodiment 4
Tetrahydroisoquinoliderivs derivs 1- made from Example 3 (nafoxidine -1- methyl) -2- (2,3- dihydros-indenes -
3- ketone -1- carbonyl) -1,2,3,4- tetrahydroisoquinoline 10mg, starch 70mg, maltodextrin 70mg mechanical stirring after mixing,
Ethyl alcohol is added and continues stirring to agglomerating, tabletting later is dry, and tablet is made.
Embodiment 5
Mice pain test:
Mouse 40 for choosing health status, half male and half female are divided into two groups, every group male and female quantity quantity each 10, remember
B group is combined for A；
A group is experimental group, is randomly divided into 5 groups, every group 2, is denoted as A1, A2, A3, A4, A5；
B group is control group, is randomly divided into 5 groups, every group 2, is denoted as B1, B2, B3, B4, B5；
1- made from A group subcutaneous administration embodiment 3 (nafoxidine -1- methyl) -2- (2,3- dihydros-indenes -3- ketone -1- carbonyl
Base) -1,2,3,4- tetrahydroisoquinolines are fine with the von Frey of 15.0g when being administered 5,10,15,30,45,60,70,80,90 minutes
Full scale determines mice pain reaction, if mouse paw withdrawal occurs when removing after von Frey cilium stimulates 8s or licks sufficient reaction, is denoted as
X is denoted as O if reactionless；
B group as a control group, is directly ached with the von Frey cilium measurement mouse of 15.0g within the time corresponding with A group
Pain reaction is denoted as X if mouse paw withdrawal occurs when removing after von Frey cilium stimulates 8s or licks sufficient reaction, if reactionless, note
For O；
Test result is as follows:
From the foregoing, it will be observed that the compound of the present invention has good analgesic activity to mouse within a certain period of time, can be used for controlling
Treat the pharmaceutical composition of pain.
Each embodiment in this specification is described in a progressive manner, the highlights of each of the examples are with other
The difference of embodiment, the same or similar parts in each embodiment may refer to each other.For device disclosed in embodiment
For, since it is corresponded to the methods disclosed in the examples, so being described relatively simple, related place is said referring to method part
It is bright.
The foregoing description of the disclosed embodiments enables those skilled in the art to implement or use the present invention.
Various modifications to these embodiments will be readily apparent to those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, of the invention
It is not intended to be limited to the embodiments shown herein, and is to fit to and the principles and novel features disclosed herein phase one
The widest scope of cause.
Claims (10)
1. a kind of preparation method of tetrahydroisoquinoliderivs derivs, which comprises the following steps:
1- (nafoxidine -1- methyl) -1,2,3,4- tetrahydroisoquinolines and 2,3- dihydro-indenes -3- ketone -1- are added in three-necked bottle
Then catalysts and solvents are added in carboxylic acid, condensing agent is added in ice bath stirring 0.5-1h later, reacts at room temperature 8-12h, filter, filter
Liquid crosses chromatographic column, and obtaining white solid is tetrahydroisoquinoliderivs derivs 1- (nafoxidine -1- methyl) -2- (2,3- dihydros -
Indenes -3- ketone -1- carbonyl) -1,2,3,4- tetrahydroisoquinolines.
2. a kind of preparation method of tetrahydroisoquinoliderivs derivs according to claim 1, which is characterized in that by substance
Measure ratio, the 1- (nafoxidine -1- methyl) -1,2,3,4- tetrahydroisoquinolines: carboxylic acid=5 2,3- dihydros-indenes -3- ketone -1-: 6.
3. a kind of preparation method of tetrahydroisoquinoliderivs derivs according to claim 1, which is characterized in that the solvent
For methylene chloride, 1,2- dichloroethanes, acetonitrile, n,N-Dimethylformamide, n,N-dimethylacetamide or dimethyl sulfoxide；It is described
Catalyst is 4-dimethylaminopyridine or I-hydroxybenzotriazole；The condensing agent is dicyclohexylcarbodiimide or 1- ethyl-
3- (3- dimethylamino-propyl) carbodiimide hydrochloride.
4. a kind of preparation method of tetrahydroisoquinoliderivs derivs according to claim 1, which is characterized in that by substance
Measure ratio, the catalyst: carboxylic acid=10 2,3- dihydros-indenes -3- ketone -1-: 9.
5. a kind of preparation method of tetrahydroisoquinoliderivs derivs according to claim 1, which is characterized in that the chromatography
Column is petroleum ether: ethyl acetate: triethylamine=4: 1: 0.1 chromatographic column.
6. a kind of preparation method of tetrahydroisoquinoliderivs derivs according to claim 1, which is characterized in that the 1-
(nafoxidine -1- methyl) -1,2,3,4- tetrahydroisoquinolines are prepared using following methods:
(1) β-phenyl ethylamine, sodium carbonate and dichloromethane solvent are added in three-necked bottle, chlorine is slowly added dropwise under stirring condition in ice bath
Chloroacetic chloride, by the mass ratio of the material, β-phenyl ethylamine: sodium carbonate: chloracetyl chloride=1: 1: 1.2, it is warming up to 5-10 DEG C of reaction 2-4h, it
After ice water is added, isolate organic layer and successively washed with dilute hydrochloric acid and saturated sodium-chloride, drying remove solvent, then recrystallize, mistake
It is filtered dry dry, obtains white needle-like crystals one；
(2) xylene solvent and phosphorus pentoxide are added in three-necked bottle, stirring is warming up to 140-150 DEG C, adds under nitrogen protection
The white needle-like crystals for entering step (1), by the mass ratio of the material, phosphorus pentoxide: white needle-like crystals=25: 6, back flow reaction 2-
3h, it is cooling later to pour out dimethylbenzene, ice water is added in remaining solid object and stirs 0.5-1h, adjusts 50% sodium hydroxide and adjusts pH=
11, ether extracts, and filters after the dry 8-12h of anhydrous sodium sulfate, filtrate is passed through HCl gas under the conditions of ice-water bath, topples over later
Solvent out dries to obtain solids, is dissolved in methanol later；
(3) methanol solvate and nafoxidine, ice bath and under nitrogen protection agitation and dropping step (2) solid are added in three-necked bottle
The methanol solution of object, by the mass ratio of the material, nafoxidine: solids=4: 1, it is warming up to 25-30 DEG C of reaction 8-12h, ice bath adds
Enter sodium borohydride, by the mass ratio of the material, nafoxidine: solids: sodium borohydride=2: then 0.5: 0.1, reaction 2-3h heat up
To 25-30 DEG C of removing solvent, residue extraction goes out solvent up to 1- (nafoxidine -1- methyl) -1,2,3 after drying, filtering,
4- tetrahydroisoquinoline.
7. a kind of preparation method of tetrahydroisoquinoliderivs derivs according to claim 1, which is characterized in that described 2,3-
Dihydro-indenes -3- ketone -1- carboxylic acid is prepared with the following method:
(1) addition aniline, fluoborate solution are mixed evenly in three-necked bottle, and it is molten that sodium nitrite is added dropwise under the conditions of ice-water bath
Liquid, by the mass ratio of the material, aniline: fluoboric acid: sodium nitrite=1: 2: 1,0-5 DEG C of reaction 0.5-1h, filtering successively use later
Dehydrated alcohol and ether washing, the diazobenzene borofluoride after natural drying；
(2) titanium trichloride solution is added in three-necked bottle, the mixed solution of maleic anhydride and sodium hydroxide is added under ice bath stirring,
Acetone solvent is added in 0-5 DEG C of reaction 0.5-1h, and the diazobenzene borofluoride in step (1) is added under agitation later, presses
The mass ratio of the material, titanium trichloride: maleic anhydride: sodium hydroxide: diazobenzene borofluoride=6: 0.1: 0.2: 0.1, it is warming up to 25-
30 DEG C of removing acetone, residue refrigerate crystallization, and filtering ice water is washed, recrystallizes, obtain phenylsuccinic acid；
(3) phenylsuccinic acid and chlorinating agent are added in three-necked bottle, by the mass ratio of the material, phenylsuccinic acid: chlorinating agent=1:
3.5, flow back 1-2h, is added dropwise in the solvent A solution of alchlor later, and flow back 2-3h, and dilute salt is added in reaction solution
Filtered after acid, solid dissolved with ethyl acetate, saturated sodium carbonate extract combining water layer, ether washing, water layer hydrochloric acid tune
PH=2 is saved, solid filtering is generated, is drying to obtain 2,3- dihydro-indenes -3- ketone -1- carboxylic acid after ice water washing；
Wherein chlorinating agent is thionyl chloride, and solvent A is anhydrous methylene chloride.
8. a kind of its pharmaceutically acceptable salt of tetrahydroisoquinoliderivs derivs, which is characterized in that derivative for tetrahydroisoquinolicompounds
The acid-addition salts that object and following acid are formed: hydrochloric acid, hydrobromic acid, sulfuric acid, carbonic acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetone
One of acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or arginine.
9. a kind of pharmaceutical composition, which is characterized in that tetrahydroisoquinolicompounds prepared by the claim 1 containing therapeutically effective amount spread out
Biology and pharmaceutically acceptable carrier.
10. a kind of tetrahydroisoquinoliderivs derivs are preparing the purposes in the drug for preventing or treating neuropathic pain.
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| CN201811412473.7A Pending CN109369523A (en) | 2018-11-21 | 2018-11-21 | A kind of preparation method and use of tetrahydroisoquinoline derivatives |
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| Country | Link |
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| CN (1) | CN109369523A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110041257A (en) * | 2019-04-25 | 2019-07-23 | 河南师范大学 | A method of synthesis indenes spiral shell indenes [1,2-c] isoquinolin trione compounds |
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| CN1887872A (en) * | 2006-07-12 | 2007-01-03 | 中国药科大学 | Tetrahydro isoquinoline derivative and its prepn process and medicine use |
| CN102190650A (en) * | 2011-03-30 | 2011-09-21 | 中国药科大学 | Method for preparing indoquinoline tartrate |
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- 2018-11-21 CN CN201811412473.7A patent/CN109369523A/en active Pending
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| CN1887872A (en) * | 2006-07-12 | 2007-01-03 | 中国药科大学 | Tetrahydro isoquinoline derivative and its prepn process and medicine use |
| CN102190650A (en) * | 2011-03-30 | 2011-09-21 | 中国药科大学 | Method for preparing indoquinoline tartrate |
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| ZONG-JIE GAN ET AL.: "Discovery, stereospecific characterization and peripheral modification of 1-(pyrrolidin-1-ylmethyl)-2-[(6-chloro-3-oxo-indan)-formyl]-1,2,3,4-tetrahydroisoquinolines as novel selective κ opioid receptor agonists", 《ORG.BIOMOL.CHEM.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110041257A (en) * | 2019-04-25 | 2019-07-23 | 河南师范大学 | A method of synthesis indenes spiral shell indenes [1,2-c] isoquinolin trione compounds |
| CN110041257B (en) * | 2019-04-25 | 2021-08-03 | 河南师范大学 | A kind of method for synthesizing indenespiroindene[1,2-c]isoquinolinetrione compounds |
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