CN1042895C - Medicines composition and its method for treating drop syndrome and de-addiction of drugaddict - Google Patents
Medicines composition and its method for treating drop syndrome and de-addiction of drugaddict Download PDFInfo
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Abstract
The present invention relates to a medical composition and a method for treating drop syndrome and de-addiction of a drug addict. The medical composition contains aconitane derivatives and tetrahydro protoberberine derivatives. The medical composition contains cholinolytic medicine and excipient vehicle which is frequently used in the field of pharmacy, or does not contain the cholinolytic medicine or the excipient vehicle which is frequently used in the field of pharmacy.
Description
The present invention relates to treat the pharmaceutical composition of junkie withdrawal syndrome and withdrawal.
Used term " drugs " means that continuous use can make the people produce dependent material among the present invention, as opium, morphine, heroin, cocaine, Fructus Cannabis and amphetamine etc.
When term used herein " dependency " means the continuous application drugs, a kind of health (physiology) state or spirit (psychology) state that drugs and body interact and caused, show as of behavior or other reaction of a kind of non-under compulsion therapeutic purposes prison with drugs, in order to avoid because disconnected with the caused withdrawal syndrome of drugs, or in order to experience its spiritual effect.
Used term " withdrawal syndrome " means owing to use drugs continuously among the present invention, thereby the patient who becomes dependent on drugs, in case interrupt using, the violent physiological reaction that health produced and a series of symptoms of occurring, as perspire, shed tears, yawn, shiver with cold, cover with gooseflesh, platycoria, vomiting, diarrhoea, stomachache, rhythm of the heart increase, increased blood pressure, insomnia, mad dry, tremble and symptomes complice such as delirium.
It is reported that whole world junkie has 5,000 ten thousand people at present.Sale of drugs turnover is about 5,000 hundred million dollars/year.Take drugs and to bring grievous injury on the one hand people's mind ﹠ body, as forfeit personal dignity, morals are fallen low, and health level descends, the lost of life, and serious withdrawal syndrome can appear in the disconnected time spent, sometimes even threat to life; On the other hand, take drugs and bring factor leading to social instability to society again, because junkie is one of important root of various crimes for obtaining drugs often by fair means or foul.Therefore, social drug abuse phenomenon serious threat the progress and the safety of human society.At the phenomenon of day by day seriously taking drugs, countries in the world government has taked to forbid the drug abuse measure, but the drug abuse phenomenon still is the gesture of the development of stretching.Therefore, seek the curative effect height, anti-additive medicament that side effect is little and drug rehabilitation method have become the urgent task of human society.
At present, the drug rehabilitation method that adopt countries in the world mainly is the medicine method of abstention, and following three kinds of methods are generally arranged:
1. diminishing method: the Main Ingredients and Appearance of the used medicine of this method is an opium.During treatment, press treatment stage, opium content is successively decreased gradually, until finally being kept to zero.
2. the method for substitution: this method is with analgesic cethadone treatment junkie.
3. other drug therapy: the medicine that is used to quit drug abuse still has buprenorphine (Bupre-norphine), clonidine (Clonidine), Cyc (Cyclazocine) and dihydroetorphine hydrochlorate (Dihydroetor phine hydrochloride) etc., easily cause mental disorder, excitement but these medicines have, the drug withdrawal that has promptly produces withdrawal syndrome or the drug withdrawal syndrome occurs.
Practice shows that above-mentioned three kinds of drug rehabilitation methods all exist major defect.For example, the required drug rehabilitation time of diminishing method is long, and can not be from removing the dependency of junkie to drugs in essence, and the drug rehabilitation back is junkie ratio height heavily again; The used methadone of the method for substitution is narcotics and has drug dependence that the drug dependence that oral 100mg methadone is produced is identical with injection 10mg morphine.In addition, methadone itself also has many side effect, and as the poisoning that emphysema, immunology symptom, sexual impotence and body accumulation cause, severe patient can cause loses the sight of both eyes, the women of life-time service methadone, and its neonate also has withdrawal symptom.The used drug side effect of aforementioned other medicines therapy is bigger, and have drug dependence arranged.
At present, the medicine of developing that is used to quit drug abuse also has: Abboll 69024, A-manlidin, Bupropion, Buprenorphine, Bromocripline, Buspirone, Carbamazepine (Tegrelol), Fluoxeline (Prozac), Flupenthixol, Gepirone, Laam, Mazindol, (see Scientific American, March 1991, PP71-79) for Nallrexone and Schering23390 etc.Said medicine is except that having been negated individually, and all the other still are in conceptual phase.Therefore, very press for no drug dependence, curative effect height, the medicine that is used to quit drug abuse that side effect is little.
The objective of the invention is to seek no drug dependence, curative effect height, the anti-additive medicament that side effect is little and with its method of quitting drug abuse.
The present inventor finds unexpectedly that through research extensively and profoundly the aconitane derivant or its inorganic acid salt, the tetrahydrochysene protoberberine derivant of formula III or the pharmaceutical composition of its inorganic acid salt that contain following formula I or formula II have good drug abstinence and do not have drug dependence.
Wherein, in formula I,
R=α OCH
3, α OH or β OCH
3,
R
1=OAcABz, OH, OABz or H,
R
2=H or OH,
R
3=H or OH,
R
4=H or OH,
R
5=H or OH,
R
6=OCH3, OBz, OAc or OH.
In formula II,
R
1=R
2=R
3=OH。
In formula III,
R
1=OCH
3Or OH,
R
2=OCH
3，
R
3=OCH
3Or H,
R
4=OCH
3Or OH,
R
5=H or OCH
3,
R
6=H or CH
3
Can in 3-4 days, remove junkie to the dependency of drugs and can cure withdrawal syndrome with the medicine composite for curing junkie of the tetrahydrochysene protoberberine derivant that contains formula I and/or formula II aconitane derivant or its inorganic acid salt and formula III of the present invention or its inorganic acid salt, and there is not drug dependence, side effect is little, based on above-mentioned discovery, the present inventor has finished the present invention.
What one of theme of the present invention related to is the pharmaceutical composition that contains formula I and/or formula II aconitane derivant or its inorganic acid salt and formula III tetrahydrochysene protoberberine derivant or its inorganic acid salt.
Wherein, in formula I,
R=α OCH
3, α OH or β OCH
3,
R
1=OAcABz, OH, OABz or H,
R
2=H or OH,
R
3=H or OH,
R
4=H or OH,
R
5=H or OH,
R
6=OCH
3, OBz, OAc or OH.
In formula II,
R
1=R
2=R
3=OH。
In formula III,
R
1=OCH
3Or OH,
R
2=OCH
3，
R
3=OCH
3Or H,
R
4=OCH
3Or OH,
R
5=H or OCH
3, R
6=H or CH
3
It is disconnected with the caused withdrawal syndrome of drugs to the dependency and the healing of drugs that this pharmaceutical composition can be removed junkie, and do not have drug dependence, and side effect is little.
According to the present invention, pharmaceutical composition of the present invention can contain or not contain cholinolytic class medicine, as hyoscine hydrobromate and hydrobromic acid anisodamine etc.
According to the present invention, formula I and/or formula II aconitane derivant are selected from the aconitane derivant in table 1 and the table 2, and the tetrahydrochysene protoberberine derivant of formula III is selected from the tetrahydrochysene protoberberine derivant in the table 3.
More exactly, pharmaceutical composition of the present invention contains formula I and/or formula II aconitane derivant or its inorganic acid salt and formula III tetrahydrochysene protoberberine derivant or its inorganic acid salt, contains or do not contain cholinolytic class medicine, and pharmaceutical excipient.According to the present invention, aconitane derivant or its inorganic acid salt of formula I or formula II preferentially are selected from: the hydrobromic acid lappaconitine, Lappaconine hydrobromide, N-Deacetyllappaconitine hydrobromide, hydrobromic acid Aconitum sinomontanum Nakai total alkaloids: tetrahydrochysene protoberberine derivant or its inorganic acid salt of formula III are preferably: l-tetrahydropalmatine, dl-Tetrahydropalmatine and hydrobromic acid Radix Stephaniae Japonicae are halted; Cholinolytic class medicine is preferably: hydrobromic acid anisodamine and hyoscine hydrobromate.
According to the present invention, when containing anticholinergic agent in the present composition, this pharmaceutical composition demonstrates good drug abstinence.Therefore, pharmaceutical composition of the present invention is preferably selected from following prescription:
1. prescription comprises that hydrobromic acid lappaconitine and l-tetrahydropalmatine or dl-Tetrahydropalmatine or hydrobromic acid Radix Stephaniae Japonicae halt, contain or do not contain hydrobromic acid anisodamine and hyoscine hydrobromate, and excipient commonly used in the pharmaceutical field;
2. prescription comprises that Lappaconine hydrobromide and l-tetrahydropalmatine or dl-Tetrahydropalmatine or hydrobromic acid Radix Stephaniae Japonicae halt, contain or do not contain hydrobromic acid anisodamine and hyoscine hydrobromate, and excipient commonly used in the pharmaceutical field;
3. prescription comprises that N-Deacetyllappaconitine hydrobromide and l-tetrahydropalmatine or dl-Tetrahydropalmatine or hydrobromic acid Radix Stephaniae Japonicae halt, contain or do not contain hydrobromic acid anisodamine and hyoscine hydrobromate, and excipient commonly used in the pharmaceutical field;
4. prescription comprises that hydrobromic acid Aconitum sinomontanum Nakai total alkaloids and l-tetrahydropalmatine or dl-Tetrahydropalmatine or hydrobromic acid Radix Stephaniae Japonicae halt, contain or do not contain hydrobromic acid anisodamine and hyoscine hydrobromate, and excipient commonly used in the pharmaceutical field;
According to the present invention, pharmaceutical composition of the present invention can be made into tablet, powder, capsule, or injection.Preferred preparation formulation is tablet or capsule.
Another theme of the present invention relates to is method with medicine composite for curing junkie withdrawal syndrome of the present invention and withdrawal, and it comprises that with pharmaceutical composition of the present invention to the medicine patient that takes drugs, route of administration can be oral, subcutaneous injection, intramuscular injection, intravenous drip etc.The preferred oral administration.In Therapeutic Method of the present invention, route of administration is generally oral, the oral dose scope be generally aconitane derivant or its inorganic acid salt be the 0.05-0.25mg/kg body weight/time, tetrahydrochysene protoberberine or its inorganic acid salt derivant be the 1-2.5mg/kg body weight/time, hyoscine hydrobromate be the 0.00033-0.005mg/kg body weight/time, the hydrobromic acid anisodamine be the 0.066-0.16mg/kg body weight/time.
Generally speaking, medicine of the present invention is with oral form administration, and preceding four days per six hours clothes are once obeyed four times every day, and each oral two or two, back three days, per eight hours clothes were once obeyed three times every day, each oral two or two.
The present invention further specifies with following test, but this is not meant to limit the present invention in any manner.
One. the addiction test of hydrobromic acid lappaconitine
1. mouse jump reaction test
Use the male mice of the body weight 18-22g animal of doing experiment, be divided into three groups, every group 10, one group of mice subcutaneous injection every day 80mg/kg morphine hydrochloride, injection is 20 days continuously, one group of mice subcutaneous injection every day hydrobromic acid lappaconitine 8mg/kg injected 20 days continuously, and the 3rd group is physiology saline control group.After last administration 6 hours, to each group mouse peritoneal injection propylene 10mg/kg that mutters, then mice is put in (diameter 30cm, high 35cm) in the cylinder, write down the hopping response number of times of mice in 60 minutes.The outward appearance excitement after administration of morphine group mice is frequently run and obvious straub tail reaction is arranged, and after the injection propylene was muttered, tangible hopping response appearred in mice; After perverse aconitine group mice was given the hydrobromic acid lappaconitine, outward appearance was quiet few moving, and no straub tail reaction after the injection propylene is muttered, hopping response all do not occur.
Other gets four groups of body weight 18-22g male mices, 10 every group.Two groups of subcutaneous injection hydrobromic acid lappaconitines 7 times in 2 days wherein, initial dose is 3.5mg/kg, each dosage increases progressively 0.5 and 1.0mg/kg respectively.Another group mice is in two days subcutaneous injection morphine hydrochlorides 7 times, and initial dose is 2.5mg/kg, later on by 5,10,20,30,40, and the 50mg/kg dosage escalation.Another group is physiology saline control group.After last 1 administration, gave above-mentioned four groups of male mice lumbar injection nalorphine 50mg/kg in 2 hours, write down in 10 minutes and respectively organize the mouse jump reaction times.Result of the test sees Table 4.
Table 4 result of the test shows that the hydrobromic acid lappaconitine obviously is different from morphine hydrochloride, shows that the former does not have drug dependence.
2. rely on the body weight loss of weight alternate test of morphine rat
With body weight 200-250gWister male rat, 10 every group, totally three groups.Three groups of rats are subcutaneous injection morphine hydrochloride 25mg/kg all, injects for 12 weeks continuously every day twice, rat is produced morphine rely on.After stopping to inject morphine, the rat outward appearance is and suppresses few moving, does not eat, and body weight obviously descends, after 24 hours, and rat body weight about 25g that on average descends.Inject morphine, perverse aconitine and normal saline respectively for then these three groups of rats, observe rat body weight and change.Result of the test such as Fig. 1.
Fig. 1 explanation:
Abscissa-express time (hour): three groups of rats stopped to inject morphine after 24 hours, every group respectively subcutaneous injection morphine, system aconitine, the normal saline average weight of organizing in 8 hours change.When stopping to inject morphine and being decided to be zero in the time of 24 hours.
Vertical coordinate-expression rat body weight changes: three groups of rats stop to inject 24 hours weight average loss of weight situation of morphine and stop to inject morphine every group of subcutaneous injection morphine, normal saline and perverse aconitine average weight variation in 8 hours respectively after 24 hours.But stop to inject the preceding average weight of morphine and be made as zero.
I: morphine hydrochloride 25mg/kg, sc
II: normal saline 2ml/kg, sc
III: hydrobromic acid lappaconitine 8mg/kg.sc
Shown in Figure 1, injection morphine group rat, outward appearance is very fast to change excitement over to by inhibition, and activity increases in cage, frequent food and drinking-water, body weight goes back up to very soon cutoffs morphine preceding level.Injection lappaconitine group rat, outward appearance still is in inhibitory state, and the rat body weight loss of weight is not seen rise.Result of the test shows that perverse aconitine does not have alternative morphinization.
3. monkey addiction test
6 of Rhesus Macacus (Macaca mulatta), average weight 2.75-4.75kg.Get 3 perverse aconitines of each subcutaneous injection every day twice, dosage is begun by 0.1 mg/kg, be incremented to maximum tolerated dose 2mg/kg gradually in 50 days, be maintained to respectively the the 53rd, the 67th and the 92nd day by this dosage then, the accumulation injected dose of three monkeys is respectively 196,400 and 635mg.Administration the 63rd day and the 92nd day, stop respectively to monkey injection lappaconitine, observed 24 hours, be as good as before outward appearance behavior, appetite and the drug withdrawal of monkey as a result, drug withdrawal respectively in the 29th, 53,59,67 and 90 day in administration, subcutaneous injection nalorphine 4 or 8mg/kg after 18 hours there is no the monkey outward appearance and withdrawal syndrome occurs.3 monkeys in addition, respectively every day subcutaneous injection morphine secondary, initial dose was 2.5mg/kg, was incremented to 25mg/kg in the 21st day, then by this dose maintenance, monkey has produced morphine and has relied on after 30 days.Stop to inject morphine after 18 hours, obvious withdrawal syndrome appears in the monkey outward appearance, and performance has: in cage dysphoria, roll, the time and lie prone crouch or the cage of lying on one's side at the bottom of, disorderly grab, sting chain, yelp, vomit, shake all over or paroxysmal is trembled etc.This moment, above-mentioned symptom showed more obvious as giving monkey subcutaneous injection nalorphine.To monkey injection morphine, then above-mentioned withdrawal symptom obviously weakened after 3-5 minute or disappears.Subcutaneous injection lappaconitine 2mg/kg then can not cancel or weaken above-mentioned withdrawal symptom.This shows that perverse aconitine does not have alternative morphinization.Result of the test sees Table 5.
Above result of the test shows that perverse aconitine is different from morphine, and prolonged application can not produce dependency.
Two. toxicity test
1. acute toxicity test
Body weight 18-22g healthy mice is after irritating stomach, subcutaneous injection, intravenous injection lappaconitine toxicity dose, and the outward appearance toxic reaction has paroxysm restless, and forelimb continues to twitch, and during near fatal dose, paroxysmal also occurs and faints from fear, and respiration inhibition is until death by suffocation.It irritates stomach, subcutaneous injection and intravenous LD
50(95% fiducial limit) is respectively 32.4 (25.9-40.5), 11.7 (9.2-14.9) and 8.4 (7.2-9.7) mg/kg.Behind the rats by intraperitoneal injection lappaconitine toxicity dose, outward appearance suppresses few to be moved, and climbs in the volt cage, breathes obviously and suppresses, and dead preceding the appearance faints from fear, and its LD50 is 16.5 (15.0-18.1) mg/kg.
2 of Rhesus Macacus, subcutaneous injection lappaconitine 2mg/kg, the outward appearance non-toxic reaction does not have influence to electrocardiogram yet.Subcutaneous injection lappaconitine 3mg/kg, then restless, sialorrhea appears in monkey after 30 minutes, swallowing act increases, blepharoptosis, limb muscle tensity increase, after 45 minutes, and wherein 1 restless aggravation of monkey, develop into and occur fainting from fear, during the convulsions, respiratory arrest is rescued recovery through the artificial respiration, but still have interrupted convulsions to take place, dead after 1 hour.Fainting from fear does not appear in the another monkey, and above-mentioned toxic reaction continues to fade away after 2 hours.Electrocardioscopy, the T ripple is raised, and T ripple and P ripple merge, and the R ripple diminishes incisura, and it is normal that inferior daily inspection electrocardiogram recovers.
2. subacute toxicity test
Get 10 of the Wister rats of body weight 200-250g, be divided into two groups, 5 every group, every group of every day be lumbar injection lappaconitine 5mg/kg and 10mg/kg respectively, injects continuously 30 days.5 Wister rats of matched group, subcutaneous injection normal saline 2ml/kg.The administration group is compared with matched group by rat, the body weight gain of administration group rat all has inhibition in various degree, significant change is not seen in Electrocardioscopy, and the hepatic and renal function inspection (comprising GPT, zinc turbidity, blood urea nitrogen, creatinine) and the histopathological examination of each internal organs there is no ANOMALOUS VARIATIONS.
Other gets 10 of Wister rats, adopts progressively increased dosage amount, and promptly first lumbar injection lappaconitine 8mg/kg increases to 10mg/kg after 1 week, increases to 12mg/kg after 2 weeks, increases to 14mg/kg after 16 days, and with this dose maintenance to the 28 days.The result shows that the body weight gain of rat has inhibition slightly than matched group, and each organs and tissues pathological examination shows that except that cardiac muscle had slight cloudy swelling and hydropic degeneration, other was close with matched group.
3 of Rhesus Macacus, body weight 2.75-4.75kg, the perverse aconitine of difference subcutaneous injection every day 2 times, dosage begins progressively to be incremented to maximum tolerated dose 2mg/kg by 0.1mg/kg in 50 days, be maintained to respectively 53,67 and 92 days by this dosage then, the accumulation injected dose is respectively 196,400 and 635mg, in the administration process, do not see the toxic reaction of monkey outward appearance, follow the trail of Electrocardioscopy continuously, also not seeing has significant change, and tissue pathology checking mainly shows as irritant reaction, except that liver had slight cloudy swelling hydropic degeneration, brain had glial cell to increase.
Three. rely on morphine, the mice therapeutic test of cocaine
Body weight 18-22g male mice, difference subcutaneous injection morphine 100mg/kg, inject every day twice, injection is 8 days continuously, in the last administration after 6 hours, inject nalorphine 50mg/kg respectively to mice, then the mice outward appearance presents movable phenomenon frequent and poised for battle and obvious hopping response is arranged, and hopping response is the strongest in 30 minutes.With the mouse jump reaction is index, selects in 30 minutes 60% dependence morphine mice greater than average number of skips, is divided into 8 groups at random, 10 every group.
Free the treatment that relies on morphine, 7 days courses of treatment to producing the mice of respectively organizing that relies on morphine by the medicine shown in the table 6, dosage and route of administration.Per 6 hours of 1-4 day administration 1 time, administration every day 4 times, 5-7 day, administration was 1 time in per 8 hours, administration every day 3 times.Administration the 5th, 8 days, subcutaneous injection nalorphine 50mg/kg urged the addiction checking respectively.Result of the test shows, except that the control group mice that relies on morphine has most of death in 7 days of injecting normal saline, all the other each groups are to the nalorphine reaction that all is negative.Continue to observe 3, do not see that mice produces withdrawal symptom.Justice to treatment group mouse subcutaneous injection nalorphine 50mg/kg, is not also seen the generation withdrawal symptom respectively.Result of the test sees Table 6.
With above-mentioned same test method, give mouse subcutaneous injection cocaine 10mg/kg, inject every day twice, injection is 7 days continuously, and mice is during the injection cocaine, and outward appearance presents appetite and reduces, perpendicular hair and hangover do not stop to walk about and wait abnormal phenomena, with promptly recovering normally after the lappaconitine treatment.
The test of four clinical treatments:
Patient's sex: man.Age: 29.The product of taking drugs: heroin.Drug abuse mode: suck.History of drug abuse: about 4 years.Before the patient violates addiction, pharmaceutical composition of the present invention is delivered medicine to this patient.First day of administration, the patient other withdrawal symptom do not occur except that occurring the perspiration symptom discontinuously.Second day of administration, the patient remove occur discontinuously light
*Based on the aching and tired withdrawal symptom of ancon (approximately be interrupted continue 16 hours) and heavier
*Nervous (be interrupted approximately and continue 4 hours) outside, slight perspiration also occurs, yawn, shed tears and platycoria etc. is given up at shape, and each 1 time is write in vomiting, abdomen.But sleep, diet is all more normal.From second day evening of administration, above-mentioned withdrawal symptom disappears and no longer occurs.Clinical cure.
Case 2:
Patient's sex: man.Age: 27.The product of taking drugs: heroin.Drug abuse mode: suck.History of drug abuse: about 6 years.Before the patient violates addiction, pharmaceutical composition of the present invention is delivered medicine to this patient.In administration first day withdrawal symptom do not occur in 10 hours after the administration, in administration after 10 hours the patient remove occur discontinuously light
*Reach heavier based on nervous, shank, the aching and tired withdrawal symptom (be interrupted and continue 38 hours) of upper arm
*Nervous (be interrupted and continue 5 hours) outside, also occur slight saying withdrawal symptoms such as ravings and platycoria in yawning, sleep, and occur vomitting once, suffering from abdominal pain and suffer from diarrhoea twice.Sleep, appetite is more normal.Promptly offerd medicine back 60 hours the 3rd day of administration, above-mentioned withdrawal symptom disappears and no longer occurs.Clinical cure.
Case 3
Patient's sex: man.Age: 29.The product of taking drugs: heroin.Drug abuse mode: suck.History of drug abuse: about 5 years.Before the patient violates addiction, pharmaceutical composition of the present invention is delivered medicine to this patient.In administration first day withdrawal symptom do not occur in 8 hours after the administration, in administration after 8 hours the patient remove occur discontinuously light
*Based on outside the aching and tired withdrawal symptom of waist, shank (be interrupted and continue 40 hours), withdrawal symptoms such as slight nervous, perspiration and platycoria also occur, and vomit three times, diarrhoea twice.Sleep and appetite are more normal.Promptly offerd medicine back 63 hours the 3rd day of administration, above-mentioned withdrawal symptom disappears and no longer occurs.Clinical cure.
Above clinical test results shows that pharmaceutical composition of the present invention does not have drug dependence, withdrawal symptom disappear and withdrawal fast, onset is rapid, and the patient shows steadily, the obstacle symptom that is a cup too low takes place, and has good curing really, has no side effect substantially.
Gently
*: with+number expression, it is nervous to show as readme, and the waist lower limb is aching and tired, can lie and can sit, and lie in bed sometimes again and again, but facial no pain expression has fashion to fall asleep a few hours.
Heavier
*: with ++ number expression, show as uneasy in either sitting or lying, walk about frequently back and forth indoor, or the waist lower limb to be aching and tired, uneasy in either sitting or lying need stretch one's limbs, and face has painful expression.
Heavy
* *: with +++number expression.Shown as mad dry behavior, may meet and discuss, bloody behavior such as autotomy.In treatment case of the present invention, " weight " person was not taken place.
Table 1-1 causes the smelting of freeing of dependency drugs (opium, morphine, heroin, Fructus Cannabis and amphetamine) and treats material (comprising its inorganic acid salt)
| Numbering | Title | Molecular formula | Molecular weight | mp(℃) | Specific optical rotation | R 1 | R t |
| 1 | Lappaconitine | C 12H 44N rO 6 | 584 | 224-225 | 〔α〕 25 υ27.0°(C=0.22.CHCl 3) | OAcABz | H |
| 2 | O1-Methyllappaconidine. | C 13H 27NO 6 | 423 | 78-80 | OH | H | |
| 3 | N-takes off the acetyl lappaconitine | C 30H 42N rO 7 | 542 | 117-119 | 〔α〕 22 υ39.9°(C=1.5.CHCl 3) | OABz | H |
| 4 | Different lappaconitine | C 18H 44N rO 4 | 584 | 198-200 | OAcABz | OH | |
| 5 | The deoxidation lappaconitine | C 18H 44N rO 7 | 563 | 212-214 | OAcABz | H | |
| 6 | The new alkali of Gong crow | C 20H 41N rO 6 | 526 | OABz | H | ||
| 7 | Ranaconitine | C 12H 44N rO 1 | 600 | 130-131 | 〔α〕 22 υ40.2°(C=0.19,MeOH) | OAcABz | OH |
| 8 | Ran's aconine | C 22H 32NO r | 439 | 105-107 | OH | OH | |
| 9 | The N-deacetylranconitine | C 30H 42N rO t | 558 | 125-127 | 〔α〕 25 υ43.7°(C=2.0,CHCl 3) | OABz | OH |
| 10 | The Gong aconitine | C 25H 44N rO 10 | 616 | 220-221 | 〔α〕 22 υ44.7°(C=0.1MeOH) | OAcABz | OH |
| 11 | N-Tuo Yi Xian Gong aconitine | C 10H 41N rO t | 574 | 121-123 | 〔α〕 10 υ34.9°(C=0.46,CHCl 3) | OABz | OH |
| 12 | Puberanine | C 12H 14N rO t | 600 | 〔α〕 20 υ16.6°(C=0.6,CHCl 3) | OAcABz | OH | |
| 13 | Purple crow gives birth to | C 11H 35NO 6 | 497 | 〔α〕 21 υ-11.2°(C=3.2,EtOH) | H | H | |
| 14 | Episcopalisinine | C 22H 33NO 5 | 393 | 152-154 | 〔α〕 24 υ-8.7°(C=6.8,EtOH) | H | H |
| 15 | Episcopalitine | C 24H 35NO 5 | 419 | 〔α〕 22 υ-0.90°(C=14.9,EtOH) | H | H | |
| 16 | Delavaconitine | C 23H 22NO 6 | 497 | 〔α〕 17 υ-9.56°(C=7.0,EtOH) | H | H | |
| 17 | The former alkali of delavaconitine | C 11H 35NO 5 | 393 | 152 | 〔α〕 14 υ-6.4°(C=1.23,CHCl 3) | H | H |
| 18 | The hot alkali of Acker promise | C 22H 33NO 4 | 377 | 142-143 | 〔α〕 22 υ-25.4°(C=4.0,MeOH) | H | H |
| 19 | Gong crow alkali | C 21H 22NO 4 | 363 | 167-169 | H | H |
Table 1-2
Ac=-COCH
3
| Numbering | R 1 | R 4 | R 5 | R 6 | R | Former plant |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 | OH OH OH H H H OH OH OH OH OH OH OH OH H H H H H | H H H H H H H H H OH OH H H H H H H H H | H H H H H H H H H H H H H H H OH OH H H | OCH 2OCH 3OCH 3OCH 2OCH 2OCH 2OCH 3OCH 3OCH 2OCH 2OCH 3OCH 3OBz OH OAc OBz OH OH OH | αOCH 2αOCH 2αOCH 3αOCH 2αOCH 2αOCH 3αOCH 3αOCH 3αOCH 2αOCH 3αOCH 3βOCH 3αOCH 3αOCH 3αOCH 3αOCH 2αOCH 3αOCH 3αOH | The high rhizome of Chinese monkshood of the high rhizome of Chinese monkshood (Aconitum sinomontanwn Nakai) finet monkshood root (A.finetianum Hand-Mazz) finet monkshood root (formal name used at school is the same) finet monkshood root (formal name used at school is the same) finet monkshood root (formal name used at school is the same) finet monkshood root (formal name used at school is the same); Finet monkshood root, (formal name used at school is the same) finet monkshood root, (formal name used at school is the same) finet monkshood root, (formal name used at school is the same) finet monkshood root, (formal name used at school is the same) ox piece of writing rhizome of Chinese monkshood, (A.barbatum uar.puberulum) purple monkshood root, (A.episcopale Le ＇ el) purple monkshood root, (formal name used at school is the same) purple monkshood root, (formal name used at school is the same) Yunnan Purple radix aconiti agrestis, (A.delavayi Franch) forrest monkshood root, (A.forest ü Diels) Heqing Asian puccoon crow, (A.episcopale Le ＇ vl) |
What table 2 caused dependency drugs (opium, morphine, heroin, Fructus Cannabis and amphetamine) frees therapeutant (comprising its inorganic acid salt)
| Title | Molecular formula | Molecular weight | mp(℃) | Specific optical rotation | R 1 | R 2 | R 3 | Former plant |
| Aconine | C 25H 41NO 9 | 499 | 132 | 〔α〕 υ+23° | OH | OH | OH |
What table 3-1 caused dependency drugs (opium, morphine, heroin, Fructus Cannabis and amphetamine) frees therapeutant (comprising its inorganic acid salt)
| Numbering | Title | Molecular formula | Molecular weight | mp (℃) | Specific | R | 1 |
| 1 2 3 4 5 | The l-tetrahydropalmatine dl-tetrahydropalmatine Radix Stephaniae Japonicae corydaline xylopinine of halting | C 21H 25NO 4 C 21H 25NO 4 C 19H 21NO 4 C 22H 27NO 4 C 21H 25NO 4 | 355 355 327 369 355 | 144 148-149 129-133 135 181-182 | 〔α〕 υ 15-295°(C=0.8,EtOH) 〔α〕 υ0° 〔α〕 υ 21-263°(C=0.337,MeOH) 〔α〕 υ 20+311°(C=0.8,EtOH) 〔α〕 υ 15-177.2°(C=4.07,CHCl 2) | OCH 3 OCH 3 OH OCH 3 OCH 3 |
Table 3-2
| Numbering | R 2 | R 3 | R 4 | R 5 | R 6 | |
| 1 2 3 4 5 | OCH 3 OCH 3 OCH 3 OCH 3 OCH 3 | OCH 3 OCH 3 OCH 3 OCH 3 H | OCH 2 OCH 3 OH OCH 3 OCH 3 | H H H H OCH 3 | H H H CH 3 H | ( Stephania viridiflavens H.S.Lo et M.Yang. ) ( S.kwangsiensis H.S.Lo ) ( S.rotunda Lour. ) ( S.sinica Diels ) ( Corydalis pallida ( Thumb ) Pers. ) ( C.yanhusuo W.T.Wang ) ( C.decumbens ( Thunb. ) Pers. ) ( C.racemosa ( Thunb. ) Pers. ) ( Menis permum dauricum DC. ) ( ) ( ) ( C.ambigua Chem.et Schlecht uar.amurensis Maxim. ) ( C.koidzumiana Ohwi ) ( C.marschalliana Pers. ) ( Xylonia discreta ( Lifil. ) Sprague et Hutchins ) ( ) |
The mouse jump reaction is observed after table 4 multiple subcutaneous injections lappaconitine or the morphine
*20 days be every day 1 time.2 days injection in the 1st day 5 times, injection in second day 2 times.
*Administration is midway because of dead 5 of cumulative toxicity.
| Medicine | Dosage (mg/kg) | Administration * (d) | Accumulation accumulated dose (mg/kg) | Number of mice (only) | mg/kg ip | Jump Mus number (only) | Number of skips/only | ||
| Administration | Test | Nalorphine | Propylene is muttered | ||||||
| Normal saline morphine lappaconitine | - - 2.5 80 3.5 3.5 8.0 | 2 20 2 20 2 2 20 | 157.5 1600 35 45.5 160 | 10 10 10 10 10 10 18 | 10 10 10 10 10 5 ** 18 | 50 50 50 50 | 10 10 10 | 0 0 7 9 0 0 1 | 0 0 9 34 0 0 0.2 |
Table 5 lappaconitine is observed the vicarious function of morphinomania monkey withdrawal syndrome
| Monkey number | Injection morphine (d) | Accumulation accumulated dose (g) | Withdrawal syndrome | Lappaconitine (2mg/kg sc) | |
| Stop morphine 18h | Nalorphine 0.5mg/kg sc | ||||
| 6 7 8 | 42 40 62 69 91 33 49 | 4.66 3.56 6.59 7.56 10.97 3.61 6.06 | + + + + | + + + | - - - - - - - |
Table 6 relies on the treatment of morphine mice and observes
*Be clinical formulation, but hyoscine hydrobromate is greater than clinical formulation.
*4 jumps of 6 survivals.Be respectively 17,14,8 and 16 times; 3 jumps of 3 survivals are respectively 12,10 and 9 times, and 21 of survivals are jumped 7 times.* 3 10 1 of survivals are jumped 5 times.* 1 jump of 4 10 survivals.Treating the 5th day, drug withdrawal the 1st day and drug withdrawal was followed successively by 1 of 5 10 survival of 10,6 and 1 * on the 4th and jumps 16 times.
| Medicine | Dosage mg/kg (route of administration) | The administration number of days | Accumulative total accumulated dose (mg/kg) | The mice number of elements | Nalorphine mg/kg (sc) | Jump Mus number (jump Mus number/survival Mus number) | ||||
| 1-4 day | 5-7 day | Rely on morphine | Experimental therapy | Treated the 5th | After the drug withdrawal the 1st day | After the drug withdrawal the 4th day | ||||
| (number of times/hour) | ||||||||||
| The total acetyl lappaconitine of the perverse aconitine scopolamine hydrobromide of physiological saline lappaconitine hydrobromide lappaconitine hydrobromide hyoscine hydrobromate hydrobromic acid lappaconitine hydrobromide scopolamine hydrobromide lappaconitine hydrobromide scopolamine hydrobromide hydrobromic acid N-Lappaconine hydrobromide | 10ml/kg (sc) 0.45 (sc) 0.225 0.05 (sc) 0.45 0.1 (sc) 0.9 0.2 (ig) 0.45 0.1 (ig) 5 (sc) 5 (sc) | 1/6 1/6 1/6 1/6 1/6 1/6 1/6 1/6 | 1/8 1/8 1/8 1/8 1/8 1/8 1/8 1/8 | 250ml 11.25 5.63 11.25 2.5 22.5 5.0 11.25 2.5 12.5 12.5 | 10 10 10 10 10 10 10 10 | 8 10 10 10 10 10 10 10 | 50 50 50 50 50 50 50 50 | 4/6 **1/10 *31/10 *4 0/10 0/10 1/10 *5 0/10 0/10 | 3/3 **0/10 1/10 *40/9 0/8 0/9 0/10 0/10 | 1/2 ** 0/10 1/10 *4 0/9 0/8 0/9 0/10 0/10 |
Claims (12)
1. be used for the treatment of the withdrawal symptom of junkie and the pharmaceutical composition of withdrawal, it comprises: the tetrahydrochysene protoberberine derivant of the aconitane derivant of formula I or II or their inorganic acid salt or the mixture of the two and general formula III, and contain or do not contain excipient commonly used in anticholinergic agent and the pharmaceutical field;
Wherein in formula I,
R=α OCH
3, α OH or β OCH
3,
R
1=OAcABz, OH, OABz or H,
R
2=H or OH,
R
3=H or OH,
R
4=H or OH,
R
5=H or OH,
R
6=OCH
3, OBz, OAc or OH,
In the general formula II,
R
1=R
2=R
3=OH；
In the general formula III,
R
1-OCH
3Or OH,
R
2=OCH
3，
R
3=OCH
3Or H,
R
4=OCH
3Or OH,
R
5=H or OCH
3,
R
6=H or CH
3
2. the pharmaceutical composition of claim 1, wherein said aconitane derivant is lappaconitine or its inorganic acid salt.
3. the pharmaceutical composition of claim 1, wherein said aconitane derivant is that N-takes off acetyl lappaconitine or its inorganic acid salt.
4. the pharmaceutical composition of claim 1, wherein said aconitane derivant is O1-Methyllappaconidine. or its inorganic acid salt.
5. the pharmaceutical composition of claim 1, wherein said aconitane derivant is aconine or its inorganic acid salt.
6. the pharmaceutical composition of claim 1, wherein said aconitane derivant is Aconitum sinomontanum Nakai total alkaloids or its inorganic acid salt.
7. the pharmaceutical composition of claim 1, wherein said tetrahydrochysene protoberberine derivant is the l-tetrahydropalmatine.
8. the pharmaceutical composition of claim 1, wherein said tetrahydrochysene protoberberine derivant is the dl-tetrahydropalmatine.
9. the pharmaceutical composition of claim 1, wherein said tetrahydrochysene protoberberine derivant is that Radix Stephaniae Japonicae is halted.
10. the pharmaceutical composition of claim 1, wherein said tetrahydrochysene protoberberine derivant is a corydaline.
11. the pharmaceutical composition of claim 1, wherein said tetrahydrochysene protoberberine derivant is an xylopinine.
12. the pharmaceutical composition of claim 1, wherein anticholinergic agent is selected from hydrobromic acid anisodamine and hyoscine hydrobromate.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93106028A CN1042895C (en) | 1992-09-23 | 1993-05-27 | Medicines composition and its method for treating drop syndrome and de-addiction of drugaddict |
| GB9319500A GB2271059B (en) | 1992-09-23 | 1993-09-21 | Pharmaceutical compositions comprising aconitane derivatives and tetrahydroprotoberberine derivatives. |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN92112022 | 1992-09-23 | ||
| CN92112022.2 | 1992-09-23 | ||
| CN93106028A CN1042895C (en) | 1992-09-23 | 1993-05-27 | Medicines composition and its method for treating drop syndrome and de-addiction of drugaddict |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1087516A CN1087516A (en) | 1994-06-08 |
| CN1042895C true CN1042895C (en) | 1999-04-14 |
Family
ID=25742810
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93106028A Expired - Fee Related CN1042895C (en) | 1992-09-23 | 1993-05-27 | Medicines composition and its method for treating drop syndrome and de-addiction of drugaddict |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1042895C (en) |
| GB (1) | GB2271059B (en) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5547956A (en) * | 1991-07-18 | 1996-08-20 | Yueqian Qu | Pharmaceutical composition and the method for treating drug addicts' withdrawal syndromes and detoxifying addicts by the same |
| AU754088B2 (en) | 1997-09-04 | 2002-11-07 | Demerx, Inc. | Noribogaine in the treatment of pain and drug addiction |
| US7220737B1 (en) | 1997-09-04 | 2007-05-22 | Novoneuron, Inc | Noribogaine in the treatment of pain and drug addiction |
| CN1116040C (en) * | 2000-01-19 | 2003-07-30 | 曲日谦 | Medicinal composition and its antalgic purpose |
| CN100443083C (en) * | 2005-03-25 | 2008-12-17 | 成都高新区智爽天然产物科技有限责任公司 | Use of aconine in medicine manufacture |
| CN1875968B (en) * | 2005-06-08 | 2010-05-05 | 郑萍 | Application of anisodamine in preparation of smoking-stopping medicament |
| US8765737B1 (en) | 2010-05-11 | 2014-07-01 | Demerx, Inc. | Methods and compositions for preparing and purifying noribogaine |
| US9394294B2 (en) | 2010-05-11 | 2016-07-19 | Demerx, Inc. | Methods and compositions for preparing and purifying noribogaine |
| US8362007B1 (en) | 2010-05-11 | 2013-01-29 | Demerx, Inc. | Substituted noribogaine |
| US8741891B1 (en) | 2010-06-22 | 2014-06-03 | Demerx, Inc. | N-substituted noribogaine prodrugs |
| US9586954B2 (en) | 2010-06-22 | 2017-03-07 | Demerx, Inc. | N-substituted noribogaine prodrugs |
| US8637648B1 (en) | 2010-06-22 | 2014-01-28 | Demerx, Inc. | Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier |
| US8802832B2 (en) | 2010-06-22 | 2014-08-12 | Demerx, Inc. | Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier |
| WO2012012764A1 (en) | 2010-07-23 | 2012-01-26 | Demerx, Inc. | Noribogaine compositions |
| EP2481740B1 (en) | 2011-01-26 | 2015-11-04 | DemeRx, Inc. | Methods and compositions for preparing noribogaine from voacangine |
| CN102796096B (en) * | 2011-05-27 | 2016-09-14 | 中国科学院上海药物研究所 | Hexahydro dibenzo [a, g] quinolizine compounds, its preparation method, pharmaceutical composition and application thereof |
| US9617274B1 (en) | 2011-08-26 | 2017-04-11 | Demerx, Inc. | Synthetic noribogaine |
| WO2013085922A1 (en) | 2011-12-09 | 2013-06-13 | Demerx, Inc. | Phosphate esters of noribogaine |
| US9150584B2 (en) | 2012-01-25 | 2015-10-06 | Demerx, Inc. | Indole and benzofuran fused isoquinuclidene derivatives and processes for preparing them |
| US8877921B2 (en) | 2012-01-25 | 2014-11-04 | Demerx, Inc. | Synthetic voacangine |
| US8940728B2 (en) | 2012-12-20 | 2015-01-27 | Demerx, Inc. | Substituted noribogaine |
| US9783535B2 (en) | 2012-12-20 | 2017-10-10 | Demerx, Inc. | Substituted noribogaine |
| US9045481B2 (en) | 2012-12-20 | 2015-06-02 | Demerx, Inc. | Substituted noribogaine |
| US9345711B2 (en) | 2014-02-18 | 2016-05-24 | Demerx, Inc. | Methods for acute and long-term treatment of drug addiction |
| CA2989550C (en) | 2014-06-18 | 2023-08-08 | Demerx, Inc. | Halogenated indole and benzofuran derivatives of isoquinuclidene and processes for preparing them |
| CN110478350A (en) * | 2018-07-27 | 2019-11-22 | 上海品姗医药咨询有限公司 | The application of bulleyaconitine A and its derivative in the preparation inhibition addicted drug of drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55167226A (en) * | 1979-06-14 | 1980-12-26 | Osaka Chem Lab | Analgesic and antinflammatory agent, and its preparation |
| CH661208A5 (en) * | 1983-09-01 | 1987-07-15 | Inst Khim Rastitelnykh Vesches | MEDICINAL PRODUCT WITH ANTI-ARRHYTHMIC EFFECT. |
-
1993
- 1993-05-27 CN CN93106028A patent/CN1042895C/en not_active Expired - Fee Related
- 1993-09-21 GB GB9319500A patent/GB2271059B/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| 中国药学通报，1989(5) 1989.5.1 宋东江等，"乌头碱类化合物毒理学的研究概况" * |
| 科学通报1985,30(6) 1985.6.1 许守玺等，"四氢原小檗大碱同类物对脑内多巴胺妥体的和力比较";中国药学通报，1989(5) 1989.5.1 宋东江等，"乌头碱类化合物毒理学的研究概况" * |
| 科学通报1985,30(6) 1985.6.1 许守玺等，"四氢原小檗大碱同类物对脑内多巴胺妥体的和力比较" * |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9319500D0 (en) | 1993-11-03 |
| GB2271059A (en) | 1994-04-06 |
| CN1087516A (en) | 1994-06-08 |
| GB2271059B (en) | 1996-09-18 |
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