CN1081034C - Medicine of diguanidino-prine-hydride compounds for giving up drug-taking - Google Patents

Abstract

The present invention relates to an application of a diguanidino-prine-hydride compound which comprises saxitoxin, new saxitoxin and gonyatoxine I, II, III in preparing medicine for giving up drug-taking. The compound can be used for giving up drug dependence on addiction medicine, such as opium, heroin, morphine, dolantin, etc., in oral, muscle, subcutaneous and intravenous injection or respiratory tract inhaling modes. The compound has the advantages of no addiction and rapid withdrawal, and has small toxic and side effect in strictly specified dose ranges.

Description

A kind of drug-breaking medicine of diguanidino-prine-hydride compounds

The present invention relates to the heterocyclic compound of purine lopps, or rather, the present invention relates to the application of diguanidino-prine-hydride compounds in the preparation drug-breaking medicine.

The harm of taking drugs is well-known, and the method for various drug rehabilitations is all being sought in countries in the world.At present, various countries mainly adopt the medicine method of abstention, generally have following several method (Jiang Zuoning etc., " drug dependence ", 1992 the 1st edition, Beijing, Science Press,, 118-120 in 1992; China's drug dependence control magazine, 1996 (3), 2):

One, opioid receptor agonist or partial agonist class drug rehabilitation method comprise that drugs successively decrease, methadone substitutes, dihydroetorphine (DHE) substitutes, buprenorphine treatment and the withdrawal of tinctura opii pills for curing opium smokers etc.

Two, non-opioid receptor agonist or antagonist drug rehabilitation method comprise drug-breaking medicine relevant with neurotransmitter such as clonidine (Clonidine), Luo Feixiding (Lofexidine), propranolol, verapamil, cholinomimetic etc.; Drug-breaking medicine relevant such as interferon, cyclocyto polypeptide, actinomycin D etc. with immunologic active material; Hormones; Central depressant such as chlorpromazine, haloperidol, the stable clonazepam etc. that reaches; Hyoscyami class medicine such as scopolamine, Anisodamine, atropina etc. are joined the so-called subhibernation therapy that Chinese herbal medicine and hyoscyami class medicine and central depressant such as chlorpromazine, promethazine etc. share; Various Chinese herbal medicine.

Facts have proved that said method all exists major defect.For example opiates agonist itself also is drugs, is easy to be addicted, and usually is that former drugs are not given up as yet, and the withdrawal medicine that is used for the treatment of is habit-forming again, causes the intersection addiction of multiple drugs.The partial agonist onset is slow, if withdrawal is not resolute, also may make the patient produce dependence.The present non-opium drug-breaking medicine of using, insufficient strength is cannot kept under control withdrawal symptom mostly, and the own toxicity, side effect that has is obvious, as everybody familiar clonidine, owing to its position hypotensive effect the patient is tumbled; Chlorpromazine and hyoscyami class make easily that the patient produces that cardiopalmus, muscular tremor, the dyskinesia, orthostatic collapse, blurred vision, airway secretions are dry and hard, xerostomia, urinary incontinence, fervescence, delirium, hallucination, uneasiness, convulsions, heart failure, oligopnea, respiratory center paralysis, thereby mortality rate is higher.

The objective of the invention is to overcome the defective of said medicine method of abstention, seek no drug dependence, curative effect height, the anti-additive medicament that toxicity, side effect is little.

Through research for many years, find that diguanidino-prine-hydride compounds comprises saxitoxin (STX), new saxitoxin (Neo-STX), gonyatoxin I (GTX ₁), gonyatoxin II (GTX ₂), gonyatoxin III (GTX ₃) have good drug abstinence and do not have drug dependence, therefore purpose of the present invention realizes by diguanidino-prine-hydride compounds should be used in the preparation drug-stopping medicine.

Diguanidino-prine-hydride compounds of the present invention has following general formula:

In the formula, R ₁Be selected from H, OH, Cl, Br, OSO ₃ ^-Or C _1-3Alkyl; R ₂, R ₃Be selected from H, α, β-OH, α, β-OSO ₃ ^-R ₄Be selected from H, CONH ₂, CONH-SO ₃ ^-, C _1-5Alkyl, [wherein R ' is selected from-NH COR ' ₂, NHR " (R " be selected from SO ₃, Cl, Br and C _1-5Alkyl or aryl)]; R ₅, R ₆Be selected from H, α, β-OH, α, β-OSO ₃ ^-, α, β-X, wherein (X can be selected from and comprise Cl, Br halogen, α, β-C _1-3Alkoxyl.

The preferred following general formula of the present invention (II)-(VII) 6 compounds:

1. the diguanidino-prine-hydride compounds that has general formula (II) is: In the formula, R ₄Be selected from H, COR ', CONR ", R ' wherein is selected from C _1-5Alkyl, aryl, Cl, Br halogen; R " be H, C _1-3Alkyl, Cl, Br, OSO ₃ ^-

The chemical compound of described general formula (II) is R more preferably ₄=CONH ₂STX chemical compound, R ₄The De(carbamoyloxy)saxitoxin of=H (DC-STX) chemical compound.

2. the diguanidino-prine-hydride compounds that has general formula (III) is:

In the formula, R ₁Be selected from H, OH, Cl, Br, OSO ₃ ^-, C _1-3Alkyl.

The chemical compound of described general formula (III) is more preferably: the Neo-STX chemical compound of R1=OH, R ₁The STX chemical compound of=H.

3. the diguanidino-prine-hydride compounds that has general formula (IV) is:

In the formula, R ₂, R ₃Be selected from H, OSO ₃ ^-, OR ', X, wherein R ' is C _1-3Alkyl, X are F, Cl, Br, halogens such as I.

The chemical compound of described general formula (IV) is more preferably: R ₂=H and R ₃=OSO ₃ ^-GTX ₃, R ₂=OSO ₃ ^-And R ₃The GTX of=H ₃Chemical compound, R ₂=R ₃The STX chemical compound of=H.

4. the biguanide base hydrogenation purine compound that has logical formula V is: In the formula, R ₂, R ₃Be selected from H, OSO ₃ ^-, OR ', X, wherein R ' is e _1-3Alkyl, X are F, Cl, Br, I halogen.

The chemical compound of described logical formula V is more preferably: R ₂=R ₃The Neo-STX chemical compound of=H, R ₂=H and R ₃=OSO ₃ ^-GTX ₁Chemical compound, R ₂=OSO ₃ ^-And R ₃Gonyatoxin IV (the GTX of=H ₄) chemical compound.

5. the diguanidino-prine-hydride compounds that has general formula (VI) is: In the formula, R ₅, R ₆Be selected from OH, H, OSO ₃ ^-, OR ', X, wherein R ' is C _1-3Alkyl, X are F, Cl, Br, I halogen.

The chemical compound of described general formula (VI) is more preferably: R ₅=R ₆The DC-STX chemical compound of=OH, R ₅=OH and R ₅12 Alpha-hydroxy saxitoxin (STX-OL) chemical compounds of=H.

6. the diguanidino-prine-hydride compounds and the derivation compound thereof that have general formula (VII) are:

In the formula, R1 is selected from H, OH, Cl, Br, OSO ₃ ^-, C _1-3Alkyl; R ₂, R ₃Be selected from H, OSO ₃ ^-, OR ', X, wherein R ' is C _1-3Alkyl, X is F, Cl, Br, I halogen.

Diguanidino-prine-hydride compounds of the present invention more preferably is selected from any chemical compound of saxitoxin, new saxitoxin, De(carbamoyloxy)saxitoxin, gonyatoxin I, gonyatoxin II, gonyatoxin III, gonyatoxin IV, 12 Alpha-hydroxy saxitoxins.

Biguanide base hydrogenation purine compound of the present invention can it become compositions to use in preparing drug-breaking medicine for Main Ingredients and Appearance by acceptable carrier, excipient, adjuvant, mixing diluents on effective dose and the materia medica.Described biguanide base hydrogenation purineization contains thing or its compositions can be made various dosage forms according to prior art, as make injection, comprise subcutaneous, muscle, intravenous injection and oral agents, comprise the sublingual administration agent and, comprise aerosol and microcapsule etc. by the respiratory tract inhalant.But the effective dose that oral effective dose will be higher than injection and suck, the 5-100 that the former is about the latter doubly, so optimizing injection and inhalant, preferably with diguanidino-prine-hydride compounds and composition dissolves thereof in the acidic aqueous solution that comprises hydrochloric acid, sulphuric acid, citric acid, PH is 4-6.

Chemical compound of the present invention, in the application of giving up drug dependence, as the drug dependence patient to general body weight 50-70kg, when adopting oral, subcutaneous, muscle or intravenously administrable, effective dose is that 0.5 μ g is to 300 μ g.

The method for extraction and purification and the artificial synthesis of biguanide base hydrogenation purine compound of the present invention early have report.Kind (seeing Table 1) surplus the biguanide base hydrogenation purine compound that (Biochem.Biophy.Res.Commun, 1975,66,731) introduce isolation identification in people's such as YShimizu article has 10; (J.Am.Chem.Soc.1957,79,5235～5320 in people's such as E.Schantz and Kishi article; 1977,99,2818) purification and the synthetic method of the saxitoxin (STX) in this compounds have been reported; People such as Chen Changying also introduce about its structure of quantum chemistry calculation of this compounds and activity relationship (chemistry circular, 1994,52,441～447).

The STX compounds only is used as indivedual clinic trial of local anesthesia and anticarcinogen.

The application of diguanidino-prine-hydride compounds of the present invention in the preparation drug-breaking medicine can suppress the withdrawal symptom of morphine dependence, also not by addiction that antagonist is urged.When withdrawal symptom is the fiercest, treat, promptly adopt this an amount of compounds, can suppress and alleviate withdrawal symptom effectively, eliminate patient's uneasiness sense, received treatment back 3-30 minute, withdrawal symptom is all obviously alleviated or is disappeared, nearly all show little picotement at positions such as outlet, tongue, lip, but the patient does not have unhappy sensation, this little fiber crops have been offset the serious hope to drugs such as heroin, keep (being generally 2-3 days) 2-8 days, the withdrawal symptom complete obiteration, turning out cloudy property of urine morphine check reaches clinical withdrawal.After this drug-breaking medicine of stopping using, this medicine is not had dependence, have no adverse reaction and side effect.

When using this drug-breaking medicine, among the patient none example because of feel sick, vomiting, collapse, stupor etc. use other drug to treat, do not adopt opiate agonist DHE and side effect such as drug dependence that cethadone treatment produced, there is not clonidine, the position blood pressure lowering of hyoscyami compounds, thirsty, toxicity, side effect such as diplopia is gone into a coma even yet.

Adopt drug-breaking medicine of the present invention or cooperate other drug-breaking medicine to use jointly, can give up as opium, heroin, morphine, ***e, amphetamine (methamphetamine hydrochloride), pethidine, dihydroetorphine, methadone and the alkaloidal drug dependence of this class addiction at 3-5 days, do not have addiction, and the drug rehabilitation time is short, side effect is little, physical recovery very fast (7-10 days).

Following test further specifies characteristics of the present invention, but is not meant to limit the present invention in any manner.

Embodiment 1

Present embodiment is the addiction test of saxitoxin hydrochlorate (STX2HCl).

1, the perpendicular tail test of mice

Test is carried out (Journal of physiology, 1978,30,67-71 with reference to existent method; Acta Pharmacologica Sinica, 1982,3,223).

40 of the ♂ mices of body weight 14-16g are divided into 4 groups at random, respectively sc morphine 15mg/kg and 20mg/kg, STX0.6 μ g/kg and 1.0 μ g/kg.Observe mice active situation in the 2h.S shape straub tail reaction appears in morphine group mice, and excitement is run; And STX group mice does not have straub tail reaction, outward appearance and injectable drug group indistinction almost not.Repeat above test behind the 8h, morphine group mice, perpendicular tail phenomenon is more obvious, and STX group mice does not still have perpendicular tail phenomenon.Proof STX does not belong to morphine class medicine.

Other gets 40 of mices, is divided into 2 groups at random.Respectively sc morphine and STX intersect alternate test then.Morphine group dosage increases to 45mg/kg after 25 days day by day from 20mg/kg, and STX group dosage increases to 2.6 μ g/kg day by day from 0.1 μ g/kg.Morphine group mice all has perpendicular tail phenomenon.The STX group does not then have.Former morphine group mice is used STX2.6 μ g/kg instead after 25 days.The not perpendicular tail of animal.And use former STX group mice instead morphine 45mg/kg, then perpendicular tail phenomenon appears in mice.

2, mouse jump reaction test

Test is carried out (Acta Pharmaceutica Sinica 1983,18,574) with reference to existent method.

Adopt 30 of the male ♂ mices of purebred Kunming white, 10 every group, A group sc morphine 2.5mg.kg, B group STX0.5 μ g/kg and isopyknic normal saline NS (C group).First day the injection 5 times (9:00,10:00,11:00,13:00,15:00), second day the injection 2 times (9:00,11:00).Dosage escalation.2h after the last administration, ip nalorphine 50mg/kg observes hopping response in the mice 10 minutes, the results are shown in Table 2, occur hopping response by the visible morphine group mice of table 2 behind the ip nalorphine, and hopping response does not appear in the STX group.

Adopt the male ♂ mice of purebred Kunming white of body weight 18-24g to be divided into A, B, C group at random, every group 20, A group subcutaneous injection morphine hydrochloride aqueous solution every day, dosage is 80mg/kg, injection is 20 days continuously, B group subcutaneous injection STX1.0 μ g/kg every day injected 20 days continuously, and the C group is physiology saline control group.After last administration 6 hours, to each group mouse peritoneal injection nalorphine 50mg/kg, (Φ 25, h35cm) observe the reaction of mice, and write down the hopping response of mice in 60 fens kinds, the results are shown in Table 2 then mice to be put in Plastic Drum.Morphine group (A group) mice seems very excited after administration, it is frequent to run, and straub tail reaction is obvious, and behind the injection nalorphine, tangible hopping response appears in mice; After (B group) the mice administration of STX group, the same matched group of outward appearance, no straub tail reaction behind the injection nalorphine, hopping response all do not occur.

Table 2, result of the test show that STX obviously is different from morphine hydrochloride, illustrate that STX does not have drug dependence.

3, rely on the morphine rat body weight loss of weight alternate test (Hosoya E:PharmacTher1979,5,515-517)

Adopting purebred Wister is male rat body weight 200-250g, 10 every group, is divided into three groups at random.Three groups are all adopted subcutaneous injection morphine hydrochloride 25mg/kg, inject for ten weeks continuously every day twice, rat is produced morphine rely on.After stopping to inject morphine, the rat outward appearance is inhibitory state, the movable minimizing, do not eat, body weight obviously descends, after 24 hours, rat body weight about 25g that on average descends injects morphine, STX and normal saline respectively for then these three groups of rats, and observes the rat body weight situation of change.

The result shows, injection morphine group rat, and outward appearance is very fast by suppressing to change over to excitement, activity increases in cage, frequent food and drinking-water, body weight go back up to very soon cutoffs morphine preceding level, injection STX group rat, outward appearance still is in the part inhibitory state, but with the contrast of control group, activity increases to some extent, and food and drinking-water situation are arranged, the body weight loss of weight is not seen rebound significantly in the 8h, and result of the test shows that STX does not have alternative morphinization.

4, monkey addiction test

8 of Rhesus Macacus (Macaca rhesus), body weight 2.85-4.95kg, get twice of each subcutaneous injection STX, 4 every days, dosage is begun by 0.1 μ g/kg, in 50 days, be incremented to maximum tolerated dose 2 μ g/kg gradually, be maintained to respectively the 53rd, 67 and 92 day by this dosage then, the accumulation injected dose of 4 monkeys is respectively 176,410,600 and 720 μ g medicines.The 63rd day and the 92nd day, stop respectively to monkey injection STX, observed 24 hours, the outward appearance behavior of monkey as a result, be as good as before appetite and the drug withdrawal, in the 29th of administration, 53,59, drug withdrawal respectively in 67 and 90 days, subcutaneous injection nalorphine 4 or 8mg/kg after 18 hours, there is no the monkey outward appearance and withdrawal syndrome occurs, this shows that STX does not produce drug dependence, 4 monkeys are distinguished subcutaneous injection morphine secondary every day in addition, and initial amount is 2.5mg/kg, be incremented to 25mg/kg in the 21st day, by this dose maintenance, monkey has produced the horse coffee and has relied on after 30 days, stops to inject morphine after 18 hours then, obvious withdrawal syndrome appears in the monkey outward appearance, performance has: dysphoria in cage, 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, vomiting, shake all over or paroxysmal is trembled etc., this moment as give monkey subcutaneous injection nalorphine, the above-mentioned symptom performance is more obvious, to monkey injection morphine, then above-mentioned withdrawal symptom obviously weakened disappearance after 3-5 minute.Subcutaneous injection STX0.5 μ g/kg, above-mentioned withdrawal syndrome obviously alleviates or disappears, and this shows that STX has the drug action of antagonism morphine abstinence syndrome syndrome.

The preparation of above result of the test proof STX.2HCl is different from the opiates medicine, and life-time service also can not produce dependency.

5, rely on the mice treatment detoxification test of morphine, ***e

5 groups of the purebred mices of body weight 18-22g male (♂) Kunming white, every group 40, each organizes mice subcutaneous injection morphine 50mg/kg respectively, injection is after 5 days continuously to inject twice every day, and dosage increases to 100mg/kg, 2 times/day, injection is 5 days continuously, and in the last administration after 6 hours, inject nalorphine 50mg/kg respectively to each group mice, urge the addiction test.Behind the injection antagonist, the mice outward appearance presents movable frequent, poised for battle phenomenon and obvious hopping response is arranged.Hopping response was strong in 30 minutes.As index, selects in 30 minutes 60% dependence morphine mice with mouse jump reaction, be divided into 11 groups at random, 10 every group greater than average number of skips.

The mice of respectively organizing that produce to rely on morphine is relied on the detoxification treatment of morphine mice by medicine, dosage and the route of administration shown in the table (3), 5 days courses of treatment of test, per 8 hours of 1-3 day administration 1 time, administration every day 3 times, back two days, administration was 1 time in per 12 hours, administration every day 2 times.Administration the 5th, 7 days, subcutaneous injection nalorphine 50mg/kg urged the addiction test respectively.Result of the test shows, except that the control mice that relies on morphine has most of death in 5 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.Also do not see the generation withdrawal symptom to treatment group mouse subcutaneous injection nalorphine 50mg/kg respectively again.Result of the test sees Table 3.

With above-mentioned same test method, give mouse subcutaneous injection ***e 10mg/kg, inject every day 2 times, injection is 7 days continuously, mice is during the injection ***e, and outward appearance presents that appetite reduces, perpendicular hair, the abnormal phenomena such as frequent that trails, walks about, with promptly recovering normal after the STX.2HCl treatment.

Above evidence STX has the curative effect of detoxification to the animal that relies on drugs such as morphine, ***e.

Embodiment 2-7

Take by weighing 0.3mg respectively, STX, Neo-STX, DC-STX, GTX ₁, GTX ₂, GTX ₃Compound dissolution respectively is distributed into 10 parts in PH is 20 milliliters of hydrochloric acid normal saline of 4.5, every part contains these 6 kinds of chemical compounds 30 μ g, makes injection (1)-(6) respectively.

Embodiment 8-13

Take by weighing 0.3 milligram of described 6 kinds of compound dissolution of embodiment 2-7 respectively in PH is 20 milliliters of hydrochloric acid normal saline of 4, respectively be distributed into 10 parts, every part contains these 6 kinds of chemical compounds 30 μ g, makes injection (7)-(12) respectively.

Embodiment 14-15

Take by weighing 3 milligrams of GTX respectively ₄, two kinds of compound dissolutions of STX-OL in PH is 40 milliliters of hydrochloric acid normal saline of 4, respectively be distributed into 20 parts, every part contains STX150 μ g, makes injection (13)-(14) respectively.

Embodiment 16

0.3 the propranolol of milligram compound S TX50mg is dissolved in PH and in 6 20 ml physiological salines, is distributed into 10 parts, every part contains STX30 μ g and propranolol 5mg, makes injection (15).

Embodiment 17

0.3 milligram compound S TX is dissolved in PH and in 5 the 200ml aqueous solution of citric acid, is distributed into 100 parts, every part contains STX3 μ g, makes injection (16).

Embodiment 18

0.3 milligram NeO-STX compound dissolution is distributed into 30 parts in PH is 60 milliliters of aqueous acetic acids of 4, every part contains 10 μ g, makes injection (17).

Embodiment 19-21

Taking by weighing 0.3 milligram of STX, Neo-STX, three kinds of compound dissolutions of DC-STX respectively is that 5 concentration is in 10 milliliters of lidocaine injections of 2% in PH, be distributed into 50 parts after the normal saline dilution, every part of lignocaine that contains these three kinds of chemical compounds 6 μ g and 4mg is made injection (18)-(20).

Table 4-6 is listed in the application of embodiments of the invention 2-21.

Embodiment 22

Present embodiment is that the clinical treatment formula is tested.

1. sweet * *, man 25 years old sucks heroin, history of drug abuse 2 years to scald the suction mode.Suck 4 every day ^#The about 1g of heroin, urine morphine detect and to be (+++), and naloxone is urged the addiction positive.The patient sends out addiction behind 12h.Cardinal symptom is yawn, shed tears, rhinorrhea, perspiration, goose pimples, agitation, stomachache, fear are cold, tremble, nausea and vomiting etc.Medicine STX of the present invention is entered im, 30 μ g, in about 5 minutes, mainly sends out the addiction transference cure the patient, observe about 1h, the patient is conscious good.After the sleep of 8h, the patient requires feed, and defecation is normal.The patient has slight addiction to send out the symptom appearance again behind 36h, and im, 30 μ g transfer to normal again.48h urinates morphine and detects and to have transferred (+) to, transfers in the 3rd day (-).Other are normal except that muscular soreness of whole body.The back health check-up of one week is normal.Weight increase 2kg.Naloxone urges addiction negative.The urine morphine detects and is (-).Go back to tame rehabilitation.

Section * *, man 21 years old, with iv heroin, every day, about 0.8g took drugs 3.5 years, urinated morphine and naloxone and urged addiction all positive.The patient begins to send out an addiction behind 8h, when adhering to 14h voluntarily, feel incessantly anti-, this moment addiction to send out symptom be successive yawn, shed tears, nasal congestion, nervous, agitation, goose pimples, stomachache, nauseating etc.With medicine Neo-STXiv30 μ g of the present invention, nearly all transference cure after 4 minutes is observed 0.5h, and the patient is conscious fully good, requires to leave hospital, and it is fine to sleep, feed next day, and it is normal that defecation is recovered.Require im.30 μ gNeo-STX night, 48h urine morphine detects and is (-), and it is (-) that the 72h Allylnoroxymorphone is urged addiction.7 days body weight weightening finish 2kg do not have knock-on in hospital, transfer rehabilitation to.

Poplar * *, 29 years old, opium eating 5 years, 49kg when being admitted to hospital, behind the 10h yawn continuous, imDC-STX30 μ g, conscious fully good, little addiction arranged, imDC-STX30 μ g behind the 24h, conscious malaise, aching and limp, sleeping and eating are normal, stool is normal after 2 days, the urine morphine detected to (-) in 4 days, left hospital weight increase 5kg when leaving hospital after 10 days.

The Yin Dynasty *, the woman, 24 years old, cigarette was inhaled one and is scalded and inhale an iv heroin, 2 years about half, about every day 1g, when being admitted to hospital, urine morphine and Allylnoroxymorphone urged addiction to be (+), 6h, imGTX ₄The conscious improvement of 100 μ g, diet sleep is normal, and the 4th day urine morphine and naloxone urge addiction to be (-).Be in hospital and required to go home rehabilitation in 6 days.

Above clinical test results shows that medicine of the present invention does not have drug dependence.Withdrawal symptom disappearance and detoxification are fast, onset rapid and be a cup too low obstacle and adverse side effect.

In the most of patient who gives up, all can mainly send out the addiction transference cure, wholely give up in the process patient and all be in highly clear-headedly, except the part patient has slight tongue, lip numbness, difference sensation, there is no discomfort in administration onset about 5 minutes.Most of patient was from the 4th day, and whole body has aching and limp, weak sense.This is the problem that junkie needs rehabilitation.The table 1. diguanidino-prine-hydride compounds of isolation identification [notes] NO toxin title is called for short Chinese R1 R2 R3 R4 R5 R6 virulence MU ^*/ mg1 Saxltoxin STX saxitoxin H H H CDNH ₂The new saxitoxin OH of OH OH 55002 Ncosoxlloxin Nco STX H H CONH ₂OH OH 39003 DccoibmmooylSTX DC-STX De(carbamoyloxy)saxitoxin H H H H OH OH 42004 GonynuloxlnI GTX ₁Knee joint ditch bath toxin I OH H OSO ₃ ^-CONH ₂OH OH 50005 GooyauloxlnII GTX ₂Knee joint ditch bath toxin II H H OSO ₃ ^-CONH ₂OH OH 42006 GonynuloxlnIII GTX ₃Knee joint ditch bath toxin III H OSO ₃ ^-H CONH ₂OH OH 59007 GonyouloxlnIV GTX ₄Knee joint ditch bath toxin IV OH OSO ₃ ^-H CONH ₂OH OH 16008 Snxltoxlnol-12 α STX-OL 12 Alpha-hydroxy saxitoxin H H H CONH ₂OH H 5509 Saxlloxinol-12 β STX-OL 12 beta-hydroxy saxitoxin H H H CONH ₂H OH 5.510 GonyouloxinV GTX ₅B ₁Knee joint ditch bath toxin V H H H CONHSO ₃ ^-H OH OH 26011 GonyouloxinVI GTX ₆Knee joint ditch bath toxin VI H H H CONHSO ₃ ^-H OH OH 20012 GonnyouloxinVII GIX ₀TX ₆Knee joint ditch bath toxin VII H SO ₃ ^-H CONHSO ₃ ^-H OH OH 3-60013 EpigouyoutoxinVIII EpiGTX ₀TX ₄Table knee joint ditch bath toxin VIII H H OSO ₃ ^-CONHSO ₃ ^-H OH OH 3-4014 Snllocorbomoyl PX ₃G ₃Knee joint ditch bath toxin OH H OSO ₃ ^-CONHSO ₃ ^-H OH OH

Gonyouloxinl knee joint ditch bath toxin I15 Sullocnrhomoyl TX ₄C ₄Sulphuric acid argon formyl OH SOO ₃ ^-H CONHSO ₃ ^-H OH

GonyoutoxinIV knee joint ditch bath toxin III

In [notes] table is by general formula of the present invention (I) R that gives ₁R ₁₃Substituent group;

* MU is an allen-Doisy unit, the used toxin dose of mice of 1 the body weight 20g that causes death in the expression 15-30min.

Mouse jump reaction after table 2. multiple subcutaneous injections STX or the morphine

Animal groups	Accumulated dose (mg/kg)	Administration natural law (d)	Number of animals (only)	Number of hops (%)
					A organizes morphine group (mg/kg)	157.5 1600	2 20	10 20	70 68
B group STX group (μ g/kg)	11.2 21.7	2 20	10 20	0 0
					C organizes normal saline (ml/kg)		2 20	10 20	0 0

Table 3. morphine-dependent mice detoxification treatment is observed

Pharmaceutical compounds	Dosage SC μ g/ kg	The administration natural law (inferior/h)		The total metering of accumulative total (μ g/kg)	Number of animals (only)		Nalorphine mg/kg, sc	Jump number of elements (jump/survival)
											Treated the 5th	Drug withdrawal first day	After the drug withdrawal the 4th day
								Rely on	Detoxification
					1-3	4-5
		Normal saline STX Neo STX DC-STX GTX 1 GTX 2 GTX 3 GTX 4 STX OL STX STX	10ml /kg 1 1 1 1 1 1 5 5 0.1 0.5							1/6 1/8 1/8 1/8 1/8 1/8 1/8 1/8 1/8 1/0 1/8				1/8 1/12 1/12 1/12 1/12 1/12 1/12 1/12 1/12 1/12 1/12	250ml 13 13 13 13 13 13 91 91 1.3 9.1	10 10 10 10 10 10 10 10 10 10 10	8 10 10 10 10 10 10 10 10 10 10	50 50 50 50 50 50 50 50 50 50 50	4/6 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10	3/3 0/10 0/10 0/10 0/10 0/10 0/10 0/10 1/10 1/10 0/10	1/2 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10 0/10

Table 4 dropping drug dependence using dosage of the present invention

The operating position of 20 routine model cases

Injection	Sex	The poisoning kind	The time limit	The drugs using method	Drugs use amount/day	The withdrawal medicine	Consumption	Occupation mode	Use natural law
										(1)	The man	Heroin	4	Intravenous injection	0.5g	STX	30μg×10	im	5
(2)	The man	Heroin	4	Suck	0.0g	Neo- STX	30μg×8	im	3
										(3)	The man	Heroin	1	Suck	0.6g	DC- STX	30μg×5	im	2
(4)	The man	Heroin	7 months	Suck	1.0g	GTX 1	30μg×4	im	3
										(5)	The man	Heroin	3	Suck	1.0g	GTX 2	30μg×8	im	4
(6)	The man	Heroin	1	Suck	1.0g	GTX 3	30μg×5	im	3
										(7)	The woman	Heroin	1.6	Intravenous injection	0.0g	STX	30μg×8	im	6
(8)	The man	Opium	1	Suck	0.2g	Neo- STX	30μg×7	im	3
										(9)	The man	Opium	4	Suck	0.8g	DC- STX	30μg×65	im	4
(10)	The man	Heroin	4	Suck	1.0g	GTX 1	30μg×6	im	3
										(11)	The man	Heroin	5	Suck	0.4g	GTX 2	30μg×10	im	3
(12)	The man	Heroin	4	Suck	1.0g	GTX 3	30μg×12	im	6
										(13)	The woman	Heroin	5	Intravenous injection	1.2g	GTX 4	30μg×11	im	4
(14)	The man	Heroin	6	Suck	0.5g	STX- OL	30μg×4	im	4
										(15)	The man	Heroin	5	Intravenous injection	1.5g	STX	30μg×13	im	4
(16)	The man	Heroin	1	Intravenous injection	0.5g	STX	30μg×5	im	3
										(17)	The man	Heroin	5	Suck	1.5g	Neo- STX	30μg×5	im	5
(18)	The man	Heroin	3.2	Suck	1.2g	STX	30μg×3	im	5
										(19)	The woman	Heroin	2	Suck	2.5g	Neo- STX	30μg×7	im	7
(20)	The man	Heroin	5	Intravenous injection	3.5g	DC- STX	30μg×8	im	6

Patient's withdrawal symptom before table 5. drug use of the present invention

Injection	Subjective symptoms													The objective sign shape
																																				Irritated sense	The joint extremity pain	Creeping chill	Insomnia	Excited	Thirsty	Dyspnea	Headache	Stomachache	Feel sick	Lower limb are ached	Chest is vexed	Stomachache	Yawn	Anti-skin is itched	Shed tears	Finger trembles	Rhinorrhea	Mydriasis	Myosis	Vomiting	Dysentery	Feel sick	Shed tears	Toss about	The foot foot is irritated	Abdomen	Cough	Imbalance	Groan	Diaphoresis	Urine protein	Respiration Rate	Pulse	Blood pressure
	(1)	+		+	+	+	+			+		+		+	+	+	+		+	+			+		+	+		+			+	+	+	21	78																																				95/65
(2)																																				+	+	+	+		+		+		+		+		+	+	+	+	+		+	+		+	+	+		+	+		+		+	22	82	105/70
	(3)	+	+	+	+	+	+			+	+			+	+		+		+	+		+			+				+	+				19	81																																				110/75
(4)																																				+	+	+	+						+	+			+	+	+		+			+		+	+		+		+				+	21	86	95/65
	(5)	+		+	+		+		+	+		+	+	+	+		+	+	+			+		+	+		+		+				+	21	86																																				95/65
(6)																																				+	+	+	+					+	+				+		+	+	+			+		+	+				+				+	22	91	90/50
	(7)	+		+	+					+	+	+		+	+		+		+				+	+	+	+				+	-			22	92																																				90/65
(8)																																					+	+	+	+				+	+	+	+		+	+	+	+	+			+			+									21	83	100/70
	(9)	+	+	+	+				+						+		+	+	+						+			+		+				21	89																																				95/70
(10)																																				+	+	+	+		+		+			+	+		+		+	+	+	+				+	+								+	22	86	95/65
	(11)	+	+	+	+					+	+				+		+		+				+	+	+						+		+	19	82																																				110/70
(12)																																				+	+	+	+		+			+	+	+			+	+	+		+						+									23	73	110/80
	(13)	+		+	+	+						+	+		+	+	+		+						+									22	80																																				100/70
(14)																																				+	+		+		+		+	+	+		+		+		+	+	+					+	+	+		+		+	+			21	81	90/60
	(15)		+	+	+										+		+		+			+			+								+	22	75																																				95/60
(16)																																				+		+	+		+			+	+	+			+	+	+		+	+		+			+	+		+	+					21	92	100/70
	(17)	+		+	+					+	+	+			+	+	+	+	+			+		+	+									21	91																																				90/60
(18)																																				+		+	+		+		+		+	+			+		+		+					+	+			+					+	22	86	90/65
	(19)	+		+	+				+	+	+		+	+	+	+	+		+			+		+	+	+		+	+				+	21	85																																				90/70
(20)																																				+		+	+					+	+				+	+	+		+	+		+		+	+			+					+	21	86	95/65

Patient's withdrawal situation after table 6. drug use of the present invention

Injection	The compounds of this invention injection (back) 3min-20min				The 4th day
						Tongue, lip picotement	The extremity picotement	Patient self sensation	Pulse (injection back blood pressure does not have significant change)	The urine morphine detects
	(1)	(+)	(+)	Well	68						Negative (-)
(2)						(+)	(+)	Well	80	Negative (-)
	(3)	(+)	(+)	Well	81						Negative (-)
(4)						(+)	(±)	Bad	85	Negative (-)
	(5)	(+)	(+)	Well	78						Negative (-)
(6)						(±)	(-)	Well	85	Negative (-)
	(7)	(+)	(+)	Well	84						Negative (-)
(8)						(+)	(+)	Well	79	Negative (-)
	(9)	(+)	(-)	Well	81						Negative (-)
(10)						(+)	(+)	Well	80	Negative (-)
	(11)	(+)	(-)	Well	75						Negative (-)
(12)						(+)	(-)	Well	71	Negative (-)
	(13)	(±)	(+)	Well	81						Negative (-)
(14)						(±)	(-)	Well	00	Negative (-)
	(15)	(+)	(-)	Well	75						Negative (-)
(16)						(-)	(-)	Well	85	Negative (-)
	(17)	(±)	(-)	Well	83						Negative (-)
(18)						(+)	(±)	Well	79	Negative (-)
	(19)	(+)	(+)	Well	83						Negative (-)
(20)						(+)	(+)	Well	82	Negative (-)

Claims (10)

1, the application of a kind of biguanide base hydrogenation purine compound in the preparation drug-breaking medicine is characterized in that the general formula of biguanide base hydrogenation purine compound is: In the formula, R ₁Be selected from H, OH, Cl, Br, OSO ₃ ^-, C _1-3Alkyl; R ₂, R ₃Be selected from H, α, β-OSO ₃ ^-R ₄Be selected from H, CONH ₂, CONH-SO ₃ ^-, C _1-5Alkyl, COR ', wherein R ' is selected from-NH ₂, NHR ", R " be selected from SO ₃ ^-, Cl, Br and C _1-5Alkyl, aryl; R ₅, R ₆Be selected from H, α, β-OH, α, β-OS ₃ ^-α, β-X, wherein X is selected from Cl, Br halogen, α, β-C _1-3Alkoxyl.

2, use by the described pharmacy of claim 1, it is characterized in that described diguanidino-prine-hydride compounds has the chemical compound of general formula (II)

In the formula, R ₄Be selected from H, CONH ₂, CONH-SO ₃ ^-, C _1-5Alkyl, COR ' is selected among its R '-NH ₂, NHR ", R is selected from SO ₃ ^-, Cl, Br and C _1-5Alkyl, aryl.

3, use by power and requirement 1 described pharmacy, it is characterized in that described diguanidino-prine-hydride compounds has the chemical compound of general formula (III):

In the formula, R ₁Be selected from H, OH, Cl, Br, OSO ₃ ^-, C _1-3Alkyl.

4, use by the described pharmacy of claim 1, it is characterized in that described diguanidino-prine-hydride compounds has the chemical compound of general formula (IV):

In the formula, R ₂, R ₃Be selected from H, α, β-OSO ₃ ^-

5, use by the described pharmacy of claim 1, it is characterized in that described diguanidino-prine-hydride compounds has the chemical compound of logical formula V:

In the formula, R ₂, R ₃Be selected from H, α, β-OSO ₃ ^-

6, use by the described pharmacy of claim 1, it is characterized in that described diguanidino-prine-hydride compounds has the chemical compound of general formula (VI): In the formula, R ₅, R ₆Be selected from OH, α, β-OSO ₃ ^-, α, β-X, wherein X is a Cl Br halogen, α, β-C _1-3Alkyl.

7, use by the described pharmacy of claim 1, it is characterized in that described diguanidino-prine-hydride compounds has the chemical compound of general formula (VIII):

In the formula, R1 is selected from H, OH, Cl, Br, OSO ₃ ^-, C _1-3Alkyl; R ₂, R ₃Be selected from H, α, β-OSO ₃ ^-

8, use by the described pharmacy of claim 1, it is characterized in that described diguanidino-prine-hydride compounds is selected from any chemical compound of saxitoxin, new saxitoxin, De(carbamoyloxy)saxitoxin, gonyatoxin I, gonyatoxin II, gonyatoxin III, gonyatoxin IV, 12 Alpha-hydroxy saxitoxins.

9, use according to each described pharmacy of claim 1 to 8, it is characterized in that with 1 to 8 described arbitrary diguanidino-prine-hydride compounds being that Main Ingredients and Appearance forms compositions by effective dose and pharmaceutically useful carrier, excipient, adjuvant, mixing diluents.

10,, it is characterized in that described compositions makes injection, oral agents, aerosol or aerocolloidal dosage form according to the described pharmaceutical applications of asking of claim 9.