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USOO5846975A United States Patent (19) 11 Patent Number: 5,846,975 Pan et al. (45) Date of Patent: Dec. 8, 1998

54 USE OF AMINO HYDROGENATED FOREIGN PATENT DOCUMENTS QUINAZOLINE COMPOUNDS AND B41-010330 6/1966 Japan. DERVATIVES THEREOF FOR ABSTAINING B44-010903 6/1966 Japan. FROM DRUG DEPENDENCE B44-010904 6/1966 Japan. B44-010906 6/1966 Japan. 75 Inventors: Xinfu Pan, Beijing; Fanglong Qiu, B42-009355 5/1967 Japan. Hunan, both of China B42-009356 5/1967 Japan. 1370905 10/1974 United Kingdom. 73 Assignee: Nanning Maple Leaf Pharmaceutical Co., Ltd., Guangxi Province, China OTHER PUBLICATIONS 21 Appl. No.: 640,781 Y. Kishi et al., J. Am. Chem. Soc., 94:26, pp. 9217-9221 (Dec. 27, 1972). 22 PCT Filed: Mar. 11, 1995 T. Goto et al., Tetrahedron, vol. 21, pp. 2059–2088 (1965). E. Murtha et al., Journal of Pharmacology and Experimen 86 PCT No.: PCT/CN95/00016 tal Therapeutics., vol. 122, pp. 247-254 (1958). S371 Date: May 21, 1996 Chemical Abstracts AN 1977: 268, Fredrikson et al., 1976. S 102(e) Date: May 21, 1996 Primary Examiner Keith D. MacMillan Attorney, Agent, or Firm-Birch, Stewart, Kolasch & Birch, 87 PCT Pub. No.: WO95/24903 LLP PCT Pub. Date: Sep. 21, 1995 57 ABSTRACT 30 Foreign Application Priority Data This invention relates to the use of amino hydrogenated quinazoline compounds and derivatives thereof, Such as Mar. 17, 1994 ICN China ...... 941 10873.2 tetrodotoxin, for abstaining from drug dependence in (51) Int. Cl." ...... A61K 31/505 human. Such compounds are administered by Subcutaneous, 52 U.S. Cl...... 514/282 intramuscular or intravenous injection for abstaining from 58 Field of Search ...... 514/260, 282 drug dependence, the Said drug is alkaloids and nitrogen containing non-amino acid compound, for example , 56) References Cited , and the like. Such compounds without drug dependence and low toxicity and side effect can abstain U.S. PATENT DOCUMENTS rapidly from drug dependence. 3,898,339 8/1975 Adams et al...... 424/251 5,474,547 12/1995 Aebisher et al...... 604/891 22 Claims, No Drawings 5,846,975 1 2 USE OF AMINO HYDROGENATED (2). Local anesthesia QUINAZOLINE COMPOUNDS AND TTX can be used as local and is ten thousand DERVATIVES THEREOF FOR ABSTAINING fold more powerful than those commonly used local nar FROM DRUG DEPENDENCE cotics (Kao CY and Fulman FA, J. Pharmacol., 140, 31-40, 1965). The combined preparations of TTX with widely-used TECHNICAL FIELD local have been published in U.S. Pat. No. 4,022,899 and U.S. Pat. No. 4,029,793. This invention is concerned with amino hydrogenated (3). As a potent for late cancer patients. TTX quinazoline compounds and derivatives thereof, particularly exerted Satisfactory effect of pain relieving on cancer pain, their new application for causing humans to abstain from and no drug cases were reported Kao CY, Pharm. drug dependence on alkaloids and Synthetic non-amino acid Rev. 18(2):997, 1966) nitrogen. 2. Sedation (1) AS for winter skin , prurigo, thylacitis, BACKGROUND OF THE INVENTION itch mite and Sarcoptic mite. It also facilitated recovery from these dermatosises. The research of amino-hydro quinazoline and its deriva 15 (2) AS asthma and pertusis abirritant. tives originated from the knowledge for crystal tetrodotoxin (3) AS enuresis inhabitant. 3. Antispasmodic TTX is a well-known amino-perhydro quinazoline with TTX is an effective antispasmodic for myospasm, gastro its molecular formula as CH7NOs and its molecular Spasm and other kinds of Spasms, particularly for tetano weight 319.27.The chemical structure for TTX is shown as Spasm. following: 4. Blood preSSure depressor TTX produced Strong depressing effect on blood pressure, (I) for example, administration of 2-3 ug/kg TTX to the cat (i.v.) could abruptly lower its arterial pressure as much as 25 two thirds of the normal value, and the duration of it action is fairly short, these characteristics possibly make it useful in first aid of hypertension crisis in the clinic. 5. Others (1) TTX was reportedly effective on pain relieving for lepers (Nomiyama S: Fed. Proc.31:1 117,1972) (2) Due to its function of congestion, TTX can elicit therapeutic effect on man's impotence and woman's asexu ality. Up to now, no applications of TTX, amino hydrogenated 35 quinazoline compounds and derivatives thereof in abstain ing from drug dependence have been reported in prior art. Here, the conception of drug dependence refers to Such a TTX has been found in many puffers up to one hundred, physical (or physiological) state of Subjects as we call it, Such as tetrodontidae, diodontidae, mollidae, triodontidae withdrawal Syndrome, which is produced by everlasting and other families of puffer. These puffers are classified as 40 interaction between the body and drug, the Symptoms hard-fish Sub-class, fish class. TissueS of these puffers rich in include perspiration, lacrimation, yawn, rigor, goose flesh, TTX include ovary, liver, skin, and gastrointestinal. Meth mydriasis, vomiting, diarrhea, achycadia, hypertension, ods of TTX extracting from these tissues have been reported insomnia, mania, remor and etc. Subjects are obliged to use by T. Goto et al. (Tetrohedron, 21, 2059. 1965) and E. F. drugs continuously not for therapeutic aim but for abuse Murtha (Expte. Therap., 122, 246. 1958). For TTX synthesis 45 which occurs once drug taking is Stopped. Drugs here men method, see Y. Kishi, et al., J. Am. Chem. Soc., 94(26), tioned refer to alkaloids part of drugs, Such as opium, 9217, 9219. 1972. Later studies revealed that TTX and its morphine, , amphetamine, and other Synthetic non derivatives could be detected in amphibians like amino acid nitrocompounds, Such as heroin, dollantin, Salamanders, in mollusks like Octopus, shellfish, and Snails, dihydroetorphine, , and etc. in arthropods like crabs, limulus, Starfish and in plants like 50 The frightening consequences of drug abuse make it red algae. Very recently, it was found that TTX was also desperately needed for the Society to develop new produced by Some geneses bacteria Such as Vibros, de-addiction drugs which are highly effective, short of pseusdomona, Streptomyces joSamycetinuS and etc. TTX is Severe side reactions. an extreme poison whose toxicity is 1,250 times more than So far, the methods for addiction therapy in the world that of sodium cyanide. It was estimated that dosage of TTX 55 mainly rely on Substitutive drugs. Briefly, they can be as little as 0.5 mg could bring death of a person with 70 kg Summarized as follows: body weight. In another report, Subcutaneous injection of 1. Taking Small dose of opium-containing drugs. During 300 lug TTX was enough to put death of a man with 50 kg the therapy period, opium may be gradually reduced till no body weight. opium is used in the end. This regimen lasts quite long (16 Although TTX has been long recognized, its clinical 60 days), and its curative effect is just So-So. indications limit in following aspects: 2. Taking methadone orally. Methadone is used as a 1. Analgesia Substitution for abused drugs like opiums. This therapy is (1). TTX produces pronounced analgesic effect on various currently applied as a Standard treatment for drug abuse, pains caused by burning, trauma, injuries from falls, most patients can free themselves from drug dependence fractures, contusions and Strains, especially for neuragia, 65 within 10 days. myalgia and arthralgia. Unless the diseases are inveterate, 3. Using dehydroetorphine(DHE). According to clinical TTX is a powerful analgesic. trials, dose-reducing therapy of DHE could alleviate absti 5,846,975 3 nence Symptoms within 7 to 10 days, however, during the -CH(OH)NHOMe, therapy period, DHE dependence usually occurred. -NAP-gly, 4. Administration of . 5. Other drugs, like clinidine. -NAP-en, Recently, the combination of drugs above mentioned has -CH-NH2, been coming into use, for example, DHE combined with CH-NHCH, methadone was used for heroin addiction Sha Lijun et al. Xinyao he Linchuang (New Drugs and Clinical Remedies) -AAG, 13(6), 337–339, 1994), and also small dose of DHE com -NMAG, and bined with anisodaminum possessed the Same therapeutic 1O -ANT: effect for heroin dependence Su Mujing et al.Chinese Drug when R is OH or OC(O)R and R is an alkyl with C-C, Dependence Bulletin, 2(1): 48–51, 1992). In addition, ani R can be Selected from the group consisting of: Sodaminum alone or plus chlorpromazine were also used for de-addiction therapy. -CHO, Among above drugs, methadone, and DHE are them 15 -CH2-gly, Selves addictive medicine if used for a long time. -CH-B-Ala, Anisodaminum, though lack of addictive, can produce vari CH-Lys, ous Side effects, Such as blurred vision, airway Secreta drying, thirst, enuresis and etc. For these reasons, it is -CH-en, imperative to Seek new de-addiction drugs which are highly -CH-NAP-Lys, effective, lack drug dependence and Severe Side reactions. -CH-NAP-en, The object of the present invention is to provide a novel application of amino hydrogenated quinazoline compounds -CH(OH)CH(NH)COOH; and, and derivatives thereof, including TTX, to cause humans to -NH(CH), COOH, abstain from drug dependence on alkaloids. 25 -NH(CH), NH; and The other object of the invention is to provide a pharma –NH(CH),CH(NH)COOH, ceutical composition containing amino hydrogenated wherein: quinazoline compounds and derivatives thereof for the same therapeutic use as above. n=1-6. The further object of the invention is to provide methods en is ethylene; of causing humans to abstain from alkaloids dependence by NAP is 4-triazo-2-nitrobenzoic amide, indicated as for administering amino hydrogenated quinazoline compounds mula (a); and derivatives thereof to human patients. AAG is 2-triazo-O-aminobenzoic amide, indicated as DISCLOSURE OF INVENTION 35 formular (b); The present invention relates to a use of amino hydroge NMAG is O-methylaminobenzoic amide, indicated as nated quinazoline and derivatives thereof are compounds formula (c); having the general formula I in the preparation of medica ANT is O-aminobenzoic amide, indicated as formula (d); ment for causing humans to abstain from drug-dependence, 40 O NO2 (a) I

N3 45 O N3 (b)

-HN

N H.N- 50 HN C N O NHCH H -NH

55 wherein, t R and Rs can be Selected from the group consisting of H, (d) OH, OAC, respectively; R call be H, or an alkyl with C-C, OH, OR, OC(O)R', -HN NH, NHR", NR"R", among them R can be an alkyl with 60 C-C, R' can be an alkyl with C-C, and R", R" can be an alkyl with C-C, respectively; t R and R can be =O, or Among them, three kinds of compounds with the general when R is H., R can be Selected from the group con formula II, III, IV are preferred. Sisting of: 65 The amino hydrogenated quinazoline compounds and -ROH, and R is a branched or straight chain alkyl with derivatives thereof are compounds having following general C-C-7, formula II, 5,846,975

II IV

N 1O H.N- CHOH N H

15 wherein: wherein, R can be selected from the group consisting of: R can be Selected from the group consisting of OH, an -CHO, alkyl or a oxyalkyl with C-C, NH, NHR", NR"R", -CH-Gly, among them R" and R" can be an alkyl with C-C. -CH-B-Ala, Among them, the more preferred compounds are: -CH-Lys, Tetrodotoxin R=OH (1); -CH-en, deoxytetrodotoxin R=H (2); -CH-NAP-Lys The amino hydrogenated quiniazoline compounds and 25 -CH-NAP-en, derivatives thereof are compounds having following general formula III. –NH(CH), CH(NH)COOH: -NHCHCOOH: III -NHCH-CHCOOH; and –NHCHCH-NH. Among them, the more preferred compounds are: oxytetrodotoxin R=CHO (7); chiriquitoxin R=CH(OH)CH(NH)COOH (8); 35 and the compounds with the Substituted groups of R: –NH(CH), CH(NH)COOH (9); N –NHCHCOOH (10); H.N- -NHCH-CHCOOH (11); and, N 40 -NHCHCH-NH (12). H The above-mentioned amino hydrogenated quinazoline compounds and derivatives thereof, including Tetrodotoxin, could inhibit the -dependence withdrawal Symptoms, and it is not addicted by the antagonists. It could wherein: 45 effectively and promptly inhibit and allay the withdrawal R, R are =O, or Symptoms and could dispel the restlessness of patients as use when R is H, R is Selected from the group consisting of: of these kinds of compounds with adequate dosage when the withdrawal response commences upto the most Severe. The CHOH, withdrawal Symptoms of patients were allayed and disap CH(OH)NHOMe, 50 peared from 5 to 30 min after accepted administration of the -NAP-gly, therapy. Patients could be quiet and almost feel numb in month, tongue and lips, however, no uneasy feeling. The -NAP-en, numb counteracts the desire of patients for drugs, Such as -CH-NH, heroin. After several days maintenance (2–8 days, and —CH-NHCH, 55 generally 2–3 days ), it reaches the clinical de-addiction -AAG, which shows as the withdrawal Symptoms disappeared com -NMAG, and pletely and the test of morphine in urine transforms to negative. After halt in using the above-mentioned amino -ANT. hydrogenated quinazoline compounds and derivatives Among them, the more preferred compounds are: 60 thereof, there is no dependence to them and no adverse and AAG-degradation Tetrodotoxin R=AAG (3); Side effects. AS using the above-mentioned amino hydroge NMAG-degradation Tetrodotoxin R=NMAG (4); nated quinazoline compounds and derivatives thereof to treat patients, no case developed Sicchasia, Vomiting, col ANT-degradation Tetrodotoxin R=ANT (5); and, lapse or coma as with the use of other medicines. It also has degradation Tetrodotoxin R, R is =O (6). 65 no side effects as in the treatment of methadone and DHE. The amino hydrogenated quinazoline and their derivatives The invention further involves any composition of are compounds having following general formula IV, medicines, which contains an effective dosage of above 5,846,975 7 8 mentioned amino hydrogenated quinazoline compounds and Example 9-12 their derivatives, to leave off drug dependence. The amino 6 mg compound (9)-(12) was dissolved in 200 ml pH 5 hydrogenated quinazoline compounds and their derivatives acetic acid individually, then divided the solution into 100 in this invention could be made by now available technolo parts to prepare injections (9)-(12), So each injection con gies with pharmaceutically acceptable carriers, excipients tained 60 ug compound (9)-(12). and other additives to various forms, Such as injections (including Subcutaneous, intramuscular or intravenous) or EXPERIMENT oral form (including hypoglossal etc. However, because the orally effective dosage is much higher than (about 20 times) Experiment 1: Comparison Experiment that of injections, injection is preferred. It is preferred to Materials and Methods dissolve the above-mentioned amino hydrogenated quinaZO 1. Sample Collection line compounds and their derivatives in weak acid water 2768 cases with drug-dependence were collected in TTX Solution, Such as benzoic acid or acetic acid Solution with pH de-addiction treatment, 2500 of them finished the whole being 4-5. process of treatment and 228 cases Stopped the treatment AS using to clear off drug dependence, the effective because 206 cases could not tolerate the abstinence Syn dosage of above-mentioned amino hydrogenated quinazo 15 drome in the first 3 days and required to draw out this line compounds and their derivatives is from 5 lug to 300 lug treatment, 17 cases were found in Serious infectious diseases when injected by Subcutaneous, intramuscular or intrave and other 5 cases were transferred to other hospitals. OUS. The invention also involves any method to clear off drug These 2500 patients described above were 45-13 years dependence which uses effective dosage of above old, averaged 23.5. Their drug-use period were 20-0.25 mentioned aminoperhydroquinazoline compounds and their years, averaged 1.8 years. 2125 (85%) of them were male derivatives through oral or Subcutaneous, intramuscular or and 375 (15%) were female. intravenous injections. Kinds of drug-abuse: 831 cases taking Opium, 1570 cases Although the compounds of the invention used in clearing taking Heroin, 41 cases taking Morphine, 50 cases taking one off drug dependence are all Severely toxic Substances, 25 DHE, 5 cases taking Dolantin, 2 cases taking Cocaine and 1 the administered dosage of therapy is much lower than case taking Amphetamine. intravenously toxic dosage, Such as the toxic dosage of TTX Abuse routes: iv. 930, inhalation 1570. which is 300 ug/person. Daily abuse amount were 5.0-0.1 g. Drug-addiction It takes 3-5 days to clear one off the drug dependence of degree were preliminary divided as: Light (Group A), 1050 opium, heroin, morphine, cocaine, amphetamine (ice), cases, 50 cases drawing out, 1000 cases finished the treat dolandin, dihydroetorphine and methadone and this kind of addictable alkaloid when using the aminoperhydroquinazo ment of de-addiction; Medium (Group B), 1100 cases, 100 line compounds and their derivatives of this invention alone cases drawing out, 1000 cases finished the treatment of or co-use them with other anti-addiction medicines. They do de-addiction; Serious(Group C), 568 cases,68 cases drawing not induce addiction themselves but could clear one off drug out, 500 cases finished the treatment of de-addiction; dependence within a short time, with little toxic and Side 35 Control(Group D), 60 cases randomly selected, 10 cases effects, and quick recovering of health (7–10 days). drawing out, 50 cases finished the treatment of de-addiction. 2. Accepted Cases Selection BEST MODE FOR CARRYING OUT THE INVENTION 2.1 Experiment Places and Case Resources Example 1 Experiment places were Health-Recovering Hospital and 3 mg compound (1), TTX, was dissolved in 200 ml 40 De-Drug-Addiction Agency recognized by China govern injection used water which containing 9.4 g benzoic acid ment. Accepted cases were de-addiction Volunteers of drug (pH=4) and distributed it to 100 parts. Each contains com dependence on Opium, Morphine, Dolantin, Heroin, DHE, pound (1) 30 ug and be made as injections (1). etc. Treatment formalities were voluntarily carried out by Example 2 themselves or their families. Cases were free except drug 15 mg compound (2), was dissolved in 200 ml pH 4 45 abuse during the treatment period. benzoic acid solution and distributed to 100 parts. Each 2.2 Diagnostic Criterion contains compound (2) 150 ug and be made as injections (2). According to WHO drug-dependence definition and Example 3-5 U.S.ADSM-III-R Criterion, the cases were diagnosed. Both 10 mg compound (3)–(5) was dissolved in 200 ml pH 4 their urine test and addiction-press test were acetic acid individually, then divided the solution into 100 50 positive and their addiction Syndrome were significant parts to prepare injections (3)–(5), So each injection con before TTX treatment. tained 100 ug compound (3)–(5). Example 6 3. De-Addiction Program Design 15 mg compound (6) was dissolved in 200 ml pH 4 3.1 Grouping benzoic acid, then divided the solution into 1100 parts to 55 The accepted cases were examined in detail, then accord prepare injection (6), So each injection contained 150 ug ing to their drug-taking period, amount, Species, physical compound (6). and mental conditions, they were divided into Light, Median Example 7 and Serious 3 degrees and given general, intensive and 3 mg compound (7) was dissolved in 200 ml pH 5 benzoic Special care. 4. Methods acid, then divided the solution into 100 parts to prepare 60 injection (7), So each injection contained 30 ug compound 4.1. Observation Methods (7). 4.1.1. According to clinical abstinence Syndrome and inten Example 8 sity and literature criterion, the cases were divided into III 3 mg compound (8) was dissolved in 200 ml pH 4 acetic grades generally. acid, then divided the solution into 100 parts to prepare 65 4.1.2 Given marks by abstinence Syndrome frequency before injection (8), So each injection contained 30 ug compound and after treatment. Grade I 2x5; Grade II 3x6; Grade III (8). 4x8. 5,846,975 10 4.1.3 Given marks by adverse reactions (see the table)before 1.1 Significantly effective: Physical Syndrome disappeared, and after treatment. mental syndrome alleviated obviously. Marks were lower “1” known by requiring, than 25 in 72 hours and lower than 10 at the end of the “2” could be tolerated by chief complaint; treatment. '3” could not be tolerated, drug amount needed reducing, 1.2 Effective: Physical syndrome and mental syndrome “4” stopped treatment. reduced. Marks were lower than 60 in 72 hours and lower 4.1.4 Inhibition effect was marked as the Sum of the above than 25 at the end of the treatment. 1.3 Not effective: Cases had no or just slight reduction of 2 items marks. The lower the mark, the better the inhibition physical syndrome. Their mental syndrome was still obvi effect; or the worse. Accepted cases were Systematically ous. Marks were more than 60 in 72 hours and more than 25 examined, included System examination. Abstinence Syn 1O at the end of the treatment, or Stopping drug administration drome was marked on chief complaint and physical Syn during the treatment. drome appearance. Laboratory examinations included test of 2. Evaluation of Efficacy blood, urine routine, liver function, electrocardiogram, 2.1 After drug administration the treatment groups showed X-ray for heart and lung, and drug urine test. Physical Significant inhibition effect on the generation and reaction complication, psychosis and cardiovascular diseases 15 intensity of abstinence Syndrome. The therapeutic effects patients were excluded after the treatment beginning. The were highly significantly different from control group in 72 treatment results were observed and recorded everyday and hours and at the end of the treatment (p<0.01). (see Tab.2.) marked by a proper person. Everyday, after drug 2.2 Inhibition Effect on Various Intensity of Abstinence administration, cases were measured blood preSSure, heart Syndrome rate and marked on the adverse reactions. Each treatment See Tab.3. The total syndrome marks of 6 groups were not period was Set as 3-8 dayS. Treatment efficacy was evaluated statistically different (pa0.05) before the treatment, while as Soon as the treatment finished, and the results were there were significant difference in mark reduction in 72 Statistical analysis. hours treatment (p<0.01), but there were no difference in 4.2 Treatment Methods total mark reduction in group A,B and C1,C2 after 72 hours Group A: TTX (from Case 1) treated; 25 treatment (pa0.05). Group B: TTX--Diazepamum treated; 2.3 Inhibition Effect on Various Abstinence Syndrome Group C; TTX--Agonist treated; Comparing the frequency of various abstinence Syndrome Group D: Control before and after the treatment, treatment groups showed Among them: Significant reduction in 15 min. and after 72 hours treatment, Group A: Cases of drug-taking leSS amount, shorter especially in Group A.B. Treatment results of various absti period, better physical conditions and Stronger will, could be nence Syndrome See Tab. 4. only treated by TTX i.m. 1 injection per day, for 3 days. 3. Comparison of Time of Onset of Drug Effect. Group B: Cases of drug-taking more amount, longer All accepted cases were administrated drugs when various period, worse physical conditions and weaker will, could be abstinence Syndrome reached its peak (Syndrome mark more treated by TTX with Diazepamum. In the first 3 days, i.m. 35 than 20). Noticed the time point of abstinence syndrome or iv TTX 1-2 injections/day, bid., and iv. by drop Diaz Significant alleviated or disappeared. The results are as epamum 10–20 mg in 500 ml 5-10% glucose-normal saline fellows: after 4-6 hours of the first TTX administration, bid. Cases that Still could not sleep were additionally administrated TTX.n. 3-20 min. Mean: 8.00 + 2.00 min. 50–100 mg Wintermin. 40 TTX iv. by drop 2-15 min. Mean: 5.40 + 1.20 min. Group C. Cases of drug-taking amount more than 2 g DHE i.m. 7-25 min. Mean: 10.54 - 4.50 min. daily, period longer than 2 years and had abuse experience DHE i.v. by drop 5-20 min Mean: 13.11 + 4.12 min of Opium, DHE, Diazepamum, Wintermin etc. Their physi Methadone p.o. 50-90 min. Mean: 71.00 - 21.86 min. cal and mental conditions were worst. Their aim was gen erally to reduce but not to get rid of drug-abuse. For their 45 TTX showed its effect was faster than control drug whatever treatment 2 methods were designed. the administration routes. Method C1: On day 1 to 5, i.m. TTX bid and on day 1 to 4. Gradual Changes of Hamilton 3, add agonist Such as Methadone; day 1, 30–40 mg, day 2, Results see Tab. 5. 20–30 mg, day 3–4, 20 mg, day 5, 10 mg p.o. On day 6-8, The change tendency of Hamilton anxiety was closely Symptomatic treatment. 50 related to its abstinence Syndrome in each group. Mark of 6 Methods C2: On day 1-5, i.m. TTX bid, 2 hours later p.o. groups was all reduced after treatment, group A,B,C 1 C2 Diazepamum 10 mg, Clozapinum 25 mg. More Serious cases was plateaued; on day 4.5, Group D2 elevated then reduced were iv. by drop 50-100 mg Wintermin in 5-10% glucose gradually; while Group D1 was elevated on day 8-10 after normal saline after the first TTX 2 injections. It was also administration Stopping. All of Group A,B and C showed Suggested that p.o. estaZolam 3–4 mg /day, or p.o. 55 significantly different from Group D (p<0.05 or p<0.01). Clonozepam 6-10 mg/day to Sustain 3–4 days then the 5. Drug Adverse Reactions dosage gradually reduced till day 7. No adverse reactions were found in Group A,B,C 1,C2.D1 Group D: divided to 2 methods: and D2. No abnormality was found in blood, liver, kidney D1: Methadone p.o.; function and electrocardiogram before and after treatment. D2: DHE iv. or p.o. 60 Urine drug amount and Naloxone addiction-press test were Daily dosage of each group See Tab. 1. all negative after the treatment. Results Most cases in Group A treated with TTX had the feeling 1. Criterion of numbness in tong tip and lips. So did Small number of In this program, all observations of therapeutic efficacy group B and only a few of group C. were recorded in time everyday and quantified in a table to 65 Some cases in Group D2, D1 treated with DHE and give marks, which was also referred to chief complaints to Methadone had the Syndrome of dizzle, cardiopalmus, nau certain the criterion of treatment effect. Sea and hidrosis etc. 5,846,975 11 12 Almost every Serious cases felt Systematic pain, tiredness showed cases abstinence Syndrome before treatment, includ at the later phase of the de-abstinence treatment. ing subjective and objective syndrome. Tab. 8 showed 6. De-experiment Rate de-addiction situations after the compounds administration Some cases drew out the experiment during the treatment 5-15 min. and 4 days. It Suggested that the compounds process. The rate in Group A was about 5%, Group B 10%, 5 according to the present invention could get rid of addiction Group C1 12%, Group C2 15%, Group D1 15%, Group D2 rapidly with less side effects. 35%. Experiment 2: Typical Cases Industrial Applicability Cases 1-20 Tab. 6 showed of the Sex, drug-dependent Species, drug- 10 In this invention the discovery of new uses for the titled taking period and routes of typical case 1-20, and the compounds Suggests that this type of compounds can be treatment dosage and days of administration of the injections used to prepare drugs for treatment of human drug (Example 1-8) according to the present invention. Tab. 7 dependence.

TABLE 1. Daily Dosage of TTX and Control Group Group C Group D Admini- Group A Group B C1 C2 D1 D2 stration TTX, im, lug TTX, im, ug TTX, imfiv, TTX, imfiv, Methadong, DHE, Days n = 1000 n = 1000 fig fig pO, mg fig d1 3O 60 60 + 60 + 3O 400 iv Methadone Diazepamum 10 30 mg po mg + Clorozapimum 25 mg d2 3O 60 + Diazepamum 60 + 60 + 3O 400 iv 10-20 mg in 500 Methadone Diazepamum 10 ml Glucose + N.S 30 mg po mg + Clorozapimum 25 mg d3 3O 60 + Diazepamum 60 + 60 + 3O 400 iv 10-20 mg in 500 Methadone Diazepamum 10 ml Glucose + N.S 30 mg po 20 mg po Clorozapimum 25 mg d4 60 60 + 60 + 2O 350 po Methadone Diazepamum 10 30 mg po mg + Clorozapimum 25 mg d5 3O 30 + 60 + 15 300 po Methadone Diazepamum 10 10 mg po mg + Clorozapimum 25 mg d6 3O 30 + 30 + 15 200 po Methadone Diazepamum 10 mg po 10 mg d7 3O 30 + 1O 150 po Diazepamum 10 mg d8 5 100 po

TABLE 2 Comparison of Curative Effect between Treatment Groups and Control Group Efficacy in 72 h Final Efficacy Effective Case Significant Not Significant Not Rate Group Number effective Effective effective effective Effective effective (%)

A. 1OOO 970 3O O 950 50 O 1OO B 1OOO 750 240 1O 510 488 2 98.8 C1 250 1OO 125 25 75 170 5 98 C2 250 8O 12O 50 60 183 7 97.2 D1 2O 1O 8 2 5 14 1. 95 D2 2O 12 6 2 6 13 1. 95

5,846,975 15

TABLE 6 Dosage of the Compound According to the Present Invention for De addiction Treatment Results of 20 Typical Cases Using Drug Drug De-ad- Admini Case Drug Period Dosage route of diction Route stration No. Sex type (year) (g/day) Se Comp. Dosage of use days 1. male Herion 4 O.2 iv. (1) 30 tug im 5 x 10 2 male Opium 4 0.4 inhalate (2) 150 lug im 3 x 8 3 male Opium 1. 0.4 inhalate (3) 100 lug im 2 x 5 4 male Herion 7 1.0 inhalate (4) 100 lug im 3 months x 4 5 male Herion 3 1.0 inhalate (5) 100 lug im 4 x 8 6 male Herion 1. 1.0 inhalate (6) 150 lug im 3 x 5 7 female Herion 1.6 O.8 iv. (7) 30 tug iv. 6 x 8 8 male Opium 1. 0.2 inhalate (8) 30 tug im 3 x 7 9 male Opium 4 0.8 inhalate (9) 60 pig im 4 x 6 O male Herion 4 .0 inhalate (10) 60 pig im 3 x 6 1. male Herion 5 0.4 inhalate (11) 60 pig im 3 x 10 2 male Herion 4 .0 inhalate (12) 60 pig im 6 x 12 3 male Herion 5 .2 iv. (8) 30 tug iv. 4 x 11 4 male Herion 9 0.5 inhalate (11) 60 pig im 4 x 4 5 male Herion 5 5 iv. (12) 60 pig iv. 4 x 13 6 male Herion 1. 0.5 iv. (10) 60 pig im 3 x 5 7 male Opium 5 ..5 inhalate (2) 150 lug im 5 x 5 8 male Opium 20 2 inhalate (3) 100 lug im 5 x 3 9 male Herion 2 2.5 inhalate (1) 30 tug im 7 x 7 2O male Herion 5 3.5 iv. (1) 30 tug iv. 6 x 8

TABLE 7 Withdrawal Syndrome of the Patients before Using the Compound of the Present Invention

1 1 1 1 1 1 1. Case No. 1 2 3 4 5 6 7 8 9 O 1 2 3 4 5 O Subjective symptom

Agitating ------Joint pain ------Cold ------Insomnia ------Exciting ------Thirsty ------Dyspnea Headache ------Abdominal pain ------ ------Lower ------extremity sore Thoracic ------depress Stomachache ------5,846,975 17 18

TABLE 7-continued Withdrawal Syndrome of the Patients before Using the Compound of the Present Invention

1 1 1 1 1 1 1 1 1 1 2 Case No. 1 2 3 4 5 6 7 8 9 O 1 2 3 4 5 6 7 8 9 O Objective symptom

Yamns ------Skin itch ------Lacrimation ------Finger-tremors ------Rhinorrhea ------Mydriasis ------Miosis -- Vomiting ------Dysentery ------Nausea ------Salivation ------Toss about ------Feet agitating -- -- Borborygmi ------Cough ------Disturbance ------Groan ------Diaphoresis -- Proteinuria ------Respirating 2 2 1 2 2 2 2 2 2 2 1 2 2 2 2 2 2 2 2 2 number/min O O 8 O O O O O O O 8 O O O O O O O O O Pulse 8 8 8 8 8 9 9 8 8 8 8 7 8 8 7 9 9 8 8 8 8 4 O 8 2 O O 4 8 4 O 2 4 2 6 O O 4 4 8 Blood pressure 9 1 1 9 9 9 9 1 9 9 1 1 1 9 9 1 9 9 9 9 Of O O. Of Of Of Of O 6/ Of O O O. Of 6/ O Of Of Of O 6 Of Of 8 6 6 6 Of 7 6 Of Of Of 6 6 Of 6 6 8 f O 7 7 O O O O 7 O O 7 8 7 O 8 7 O O O 7 O O O O 8 O O O

TABLE 8 Efficacy of De-addiction of the Patients after Using the Compounds of the Preseng Invention After iniecting the Compound (S-15 min Pure numbness Pure numbness Pulse rate (no significant d4 in tongue, in arms and Subjective changes in blood pressure Morphine Case month and lips legs SeSe after injection) in urine 1. (+) le 74 (-) 2 (+) (+) le 78 (-) 3 (+) (+) le 78 (-) 4 (+) not fine 86 (-) 5 (+) (+) le 8O (-) 6 (+) le 86 (-) 7 (+) le 86 (-) 8 (+) le 8O (-) 9 (+) le 82 (-) 1O (+) (+) le 8O (-) 11 (+) le 76 (-) 12 (+) le 70 (+) 13 (+) (+) le 8O (-) 14 (+) le 78 (-) 15 (+) le 74 (+) 16 (+) (+) le 86 (+) 17 (+) le 84 (-) 18 (+) le 8O (-) 19 (+ (i. le 84 (-) 2O (+) le 84 (+)

We claim: drug dependence at least one amino hydrogenated quinazo line having the general formula I in an amount effective to 1. A method of treating drug dependence in a human cause Said drug dependent human to abstain from drug which comprises administering to the human Suffering from dependence 5,846,975 19 20 -continued

I O- I

5 H.N = W W 1O CHOH

15 wherein wherein R and Rs each is selected from the group consist ing of H, OH, and OAc; R is selected from the group R can be Selected from the group conSISting of O, H. an consisting of H, C-C, alkyl, OH, OR, OC(O)R', alkyl O a oxyalkyl with C-C, NH, NHR s NR"R s 2O among them R" and R" can be an alkyl with C-C. NHNHR", and NR"R" wherein R is C-C alkyl, R' is 3. The method according to claim 1, wherein the amino C-C alkyl, and R", and R" is C-C alkyl; hydrogenated quinazoline compounds and derivatives R and R are =O; or thereof are compounds having the following general formula when Rs is H., R is selected from the group consisting of: as III, -ROH, wherein R is a branched or straight chain C-C, alkyl, III -CH(OH)NHOMe, -NAP-gly, -NAP-en, 3O -CH-NH2, H.N = was —CH-NHCH, w is -AAG, rW -NMAG, and 35 -ANT; or when R is OH or OC(O)R wherein R is C-C alkyl, R. is Selected from the group consisting of -CHO, 40 -CH2-gly, wherein: -CH-B-Ala, -CH-Lys, R, R are =O, or -CH2-en, -CH-NAP-Lys, 5 when Rs is H., R is selected from the group consisting of: -CH-NAP-en, —CH-OH, -NH(CH),COOH, -CH(OH)NHOMe, -NH(CH), NH and 50 -NAP-gly, NH(CH), CH(NH)COOH -NAP-en, -CH-NH2, wherein: —CH-NHCH, n=1-6, -AAG, en is ethylene, -NMAG, and NAP is 4-triazo-2-nitrobenzoic amide, -ANT; AAG is 2-triaZO-O-aminobenzoic amide, NMAG is O-methylaminobenzoic amide, wherein, en, NAP, AAG, NMAG and ANT have the same ANT is O-aminobenzoic amide. 60 definitions as Stated above. 2. The method according to claim 1, wherein the amino hydrogenated quinazoline compounds and derivatives 4. The method according to claim 1, wherein the amino thereof are compounds having the following general formula hydrogenated quinazoline and their derivatives are com II, pounds having the following general formula IV, 65 5,846,975 21 22 -continued dosage between 5 and 300 lug of at least one compound of O IV formula I:

wherein, R can be selected from the group consisting of: 15 H -CHO, -CH-Gly, -CH-B-Ala., -CH-Lys, wherein -CH-en, R and Rs each is Selected from the group consisting of H, -CH-NAP-Lys OH, and OAc; R is Selected from the group consisting of H, C-C alkyl, OH, OR, OC(O)R', NHNHR", and -CH-NAP-en, NR"R" wherein R is C-C alkyl, R' is C-C alkyl, -CH(OH)CH(NH)COOH: and R" and R" are C-C alkyl; -NH(CH),CH(NH)COOH: R and R are =O or when R is H, R is selected from -NHCHCOOH: 25 the group consisting of: -NHCH-CHCOOH; and -NHCHCH-NH, -ROH, wherein R is a branched or straight chain wherein en and NAP have the same definition as stated C-C, alkyl, above. -CH(OH)NHOMe, 5. The method according to claim 2, wherein the group R. -NAP-en, of the amino hydrogenated quinazoline compounds and -CH-NH2, derivatives thereof is -OH. —CH-NHCH, 6. The method according to claim 2, wherein the group R. -AAG, of the amino hydrogenated quinazoline compounds and -NMAG, and derivatives thereof is H. -ANT; 7. The method according to claim3, wherein the group R. 35 or wherein R is OH or OC(O)R wherein R is a C-C alkyl of the amino hydrogenated quinazoline compounds and and R is Selected from the group consisting of derivatives thereof is AAG. -CHO, 8. The method according to claim3, wherein the group R. -CH2-gly, of the amino hydrogenated quinazoline compounds and 40 -CH-B-Ala, derivatives thereof is NMAG. -CH-Lys, 9. The method according to claim 3, wherein the group R. -CH-en, of the amino hydrogenated quinazoline compounds and -CH-NAP-Lys, -CH-NAP-en, derivatives thereof is ANT. -CH(OH)CH(NH)COOH, 10. The method according to claim 3, wherein the group 45 -NH(CH),COOH, R, R of the amino hydrogenated quinazoline compounds -NH(CH), NH and and derivatives thereof is =O. -NH(CH),CH(NH)COOH: 11. The method according to claim 4, wherein the group wherein R of the amino hydrogenated quinazoline compounds and n=1-6, derivatives thereof is -CHO. 50 en is ethylene, 12. The method according to claim 2, wherein the group NAP is 4-triazo-2-nitrobenzoic amide, R of the amino hydrogenated quinazoline compounds and AAG is 2-triaZO-O-aminobenzoic amide, derivatives thereof is CH(OH)CH(NH)COOH. NMAG is O-methylaminobenzoic amide, 13. The method according to claim 4, wherein the group ANT is O-aminobenzoic amide. R of the amino hydrogenated quinazoline compounds and 55 18. The method according to claim 17 wherein the method derivatives thereof is NH(CH-)-CH(NH)COOH. of administration is Selected from the group consisting of 14. The method according to claim 4, wherein the group oral, Subcutaneous, intramuscular and intravenous adminis R of the amino hydrogenated quinazoline compounds and tration. 19. The method according to claim 1, wherein said amino derivatives thereof is NHCHCOOH. hydrogenated quinazoline is tetrodotoxin. 15. The method according to claim 4, wherein the group 60 20. The method according to claim 17, wherein said R of the amino hydrogenated quinazoline compounds and amino hydrogenated quinazoline is tetrodotoxin. derivatives thereof is NHCH-CHCOOH. 21. The method according to claim 1, wherein Said drug 16. The method according to claim 4, wherein the group dependence is drug dependence. R of the amino hydrogenated quinazoline compounds and 22. The method according to claim 17, wherein Said drug derivatives thereof is NHCHCH-NH. 65 dependence is opioid drug dependence. 17. A method for treating a human Suffering from drug dependence, comprising administering to Said human a daily k k k k k