JP2001511159A - Pharmaceutical composition for treating synaptic dysfunction containing oxime - Google Patents

Abstract

  (57) [Summary] Treating chronic symptoms of synaptic dysfunction and related diseases, comprising an effective amount of a physiologically active pharmaceutically acceptable oxime such as acetylcholinesterase reactivator, optionally with additional pharmacologically active agents. A pharmaceutical composition for This pharmaceutical composition may be used to treat withdrawal symptoms due to smoking cessation, respiratory disease, drug and alcohol addiction, abnormalities of the central and peripheral nervous system, treatment of antineoplastic diseases and reduced side effects of treatment of antineoplastic diseases, heart disease and It has wide application in the treatment of cardiovascular disease, obesity, chronic fatigue syndrome, endocrine and immune system abnormalities, gastrointestinal motility dysfunction, and irritable bowel syndrome, and heavy metal poisoning.

Description

DETAILED DESCRIPTION OF THE INVENTION             Pharmaceutical composition for treating synaptic dysfunction containing oxime                               Background of the invention   The pharmaceutical composition of the present invention is useful for synaptic dysfunction in mammals including humans. It is used to treat various chronic symptoms of and related diseases. The composition of the present invention comprises Naps dysfunction and related diseases such as withdrawal symptoms of smoking cessation, respiratory diseases, drugs Drug and alcohol addiction, central and peripheral nervous system disorders, And the reduction of side effects of antineoplastic treatment, obesity, endocrine and immune system disorders, cardiac disorders and And circulatory disorders, fatigue syndrome, digestive motor dysfunction, irritable bowel symptoms and heavy metals It is used to treat chronic conditions such as poisoning.   Smoking is considered to be a serious health hazard. Certain health hazards are Whether the smoke is due to normal smoking practices (ie cigarettes, cigars, pipes) Due to non-smoke-type behavior (ie smokeless or chewing tobacco) It will be different depending on the situation. Many of the health harms associated with smoking are Can be reduced. Even if not completely mitigated, there are also many health risks associated with smoking Can be lower.   Many support for those who try to reduce or stop smoking Have been proposed and tried. For example, U.S. Pat. Chewable tobacco substitute containing leukaloid), 3,901,248 (Cure containing nicotine) Bull substitute tobacco), 4,255,439 (2-imidazoline inducer combined with appetite suppressant) Conductor administration), 4,276,890 (gamma pyrone), 4,555,397 (chlorpromazine fortification) Administration of atropine and scopolamine), 4,596,706 (ethylene trithioca Administration of rubonate or colloidal sulfur), 4,800,204 (dopamine receptor jaw Nist), 4,806,356 (nicotine lozenge), 4,832,994 (administration of silver acetate) ), 4,597,961 (transdermal administration of nicotine), 4,999,382 (administration of serotonin-forming drugs) , 5,021,457 (administration of phenylpropanolamine), 5,051,426 (serotonin Administration of antagonists and CNS stimulants), 5,234,947 (potassium channel activity) 5,362,496 (continuous transdermal and transmucosal administration of nicotine), 5,409,946 (Administration of isoxazole, isothiazole, pyrazole compounds), 5,414,005 ( Lobeline), 5,480,651 (non-specific acetylcholine agonist and mu Administration of scalin-like agonist), 5,549,906 (nicotine lozenge, non-nutritive 5,574,052 (nicotine receptor activator and its antagonists) 5,592,956 (herb used for acupuncture points on body), 5,593,684 (nicotine Transdermal and transmucosal administration), 5,599,554 (nicotine and caffeine) Administration), 5,612,357 (cotinine), 5,662,920 (nicotine lozenge), 5,691, 365 (nicotine receptor antagonist), 5,696,115 (benzodiazepine), WO91 / 09599 (administration of nicotine and cyclodextrin insertion complex) When. Consult with a psychiatrist to stop smoking or strengthen your ability to suppress smoking. Talks have been made.   Unfortunately, none of these treatments has been very successful. The Even if the treatment is a short-term treatment, long-term success is not easily achieved. The treatment The general degree of success of an individual cannot be predicted by the individual smoker's feelings about the treatment. Success depends on the receptivity. In fact, some are better than others Is also susceptible to tobacco, and normal treatment can easily quit smoking Seems to be impossible. In particular, he started smoking in his teens and continued to grow up Sometimes it seems difficult to stop. Smoking frequency (frequency), smoking type ( Factors such as regular or non-smoking tobacco) This has a significant effect on the degree of difficulty in those who attempt to do so. Also coexistence addiction (com orbid addictions), stress, mental illness and environmental factors also try to stop smoking It brings difficulties to those who try. For example, pesticides, insecticides, fungicides, oxidants, Environmental poisons (eg, contamination of drinking water and / or food by solvents and various routes) ) And the ability to stop or reduce smoking It is thought to lower. Desirable is to reduce withdrawal symptoms due to smoking cessation. The purpose is to provide a method to assist smoke cessation.   There are many respiratory diseases. For example, bronchoconstriction associated with lung disease is very common. It is related to many diseases. Asthma, chronic obstructive pulmonary disease (COPD), lung overload Such as sensitivity.   In asthma, the patient wheezes and the air passages in the lungs contract, making breathing difficult. This Symptoms are due to some or generally unclear allergic reactions It is believed that. For example, 5 million children in the United States alone have asthma It is estimated to be. According to reports, every year 500,000 people are hospitalized for asthma and 5,000 People have died. COPD affects 15 million people in the United States. COPD is With chronic cough, short breathing, dyspnea, most in chronic bronchitis and emphysema Often seen. Other respiratory diseases such as allergic rhinitis, conjunctivitis, epiglottis, larynx Tracheitis, urticaria and other allergic / neurogenic dermatitis are associated with these symptoms are doing.   Various treatments have been attempted to reduce or control the symptoms. Current asthma Treatment includes methods of reducing contact with allergens and the use of bronchodilators. is there. However, the use of bronchodilators, in some cases, is dependent on gas delivery systems. It may exacerbate the condition rather than provide long-term treatment for the condition. You. For the treatment of bronchial stenosis, a β-adrenergic agonist, ipratropin, And administration of methylxanthine. For treatment of COPD, ipratropin ( Atrovent), albuterol (proventil, bentrin) and theophylline There is administration of phosphorus. In extreme cases, pulmonary amputation or transplantation is recommended.   Examples of therapies are disclosed as follows. US Patent 1,794,292 (Atropine ), 3,950,519 (cedar resin), 4,031,218 (xanthine), 4,089,959 ( Xanthine), 4,120,947 (xanthine), 4,353,922 (anticholinergic bronchodilator) ), 4,689,213 (calcium channel inhibitor), 4,816,487 (1- (2-hydroxy Cyaryl) -alkane-1-one-oximes), 5,096,916 and 5,250,286 ( Imidazoline), 5,124,455 (oxime carbonate and oxime carbamate G), 5,171,744 and 5,292,749 (antimuscarinic bronchodilators), 5,234,947 (Potassium channel activator), 5,362,755 and 5,547,994 (albutenol) , 5,409,934 (xanthine), 5,552,407 (methylecgonidine), 5,650,444 ( Biphenyl oxime derivatives) and 5,693,659 (substituted oxime derivatives).   Comorbid addiction is a factor complicating the treatment of respiratory diseases and allergies Factors such as stress, mental illness and environmental factors may cause respiratory To It appears to have a major role in the extent of morbidity. For example, Pesticides, pesticides, fungicides, oxidants, solvents and other environmental factors (such as drinking water and In vitro substances such as food contamination and smoking) Affects the sensitivity and severity of the disease.   The underlying cause of respiratory disease and allergies in mammals, especially humans, Method must be provided, which eliminates the development of diseases and allergies, At least it should be reduced. For example, in the case of extreme COPD, It is possible to omit the surgery required to restore lung function.   Drug and alcohol addiction and / or abuse are very widespread. Indulgence Is a chronic or chronic addiction that is harm from repeated medications. Generally defined. Those who are addicted are addictive substances (alcohol or cocaine) , Heroin, usual drugs such as painkillers) Withdrawal symptoms.   Numerous treatments have been attempted for alcohol and drug addiction with varying success. There is fruit. For example, U.S. Patents 4,786,653; 4,847,281; 4,919,916; 4,935,429; 4,942, 182; 4,948,803; 4,956,391; 5,028,611; 5,051,426; 5,059,600; 5,075,341; 5,093,12 9; 5,102,913; 5,114,942; 5,130,338; 5,180,729; 5,185,329; 5,189,064; 5,223,497; 5,232,934; 5,397,782; 5,462,948; 5,556,837; and 5,703,100.   Unfortunately, all of the above treatments have met with little success. Such treatment Can provide short-term relief for humans, but long-term success has not been easily achieved. The degree of success of such methods is generally dependent on the particular treatment used. Cannot be predicted due to the fact that it depends on the sensitivity of humans. Xenobiotic toxins (agriculture (Such as medicines, bactericides, solvents, heavy metals, food additives etc. and other environmental pollutants) Possible effects include the occurrence of alcohol and drug addiction and / or abuse. And has not been well studied in relation to its severity. However, drugs and alcohol It is desirable to provide a treatment that can help overcome indulgence.   Diseases of the central and peripheral nervous system are numerous. In general, such neurological disorders The list includes ALS, senile dementia, epilepsy, vascular headache, presenile dementia, hyperactivity, Rett syndrome, Parkinson's disease, stroke, attention deficit disorder, schizophrenia, chronic fatigue Neurological disorders such as syndrome, and depression, anxiety, obsession, personality abnormalities, anorexia And neuropsychiatric injuries such as bulimia and bulimia. Many treatments are available for these diseases Attempts have been made to alleviate or treat this, as described in US Pat. No. 5,583,140. There are various degrees of success. Methods for treating various types of central and peripheral nervous system disorders Nos. 5,051,410; 5,069,904; 5,11. No. 4,986; No. 5,171,745; No. 5,206,371; No. 5,242,9 No. 35; No. 5,409,946: No. 5,434,179; No. 5,472,958 No. 5,589,512; No. 5,585,388; No. 5,696,142; See also No. 5,703,100.   Recognize that nervous system disorders can be largely due to impairment of the nervous system itself Have been. For example, as a result of cholinergic or dopaminergic deficiency Imbalance between synaptic neurotransmitters and neuroreceptors plays a role in such diseases Can carry. However, to date, xenobiotic toxins (pesticides, fungicides, solvents, heavy (Like metals, food additives, etc. and other environmental pollutants) Given that they have not been well studied in relation to the onset and severity of central nervous system disorders To properly provide neurotransmitters and neuroreceptors in a way that provides meaningful treatment No rebalancing treatment is provided.   The nervous system itself, which has the effect of eliminating previously occurring symptoms or reducing their severity To provide treatment of central and autonomic nervous system disorders for potential dysfunction Is therefore useful. In fact, even a reduction in the severity of such symptoms can lead to human longevity. Extend your life.   Treatment of heart disease and cardiovascular disease is conventional. Such diseases can be heart irregular Includes diseases related to pulse and heart disorders. Various oximes and oxime derivatives It is known to have pharmacological effects on heart and cardiovascular disorders. example See, for example, U.S. Pat. Nos. 3,875,149; 4,92,314; 4,461,763. Nos .: 4,883,796; and 5,703,100. However, It would be desirable to provide a method for treating heart disease and cardiovascular disorders that provides an enhanced effect. ing.   Treatment of cancer using chemotherapy is now routine. Such treatment alone Or it may be performed in combination with surgical removal of the tumor and / or radiation therapy. this Such treatments are not without side effects for the patient. Chemotherapy drugs that are toxic to cancer cells It is also toxic to non-cancer cells. The patient's most sensitive cells have the highest cell differentiation For example, bone marrow, hair and gastrointestinal tract. Patients undergoing cancer treatment should follow Nausea, vomiting, diarrhea, hair loss and reduced immune function (reduced bone marrow (Due to hematopoietic function). Administration of high-level taxol treatment in peripheral nerves It has also been found that severe neurotoxicity in the form of a disorder can result (US Pat. 496, 804). Adriamycin (doxorubicin hydrochloride) Such chemotherapeutic agents are also in limited dosage due to the cardiotoxicity of the agent.   Many methods have been proposed to reduce the toxic effects of antineoplastic disease treatment. For example, U.S. Patent Nos. 4,581,224; 4,594,238; 4,620, No. 973; 4,938,949; 4,980,149; 5,002,755. No. 5,035,878; No. 5,292,497; No. 5,294,430; 5,496,804; and 5,667,776.   Unfortunately, none of the above treatments has been very successful. Such person The degree of success of a method is generally the degree of success of the human being to the particular treatment used. Unpredictable due to the fact that it depends on gender. In fact, some patients have co-morbid Antineoplastic disease due to chemotherapy and / or radiation therapy due to drowning and environmental factors It is presently believed that they are even more susceptible to the adverse effects of treatments of For example The patient may encounter pesticides, killing by various means (e.g., drinking water, food contamination, etc.). Biological differences such as insecticides, fungicides, heavy metals, oxidants, solvents and other environmental toxins Potential toxins may enhance patient susceptibility to the toxic effects of such treatments It is. The ability of the nervous system to effectively transmit nerve impulses along synapses Because of this inhibition, such static exotoxins (both central and peripheral) Load. Treatment of such patients in anti-neoplastic diseases, therefore, Emphasizes the degree of reduced function of the nervous system and, therefore, the side effects suffered by the patient obtain. It would be desirable to provide a method with reduced such severe side effects.   Obesity is well understood to be a widespread problem. Obesity, high blood pressure, diabetes, heart It is associated with various medical conditions, such as vascular disease. Obesity is also associated with various psychological disorders. It is also associated with adaptation. Due to current medical standards, fewer obese people It is judged that it is at least 10% overweight. Currently, only a few treatments are useful for treating obesity. Not available. Examples of treatments are described in U.S. Pat. No. 3,867,539 (Histidine injection). No. 4,446,138 (administration of L-Dopa); No. 4,588,724 (β- Administration of a drenergic stimulant or an alpha-2 adrenergic quiescent inhibitor); No. 745,122 (administration of paroxetine); No. 5,019,594 (sympathomimetics) And tyrosine); 5,400,298 (administration of 8-phenylxanthine); No. 5,403,851 (tryptamine); No. 5,567,714 (for neuropeptide Y) No. 5,573,774 (nicotine-like metabolite): No. 5,578,613 (2- Administration of phenyl-3-aroylbenzothiophene); No. 5,668,155 (Mus. Karin receptor antagonist); and No. 5,703,100 (Acetyl coli Receptor modulator). Amphetamine is also used as an appetite suppressant Have been.   Unfortunately, all of the above treatments have met with little success. Such treatment Can provide short-term relief for humans, but long-term success has not been easily achieved. Smoking cessation often results in weight gain. Also, simultaneous morbidity, stress, psychiatry Diseases and environmental factors can exacerbate the difficulties individuals face in reducing obesity You. For example, by various means (eg, via drinking water and / or food impurities). Pesticides, pesticides, fungicides, oxidants, solvents and other Xenobiotic toxins, such as environmental toxins, make it impossible for some people to control obesity. It is thought to get. It is desirable to provide a way to help overcome obesity.   Treatment of gastrointestinal motility and dysfunction, irritable bowel syndrome and related disorders is often It is often necessary. For example, U.S. Pat. No. 5,703,100 treats such diseases. Teaches the use of acetylcholine receptor modulators in a device. With improved results It is desirable to provide further treatments that may be possible.   Fatigue syndrome has no underlying illness that is determined to be the cause of fatigue It is characterized by fatigue being the main symptom. Examples of such fatigue syndrome are chronic Fatigue syndrome, post-infection fatigue syndrome, chronic Epstein-Barr virus and humans Exemption Fatigue associated with epidemic disease virus (HIV) and total environmental allergy.   More specifically, chronic fatigue syndrome has become more prominent in recent years. American It can be estimated that 1 in 500 suffers from various chronic fatigue syndromes (CFS). CFS Is memory, mood, concentration, talk, sensation, balance, vision, listening, sleep, appetite, hormones Affects production and response to stress. Examples of symptoms include chronic or recurrent severe fatigue Labor, weakness, malaise, hotness, sore throat, headache, memory loss, difficulty concentrating and depression . Exercise, special diet, vitamin treatment, antihistamine, immunoglobulin, antidepressant, etc. Various treatments have been attempted with little success. An example of a treatment is US No. 5,013,739; 5,055,296; 5,189,022; No. 5,312,817; 5,424,300 and 5,545,670 Have been.   Interestingly, the symptoms of CFS are associated with the Gulf War Syndrome (many of the Persian Gulf Wars). Rescued by old soldiers). The main symptoms are thinking, memory and sleep disorders, Includes confusion, dizziness, pain in joints and muscles, burning in hands and feet. Reducing Gulf War Syndrome (GWS) Symptoms More Successful than Reducing Fatigue Syndrome Symptoms Not in.   Fatigue syndrome and the Gulf War syndrome do not share all symptoms, but There are rarely defined symptoms that share what makes a device impossible. This Symptoms such as chronic myofascitis and recurrent tension wounds (repe titive strain injury).   Such diseases are mostly due to disorders of the central and autonomic nervous system itself. It is thought to get. For example, with the consequences of cholinergic or dopaminergic deficiency The imbalance between neurotransmitters and neuroreceptors in the synapse, Can play a role. However, to date, in a way that provides meaningful treatment No treatment has been provided to properly rebalance neurotransmitters and neuroreceptors. No. Xenobiotic toxins (pesticides, fungicides, heavy metals, solvents, food additives, etc. and other Potential effects (such as environmental contaminants) and the combined effects of nerve agent antidote. Has not been well studied in relation to the onset and severity of such diseases. CFS symptoms It would be desirable to provide a treatment that reduces this.   Toxic contaminants such as heavy metals are widely present in the environment. Such contaminants are Contact with mammals, such as animals, on a regular basis. Such heavy metals include lead, cadmium , Mercury, iron, etc. Examples of sources of such metals include contaminated water, contaminated wildlife ( Including fish), plumbing, paint, autocrine and manufacturing processes. In recent years, mercury in teeth There are concerns about the safety of amalgam fillers. Unfortunately, the body The presence of such contaminants can indicate chin dysfunction, coronary problems, circulation problems, nervous system Causes various health problems, including disability.   An example of a heavy metal detoxification procedure is described in U.S. Pat. No. 2,847,308 (Calcium Chelate). No. 2,875,129 (calcium chelate); No. 2,947 No. 782 (aminoacetamidoxime); 3,072,529 (5-aminohexyl) No. 4,043,998 (1- (p-benzenediazonium) No. 5,217,998 (with bound chelate) No. 5,443,847 (soluble manganese salt) Has been described. Unfortunately, none of the above procedures have been successful at all. Not only help eliminate such substances, but also reduce the symptoms of such poisons. It would be desirable to provide a way to help.   Treatment of cancer by the use of chemotherapeutic agents is now routine. Such measures are simply It can be done alone or in combination with surgical removal of tumor and / or radiation therapy. Such treatment is not without side effects for the patient. Chemotherapy toxic to cancer cells The agent is also toxic to non-cancerous cells. The patient's most sensitive cells have the highest cell differentiation Some are; for example, bone marrow, hair and gastrointestinal tract. Patients undergoing cancer treatment Therefore, often nausea, vomiting, diarrhea, hair loss and reduced immune function (bone marrow loss (Hematopoietic function). Administration of high-level taxol is peripheral It has also been discovered that severe neurotoxicity can be caused in the form of neuropathy (U.S. Patent No. 5,496,804). Adriamycin (doxorubicin hydrochloride Chemotherapeutic agents such as (d) also have a limited dose due to the cardiotoxicity of the drug. I have. In fact, many approaches have been proposed to reduce the toxic effects of antineoplastic disease treatment. Have been. For example, U.S. Patent Nos. 4,581,224; 4,594,238; No. 4,620,973; No. 4,938,949; No. 4,980,149; No. 5,0 No. 02,755; No. 5,035,878; No. 5,292,497; No. 5,294, No. 430; and 5,496,804.   Unfortunately, none of the above treatments has been very successful. Such person The degree of success of a method is generally the degree of success of the human being to the particular treatment used. Unpredictable due to the fact that it depends on gender. In fact, some patients have co-morbid Antineoplastic disease due to chemotherapy and / or radiation therapy due to drowning and environmental factors It is presently thought to be even more susceptible to the adverse effects of the treatment of E. coli. For example, Pesticides, insecticides encountered by patients by various means (e.g., drinking water, food contamination, etc.) Xenobiotics such as agents, fungicides, heavy metals, oxidants, solvents and other environmental toxins It is believed that toxins may enhance a patient's sensitivity to the toxic effects of such treatments. You. In addition, xenobiotics can lead to immunological, neuroimmunological and / or neurological dysregulation. Many mechanisms, including harm, can act synergistically to induce cancer. Central and peripheral nerves In both systems, these xenobiotic agents provide effective transmission of impulses along synapses. Inhibits the ability of the nervous system to Treatment of neoplastic disease allows normalization of neurological function Can be achieved by improving the effects of synapses that act on and treat neoplastic disease by non-toxic means. It would be desirable to provide a treatment that would assist in placement.                               SUMMARY OF THE INVENTION   According to the present invention, in mammals including humans, synaptic dysfunction and related Mammals, including humans, used to treat chronic conditions caused by the disease. And are active in vivo, such as acetylcholinesterase reactivator. An effective amount of at least one pharmaceutically acceptable oxime is optionally one or more. Pharmaceutically acceptable in combination with an effective amount of one or more additional pharmacologically active agents. A pharmaceutical composition comprising a carrier is provided.                            Detailed description of the invention   Pharmaceutical compositions of the invention result from synaptic dysfunction and related diseases Can be used to treat chronic conditions.   Synaptic dysfunction is an inappropriate level of neurotransmitter release, Inappropriate phases of transmitters and neurotransmitters and neurotransmitter receptors Regarding interactions. Examples of neurotransmitters and receptors include acetylcholine and acetylcholine. Includes tilcholine receptor respectively. Such dysfunction is also cholinergic Deficiency, dopaminergic deficiency, adrenergic deficiency and / or serotoni It may also be attributed to deficiency of action. Inappropriate levels of acetyl at synapses Inappropriate levels of acetylcholine corresponding to deactivation of rucholinesterase It is believed that many chronic symptoms of synaptic dysfunction can be responsible.   Symptoms of synaptic dysfunction and related disorders include toxic symptoms of smoking cessation, and respiratory illness Addiction, drugs and alcohol, diseases of the central and peripheral nervous system, anti-neoplastic diseases and Antineoplastic treatment effects, eating disorders, heart and circulatory disorders, fatigue syndrome, gastrointestinal tract Dysfunction and irritable bowel syndrome, endocrine and immune system disorders and heavy metals Includes, but is not limited to, chronic conditions usually associated with poisoning.   The oximes used in the present invention contain a -C = NOH group and are physiologically in vivo. Active in Such compounds include, for example, cholinergic or muscarinic Activity, antiallergic, antihypertensive, antithrombotic, antiasthmatic, antiinflammatory, antiriu Gusset or bronchodilator activity, cognitive or memory disease activity, taste activity Exhibit one or more in vivo properties of and / or organic phosphate chemical poisoning Has the ability to reactivate acetylcholinesterase that has been deactivated by One. In the present invention, one or more oximes can be employed.   The oxime acetylcholinesterase reactivating factor that can be employed in the present invention is It is well known to traders and is well described in the literature. Such reactivation Initially, its use as an antidote for nerve agent and toxic pesticide poisoning It's been found. Examples of oxime acetylcholinesterase reactivating factor U.S. Pat. Nos. 2,816,113; 2,996,510; 3,063,901. No. 3,077,476; No. 3,137,702; No. 3,773,775; No. No. 3,852,294; No. 3,928,594; No. 4,002,760; No. 4,1 No. 28,651; No. 4,352,810; No. 4,675,326; No. 4,865, No. 837; No. 4,925,856; No. 4,988,710; No. 5,130,438. No. 5,206,371 and United Kingdom Application No. 2,016,920, explicitly cited Including, but not limited to, the compounds disclosed herein. .   Another oxime that can be used is their prodrug derivatives and their pharmaceuticals It is an acceptable salt.   One example of an oxime salt is of the formula (R¹-CR = NOH)⁺X^-Where R is hydrogen, C_1-5A Alkyl, phenyl optionally substituted with halogen, or NH_TwoAnd X^-Is A pharmaceutically acceptable anion derived from a salt of an inorganic or organic acid. Is defined. X^-The pharmaceutically acceptable anion defined by Hydroic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, acetic acid, propylene On-acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, Enoic acid, ascorbic acid, pamoic acid, maleic acid, hydroxymale Acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfamic acid, It can be derived from fumaric acid, toluenesulfonic acid and related organic and inorganic acids. R¹ Takes many forms. For example, R¹Is C_1-5Alkyl, aryl (e.g., C_1-8Alkyl, hydroxy, halogen, C_1-8Alkoxy, O-cycloalkyl Phenyl substituted with phenyl, etc.), or one of a variety of unsaturated or saturated heterocycles. And may be a 5- or 6-membered heterocyclic moiety having three nitrogen atoms.   Other examples of oxime salts are of the formula R¹-CR = NOH X^-Where R is hydrogen, C_{1 -Five} Alkyl, or NH_TwoAnd R¹IsWhere R^TwoIs: Or Wherein Z is, for example, optionally at least one Ether linkage, for example, -CH_TwoCH_Two-, -CH_TwoOCH_Two-, -CH_TwoCH_TwoOCH_TwoC H_Two-, -CH_TwoOCH_TwoCH_TwoOCH_Two ^-Having 1 to 10 carbon atoms, including Alkylene group; butenylene; or-(CH_Two) n-phenyl- (CH_Two) n- Where n ranges from 1 to 6 and the phenyl moiety is C_1-5Substituted with alkyl May be; R^ThreeIs hydrogen, C_1-5Alkyl, COR^Four, CONR^FiveR⁶Or CO OR⁷And R^FourIs C_1-6With alkyl, cyclohexyl, Ar, or benzyl Yes; R^FiveAnd R⁶Is hydrogen, C_1-6Alkyl, cyclohexyl, Ar, C_7-13A Aralkyl, or 2-pyrimidyl; and R⁷Is C_1-6Alkyl, cyclohe Xyl, benzyl or Ar; Ar is optionally one or more C_1-4Alkyl , C_1-6Phenyl substituted with alkoxy, halide or naphthyl, of the formula Medium X^-Is a pharmaceutically acceptable salt derived from a salt of an inorganic or organic acid as defined above. Bicyclic in nature, as defined by being a nonion.   The above formulas are merely examples, and various oxime types that can be employed in the present invention It does not limit the identity of   Examples of acetylcholinesterase reactivating factors include the following oximes and / or Or an oxime salt: 2-pyridinealdoxime methoxide, 4-pyridine Rudoxime methoxide, methyl-2-pyridylketoxime methoxide, 1-methyl- Pyridinium-2-aldoxime (or 2-formyl-1-methylpyridinium ) (2-PAM); 1-methyl-pyridinium-3-aldoxime (3-PAM); 2,3- Butanedione-2-oxime (DAM), pyruvaldehyde aldoxime (MINA) 2-formyl-1-methylpyridinium chloride (2-PAM-Cl) (PROTOPAM Pyridinium chloride, which is commercially available as Fate (commercially available as CONTRATHION), N, N-dimethyleneoxy-bis- ( Pyridine-4-aldoxime) -dichloride (an commercially available product as TOXOGONIN) (Bidoxime chloride), 1,1'-polymethylenebis (4-formylpyridinium) Ride oxime, N-methyl 2-hydroxyiminomethylpyridinium methanesul Phonate, N-methyl 4-hydroxyiminomethylpyridinium methanesulfone G; 1,1 '-(2,5-dimethyl-p-phenylenedimethylene) bis (4-formylpyri) 1,1'-polymethylenebis (3-formylpyridini) Um) halide dioxime; 1,1 '-(p-phenylenedimethylene) bis (3-formi Rupyridinium) halide dioxime; bisquaternary 4-formylpyridinium halide Domonooxime; 1,1'-trimethylenebis (3-amidooximopyridinium) Ride, quaternary pyridine aldoxime (TMB-4); 1-[[[4- (aminocarbonyl) Pyridino] methoxy] methyl] -2-[(hydroxyimino) methyl] pyridinium dic Chloride (asoximine chloride or HI-6); diacetylmonoxime; [(2-H Droxyiminomethyl) -pyridinium- (1) -methyl]-[(3-carbamoyl) -pyri Dinium- (1) -methyl] -ether dichloride (HS-6); 3- (hydroxyimino) Methyl-1-methyl-4- (2'-methylsulfonyl-1-ethyl) -1,2,4-triazolyl Aldoxime-substituted triazolium compounds containing um chloride; 1,4-dimethyl- 3- (hydroxyimino) methyl-1,2,4-triazolium chloride, 1-benzyl -3- (hydroxyimino) methyl-4-methyl-1,2,4-triazolium chloride, And 3- (hydroxyimino) methyl-1-methyl-4- (2′-methylsulfonyl- 1'-ethyl) -1,2,4-triazolium chloride; and aldoxime-substituted imines Dazolium derivatives such as 1-([1 ′-(2′-butynyloxy) methyl] -2- (hydr Roxyimino) methyl-3-methylimidazolium chloride, 2- (hydroxyimi G) -Methyl-3-methyl-1- [1'-2 '-(methylsulfonyl) ethyloxy) methyl)- Imidazolium chloride, 2- (hydroxyimino) methyl-3-methyl-1-[(2'- Methyl-2'-nitropropyloxy) methyl] -imidazolium chloride, 1-[(2 ' -N, N-dimethylaminium) -1'-ethyl] 2- (hydroxyimino) methyl-3-meth Tylimidazolium chloride, 1- [2 '-(hydroxyimino) methyl-3'-methyl- 1′-imidazolo] -3- (4 ″ -carbamoyl-1 ″ -pyridino) propane dichloride, 1- (3'-bromopropyl-1'-oxy) methyl-2- (hydroxyimino) methyl-3- Methylimidazolium chloride, 2- (hydroxyimino) methyl-3-methyl-1- (2′-pyridinium-1 ′-) ethylimidazolium chloride hydrochloride, 1- (3′-butyl Tyl-1'-thio) methyl-2- (hydroxyimino) methyl-3-methylimidazolium Chloride and 1-[(2'-N-ethyl-N-trifluoromethanesulfonyl) amido [No-1 '-] ethyl-2-hydroxyimino) methyl-3-methylimidazolium chloride De.   Preferred oximes suitable for use in the present invention have the formula: Where R is hydrogen, C_1-5Alkyl or NH_TwoAnd R¹Is C_1-5Alkyl (especially X is a salt R¹Which is an anion moiety of X Can be. Preferred acid addition salts include chloride salts, iodide salts and C_1-5Al There is a kill sulfonate salt, for example, a methane sulfonate salt.   A specific oxime that is preferred for use in the present invention is 2-PAM chloride (PROT OPAM chloride, pralidoxime chloride), represented by the following formula:   Obidoxime is also a particularly preferred oxime for use in the present invention.   Oximes disclosed in U.S. Patent Nos. 3,929,813 and 3,962,447 It may also be advantageous to administer a prodrug derivative of Inviting such prodrugs Conductors exhibit high blood / brain barrier traversing ability.   Another oxime that exhibits physiological properties in vivo and can be used in the present invention is rice. National Patent Nos. 3,780,194; 3,875,149; 3,883,654; No. 3,919,318; No. 3,952,114; No. 4,141,995; Nos. 678,810; 4,798,841; 4,816,487; 5,026. , No. 724; 5,219,872; 5,650,444; 5,693,659 No.   Acetylcholinesterase reactivator (eg, 2-PAM and HI-6) To protect in vivo against nerve agents and other organic phosphate poisons It has been used in combination with acetylcholine receptor antagonists (eg, atropine). For example, U.S. Patent Nos. 2,996,510; 3,063,901; 3,077, No. 476; 4,128,651; 4,713,391; 4,865,837 And No. 4,925,856. Atropine (acetylcholine receptor Tagonist) has also been used to treat bronchitis, rhinitis, hay fever and the like. USA See patent 1,794,292.   However, physiologically active substances such as acetylcholinesterase reactivating factor Pharmaceutical composition containing a soluble oxime (optionally, acetylcholine receptor antagonist (In combination with additional pharmacologically active substances such as), chronic symptoms of synaptic dysfunction Have not been used to mitigate the effects of another type of synaptic dysfunction Similar to chronic symptoms, for example, withdrawal symptoms associated with quitting tobacco use It has never been used to alleviate reams. In fact, the benefits of the invention The required amount of each component to be used is from nerve agent and toxic organophosphate poisoning. It is orders of magnitude less than the amount normally administered to protect.   According to the invention, if desired, the active ingredient can be added to one or several additional pharmacologically active substances May be used with quality. Additional compounds may be administered together to achieve the desired result. It is within the scope of the present invention to assist or to combine additional treatments. Administer together The selection of the compound (group) is made depending on what kind of chronic condition is to be targeted.   Drugs come in various types and pharmacological effects. Additional pharmacological ingredients include: The choice depends on the particular condition you are trying to alleviate. Typical additional pharmacological ingredients Listed, but not limited to: cholinergic agents (nicotine and Muscarinic agonists and antagonists), adrenergic agonists And antagonists, serotonergic activators, GABA agonists and And antagonists, adenosine activators, dopaminergic activators, anti-inflammatory drugs, Stimulants, heavy metal antagonists and chelating agents, acetylcholinesterase inhibitors Harmful factors, antiallergic drugs, antihypertensive drugs, antithrombotic drugs, antiasthmatic drugs, antirheumatic drugs, Antidepressants, antiobesity agents, antiepileptics, antioxidants, antiarrhythmics, antianginals, calciu Channel blockers, bronchodilators, cognitive or memory disease enhancers, antineoplastic There are drugs for treating ulcer diseases, vitamins, nutritional supplements, cardioactive drugs and binding resins.   The acetylcholine receptor antagonist optionally used in the present invention can be It is well known and well documented in the literature. List typical antagonists Is not limited to these (used alone or in combination): Lamin, homatropine, atropine, methylscobolamin, methylatropine, Ipratropium, methylecgonidine (MEG), mechanil Amines, benactidine, benztropine, trihexyphenidyl, biperiden, Procyclidine, benzethamide, dexetimide, iaprofen (iaprophen) and pharmaceutically acceptable derivatives, or mixtures thereof. example U.S. Pat.No. 5,011, discloses a typical acetylcholine receptor antagonist See 1,853 and 5,552,407. Preferred antagonists are scopolamine and ipratropi Um. Anticholinergic, such as ipratropium bromide (atrovent) Agonists are known for use in treating bronchoconstriction. Goodman & Gilm an'sThe Pharmacological Basis of Therapeutics,Five^th See Edication, 1996. .   Further, for example, chronic symptoms of synaptic dysfunction related to respiratory diseases such as asthma Depending on the severity of the disease, administration of an anti-asthmatic drug is desirable. Typical anti-asthmatics are (1) Coid steroids (beclomethasone dispropionic acid, budesonide, flunisoli , Triamcinolone acetonide, prednisone, etc.), cromolyn and nedoc Anti-inflammatory drugs such as nedocromit, and (2) B2-selective adrenergic action Drugs (albuterol, bitolterol mesylate, pyrbuterol, salmetero Bronchodilators such as salmeterol and terbutaline) and theophylline including.   Further, for example, cholinesterase, especially when treating tobacco withdrawal symptoms It is advantageous to administer the stimulant together with the reactivating factor. . Preferred stimulants are Nicotine. Nicotine is administered simultaneously with the active ingredient (group), nicotine gum, nicotine It can be administered in any suitable manner, such as a chin patch. Nicotine administration, other Before, during or after the administration of the compound. Treat tobacco addiction If so, the nicotine dose should be less than the total amount on a patch or nicotine gum stick. (Eg, around 1 mg, but not particularly limited) . Nicotine or other stimulants may be used to treat other related disease symptoms such as asthma. It is also useful.   Replace other normal stimulants (such as dopaminergic stimulants) with nicotine. Or in addition to it. List those alternative stimulants But not limited to: mineptine, amphetami , Amphetaminil, bemegrid, benzphetamine, bruci , Corphentermine, clofenciclan ), Chlortermine, cocoa, demanyl phosphate, Dexoxadrol, dextroamphetamine sulfate ( Dexedrine), diethpropion, N-ethylamphetamine, Etamiban, etifelmin, etryptamine, Camphamamine, phenethylline, fenosolone, Enfluramine, flurotyl, hexacyclonate, sodium, homocampine , Matindole, megexamide, methamphetamine, methylphen Nidate, nicotine agonist, niketamide, pemoline, pentylenetetrazole, Phenidimetrazine, phenmetrazine, phentermine, Picrotoxin, pipradrol, prolintane, pirovalerone and And tetrahydrobenzothienopyridine and mixtures thereof.   Xanthines are acetylcholinesterase reactivators and dendrites Administered together with one or more other active ingredients to assist in a single preparation along Additional compounds that may be present. U.S. Patent Nos. 4,364,922, 4,980,379, 5,288,721 , 5,340,813, 5,354,756, 5,440,041, 5,473,070, 5,567,704, 5,580,873 and No. 5,580,874 discloses a typical xanthine that can be used in the present invention, Each is hereby incorporated by reference. A typical xanthine is These include, but are not limited to: propylxanthine and methylxanthine Any alkyl xanthine and the like. Methylxanthine is 1,3,7-trimethyl Luxanthin (caffeine), 3,7-dimethylxanthine (theobromine), 1,3- Dimethylxanthine (theophylline), aminophylline, 1,8-dimethyl-3- (2- Methyl-1-butyl) xanthine, 1,3-dimethyl-8- (n-propyl) xanthine, 1,4- (4-hydroxypentyl) -3,7-dimethylxanthine and 7- (3-fe Nylprophenyl) theophylline. Examples of propylxanthine include (E) -4 -(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-9H-purine-8- Yl) cinnamic acid and (E) -4- (1,2,3,6-tetrahydro-2,6-dioxo-1,3- Dipropyl-9H-purin-8-yl) cinnamic acid. Xanthine prodrug U.S. Pat.Nos. 3,935,196 and 4,061,753 (both incorporated by reference in this document). May be used as disclosed in US Pat. Their form is the high The measured lipid solubility is shown.   Adenosine antagonists may also be used with one or more of the above. Can be used. These compounds reduce interstitial levels of adenosine in myocardial tissue . These compounds are antagonistic inhibitors or reduce adenosine levels. Substance. Various compounds include xanthine (as discussed above), Imidazopyrimidine, pyrazolopyridine, etazolate, pyrazolo Use as adenosine antagonists including quinoline and triazoloquinazoline Can be done. Examples of adenosine antagonists are described in U.S. Patent Nos. 4,364,922; 79 and 5,364,922, both incorporated by reference into this document.   At present, other alternatives that can be administered with one or more of the above The compound is an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) or L-glutamic acid. Its precursors, such as acid. GABA receptor agonists and other anti- Epileptic agents may be used, such as Epibal, Baclofen, (Sabril), barbitur, Gabapentin, Lamotrigine (Lamot) Rizine) and Riluzolo.   Phytostigmine, Neostigmine, Demecari Um (Demecarium), pyridostigmine (Pyridostigmine), bernacrine (Velnacrine), Huperzine A, Tacrine, Aricept (A ricept) (Donepezil hydrochloride), Memric, Artane (Trihexyphenidyl), cogentin (Cogentin) (benzotropine mesylate), Benedryl (diphenhydramine hydrochloride), donepezil hydrochloride (Donepezil) Acetylcholinesterase inhibitor may be additionally administered. It can also be useful.   The administration of the active ingredient and the use of antioxidants, vitamins, chelating agents Combine with more conventional treatments, such as metal antagonists and bile acid binding resins This is also within the scope of the present invention. The identity of those compounds was determined by Goodman & Gi. lman'sThe Pharmacological Basis of Therapeutics, 9th edition, 1996 And are known to those skilled in the art.   Pharmaceutically acceptable prodrugs and analogs and tautomers, isomers and the like of the above compounds. Both the use of salts and salts are within the scope of the present invention. Analogs of the above compounds Are added alkyl or aryl substituents, added or removed halogen components , Differing in the presence of different bonds, such as ether bonds, saturated or unsaturated. Use As salts that can be used, the present invention includes within its scope alkali metals, alkaline earth metals And hydrogen chloride, hydrogen bromide, sulfur, sulfamic acid, phosphoric acid, acetic acid, On-acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, Enic acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, Nilacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, fumaric acid, etc. And the like.   The compounds of the present invention may be pharmaceutically acceptable by any pharmaceutically acceptable means. It can be administered in any form. For example, the compound may be a pill, tablet, capsule, granule, It can be administered orally in the form of a suspension, syrup, lozenge, etc. It is a single or synergistic ingredient. The compound can also be non-toxic with a pharmaceutically acceptable carrier. It can be administered orally (eg, intravenous, intramuscular, or subcutaneous). Local throw Ointments, creams or ointments that apply the transdermal patch or active agent percutaneously to the skin Such as by administration in combination with a suitable pharmaceutically acceptable topical base such as a drug This can be done by various means. Its transdermal penetration is a pharmacologically active agent by topical administration For transdermal administration of the drug, it can be effected by a transdermal penetration enhancer whose use is well known. ointment Dimethyl sulfoxide (DMSO), especially from the viewpoint of It is a percutaneous penetration enhancer that is acceptable in the medical world. The active ingredient is also It can be administered by injection or by rectal suppository or enema.   Solid carrier substances for use with tablets and / or pills are mixed with the active ingredients. Any pharmaceutically acceptable solid carrier, shaped into the desired shape and size Can be quality. Suitable carriers include, but are not limited to, magnesium carbonate, Magnesium stearate, talc, lactose, sugar, pectin, dextrin , Starch, methylcellulose, sodium carboxymethylcellulose and the like.   Tablets or pills contain the usual pharmaceutically acceptable excipients (i.e., inert dilutions). Agent) as a mixture with the active ingredient. The tablets or pills are coated It may not be present or may be coated. The tablets or pills are enteric Includes coating to ensure intestinal degradation and absorption. The coating includes cellulose Cellulose lower fatty acids such as phthalic acid succinate are usually included. Oral administration Sustained-release forms are also anticipated and desirable.   Can dissolve and / or disintegrate in tongue or mouth for oral delivery of active ingredient A drug in an oral dosage form comprising the active ingredient in a pharmaceutically acceptable solid matrix material. Preferably, the pharmaceutical composition is administered.   The oxime (and optionally one or more additional pharmaceutically active agents) Effective in calming or preventing chronic symptoms of synaptic dysfunction or related disorders Used or administered in amounts.   For example, when administered to alleviate tobacco withdrawal symptoms, the active ingredient Psychological and physiological effects of tobacco withdrawal symptoms to reduce or eliminate An amount effective to calm or prevent sound is administered. The term "calm down or prevention" If given before symptoms appear, the patient's withdrawal symptoms will be somewhat reduced, and It is intended to refer to some degree of prevention of the suffering of the condition. That is, the book The invention is used prophylactically and withdrawal caused immediately by cessation of tobacco use The shape can be used for treatment.   In conjunction with the above considerations, the various compounds of the present invention enable the advantages attained by the present invention. As far as possible, it can be administered in a wide range of doses. For example, the acetylcholine receptor When using an antagonist, a dose of about 0.001 to 100 mg is usually preferred. Or a dose of 0.001 to 25 mg, more preferably 0.001 to 10 mg. Is done. Oximes such as acetylcholinesterase activators are, for example, It can be administered in doses of about 1.0 mg to 10 g. However, usually acetylcholine The esterase activator is present in an amount of 0.1 to 300 mg, more usually 0.1 to 25 mg. Administered in mg amounts. 0.1 to 10 mg of acetylcholinesterase activator The child's (tongue or mouth) dose can be used to treat various chronic conditions, such as tobacco withdrawal. The dose of 0.001 to 0.1 mg of acetylcholine antagonist, if desired. In this regard, it has been found to be useful. The dose is a standard adult weight of 70 kg Based on Additional ingredients such as irritants are usually present in doses of about 0.1 to 10 mg. Is administered. Once administered, the xanthine component is delivered in doses of 25 to 300 mg. Administered regularly. Other components that may be co-administered will depend on the particular condition being treated. Can be administered in normal volumes. The dose administration can be repeated if necessary. Results were obtained and dosing was observed every 4 to 36 hours or more. It is repeated depending on the degree of symptoms.   Pharmaceutical compositions of the invention may control and / or reduce the use of any form of tobacco Especially applicable to: The use of tobacco is limited to smoking (i.e., cigarettes, cigars or Is a pipe). Can be smoke. Tobacco use, chronic cigarettes and smokeless tobacco or Various methods of chewing tobacco use are the most difficult controls or discontinuations I know that. Certainly, if you started in your teen, its use is especially Has been known to be difficult to stop. However, the pharmaceutical combination of the present invention Those who wish to control or discontinue their use by administering the substance are likely to succeed It is possible to reach this goal.   The pharmaceutical compositions of the invention can be used for treatment of both animals and humans. Sina Veterinary treatment of animals always succeeds, even when trying to alleviate the chronic symptoms of dysfunction I do not. It can be regularly exposed to pesticides and / or herbicides With regard to farm animals, this seems particularly true. In fact, horses call like asthma Often it is necessary to treat a sucking disease. Other livestock, such as sheep, have synaptic dysfunction We often come across pesticides that can provoke chronic symptoms of the disease. Domestic like dogs and cats Exposed animals can also contain residential pesticides and herbicides, and / or other xenobiotic contaminants. Due to exposure to staining, they often suffer from chronic symptoms of synaptic dysfunction. Active ingredient Oxime with topical carriers suitable for promoting transdermal absorption of Topical administration is particularly useful for veterinary treatment of mammals.   The invention is illustrated by the following examples, which do not limit the scope of the invention, It is merely illustrative of various preferred and specific embodiments.Example 1   40-year-old with moderate history of smoking for 25 years and wanting to stop smoking cigarettes Of acetylcholine receptor antagonist (scopolamine) Administration via the oral mucosa followed by oxime acetylcholinesterase activation Factor (2-PAM-Cl) was administered orally (each in a pharmaceutically acceptable solution). ). The nicotine patch is applied directly to the human torso, after which the two compounds are administered. Scopolamine was administered in a dose range of 0.001 to 10 mg and 2-PAM-Cl was administered in 2 doses. Was administered in a dose range of In humans, the desire to use tobacco disappears relatively quickly. Lost experience (in this example cigarette smoking). Cigarette Control of the desire to smoke for 8 hours lasted. Similar results were obtained in tablet form 2 Two compounds were observed in the tongue administration. Chew with administration of two compounds Nicotine administration in the ingham form was also effective.Example 2   39-year-old male smoker with a history of 25-30 bags per month (per day 1-2 pack) had a strong desire to stop smoking. To him, in various cases, Give oxime protopam 5 mg via oral mucosa by instillation and gum, then , (Nicotine 1 mg and scopolamine 0.1 mg) or (nicotine 1 mg and ipra Tropium (0.1 mg). The individual reports that he is in 6-36 hours. And no withdrawal symptoms. He then continued with iprat with 2.5 mg of protopam. B Lozenges containing 0.1 mg of either pium or scopolamine were taken. Nicochi In the twice daily dose of any lozenge in combination with the patch, No smoking with no withdrawal symptoms, no urge to smoke during the 10-day test period won.Example 3   35-year-old man with a history of smoking 30 packs per month (1.5 bags per day At 8 a.m. before the first cigarette of the day, the tongue (sl) 5 mg, followed by 0.1 mg of ipratropium and 1 mg of nicotine. he Reports that they have been awake for the past five years, usually two to the first cigarette of the day. I didn't have 0 minutes. This medical test date is managed by noon by the first cigarette. After 3 o'clock. By 5:00 pm he smoked three cigarettes, but always It was too strong and I was not very satisfied. Continue the second dose in the same way in the afternoon When given at 6:00, he was more satisfied and surprised than the first cigarette of the day. The patient has reported. A third dose of protopam (5 mg) was given at 10 pm. The patient reported at the same time that he was deeply satisfied and refreshed.Example 4   A 37-year-old adult male smoker wanted to quit smoking. He per month He smoked 25 packs and continued to smoke 12 cigarettes per day. this person Also suffers from Wolf-Parkinson-White syndrome and has an irregular rapid heart rate (irr (egular rapid heart rate) and intermittent atrial fibrillation Was. He also noted diffuse muscle spasms and recurrent tendonitis. She was suffering from chronic myofascial syndrome. Protopam (sl) 5mg for the person Nicotine and then ipratropium 0.01 mg four times . In each case, he reported that within 1 to 2 minutes of receiving the protopam No need for baco, myofascial syndrome subsides, and continues 2-5 days Meanwhile, his heartbeat became regular.Example 5   To report a 24-year-old woman with a history of smoking half a pack per day for 10 years, She occasionally smoked to control her weight. Give her 1mg of nicotine And 0.01 mg of ipratropium followed by 2.5 mg of protopam. They were given 10 times over 2 months by the route of administration of the membrane. In each case, she wants to report The withdrawal symptoms were alleviated, and they were satisfactory for 6 to 12 hours without any side effects. “Full Feet "reported as deep as cigarettes but more permanent . Calf muscle spasm, restricted breathing (bronchospasm and Reduction of negative symptom, such as bronchial secretions, nasal congestion and fatigue Have also been reported. Separate days to smoke the next cigarette, 2 Twice, the test drug was administered consecutively before lunch and meals. In both cases, she reports Not only has the need for cigarettes gone, but also the demand for sweets Like, her desire was reduced.Example 6   To report a 24-year-old woman with a history of smoking half a pack per day for 10 years, She occasionally smoked to control her weight. Nicotine 1 for her mg and ipratropium, 0.01 mg, followed by 2.5 mg of protopam. Oral mucosa was given 10 times over 2 months. Calf muscle spasm, breathing Restricted breathing (bronchospasm and bronchial secretions), nasal congestion and fatigue Reduction of negative symptom, such as effort, has been reported.Example 7   39-year-old woman with mild asthma and allergy has "chest and nose" disease When I felt the disease, I took 3 mg of protopam 3 times by the oral mucosal route, 0.01 mg of tropium was given. 12 to 36 hours after each consecutive test Reported lasting.Example 8   Mild asthma and allergies with tension on the neck, shoulders and upper back -A 35-year-old male competitive fitness trainer with chronic muscle fatigue In order to mitigate the problem, consulting a specialist in another field did not work. Twice, At another time, 5 mg (sl) of protopam, followed by 1 mg of nicotine by the daily mucosal route of administration And 0.01 mg of ipratropium. After each dose the patient reports The profound relief of his symptoms lasted about four days.Example 9   Treatment with various vitamins, minerals and antioxidants (self-medication) If a 71-year-old man with early dementia receives 2.5 mg (sl) of protoppam, other family members Testimony suggests that memory density is improved and confusion and emotional "mist" are reduced Was reported. The benefit lasted three to five days.Example 10   A 67-year-old plump elderly smoker with an elderly dementia 2.5 mg (sl) was given for the trial. The patient received a low dose of valproic acid 125 mg daily I have been taking twice and using nicotine patches twice a week for the past two years Was. In the administration of sl protopam, she reported for 5 to 7 days. "I feel refreshed," she said, with few requests. The manifestation is family testimony According to the report, it reappeared three times over a six-week period.   From the foregoing, those skilled in the art can readily ascertain the nature of the invention. Making various variations and / or variations without departing from the scope of the invention And it is still within the scope of equivalents to the appended claims.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 1/00 A61P 1/00 3/04 3/04 9/00 9/00 11/00 11/00 25 / 00 25/00 25/32 25/32 25/34 25/34 25/36 25/36 35/00 35/00 37/08 37/08 43/00 111 43/00 111 // C07D 417/12 C07D 417/12 (31) Priority claim number 08 / 801,801 (32) Priority date February 14, 1997 (Feb. 14, 1997) (33) Priority claim country United States (US) (31) Priority Claim number 08 / 801,802 (32) Priority date February 14, 1997 (Feb. 14, 1997) (33) Priority claim country United States (US) (31) Priority claim number 08 / 803,719 ( 32) Priority date February 21, 1997 (Feb. 21, 1997) (33) Priority claim country United States (US) (31) Priority claim number 08 / 803,721 (32) Priority date February 21, 1997 (Feb. 21, 1997) (33) Priority claim country United States (US) (31) Priority claim number 08 / 803,722 (32) Priority date February 21, 1997 ( (Feb. 21, 1997) (33) Priority country United States (US) (31) Priority claim number 08 / 803,723 (32) Priority date Feb. 21, 1997 (Feb. 21, 1997) (33) ) Priority claim country United States (US) (31) Priority claim number 08 / 807,273 (32) Priority date February 28, 1997 (Feb. 28,1997) (33) Priority claim country United States (US (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM) , AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN , MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW

Claims (1)

[Claims] 1. In a pharmaceutically acceptable carrier, (1) at least one pharmaceutically acceptable oxime that is physiologically active in vivo in a mammal, and (2) at least one additional pharmacological activity. A unit dosage form administered to a mammal, including a human, for alleviating chronic symptoms of synaptic dysfunction and related diseases, comprising an effective amount of the agent, wherein the oxime comprises 0.1 mg to 10 gm / 70 kg body weight. A unit dosage form that is present in the dosage form in an amount sufficient to provide a dosage of 2. An effective amount of at least one pharmaceutically acceptable oxime that is physiologically active in vivo in a mammal, optionally together with an effective amount of at least one additional pharmacologically active agent. A pharmaceutical composition for administration to a mammal, including a human, for alleviating chronic symptoms of synaptic dysfunction and related diseases, comprising a pharmaceutical carrier suitable for topical administration to the mammal. 3. A transdermal drug delivery system for administering a pharmacological agent to a mammal, including a human, using a patch that is applied to the skin of the mammal, wherein the delivery system alleviates chronic symptoms of synaptic dysfunction and related disorders. In order to administer the active ingredient to the mammal, an effective amount of at least one pharmaceutically acceptable oxime that is physiologically active in vivo in the mammal, optionally with at least one additional An improvement comprising an effective amount of a pharmacologically active agent. 4. The at least one additional pharmacologically active agent is a cholinergic agent, an adrenergic agonist and antagonist, a serotonergic active agent, a GABA agonist and antagonist, an adenosine active agent, a dopaminergic active agent, an anti-inflammatory agent, Stimulants, heavy metal antagonists and chelators, acetylcholinesterase inhibitors, antiallergic drugs, antihypertensive drugs, antithrombotic drugs, antiasthmatic drugs, antirheumatic drugs, antidepressants, antiobesity drugs, antiepileptics, antioxidants, A group consisting of antiarrhythmic drugs, antianginal drugs, calcium channel blockers, bronchodilators, cognitive or memory disease enhancers, antineoplastic drugs, vitamins, nutritional supplements, cardioactive drugs, binding resins, and mixtures thereof The product according to claims 1 to 3, which is selected from the group consisting of: 5. 5. The product of claim 4, wherein said additional pharmacologically active agent is an acetylcholine receptor antagonist. 6. 6. The product of claim 1, wherein said acetylcholine receptor antagonist is selected from the group consisting of scopolamine, homatropine, atropine, methscopolamine, methylatropine, ipatropium, mecamylamine and mixtures thereof. 7. 7. The product according to claims 1 to 6, wherein said oxime is an acetylcholinesterase reactivator, a pharmaceutically acceptable prodrug derivative thereof, or a pharmaceutically acceptable salt thereof. 8. The oxime is 1-methyl-pyridinium-2-aldoxime (2-PAM), obidoxime, 2,3-butanedione-2-oxime (DAM), pyruvaldehyde aldoxime (MINA), bisquaternary pyridine aldoxime ( The product according to claims 1 to 7, which is selected from the group consisting of TMD-4), their pharmaceutically acceptable prodrug derivatives and their pharmaceutically acceptable salts. 9. 9. The product according to claim 1, wherein said at least one additional active agent comprises a stimulant. 10. 10. The product of claim 9, wherein the stimulant is selected from the group consisting of nicotine, muscarinic, arecoline, lobeline, cotinine, kart, niketamide, etamiban, bethanechol, pilocarpine and mixtures thereof. 11. The oxime is of the formula (R ¹ -CR = NOH) ⁺ X ⁻ , wherein R is hydrogen, C _1-5 alkyl, optionally substituted phenyl, or NH ₂ , and R ¹ is C _1-5 aryl Or a 5- or 6-membered heterocyclic moiety having 1 to 3 nitrogen atoms in the heterocycle, and X ⁻ is a pharmaceutically acceptable anion derived from a salt of an inorganic or organic acid. The product according to claims 1 to 10, wherein 12. The oxime is of the formula R ¹ —CRＣＲNOH X ⁻ , wherein R is hydrogen, C _1-5 alkyl, optionally substituted phenyl, or NH ₂ , and R ¹ is Wherein R ² is: Or It is selected from the group consisting of wherein, Z is optionally contain at least one ether bond, one to ten polyalkylene group having carbon atoms, butenylene or, - (CH ₂₎ n-phenyl - (CH ₂₎ an n-, where, n is in the range of 1 to 6, the phenyl moiety may be substituted by C _1-5 alkyl optionally, R ³ is hydrogen, C _1-5 alkyl, COR ⁴ , CONR ⁵ R ⁶ or COOR ⁷ , wherein R ⁴ is C _1-6 alkyl, cyclohexyl, Ar, or benzyl; R ⁵ and R ⁵ are hydrogen, C _1-6 alkyl, cyclohexyl, Ar, C _{7 -13} aralkyl or 2-pyrimidyl, wherein R ⁷ is C _1-6 alkyl, cyclohexyl, benzyl or Ar; Ar is optionally substituted phenyl, wherein X ⁻ is a salt of an inorganic or organic acid. Derived from A product according to claims 1 to 10, defined by being a pharmaceutically acceptable anion. 13. The product of claim 1, wherein said oxime is administered in an amount in the range of about 0.1 to 300 mg / 70 kg body weight. 14． 14. The product of claim 13, wherein said oxime is administered in an amount in the range of about 0.1 to 25 mg / 70 kg body weight. 15. The product of claim 1, wherein the pharmaceutically acceptable carrier dissolves and / or degrades in the mouth to allow sublingual or buccal administration. 16. A product according to claim 1 in the form of a pill, tablet, granule, syrup, lozenge, capsule, injection solution, ointment, cream, salve, suppository or transdermal patch. 17． 3. The product according to claim 2, in the form of an ointment, cream or salve, optionally containing dimethylsulfoxide (DMSO). 18. Use of a pharmaceutically acceptable oxime that is physiologically active in vivo in a mammal, including a human, to alleviate the chronic symptoms of synaptic dysfunction and related diseases in a mammal, including a human. 19. Use according to claim 18 in combination with at least one additional pharmacologically active agent. 20. The at least one additional pharmacologically active agent is a cholinergic agent, an adrenergic agonist and antagonist, a serotonergic active agent, a GABA agonist and antagonist, an adenosine active agent, a dopaminergic active agent, an anti-inflammatory agent Stimulants, heavy metal antagonists and chelating agents, acetylcholinesterase inhibitors, antiallergic drugs, antihypertensive drugs, antithrombotic drugs, antiasthmatic drugs, antirheumatic drugs, antidepressants, antiobesity drugs, antiepileptics, antioxidants , Antiarrhythmic drugs, antianginal drugs, calcium channel blockers, bronchodilators, cognitive or memory disease enhancers, anticancer drugs, vitamins, nutritional supplements, cardioactive drugs, binding resins, and mixtures thereof. 20. Use according to claim 19, selected from the group. 21. 20. Use according to claim 19, wherein said at least one additional active agent is an acetylcholine receptor antagonist. 22. 22. The use according to claim 21, wherein said acetylcholine antagonist is selected from the group consisting of scopolamine, homatropin, atropine, methscopolamine, methylatropine, ipatropium, mecamylamine and mixtures thereof. 23. 23. Use according to claims 18 to 22, wherein said oxime is an acetyltylcholinesterase reactivator, a pharmaceutically acceptable prodrug derivative thereof, or a pharmaceutically acceptable salt thereof. 24. The oxime is 1-methyl-pyridinium-2-aldoxime (2-PAM), obidoxime, 2,3-butanedione-2-oxime (DAM), pyruvaldehyde aldoxime (MINA), bisquaternary pyridine aldoxime ( 24. The use according to claims 18 to 23, wherein the use is selected from the group consisting of TMD-4), their pharmaceutically acceptable prodrug derivatives and their pharmaceutically acceptable salts. 25. Use according to claims 18 to 24 in combination with a stimulant. 26. 26. The use according to claim 25, wherein said stimulant is selected from the group consisting of nicotine, muscarinic, arecoline, lobeline, cotinine, cut, niketamide, etamiban, bethanechol, pilocarpine and mixtures thereof. 27. The oxime is of the formula (R ¹ -CR = NOH) ⁺ X ⁻ , wherein R is hydrogen, C _1-5 alkyl, optionally substituted phenyl, or NH ₂ , and R ¹ is C _1-5 alkyl Or a 5- or 6-membered heterocyclic moiety having 1 to 3 nitrogen atoms in the heterocycle, and X ⁻ is a pharmaceutically acceptable anion derived from a salt of an inorganic or organic acid. 27. The use according to claims 18 to 26, wherein 28. The oxime is of the formula R ¹ —CRＣＲNOH X ⁻ , wherein R is hydrogen, C _1-5 alkyl, optionally substituted phenyl, or NH ₂ , and R ¹ is Wherein R ² is: Or Wherein Z is a polyalkylene group having 1 to 10 carbon atoms, optionally containing at least one ether bond, butenylene, or-(CH ₂ ) n-phenyl- (CH ₂₎ an n-, where, n is in the range of 1 to 6, the phenyl moiety may be substituted by C _1-5 alkyl optionally, R ³ is hydrogen, C _1-5 alkyl, COR ^4, CONR ⁵ is R ⁶ or COOR ^7, R ⁴ is an C _1-6 alkyl, cyclohexyl, Ar or benzyl,; R ⁵ and R ⁶ are hydrogen, C _1-6 alkyl, cyclohexyl, Ar, C _{7 -13} aralkyl or 2-pyrimidyl, wherein R ⁷ is C _1-6 alkyl, cyclohexyl, benzyl or Ar; Ar is optionally substituted phenyl, wherein X ⁻ is a salt of an inorganic or organic acid. Derived from A drug acceptable anions, defined by use according to the 18 to 26 wherein the claims. 29. 27. Use according to claims 18 to 26, wherein said oxime is administered in an amount in the range of about 0.1 mg to 10 g per 70 kg body weight. 30. 30. Use according to claim 29, wherein said oxime is administered in an amount in the range of about 0.1 to 300 mg / 70 kg body weight. 31. 23. Use according to claims 21 to 22, wherein said acetylcholine receptor antagonist is administered in an amount in the range of about 0.001 to 100 mg / 70 kg body weight. 32. 32. The use according to claim 31, wherein said acetylcholine receptor antagonist is administered in an amount in the range of about 0.001 to 25 mg / 70 kg body weight. 33. 33. Use according to claims 18 to 32 in combination with a pharmaceutically acceptable carrier that dissolves and / or degrades in the mouth to allow sublingual or buccal administration. 34. 33. Use according to claims 18 to 32 in the form of pills, tablets, granules, syrups, lozenges, capsules, injection solutions, ointments, creams, salves, suppositories or transdermal patches. 35. Use according to claims 18 to 34 for treating withdrawal symptoms caused by smoking cessation. 36. Use according to claims 18 to 34 for treating obesity symptoms. 37. Use according to claims 18 to 34 for treating drug and alcohol addiction, heavy metal poisoning, side effects of the treatment of antineoplastic diseases, antineoplastic diseases and endocrine and immune system abnormalities. 38. 35. The method according to claims 18 to 34 for treating respiratory disease, central and peripheral nervous system abnormalities, heart failure and cardiovascular disease, and gastrointestinal motility dysfunction, and irritable bowel syndrome, and chronic fatigue syndrome. use.