Agent for treating disorders from cerebral neuro-degeneration

Abstract: A therapeutic agent for alleviating disorders caused by nerve cell degeneration in the brain which contains a cyclopropachromen derivative represented by the following general formula (I): wherein n is an integer of from 2 to 5; the carbon atom in the -(CH₂) n - moiety may be optionally substituted with a methyl group or a hydroxyl group; R¹ and R² independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a phenyl group or an aralkyl group having 7 to 10 carbon atoms; or alternatively R¹ and R² form together with the nitrogen atom to which they are attached, a morpholino group, a thiomorpholino group, a pyrrolidinyl group, a piperidinyl group, a homopiperidinyl group, a piperazinyl group, a homopiperazinyl group, an N-alkylpiperazinyl group, N-alkylhomopiperazinyl group, an N-hydroxyalkylpiperazinyl group or a pyrrolidonyl group or alternatively R¹ and R² form together with the nitrogen atom to which they are attached, and further a carbon atom to which said nitrogen atom is bound, a pyrrolitidinyl group; A¹ and A² independently represent a hydrogen atom, a hydroxyl group, a halogen atom, an optionally halogenated alkyl group having 1 to 5 carbon atoms, an optionally substituted alkoxy group, an acyloxy group, a carbamyloxy group or an optionally substituted carboxyl group; and B¹ and B² independently represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, an optionally halogenated alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms or an optionally substituted carboxyl group; or a pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutical carrier or adjuvant.

Description: This invention relates to an agent for treating disorders from cerebral neuro-degeneration comprising a specified cyclopropachromen derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Organic and functional disorders in the human brain which controls high grade mental actions and motor functions are critical diseases that concern not only the physical but also the mental well-being of a person. In a rapidly aging society, the development of effective methods of treating brain disorders as well as therapeutic drugs is of pressing importance. However, despite many years of studies conducted to unravel the functions of the brain, only a partial understanding has so far been achieved and an understanding of individual diseases, still less a comprehensive and systematic knowledge of the brain, has not yet been obtained. While many brain diseases are known today, Alzheimer's disease (hereinafter sometimes abbreviated as AD) and senile dementia of the Alzheimer's type (hereinafter sometimes referred to as SDAT), both of which are progressive organic diseases of the brain that are characterized by lowered cognitive capabilities due to the degenerative atrophy of neurocytes in the brain, are becoming major social concerns requiring the implementation of effective care methods since the number of patients suffering from these diseases, especially in industrialized countries is rapidly increasing, and the progression of these diseases results in severe disability and ultimate death for those afflicted. Under these circumstances, industrialized countries are engaged in nationwide projects for the establishment of effective methods for treating AD and SDAT. However, even the causes of the diseases have not been properly elucidated. Only the morphological changes that can be observed in the brain or the biochemical changes as the consequences have been partly unravelled, but no effective therapy has yet been established. Cholinergic agents including choline precursors, cholinesterase inhibitors, etc. are being tested, on the basis of the cholinergic theory, in clinical fields as nosotropic agents for treating AD and SDAT. However, the evaluation on the utility of these therapeutics is varied and no single drug exhibits definite therapeutic effects. Three basic methods may be conceived of to treat neurodegenetative diseases including AD and SDAT: (1) suppressing or preventing the degenerative process of neurons; (2) compensating for the lost function of neurons with a drug; and (3) promoting the plasticity of remaining neurons to form a new neuro-circuit. The aforementioned cholinergic agents and cholinesterase inhibitors are within the class (2) since they are focused on the fact that, in a characteristic pathological symptom of AD and SDAT, cholinergic nerve fascicles that project from the basal forebrain to the cerebral cortex and the hippocampus undergo atrophic degeneration, yet acetylcholine receptors in the cerebral cortex and the hippocampus which are the cells that control those cholinergic nerve fascicles remain in a normal state. These drugs are expected to work effectively in the case of dysfunction of acetylcholine systems but no definite therapeutic effects are anticipated for diseases such as AD and SDAT which cannot be fully explained solely on the basis of the dysfunction of acetylcholine systems. Aggravation of brain diseases could be prevented if the degenerative process of neurons could be suppressed as in (1). If a new neuron network could be formed by promoting the compensatory functional recovery of remaining neurons as in (3), not only could the progress of the diseases be prevented but also positive recovery of neurofunctions could reasonably be expected. A drug that has been proposed in line with these approaches is a nerve growth factor (which is hereinafter referred to as "NGF"). NGF has long been known as a factor that is essential to the existence of sympathetic ganglion and sensory ganglion neurons in the peripheral nervous system, and hence extensive studies have been conducted on NGF. Recently, it has become clear that NGF also takes part in the existence and sustained functions of cholinergic neurons in the basal forebrain which are important to memory and learning. Thus the possibility of using NGF as an effective means of recovering part of the brain functions has been studied. However, NGF is a basic protein having a molecular weight of ca. 27,000 and the efforts to develop a direct method of compensatory therapy using NGF have not yet achieved a prospect for application in clinical fields since they involve many problems to be solved as regards the methods of its production and administration. Under these circumstances, increasing attention has recently been drawn by ganglioside as a non-peptide trophic factor like substance. For example, L. Facci et al. reported in J. Neurochem., 42 , 299-305 (1985) that monosialoganglioside (GM 1 ) promoted the formation of nerve dendrites in cultured cells derived from mouse neuroblasts. L. F. Agnati et al., Acta Physiol. Scand., 119 , 347-364 (1983) and G. Toffano et al., Brain Res., 296 , 233-239 (1984) reported that GM 1 inhibited the degeneration of the cell body of nigra dopamine neurons that occurred after the removal of the cortex on one side of the brain. Further, G. Jonsson et al. reported in Neurosci. Lett. (Suppl.), 14 , 185 (1983) that GM 1 worked suppressively on the decrease in 5-HT in the frontal and occipital lobes that was caused by pretreatment with 5,7-dihydroxytriptamine. These reports did not make it clear whether the action of ganglioside was direct or indirect in relation to the intermediary of the neurotrophic factor in NGF but they did show that ganglioside had the ability to either inhibit the degeneration of neurons or promote the compensatory functional recovery of a degenerated nerve circuit. Therefore, these observations suggest the possibility of new pharmaceutical therapy of AD and SDAT. In fact, however, ganglioside is a glycosphingolipid containing sialic acid and GM 1 , too, is a high-molecular weight compound that is the condensate of sialic acid, four saccharides and ceramide. Hence, the use of ganglioside as a drug for treating AD and SDAT involves several problems to be solved in terms of the methods of preparation and administration. Under these circumstances, the present inventors conducted intensive studies and found compounds that were easy-to-synthesize. They are low molecular weight compounds that are capable of promoting the extension of nerve dendrites and that are as effective as NGF and ganglioside in suppressing the degenerative process of nerves or regenerating a damaged nerve network to promote the recovery of its functions. The present invention has been accomplished on the basis of this finding and has as an object the provision of an entirely new therapeutic agent that relies upon the concept of recovering the functions of cerebral nerves by enhancing the plasticity of synapses and the level of learning activities. The present invention, relates to the use of a cyclopropachromen derivative represented by the following general formula (I): wherein n is an integer of from 2 to 5; the carbon atom in the -(CH 2 ) n - moiety may be optionally substituted with a methyl group or a hydroxyl group; R 1 and R 2 independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a phenyl group or an aralkyl group having 7 to 10 carbon atoms; or alternatively R 1 and R 2 form together with the nitrogen atom to which they are attached, a morpholino group, a thiomorpholino group, a pyrrolidinyl group, a piperidinyl group, a homopiperidinyl group, a piperazinyl group, a homopiperazinyl group, an N-alkylpiperazinyl group, N-alkylhomopiperazinyl group, an N-hydroxyalkylpiperazinyl group or a pyrrolidonyl group or alternatively R 1 and R 2 form together with the nitrogen atom to which they are attached, and further a carbon atom to which said nitrogen atom is bound, a pyrrolizidinyl group; A 1 and A 2 independently represent a hydrogen atom, a hydroxyl group, a halogen atom, an optionally halogenated alkyl group having 1 to 5 carbon atoms, an optionally substituted alkoxy group, an acyloxy group, a carbamyloxy group or an optionally substituted carboxyl group; and B 1 and B 2 independently represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, an optionally halogenated alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms or an optionally substituted carboxyl group; or a pharmaceutically acceptable salt thereof, for making a medicament being effective in alleviating a disease due to atrophic nerve cell degeneration in the brain The term "halogen" as used herein includes fluoro, chloro, bromo or iodo, and fluoro, chloro and bromo are preferred. The integer represented by n is preferably 2 - 4 and more preferably 2 or 3. Examples of the alkyl group represented by R 1 and R 2 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and neopentyl. Those having 1 - 3 carbon atoms such as methyl, ethyl, propyl and isopropyl are preferred. Examples of the aralkyl group represented by R 1 and R 2 include benzyl, phenethyl, phenylpropyl, phenylbutyl, tolylmethyl, tolylethyl, tolylpropyl, pyridylmethyl and pyridylethyl. When R 1 and R 2 form together with the nitrogen atom, to which they are attached, an N-alkylpiperazinyl group, N-alkyl-homopiperazinyl group or an N-hydroxyalkylpiperazinyl group, examples of the alkyl moiety include methyl, ethyl and propyl. When A 1 and A 2 independently represent an optionally halogenated alkyl group, examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl and trifluoromethyl. Those having 1 - 3 carbon atoms such as methyl, ethyl, propyl and isopropyl are preferred. When A 1 and A 2 independently represent an optionally substituted alkoxy group, examples of the substituent include phenyl and pyridyl. When A 1 and A 2 independently represent an optionally substituted carboxyl group, examples of the substituent include methyl, ethyl, propyl, butyl, phenyl, benzyl, pyridyl and pyridylmethyl. Methyl and ethyl are preferred. When B 1 and B 2 independently represent an optionally halogenated alkyl group, the alkyl group has preferably 1 - 5 carbon atoms. Examples of such groups include methyl, ethyl, propyl and trifluoromethyl. When B 1 and B 2 independently represent an optionally substituted carboxyl group, examples of the substituent include methyl, ethyl, propyl, butyl, phenyl, benzyl, pyridyl and pyridylmethyl. Methyl and ethyl are preferred. It should be understood that the compound of the present invention comprises several isomers as schematically illustrated below. Namely, there are two geometrical isomers (E-form and Z-form) at the oxime structure, and further, each of the geometrical isomers has two optical isomers. Each isomers can be separated by a conventional manner by way of, e.g. recrystallization, column chromatography, TLC, HPLC or by using a chemical substance commonly used in the separation of optical isomers. Typical examples of disorders resulting from cerebral neuro-degeneration to be treated with the use of the therapeutic agent of the present invention are progressive idiophrenic disorders, wherein cognitive capabilities deteriorate as a result of a degenerative atrophy of neurocytes in the brain, observed in Alzheimer's disease (AD) and senile dementia of an Alzheimer's type (SDAT). Some of the cyclopropachromen derivatives represented by the above general formula (I) are described in Japanese Patent Laid-Open No. 198676/1987. However, these compounds are disclosed in the aforesaid Laid-Open patent as a therapeutic agent for postapopletic sequence, an antiamnestic agent and an antidepressant mainly based on the effect of preventing hypofunction of the brain in an ischemic state, namely, as a therapeutic agent for symptomatic treatment. In contrast thereto, the therapeutic agent of the present invention is a drug for causal treatment whereby degenerated cerebral neurocytes are restored and thus normalized. Therefore, the therapeutic agent of the present invention enables the treatment of kern-neurosis such as AD and SDAT caused by neuro-degeneration in the brain, differing from the case of the aforesaid therapeutic agent described in Japanese Patent Laid-Open No. 198676/1987. Among the compounds of the general formula (I), novel ones may be synthesized in the following manner in accordance with a method described in Japanese Patent Laid-Open No. 198676/1987. Namely, the compound of the general formula (II) is reacted with hydroxylamine hydrochloride in pyridine to give the compound (III). The compound (III) is then condensed with an aminohalide represented by the following formula: wherein R 1 , R 2 and -(CH 2 ) n - are as defined above; and X represents a halogen atom; to give the compound (I). Alternatively, the compound (III) is condensed with a bifunctional compound represented by the following formula: X 1 - (CH 2 ) n - X 2 wherein -(CH 2 ) n - is as defined above; X 1 represents a halogen atom; and X 2 represents a halogen atom or an epoxyethyl group; to give the compound (IV). The compound (IV) is further reacted with an appropriate amine to give the compound (I). The starting compound (II) to be used in the above synthesis is either a known compound reported by P. Bennett et al. [J. Chem. Soc., Perkin Trans., I , 2990 (1979)] or one which may be synthesized by a similar method. The active ingredient of the present invention may be formulated into pharmaceutical compositions together with commonly known carriers either as such or in the form of a pharmaceutically acceptable salt, for example, an inorganic acid salt such as hydrochloride, sulfate, nitrate or phosphate, an organic acid salt such as acetate, propionate, butyrate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, malate, p-toluenesulfonate or methanesulfonate, or an alkali metal salt such as sodium or potassium salt when either A 1 or A 2 in the general formula (I) is a hydroxyl group. For example, the active ingredient may be formulated, optionally together with a common filler etc., into an appropriate preparation such as a capsule, tablet or injection and then orally or parenterally administered. These preparations may be obtained by, for example, the following methods. The active compound in the form of a powder is mixed with a filler such as lactose, starch or a derivative thereof or a cellulose derivative and then filled in a gelatin capsule to give a capsule. A tablet may be obtained by admixing the active compound together with an above-mentioned filler, a binder such as sodium carboxymethyl cellulose, alginic acid or gum arabic and water, optionally formulating into the kneaded mixture into granules, adding a lubricant such as talc or stearic acid thereto and then tableting the obtained mixture with a common compression tableting machine. In the case of parenteral administration by injection, the active compound is dissolved together with a dissolving aid in sterile distilled water or sterile physiological saline and then sealed in an ample to thereby give an injection preparation. The product may further contain a stabilizer or a buffer, if required. The content of the active ingredient in the therapeutic agent may vary depending on the type of the disease, conditions, administration method and physical factors of the patient. In general, the content should be adjusted in such a manner as to give the active ingredient in an amount sufficient to alleviate the symptoms of the disease. For example, it may be administered to an adult in a dose of from approximately 0.1 to 1,000 mg, preferably from 1 to 500 mg, per day via oral administration, intravenous injection or application to mucosa. In the following Reference Examples and Examples, the synthesis of the active ingredient compound of the present invention will be illustrated. In the Reference Examples given first, the preparation of a starting material to be used for synthesizing the active ingredient will be described. Each Reference Example is expressed in a combination of two numbers and the former number corresponds to the number of the above-mentioned general formulae (II) to (IV). [Namely, Reference Example II-1 shows the preparation of the starting material of the above-mentioned formula (II).] Reference Example II-1 1a,7a-Dihydro-1a-phenylcyclopropa[b]chromen-7(1H)-one Although the method for synthesizing the titled compound is described by P. Bennett et al. [J. Chem. Soc., Perkin Trans. I , 2990 (1979)], no detailed description on a practical test method is given therein. By reference to their report, we have examined reaction conditions in detail and thus synthesized the titled compound by the following method. 11.2 g (50 mmol) of trimethylsulfoxonium iodide was dissolved in 100 mℓ of dimethylsulfoxide and 2.0 g (50 mmol) of sodium hydride (60% oil-dispersion) was added thereto by portions. The mixture was stirred at room temperature until no hydrogen evolved any more. To the obtained reaction mixture, was added a dimethylsulfoxide solution in which 11.1 g (50 mmol) of flavone had been dissolved. After stirring at room temperature for 2 hours and at 50°C for 1 hour, the reaction mixture was poured onto ice/water and then extracted with ether. The extract was washed with water, dried and concentrated. The residue thus obtained was purified by silica gel chromatography (eluent: hexane:ethyl acetate = 9:1) to give 6.01 g (yield: 48%) of the titled compound. The physicochemical data of the obtained product are shown in the following Table 1. The compounds of Reference Examples II-2 to II-35 were each produced in the same manner as the one described in Reference Example II-1. Reference Example III-1 1a,7a-Dihydro-7(1H)-hydroxyimino-1a-phenylcyclopropa[b]chromen 2.36 g (10 mmol) of the compound of Reference Example II-1 was dissolved in 80 mℓ of pyridine. 2.78 g (40 mmol) of hydroxylamine hydrochloride was added thereto and the obtained mixture was stirred at 55°C for 2 hours. The reaction mixture was concentrated, diluted with water and then extracted with chloroform. The extract was washed with water, dried and concentrated. The residue thus obtained was purified by silica gel chromatography (eluent: hexane:ethyl acetate = 9:1) to give 2.31 g (yield: 92.1%) of the titled compound. The physicochemical data of this product are shown in the following Table 2. Table 2 further shows the compounds of Reference Examples III-2 to III-35 which were produced by reacting the compounds of Reference Examples II with hydroxylamine hydrochloride followed by the treatment as the aforesaid manner. Reference Example IV-1 7(1H)-(2-Bromoethyloxyimino)-1a,7a-dihydro-1a-phenylcyclopropa[b]chromen 700 mg of the compound of Reference Example III-1 was dissolved in 60 mℓ of tetrahydrofuran and 223 mg (2 equivalents) of sodium hydride (60% oil-dispersion) was added thereto. After refluxing for 1 hour, 3.14 g (6 equivalents) of ethylene dibromide was added thereto and the mixture was refluxed for 5 hours. The reaction mixture was concentrated and ice/water was added thereto followed by extracting with ether. The extract was washed with water, dried and concentrated. The residue thus obtained was purified by silica gel column chromatography (eluent: hexane:ethyl acetate = 95:5) to give 911 mg (yield: 91.3%) of the titled compound. The physicochemical data of the obtained product are shown in the following Table 3. Reference Example IV-2 7(1H)-(2-Chloroethyloxyimino)-1a,7a-dihydro-1a-phenylcyclopropa[b]chromen 1.5 g of the compound of Reference Example III-1 was dissolved in 40 mℓ of dioxane and 718 mg (3 equivalents) of sodium hydride (60% oil-dispersion) was added thereto. After adding 5.13 g (6 equivalents) of 1-bromo-2-chloroethane, the mixture was heated under reflux at 100°C for 5 hours. The reaction mixture was concentrated and ice/water was added thereto followed by extracting with ether. The extract was washed with water, dried and concentrated. The residue thus obtained was purified by silica gel chromatography (eluent: hexane:ethyl acetate = 50:1) to give 1.78 g (yield: 95.1%) of the titled compound. The physicochemical data of the obtained product are shown in the following Table 3. Table 3 further shows the compounds of Reference Examples IV-3 to IV-16 which were produced in the same manner as the one described in this Reference Example. Reference Example IV-17 4-Chloro-1a,7a-dihydro-7(1H)-(2,3-oxypropyloxyimino)-1a-phenylcyclopropa[b]chromen 340 mg of the compound of Reference Example III-3 was dissolved in 12 mℓ of THF and 95.2 mg (2 equivalents) of sodium hydride (60% oil-dispersion) and 440 mg (4 equivalents) of epichlorohydrin were added thereto. After refluxing for 2 hours, the reaction mixture was poured onto ice/water and then extracted with ether. The extract was washed with water and dried. The residue thus obtained was purified by silica gel column chromatography (eluent: hexane:ethyl acetate = 9:1) to give 307 mg (yield: 79.2%) of the titled compound. The physicochemical data of the obtained product are shown in the following Table 3. Example 1 1a,7a-Dihydro-7(1H)-(2-methylaminoethyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 2] 260 mg of the compound of Reference Example IV-2 was dissolved in 10 mℓ of dioxane and 10 mℓ of monomethylamine-saturated dioxane was added thereto. The mixture was heated to 100°C in a sealed tube for 17 hours. After distilling off the dioxane, water and an aqueous solution of sodium hydroxide were added thereto followed by extracting with methylene chloride. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtering and concentrating the solution, the obtained residue was eluted with silica gel column chromatography by using methylene chloride/methanol (9:1). Thus 213 mg (yield: 83.4%) of the titled compound was obtained. The product thus obtained was further converted into the tartrate in a conventional manner. Example 2 4-Chloro-1a,7a-dihydro-7(1H)-(2-methylaminoethyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 2] Starting from the compound of Reference Example IV-3, the titled compound was produced in the same manner as the one described in Example 1. Example 3 4-Bromo-1a,7a-dihydro-7(1H)-(2-methylaminoethyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Br; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 2] Starting from the compound of Reference Example IV-4, the titled compound was produced in the same manner as the one described in Example 1. Example 4 1a,7a-Dihydro-4,5-dimethoxy-7(1H)-(2-methylaminoethyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCH 3 ; A 2 = 5-OCH 3 ; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 2] Starting from the compound of Reference Example IV-5, the titled compound was produced in the same manner as the one described in Example 1. Example 5 1a-(4-Chlorophenyl)-1a,7a-dihydro-7(1H)-(2-methylaminoethyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = 4-Cl; NR 1 R 2 = NHCH 3 and n = 2] Starting from the compound of Reference Example IV-6, the titled compound was produced in the same manner as the one described in Example 1. Example 6 4-Chloro-1a-(4-chlorophenyl)-1a,7a-dihydro-7(1H)-(2-methylaminoethyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = H; B 2 = 4-Cl; NR 1 R 2 = NHCH 3 and n = 2] Starting from the compound of Reference Example IV-7, the titled compound was produced in the same manner as the one described in Example 1. Example 7 1a,7a-Dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] 600 mg (2.4 mmol) of the compound of Reference Example III-1 was dissolved in 20 mℓ of tetrahydrofuran and 382 mg (9.6 mmol) of sodium hydride (60% oil-dispersion) and 1.54 g (7.2 mmol) of dimethylaminoethyl chloride were added thereto. The obtained mixture was heated under reflux over a day and night. The reaction mixture was concentrated and ice/water was added thereto followed by extracting with ether. The ether phase was washed with water and dried over anhydrous magnesium sulfate. After filtering and concentrating, the residue thus obtained was eluted by neutral silica gel column chromatography by eluting with methylene chloride/methanol (95:5) to give 220 mg (yield: 30.2%) of the titled compound. The product thus obtained was further converted into the maleate by a conventional manner and crystallized from ethanol/ether. Example 8 1a,7a-Dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-4-fluoro-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-F; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-2, the titled compound was produced in the same manner as the one described in Example 7. Example 9 4-Chloro-1a,7a-dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-3, the titled compound was produced in the same manner as the one described in Example 7. Example 10 4-Bromo-1a,7a-dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Br; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-4, the titled compound was produced in the same manner as the one described in Example 7. Example 11 1a,7a-Dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-4-methoxy-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCH 3 ; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-5, the titled compound was produced in the same manner as the one described in Example 7. Example 12 5-Chloro-1a,7a-dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 5-Cl; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-7, the titled compound was produced in the same manner as the one described in Example 7. Example 13 1a,7a-Dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-5-methoxy-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 5-OCH 3 ; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-8, the titled compound was produced in the same manner as the one described in Example 7. Example 14 1a,7a-Dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-6-methoxy-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 6-OCH 3 ; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-9, the titled compound was produced in the same manner as the one described in Example 7. Example 15 4,5-Dichloro-1a,7a-dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = 5-Cl; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-11, the titled compound was produced in the same manner as the one described in Example 7. Example 16 1a,7a-Dihydro-4,5-dimethoxy-7(1H)-(2-dimethylaminoethyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCH 3 ; A 2 = 5-OCH 3 ; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-12, the titled compound was produced in the same manner as the one described in Example 7. Example 17 1a-(4-Chlorophenyl)-1a,7a-dihydro-7(1H)-(2-dimethylaminoethyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-Cl; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-19, the titled compound was produced in the same manner as the one described in Example 7. Example 18 1a,7a-Dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-1a-(4-methoxyphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-OCH 3 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-20, the titled compound was produced in the same manner as the one described in Example 7. Example 19 1a,7a-Dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-1a-(4-methylphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-CH 3 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-21, the titled compound was produced in the same manner as the one described in Example 7. Example 20 1a,7a-Dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-1a-(4-trifluoromethylphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-CF 3 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-22, the titled compound was produced in the same manner as the one described in Example 7. Example 21 1a,7a-Dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-1a-(4-methoxycarbonylphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-CO 2 CH 3 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-23, the titled compound was produced in the same manner as the one described in Example 7. Example 22 1a-(4-Cyanophenyl)-1a,7a-dihydro-7(1H)-(2-dimethylaminoethyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-CN; B 1 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-24, the titled compound was produced in the same manner as the one described in Example 7. Example 23 1a,7a-Dihydro-7(1H)-(2-dimethylaminoethyloxyimino)-1a-(4-nitrophenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-NO 2 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-25, the titled compound was produced in the same manner as the one described in Example 7. Example 24 1a-(3,4-Dichlorophenyl)-1a,7a-dihydro-7(1H)-(2-dimethylaminoethyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 3-Cl; B 2 = 4-Cl; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-26, the titled compound was produced in the same manner as the one described in Example 7. Example 25 4-Chloro-1a-(4-chlorophenyl)-1a,7a-dihydro-7(1H)-(2-dimethylaminoethyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = 4-Cl; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 2] Starting from the compound of Reference Example III-28, the titled compound was produced in the same manner as the one described in Example 7. Example 26 7(1H)-(2-Diethylaminoethyloxyimino)-1a,7a-dihydro-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(C 2 H 5 ) 2 and n = 2] Starting from the compound of Reference Example III-1, the titled compound was produced in the same manner as the one described in Example 7. Example 27 7(1H)-(2-Diethylaminoethyloxyimino)-1a,7a-dihydro-4,5-dimethoxy-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCH 3 ; A 2 = 5-OCH 3 ; B 1 = H; B 2 = H; NR 1 R 2 = N(C 2 H 5 ) 2 and n = 2] Starting from the compound of Reference Example III-12, the titled compound was produced in the same manner as the one described in Example 7. Example 28 1a,7a-Dihydro-7(1H)-(2-morpholinoethyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = morpholino and n = 2] Starting from the compound of Reference Example IV-1, the titled compound was produced in the same manner as the one described in Example 1. Example 29 Starting from the compound of Reference Example IV-2, the titled compound was produced in the same manner as the one described in Example 1. Example 30 1a,7a-Dihydro-1a-phenyl-7(1H)-[2-(1-piperidinyl)ethyloxyimino]-cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = piperidinyl and n = 2] Starting from the compound of Reference Example IV-2, the titled compound was produced in the same manner as the one described in Example 1. Example 31 1a,7a-Dihydro-7(1H)-[2-(1-homopiperidinyl)ethyloxyimino]-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = homopiperidinyl and n = 2] Starting from the compound of Reference Example IV-2, the titled compound was produced in the same manner as the one described in Example 1. Example 32 7(1H)-(3-aminopropyloxyimino)-1a,7a-dihydro-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NH 2 and n = 3] Starting from the compound of Reference Example III-1, the titled compound was produced in the same manner as the one described in Example 7. Example 33 1a,7a-Dihydro-7(1H)-(3-methylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example IV-9, the titled compound was produced in the same manner as the one described in Example 1. Then the obtained product was converted into the fumarate (m.p.: 131 - 133°C), the maleate (m.p.: 160 - 162°C) and the oxalate (m.p.: 168 - 171°C), in addition to the tartrate. Example 34 1a,7a-Dihydro-4-fluoro-7(1H)-(3-methylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-F; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-2, the titled compound was produced in the same manner as the one described in Example 7. Example 35 4-Chloro-1a,7a-dihydro-7(1H)-(3-methylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-3, the titled compound was produced in the same manner as the one described in Example 7. Example 36 4-Bromo-1a,7a-dihydro-7(1H)-(3-methylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Br; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-4, the titled compound was produced in the same manner as the one described in Example 7. Example 37 1a,7a-Dihydro-4-methoxy-7(1H)-(3-methylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCH 3 ; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-5, the titled compound was produced in the same manner as the one described in Example 7. Example 38 5-Chloro-1a,7a-dihydro-7(1H)-(3-methylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 5-Cl; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-7, the titled compound was produced in the same manner as the one described in Example 7. Example 39 4,5-Dichloro-1a,7a-dihydro-7(1H)-(3-methylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = 5-Cl; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-11, the titled compound was produced in the same manner as the one described in Example 7. Example 40 1a,7a-Dihydro-4,5-dimethoxy-7(1H)-(3-methylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCH 3 ; A 2 = 5-OCH 3 ; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-12, the titled compound was produced in the same manner as the one described in Example 7. Example 41 1a,7a-Dihydro-7(1H)-(3-methylaminopropyloxyimino)-1a-(4-methoxyphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-OCH 3 ; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-20, the titled compound was produced in the same manner as the one described in Example 7. Example 42 1a-(3,4-Dichlorophenyl)-1a,7a-dihydro-7(1H)-(3-methylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 3-Cl; B 2 = 4-Cl; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-26, the titled compound was produced in the same manner as the one described in Example 7. Example 43 1a,7a-Dihydro-4-fluoro-1a-(4-fluorophenyl)-7(1H)-(3-methylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-F; A 2 = H; B 1 = 4-F; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-30, the titled compound was produced in the same manner as the one described in Example 7. Example 44 4-Chloro-1a,7a-dihydro-1a-(4-fluorophenyl)-7(1H)-(3-methylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = 4-F; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-31, the titled compound was produced in the same manner as the one described in Example 7. Example 45 4-Chloro-1a-(4-chlorophenyl)-1a,7a-dihydro-7(1H)-(3-methylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = 4-Cl; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-28, the titled compound was produced in the same manner as the one described in Example 7. Then the product was converted into the maleate (m.p.: 105 - 107°C) and the fumarate (m.p.: 155 - 157°C), in addition to the tartrate. Example 46 1a-(4-Bromophenyl)-4-chloro-1a,7a-dihydro-7(1H)-(3-methylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = 4-Br; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-32, the titled compound was produced in the same manner as the one described in Example 7. Example 47 4-Bromo-1a,7a-dihydro-1a-(4-fluorophenyl)-7(1H)-(3-methylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Br; A 2 = H; B 1 = 4-F; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-33, the titled compound was produced in the same manner as the one described in Example 7. Example 48 4-Bromo-1a-(4-chlorophenyl)-1a,7a-dihydro-7(1H)-(3-methylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Br; A 2 = H; B 1 = 4-Cl; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-34, the titled compound was produced in the same manner as the one described in Example 7. Example 49 4-Bromo-1a-(4-bromophenyl)-1a,7a-dihydro-7(1H)-(3-methylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Br; A 2 = H, B 1 = 4-Br; B 2 = H; NR 1 R 2 = NHCH 3 and n = 3] Starting from the compound of Reference Example III-35, the titled compound was produced in the same manner as the one described in Example 7. Example 50 1a,7a-Dihydro-7(1H)-(3-ethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHC 2 H 5 and n = 3] Starting from the compound of Reference Example III-1, the titled compound was produced in the same manner as the one described in Example 7. Example 51 1a,7a-Dihydro-4-fluoro-7(1H)-(3-ethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-F; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHC 2 H 5 and n = 3] Starting from the compound of Reference Example III-2, the titled compound was produced in the same manner as the one described in Example 7. Example 52 4-Chloro-1a,7a-dihydro-7(1H)-(3-ethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHC 2 H 5 and n = 3] Starting from the compound of Reference Example III-3, the titled compound was produced in the same manner as the one described in Example 7. Example 53 4-Bromo-1a,7a-dihydro-7(1H)-(3-ethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Br; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHC 2 H 5 and n = 3] Starting from the compound of Reference Example III-4, the titled compound was produced in the same manner as the one described in Example 7. Example 54 5-Chloro-1a,7a-dihydro-7(1H)-(3-ethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 5-Cl; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHC 2 H 5 and n = 3] Starting from the compound of Reference Example III-7, the titled compound was produced in the same manner as the one described in Example 7. Example 55 4,5-Dichloro-1a,7a-dihydro-7(1H)-(3-ethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = 5-Cl; B 1 = H; B 2 = H; NR 1 R 2 = NHC 2 H 5 and n = 3] Starting from the compound of Reference Example III-11, the titled compound was produced in the same manner as the one described in Example 7. Example 56 1a-(3,4-Dichlorophenyl)-1a,7a-dihydro-7(1H)-(3-ethylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 3-Cl; B 2 = 4-Cl; NR 1 R 2 = NHC 2 H 5 and n = 3] Starting from the compound of Reference Example III-26, the titled compound was produced in the same manner as the one described in Example 7. Example 57 4-Chloro-1a-(4-chlorophenyl)-1a,7a-dihydro-7(1H)-(3-ethylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = 4-Cl; B 2 = H; NR 1 R 2 = NHC 2 H 5 and n = 3] Starting from the compound of Reference Example III-28, the titled compound was produced in the same manner as the one described in Example 7. Example 58 1a,7a-Dihydro-7(1H)-(3-propylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 2 CH 2 CH 3 and n = 3] Starting from the compound of Reference Example III-1, the titled compound was produced in the same manner as the one described in Example 7. Example 59 1a,7a-Dihydro-7(1H)-[3-(N-isopropylamino)propyloxyimino]-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-1, the titled compound was produced in the same manner as the one described in Example 7. Example 60 7(1H)-[3-(N-Benzylamino)propyloxyimino]-1a,7a-dihydro-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 2 -C 6 H 5 and n = 3] Starting from the compound of Reference Example IV-9, the titled compound was produced in the same manner as the one described in Example 1. Example 61 1a,7a-Dihydro-1a-phenyl-7(1H)-[3-(N-phenylethylamino)propyloxyimino]cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 2 CH 2 -C 6 H 5 and n = 3] Starting from the compound of Reference Example IV-9, the titled compound was produced in the same manner as the one described in Example 1. Example 62 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-1, the titled compound was produced in the same manner as the one described in Example 7. Example 63 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-4-fluoro-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-F; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-2, the titled compound was produced in the same manner as the one described in Example 7. Example 64 4-Chloro-1a,7a-dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-3, the titled compound was produced in the same manner as the one described in Example 7. Example 65 4-Bromo-1a,7a-dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Br; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-4, the titled compound was produced in the same manner as the one described in Example 7. Example 66 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-4-methoxy-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCH 3 , A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-5, the titled compound was produced in the same manner as the one described in Example 7. Example 67 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-4-benzyloxy-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCH 2 -C 6 H 5 , A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-6, the titled compound was produced in the same manner as the one described in Example 7. Example 68 5-Chloro-1a,7a-dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 5-Cl; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-7, the titled compound was produced in the same manner as the one described in Example 7. Example 69 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-5-methoxy-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 5-OCH 3 , A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-8, the titled compound was produced in the same manner as the one described in Example 7. Example 70 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-6-methoxy-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 6-OCH 3 ; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-9, the titled compound was produced in the same manner as the one described in Example 7. Example 71 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-3,4-dimethoxy-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 3-OCH 3 ; A 2 = 4-OCH 3 ; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-10, the titled compound was produced in the same manner as the one described in Example 7. Example 72 4,5-Dichloro-1a,7a-dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = 5-Cl; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-11, the titled compound was produced in the same manner as the one described in Example 7. Example 73 1a,7a-Dihydro-4,5-dimethoxy-7(1H)-(3-dimethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCH 3 ; A 2 = 5-OCH 3 ; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-12, the titled compound was produced in the same manner as the one described in Example 7. Example 74 4,5-Dibenzyloxy-1a,7a-dihydro-7(1H)-(3-dimethylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCH 2 -C 6 H 5 ; A 2 = 5-OCH 2 -C 6 H 5 ; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-13, the titled compound was produced in the same manner as the one described in Example 7. Example 75 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-(2-methoxyphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 2-OCH 3 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-14, the titled compound was produced in the same manner as the one described in Example 7. Example 76 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-(2-methylphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 2-CH 3 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-15, the titled compound was produced in the same manner as the one described in Example 7. Example 77 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-(3-chlorophenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 3-Cl; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-16, the titled compound was produced in the same manner as the one described in Example 7. Example 78 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-(3-methoxyphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 3-OCH 3 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-17, the titled compound was produced in the same manner as the one described in Example 7. Example 79 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-(3-methylphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 3-CH 3 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-18, the titled compound was produced in the same manner as the one described in Example 7. Example 80 1a-(4-Chlorophenyl)-1a,7a-dihydro-7(1H)-(3-dimethylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-Cl; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-19, the titled compound was produced in the same manner as the one described in Example 7. Example 81 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-(4-methoxyphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-OCH 3 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-20, the titled compound was produced in the same manner as the one described in Example 7. Example 82 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-(4-methylphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-CH 3 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-21, the titled compound was produced in the same manner as the one described in Example 7. Example 83 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-(4-trifluoromethylphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-CF 3 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-22, the titled compound was produced in the same manner as the one described in Example 7. Example 84 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-(4-methoxycarbonylphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-CO 2 CH 3 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-23, the titled compound was produced in the same manner as the one described in Example 7. Example 85 1a-(4-Cyanophenyl)-1a,7a-dihydro-7(1H)-(3-dimethylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-CN; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-24, the titled compound was produced in the same manner as the one described in Example 7. Example 86 1a,7a-Dihydro-7(1H)-(2-dimethylaminopropyloxyimino)-1a-(4-nitrophenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 4-NO 2 ; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-25, the titled compound was produced in the same manner as the one described in Example 7. Example 87 1a-(3,4-Dichlorophenyl)-1a,7a-dihydro-7(1H)-(3-dimethylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 3-Cl; B 2 = 4-Cl; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-26, the titled compound was produced in the same manner as the one described in Example 7. Example 88 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-(3,4-dimethoxyphenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = 3-OCH 3 ; B 2 = 4-OCH 3 ; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-27, the titled compound was produced in the same manner as the one described in Example 7. Example 89 4-Chloro-1a-(4-chlorophenyl)-1a,7a-dihydro-7(1H)-(3-dimethylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = 4-Cl; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-28, the titled compound was produced in the same manner as the one described in Example 7. Example 90 4-Chloro-1a,7a-dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-(4-nitrophenyl)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = 4-NO 2 , B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-29, the titled compound was produced in the same manner as the one described in Example 7. Example 91 1a,7a-Dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-4-hydroxy-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OH; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] 93 mg of 10% palladium on carbon was suspended in 6 mℓ of ethyl acetate and subjected to hydrogen-replacement under suction. Next, 311 mg of the compound of Example 67 was added thereto and the mixture was stirred under a hydrogen gas stream (atmospheric pressure) at room temperature for 24 hours. After filtering, the filtrate was concentrated and introduced through a silica gel column chromatography with the use of methylene chloride/methanol (9:1) as the eluent. Thus 195 mg (yield: 78%) of the titled compound was obtained. Example 92 4-Acetyloxy-1a,7a-dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCOCH 3 ; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] 300 mg of the compound of Example 91 was dissolved in 10 mℓ of pyridine and 5 mℓ of acetic anhydride. After stirring at room temperature for 1 hour, the solvent was distilled off and the residue was dissolved in methylene chloride. Next it was washed with an aqueous solution of sodium hydrogencarbonate and then with water and dried over anhydrous magnesium sulfate. After filtering, the filtrate was concentrated and introduced through a silica gel column chromatography with the use of methylene chloride/methanol (9:1) as the eluent. Thus 329 mg (yield: 98.0%) of the titled compound was obtained. Example 93 1a,7a-Dihydro-4-(N,N-dimethylcarbamoyloxy)-7(1H)-(3-dimethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCON(CH 3 ) 2 ; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] 139 mg of the compound of Example 91 was dissolved in 20 mℓ of methylene chloride. After adding 0.11 mℓ (3 equivalents) of N,N-dimethylcarbamoyl chloride and 0.55 mℓ (10 equivalents) of triethylamine, the mixture was heated under reflux for 7 hours. The reaction mixture was cooled, washed with an aqueous solution of sodium hydrogencarbonate and then with water and dried over anhydrous magnesium sulfate. After filtering and concentrating, the obtained residue was purified through silica gel column chromatography by using methylene chloride/methanol (95:5) as the eluent. Thus 144 mg (yield: 86.2%) of the titled compound was obtained. Example 94 4-(2-Amino-2-oxoethyloxy)-1a,7a-dihydro-7(1H)-(3-dimethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OCH 2 CONH 2 ; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] 129 mg of the compound of Example 91 was dissolved in 20 mℓ of dioxane. After adding 21.9 mg (1.5 equivalents) of sodium hydride (60% oil dispersion), the mixture was heated to 100°C for 30 minutes. Next, 72.2 mg (2 equivalents) of 2-chloroacetamide and 0.5 mℓ of dimethylsulfoxide were added thereto and the mixture was stirred at 100°C for 3 hours. The reaction mixture was concentrated and ice/water was added thereto. After extracting with ether, the ether layer was washed with water and dried over anhydrous magnesium sulfate. After filtering and concentrating, the obtained residue was purified with a silica gel column chromatography by using methylene chloride/methanol (9:1) as the eluent. Thus 94.3 mg (yield: 62.9%) of the titled compound was obtained. Example 95 1a,7a-Dihydro-4,5-dihydroxy-7(1H)-(3-dimethylaminopropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-OH; A 2 = 5-OH; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 3] 48 mg of 10% palladium on carbon was suspended in 20 mℓ of ethyl acetate and subjected to hydrogen-replacement under suction. 240 mg of the compound of Example 74 was added thereto and the mixture was stirred under a hydrogen stream (atmospheric pressure) at room temperature for 5 hours. Then it was treated in the same manner as the one described in Example 91. Thus 67.0 mg (yield: 41.5%) of the titled compound was obtained. Example 96 1a,7a-Dihydro-7(1H)-(3-diethylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(C 2 H 5 ) 2 and n = 3] Starting from the compound of Reference Example IV-9, the titled compound was produced in the same manner as the one described in Example 1. Example 97 1a,7a-Dihydro-7(1H)-(3-dipropylaminopropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 2 CH 2 CH 3 ) 2 and n = 3] Starting from the compound of Reference Example IV-8, the titled compound was produced in the same manner as the one described in Example 1. Example 98 1a,7a-Dihydro-1a-phenyl-7(1H)-(3-pyrrolidinylpropyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = pyrrolidinyl and n = 3] Starting from the compound of Reference Example IV-9, the titled compound was produced in the same manner as the one described in Example 1. Example 99 Starting from the compound of Reference Example IV-9, the titled compound was produced in the same manner as the one described in Example 1. Example 100 1a,7a-Dihydro-1a-phenyl-7(1H)-[3-(1-piperidinyl)propyloxyimino]-cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = piperidinyl and n = 3] Starting from the compound of Reference Example IV-9, the titled compound was produced in the same manner as the one described in Example 1. Example 101 1a,7a-Dihydro-7(1H)-[3-(1-homopiperidinyl)propyloxyimino]-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = homopiperidinyl and n = 3] Starting from the compound of Reference Example IV-9, the titled compound was produced in the same manner as the one described in Example 1. Example 102 1a,7a-Dihydro-7(1H)-(3-dimethylamino-2-methylpropyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NO(CH 2 ) n NR 1 R 2 = NOCH 2 CH(CH 3 )CH 2 N(CH 3 ) 2 and n = 3] Starting from the compound of Reference Example III-1, the titled compound was produced in the same manner as the one described in Example 7. Example 103 7(1H)-[3-(N-Benzyl-N-methylamino)propyloxyimino]-1a,7a-dihydro-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 )CH 2 -C 6 H 5 and n = 3] Starting from the compound of Reference Example IV-9, the titled compound was produced in the same manner as the one described in Example 1. Example 104 1a,7a-Dihydro-1a-phenyl-7(1H)-[3-(1-pyrrolidonyl)propyloxyimino]cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = pyrrolidonyl and n = 3] Starting from the compound of Reference Example IV-9, the titled compound was produced in the same manner as the one described in Example 1. Example 105 Starting from the compound of Reference Example III-1, the titled compound was produced in the same manner as the one described in Example 7. Example 106 Starting from the compound of Reference Example IV-17, the titled compound was produced in the same manner as the one described in Example 1. Example 107 1a,7a-Dihydro-7(1H)-(4-methylaminobutyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = NHCH 3 and n = 4] Starting from the compound of Reference Example IV-14, the titled compound was produced in the same manner as the one described in Example 1. Example 108 1a,7a-Dihydro-7(1H)-(4-dimethylaminobutyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 4] Starting from the compound of Reference Example IV-14, the titled compound was produced in the same manner as the one described in Example 1. Example 109 1a,7a-Dihydro-7(1H)-(5-dimethylaminopentyloxyimino)-1a-phenylcyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = H; A 2 = H; B 1 = H; B 2 = H; NR 1 R 2 = N(CH 3 ) 2 and n = 5] Starting from the compound of Reference Example IV-15, the titled compound was produced in the same manner as the one described in Example 1. Example 110 4-Chloro-1a-(4-chlorophenyl)-1a,7a-dihydro-7(1H)-(4-methylaminobutyloxyimino)cyclopropa[b]chromen [Compound of the general formula (I) wherein A 1 = 4-Cl; A 2 = H; B 1 = 4-Cl; B 2 = H; NR 1 R 2 = NHCH 3 and n = 4] Starting from the compound of Reference Example IV-16, the titled compound was produced in the same manner as the one described in Example 1. The physicochemical data of the compounds produced in the above Examples are given in Table 4. Test Example The compound of the present invention was capable of promoting the extension of nerve dendrites as observed when it was added to a culture cells (NG108-15). Furthermore, it effectively alleviated the defects concerning directional cognition as observed in a model system by performance after the compound had been given to rats suffering from focal resion in the brain, by injection of AF64A into the basal of their forebrain. These effects of the compound of the present invention have been confirmed by the following tests. (1) Effect of Promoting the Extension of Nerve Dendrites Method The effect on the extension of nerve dentrites was examined in accordance with a method reported by Nakagawa et al. [Brain Res., 439 , 11 - 18 (1988)]. A specimen was added to NG108-15 cells which had been cultured in Dulbecco's minimum essential medium (DMEM) containing 5% fetal calf serum at 37°C under 10% CO 2 . Three days later, the extension of nerve dendrites was observed under a phase-contrast microscope. Results Among the test compounds, those produced in Examples 1, 4, 14, 18, 19, 21, 33, 36, 39, 45, 54, 62, 66, 69, 73, 89, 90, 95, 96, 98 and 102 showed an effect of promoting the extension of nerve dendrites when examined at a concentration of from 1 to 15 µM. (2) Effect on Morris's Learning Suppression in Water-Labyrinth in an Animal Model Using Rats Suffering from Focal Resion in the Brain Male rats of Fisher strain weighing 290 to 330 g were used. The focal resion (destruction) in the brain were formed in accordance with a method described in Behav. Brain Res., 19 , 119 - 126 (1988). Training was initiated 1 week after the destruction by using a stainless cylindrical vessel (diameter: 132 cm, depth: 60 cm). On the first day of the training, each test animal was allowed to swim freely for 60 seconds without providing any platforms. From the next day, a labyrinth test was performed for 4 days. On the fifth day, a transfer test was performed for 60 seconds without providing any platform so as to examine whether the animal remembered the location of the platform or not. The test items involved (1) the time required for the animal to reach the platform; (2) the residence time in the quarter circle where the platform had been provided; and (3) the frequency at which the animal crossed the place where the platform had been provided. Results Among the test compounds, those produced in Examples 33 and 45 significantly prevented the aforesaid Morris's learning suppression in water-labyrinth, when administered continuously in a dose of 10 mg/kg. The improvement was confirmed by intraperitoneal as well as oral administration. Formulation Example 1 (capsule) 10 g of the compound of the present invention, 165 g of corn starch, 164 g of crystalline cellulose and 1 g of magnesium stearate were uniformly mixed together and then filled in hard gelatin capsules. Each capsule comprised the following composition. compound of the invention 10 mg corn starch 165 mg crystalline cellulose 164 mg magnesium stearate 1 mg 340 mg Formulation Example 2 (tablet) 1 g of the compound of the present invention, 150 g of lactose, 14 g of corn starch, 4 g of polyvinylpyrrolidone and 2 g of magnesium stearate were uniformly mixed together and formulated into tablets by direct-tableting method. Each tablet comprised the following composition. compound of invention 10 mg lactose 150 mg corn starch 14 mg polyvinylpyrrolidone (K90) 4 mg magnesium stearate 2 mg 180 mg Formulation Example 3 (injection) 1 g of the compound of the present invention and 50 g of mannitol were dissolved in purified water in such a manner as to adjust the total volume to 1000 mℓ. The obtained solution was aseptically filled in glass ampuls. This injection comprised the following composition per ampul. compound of invention 1 mg mannitol 50 mg purified water balance 1 mℓ As described above, the therapeutic agent of the present invention, which promotes the compensatory recovery of the function of a degenerated neuro-circuit, is an epoch-making drug based on a novel conception depending on the plasticity of synapses in the brain nerves and a learning behavior level. The active ingredient of the therapeutic agent of the present invention can be easily and economically synthesized in order to consistently supply commercial products.

Claims: Use of a cyclopropachromen derivative represented by the following general formula (I): wherein n is an integer of from 2 to 5; the carbon atom in the -(CH 2 )n- moiety may be optionally substituted with a methyl group or a hydroxyl group; R 1 and R 2 independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a phenyl group or an aralkyl group having 7 to 10 carbon atoms; or alternatively R 1 and R 2 form together with the nitrogen atom to which they are attached, a morpholino group, a thiomorpholino group, a pyrrolidinyl group, a piperidinyl group, a homopiperidinyl group, a piperazinyl group, a homopiperazinyl group, an N-alkylpiperazinyl group, N-alkylhomopiperazinyl group, an N-hydroxyalkylpiperazinyl group or a pyrrolidonyl group or alternatively R 1 and R 2 form together with the nitrogen atom to which they are attached, and further a carbon atom to which said nitrogen atom is bound, a pyrrolizidinyl group; A 1 and A 2 independently represent a hydrogen atom, a hydroxyl group, a halogen atom, an optionally halogenated alkyl group having 1 to 5 carbon atoms, an optionally substituted alkoxy group, an acyloxy group, a carbamyloxy group or an optionally substituted carboxyl group; and B 1 and B 2 independently represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, an optionally halogenated alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms or an optionally substituted carboxyl group; or a pharmaceutically acceptable salt thereof for making a medicament for the treatment of diseases caused by atrophic nerve cell degeneration in the brain. Use of a cyclopropachromen derivative as claimed in claim 1 wherein R 1 and R 2 both represent a hydrogen atom. Use of a cyclopropachromen derivative as claimed in claim 1 wherein one of R 1 and R 2 represents a hydrogen atom and the other represents an alkyl group having 1 to 5 carbon atoms, a phenyl group or an aralkyl group having 7 to 10 carbon atoms. Use of a cyclopropachromen derivative as claimed in claim 1 wherein R 1 and R 2 independently represent an alkyl group having 1 to 5 carbon atoms, a phenyl group or an aralkyl group having 7 to 10 carbon atoms. Use of a cyclopropachromen derivative as claimed in claim 1 wherein R 1 and R 2 form together with the nitrogen atom, to which they are attached, a morpholino group, a thiomorpholino group, a pyrrolidinyl group, a piperidinyl group, a homopiperidinyl group, a piperazinyl group, a homopiperazinyl group, an N-alkylpiperazinyl group, N-alkylhomopiperazinyl group, an N-hydroxyalkylpiperazinyl group or a pyrrolidonyl group or alternatively R 1 and R 2 form together with the nitrogen atom to which they are attached, and further a carbon atom to which said nitrogen atom is bound, a pyrrolizidinyl group; and A 1 , A 2 , B 1 and B 2 all represent a hydrogen atom. Use of a cyclopropachromen derivative as claimed in claim 1 wherein R 1 and R 2 form together with the nitrogen atom, to which they are attached, a morpholino group, a thiomorpholino group, a pyrrolidinyl group, a piperidinyl group, a homopiperidinyl group, a piperazinyl group, a homopiperazinyl group, an N-alkylpiperazinyl group, N-alkylhomopiperazinyl group, an N-hydroxyalkylpiperazinyl group or a pyrrolidonyl group or alternatively R 1 and R 2 form together with the nitrogen atom to which they are attached, and further a carbon atom to which said nitrogen atom is bound, a pyrrolizidinyl group; and at least one of A 1 , A 2 , B 1 and B 2 represents a meaning other than a hydrogen atom. Use of a cyclopropachromen derivative as claimed in claim 1 wherein A 1 and A 2 both represent a hydrogen atom. Use of a cyclopropachromen derivative as claimed in claim 1 wherein one of A 1 and A 2 represents a hydrogen atom and the other represents a hydroxyl group, a halogen atom, an optionally halogenated alkyl group having 1 to 5 carbon atoms, an optionally substituted alkoxy group, an acyloxy group, a carbamyloxy group or an optionally substituted carboxyl group. Use of a cyclopropachromen derivative as claimed in claim 1 wherein A 1 and A 2 independently represent a hydrogen group, a halogen atom, an optionally halogenated alkyl group having 1 to 5 carbon atoms, an optionally substituted alkoxy group, an acyloxy group, a carbamyloxy group or an optionally substituted carboxyl group. Use of a cyclopropachromen derivative as claimed in claim 1 wherein B 1 and B 2 both represent a hydrogen atom. Use of a cyclopropachromen derivative as claimed in claim 1 wherein one of B 1 and B 2 represents a hydrogen atom and the other represents a halogen atom, a nitro group, a cyano group, an optionally halogenated alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms or an optionally substituted carboxyl group. Use of a cyclopropachromen derivative as claimed in claim 1 wherein B 1 and B 2 independently represent a halogen atom, a nitro group, a cyano group, an optionally halogenated alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms or an optionally substituted carboxyl group.

Inventors: TATSUOKA TOSHIO, NAKAGAWA, YUZO, NAKAMURA, SHIZUO, NOMURA, KAYOKO, TATSUOKA, TOSHIO
Applicants: SUNTORY LTD, SUNTORY LIMITED
Application year: 1991
Main classification: A61K31
IPC codes: A61P25, C07D315, A61K31, C07D311