TW438800B - N-(2-benzothiazolyl)-1-piperidineethanamine derivatives, their preparation and their use in therapy - Google Patents

Abstract

Compounds corresponding to the general formula (I), in which n represents the number 0, 1, 2 or 3, R1 represents a hydrogen or halogen atom or a methyl or methoxy group, R2 represents a hydrogen atom or a methyl group and R3 represents a hydrogen atom or one or two halogen atoms. Use in therapy.

Description

Β ^ ί0,2 7 Β7_Amendment page of the Chinese specification of the application for guaranty application (1989 丨 0) V. Description of the invention (1) Invention scene EP 0184257 ′ EP 0199400 and G. Foscolos et al., &Quot; Synthose et etude pharmacodynamique de nouveaux derives du benzothiazole, " Annales Pharmaceutiques Francaises' Vol. 35, No. 7, July 1997 describes benzopyrazole derivatives. The structure of the compounds disclosed in these three documents is not the same as the structure of the compounds of the present invention 'and no compound has affinity for D4 dopamine reception. The compound of the present invention is equivalent to the compound of general formula (I) (please read the precautions on the back before filling this page)

Ordered by the Ministry of Economic Affairs and the Bureau of Standards, Wci Consumer Cooperatives. «Where * n represents the number 0, 1, 2 or 3, heart represents argon or halogen atom or methyl or methoxy group, R2 represents hydrogen atom or methyl group, And R3 represents a hydrogen atom or 1 or 2 halogen atoms. The compounds of the invention may be in the form of a free base or in the form of an addition salt with an acid. According to the present invention, the compound of the general formula (I) can be prepared according to the method illustrated below. If a compound in which Rz represents an argon atom in the formula is prepared according to FIG. 1, a compound of the general formula (Π) in which R, as defined above, and the formula (melon) chloroacetamidine is similar to the French Chemical Association announcement (Bull Soc. Chim.) (1962) 736-737 -4- This paper uses the national standard of China (CNS) A4 specification (2 丨 0X29? Mm) A7. B7 3 ^ 861 ^ 42¾ patent application Correction page of the Chinese manual (October 89) 5. Description of the invention (2a) „The reaction under the above conditions 'that is, aprotic; cereals' For example: in a dioxin garden, at a temperature of 20 to 100 ° C The obtained amines of the general formula (IV) and the hexamers of the general formula (V) ", as defined above, in the aprotic polar solvent at a temperature of 50 ° C to 80 ° C, such as N, N-dimethylformamide 'and the reaction in the presence of an inorganic base (such as potassium carbonate). The resulting formula (VI) of amidine' is finally passed through a simple or complex reducing agent, such as an alkali metal hydride or other metal Argonization, for example, argonization --------, --- equipment-(Please read the precautions on the back before filling out this page} Order --- Wei

The Ministry of Economic Affairs, the Interim Bureau, Industrial and Consumer Cooperation, Du Yin A 4a This paper size is applicable to China's Jiaxian · (CNS) AH specification (2 丨 OX 297 mm) A7 B7 V. Description of the invention (2) Shed 'Hydrogenated Shed / Tetrachlorofuran' or Nitrogenated Shed / Dimethylpyrene Complex or Aluminum Hydride, in aromatic or ether-based inert solvents such as toluene, dioxane, ether, tetrahydrofuran or dioxolane Depending on the solvent, it is reduced to an amine of the general formula (I, R2 = Η) at a temperature of 30 to 140 ° C. I --------- ¢ ------ ir ------ d, (Please read the notes on the back before filling in this page) Printed by the Central Standard of the Ministry of Economic Affairs and Consumer Cooperatives -5- This paper size applies Chinese National Standard (CNS) Α4 grid (210 X 297 mm) 43 88 Ο Ο A7 B7 V. Description of the invention (3 Figure R ·

m2 (ιΐ) cich2coci (in) R,

NH Cl (IV) .HC1

Rr Booking Travel (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs,

(I. R2 = H) R3 -6- This paper size applies Chinese National Standard (CNS) (21 OX297 mm) Α7 ____ Β7 V. Description of the invention (4) If R · 2 in the formula is a compound of methyl group, Based on Figure 2, a compound of general formula (II), where Ri is as defined above, is a mixture of light and acetic acid, and formic acid, similar to "Tetrahedron Letters (1982) 23 (33) 3315 -3318 and the Journal of Medicinal Chemistry ( J. Med. Chem.) (1966) 9 830-832, that is, in an inert solvent, for example, tetrahydrofuran, at a temperature of 20 to 40 ° C, the resulting N-formamyl intermediate , Followed by reduction according to the instructions of the compound of the general formula (VI), to obtain N-methyl-2 -benzopyrazolamine of the general formula (VI 丨). In addition, hexahydropyridine of the general formula (V), wherein n and r3 is as defined above and reacts with 1-bromo-2-gasethane under standard conditions, that is, in a polar solvent such as N, N-dimethylamidine in the presence of an inorganic base such as potassium carbonate The reaction is performed at a temperature of 50 to 8 ° C. The obtained chlorinated derivative of the general formula (IX) is finally plugged with the general formula (VII) N-methyl-2 -benzo-p Toluidine is reacted in a polar solvent such as N, N-dimethylformamide in the presence of an inorganic base such as potassium carbonate at a temperature of 80 to 100 ° C to obtain a compound of general formula (I '= CH3) ---------- ^ .------ ti ------. 4. •, * (Please read the notes on the back before filling in this I) Central Bureau of Standards, Ministry of Economic Affairs Printed in I paper by Beigong Consumer Cooperative: 逋 '搮 家 ii 公公 A7 B7 V. Description of invention (5) Figure 2

ΓΥ HN, J (CH2) rvv (V) (II)

1) (CH3C0) 20 / HCOgH

Z) UA1H

BrCH2CH2Cl (VIII) 4

Printed by the Central Laboratories Bureau of the Ministry of Economic Affairs and Consumer Cooperatives The starting compounds of general formula (Π) can be purchased on the market. The starting compounds of formula (V) are commercially available or have been described in patent applications EP-01093Π and EP-0524846. The following examples detail the preparation of several compounds among the compounds according to the invention. The structure of the obtained compound was confirmed by a elementary element differential chair and (infrared spectrum) IR and (Gui magnetic resonance) NMR. The compound number shown in parentheses in the title is equivalent to the following table 'No. 0 Example 1 (Compound No. 1) 8- This paper size applies to the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm) ---- ----- # ------ 11 ------ ^--C Please read the notes on the back before filling out this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, A7 __B7_ Description of the invention (6) N- (2-Benzobenzophenytyl) _ 4 -fluorenyl '1-7T ammonia' ^ Ethylamine 1.1. N- (2-benzoxazolyl) -2- Add 15 g (0.1 mol) of 2-benzoxazolamide and 200 ml of dioxolane to a 1-liter round-bottomed flask. Stir the mixture until completely dissolved. Add 11.3 g (0-1 Mol) gas acetonitrile chloride solution mixture was heated on a 50 ° C oil bath for 24 hours. Add 50 ml of dioxolane solution containing 5.6 g (0.05 mol) of acetam gas and continue to heat at 50 ° C overnight. The mixture was cooled, the precipitate was separated by filtration, washed with a little dioxin, then washed with petroleum acid, and dried in the presence of pentoxide 3 to obtain 25.49 g of product, which was used in the next step without further processing. 1.2_ N- (2-Benzamidine petulyl) -4-phenyl-1-hexahydrop-pyridylamine was added with 2.63 g (0.01 mol of 0- (2-phenylhydrazone) ) _2-Acetochloramine hydrochloride, 1.61 g (0.01 mole) of 4-phenylhexahydrone, 2.76 g of potassium oxalate and 80 ml of N, N-dimethylformamide to 50 In a 0 ml round bottom flask, the mixture was heated at 50 ° C for 3 hours and 30 minutes. The mixture was cooled, 160 ml of water was added, and the precipitate was collected by filtration and dried. 3.15 g of product was obtained, which was used without further treatment. In the next step: I.3. N- (2-benzoxazolyl) _4_benzene-yl_ 丨 _hexahydropyridineethylamine was added with 430 mg (0.0112 mol) of lithium aluminum hydride and 6〇. Tetrahydrofuran (500 ml) was placed in a 500 ml round-bottomed flask, and the supernatant was heated to reflux. Add 2 g (0.0056 mol) of N_ (2_benzene 弁 ρ 塞 also 卜 4_phenylpentachlorochloretamine acetamide. (30 milliliters of tetrahydrofuran solution, and keep heating for another 15 minutes. -9- 私 纸张 新 纠 tit 目 家 鲜 ^^-1T ------. # ≫. (Please first After reading the notes on the back, please fill in this S ··) Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs« 43 8 005. Description of the invention (The mixture is cooled, 56 ml of ethyl acetate and 22 ml of water are added, the layers are separated after precipitation, the solvent is evaporated under reduced pressure, and the oily residue is dried under reduced pressure. 2.48 g of crude The product was purified by silica gel column chromatography and extracted with a mixture of 9: i digas and methanol to obtain 16 g of a light yellow oil, which will crystallize from 2-propanol and dry under reduced pressure. 〇8 丨 Melting point of the compound: 140-141 X. Example 2 (Compound No. 3) N- (2-Benzobenzoyl) -4-((4-Benzylphenyl) methyl] _1_hexahydro Ethylamine oxalate, 2'1 · N- (2-benzoxazolyl) -4-[(4-fluorophenyl) methyl] -1-hexahydropyridineacetamide. Add 2.26 g (0.00S6 mole) of N- (2-benzopyrazolyl) -2-chloroacetamidine hydrochloride, 2.29 g (0.01 mole) of 4 · [(4-fluorophenyl) fluorenyl] Hexahydropyridine hydrochloride, 4.14 g (0.03 mol) of potassium carbonate and 80 ml of N, N-dimethylformamide in a 500 ml round bottom flask, and the mixture was heated to 50 ° C for 2 hours and 30 minutes. Allow the mixture to cool, add 240 milliliters of water, mix The product was cooled in a water bath, and the white precipitate was collected by filtration, washed thoroughly with water, and dried in the presence of phosphorus pentoxide. 2.9 g of the product was obtained, which was recrystallized and dried from 30 ml of ethanol to obtain 2.42 g of the compound. -10- Paper Applicable Chinese National Standard (CNS) A4 standard (210 X 297 mm) ---------- ^ ------ 1T ------ ^ (Please read the note on the back first Please fill in this page again for the matter) ΒΔ3 38 0 Printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (8) Melting point: 141-142 * C. 2.2. N- (2-benzopyrazolyl) -4-[(4-fluorophenyl) methyl] hexachloropyridineethylamine ethylene diacetate. Take 1.3 g (0.0034 9 mol) of N-(2-benzoxazolyl) _ 4-[(4-fluorophenyl) methyl] -1-hexahydropyridineacetamide, and dissolve in 25 ml of anhydrous tetrahydrofuran In a 250 ml three-necked round bottom flask under nitrogen, 109 ml, that is, 3 equivalents of a borane / dimethylsulfide complex was added, and the mixture was heated to reflux for four hours. The mixture was cooled to room temperature, a mixture of 53 ml of 2 N hydrochloric acid and 25 ml of methanol was added, and the mixture was heated to reflux again for hr 30 minutes' and allowed to stand overnight. Concentrated sodium hydroxide was added to the mixture until the acid and base were alkaline, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with water, dehydrated with sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. 1.6 g of oily product was found, purified by column chromatography with Huan gum, and washed with a mixture of methane and methanol. 0.83 g of an opaque oil was obtained. This oil was dissolved in propanol containing 1 equivalent of oxalic acid. After recrystallization, filtration and drying, 0.73 g of the character was finally isolated. Melting point: 155-156 ° C. Example 3 (Compound No. 4) — N- (2-benzoxanthenyl) -N-methyl-4- (benzylhexahydropyridineamine oxalate. 3.1. N-methyl- 2-Benzamazolamide was added to 10.2 ml of glacial acetic acid into a round-bottomed flask, and the mixture was added dropwise with 4 3 mmol-11.-This paper uses China National Standard (CNS) Α4 (2 丨 0X297 mm) (Please read the note on the back before filling out this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 _____ B7 V. Description of the invention (9) Formic acid, then heat the mixture to 50 ° C for 2 hours. The mixture was cooled to room temperature, 10 ml of anhydrous tetrahydrofuran was added, and then 11.25 g (0.075 mol) of 2-benzo, sedazolamide dissolved in 30 ml of anhydrous tetrahydrofuran was added dropwise, and the temperature was not allowed to exceed 40 Ό The mixture was allowed to stand for 2 days. The solvent was evaporated under reduced pressure, the crystalline residue was washed twice with petroleum ether, and dried in the presence of phosphorus pentoxide. 13 g of N- (2-benzothiazolyl) formamide are obtained. Prepare a suspension of 0.854 g (0.0224 moles) of aluminum hydride in 50 ml of tetrahydrofuran, heat to reflux, add 100 ml of tetrahydrofuran solution containing 2 g (0.0112 moles) of formamidine intermediate, and continue heating 30 minutes. The mixture was cooled, 100 ml of ethyl acetate was added, 38 ml of water was added dropwise, and after settling, the organic layer was separated and evaporated under reduced pressure. The crystalline residue was triturated in petroleum ether, filtered, and dried in the presence of phosphorus pentoxide. 1.5 g of compound are obtained. 3.2. 1- (2-chloroethyl) -4- (benzyl) hexahydropyridine will be dissolved in 50 ml of Ν, Ν-dimethylformamide 3.5 g (0.02 mole) 4- (Benzyl) hexahydropyridine was added to a round-bottomed flask, and 2 86 g (002 mol) of 1-bromo-2-chloroethion and 2.76 g (0.02 mol) of potassium carbonate were added. The mixture was vigorously stirred at room temperature. Stir for 1 hour. The mixture was poured into 250 ml of ice-water and extracted twice with 150 ml of ethyl acetate. The organic layer was washed with physiological saline, and the solvent was evaporated under reduced pressure. 7 g of product was obtained, purified by silica gel column chromatography, and extracted with ethyl acetate. 2.1 g of purified product was obtained as an oil. 3.3. Ν- (2-Benzylpyrazolyl) _Ν-methyl-4- (benzyl) _ 丨 _hexahydropyridine-12- This paper size applies to China National Standards (CNS) M specifications ( 210X297 mm) ί Please read the precautions on the back before filling out this page) Binding · Binding = 43 88 〇〇Α7 Β7 Central Industry Bureau, Ministry of Economic Affairs, Industrial and Consumer Cooperation, Du Print 13 V. Description of the invention (1〇 Dibasic acid salt: Take 1 g (0.004221 mole) of 1- (2-gasethyl) -4- (benzyl) hexahydropyridine and place it in 25 ml of N, N-dimethylformamide. 0,7 g (0.00426 mol) of N-fluorenylbenzothiazolamide and 0.8 g of potassium carbonate were added, and the mixture was heated to 100 ° C for 1 hour. Cool in a water bath and add 50 ml of water to 100%. The mixture was extracted twice with ml of ethyl acetate, and the organic layer was washed with physiological saline and evaporated. The oily residue was purified by column chromatography on a broken gel column, and purified twice in succession. 〇: 10 The mixture was eluted, and the second time with ethyl acetate. 0.3 g of compound was obtained, and 01 g was taken out to form oxalate in ethanol. Melting point: 164-166 ° C. Example 4 (Compound No. 11) N- (2-benzoxazolyl) · 4- [2- (4-fluorophenyl) ethyl] hexahydropyridine ethylamine. 4.1 · Ν- (2-benzo Oxazolyl). 4_ [2- (4_fluorophenyl) ethyl] -ι-hexahydropyridineacetamidoamine 2.63 g (0.01 mol) of ^ (2_benzoxazolyl) acetamidine Hydrochloride, 2.44 g (0.01 mole) 4] 2- (4: fluorophenyl) ethyl) hexahydropyridine hydrochloride, 4.14 g (0.03 mole) potassium carbonate, and 80 ml of Ν, Ν-dimethylamidamine was added to a milliliter round bottom flask, and the mixture was heated to 50 ° C for 3 hours and 30 minutes. It was allowed to cool, 240 ml of water was added, and the mixture was extracted with 300 ml of ethyl acetate. The organic layer was washed with water and then saturated with gasification #] solution, washed, and this paper was prepared by CNS (CNS) (21G > < 297) ^ ------ ΐτ ------. 41 •-(谙 Please read the notes on the back before filling this page) 4 .ο ~ — * '3 A7 --------- B7 Five' invention description (11) Dehydrate with sodium sulfate, filter, and decompress The filtrate was evaporated. A brown oily product was obtained and used in the next step without further processing. (Please read the note ^^ on the back before filling this page) 4.2 · N- (2_benzoxazolyl) _4_ [ 2- (4-fluorophenyl) ethyl] -i-hexahydropyridineethylamine 'under nitrogen was added with 0.96 g (0.025 mole) of lithium aluminum hydride and 14 ml of anhydrous tetrahydroanhydrone to 500 ml In a three-necked round-bottomed flask, the suspension was heated to reflux and added dropwise to a solution of 60 g of anhydrous tetrahydrofuran in gram (0.01 mol) N _ (2-benzylPsethyl) _4_ [2 · (4_ Fluorophenyl) ethyl]. Hexahydropyridine. Continue heating for 30 minutes. Cool the mixture and add 14 ml of ethyl acetate and 51 ml of water. Separate the organic layer and reduce it to evaporation. Analyze and purify the residue with digas methane methanol 9: 1 mixture. 3 得到 6 grams of oil will be crystallized. Recrystallize it from a mixture of ethanol and water, and dry it under reduced pressure to isolate 23 grams of compounds. Melting point: 107-108 X :. Printed by the Ministry of Economic Affairs, Central Standards Bureau, Consumers Cooperative The following table illustrates the chemical structure and physical properties of some compounds according to the present invention. In the "Salts" column, "" indicates that the compound is in a basic state, and "〇χ" indicates oxalic acid or oxalic acid salt, and 11 fum ”Means fumaric acid or (Ε) _ 2 _ butenedioate. The acid / alkali mol ratio is shown in brackets. -14-This paper size applies to China National Standards (CNS) A4 (210x297) ) A7 B7 V. Description of the invention (12) Table _

Printed by Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs η __ Rn Melting point of salt (...) 1 0 Η Η Η-140-141 2 1 Η -Η Η Οχ, {1.05: 1) 141-142 οχ. (1: 1) 155-156 3 1 Η Η 4-F, fum. (1.2: 1) 150-151 4 1 Η ch3 Η οχ. (1.15: 1) 164-166 5 1 Η ch3 4-F fum. (1.9: 1) 137-140 6 1 6-C1 Η 4-F-118-119 7 1 6-CH3 Η 4-F-148-149 8 X 6-OCH3 Η Η-123-124 9 1 6-OCH3 Η 4-F-107-108 10 2 Η Η 〇〇. (2: 1) 189-190 11 2 Η Η 4-F 107-108 12 2 6-OCH3 Η Κ-129-130 13 3 Η Η Η ϋ οχ. (2: 1) 179-ISO 14 2 Η Η 2-F f um. (1: 2) 159-160 15 2 Η Κ 3-F f um. (1: 2) 168-169 16 2 Η Η 2,4-Ρ fum. (2: 1) 15G-153 17 2 Η Η 3,4-F f um. (1.2: 1) 100-138 18 2 Η Η 3,5-F fum. (1: 2 ) 158-159 Binding ------ Line-^-(Please read the notes on the back before filling in this X ·) -15- This paper size applies to China National Standard (CNS) A4M (210X297mm) Ministry of Economic Affairs A7 printed by the Consumer Standards Cooperative of the Central Bureau of Standards _____B7 _ V. Description of Invention (13) Invented by the invention The test substance which is displayed as a monovalent Zhi of medical active. Therefore, it is similar to the method described by Stroke (1989) 20 84-91. In rats, the intraluminal closure of the cerebral arteries causes a permanent ischemic lesion pattern, to explore | Under methohexitcme sodium anesthesia, the pterygoid was connected to the 'arterial carotid artery' and the left lateral carotid artery, and the polyamide line was introduced into the medial carotid artery approximately 18 mm in length, which is equivalent to the medial carotid Distance from the starting point to the middle cerebral artery. Test compounds are administered intravenously after closure. Twenty-four hours after the middle cerebral artery was closed, the animals were killed and the brain was removed. Cerebral infarct volume was measured by vaporizing 2,3,5-triphenyltetrazole radium salt on six coronal sites in the necrotic area. For example, compound No. 11 in the table above, after 10 minutes of closure, 1 hour and 30 minutes, 3 hours, and 6 hours, can significantly reduce the infarct volume by about 1% when administered intravenously at a dose of 1 mg / kg. The compounds of the present invention were also subjected to a spheroid brain ischemia test in mice. A rapid intravenous injection of magnesium carbide causes cardiac arrest and ischemia. In this test, "survival time" was measured as the time interval from the injection of magnesium chloride to the last observed breathing movement of each mouse. This last movement was considered to be the last function of the central nervous system, the IT number. After about 19 seconds of magnesium, breathing will stop. A group of 10 male rats (Charles River CD 1) will be studied. Free drinking water and ingestion of the compound of the present invention by intraperitoneal administration will be allowed for 10 minutes before the test. The survival time was measured. The result was a group of 10 that accepted the compound-16- This paper is scaled to the Chinese National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling out this page ). Pack. Order 〇〇A7 B7 Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, V. Invention Description (14) The difference in survival time between a rat and a group of 10 mice that received the carrier liquid is shown. Record The relationship between the change in survival time and the dose of the compound is drawn from a semi-logarithmic curve. From this curve, the "three-second effective dose · _ (ED3)" can be calculated, that is, relative to 10 The control group of mice increased the dose (mg / kg) at the survival time of 3 seconds. Increasing the survival time of 3 seconds was statistically significant and reproducible. Most of the active compounds of the present invention passed the intraperitoneal route of ED3 Both are below 5 mg / kg. The compounds according to the present invention are substantially as described by Van Tol. Et al., Nature (1991) 350 610-614 and Van Tol et al., Nature (1992) 358 149-152 Methods: An in-tube test was performed, which transfected the human D4.4 receptor into CHO cells to investigate the affinity of the compound for the D4 dopamine-stimulated receptors obtained. On the day of the experiment, samples were stored at minus 80 ° C. Cell membrane specimens (Receptor Biology, Inc., (Glen Echo, MD 20812, USA)), quickly thawed, and then culture buffer (50 mM Tris-HCl, 120 mM NaCl, 5 mM KC1) at 20 times the volume , 2mM CaCl2j 5mM MgCl2 5 ^ Alkaline 7.5) diluted. Cell membrane suspension (100 μl, 78 μg cell membrane) in a final volume of 1 ml of culture buffer containing 0.5 nM [4] spiperone (specific activity 17 To 20 Ci / mmol, New England / (New England Nuclear / de Nemours, Boston, MA, USA) and with or without test compounds, incubate at 25 ° C for 60 minutes. Use Walter previously treated with polyethyleneimine (0.5%)曼 （Whatman) -17- This paper is a fast-moving Chinese national standard ((^ 5) is 4 ^ 1 ^ (210 乂 297mm) ------_--- ^ ------ 1T ------ ^ (Please read and read the notes on the back before filling in this page) Printed by A7 __B7, A7 __B7 by the Ministry of Economic Affairs, Central Standards Bureau, V. Invention Description (15) GF / B® filtration, End cultivation. Each reaction tube was washed three times with 3 ml of Tris-NaCl buffer solution (50, 001, 1,2, and 11 (: 1, 120, 011, 仏 (: 1, acid test 7 .: 5)). The filter paper was in an oven Dry at 120 ° C for 5 minutes. Use a liquid scintillation counter to measure the radioactivity remaining on the filter paper. Determine non-specific binding in the presence of 1 μM haloperidol. Calculate the concentration of each test compound The percentage inhibition of [3H] spiperone specific binding, and then determine the ICw, that is, the concentration at which the binding is inhibited by 50 0/0. The ICh of the compound of the present invention is 3 to 30 nM. The test results show that ' In vivo, the compounds according to the invention have neuroprotective properties. 'In a test tube, they can replace the specific binding of [3H] spiperone to human dopamine-stimulating receptors. Therefore,' they can be used on the one hand Treatment and prevention of cerebrovascular diseases at ischemia or hypoxia (cerebral infarction, traumatic brain or nerve cord trauma, cardiac or respiratory arrest, transient ischemic attack 'perinatal asphyxia), glaucoma, progressive neurodegeneration (senile dementia Alzheimer's Vascular dementia, Parkinson's disease, U-Tydenton's disease, pontine cerebellar atrophy, amyotrophic lateral sclerosis, virus-induced neurodegeneration, and similar conditions), and can prevent heart and blood Accidents related to brain ischemia related to official surgery or endovascular therapy. In addition-can be used to treat mental illness, such as schizophrenia (insufficient and steep forms) and caused by sedatives or by Parkinson's disease Acute and chronic extrapyramidal symptoms, which can be used to treat various forms of anxiety, painful sending, panic, obsessive-compulsive disorder, can treat different forms of depression, including mental depression, can treat narcotic and alcoholic slander The upper -18- scale scale frontal scale {CNS) --- < Please read the precautions on the back before filling out this page) A7 B7 V. Description of the invention (hypoxia) and abnormal hypothalamus hypothalamus function, And treatment of cognitive abnormalities related to age or Alzheimer's disease. For this purpose, they can be combined with appropriate excipients. Q's King's various dosage forms are 'for enteral, parenteral, or transdermal administration, for example, in the form of tablets, dragees, capsules (including Hard Ming Capsules) 'solution or suspension, for oral administration, or for injection, suppository, patch and the like, which contains a dose of 1 to 500 mg of active substance per day. -; --- ¾ ------ ΤΓ ------ ^ ί #Read the precautions on the back first and then fill out this page. Using the Chinese National Standard (CNS) A4 specification (210X25 »7 mm) Patent Application No. 8 6114229 ---- Chinese Supplementary Specification (October 89) Example n {Crn mg / kg Intravenous injection of D4, Clg. , ΠM 1 10 3 1.5 10 5 1.48 480 6 0,44 40 7 0.86 30 8 70 9 70 10 0.1 10 11 1 10 12 0.13 40 13 10 14 40 15 10 16 40 17 10 18 10

Claims (1)

Patent Application No. 86Π4229 Chinese Patent Application Scope Amendment (March 90) ABC Patent application scope A compound of general formula (I) (I) where η is the number 0, 1, 2 or 3, Rt is hydrogen or _ atom or methyl or methoxy, R2 is hydrogen atom or methyl, R3 is hydrogen atom or 1 or 2 fluorene atom, It is in the state of free base or forms an addition salt with acid. 2. A method for preparing a compound according to item 1 of the scope of the patent application is characterized in that: a compound of 112 in the formula is represented by a hydrogen atom, which is composed of a compound of general formula (Π) and a binding line (please read the precautions on the back first) Refill this f) Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (II) where R! Is defined in item 1 of the scope of the patent application, and reacts with gas and gas to obtain the general formula (IV) amidine. This paper size applies to China National Standard (CNS) A4 (210X297 mm) » = 4 3 88 0 0 A8 B8 C8 D «Application scope NH Cl .HC1 (IV) which reacts with hexahydropyridine of general formula (V) (CH; Rr (V) where n and R3 are as defined in item 1 of the scope of the patent application, and the general formula (VI) amines are obtained, printed by the Shellfish Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs It is finally reduced to the general formula (I, R2 = H) amine-2- This paper size is in Chinese National Standard (CNS) A4 format (210X297 mm) I Packing.. Order the n line (please read the first Please fill in this page again for attention) (VI) η Α8 Β8 CS D8 VI Patent application scope U, R2 = H) i Alternatively, when preparing a compound in which R2 represents a methyl group, a compound of general formula (Π) Among them, R! Is as defined in the scope of the first patent application. First, it is reacted with a mixture of acetic anhydride and formic acid, and the obtained N · methylfluorenyl intermediate is subsequently reduced to obtain the general formula (W) N_methyl-2-benzene. Pyrimazolid, 1 I nn I n--mnnn I n _ T 1 I --- I n -.- i (Please read the note on the reverse side first and then fill out this page) Central Bureau of Standards, Ministry of Economic Affairs Industy Consumer Cooperative -3- ^ Paper ruler ztii Cai 0® Family rate (CNS) A4 (210X297 mm) Application scope of patent A8 B8 C8 D8 and, in addition, by the general formula (v) hexahydropyridine, (CH2) i rr HN , '' (V) where n and R3 are as defined in item 1 of the scope of the patent application, and reacted with 1-brook-2-gas ethane to obtain a chlorinated derivative of the general formula (K), (IX) It is finally reacted with the general formula (vn) N -methyl-2 -benzoxazolid to obtain the compound of the general formula (I, R2 = CH3). (I, 3. A pharmaceutical composition having D 4 dopamine receptor affinity, which comprises a compound according to item 1 or 2 of the patent application, combined with an excipient. 4. According to item 3 of the patent application, Pharmaceutical composition for treatment and " 4-This paper size applies to the Chinese national standard (CNS > A4 size (210X297 mm) --------- ^ ------ ΐτ- -----.il (Please read the notes on the back before filling this page) 'Scope of patent application: Central Standards Bureau, Ministry of Economic Affairs, Shellfish Consumer Cooperative, India Ben Ben, Prevents cerebral vascular disease and glaucoma at ischemia or hypoxia' Progressive neurodegeneration, prevention of brain related to heart and vascular surgery or endovascular therapy Ischemic accident. 5. The pharmaceutical composition according to item 4 of the scope of the patent application, wherein the cerebrovascular disease is cerebral infarction, trauma of the skull or nerve cord, cardiac or respiratory arrest, transient ischemic attack, and perinatal asphyxia. 6. The pharmaceutical composition according to item 4 of the scope of patent application, wherein the progressive neurodegenerative disease is senile dementia, such as Alzheimer's disease, vascular travel dementia, Parkinson's disease, Huntington's disease, olive body Cerebellar atrophy, amyotrophic lateral sclerosis, virus-induced neurodegeneration and similar conditions. 7 _Pharmaceutical composition according to item 3 of the scope of patent application, for the treatment of mental illness, especially schizophrenia (insufficient and productive forms) and acute and chronic extrapyramidal symptoms caused by sedatives or by Parkinson's disease , Various forms of anxiety, painful sending, panic, obsessive-compulsive disorder, different forms of depression (including mental depression), narcotic and alcohol-induced addiction and hypothalamus subglandular abnormalities and age Or cognitive abnormalities related to Alzheimer's. The size of this paper is in accordance with Chinese National Standard (CNS) A4 Washing (210X ^ 7mm) ^ --- JIIIII II 1 Order I! I line (please read the precautions on the back before filling this page) Application date 86.9.30 Case No. 86114229 Category (the above palms are filled by the Bureau) Invention name 433800 A4 C4 Chinese specification amendment page (June 89) | Dance | Patent Specification I Ν · (2-benzopyrazolyl ) -1-hexahydropyridineethylamine derivative, its preparation and | its therapeutic use, ilN- (2-BENZOTHTAZOLYL) -1-PIPERIDINEETHANAMNE * DERIVATIVES, THEIR PREPARATION AND THEIR USE IN THERAPY "^, Invention— 、 Creator 1. Jihada Gejanli Name I 2. Baska George 3. Bartrak Laudnos 4. Jonathan Frost Nationality 1.3.6.7, both France 2. Belgium 4. United Kingdom 5. The Netherlands 1. No. 13 Chiflicorol Road, Harreiros, France, 4 Residence, Residence 2 'No. 19 Quetzingwenz Road, Saint-Anoyevlin, France 3. Valencia Road, Berglarion, France No. 18 4. No. 12 Bac Road, Vesso, France 5. No. 80 Lananty Lane, Givisoyet, France 6. No.8 Domanson Road, Inham-le-Ban, France. No. 〇0, Leclerc District Road, Chilimazarin City. 5. Joan Scocomark 6. Marie-Carmeneros 7. Binding of Bascamaguette Applicant's name (name) Nationality, residence (office) Representative name French merchant Shaunofe-Sintra Rabao Company Paris, France, 174th Avenue Elisabeth Sommer_Lemmett Line ^ ί 0,2 7 Β7_ Chinese Version Correction Sheet for the Application for Preserving Cavernous Applications (Year 89 / October) V. Description of the Invention (1) Invention Landscape EP 0184257 ′ EP 0199400 and G. Foscolos et al., " Synth0se et etude pharmacodynamique de nouveaux derives du benzothiazole, " Annales Pharmaceutiques Francaises' Vol. 35, No. 7, July 1997 describes benzopyrazole derivatives. The structures of the compounds disclosed in these three documents are not the same as the compounds of the present invention. 'No compound has an affinity for D4 dopamine reception. The compound of the present invention is equivalent to the compound of general formula (I) (please read the precautions on the back before filling this page) Ordered by the Ministry of Economic Affairs and the Bureau of Standards, Wci Consumer Cooperatives. «Where * n represents the number 0, 1, 2 or 3, heart represents argon or halogen atom or methyl or methoxy group, R2 represents hydrogen atom or methyl group, And R3 represents a hydrogen atom or 1 or 2 halogen atoms. The compounds of the invention may be in the form of a free base or in the form of an addition salt with an acid. According to the present invention, the compound of the general formula (I) can be prepared according to the method illustrated below. If a compound in which Rz represents an argon atom in the formula is prepared according to FIG. 1, a compound of the general formula (Π) in which R, as defined above, and the formula (melon) chloroacetamidine is similar to the French Chemical Association announcement (Bull Soc. Chim.) (1962) 736-737 -4- This paper uses the national standard of China (CNS) A4 specification (2 丨 0X29? Mm) A7. B7 3 ^ 861 ^ 42¾ patent application Correction page of the Chinese manual (October 89) 5. Description of the invention (2a) „The reaction under the above conditions 'that is, aprotic; cereals' For example: in a dioxin garden, at a temperature of 20 to 100 ° C The obtained amines of the general formula (IV) and the hexamers of the general formula (V) ", as defined above, in the aprotic polar solvent at a temperature of 50 ° C to 80 ° C, such as N, N-dimethylformamide 'and the reaction in the presence of an inorganic base (such as potassium carbonate). The resulting formula (VI) of amidine' is finally passed through a simple or complex reducing agent, such as an alkali metal hydride or other metal Argonization, for example, in argonization --------, --- equipment-(Please read the precautions on the back before filling this page} Order --- Wei Jing The Ministry of Industry and Commerce, Industrial and Commercial Cooperation, Du Yin A 4a The paper size is applicable to China's Jiaxian · (CNS) AH Specification (2 丨 OX 297mm) Patent Application No. 8114114 ----- -Chinese Supplementary Manual (October 1989) Example n {Crn mg / kg, D4, Clg., ΠM 1 10 3 1.5 10 5 1.48 480 6 0,44 40 7 0.86 30 8 70 9 70 10 0.1 10 11 1 10 12 0.13 40 13 10 14 40 15 10 16 40 17 10 18 10 Patent Application No. 86Π4229 Chinese Patent Application Amendment (March 90) ABC Patent application scope A compound of general formula (I) (I) where η is the number 0, 1, 2 or 3, Rt is hydrogen or _ atom or methyl or methoxy, R2 is hydrogen atom or methyl, R3 is hydrogen atom or 1 or 2 fluorene atom, It is in the state of free base or forms an addition salt with acid. 2. A method for preparing a compound according to item 1 of the scope of the patent application is characterized in that: a compound of 112 in the formula is represented by a hydrogen atom, which is composed of a compound of general formula (Π) and a binding line (please read the precautions on the back first) Refill this f) Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (II) where R! Is defined in item 1 of the scope of patent application, and reacts with gas and gas to obtain the general formula (IV) pyramine. This paper size applies to China National Standard (CNS) A4 (210X297 mm)