HK1014945B - 2-aminoindan compounds, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Description

2-amino-1, 2-indane compound, preparation method and pharmaceutical composition thereof

The present invention relates to a novel 2-amino-1, 2-indane compound, a process for the preparation thereof and a pharmaceutical composition comprising such a compound.

In particular, the present invention relates to 2-amino-1, 2-indane compounds represented by the following formula I, in the form of a racemic mixture or in the form of an optical isomer, and to physiologically tolerable acid addition salts thereof:in the formula: -n is 1 or 2; -Ar is:(wherein X is a hydrogen or fluorine atom)R is a hydrogen atom, linear or branched (C)₁-C₅) Alkyl or aralkyl; - -E is a hydrogen atom or a methyl group, and- -X₁，、X₂、X₃And X₄May be the same or different and each represents a hydrogen atom or a halogen atom, a straight chain or a branched chain (C)₁-C₅) Alkyl or (C)₁-C₅) Alkoxy, trifluoromethyl, hydroxy, cyano or nitro radicals, or radicalsWherein: r₁、R₂And R₃May be the same or different and each represents a hydrogen atom or a straight chain or branched chain (C)₁-C₅) Alkyl, and R₄Is straight-chain or branched (C)₁-C₅) Alkyl, and/or two X's adjacent to each other form, together with the carbon atom of the benzene ring to which they are attached, a 5-or 6-membered ring consisting of atoms selected from carbon atoms, oxygen atoms, nitrogen atoms and sulfur atoms.

The products of the invention can be used for the treatment of diseases which have been identified as being associated with the 5-hydroxytryptamine energy system, such as: psychosis such as depression, anxiety, phobia, schizophrenia, aggression, impulsiveness, obsessive-compulsive disorder, etc.; degenerative diseases such as Parkinson's disease and Alzheimer's disease; pain, migraine, headache, accidental injury of cerebral vessels, hyperphagia, anorexia and drug abuse, as well as the central nervous system,the cardiovascular region also presents a 5-hydroxytryptamine-competent system and can therefore also be used as a drug for the treatment of cardiovascular diseases (unstable angina). Many serotonin receptors have been identified and have recently been cloned. These receptors have been classified as 5HT according to their primary structure and mode of linkage to transduction systems₁--5HT₇Seven major classes (see: f.g. boess, molecular biology of the 5-hydroxytryptamine receptor, neuropharmacol, 1994, 33, 275). These classes are themselves divided into subtypes. Known subtype 5HT_1A、5HT_1B(formerly 5 HT)_1Dβ) And 5HT_1D(formerly 5 HT)_1Dα) Is 5HT₁The receptor subtype (see: R.P.Hartig, Trends in Pharmacol. sciences.1996.17.103 for recent comments and discussion on this nomenclature).

Since the product of the invention is 5HT_1BPotent and selective ligands for receptors, the present application is therefore directed in particular to 5HT_1BA receptor. 5HT_1BReceptors are located in the brain area postsynaptic and peripheral sympathetic nerve terminals, cerebral vessels, and trigeminal primary afferents (g.j. moldering, nauyn-Schmiedeberg's arch. pharmacol., 1990.342, 371; e.hamel, mol.pharmacol., 1993, 44, 242; a.t.bruinells, eur.j.pharmacol., 1992, 227, 375). The location of the receptors means that it is possible to treat migraine and headache with agonists via vascular and neurogenic effects by activating the 5HT1B receptor population. It is possible to treat diseases of the cardiovascular system, such as unstable angina, with antagonists by acting on peripheral receptors. In addition, 5HT, also present in high concentrations in the dorsal horn of the spinal cord, basal ganglia, hippocampus and other frontal cortex limbic structures_1BReceptor populations (c.del Arco, nauyn-Schmiedeberg' sarch. pharmacol., 1992, 347, 248; s.lowther, eur.j. pharmacol., 1992, 222, 137; X Langlois, j.neurohem, 1995, 65, 2671) can cause mood and behavior disorders in part and may be associated with nociceptive mechanisms. Based on the two positions of the receptors (on the one hand on postsynaptic 5-hydroxytryptamine neurons and on the other hand on the cell body as autoreceptors), it can be easily concluded that they are involved in pathogenesis, and that selective ligands for these receptors are therefore usefulTreatment of depression, anxiety, impulsive diseases and other neurological disorders associated with dysfunction in 5-hydroxytryptamine transport (C.Waeber, neurohem. Res., 1990, 15, 567; K.Herrick-Davis, J.neurohem., 1988, 51, 1906).

In respect of 5HT_1B(formerly-5 HT)_1Dβ) For receptors, the central nervous system is mainly in humans and guinea pigs. Furthermore, only 5HT_1BIs an autoreceptor, and 5HT_1D(formerly 5 HT)_1Dα) The acceptor is not. 5HT is described in WO96/00720 and WO 96/12713 patent applications_1B/5HT_1DReceptor ligands: they are naphthalene piperazine compounds. WO 96/19477 patent application describes 5HT having a biphenyl structure_1B/5HT_1DA receptor antagonist. The compounds of the present invention are not derived at all from these structures. The use of compounds having the 4-aminopiperidine structure for the treatment of central nervous system disorders is described in the patent application WO 95/07274. In this compound formula, the exocyclic nitrogen is attached to the benzodioxan, tetrahydronaphthalene and chroman ring through an alkane. These structures do not lead to the structures of the compounds of the invention.

The activity of the products of the invention has been demonstrated in a number of biological and pharmacological tests in the pharmacological studies disclosed in example 30 below.

Can be tested by binding, in particular with 5HT_1AComparison of receptors to assess 5HT in vitro_1BSelectivity of the receptor.

The agonist or antagonist properties of the products of the invention can be determined by means of low temperature experiments (m.sting et al j.of psychopharmacology, 1994, 8, 14) performed in guinea pigs.

The micro dialysis experiments prove that the product has value in treating various central nervous system diseases. In case the product is able to increase the release of serotonin, it is then possible to observe its use for the treatment of depression, impulsive diseases and obesity by frontal cortex experiments. If they can reduce the release of serotonin, they are beneficial for the treatment of anxiety disorders, phobias, cognitive problems and drug abuse problems. The last point is that they are beneficial for the treatment of schizophrenia if they can increase dopamine and/or norepinephrine, and for the treatment of depression and cognitive problems, as described above.

The invention also relates to pharmaceutical compositions containing as active ingredient a compound of formula I or a physiologically tolerable salt thereof, in admixture with or containing one or more suitable pharmaceutical excipients.

The compositions thus obtained are generally presented in a dosage form containing 0.5-25mg of active ingredient. They may be, for example, tablets, dragees, gelatin capsules, suppositories or injectable or drinkable solutions and the like, and may be administered orally, rectally or parenterally, depending on the dosage form used.

The specific dose depends on the age and weight of the patient, the route of administration and the relevant treatment, and is generally 0.5-25mg/1-3 times/day.

The invention also relates to a process for the preparation of compounds of formula I, characterized in that: reacting a compound of formula IIWherein X₁、X₂、X₃And X₄Is as defined above and L is a labile group, e.g. -OSO₂CH₃，-OSO₂CF₃， Or a halogen atom selected from chlorine, bromine and iodine atoms, with a compound of formula III:wherein R, E, n and Ar are as defined above; the reaction is preferably carried out in a solvent such as methyl isobutyl ketone, in the presence of an alkali metal carbonate such as sodium or potassium carbonate, or in toluene in the presence of triethylamine; or, in the presence of sodium borohydride in tetrahydrofuran or in the presence of sodium triacetoxyborohydride in dichloroethane, by reductive amination of the compound IV with the compound III defined above,x in IV₁、X₂、X₃And X₄The definition of (1) is as before; or, when E is exclusively a hydrogen atom, subjecting compound V and compound VI, wherein n and Ar have the same meanings as those described above, to reductive amination in tetrahydrofuran in the presence of sodium borohydride or in dichloroethane in the presence of sodium triacetoxyborohydride to give the following compound I'V, in the step (A): x₁、X₂、X₃、X₄And R is as defined above,in I': x₁、X₂、X₃、X₄R, Ar and n are as defined above, (compound I' is a subgroup of compound I); - - (Y- -O) - -or, finally, when Ar isReacting compound VII with compound VIII in a solvent such as pyridine by heating to obtain compound II ",in VII:

hal is a halogen atom selected from chlorine, bromine and iodine,in VIII:

X₁、X₂、X₃、X₄r, E and n are as defined above,in I': x₁、X₂、X₃、X₄R, E and n are as defined above, (Compound I "is another subgroup of Compound I); and when X is present₁、X₂、X₃And X₄When one or more of the substituents is hydroxy, X₁、X₂、X₃And X₄The compounds of formula I as defined above in which one or more of the substituents is hydroxy can be prepared by reacting a compound of formula I as defined above,prepared by treating the corresponding methoxy compound with pyridine hydrochloride; furthermore, when the compounds I contain one or more asymmetric carbon atoms, if desired, their optical isomers can be prepared by conventional resolution methods described in the literature.

Optical isomers can also be prepared from optically active starting materials.

Salts of the compounds of formula I with pharmaceutically acceptable acids may be prepared according to conventional methods as described in the examples below.

The starting materials may be either known products or products prepared from known substances according to known methods, as described in the following preparations 1 to 13.

The following non-limiting examples are illustrative of the present invention.

Melting points were determined with a Kofler hot plate (K) or under a microscope with a hot plate (MK).

Synthesis of starting materials

The starting materials used in the following examples were prepared as follows: preparation example 1: 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4-aminopiperidine step 1: 4-hydroxyiminotetrahydro-4H-pyrans

40.6g (0.406mol) of tetrahydro-4H-pyran-4-one, 118.7g (1.71mol) of hydroxylamine hydrochloride and 118.1g (1.44mol) of sodium acetate are mixed in 810ml of ethanol at room temperature, the mixture is heated under reflux for 20 hours, then allowed to cool, the solid is filtered off, the filtrate is rinsed with ethanol and concentrated. The residue was taken up in 500ml of ether and stirred well for 2 hours to give a whitish, very viscous, insoluble product. Insoluble matter was removed by filtration, and the filtrate was concentrated to give 49.5g (theoretical value: 46.7g) of the desired product containing 15% by weight of acetic acid (corrected yield: about 90%), which was used as it was. Step 2: 4-Aminotetrahydro-4H-pyran hydrochloride

49.3g (. apprxeq.0.405 mol) of the above-mentioned compound are mixed with 15ml of Raney nickel in 600ml of ethanol and then at room temperature under a pressure of 5X 10⁵Hydrogen hydrogenation of Parta 4And (4) hours. After the Raney nickel had been filtered off, 200ml of 4.1N ethereal hydrochloric acid (approx. 2 equivalents) were added and the solvent was distilled off to give 52.6g (theoretical: 55.7g) of the desired product, which was used as is. And step 3: 1, 5-dibromo-3-aminopentane hydrobromide

52.3g (380mmol) of the above compound are dissolved in 380ml of oleum (60%) at room temperature, and the solution is heated at reflux for 24 hours. After allowing to cool, 500ml of water were added and after a few minutes a solid appeared. After ice-cooling, the solid was filtered off, then rinsed with a very small amount of water, then slurried with 200ml of diethyl ether, after filtration, rinsed with diethyl ether, and dried with potassium hydroxide in vacuo, whereby 69.5g (yield: 56%) of the desired product was obtained as a gray powder, step 4: the title product

20g (59.0mmol) of the above-mentioned compound are mixed with 8.9g (58.9mmol) of 5-amino-1, 4-benzodioxan in 120ml of chlorobenzene at room temperature, the mixture is heated under reflux overnight, after cooling the product deposits on the wall of a three-necked flask, the chlorobenzene phase is decanted off, the residue is taken off in 50ml of water and then in 200ml of 1N hydrochloric acid and washed with diethyl ether (macroemulsion). After being made basic with concentrated sodium hydroxide solution under cooling, it was extracted three times with 200ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, concentrated (15g) and purified by chromatography on a silica gel column (eluent: dichloroethane/methanol/ammonium hydroxide: 95/50/0.5) to give 4.7g of the desired product in the form of a syrup, theory: 13.8g. preparation 2: 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4-methylaminopiperidine step 1: 1- (2, 3 dihydro [1, 4] benzodioxin-5-yl) -4-ethoxycarbonylaminopiperidine

2.1ml (14.9mmol) of triethylamine was added to a solution of the title compound of preparation 1 (1.6g, 6.8mmol) in dichloromethane (20ml) at room temperature, to which 0.71ml (7.5mmol) of ethyl chloroformate was added dropwise over 30 minutes. After stirring overnight at room temperature, 100ml of dichloromethane were added and the mixture was washed with 100ml of water, 100ml of 1N hydrochloric acid (twice for washing) and 100ml of water. The organic phase dried over magnesium sulfate was concentrated to give 1.3g of the desired product (yield: 65%). Step 2: the title product

A solution of the above compound (1.3g, 4.2mmol) in tetrahydrofuran (13ml) was added dropwise to a solution of lithium aluminium hydride (0.32g, 8.5mmol) in tetrahydrofuran (7ml) at room temperature over 15 minutes. Heat at reflux for 1 hour 30 minutes. Then it was allowed to hydrolyze overnight at room temperature under cooling with 0.22ml of water, 0.18ml of 20% sodium hydroxide solution and 0.81ml of water in that order. After filtration of the salts and evaporation of the solvent, 0.77g of the desired product are obtained, yield: 73%. preparation example 3: 1- (thiochroman-8-yl) -4-aminopiperidine step 1: 8-tert-butoxycarbonylaminothiochroman

9.0ml (64.4mmol) of triethylamine and 13.9ml (64.4mmol) of diphenylphosphoryl azide were successively added to a solution of thiochroman-8-carboxylic acid (10g, 51.5mmol) in toluene (260ml) at room temperature. After heating at 90 ℃ for 2 hours, a solution of t-butanol (4.8g (64.4mmol)) in toluene (10ml) was added dropwise, followed by holding at 90 ℃ for 20 hours. After allowing to cool, washing was carried out with 120ml of water, 120ml of 0.1N hydrochloric acid, 120ml of water, 120ml of a saturated aqueous sodium bicarbonate solution and 120ml of water. After drying over magnesium sulphate and evaporation, the residue is taken up in cyclohexane, triturated, the solid is filtered off, the filtrate (13.3g) is concentrated and purified by chromatography on 1kg of silica gel (eluent: dichloromethane) to give 11.2g of the expected product, yield: 82 percent. Step 2: 8-Aminothiochromanes

A solution of 10g (37.7mmol) of the compound obtained in step 1 above in 50ml of dichloromethane is mixed with 50ml of trifluoroacetic acid, stirred at room temperature for 30 minutes, then evaporated to dryness, the residue taken up in diethyl ether, the solid filtered off and treated with 1N sodium hydroxide solution. The aqueous phase is extracted with diethyl ether, the diethyl ether phases are combined, dried over magnesium sulfate and concentrated to give the desired product 4.48g, theory: 6.2 g. And step 3: the title product

3.38g of the desired product was obtained by the method of step 4 of preparation 1, using the compound obtained in the above-mentioned step 2 (4.6g, 27.8mmol) and 1, 5-dibromo-3-aminopentane hydrobromide (9.4g, 27.8mmol) described in step 3 of preparation 1 as starting materials in 60ml of chlorobenzene, in yield: 49%. preparation example 4: 1- (2, 3-dihydro [1, 4] benzothiepin-5 yl) piperidin-4-one step 1: 3-Hydroxycyclohexanecarboxylic acid methyl ester

14.6g of the expected product are obtained by reducing 30.4g (0.2mol) of methyl 3-hydroxybenzoate as described in F.Fache et al (Tetrahedron Letters, 1995, 36(6), p 885-888). Step 2: 3-methoxycarbonylcyclohexanone

By oxidizing 14.4g of the compound obtained in step 1, as described in j.org.chem., 1965, 30, 145-150, 11.7g of the expected product are obtained (b.p./133.28Pa 80-85 ℃), yield: 82 percent. And step 3: 3-methoxycarbonylcyclohexanone ethylene monothioacetal

Under reflux, 11.5g (73.6mmol) of the product obtained in step 2, 10.3g of 2-mercaptoethanol, 50mg of p-toluenesulfonic acid and 10ml of toluene were heated together for azeotropic distillation for 19 hours, and after the solvent and excess 2-mercaptoethanol were distilled off, 6.2g of the expected product was obtained as the residue by distillation (b.p./66.64 Pa.: 100 ℃ C.). And 4, step 4: 5-methoxycarbonyl-2, 3-dihydro [1, 4] benzothioxanone

34.1g (0.16mol) of the product obtained in the above step was treated according to J.Y.Stath (J.chem.Soc.chem.Com., 1985, 1645-6) and purified twice by flash chromatography on silica gel (eluent: dichloromethane) to obtain 1.7g of the desired product. And 5: 2, 3-dihydro [1, 4] benzothiepin-5-carboxylic acid

The product from step 4 (1.6g) was treated with 2N sodium hydroxide solution (8ml) and methanol (8ml) at room temperature, after which the desired acid (1.3g) was isolated. Step 6: n- (2, 3-dihydro [1, 4] benzothiepin-5-yl) carbamic acid tert-butyl ester

1.25g of the product obtained in the above step, 1.12ml of triethylamine, 1.73ml of diphenylphosphoryl azide and 32ml of toluene were mixed in a 100ml two-necked flask and heated at 90 ℃ for 3 hours. 1.2ml of tert-butanol are added dropwise over 5 minutes, and heating is continued at 90 ℃ for 20 hours. The mixture was allowed to cool, 70ml of toluene were added, washed twice with 50ml of 10% sodium carbonate solution and then with 50ml of water. After drying, evaporation gave 1.7g of the desired product. And 7: 5-amino-2, 3-dihydro [1, 4] oxathiazepines

1.5g of the compound obtained in the above step 6 was dissolved in ethyl acetate, the solution was cooled to 0 ℃ and then 5.5g of hydrogen chloride gas was introduced, the mixture was stirred for 24 hours, and 0.73g of the hydrochloride of the desired product was obtained after filtration through a frit. And 8: 1- (2, 3-dihydro [1, 4] benzothiepin-5-yl) piperidin-4-ol

0.44g of the free base obtained in step 7 was mixed with 0.41g of ω, ω' -dichloropentan-3-ol, 0.20g of sodium iodide, 0.72g of potassium carbonate and 1ml of dimethylformamide, heated under reflux for 2 hours, the mixture was diluted with 50ml of water, extracted with diethyl ether, washed with brine and distilled water, dried and evaporated. Purification on silica gel gives 0.38g of the desired product. And step 9: the title product

0.35g of the product of step 8, 0.87g of dicyclohexylcarbodiimide, 0.16ml of pyridine, 4ml of dimethyl sulfoxide and 7.5ml of benzene were mixed at 5 ℃. 0.1ml of trifluoroacetic acid is added dropwise, stirred at room temperature for 21 hours, diluted with ethyl acetate, insoluble is filtered off, the filtrate is washed with water, dried, evaporated and purified with a silica gel column to give 0.28g of the desired product. Preparation example 5: 5- ([1, 2, 4] triazol-4-yl) -2, 3 indan-2-ylamine step 1: 5-Nitro-2- (2-phthalimido) -1, 3-indanes

3.1g (17.2mmol) of 5-nitro-1, 2-indan-2-ylamine are suspended in 23ml of dimethylformamide. 2.75g (18.6mmol) phthalic anhydride were added. Reflux heating for 10 min, cooling to room temperature, pouring the reaction mixture into 500ml of ice-water mixture to obtain the desired product (m.p. (MK): 195-: 5-amino-2- (2-phthalimido) -1, 3-indanes

2g (6.5mmol) of the compound obtained in the above step was suspended in 25ml of methanol. 100mg of platinum oxide was added. Hydrogenation was carried out at room temperature under atmospheric pressure, the catalyst was filtered off and the solvent was evaporated, yielding 1.7g of the desired product (m.p. (MK): 294- & gt 296 ℃), yield: 94 percent. And step 3: 5- ([1, 2, 4] triazol-4-yl) -2- (2-phthalimido) -1, 2-indane

0.5g (1.8mmol) of the compound obtained in the above step 2 and N, N-dimethylformamide azine were heated under reflux in the presence of 17mg of p-toluenesulfonic acid in 14ml of toluene for 17 hours. The precipitate is filtered off, washed with toluene and dried, giving 0.22g of the desired product (m.p. (MK): 224 ℃ C.) and 226 ℃ C.), in terms of yield: 37 percent. And 4, step 4: the title product

0.22g (0.6mmol) of the product obtained in step 3 and 43. mu.l of hydrazine hydrate were added to 30ml of ethanol and heated under reflux for 30 hours. After addition of 100ml of 1N hydrochloric acid, the precipitate is filtered off, the filtrate is made alkaline with 1N sodium hydroxide solution and extracted with dichloromethane to give 0.13g of the desired product, yield: 100 percent. Preparation example 6: 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) pyrrolidin-3-one step 1: 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) pyrrolidin-3-ol

A solution of 10g (66mmol) of 5-amino-2, 3-dihydro [1, 4] benzodioxin, 7.65ml of ω, ω' -dibromobutane-2-ol and 18.25g of potassium carbonate in chlorobenzene (125ml) was heated at reflux for 18 hours. After evaporation of the solvent, the residue is taken up in dichloromethane, washed with water, dried and evaporated to give 17.6g of an oily product corresponding to the expected product. Step 2: the title product

To a mixture composed of 2g (9.04mmol) of the product of step 1, 5.6g (27mmol) of N, N-dicyclohexylcarbodiimide, 1.03ml of pyridine, 25.8g of dimethyl sulfoxide and 48ml of benzene, 0.51ml of trifluoroacetic acid was added dropwise while keeping the temperature at 5 ℃. The mixture was stirred at room temperature for 20 hours. After dilution with ethyl acetate, the insoluble material was filtered off, the filtrate was washed with water, dried over magnesium sulphate and evaporated to give 2.5g of product corresponding to the expected product. Preparation example 7: 1- (chroman-8-yl) -4 aminopiperidine step 1: 1- (chroman-8-yl) piperidin-4-ones

Prepared by the method of steps 8 and 9 of preparation example 4 starting from 8-aminochroman. Step 2: 1- (chroman-8-yl) -4-hydroxyiminopiperidines

A mixture consisting of 1g (4.32mmol) of the product from step 1, 1.26g of hydroxylamine hydrochloride, 1.26g of sodium acetate and 20ml of ethanol was heated at reflux for 1 hour. After evaporation of the solvent, the residue is taken up in 100ml of dichloromethane, washed with water, dried and evaporated to give 0.9g of the desired product. And step 3: the title product

The product of step 2 (0.9g) was hydrogenated at room temperature and atmospheric pressure in the presence of 1ml of Raney nickel and 1ml of concentrated ammonium hydroxide in 20ml of methanol. After 5 hours of contact, the catalyst was filtered off and the filtrate was evaporated to dryness. The residue is taken off in 100ml of dichloromethane, extracted with 1N hydrochloric acid, the acid phase is made alkaline with concentrated sodium hydroxide, and after extraction with dichloromethane, washing, drying and evaporation, 0.76g of the desired product is isolated. Preparation example 8: 1- (2, 3-dihydrobenzofuran-7-yl) -4-aminopiperidine

The procedure was the same as for the product prepared in preparation 7, but using 7-amino-2, 3-dihydrobenzofuran in step 1. Preparation example 9: 1- (benzofuran-7-yl) -4-aminopiperidine

The procedure was the same as for the product of preparation 7, but 7-amino-benzofuran was used in step 1. Preparation example 10: 1- (6-fluoro chroman-8-yl) piperidin-4-one step 1: 6-fluorobenzchroman-8-carboxaldehyde

13.74g (90.28mmol) of 6-fluorodihydropyran are dissolved in 250ml of dichloromethane. It was allowed to cool to 0 ℃ and 20.15ml of titanium tetrachloride were added dropwise, the solution turned brown, stirred at room temperature for 10 minutes, added with 8.78ml (99.3mmol) of α, α -dichloromethyl ether, stirred at room temperature overnight, poured into ice-cooled water, the organic phase was dried after pouring off, and after evaporation, 17.7g of the residue was purified by a silica gel column (eluent: dichloromethane/cyclohexane: 50/50) to obtain 6.3g of the desired product, chlorine yield: 38.7 percent. Step 2: 6-fluorobenzchroman-8-carboxylic acid

The aldehyde obtained in step 1 was dissolved in 52ml of acetone, the solution was cooled to 0 ℃ and 17.43ml of jones reagent was slowly added while keeping the temperature below 10 ℃. Stirring is carried out at room temperature for 4 hours, the acetone is evaporated off, the residue is taken off in 60ml of water and extracted with diethyl ether, and the diethyl ether phase is extracted with 1N sodium hydroxide solution. The base phase was changed to acidic with concentrated hydrochloric acid and extracted with ether to give 5.31g of the desired product, chlorine: 77.5 percent. And step 3: benzyl N- (6-fluorobenzchroman-8-yl) carbamate

A solution consisting of 137ml of toluene, 5.3g (27.07mmol) of the acid obtained in the above step, 4.72ml of triethylamine and 7.29ml (33.83mmol) of diphenylphosphorylazide was heated at 90 ℃ for 2 hours. While the temperature was kept at 90 ℃, 3.52ml of benzyl alcohol was added, and the temperature was kept constant for 20 hours, successively washed with water, 0.5N hydrochloric acid, water, a sodium hydrogen carbonate solution and water. Drying and evaporation gave 8.2g of the desired product. And 4, step 4: 8-amino-6-fluorobenzchromans

8.1g of the compound of step 3 are dissolved in 80ml of ethanol. This solution was hydrogenated in the presence of 0.39g of palladium on carbon at normal pressure and room temperature. Filtration and evaporation gave 4.6g of liquid product corresponding to the expected product. And 5: the title product

4.5g of the compound obtained in the above step was treated in the same manner as in steps 8 and 9 of production example 4 to obtain 2.9g of the desired product. Preparation example 11: 1- (4-acetoxychroman-8-yl) -4-aminopiperidine step 1: 4-acetoxy-8-nitrobenzchromans

5.7g (29.2mmol) of 4-hydroxy-8-nitrobenzchroman are dissolved in 100ml of dichloromethane, 5ml of triethylamine are added and 2.6ml of acetyl chloride are slowly added thereto. After allowing the reaction to contact for 1 hour 30 minutes, 2ml of triethylamine was added, 1ml of acetyl chloride was slowly added thereto, and it was allowed to stand at room temperature for another 1 hour. After dilution with dichloromethane, washing with water, 1N hydrochloric acid, 5% sodium carbonate solution and 100ml of water in succession, drying and evaporation, 6.6g of an orange oil are obtained, corresponding to the expected product. Yield: 95 percent. Step 2: 4-acetoxy-8-aminochroman

6.6g (27.8mmol) of the product of step 1 were dissolved in 85ml of methanol. 0.43g of platinum oxide was added and hydrogenated at room temperature and atmospheric pressure for 4 hours. The catalyst was filtered off, rinsed and the filtrate evaporated to give 5.5g of a viscous oil which was the desired corresponding product. Yield: 96 percent. And step 3: 1- (4-acetoxychroman) piperidin-4-one

7.5g (30.7mmol) of the base obtained in the above step 2 was treated in the same manner as in steps 8 and 9 of preparation example 4 to obtain 0.4g of the desired product. And 4, step 4: 1- (4-acetoxychroman-8-yl) -4-hydroxyaminopiperidine

0.4g of the compound obtained in the above step was treated in the same manner as in step 2 of production example 7 to obtain 0.28g of the desired product, yield: 66 percent. And 5: the title product

0.28g of the compound of step 4 was dissolved in 6ml of an ethanol solution and 0.3ml of an ammonium hydroxide solution, 0.3ml of Raney nickel was added, and hydrogenated at room temperature and atmospheric pressure. The catalyst was filtered off, rinsed and evaporated to give 0.25g of the desired product, yield: 96%. preparation example 12: 4-amino-1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4-methylpiperidine step 1: 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4-hydroxy-4-methylpiperidine

3.5g (15mmol) of 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) piperidin-4-one are dissolved in 30ml of diethyl ether. The solution was allowed to cool to 0 ℃ and 10ml of a 3M solution of methylmagnesium bromide in ether was added while maintaining the temperature at this temperature. After stirring at 0 ℃ for 1 hour, it was poured into 100ml of a saturated aqueous ammonium chloride solution, hydrolyzed at room temperature for half an hour, and extracted with 100ml of diethyl ether. The extracts are dried and evaporated to give a residue of 3.3g which is purified by flash chromatography on silica gel (eluent: dichloromethane/ethyl acetate 90/10). This was isolated in this manner to give 1.3g of the desired product. Step 2: 4-acetylamino-1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4-methylpiperidine

1.03g (4.1mmol) of the product of step 1 was dissolved in 4ml of acetonitrile, and 1ml of concentrated sulfuric acid was added dropwise over 5 minutes while maintaining the temperature below 40 ℃. After stirring overnight at room temperature, it was poured into ice-cold 1N sodium hydroxide solution (50ml), extracted with dichloromethane, washed with water, dried and evaporated to give 0.85g of residue which was purified by flash chromatography (eluent: dichloromethane/ethyl acetate 50/50, eluting again with eluent: dichloromethane/ethanol 98/2) to give 0.54g of the desired product. And step 3: the title product

After the compound (0.51g, 1.76mmol) obtained in step 2 was treated with 3ml of 3N hydrochloric acid under reflux overnight, 1ml of concentrated hydrochloric acid was added, heated under reflux for 24 hours, made basic with 2N sodium hydroxide, and extracted with 30ml of dichloromethane, and extracted three times in this manner. The washed organic phase was dried to give 0.32g of the desired product. Yield: 73 percent. Preparation example 13: 6-Aminocyclopenta [ f ] [2.1.3] benzoxadiazoles and hydrochloride salts thereof step 1: 2-acetamido-5-amino-6-nitro-1, 2-indane

To a solution of 2-acetylamino-5-amino-1, 2-indane (2.85g, 15mmol) in concentrated sulfuric acid (7.5ml) cooled to 0 ℃ was added 1.62g of potassium nitrate in portions, stirred at 0 ℃ for 3 hours, then poured into ice-cold sodium hydroxide solution (6N), after stirring, extraction with dichloromethane, washing, drying and evaporation, 2.8g of black solid was isolated and purified with a silica gel column (eluent: dichloromethane/methanol ═ 97/3). 1.46g of the desired product are isolated in this way, yield: 42 percent. Step 2: 6-Acetylamidocyclopenta [ f ] [2, 1, 3] benzoxadiazoles

After a solution of sodium nitrite (0.46g, 6.6mmol) and the product of step 1 (1.4g, 6mmol) in acetic acid (10ml) was added successively to 3ml of sulfuric acid at 0 ℃ for 15 minutes, the mixture was poured onto 20g of ice, and the solution thus obtained was added dropwise to a vigorously stirred solution of sodium azide (600mg, 9.2mmol) in water (12ml) and stirred for 10 minutes at room temperature, and extracted three times with 40ml of dichloromethane each time. The organic phase is washed with a 10% aqueous solution of sodium carbonate, dried over magnesium sulphate, filtered and 100ml of anhydrous toluene are added. The methylene chloride was distilled off, and the toluene solution thus obtained was heated under reflux for 3 hours. It was allowed to cool, the solid was filtered off, washed with toluene and dried in vacuo. The solid was dissolved in 50ml ethanol and 5ml triethyl phosphite was added. Evaporation separation after heating at reflux for 1 hour 30 minutes gives 0.91g of the desired product. And step 3: the title product

0.87g of the product obtained in step 2 was dissolved in 10ml of methanol, 5ml of 6N hydrochloric acid was added, and the mixture was heated under reflux for 24 hours to obtain 0.88g of the hydrochloride of the desired product after evaporation.

Example 11- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (1, 2-indan-2-yl) amino ] piperidine and its dihydrochloride

A mixture consisting of 1, 2-indan-2-ol tosylate (11g, 38mmol), the title compound of preparation 1 (9 g (38mmol), triethylamine (7.7g, 76mmol) and toluene (150ml) was heated at reflux for 24 hours. The evaporation to dryness is carried out, the residue taken off is taken up in, for example, dichloromethane and 1N sodium hydroxide solution, the organic phase is washed with water after decanting, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: dichloromethane/ethyl acetate-90/10) to give the product corresponding to the expected structure, which was converted to the dihydrochloride by the action of ethereal hydrochloric acid in yield: 15 percent. M.p. > 260 ℃.

Example 21- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (1, 2-indan-2-yl) -N-methylamino ] piperidine and its fumarate

After mixing 0.77g (3.1mmol) of 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4-methylaminopiperidine, 1, 2-indan-2-ol tosylate (0.89g, 3.1mmol), potassium carbonate (1.3g, 9.3mmol) and methylisobutylketone (32ml) of preparation example 2 at room temperature, heating was performed under reflux for 26 hours, and after 1 hour 30 minutes, 3 hours 30 minutes, 6 hours 30 minutes and 24 hours, 0.2g (0.7mmol) of 1, 2-indan-2-ol tosylate was further added. The evaporation to dryness is carried out and the residue taken off is taken up in 100ml of dichloromethane, washed with 100ml of water each time, 3 times in total, dried over magnesium sulfate and concentrated. 1.3g of the residue are purified by chromatography on a column of 130g silica gel (eluent: dichloromethane/ethyl acetate 90/10, eluting again with dichloromethane/ethyl acetate/methanol 90/10/1) to yield 0.16g of the desired product in the form of the free base. An ethanol solution (2%) of fumaric acid (1N) was added to give the corresponding fumarate salt, which after filtration and drying gave 0.11g of the title compound as a solid having a melting point (MK) of 188-. Yield: 12 percent.

Example 31- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5, 6-methylenedioxy-1, 2-indan-2-yl) amino ] piperidine and its fumarate salt

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4-aminopiperidine (1.0g, 4.3mmol), 5, 6-methylenedioxy-1, 2-indan-2-one (0.75g, 4.3mmol) described in preparation 1 and 2g of 4 * molecular sieve were stirred in 16ml of chloroform at room temperature overnight. After filtering off the molecular sieve, the filtrate was rinsed with a small amount of chloroform and concentrated. The residue was taken up in 16ml of methanol and 4ml of tetrahydrofuran, 0.32g (8.5mmol) of sodium borohydride was added in one portion, stirred overnight at room temperature, evaporated to dryness, taken up in 100ml of dichloromethane, washed twice with 50ml of water each time, dried over magnesium sulfate and concentrated, and the residue was purified by column chromatography over silica gel (160g) (eluent: dichloromethane/methanol-98/2) to give 0.71g of the desired product in free base form (1.66 g).

An ethanol solution (2%) of fumaric acid (1N) was added to give the corresponding fumarate salt, which after filtration and drying gave 0.68g of the desired fumarate salt having a melting point (MK) of 255-. Yield: 31 percent.

Example 44- [ N- (1, 2-indan-2-yl) amino ] -1- (thiochroman-8-yl) piperidine

The same procedure as used for the preparation of the compound of preparation 3 was used, except that the compound of preparation 3 was used instead of 4-amino-1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) piperidine and 1, 2-indan-2-one was used instead of 5, 6-methylenedioxy-1, 2-indan-2-one. After purification on a silica gel column (eluent: dichloromethane/methanol-98/2), the desired product is obtained with a melting point (MK) of 109 ℃ and 112 ℃. Yield: 8 percent.

Example 51- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5, 6-dimethoxy-1, 2-indan-2-yl) amino ] piperidine and its fumarate

Using the procedure as for the preparation of the compound of example 3, but using 5, 6-dimethoxy-1, 2-indan-2-one instead of 5, 6-methylenedioxy-1, 2-indan-2-one, purification on silica gel (using the same eluent) gives the desired product which is converted into the corresponding fumarate having a melting point (MK) of 212-. Yield: 12 percent.

Example 61- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-methyl-1, 2-indan-2-yl) amino ] piperidine and its fumarate

Using the procedure for the preparation of the compound of example 3, but using 5-methyl-1, 2-indan-2-one instead of 5, 6-methylenedioxy-1, 2-indan-2-one, the desired product is obtained by purification under the same conditions as the corresponding fumarate salt with a melting point (MK) of 239 ℃ -. Yield: 19 percent.

Example 71- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-chloro-1, 2-indan-2-yl) amino ] piperidine and its fumarate

Using the procedure for the preparation of the compound of example 3, but using 5-chloro-1, 2-indan-2-one instead of 5, 6-methylenedioxy-1, 2-indan-2-one, purification on silica gel (using the same eluent) gives the desired product, which corresponds to the fumarate salt with a melting point (MK) of 238-. Yield: 9 percent.

Example 81- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-methoxy-1, 2-indan-2-yl) amino ] piperidine and its fumarate

Using the procedure for the preparation of the compound of example 3, but using 5-methoxy-1, 2-indan-2-one instead of 5, 6-methylenedioxy-1, 2-indan-2-one, the fumarate melting point (MK) of the desired product is 222-.

Example 91- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5, 6-dimethyl-1, 2-indan-2-yl) amino ] piperidine and its fumarate salt

Using the procedure for the preparation of the compound of example 3, but using 5, 6-dimethyl-1, 2-indan-2-one instead of 5, 6-methylenedioxy-1, 2-indan-2-one, the fumarate melting point (MK) of the desired product is 232-235 ℃.

Example 101- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-trifluoromethyl-1, 2-indan-2-yl) amino ] piperidine and its fumarate

Using the procedure for the preparation of the compound of example 3, but using 5-trifluoromethyl-1, 2-indan-2-one instead of 5, 6-methylenedioxy-1, 2-indan-2-one, the fumarate melting point (MK) of the desired product is 228-.

Example 111- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (4, 7-dimethoxy-1, 2-indan-2-yl) amino ] piperidine and its hemifumarate

Using the procedure for the preparation of the compound of example 3 but using 4, 7-dimethoxy-1, 2-indan-2-one instead of 5, 6-methylenedioxy-1, 2-indan-2-one, the melting point (MK) of the hemifumarate salt of the desired product is 217-220 ℃.

Example 12: 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-fluoro-1, 2-indan-2-yl) amino ] piperidine and fumarate salts thereof

Using the procedure for the preparation of the compound of example 3, but using 5-fluoro-1, 2-indan-2-one instead of 5, 6-methylenedioxy-1, 2-indan-2-one, the fumarate melting point (MK) of the desired product is 216-220 ℃.

Example 13: 4- [ N- (1, 2-indan-2-yl) -N-methylamino ] -1- (2, 3-dihydro-1, 4-dioxino [2, 3-b ] pyridin-8-yl) piperidine

1.1g (6.5mmol) of 8-chloro-2, 3-dihydro-1, 4-dioxino [2, 3-b ] pyridine, 3g (13mmol) of 4- [ N- (1, 2-indan-2-yl) -N-methylamino ] piperidine and 5ml of pyridine are placed in a reactor and heated at 130 ℃ for 8 hours. After cooling, the reaction was taken out into toluene and concentrated. Purification by chromatography on 130g of silica gel (eluent: dichloromethane/methanol/ammonium hydroxide 95/5/0.5) gave a product with a melting point (MK) of 167-170 ℃. Yield: 8.5 percent.

Example 14: 1- (2, 3-dihydro [1, 4] benzothiepin-5-yl) -4- (1, 2-indan-2-ylamino) piperidine and hemifumarate salts thereof

0.17g (1mmol) of 1, 2-indane hydrochloride was added to 7ml of 1, 2-dichloroethane, and triethylamine (0.14ml, 1.5mmol), 0.25g of 1- (2, 3-dihydro [1, 4] benzothiepin-5-yl) piperidin-4-one (preparation 4), sodium triacetoxyborohydride (0.32g, 1.5mmol) and acetic acid (58. mu.l, 1mmol) were successively added. After stirring for 20 hours at room temperature, the mixture is poured into 10ml of 1N sodium hydroxide solution and extracted with 25ml of diethyl ether each time (twice), the combined organic phases are washed and dried and evaporated to give 0.36g of the title compound, which is converted into the hemi-fumarate salt by action of a 2% solution of fumaric acid in ethanol. 0.27g of hemifumarate salt is thus obtained. M.p (MK) at 220 ℃ and 223 ℃.

Example 151- (chroman-8-yl) -4- (1, 2-indan-2-ylamino) piperidine and its fumarate salt

A process for the preparation of the compound of example 14 but using 1- (chroman-8-yl) piperidin-4-one instead of the product of example 4 is used. The corresponding fumarate has a melting point (MK) of 236-240 ℃.

Example 161- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -3- (1, 2-indan-2-ylamino) pyrrolidine and its hydrochloride

The dihydrochloride of the title product having a melting point (MK) of 245-248 ℃ was obtained in the same manner as the preparation of the product of example 14, but without using the product of preparation 4 and using the 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) pyrrolidin-3-one of preparation 6 in ethereal hydrochloride.

Example 171- (6-Fluorochroman-8-yl) -4- (1, 2-indan-2-ylamino) piperidine and its fumarate

The fumarate salt of the desired product having a melting point (MK) of 226-230 ℃ was obtained in the same manner as the preparation of the product of example 14 except that the product of example 4 was used instead of the 1- (6-fluorobenzchroman-8-yl) piperidin-4-one of example 10.

Example 181- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- (5-nitro-1, 2-indan-2-ylamino) piperidine and its fumarate

The fumarate salt of the title product, having a melting point (MK) of 234-.

Example 191- (chroman-8-yl) -4- [5- (1, 2, 4-triazol-4-yl) 1, 2-indan-2-ylamino ] piperidine and its hemifumarate

In the same manner as in the preparation of the product of example 14, except for using the product of preparation 4, 1, 2-indan-2-ylamine hydrochloride, and using 5- (1, 2, 4-triazol-4-yl) 1, 2-indan-2-ylamine hydrochloride and 1- (chroman-8-yl) piperidin-4-one of preparation 5, the fumarate salt obtained was melted at 153 ℃ and 155 ℃ C. (MK).

Example 201- (chroman-8-yl) -4- [ (cyclopenta [2, 1, 3)]Benzo (b) isOxadiazol-6-yl) amino]Piperidine and fumarate salts thereof

The fumarate salt of the title product was melted at 225 ℃ 227 ℃ (MK) using the same procedure as for the preparation of the product of example 14, but without the product of preparation 4, 1, 2-indan-2-ylamine hydrochloride, and with the 6-aminocyclopenta [2, 1, 3] benzoxadiazole hydrochloride and 1- (chroman-8-yl) piperidin-4-one of preparation 13.

Example 211- (chroman-8-yl) -4- [ (5-fluoro-1, 2-indan-2-yl) amino ] piperidine and its fumarate salt

0.49g (3.27mmol) of 5-fluoro-1, 2-indan-2-one and 0.76g (3.27mmol) of 1- (chroman-8-yl) -4-amino) piperidine (preparation 7) are mixed in 1, 2-dichloroethane (25ml), followed by 1.1g of sodium triacetoxyborohydride and 0.19ml of acetic acid. After stirring for 24 hours, the reaction mixture is poured into 1N sodium hydroxide solution, extracted with diethyl ether, the organic phase is washed, dried and evaporated. The residue was purified by silica gel chromatography, eluent: dichloromethane/ethanol 98/2.

0.64g of a liquid corresponding in structure to the expected product are obtained. Treatment with a 2% ethanol solution of fumaric acid gave 0.67g of the fumarate salt of the desired product. Melting point: (MK)227-231 ℃.

Example 221- (2, 3-Dihydrobenzofuran-7-yl) -4- [ (5-fluoro-1, 2-indan-2-yl) amino ] piperidine and the hemifumarate salt thereof

In the same manner as in the preparation of the product of example 21, except that the product of preparation 7 was not used, but the 1- (2, 3-dihydrobenzofuran-7-yl) -4-aminopiperidine of preparation 8 was used, the hemifumarate salt of the desired product was melted at 229 ℃ C (MK) at 225-. Example 231- (chroman-8-yl) -4- [ (5, 6-methylenedioxy-1, 2-indan-2-yl) amino ] piperidine and its fumarate salt

The fumarate salt of the desired product was melted at 248-.

Example 241- (benzofuran-7-yl) -4- [ (5-fluoro-1, 2-indan-2-yl) amino ] piperidine and the hemifumarate salt thereof

In the same manner as in the preparation of the product of example 21, except that the product of preparation 7 was not used, but the 1- (benzofuran-7-yl) -4-aminopiperidine of preparation 9 was used, the hemifumarate salt of the desired product was prepared and melted at 219 ℃ and 222 ℃ (MK).

Example 251- (chroman-8-yl) -4- [ (5-methoxy-1, 2-indan-2-yl) amino ] piperidine and its fumarate salt

The fumarate salt of the desired product, prepared in the same manner as for the preparation of the product of example 21, but using 5-fluoro-1, 2-indan-2-one and 5-methoxy-1, 2-indan-2-one, was melted at 218-.

Example 261- (4-hydroxychroman-8-yl) -4- [ (5, 6-methylenedioxy-1, 2-indan-2-yl) amino ] piperidine and its hemifumarate salt step 1: 1- (4-acetoxychroman-8-yl) -4- [ (5, 6-methylenedioxy-1, 2-indan-2-yl) amino ] piperidine

Using the same procedure as for the preparation of the product of example 21, but using not 5-fluoro-1, 2-indan-2-one but 5, 6-methylenedioxy-1, 2-indan-2-one and not the product of preparation 7 but using 1- (4-acetoxychroman-8-yl) -4-aminopiperidine of preparation 11, a yellow oil corresponding to the desired product was obtained which was isolated and the product was obtained in 26% yield. Step 2: the title product

The product of step 1 (100mg, 0.22mmol) was dissolved in 2ml of methanol and 1.5ml of 1N sodium hydroxide solution, the reaction was allowed to contact for 1 night, then at 60 ℃ for 1 hour, after allowing the temperature to fall to room temperature, the methanol was distilled off, the residue was diluted with water, extracted with dichloromethane, after drying and evaporation, 60mg of the product corresponding to the expected structure was isolated and converted into the fumarate with 2% ethanol solution of fumaric acid. The hemifumarate salt corresponding to the desired product was isolated, M.P. (MK) 252-.

Example 271- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- (1, 2-indan-2-ylamino) -4-methylpiperidine and the fumarate salt thereof

Using the same procedure as for the preparation of the product of example 21, but using not 5-fluoro-1, 2-indan-2-one but 1, 2-indan-2-one, and not the product of preparation 7 but using 4-amino-1- (2, 3-5-hydro [1, 4] benzodioxin-5-yl) -4-methylpiperidine (preparation 12), the fumarate product, which melts at 218 ℃ and 223 ℃ (MK), is obtained.

Example 281- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-hydroxy-1, 2-indan-2-yl) amino ] piperidine and the hemifumarate salt thereof

A mixture consisting of dihydrochloride salt (1g, 2.2mmol) and pyridine hydrochloride salt (0.77g, 6.6mmol) of the product from example 8 was heated at 200 ℃ for 1 hour. It was allowed to cool to room temperature and added to a dilute solution (100ml) of dichloromethane (100ml) and ammonium hydroxide. The phases were separated, the organic phase was dried and the solvent was evaporated to give 0.78g of the desired product which was converted to the corresponding hemi-fumarate salt (0.61 g). Melting point (MK): 250 ℃ and 260 ℃.

Example 291- (chroman-8-yl) -4- [ N- (5-hydroxy-1, 2-indan-2-yl) amino ] piperidine and the hemifumarate salt thereof

The procedure of example 28 was followed using the product of example 25 instead of the product of example 8. The hemifumarate salt of the desired product Melts (MK) above 350 ℃.

Example 30 pharmacological Studies. binding Studies. 5-HT_1BBonding of

a) Preparation of the film

Cutting the brain of the ragweed, freezing the extracted striatum, and then adding 4mM CaCl in 20 volume (weight/volume)₂And 0.1% ascorbic acid in Tris-HCl (50mM pH7.7, room temperature). Centrifuge at 48,000g for 25 minutes at 4 ℃. The supernatant was separated and the pellet resuspended in the same volume of buffer and then incubated at 37 ℃ for 15 minutes to extract endogenous serotonin. Finally, the suspension was centrifuged at 48,000g for 25 minutes at 4 ℃ and the pellet was resuspended in 80 volumes of buffer containing 10. mu.M of bacilin.

b) Binding study

Binding studies were performed with triplicate samples in the buffer described below (,)³H]-GR 125743): containing 4mM CaCl₂0.1% ascorbic acid and 10. mu.M pargyline in Tris-HCl 50mM (pH7.7, room temperature). The final volume was made 500. mu.l with 100. mu.l radioligand, 100. mu.l buffer or compound to be tested and 300. mu.l membrane. Non-specific binding was determined using this serotonin (10. mu.M). In the competitive test, the term³H]The concentration of-GR 125743 is 1 nM. The heat preservation is started when the film product is added, and the heat preservation is continued for 60 minutes at room temperature. The reaction was stopped by rapid filtration through Whatman GF/B filters pretreated with 0.1% polyethyleneimine followed by 3 rinses with cold buffer. At radioligand concentrationNear Kd values, specific binding is approximately 90% of total binding. Analysis of data

Data were analyzed using the PRISM program (Graphpad Software Inc., San Diego, Calif.) using non-linear regression to determine Kd values (dissociation constants for radioligands), maxima for saturation experiments (number of sites maximum), and IC₅₀Values (50% inhibitory concentration) and Hill number in competition assays. The inhibition constants were calculated according to the following Cheng-Prussof formula: k_i＝IC₅₀1+ L/Kd, where L represents the radioligand concentration. The results are expressed as: pKi ═ logKi.

The results show that the compounds of the invention are directed to 5-HT_IBThe receptor has good affinity. For example, pK of the Compound of example 3_i＝8.5。·5-HT_1AIn combination with

5-HT was studied using known methods described in the literature (see, e.g., S.J.Peroutka, J.neurochem., 1986, 47, 529-40, M.J.Millan.J.Pharmacol.Exp.Ther., 1994, 268, 337-52)_1AIn combination with (1). The results were also pK_iAnd (4) showing. Compound of the present invention para 5-HT_1AThe receptor has a very low affinity. For example, pK of the compound of example 3_i＝6.2。

This indicates excellent selectivity of the product of the invention. Guinea pig hypothermia test

Guinea pigs were placed in three chambers and allowed free access to water and food, and the study was performed a week later. Guinea pigs were kept in individual cages 1 hour prior to each trial and water was taken freely. And after the test is finished, the test piece is put back to the original chamber. Body temperature was measured with a digital thermometer and a rectal probe. Each guinea pig was weighed and basal body temperature measured, and then the compound of the present invention to be assessed was injected intraperitoneally or orally. In the case of agonists, the body temperature of the guinea pigs was measured every 30 minutes for a total of 2 hours.

If it is an antagonist, the prototype agonist is injected intraperitoneally 15 minutes after injection into each guinea pig_1B：GR₄6611(5 mg/kg). Body temperature was then measured every 30 minutes for a total of 2 hours.

The evaluation criterion is the temperature difference between the body temperature and the base body temperature at a given time. For each dose of product and each time (t)₃₀、t₆₀、t₉₀、T₁₂₀) The mean and mean standard error were calculated.

For example, to illustrate the intraperitoneal administration of a product of the invention at t₉₀The results of the compound of example 1 as an antagonist are listed in the following table: injection 1(a) injection 2(a) Δ T ℃ (b)

(90 min.) vector 0. + -. 0.1 vector GR₄6611 -1.04±0.15

5mg/kg GR from example 1₄6611-0.82 + -0.300.04 mg/kg 5mg/kg GR of the product of example 1₄6611-0.75 + -0.220.16 mg/kg 5mg/kg GR of the product of example 1₄6611-0.15 ± 0.100.63mg/kg 5mg/kg (a): the route of administration is intraperitoneal (b): the values are mean ± standard error of the mean. N of each value is greater than or equal to 6: according to Dunnett's experiment, with vector/GR₄6611 comparison, p < 0.05. diamond-solid in rats for microdialysis experiments

Rats were anesthetized with pentobarbital (60mg/kg administered intraperitoneally). Placed in a Kopf stereotaxic apparatus, according to the coordinates of Paxinos and Watson atlas (1982): ap: +2.2, L:± 0.6, DV: 0.2 catheterization into frontal cutaneous band. Rats were placed in separate cages until 5 days later for dialysis experiments. On the day of dialysis, the probe was slowly inserted and the position was fixed, and 147.2ml of NaCl, 4mM KCl and 2.3mM CaCl, which were adjusted to pH7.3 with phosphate buffer (0..1M) at a rate of 1. mu.l/min, were perfused₂And (3) solution. Samples were taken every 20 minutes for 2 hours after placement for a total of 4 hours. After 3 basal samples were collected, the compounds to be tested were administered. Rats were placed in their individual cages throughout the experiment. At the end of the experiment, the rat head was cut off and the brain removed was frozen in isopentane. Sections were 100 μm thick, stained with cresyl violet and the probe was left in a vertical position.

Dopamine, norepinephrine and serotonin were quantified as follows: with 20. mu.l of mobile phase (NaH)₂PO₄: 75mM, EDTA: 20 μ M, sodium 1-decanesulfonate: 1mM, methanol: 17.5%, triethylamine: 0.01%, pH: 5.70) 20. mu.l of the dialyzed sample are diluted and 33. mu.l of the sample are analysed by high pressure liquid chromatography with a reverse phase column (Hypersil ODS 5. mu.m, C18, 150 X4.6mm, Thermo separation product, Les Ulis, France) thermostated at 45 ℃ and quantified with a coulometric detector. The voltage at the first electrode of the coulometric detector was fixed at-90 mV (reduction) and the second electrode at +280mV (oxidation). The mobile phase was injected with a Beckman116 pump at a flow rate of 2 ml/min. The limit of sensitivity for dopamine, norepinephrine and serotonin for each sample was 0.55 fmol. All compounds of the invention were injected subcutaneously in a volume of 1.0 ml/kg. These products are dissolved, if necessary, in distilled water to which a few drops of lactic acid are added.

As an agonist, a decrease in extracellular serotonin concentration was observed (see table below).

If it is an antagonist, agonist GR is observed₄6611 the phenomenon of a reduction in the extracellular concentration of serotonin is the case when the compounds to be tested according to the invention are injected after 20 minutes and allowed to recover again (see table below).

Carrier + Carrier	Carrier + GR46611(10.0mg/kg，s.c.)	Example 1 product (10.0mg/kg, s.c.) + Carrier	EXAMPLE 1 product (10.0mg/kg, S.C.) + GR46611(10.0mg/kg，s.c.)
				M±s.e.m.(n)	M±s.e.m.(n)	M±s.e.m.(n)	M±s.e.m.(n)
+2.0±2.5(10)	-40.7±2.3(5)	-9.5±3.7(8)	+0.7±3.4(6)

M ± s.e.m. mean ± standard error of the mean of the effect at each time point after administration of the product, n is the number of animals. The neurotransmitter quantity is a function of the average of the first three basic values of the product and is defined as 0%. The basal level corresponded to 0.59 ± 0.08pg/20 μ l microdialysate, evaluated when n is 10. Evaluation of GR by statistical methods by differential analysis of drugs as intermediate factors₄6611 reversal of the reduction in extracellular concentration of serotonin produced.

Claims (9)

1. 2-amino-1, 2-indane compounds represented by the following formula I in the form of a racemic mixture or in the form of an optical isomer and physiologically tolerated acid addition salts thereof:in formula I: -n is 2; -Ar is:wherein X is a hydrogen or fluorine atomR is a hydrogen atom, a linear or branched C_1-5Alkyl or aryl radicalsAn alkyl group; - -E is a hydrogen atom or a methyl group, and- -X₁，X₂，X₃And X₄May be the same or different and each represents a hydrogen atom or a halogen atom, a straight chain or a branched chain C_1-5Alkyl or C_1-5Alkoxy, trifluoromethyl, hydroxy, cyano or nitro radicals, or radicalsWherein: r₁、R₂And R₃May be the same or different and each represents a hydrogen atom or a linear or branched C_1-5Alkyl, and R₄Is straight chain or branched C_1-5Alkyl, and/or two X's adjacent to each other form, together with the carbon atom of the benzene ring to which they are attached, a 5-or 6-membered ring consisting of atoms selected from carbon atoms, oxygen atoms, nitrogen atoms and sulfur atoms.

2. A compound according to claim 1 selected from:

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (1, 2-indan-2-yl) amino ] piperidine and dihydrochloride salts thereof

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (1, 2-indan-2-yl) -N-methylamino ] piperidine and fumarate salts thereof

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5, 6-methylenedioxy-1, 2-indan-2-yl) amino ] piperidine and fumarate salts thereof

4- [ N- (1, 2-indan-2-yl) amino ] -1- (thiochroman-8-yl) piperidine

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5, 6-dimethoxy-1, 2-indan-2-yl) amino ] piperidine and fumarate salts thereof

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-methyl-1, 2-indan-2-yl) amino ] piperidine and fumarate salts thereof

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-chloro-1, 2-indan-2-yl) amino ] piperidine and fumarate salts thereof

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-methoxy-1, 2-indan-2-yl) amino ] piperidine and fumarate salts thereof

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5, 6-dimethyl-1, 2-indan-2-yl) amino ] piperidine and fumarate salt thereof

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-trifluoromethyl-1, 2-indan-2-yl) amino ] piperidine and fumarate salts thereof

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (4, 7-dimethoxy-1, 2-indan-2-yl) amino ] piperidine and hemifumarate salts thereof

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-fluoro-1, 2-indan-2-yl) amino ] piperidine and fumarate salts thereof

4- [ N- (1, 2-indan-2-yl) -N-methylamino ] -1- (2, 3-dihydro-1, 4-dioxino [2, 3-b ] pyridin-8-yl) piperidine

1- (2, 3-dihydro [1, 4] benzothiepin-5-yl) -4- (1, 2-indan-2-ylamino) piperidine and hemifumarate salts thereof

1- (chroman-8-yl) -4- (1, 2-indan-2-ylamino) piperidines and their fumarate salts

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -3- (1, 2-indan-2-ylamino) pyrrolidine and its dihydrochloride

1- (6-fluorobenzchroman-8-yl) -4- (1, 2-indan-2-ylamino) piperidine and fumarate salts thereof

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- (5-nitro-1, 2-indan-2-ylamino) piperidine and fumarate salts thereof

1- (chroman-8-yl) -4- [5- (1, 2, 4-triazol-4-yl) 1, 2-indan-2-ylamino ] piperidine and hemifumarate salts thereof

1- (chroman-8-yl) -4- [ (cyclopenta [ f)][2，1，3]Benzo (b) isOxadiazol-6-yl) amino]Piperidine and fumarate salts thereof

1- (chroman-8-yl) -4- [ (5-fluoro-1, 2-indan-2-yl) amino ] piperidine and fumarate salt thereof

1- (2, 3-dihydrobenzofuran-7-yl) -4- [ (5-fluoro-1, 2-indan-2-yl) amino ] piperidine and hemifumarate salt thereof

1- (chroman-8-yl) -4- [ (5, 6-methylenedioxy-1, 2-indan-2-yl) amino ] piperidine and fumarate salt thereof

1- (benzofuran-7-yl) -4- [ (5-fluoro-1, 2-indan-2-yl) amino ] piperidine and hemifumarate salt thereof

1- (chroman-8-yl) -4- [ (5-methoxy-1, 2-indan-2-yl) amino ] piperidine and fumarate salt thereof

1- (4-hydroxychroman-8-yl) -4- [ (5, 6-methylenedioxy-1, 2-indan-2-yl) amino ] piperidine and hemifumarate salts thereof

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- (1, 2-indan-2-ylamino) -4-methylpiperidine and fumarate salt thereof

1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-hydroxy-1, 2-indan-2-yl) amino ] piperidine and hemifumarate salts thereof

1- (chroman-8-yl) -4- [ N- (5-hydroxy-1, 2-indan-2-yl) amino ] piperidine and the hemifumarate salt thereof.

3. A compound according to claim 1 or 2 which is 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (1, 2-indan-2-yl) amino ] piperidine or its dihydrochloride.

4. A compound according to claim 1 or 2, which is 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5, 6-methylenedioxy-1, 2-indan-2-yl) amino ] piperidine or a fumarate salt thereof.

5. A compound according to claim 1 or 2 which is 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-fluoro-1, 2-indan-2-yl) amino ] piperidine or a fumarate salt thereof.

6. A compound according to claim 1 or 2 which is 1- (chroman-8-yl) -4- (1, 2-indan-2-ylamino) piperidine or a fumarate salt thereof.

7. A compound according to claim 1 or 2 which is 1- (2, 3-dihydro [1, 4] benzodioxin-5-yl) -4- [ N- (5-hydroxy-1, 2-indan-2-yl) amino ] piperidine or a hemi-fumarate salt thereof.

8. A process for preparing a compound of claim 1, characterized in that:

- - (II) CompoundWherein X₁、X₂、X₃And X₄Reacting a compound of formula III, as defined in claim 1 and L is a labile groupWherein R, E, n and Ar are as defined in claim 1, or in tetrahydrofuran in the presence of sodium borohydride or in dichloroethane in the presence of sodium triacetoxyborohydrideWherein X₁、X₂、X₃And X₄As defined hereinbefore, by reductive amination with compound III as defined above, or, when E is only a hydrogen atom, reacting compound V in tetrahydrofuran in the presence of sodium borohydride or in dichloroethane in the presence of sodium triacetoxyborohydrideWherein X₁、X₂、X₃、X₄And R is as previously defined, to compounds of formula VI:wherein n and Ar are as previously defined, to give a compound of formula I':wherein X₁、X₂、X₃、X₄R, Ar and n are as previously defined, compound I' is a subgroup of compound I; - - (Y- -O) - -or, finally, when the group Ar representsHeating the compound VII in a suitable solventWherein Hal represents a halogen atom selected from chlorine, bromine and iodine atoms, with a compound of formula VIII:wherein X₁、X₂、X₃、X₄R, E and n are as defined above, and reacting to give compound II ″)Compound I' is another subgroup of compound I; and when X is₁、X₂、X₃And X₄When one or more of the substituents is hydroxy, X₁、X₂、X₃And X₄Compounds of formula I as defined above wherein one or more of the substituents is hydroxy may be prepared by treating the corresponding methoxy compound with pyridinium hydrochloride at a temperature of 200 ℃; furthermore, when the compounds I contain one or more asymmetric carbon atoms, if desired, their optical isomers can be prepared by conventional resolution methods described in the literature or with optically active substances; and, optionally, the compound I thus obtained is treated with a pharmaceutically acceptable acid to obtain the corresponding acid addition salt.

9. A pharmaceutical composition for the treatment of depression, anxiety, impulse behaviour, obesity and psychosis associated with dysfunction of 5-hydroxytryptamine energy delivery, comprising a compound according to any one of claims 1 to 6 as an active ingredient together with one or more pharmaceutically suitable excipients.