Tricyclic3-piperidine, methods for their preparation and pharmaceutical composition based on them

 

(57) Abstract:

The present invention relates to compounds of formula I in which Alk represents a C1-6alcander; n is 0 or 1; X represents-O - or-S-; R1represents halogen, C1-6alkyl or C1-4alkyloxy; D represents a radical of formula (a)-(k). The invention also relates to a method for producing these compounds and to pharmaceutical compositions for the treatment of diseases that show antagonistic activity against Central2-adrenergic receptors. The technical result obtained new compounds possess valuable biological properties. 5 C. and 7 C.p. f-crystals, 3 PL.

The present invention relates to tricyclic 3-piperidine, which has antagonistic activity against Central2-adrenergic receptors. It also applies to receive them, to compositions comprising them and to their use as pharmaceuticals.

It is known that the Central antagonists2-adrenergic receptors increases the release of noradrenaline by blocking presynaptic2receptors, which provide inhibitory horsemeat,2antagonists can be used in the clinic for treatment or prevention of depression, cognitive impairment, Parkinson's disease, diabetes, sexual dysfunction and impotence, increased intraocular pressure, and diseases associated with the violation of enterokinase, because all these States are associated with deficiency of norepinephrine in the Central or peripheral nervous system.

Compounds of the present invention are new and have specific and selective binding affinity to various well-known subtypes2-adrenergic receptors, i.e., K2A,2Band2C-adrenergic receptors.

The present invention relates to compounds of the formula

to their N-oxide forms, the pharmaceutically acceptable additive salts and stereochemical isomeric forms, where:

Alk represents a C1-6alcander;

n is 1 or 2;

X1represents-O-, -S-, -S(=O)- or-S(=O)2-;

each R1independently represents hydrogen, halogen, C1-6alkyl, nitro, hydroxy or1-4alkyloxy;

D represents a radical of the formula

in which

each m the performance of is-O-, -S - or-NR11-;

X4represents-O-, -S-, -CH2-S - or-NR12-;

X5and X6each independently represent-CH2-, -O-, -S - or-NR11-;

R2represents hydrogen, C1-6alkyl, aryl or arils1-6alkyl;

R3represents hydrogen, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino or mono - or di (C1-6alkyl) amino;

R4, R5, R6, R7, R8, R9, R10, R11and R15each independently represents hydrogen or C1-6alkyl;

R12represents hydrogen, C1-6alkyl, C1-6alkalosis1-6alkyl or pyridinyl1-6alkyl;

R13, R14and R16each independently represents halogen or C1-6alkyl;

R3and R4taken together may form a bivalent radical-R3-R4formula

-CH2-CH2-CH2- (a-1)

-CH2-CH2-CH2-CH2- (a-2)

-CH=CH-CH2- (a-3)

-CH2-CH=CH- (a-4) or

-CH=CH-CH=CH- (a-5)

moreover, one or two hydrogen atoms in said radicals (a-1) to (a-5) each not the si, C1-6alkyloxy or C1-10alkylcarboxylic; or, when possible, two genialnyh hydrogen atom may be substituted C1-6alkylidene or arils1-6alkylidene; or

-R3-R4- can also be

-S-CH2-CH2- (and-6)

-S-CH2-CH2-CH2- (a-7)

-S-CH=CH- (a-8)

-NH-CH2-CH2- (a-9)

-NH-CH2-CH2-CH2- (a-10)

-NH-CH=CH- (a-11)

-NH-CH=N- (a-12)

-S-CH=N- (a-13) or

-CH=CH-O- (a-14)

one or, whenever possible, two or three hydrogen atoms in said radicals (a-6) to (a-14) each independently may be substituted C1-6the alkyl or aryl; and

aryl represents phenyl or phenyl substituted one, two or three substituents selected from halogen, hydroxy, nitro, cyano, trifloromethyl, C1-6of alkyl, C1-6alkyloxy, C1-6alkylthio, mercapto, amino, mono - and di (C1-6alkyl) amino, carboxyl, C1-6allyloxycarbonyl and C1-6alkylcarboxylic.

Used in the earlier definitions of the term halogen combines with fluorine, chlorine, bromine and iodine. The term1-4alkyl denotes a linear or branched saturated coal is iletin, 2-methylpropyl, etc., the meaning of the term C1-6alkyl include1-4alkyl radicals and the higher homologues having 5 or 6 carbon atoms, such as, for example, pentyl, hexyl, etc., the meaning of the term C1-10alkyl include C1-6alkyl radicals and the higher homologues having 7 to 10 carbon atoms, such as, for example, heptyl, octyl, nonyl, decyl, etc., the Term WITH1-5alcander denotes a bivalent alkadiene radical with a linear or branched chain, having from 1 to 5 carbon atoms, such as, for example, methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol, 1,5-pentandiol, etc. is Understood that the term C1-6alcander includes C1-5alcander and its higher homologs having 6 carbon atoms, such as, for example, 1,6-hexanediol, etc., the Term C1-6alkyliden denotes a bivalent alkylidene radical with a linear or branched chain, having from 1 to 6 carbon atoms, such as, for example, methylene, ethylidene, 1-propylidene, 1-butylidene, 1-pentylidene, 1-hexylidene etc.

It is implied that the term additive salt in this document includes therapeutically active form of additive salts that the compounds of formula (I) capable of forming with sootvetstvuyuschayatrebovaniyam or Hydrobromic acid; sulfuric; nitric; phosphoric and other acids; or organic acids, such as, for example, acetic, propanoic, hydroxyestra, lactic, pyruvic, oxalic, malonic, succinic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, reklamowa, salicylic, p-aminosalicylic, AMOVA and other acids.

It is implied that the term pharmaceutically acceptable salt additive, referred to earlier in this document, also includes the forms of the additive salts with therapeutically active non-toxic base, in particular a metal or an amine, which is able to form compounds of formula (I). The aforementioned salts can be easily obtained by treating compounds of formula (I) containing acidic hydrogen atoms, the corresponding organic or inorganic base, such salts as, for example, ammonium salts, salts of alkali and alkaline earth metals, for example, salts of lithium, sodium, potassium, magnesium, calcium, etc., salts of organic bases, for example, benzathine, N-methyl-D-glucamine, geranamine salts, and salts with amino acids such as, for example, arginine, lysine, etc.

Conversely, womanism base or acid.

The additive term salt as used above in this document also includes a solvate, which is able to form compounds of formula (I), and assume that the said solvate is included in the scope of the present invention. Examples of the solvate include, for example, hydrates, alcoholate, etc.,

The N-oxide forms of the compounds of formula (I) include compounds of formula (I) in which one or more atoms of nitrogen oxidized to the so-called N-oxide.

The term stereochemical isomeric form in this document refers to all possible isomeric forms, which can contain the compounds of formula (I). If it is not agreed or is not determined otherwise, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms, with the mentioned mixtures containing all diastereomers and enantiomers of basic molecular structure.

Some of the compounds of formula (I) may also exist in tautomeric forms. Have in mind that these forms, although they are not clearly indicated in the above formula, is included in the scope of the present invention.

Further, when reference is made to the position of the substituent R1use the following numbering is ormula (I) also includes the N-oxide forms, pharmaceutically acceptable additive salts and all stereoisomeric forms.

Particular compounds are those compounds of formula (I) in which D represents the radical of formula (a), (b), (C), (d), (e), (f), (g), (h), (i), (j), (k) or (l); m is 0; and aryl represents phenyl or phenyl substituted by halogen or C1-6the alkyl.

Compounds that deserve attention are those compounds of formula (I) in which n is 1, and R1represents hydrogen, chlorine, fluorine, methyl, methoxy or nitro, in particular when R1represents hydrogen, chlorine, methyl or methoxy.

In that case, if R1different from hydrogen, R1appropriately associated with tricyclic ring system in the 6 or 7 position.

Another group of compounds of interest are those compounds of formula I in which Alk represents methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol or 1.5-pentandiol.

The following group of compounds of interest are compounds of formula (I) in which D represents the radical of formula (a), in which R2represents aryl or methyl, and R3and R4taken together form a bivalent radical of formula (a-5) or (a-8); or D represents 6 represent methyl; or D is a radical of formula (C), in which R7represents hydrogen; or D is a radical of formula (d), in which X2is NR11-, and R11represents hydrogen; or D is a radical of the formula (e); or D is a radical of formula (f), in which X3is-S -, and R8represents hydrogen or C1-6alkyl, preferably, R8represents methyl; or D is a radical of formula (g), in which X4represents-CH2-S - or-NR12-, and R12is1-6alkalosis1-6alkyl or pyridinyl1-6alkyl, preferably, R12is acyloxyacyl or pyridinylmethyl; or D is a radical of formula (h), in which X5represents-O - or-S-, and R10represents hydrogen; or D is a radical of the formula (j); or D is a radical of formula (k), in which m is preferably 1, and R13represents halogen.

Particular compounds are those compounds of formula (I) in which X1represents-O - or-S-.

The preferred compounds are those compounds of formula (I) in which n is 1, R1represents hydrogen, chlorine, fluorine, matoi (k).

More preferred compounds are the compounds of formula (I) in which D represents the radical of formula (a), (C), (d), (f) and (h); X1represents O or S; n is 1; R1represents hydrogen, halogen or methyl, and a is a substituent in the 6 position; and Alk is 1,2-ethandiyl, 1,3-propanediyl or 1,4-butanediyl.

The most preferred compounds are the compounds shown below, or their N-oxide forms, pharmaceutically acceptable salt additive and stereochemical isomeric form.

As a rule, the compounds of formula (I) can be obtained N-alkylation of the intermediate compounds of formula (II) alkylating reagent of formula (III), following the procedure described in EP-A-0037265, EP-A-0070053, EP-A-0196132 and EP-A-0378255. In particular, the N-alkylation may be carried out in an inert towards the reaction solvent, such as, for example, methyl isobutyl ketone, N,N-dimethylformamide or N,N-dimethylacetamide, in the presence of a base, such as triethylamine, sodium carbonate or sodium bicarbonate, and optionally in the presence of a catalyst such as potassium iodide.

In the intermediate compound (III) W1is suitable reactionsultracet, 4 methylbenzenesulfonate.

In this and the following reactions, the reaction products can stand out from the reaction medium and, if necessary, further purified according to methodologies generally known in this field, such as extraction, crystallization, rubbing and chromatography.

The compounds of formula (I) in which D represents the radical of formula (f), represented by formula (I-f) can be obtained by N-alkylation of an amine of the formula (IV) intermediate compound (V), where W2represents an appropriate reactive leaving group such as, for example, halogen.

The typical method of obtaining compounds of formula (I) in which D is a radical of the formula (j), and Alk represents -(Alk’)p-CH2-, where Alk’ represents C1-5alcander, and p is 0 or 1, i.e. compounds represented by formula (I-j) includes recovery of N-alkylation of the intermediate compounds of formula (II) aldehyde derivative of formula (IV).

Mentioned reaction reductive N-alkylation may conveniently be carried out by the recovery of the mixture of the reactants in a suitable solvent inert to the reaction, following the reaction, the reaction mixture can be stirred and/or heated. Suitable solvents are, for example, water, methanol, ethanol, 2-propanol, etc., the Reaction is conveniently carried out with the use of cyanoborohydride sodium, sodium borohydride, formic acid, or their salts, and the like reducing agents, or, alternatively, in an atmosphere of hydrogen, optionally at elevated temperature and/or pressure, in the presence of a suitable catalyst, such as palladium on charcoal, platinum, coal, etc. To prevent unwanted additional hydrogenation of some functional groups in the reactants and the reaction products, it may be useful to add to the reaction mixture a suitable agent, poison the catalyst, for example, thiophene, quinoline-sulfur, etc. In some cases it may be useful to add to the reaction mixture salt of an alkali metal, such as, for example, potassium fluoride, potassium acetate and similar salts.

The compounds of formula (I) can be transformed into each other using known in the field of conversion reactions of functional groups.

The compounds of formula (I) can also be converted into the corresponding N-oxide forms using known in the field of transformation methods trivalent nitrogen into its Phnom material of the formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may include peroxyacids, such as, for example, benzonorbornadiene, or halogen-substituted benzonorbornadiene, for example, 3-chlorobenzalmalononitrile, phenoxyalkanoic acid, for example, peroxidasa acid, alkylhydroperoxide, for example, tert-butylhydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol, etc., hydrocarbons such as toluene, ketones, for example, 2-butanone, halogenated hydrocarbons such as dichloromethane, and mixtures of such solvents.

A number of intermediates and starting compounds are industrially available, or are known compounds which can be obtained in accordance with known in the field methods.

For example, some of the intermediate compounds of formula (III) and methods for their preparation are described in EP-A-0037265, EP-A-0070053, EP-A-0196132 and EP-A-0378255.

Intermediate compounds of formula (II) in which X represents-O-, can be palwasha methodology depicted in scheme 1.

Scheme 1

Intermediate compounds of formula (II) in which X represents-S-, can be obtained according to J. Med.Chem., 1992, 35(7), pp. 1176-1182, and using methods known in this field. A General method depicted in scheme 2.

Scheme 2

Alternatively, intermediate compounds of formula (II) can be obtained in accordance with the Synth. Comm., 1995, pp. 3883-3900, and using methods known in this field. A General method depicted in scheme 3.

Scheme 3

Intermediate compounds of formula (III) in which D represents the radical of formula (h), represented by formula (III-h) can be obtained by interaction of benzisoxazole or benzisothiazole formula (VII), in which3represents a suitable leaving group such as halogen, with aminopyrene derivative of the formula (VIII) in the presence of a catalyst such as potassium iodide. Usually the reaction mixture is stirred at elevated temperatures. Subsequently, a suitable leaving group such as halogen, for example chlorine, can be introduced into the thus obtained alcohol derived using known in the field of methods, for example, the interaction of alcohol with tinerilor the intermediate compounds of the present invention contain, at least one asymmetric carbon atom. Pure stereochemical isomeric forms of the above mentioned compounds and intermediate compounds can be obtained using well-known in this field procedures. For example, the diastereomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures first transformation mentioned racemic mixtures with suitable resolving agents such as, for example, chiral acids, mixtures of diastereomeric salts or compounds; then the physical separation of these mixtures of diastereomeric salts or compounds with, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally, turning referred separated diastereomeric salts or compounds into the corresponding enantiomers.

Pure stereochemical isomeric forms of the compounds of formula (I) can be also obtained from pure stereochemical isomeric forms of the appropriate temporarily is blowing to keep in mind what pure and mixed stereochemical isomeric forms of the compounds of formula (I) are included in the scope of this invention.

The compounds of formula (I), their N-oxides, pharmaceutically acceptable salt additive and stereochemical isomeric form block presynaptic 2receptors on Central noradrenergic neurons, thereby increasing the release of norepinephrine. Blocking the mentioned receptors inhibits or facilitates a number of symptoms associated with deficiency of norepinephrine in the Central or peripheral nervous system. Therapeutic indications for the use of the compounds of the present invention are depression, cognitive impairment, Parkinson's disease, diabetes, sexual dysfunction and impotence, and increased intraocular pressure.

It was also shown that blocking2receptors in the Central nervous system increases the release of serotonin, which may contribute to therapeutic effect in depression (Maura et al., 1992, Naunyn-Schmiedeberg''s Arch. Pharmacol., 345:410-416).

It was also shown that blocking2receptors can cause an increase in the concentration of extracellular DOPAC (3,4-dehydrophenylalanine joining for the treatment of diseases, associated with deficiency of norepinephrine in the Central nervous system, particularly depression and Parkinson's disease, the present invention provides a method of treating warm-blooded animals suffering from such diseases, in particular, depression and Parkinson's disease, the said method comprises the systemic introduction of therapeutically effective amounts of compounds of formula (I) or its pharmaceutically acceptable salt additive.

Compounds of the present invention are also potentially useful for the treatment of Alzheimer's disease and dementia, as it is known that2antagonists promote the release of acetylcholine (Tellez et al., 1997, J. Neurochem. 68:778-785).

In General, it is assumed that the daily effective therapeutic amount is from about 0.01 mg/kg to 4 mg/kg of body weight.

Thus, the present invention also relates to compounds of formula (I) as defined herein above, for use as drugs. Further, the present invention also relates to the use of compounds of formula (I) in the manufacture of pharmaceutical preparations for the treatment of depression or Parkinson's disease.

Ex vivo and t is the evaluation of the2adrenoreceptor antagonism of these compounds. As indicators of Central blockade 2-adrenergic receptors in vivo can be used to restore lost straightening reflex in rats observed after intravenous injection of xylazine, and inhibition of tremor caused by reserpine, in rats.

Compounds of the present invention also have the ability to quickly penetrate into the Central nervous system.

With the aim of introducing the discussed compounds may be converted to various forms of pharmaceutical compositions comprising pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of the compounds of formula (I). To obtain pharmaceutical compositions of this invention an effective amount of a specific compound in the form of additive salt or free form acid or base as the active ingredient together in a close mixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the form of preparation is required for injection. Preferably, these pharmaceutical compositions were presented in unit dosage form upon receipt of the compositions in dosage forms for oral administration, you can use any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols, etc., in the case of liquid preparations for oral administration such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, loosening agents, etc. in the case of powders, pills, capsules and tablets. Due to the simplicity of the introduction of tablets and capsules represent the most advantageous unit dosage forms for oral administration, in this case, obviously, apply solid pharmaceutical carriers. In the case of compositions for parenteral administration, the carrier typically includes sterile water, at least, it is the most part, although there may be included other components, for example, facilitate solubility. For example, can be obtained solutions for injection, in which the carrier comprises saline or saline solution, a glucose solution, or a mixture of these solutions. Injectable solutions containing the compounds of formula (I), can be cooked in oil for prolonged action. Suitable for this purpose oils are, for example, peanut mo-chain fatty acids, and mixtures of these and other oils. Can be also obtained suspension for injection, in this case, you can apply the appropriate liquid carriers, suspendresume agents, etc. In the compositions suitable for percutaneous administration, the carrier optionally includes an agent that increases the penetration and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor quantities, these additives should not exert any harmful effects on the skin. The aforementioned additives may facilitate the introduction into the skin and/or may be useful to obtain the desired compositions. Song data can be entered in various ways, for example, in the form of transdermal patches, pads, or in the form of ointment. Additive salts of the compounds of formula (I) due to their increased water solubility compared to the free basic or forms of free acids, obviously, are more appropriate when receiving water compositions.

Particularly advantageous is receiving any of the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. A unit dosage form in the description and formulas, each unit contains a defined quantity of active ingredient calculated to obtain the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including tablets with notches and coated tablets), capsules, pills, sachets of powder, pills, solutions or suspensions for injection, the capacity of a teaspoon, tablespoon, etc., and divided plural forms.

The following examples are intended to illustrate the present invention.

Experimental part

Later in this document, the term CT denotes room temperature, THF refers to tetrahydrofuran, DIPA refers to diisopropyl ether.

The intermediate compounds

Example A1

a) a Mixture of 3-chloro-1,2-benzisoxazole (0.08 mol), 4-amino-1-butanol (0.24 mol) and KI (1 g) is stirred for 4 days at 80°C. the Reaction mixture is cooled, dissolved in CH2Cl2and purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE 95/5). Pure fractions are collected, and the solvent evaporated, getting to 15.4 g (93%) of 4-(1,2-benzisoxazol-3-ylamino)-1-bregetova connection 1 (0,048 mol) in Cl3(20 ml) and the reaction mixture was stirred over night at RT. The solvent is evaporated. The residue is washed with water. The reaction mixture was extracted with CH2Cl2. The separated organic layer is dried (gS4), filtered and the solvent evaporated, getting 10.4 g of N-(4-chlorobutyl)-1,2-benzisoxazol-3-amine (ex. Conn.2).

Example A2

a) the Reaction takes place in an atmosphere of N2. NaH 60% (to 0.17 mol) is stirred in THF (350 ml). Add dropwise a solution of diethyl(cyanomethyl)phosphonate (to 0.17 mol) in THF (150 ml) within ±20 min (exothermic temperature rise to 30°C). The mixture is stirred for 20 min at RT, then cooled to 0°C. for 30 min at 0°C is added dropwise a solution of 5-methyl-3-benzofuranol (0.15 mol) in THF (350 ml). The reaction mixture is stirred overnight at RT, then poured into water (1500 ml) and stirred. The mixture is extracted with ether, DIPA (2), dried (gSO4), filtered and the solvent evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2/hexane 50/50). The target fractions are collected and the solvent evaporated, receiving of 21.2 g (82%) of 5-methyl-3-benzofurazanyl (ex. Conn.3).

b) a Mixture of intermediate compound (3) (0.12 mol) in NH3(2 EQ.) the catalyst is filtered off and the filtrate evaporated. The residue is purified on silica gel on a glass filter (eluent: CH2Cl2/(CH3HE/NH3from 98/2 to 96/4). The target fractions are collected and the solvent evaporated. The remainder (±2.1 g) is dissolved in 2-propanol (500 ml) and converted into the salt of hydrochloric acid (1:1) using HCl/2-propanol. The mixture is stirred at RT. The solvent is evaporated. The residue is stirred in DIPE, filtered and dried, obtaining 24.4 g (96%) of the hydrochloride of 5-methyl-3-benzoguanamine (1:1) (elapsed. Conn.4).

c) a Mixture of intermediate compound (4) (0,0024 mol) in N2About (2 ml), acetic acid (2 ml) and 37% formaldehyde (2 ml) is stirred for one hour at 100°C. the Reaction mixture is cooled and poured into 1M NaOH (50 ml). The precipitate is filtered off, washed with water, then dissolved in 1N HCl (100 ml). The mixture is stirred for 15 min on a hot water bath (80°C). The solvent is evaporated. Add 2-propanol. The solvent is evaporated. The residue is stirred in boiling 2-propanone, then leave to cool to CT under stirring. The precipitate is filtered off and dried, obtaining 0.40 g of 1,2,3,4-tetrahydro-6-methylbenzofuran[2,3-C]pyridine monohydrochloride. monohydrate (ex. Conn.5).

Example A3

the (0,025 mol) in acetonitrile (50 ml) and methylbenzene (150 ml) is stirred and heated under reflux overnight, then cooled, filtered and the filtrate evaporated. The residue (oil) is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE 98/2). Pure fractions are collected and the solvent evaporated, receiving of 5.2 g of 3,4-dihydrobenzofuran[2,3-C]pyridine-2(1H)-butanetriol (ex. Conn.6).

b) a Mixture of intermediate compound (6) (0,0195 mol) in NH3/CH3HE (200 ml) hydronaut using Raney Nickel (4 g) as the catalyst in the presence of a solution of thiophene (4 ml). After absorption of H2(2 EQ.) the catalyst is filtered off through dicalite and the filtrate is evaporated, receiving of 3.9 g of 3,4-dihydrobenzofuran[2,3-C]pyridine-2(1H)-butanamine (ex. Conn.7).

Example A4

a) a Mixture of 6-chloro-1,2,3,4-tetrahydro[1]benzothieno [2,3-C]pyridine (0.02 mol), 1,1-dimethylethyl(4-chlorobutyl) carbamate (0.02 mol), Na2CO3(3.5 g) and KI (0.1 g) in 4-methyl-2-pentanone (300 ml) is stirred and heated under reflux overnight. The reaction mixture is cooled, filtered and the filtrate evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2/CH3OH 96/4). The target fractions are collected and the solvent evaporated, receiving of 5.2 g of 1,1-dimethylethyl[4-(6-chloro-3,4-dihydrobenzo) (0,013 mol) in HCl/2-propanol (50 ml) and 2-propanol (100 ml) is stirred and heated under reflux for 30 minutes The reaction mixture is cooled. The precipitate (Hcl salt) is filtered off and converted into the free base using NH4OH. The mixture is extracted with CH2Cl2. The separated organic layer is dried, filtered and the solvent evaporated. The residue is triturated in CH3SP/DIPE, filtered and dried, obtaining 2.2 g of 6-chloro-3,4-dihydrobenzo[1]thieno[2,3-C]pyridine-2(1H)-yl)butanamine (ex. Conn.9).

Example A5

a) a Mixture of 37% formaldehyde (31 g) and ZnCl2(10 g) in ethyl acetate (90 ml) and 12N Hcl (190 ml) was stirred at -10°C. HCl (gaseous) provide an opportunity to barbthroat through the mixture until saturation (-10°C). At a temperature <0°C is added dropwise 5-toranzo[b]thiophene (0.35 mol). The reaction mixture was stirred over night at room temperature. Add toluene (200 ml) and the mixture vigorously stirred. The organic layer is separated, washed with aqueous solution of NaHCO3and water, dried, filtered and the solvent evaporated. The residue is triturated in hexane, filtered and dried, obtaining 58 g of 3-(chloromethyl)-5-toranzo[b]thiophene (82,6%) (ex. Conn.10).

b) a Mixture of sodium cyanide (0.33 mol) and octagenarians[b,k][1,4,7,10,13,16]hexaoxacyclooctadecane (0,050 g) in dimethyl sulfoxide (110 ml) was stirred at 30°C. On p is the temperature under stirring. Then the reaction mixture is stirred in water with ice. The precipitate is filtered off, washed with water and dissolved in CH2Cl2. The organic solution is dried, filtered and the solvent evaporated, receiving 5-toranzo[b]thiophene-3-acetonitrile (ex. Conn.11).

c) a Mixture of intermediate (11) (0.29 mol) in NH3/CH3HE (700 ml) hydronaut at 14°C, using a Raney Nickel (5 g) as a catalyst in the presence of a solution of thiophene (10 ml). After absorption of H2(2 EQ.) the catalyst is filtered off through dicalite and the filtrate evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/(CH3OH/NH3) 96/4). The target fractions are collected and the solvent evaporated. The residue is dissolved in DIPE and transformed into a salt of hydrochloric acid (1:1) using Hcl/2-propanol. The precipitate is filtered off, washed, DIPE and dried, obtaining of 48.5 g of the hydrochloride of 5-toranzo[b]thiophene-3-ethanamine (1:1) (elapsed. Conn.12).

d) a Mixture of intermediate (12) (0.21 mol) in N2(190 ml), acetic acid (190 ml) and 37% formaldehyde (190 ml) is stirred and heated under reflux for one hour. The reaction mixture is allowed to cool to room totaltravel, washed DIPE and dried, obtaining 21 g of the hydrochloride 1,1’-Methylenebis[6-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-C]pyridine (ex. Conn.13).

e) a Mixture of intermediate (13) (0,049 mol) in water (1700 ml) and 12N Hcl (285 ml) is stirred and heated under reflux for one hour. The precipitate is filtered off, washed with CH3CN, DIPE and dried, obtaining of 17.7 g of the hydrochloride of 6-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-C]pyridine (ex. Conn.13).

Example A6

The reaction takes place in an atmosphere of N2. A solution of 1,2-dichlorethane (0,026 mol) in CH2Cl2(60 ml) was stirred at -60°C. is Added dropwise dimethyl sulfoxide (3.8 ml) at -60°C and the mixture is stirred for 10 minutes a Solution of intermediate compound (1) (0,024 mol) in CH2Cl2(120 ml) is added dropwise at -60°C and the mixture is stirred for one hour at -60°C. is Added dropwise N,N-diethylethanamine (13,7 ml) and the reaction mixture stirred for 10 min at -60°C, then allowed to warm to room temperature. The mixture was poured into water (250 ml). The mixture is stirred for 10 minutes Separated the organic layer is dried, filtered and the solvent evaporated. The residue is triturated in hexane, filtered and dried, produces the ASS="ptx2">

Example B1

a) a Mixture of the hydrochloride 1,2,3,4-tetrahydrobenzo[2,3-C]pyridine (1:1) (0,007 mol), 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]-pyrimidine-4-it (0.012 mol), Na2CO3(0.015 mol) and KI (catalytic amount) in 2-butanone (100 ml) is stirred and heated under reflux overnight. The reaction mixture is filtered hot and the filtrate evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/(CH3HE/NH3from 98/2 to 97/3). The most pure fractions are collected and the solvent evaporated. The residue is dissolved in 2-propanol and added (E)-2-butandiol acid (1 g). The mixture is boiled and then stirred at RT. The precipitate is filtered off and dried, obtaining a 2.00 g(61%) 3-[2-(3,4-dihydrobenzofuran[2,3-C]pyridine-2(1H)-yl)ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-it (E)-2-butene-dioate (2:1) (Conn.1).

Example B1b

A mixture of the hydrochloride of 6-chloro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-C]pyridine (1:1) (0.01 mol), 1-(4-chlorobutyl)-1,3-dihydro-3-(1-methylethenyl)-2H-benzimidazole-2-she (0.01 mol), Na2CO3(3.5 g) and KI (0.1 g) in 2-butanone (200 ml) is stirred and heated under reflux overnight, then cooled, filtered and the filtrate evaporated. The residue is purified using couraud and the solvent evaporated. The residue is stirred in a boiling mixture of HCl/2-propanol. Add DIPA and the mixture is stirred. The precipitate is filtered off, washed, DIPE and dried. This fraction is transformed into free base is then extracted with CH2CL2. The separated organic layer is dried, filtered and the solvent evaporated. The residue is dissolved in 2-propanone and converted into the salt (E)-2-butandiol acid (1:1). The precipitate is filtered off, washed, DIPE and dried, obtaining of 0.82 g of 1-[4-(6-chloro-3,4-dihydrobenzofuran[2,3-C]pyridine-2(1H)-yl)butyl]-1,3-dihydro-2H-benzimidazole-2-it (E)-2-butenedioate (1:1) (compound 21).

Example B2

A mixture of the hydrochloride of 6-chloro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-C]pyridine (1:1) (0,00057 mol), 7-(2-chloroethyl)-1,3-dimethyl-7H-purine-2,6-(1H,3H)-dione (0,100 g) and PA2CO3(0,100 g) in 2-butanone (2 ml) is stirred over the weekend at 100°C. of the Target compound is isolated and purified by high performance liquid chromatography on a Kromasil unmodified silica gel with spherical particles (55 g, 60A, 5 μm) (column: 2 cm I. D.; eluent: CH2CL2/(CH2CL2/CH3HE 90/10)/CH3HE (0 min) 100/0/0, (10,50 min) 0/100/0, (12,50 min) 50/0/50, (14,00 min) 0/0/100, (15,01-20,00 min) 100/0/0). Pure fractions are collected, and the solvent evaporated, p is S="ptx2">

Example B3

A mixture of intermediate (9) (0,007), 2-chlorobenzothiazole (0.01 mol) and Na2CO3(2 g) in 2-ethoxyethanol (50 ml) is stirred and heated under reflux for 3 hours, the Reaction mixture is cooled, filtered and the filtrate evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE 96/4). Pure fractions are collected and the solvent evaporated. The residue is triturated in DIPE/CH3JV, is filtered off, washed, DIPE and dried, obtaining of 1.75 g of N-2-benzothiazolyl-6-chloro-3,4-dihydrobenzo[1]thieno[2,3-C]pyridine-2(1H)-butanamine (58,3%) (compound 64).

Example B4

A mixture of 3,4-dihydro-7-methoxybenzoate[2,3-C]pyridine-2(1H)-butanamine (0,0055), 3-chloro-1,2-benzisothiazole (0,0089 mol) and Panso3(0.01 mol) is stirred for 1.5 h at 120°C (water.) Add 1-butanol (0.5 ml). The reaction mixture is cooled and then dissolved in CH2Cl2and purified by column chromatography on silica gel (eluent: CH2CL2/(CH3HE/NH3) 98/2). The target fractions are collected and the solvent evaporated. The residue is dissolved in 2-propanone and converted into the salt of hydrochloric acid (1:2) using HCl/2-propanol. The mixture was stirred at thiazol-3-yl)-3,4-dihydro-7-methoxybenzoate[2,3-C]pyridine-2(1H)-butanamine (61%) (compound 55).

Example B5

Acetic acid (0,005 mol) are added to a monohydrate monohydrochloride 1,2,3,4-tetrahydro-7-methoxybenzoate[2,3-C]pyridine (0,005 mol) in 1,2-dichloroethane (30 ml). Add intermediate compound (15) (0,005 mol) and the mixture is stirred until complete dissolution. Add the N(SLA)3(0,005 mol) and the reaction mixture was stirred over weekend at room temperature. The reaction mixture was diluted with CH2CL2(100 ml), washed with 10% aqueous NaOH solution, then dried (MgSO4), filtered and the solvent evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2/(CH3HE/NH3) 98/2). The target fractions are collected and the solvent evaporated. The residue is dissolved in 2-propanone and converted into the salt (E)-2-butandiol acid (2:1), using (E)-2-butandiol acid (0.8 g). The mixture boil, then leave to cool to room temperature with stirring. The precipitate is filtered off and dried, obtaining 1.50 g of N-(1,2-benzisoxazol-3-yl)-3,4-dihydro-7-methoxybenzoate[2,3-C] pyridine-2(1H)-butanamine (68%) (compound 65).

Example B6

A mixture of intermediate compound (7) (0.015 mol), 2-chlorobenzothiazole (0.015 mol), Na2CO3(3 g) and KI (catalytical cooled to 50°C. The reaction mixture is filtered and the filtrate evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/CH3HE 95/5). Pure fractions are collected and the solvent evaporated. The residue is crystallized from CH3JV, filtered and dried, obtaining 2.4 g of N-2-benzothiazolyl-3,4-dihydrobenzofuran[2,3-C]pyridine-2(1H)-butanamide (compound 25).

Example B7

Hydrochloride 1,2,3,4-tetrahydrobenzo[2,3-C]pyridine (1:1) (0.01 mol) is transformed into the free base using CH2CL2/N2ARF4HE. The mentioned mixture of the free base, the intermediate (2) (0.019 mol) and triethylamine (0.015 mol) in N,N-dimethylacetamide (50 ml) was stirred at 70°C for 48 hours, the Solvent is evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2CL2/(CH3HE/NH3) 98/2). The target fractions are collected and the solvent evaporated. The residue is dissolved in 2-propanol and treated with (E)-2-butandiol acid (1 g). The mixture boil, then stirred at RT. The solvent is evaporated. The residue is dissolved in 2-propanone, boil, and then stirred at RT. The solvent is evaporated. The residue is dissolved in 2-propanol is acidified to shift the N-1,2-benzisoxazol-3-yl-3,4-dihydrobenzofuran[2,3-C]pyridine-2(1H)-butanamine (61%) (compound 36).

Example B8

The original substance hydrochloride 1,2,3,4-tetrahydrobenzo[2,3-C]pyridine (1:1) (0.01 mol) is alkalinized, extracted and the solvent evaporated, obtaining the free base (1.4 g 0,008 mol). The mentioned mixture of free base and 4-phenoxybenzaldehyde (0.01 mol) in methanol (150 ml) hydronaut using 10% Pd/C (1 g) as a catalyst in the presence of 4% thiophene (1 ml). After absorption of H2(1 EQ.) the catalyst is filtered off and the filtrate evaporated. The residue is purified by column chromatography on silica gel (eluent: CH2Cl2/ (CH3HE/NH3) 98/2). The target fractions are collected and the solvent evaporated. The residue is dissolved in 2-propanol and converted into the salt (E)-2-butandiol acid (1:1), using (E)-2-butandiol acid (1.2 g). The mixture boil, then leave to cool to CT under stirring. The precipitate is filtered off and dried, obtaining of 1.80 g (49%) of 1,2,3,4-tetrahydro-2-[(4-phenoxyphenyl)methyl]benzofuro[2,3-C]pyridine (E)-2-butenedioate (1:1) (compound 33).

Example B9

A mixture of the hydrochloride 1,2,3,4-tetrahydro-[1]benzothieno[2,3-C]pyridine (1:1) (0.01 mol) and phenoxybenzaldehyde (0.01 mol) in methanol (150 ml) hydronaut at 50°C, using 10% Pd/C (1 g) as a catalyst in prisudstvivala. The residue is crystallized from CH3JV, filtered and evaporated. This fraction (3 g) is stirred in water with a small amount of NH4OH and the mixture extracted with CH2Cl2. The separated organic layer is dried (gSO4), filtered and the solvent evaporated. The residue is crystallized from CH3JV, filtered and dried, obtaining 2.7 g of 1,2,3,4-tetrahydro-2-[(4-phenoxyphenyl)methyl]benzothieno[2,3-C] pyridine (compound 34).

Table 1 lists the compounds of formula (I), which were obtained in accordance with one of the above examples.

C. Pharmacological examples

Example C. 1: Binding affinity to2receptors in vitro Interaction of compounds of formula (I)2receptors evaluated in experiments in vitro binding radiometric ligands.

Typically, a low concentration radiochango ligand with high binding affinity to a specific receptor is incubated with the sample preparation tissue enriched with a particular receptor, or with a preparation of cells expressing the cloned human receptors in the buffer medium. In the process iception radioactivity was separated from unbound radioactivity, and count associated with receptor activity. The interaction of test compounds with the receptor evaluated in experiments on competitive binding. To the incubation mixture containing the drug and receptor radiolucency ligand add different concentrations of the tested compounds. Linking radiochango ligand inhibited by the test compound is proportional to its binding affinity and concentration.

As radiochango ligand to bind with the2A-,2B-,2Creceptors used 3H-rauwolscine and as a receptor preparation used cells of the Chinese hamster ovary (Cho) expressing the cloned human2A-,2Band2C- receptors.

Among the tested compounds connection№1, 5, 7, 8, 11, 12, 13, 16, 17, 19, 24, 28, 29, 20, 32, 33 and 36 inhibited each of the three receptors more than 50% in the tested concentration ranges from 10-6up to 10-9M

D. Examples of compositions

"Active ingredient" (A. I.), used throughout these examples relates to a compound of formula (I), its pharmaceutically acceptable additive salt or a stereochemical isomeric form.

Example D. 1: Kiya and 1.2 g of magnesium stearate are intensively mixed together. The resulting mixture is subsequently filled into 1000 suitable hard gelatin capsules, each containing 20 mg A. I.

Example D. 2: Tablets, film-coated

Obtain core tablets

A mixture of 100 g A. I., 570 g lactose and 200 g starch is mixed well and then moisturize using a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone approximately 200 ml of water. Wet powder mixture is sieved, dried, and sift again. Then add 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All together, mixed well and compressed into tablets, receiving 10,000 tablets each containing 10 mg of active ingredient.

Coating

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane.

Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. Melt 10 g of polyethylene glycol and dissolved in 75 ml of dichloromethane. The last solution is added to the first and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension and homogenized. The core table is solution for oral administration

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate dissolved in 4 l of boiling purified water. In 3 l of this solution are dissolved first 10 g of 2,3-dihydroxybutanedioate acid and then 20 g of A. I. the Latter solution is combined with the remaining part of the first solution and then add 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 g sodium saccharin dissolved in 0.5 l of water and add 2 ml of raspberry and 2 ml of gooseberry family essences. The latter solution is combined with the first, water is added in sufficient quantity to obtain a volume of 20 l, obtaining a solution for oral administration containing 5 mg of active ingredient in a teaspoon (5 ml). The resulting solution fill in appropriate containers.

Example D. 4: Solution for injection

1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate dissolved in approximately 0.5 l of boiling water for injection. After cooling to approximately 50°C add with stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g of A. I. the Solution is cooled to CT and add water for injection sufficient to obtain a volume of 1 l, obtaining a solution containing 4 mg/ml A. I. the Solution is sterilized by filtration and filled them sterile containers.

its N-oxide form, pharmaceutically acceptable additive salt or a stereochemical isomeric form, in the formula

Alk represents a C1-6alcander;

n is 0 or 1;

X1represents-O - or-S-;

each R1replacing a hydrogen atom attached to the aromatic ring independently is halogen, C1-6alkyl or C1-4alkyloxy;

D represents a radical of the formula

in which each m is independently 0 or 1;

X2is-NR11-;

X3is-S-;

X4is-NR12-;

X5represents-O - or-S-;

R2represents C1-6alkyl, aryl or arils1-6alkyl;

R3and R4taken together may form a bivalent radical-R3-R4formula-CH=CH-CH=CH- (a-5) or-S-CH=CH- (a-8);

R5, R6, R7, R8, R9, R10and R11each independently represents hydrogen or C1-6alkyl;

R12

aryl represents phenyl or phenyl substituted by halogen or C1-6the alkyl.

2. Connection on p. 1, in which D represents the radical of formula (a), (b), (C), (d), (e), (f), (g), (h), (i), (j) or (k), in which m is 0; and aryl represents phenyl or phenyl substituted by halogen or C1-6the alkyl.

3. Connection under item 1 or 2, in which n is 1, a R1represents hydrogen, chlorine, fluorine, methyl, methoxy.

4. The compound according to any one of paragraphs.1-3, in which Alk represents methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol or 1.5-pentandiol.

5. The compound according to any one of paragraphs.1-4, in which D represents the radical of formula (a), in which R2represents aryl or methyl, and R3and R4taken together form a bivalent radical of formula (a-5) or (a-8); or D is a radical of formula (b), in which R5and R6submit C1-6alkyl; or D is a radical of formula (C), in which R7represents hydrogen; or D is a radical of formula (d), in which X2is-NR11and R11represents hydrogen; or D is a radical of the formula (e); or D is a radical of formula (f), in which X3is-S -, and R8represents hydrogen or C1-61-6alkalosis1-6alkyl or pyridinyl1-6alkyl; or D is a radical of formula (h), in which X5represents-O - or-S-, and R10represents hydrogen; or D is a radical of the formula (i) in which R9represents methyl; or D is a radical of the formula (j); or D is a radical of formula (k), in which m is 1, and R13represents halogen.

6. Connection on p. 1, representing

or its N-oxide form, pharmaceutically acceptable additive salt or a stereochemical isomeric form.

7. The compound according to any one of paragraphs.1-6, useful as an antagonist 2-adrenergic receptors.

8. The compound according to any one of paragraphs.1-5, suitable for the manufacture of pharmaceutical preparations for the treatment of depression or Parkinson's disease.

9. Pharmaceutical composition for the treatment of diseases that show antagonistic activity against Central2-adrenergic receptors, PP.1-5 and a pharmaceutically acceptable carrier.

10. The method of obtaining the compounds according to p. 1, characterized in that includes the N-alkylation of the intermediate compounds of formula (II):

where X1n and R1have the meanings given in paragraph 1, the alkylating reagent of formula (III):

D-Alk-W1,

where W1represents a suitable leaving group, and D, Alk have the meanings given in paragraph 1, in an inert towards the reaction solvent, in the presence of a base and optionally in the presence of a catalyst to obtain the compounds of formula (I); and, optionally, the conversion of compounds of formula (I) into each other by means known in the art of transformation, and, further, if desired, converting compounds of formula (I) into a therapeutically active non-toxic acid additive salt by treatment with acid, or into a therapeutically active non-toxic additive salt of the base by treatment with base, or, on the contrary, the conversion of an acid additive salt form into the free base by treatment with alkali, or the transformation of the additive salt of the base to the free acid by treatment with acid; and, optionally, obtaining their stereochemical isomeric forms, or N-oxides.

11. The way of getting connected to the SUB> X1, Alk, R1R8and n have the meanings given in paragraph 1, characterized in that includes the N-alkylation of an amine of the formula (IV)

where Alk, X1, n, R1and R8have the meanings given in paragraph 1, the intermediate compound of formula (V)

where W2represents a suitable leaving group, and X3matter specified in paragraph 1, with education, thus, the compounds of formula (I-f); and optional, the conversion of compounds of formula (I) into each other by means known in the art of transformation, and, further, if desired, converting compounds of formula (I) into a therapeutically active non-toxic acid additive salt by treatment with acid, or into a therapeutically active non-toxic additive salt of the base by treatment with a base, or conversely, converting the acid additive salt form into the free base by treatment with alkali, or the transformation of the additive salt of the base to the free acid by treatment with acid; and, optionally, obtaining their stereochemical isomeric forms, or N-oxides.

12. The method of obtaining the compounds of formula (I) according to p. 1, representing a compound of formula (I-j)

paragraph 1,

characterized in that includes the recovery of N-alkylation of the intermediate compounds of formula (II)

in which X1, R1and n have the meanings given in paragraph 1,

aldehyde derivative of formula (VI)

in which Alk’ is the values specified above, p is 0 or 1, the recovery of the mixture of the reactants in a suitable inert reaction solvent, in accordance with well-known in the art techniques reductive N-alkylation, with the formation of the compounds of formula (I-j); and, optionally, the conversion of compounds of formula (I) into each other by means known in the art of transformation, and, further, if desired, converting compounds of formula (I) into a therapeutically active non-toxic acid additive salt by treatment with acid, or into a therapeutically active non-toxic additive salt of the base by treatment with a base, or conversely, converting the acid additive salt form into the free base by treatment with alkali, or the transformation of the additive salt of the base to the free acid by treatment with acid; and, optionally, obtaining their stereochemical isomeric forms, or N-oxides.

 

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< / BR>
where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

< / BR>
is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts

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R3where R1and R2lower alkyl;

R3the rest of the group, including tetrahydrofurane, thiophene, dithiolane, dithienyl, furan, optionally substituted by a group: -CH2OH, CHO, COOH,

-CH=where Alk denotes alkyl with 1-4 carbon atoms,

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-CONHN-CH< / BR>
-CH=C< / BR>
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or R3residue selected from the group:

(CH2)1,2< / BR>
ororin VI

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< / BR>
Unsubstituted or substituted in position 1 with 3.7-dealkylation are the main four and intermediate products to obtain drugs
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