Derivatives of piperidine and pharmaceutical drugs based on them

 

(57) Abstract:

The invention relates to new derivatives of 4-hydroxypiperidine formula I

< / BR>
where X represents-O-, -NH-, -CH2-, -CH=, -SNON - or-CO-; R1-R4independently from each other denote hydrogen, a hydroxy-group, (lower) alkylsulfonyl or acetaminoph; R5-R8independently from each other denote hydrogen, a hydroxy-group, (lower)alkyl, halogen, (lower)alkoxygroup, trifluoromethyl or cryptometrics; a and b may denote a double bond, provided that when a represents a double bond, b is unable to designate a double bond; n = 0-2; m = 1-3; p = 0 or 1, and their pharmaceutically acceptable additive salts. Compounds of the present invention are selective blockers of the NMDA subtype-(N-methyl-D-aspartate)-receptor, which can participate in mediaready processes underlying the development of the CNS, including the formation and functioning of learning ability and memory. 2 S. and 9 C.p. f-crystals, 3 tables.

The present invention relates to derivatives of 4-hydroxypiperidine General formula

< / BR>
where X represents-O-, -NH-, -CH2-, -CH=, -SNON-, -CO-, -S-, -SO - or-SO2-;

R1-R4nez is silt or acetaminoph;

R5-R8independently from each other denote hydrogen, a hydroxy-group, (lower)alkyl, halogen, (lower)alkoxygroup, trifluoromethyl or cryptometrics;

a and b can denote a double bond, provided that when "a" represents a double bond, "b" may not indicate a double bond;

n is 0-2;

m is 1-3;

p is 0 or 1,

and their pharmaceutically acceptable additive salts.

The compounds of formula I and their salts possess therapeutic properties. Compounds of the present invention are selective blockers subtype of the NMDA receptor (N-methyl-D-aspartate-receptor), which has a key function in modulating neuronal activity and plasticity, which makes them key players mediaready processes underlying the development of the CNS, including in the formation and functioning of learning ability and memory.

In pathological conditions, both acute and chronic forms of neurodegeneration excessive activity of the NMDA receptor is a key factor that triggers the loss of nerve cells. NMDA receptors are composed of representatives of the families of two subunits, called NR-1 (8 different splicing variants) and NR-2 (a to D), which is the p the e in different parts of the brain. Heteromera combination of representatives of the NR-1 with different subunits NR-2 determine the expression of NMDA receptors in different pharmaceutical properties. Possible therapeutic indications for application-specific blockers subtype of the NMDA receptor include acute forms of neurodegeneration caused, for example, stroke and brain injury, and chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (als), and neurodegeneration associated with bacterial or viral infections.

The invention relates to compounds of formula I and their pharmaceutically acceptable additive salts, racemic mixtures and the corresponding enantiomers, to obtain the above-mentioned compounds containing drugs and methods for their manufacture and to the use of the above compounds for the treatment or prevention of illnesses, especially of illnesses and disorders of the above types, or in the manufacture of corresponding medicaments.

The following definitions of common terms used in the present description, applicable regardless of whether considered whether these concepts separately or in combination. is extensive circuit, containing from 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, 2-butyl and tert-butyl.

The term "halogen" includes chlorine, iodine, fluorine and bromine.

The term "(lower)alkoxy" refers to a group, where the alkyl radical has the values listed above.

The term "leaving group" has the conventional meaning and refers, for example, halogen, alkylsulfonate, arylsulfonate, etc., the Most preferred leaving group is halogen.

The term "pharmaceutically acceptable additive salts" includes salts with inorganic and organic acids, are well known to the person skilled in the technical field, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, para-toluensulfonate acid, etc.

Preferred are the compounds of formula I in which X represents-O-, -NH-, - SNON - or-CH2-.

Examples of preferred compounds in which X represents-O-, are:

(RS)-1-(5-hydroxy-2,3-dimethyl)piperidine-4-ol,

(RS)-4-(4-terbisil)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol,

(RS)-4-(4-active compounds)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl) piperidine-4-ol,

(S)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol,

(S)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-Chlorobenzyl)piperidine-4-ol,

(RS)-N-[2-{ 4-chloro-4-(4-methylbenzyl)piperidine-1-ylmethyl]-2,3-dihydrobenzofuran-5-yl]methanesulfonamide and

(RS)-N-[2-{4-hydroxy-4-(4-methylben

ZIL)piperidine-1-ylmethyl}- 2,3-dihydrobenzofuran-5-yl] methanesulfonamide.

Examples of preferred compounds in which X represents-SNON-are:

(1RS, 2RS) and (1RS, 2SR)-2-[4-hydroxy-4-(4-methylbenzyl)piperidine-1-ylmethyl] indan-1,5-diol,

(1RS, 2RS)-1-(1,6-dihydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol and

(1RS, 2RS)-2-(4-benzyl-4-hydroxypiperidine-1-ylmethyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-ol.

Other examples of preferred compounds in which X represents-CH2- are:

(RS)-1-(5-hydroxyine-2-ylmethyl)-4- (4-methylbenzyl) piperidine-4-ol and

(RS)-1-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl) piperidine-4-ol.

In addition, other preferred seeding-indol-5-ol.

The compounds of formula I of the present invention and their pharmaceutically acceptable salts can be obtained by methods well known in the art, for example the methods described below, including:

a) interaction of the compounds of formula

< / BR>
where R1-R4, X, a, b, n and m have the abovementioned meanings and L represents HE or a leaving group, for example halogen or-O-tosyl, with the compound of the formula

< / BR>
where R5-R8and R have the above values, or

b) interaction of the compounds of formula

< / BR>
where the substituents have the abovementioned meanings, with a compound of the formula

< / BR>
in the presence of paraformaldehyde with obtaining the compounds of formula

< / BR>
where m is equal to 1 and the other substituents have the above values, or

b) dehydration of the compounds of formula

< / BR>
obtaining the compounds of formula

< / BR>
where m is equal to 1 and the other substituents have the above values,

g) recovering the compounds of formula IA with obtaining the compounds of formula IB, or

e) dibenzylamine the compounds of formula

< / BR>
(e) the interaction of the compounds of formula I, where one of the radicals R1-R4denotes amino, (lower)alcalali)alkylsulfonamides, or

g) hydrogenation of an isolated double bond in the compound of formula I, or

C) removing the hydroxy - or aminosidine(Noah) group(s) present(s) in the form of substituents(I) R1-R4or in the form of group X' which implies that N(protective group), or

I) oxidation of compounds of formula I in which X represents-S - or-SO-, to obtain the corresponding sulfonylurea (SO2connection and

K) if necessary, the conversion of the compounds of formula I in a pharmaceutically acceptable additive salt.

In accordance with variant a) of the above method, the mixture of the compounds of formula II and compounds of formula III, where the leaving group L in the compound of formula II is, for example, bromine, dissolved in a suitable solvent, for example, DMF, and heated to approximately 80-90oC. This reaction is carried out in the presence of a base, preferably triethylamine. Then the compound of formula I allocate an accepted way. When one of the radicals R1-R4in formula II represents a hydroxy-group, these groups protect using commonly used for this purpose, the protective groups.

Examples of such groups are described in Green, T., Protective Groups in Organic Synthesis, Chapter 7, John Wiley and by known methods, for example, by hydrogenation in the presence of Pd/C (10%) or solution tribromide boron-dichloromethane.

In variant b) method described process of producing compounds of the formula I, in which X represents a group-CO-.

The compound of formula IV is heated in a suitable solvent, such as DMF, together with the compound of the formula IIIA in the presence of paraformaldehyde. This reaction is carried out generally accepted method at a temperature of approximately 80oC.

In accordance with variant b) of the above method, the compound of formula IB can be digidratirovannogo conventional method in the presence of ethanol solution model HC1. Thus obtain the compounds of formula I, in which "a" represents a double bond.

In variant d) the described method recovery compounds of the formula IA with obtaining compounds of formula IB. This reaction is carried out conventional manner, preferably in the presence of LiA1H4in THF and at a temperature of about 5 to 10oC.

According to variant d) of the above method are the compound of the formula I in which one of the radicals1-R4denotes a hydroxy-group. This process is performed using dibenzylamine the compounds of formula V, provided the way. For example, the compound of formula V is dissolved in a suitable solvent or mixture of solvents such as ethanol and ethyl acetate, and hydronaut in the presence of palladium on coal at room temperature and atmospheric pressure.

In accordance with variant (e) of the above method can be obtained compound of the formula I in which one of the radicals R1-R4represents (lower)alkylsulfonamides. This reaction is carried out at room temperature by treating the compounds of formula I in which one of the radicals R1-R4denotes amino, (lower)alkylsulfonates, such as methanesulfonate, in a suitable solvent, such as methylene chloride, in the presence of pyridine.

Hydrogenation of the compounds of formula I in which one of the symbols "a" or "b" denotes a double bond, in accordance with option g) of the above method is carried out the conventional way, for example, in the presence of Pd/C in ethyl acetate in a hydrogen atmosphere for about 24 hours at room temperature. Protective group, for example hidroxizina group may be removed by the above methods. Suitable protective groups and methods for their removal should be known is that can be removed under conditions which do not affect other structural elements in the compounds.

Oxidation of compounds of the formula I, in which X represents-S - or-SO-, conduct an accepted way. In accordance with a variant) of the above method, the compounds of formula I in which X represents-S - or-SO-, oxidized to obtain the corresponding sulfonylurea (SO2) connections. The oxidation can be carried out in the presence of Oxone(triple salt monopersulfate potassium) at room temperature or in the presence of metallocarboranes acid.

Additive salts of compounds of formula I are most suitable for pharmaceutical applications.

The initial products to obtain the compounds of formula I are known or can be obtained by known methods, for example, in accordance with the following reaction schemes. These reactions are described in more detail in the examples 33-75.

As indicated previously, the compounds of formula I and their pharmaceutically acceptable additive salts have useful pharmacodynamic properties. They are selective blockers subtype of the NMDA receptor, which has a key function in the modulation of neural activity and the place is the formation of learning and memory.

Compounds were tested in the following tests.

Method 1

Binding3N Ro 25-6981 (Ro 25-6981 means [R-(R*,S*)]-a-(4-hydroxyphenyl)-b-methyl-4-(phenylmethyl)-1-piperidinemethanol)

Used male rats albino line Fullinsdorf weighing 150-200 g Membrane was obtained by homogenization of the whole brain without cerebellum and medulla oblongata with the help of a centrifuge of the type transmitter station (10,000 rpm, 30 s) in 25 volumes of cold buffer containing 50 mm Tris-HCl, 10 mm add, pH of 7.1. The homogenate was centrifuged at 48000xg for 10 minutes at 4oC. Debris resuspendable using the transmitter station in the same volume of buffer and the homogenate was incubated at 37oC for 10 minutes. After centrifugation debris homogenized in the same buffer and kept at -80oC for at least 16 hours but not more than 10 days. For analysis of binding the homogenate was thawed at 37oC, centrifuged and debris were washed three times as described above, in 5 mm Tris-Hcl cold buffer, pH 7.4. The resulting debris resuspendable in the same buffer and used at a final concentration of 200 μg protein/ml

Experiments on binding3N Ro 25-6981 was performed using 50 mm Tris buffer-H using 10 μm of tetrahydroisoquinoline, and usually its contents amounted to 10% of the total. The time of incubation at 4oWith was 2 hours, and the experience was stopped by filtration through glass fiber filters type Whatmann GF/B Unifilter-96, Packard company, Zurich, Switzerland). The filters were washed 5 times with cold buffer. The radioactivity on the filter was counted using a microplate scintillation counter type Packard Top-count after adding 40 ml microcirculation fluid 40 (firm Canberra Packard, Zurich, Switzerland).

Effects of the compounds was assessed using a minimum of 8 concentrations and repeating the experience at least once. The summed normalized values were analyzed using the program for calculation by the method of nonlinear regression, allowing us to obtain the values of the IC50with 95%-tion of the upper and lower confidence limits (RS1, BBN, USA).

Method 2

Binding3H-prazosin

Used male rats albino line Fullinsdorf weighing 150-200 g Membrane was obtained by homogenization of the whole brain without cerebellum and medulla oblongata with the help of a centrifuge of the type transmitter station (10,000 rpm, 30 s) in 25 volumes of cold buffer containing 50 mm Tris-HCl, 10 mm add, pH of 7.1. The homogenate was centrifuged at 48000xg in t who has bated at 37oC for 10 minutes. After centrifugation debris was homogeneously in the same buffer and kept at -80oC for at least 16 hours but not more than 10 days. For analysis of binding the homogenate was thawed at 37oC, centrifuged and debris were washed three times as described above, in 5 mm cold buffer Tris-HCl, pH 7.4. The resulting debris resuspendable in the same buffer and used at a final concentration of 200 μg protein/ml

Experiments on binding3H-prazosin was performed using 50 mm buffer Tris-HCl, pH 7.4. For the experiments on the substitution applied 0.2 nm3H-prazosin and nonspecific binding was assessed using a 100 µm chlorpromazine. The incubation time at room temperature was 30 minutes, and the experience was stopped by filtration through glass fiber filters type Whatmann GF/B Unifilter-96, Packard company, Zurich, Switzerland). The filters were washed 5 times with cold buffer. The radioactivity on the filter was counted using a microplate scintillation counter type Packard Top-count after adding 40 ml microcirculation fluid 40 (firm Canberra Packard, Zurich, Switzerland).

Effects of the compounds was assessed using a minimum of 8 if, using the program for calculation by the method of nonlinear regression, allowing us to obtain the values of the IC50with 95%-tion of the upper and lower confidence limits (RS1, BBN, USA).

Method 3

Electrophysiological study on recombinant NMDA receptors

The cDNA clones encoding the subunit NR1C and NR2A NMDA receptor (data item subunits of the NMDA receptor, see Hollmann and Heinemann, 1994, Annu. Rev. Neurosci. 17: 31), was isolated from the cDNA library gt11 brain of the rat, as described by Sigel and others (1994, J. Biol. Chem. 269: 8204). Clone for the NR2B subunit of the NMDA receptor brain rats were obtained from S. Nakanishi (Kyoto, Japan). cDNA encoding the subunit NR1C, NR2A and NR2B rats, was subcloned into the expression vector pBC/CMV (Bertocci and others, 1991, Proc. Natl. Acad. Sci. USA 88:1416), while the transcription of cDNA under the control of the promoter of human cytomegalovirus. Purified using CsCl expression plasmids were mixed in the ratio 1:3 with NR1:NR2A or NR1C:NR2B in the buffer for injection (88 mm NaCl, 1 mm KS1, 15 mm HEPES, pH 7.0). For expression or a combination of subunits NR1C and NR2A or subunits NR1C and NR2B used the oocytes of the South African clawed frogs (Xenopus laevis). From 12 to 120 PG mix 1:3 (NR1C:NR2B) relevant species cDNA were injected with in the nucleus of each oocyte. Within two leucodon cDNA expression in oocytes and fixing voltage see, for example, Bertrand and others, 1991, Methods in Neurosciences 4: 174). Membrane potential was recorded at the level of -80 mV and the receptors activated by adding the modified ringer's solution containing such agonists of the NMDA receptor, as L-glutamate (Glu) and glycine (Gly). For each combination of subunits were chosen with different concentrations of agonist to determine different levels of sensitivity to agonists of two types of receptors (2.7 μm Glu plus of 0.9 μm Gly for NR1C+NR2A and 1.3 μm Glu plus of 0.07 μm Gly for NR1C+NR2B). Agonists were made with an interval of 15 s every 2.5 min by Express superfusion oocyte solution containing the agonist, and the amplitude caused by the agonist flow was measured immediately before the end of each treatment. After a series of initial control treatments tested antagonist was added to the main ringer's solution, and the solution containing the agonist. The concentration of the antagonist, which was treated oocytes expressing the NR2A subunit, was 10 µmol/l, and oocytes expressing NR2B, were treated with the concentration of 0.1 μmol/l For each connection and subtype of the NMDA receptor were tested from 4 to 6 oocytes. The oocytes were treated with compounds for 5-30 minutes depending on the time required to achieve equilibrium procenta from the amplitude control flow, measured before processing the connection. The data in the tables represent the average arithmetic value of the interest.

Thus defined, the activity of some compounds according to the invention are presented in table.1 (see the end of the description).

By screening among the compounds of formula I can be identified selective blockers subtype of the NMDA receptor, and for some compounds using electrophysiological method using expressed by oocytes cloned subtypes of the NMDA receptor can be demonstrated that the preferred action against NMDAR-2B-subunits.

The compounds of formula I and their salts of the present invention can be incorporated into standard pharmaceutical dosage forms, for example, for oral or parenteral administration, together with the usual pharmaceutical adjuvants, such as organic or inorganic inert carrier, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, resins, polyalkylphenol, etc., the Pharmaceutical preparations can be applied in solid form, for example in the form of tablets, suppositories, capsules, or in liquid form, which include preservatives, stabilizers, wetting or emulsifying agents, salts to change the osmotic pressure or acting as buffers. The pharmaceutical preparations can also contain other therapeutically active compounds.

Daily dose of injected compounds of formula I varies depending on the specific compound, chosen route of administration and the recipient. Typical methods of using compounds of the formula formula I are oral or parenteral route of administration. The composition for oral administration the compounds of formula I preferably is prescribed to adults at a dose of 150 mg to 1.5 g per day. The composition for parenteral administration the compounds of formula I preferably is prescribed to adults in a dose of from 5 to 500 mg per day.

Below the invention is illustrated in more detail by examples. All temperatures are in degrees Celsius.

Example 1

1-(6-hydroxy-3,4-dihydronaphthalene-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol

(1RS, 2RS)(1-1,6-dihydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4(4-methylbenzyl)piperidine-4-ol (286 mg, 0.75 mmol) was dissolved in EtOAc (25 ml) and treated 6,4 N. model HC1 in EtOH at room temperature. Then the mixture for 1 h, boiled with Obratnaya3. Then the reaction mixture was extracted with EtOAc (250 ml), washed with saturated NaCl solution (25 ml), dried over Na2SO4, was filtered and was evaporated, getting mentioned in the title compound in a solid pink color (238,8 mg, 0,657 mmol, 87%); MS: m/e=363,2 (M+H+).

Example 2

Hydrochloride, (RS)-1-(5-hydroxy-2,3-dihydrobenzofuran-2 - ylmethyl)-4-(4-methylbenzyl) piperidine-4-ol

(RS)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol (1.0 g, 2.2 mmol) in Meon (100 ml) was first made in the presence of Pd/C (10%) (200 mg) for 17 h at ambient temperature. After removal of the catalyst and evaporation was obtained a yellow foam (720 mg, 2.0 mmol, 92%). Then this product (618 mg, about 1.75 mmol) was dissolved in EtOH (20 ml) and treated 1,45 N. model HC1/tO (1.1 EQ.) at 0-5oWith getting hydrochloride, (RS)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol as a white/beige foam, a mixture of E/Z-isomers (679 mg, quantitative yield), MS: m/e=354,2 (M+H+).

According to the method described in example 2, were obtained compounds of examples 3-12.

Example 3

Hydrochloride, (RS)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methoxybenzyl) piperidine-4-ol

Specified in the header yl)piperidine-4-ol.

Example 4

Hydrochloride, (RS)-4-benzyl-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl) piperidine-4-ol

Specified in the title compound [MS: m/e=340,2 (M+H+)] was obtained from (RS)-4-benzyl-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl) piperidine-4-ol.

Example 5

Hydrochloride, (RS)-4-(4-terbisil)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol

Specified in the title compound [MS: m/e=358,2 (M+H+)] was obtained from (RS)-4-(4-terbisil)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol.

Example 6

Hydrochloride, (RS)-4-(3,4-dimethylbenzyl)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl) piperidine-4-ol

Specified in the title compound [MS: m/e=368,2 (M+H+)] was obtained from (RS)-4-(3,4-dimethylbenzyl)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol.

Example 7

Hydrochloride, (RS)-4-(4-active compounds)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol

Specified in the title compound [MS: m/e=368,2 (M+H+)] was obtained from (RS)-4-(4-active compounds)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol.

Example 8

Hydrochloride, (RS)-4-(4-isopropylbenzyl)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl) piperidine-4-ol

Specified in the header soeverein-4-ol.

Example 9

Hydrochloride, (RS)-4-(2-methylbenzyl)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol

Specified in the title compound [MS: m/e=354,2 (M+N+)] was obtained from (RS)-4-(2-methylbenzyl)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol.

Example 10

Hydrochloride, (RS)-4-(2,4-diferensial)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol

Specified in the title compound [MS: m/e=376,2 (M+N+)] was obtained from (RS)-4-(2,4-diferensial)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol.

Example 11

Hydrochloride, (RS)-4-(4-cryptomaterial)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol

Specified in the title compound [MS: m/e=424,2 (M+N+)] was obtained from (RS)-4-(4-cryptomaterial)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol.

Example 12

Hydrochloride, (RS)-4-(3-trifloromethyl)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol

Specified in the title compound [MS: m/e=408,2 (M+N+)] was obtained from (RS)-4-(3-trifloromethyl)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol.

Example 13

Hydrochloride (S)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzol), dissolved in 50 ml of CH2CL2was cooled to -78oAnd dropwise in an argon atmosphere was added a 1M solution of BBr3-CH2Cl2(12.5 ml, 2.2 EQ.). The beige suspension was allowed to warm to ambient temperature for 30 min, and then was stirred for another 1 h, during which he formed a sticky yellow solid residue. Then to terminate the reaction was added Meon (10 ml) and then distilled H2O (100 ml) and a saturated solution Panso3(25 ml); the mixture was intensively stirred for 15 minutes the Organic phase was separated, then the aqueous phase was added a saturated solution of NaCl (100 ml) and was extracted with CH2CL2(250 ml). The combined organic extracts were dried over Na2SO4and then filtered and evaporated. The resulting yellow foam was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira CH2Cl2, a then Meon-CH2CL2(3:97), then Meon-CH2CL2(7:93) to give (S)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(methylbenzyl)piperidine-4-ol (1.7 g, to 4.81 mmol, yield 84%). This compound (1,62 g, 4,58 mmol) suspended in EtOH and treated with 1.1 EQ. ethanol model HC1 solution at 0-5oWith getting hydrochloride (S)-1-(5-Gita (1,74 g, to 4.46 mmol, 97%), MS: m/e=354,2 (M+H+) []20D=+57,8o(C=1,0, EtOH).

As described in example 13 method were obtained compounds of examples 14 and 15.

Example 14

Hydrochloride (S)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-chloranil)piperidine-4-ol

Specified in the title compound [MS: m/e=374,2 (M+H+) []20D=+32,4o(C= 1,0, DMF)] , yield >99% E. E. were obtained using GHUR with chiral phase (S)-1-(5-methoxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-Chlorobenzyl)piperidine-4-ol.

Example 15

Hydrochloride (R)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl) -4-(methylbenzyl) piperidine-4-ol

Specified in the title compound, which is a mixture of E/Z-isomers, in the form of a white foam (1.64 g, 4.20 mmol, 100%) [MS: m/e=354,2 (M+H+) []20D=-58,0o(C= 1,0, tO)] was obtained from (R)-1-(5-methoxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(methylbenzyl)piperidine-4-ol.

Example 16

Fumarate (1RS, 2RS) and (1RS,2SR)-2-[4-hydroxy-4-(4-methylbenzyl) piperidine-1-ylmethyl] indan-1,5-diol

(1RS,2RS) and (1RS,2SR)-2-[4-benzyloxy-4-(4-methylbenzyl) piperidine-1-ylmethyl] indan-1,5-diol (674 mg, of 1.84 mmol) was dissolved in tO (20 ml) was added fumaric acid (106 mg, of 0.92 mmol), the mixture was stirred for 2 h at comnl)piperidine-1-ylmethyl] indan-1,5-diol in the form of a white foam (0,78 g, quantitative yield), MS: m/e=368,2 (M+H+).

Example 17

(1RS,2RS) and (1RS,2SR)-2-[4-hydroxy-4-(4-methylbenzyl) piperidine-1-ylmethyl] indan-1,5-diol

A solution containing (1RS,2RS) and (1RS,2SR)-2-14-benzyloxy-4-(4-methylbenzyl) piperidine-1-ylmethyl]indan-1,5-diol (0,83 g, 1.82 mmol) in Meon (100 ml) and 10% Pd/C (100 mg), was intensively stirred in hydrogen atmosphere for 1 h at ambient temperature. After removal of the catalyst and evaporation of the solvent has been specified in the header connection: (1RS, 2RS) and (1RS, 2SR)-2-[4-hydroxy-4-(4-methylbenzyl)piperidine-1-ylmethyl] indan-1,5-diol (664 mg, is 1.81 mmol, 99%) as an amorphous white foam, a mixture (1:1) diastereoisomers, MS: m/e=368,2 (M+H+).

Example 18

Hydrochloride, (RS)-1-(5-hydroxyine-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol

(RS)-1-(5-hydroxyine-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol (177 mg, 0,503 mmol) was dissolved in EtOH, was added to the ethanol solution model HC1 (1.7 EQ. ) and after 15 min the product was besieged, adding cooling to 4oWith diethyl ether. In this way received the product, hydrochloride, (RS)-1-(5-hydroxyine-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol (95,7 mg, 0,246 mmol, 49%) as a foam solid white, tPL88-90oC. MS: m/e=352,2 (M+N++).

Example 20

1-(6-hydroxy-1H-inden-2-ylmethyl)-4-(4-methylester)piperidine-4-ol

(1RS, 2RS) and (1RS,2SR)-2-[4-hydroxy-4-(4-methylbenzyl)piperidine-1-ylmethyl] indan-1,5-diol (310 mg, 0.84 mmol) and ethanol model HC1 solution (5 EQ.) kept in EtOAc (30 ml) at 65oC for 1.5 h were Added distilled N2O (30 ml) and 10% solution Panso3(30 ml) and the mixture was shaken, and then the aqueous phase was extracted with EtOAc (220 ml) and the combined organic extracts were washed with saturated NaCl solution (30 ml), dried (Na2SO4) and filtered. After evaporation of the solvent was obtained 1-(6-hydroxy-1H-inden-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol in the form of a solid beige color (308 mg, 0.84 mmol, 100%), tPL154-157oC, MS: m/e=350,2 (M+H+).

Example 21

(RS)-2-[4-hydroxy-4-(4-methylbenzyl)piperidine-1-ylmethyl] -2,3-dihydro-1H-indol-5-ol

To a solution of (RS)-1-(5-methoxy-2,3-dihydro-1H-indole-2-Linie 5 min 1M VVG3-CH2CL2(2,14 ml, is 2.74 mmol, 6 EQ.). The reaction mixture was stirred at room temperature for 48 h, then was added Meon (20 ml) and then 10% solution Panso3(20 ml), after which the aqueous phase was extracted with CH2CL2(250 ml) and the combined extracts were washed with saturated NaCl solution (50 ml), dried (Na2SO4), filtered and evaporated. After purification of the crude product on SiO2(Merck, 230-400 mesh mesh), elwira CH2CL2-Meon (9: 1), was obtained (RS)-2-[4-hydroxy-4-(4-methylbenzyl)piperidine-1-ylmethyl] -2,3-dihydro-1H-indol-5-ol in the form of a solid brown color (64,6 mg, 0,183 mmol, 51%), tPL90-94oC, MS: m/e=353,3 (M+N+).

Example 22

Hydrochloride, (RS)-N-{ 2-[4-(4-Chlorobenzyl)-4-hydroxypiperidine-1-ylmethyl] -2,3-dihydrobenzofuran-5-yl} methanesulfonamide

(RS)-N-(2-methyl bromide-2,3-dihydrobenzofuran-5-yl)methanesulfonamide (600 mg, a 1.96 mmol), 4-(4-Chlorobenzyl)piperidine-4-ol (514 mg, a 1.96 mmol), Et3N (400 mg, of 3.96 mmol) was dissolved in DMF (50 ml) and kept at 60oWith over 90 hours Then DMF is evaporated and the residue was dissolved in CH2Cl2and washed with N2O. the Organic phase was dried over Na2SO4and concentrated. The residue was chromatographically on SiOtarali in THF (50 ml) and treated with 1.2 N. Model HC1 (1 ml), receiving hydrochloride, (RS)-N-{2-[4-(4-Chlorobenzyl)-4-hydroxypiperidine-1-ylmethyl] -2,3-dihydrobenzofuran-5-yl} methanesulfonamide, mixture of E/Z-isomers, in the form of a white foam. MS: m/e=451,3 (M+N+).

According to the method described in example 22, received the compound from example 23.

Example 23

Hydrochloride, (RS)-N-(2-[4-hydroxy-4-(4-methylbenzyl)piperidine-1-ylmethyl] -2,3-dihydrobenzofuran-5-yl] methanesulfonamide

Specified in the title compound [MS: m/e=431,5 (M+H+)] was obtained from (RS)-N-(2-methyl bromide-2,3-dihydrobenzofuran-5-yl)methanesulfonamide and 4-(4-methylbenzyl)piperidine-4-ol.

Example 24

Hydrochloride, (RS)-1-(6-hydoxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol

(RS)-1-(6-methoxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol (1.24 g, 3,37 mmol), dissolved in 35 ml of CH2CL2was cooled to -8oAnd dropwise in an argon atmosphere was added a 1M solution of BBr3-CH2Cl2(6.8 ml, 2 EQ.). Suspension purple color was allowed to warm to room temperature and then was stirred for 30 minutes and Then the reaction mixture was cooled to 0oWith and to terminate the reaction was added Meon (9 ml), and then a saturated solution Panso3(50 ml). Organizes who left the house taking over Na2SO4, then filtered and evaporated. The resulting yellow foam was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira MeOH-CH2Cl2(1: 19), and then Meon-CH2CL2(1:9), with the yellow foam, which was dissolved in Meon (5 ml) and treated with 1 ad model HC1 (3.4 ml), receiving hydrochloride, (RS)-1-(6-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol (0,92 g, 70%), mixture of E/Z-isomers, in the form of solids in white, tPL203-205oC, MS: m/e=354,3 (M+N+).

As described in example 24 method received the compound of example 25.

Example 25

Hydrochloride of 1-(6-hydroxybenzophenone-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol

Specified in the header connection [tPL214oC, MS: m/e=352,2 (M+N+)] was obtained from 1-(6-methoxybenzophenone-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol.

Example 26

Hydrochloride, (RS)-4-benzyl-1-(6-hydroxypropan-2-ylmethyl) piperidine-4-ol

(RS)-4-benzyl-1-(6-benzyloxyindole-2-ylmethyl) piperidine-4-ol (0,58 g of 1.31 mmol) was dissolved in tO (30 ml) was added 10% Pd/C (135 mg), the mixture was placed in an atmosphere of hydrogen and intensively stirred for 17 h at ambient temperature. After removal of the catalyst and white (0,37 g, 1.04 mmol, 80%), which was dissolved in EtOH (10 ml) and at 0 to 5oWith added HCl/EtOH (1.1 EQ.). After removal of solvent received hydrochloride, (RS)-4-benzyl-1-(6-hydroxypropan-2-ylmethyl) piperidine-4-ol in the form of a white foam (0,38 g, 0.98 mmol, 95%), MS: m/e=354,4 (M+N+).

Example 27

Fumarate (1RS, 2RS)-1-(1,6-dihydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol

(1RS, 2RS)-1-(1,6-dihydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol (0,581 g, 1.53 mmol) in EtOH (20 ml) was stirred with fumaric acid (88 mg, 0,765 mmol, 0.5 EQ.) for 2 h at room temperature. The mixture is then completely evaporated and dried in high vacuum, getting mentioned in the title compound as an amorphous white foam (0.66 g, quantitative yield), MS: m/e=382,3 (M+N+).

Example 28

(1RS, 2RS)-1-(1,6-dihydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol

1-(6-benzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol (0,22 g, 0.46 mmol) in tO (60 ml) was treated with 10% Pd/C (50 mg) and was stirred for 6 h at ambient temperature in a hydrogen atmosphere. After removal of the catalyst and evaporation of the solvent has been specified in zahouania in example 28 was obtained compound from example 29.

Example 29

(1RS, 2RS)-2-(4-benzyl-4-hydroxypiperidine-1-ylmethyl)-6-hydoxy-1,2,3,4-tetrahydronaphthalen-1-ol

Specified in the title compound in the form of a solid white color tPL94-98oC, MS: m/e= 368,4 (M+H+)] was obtained from (1RS,2RS)-2-(4-benzyl-4-hydroxypiperidine-1-ylmethyl)-6-benzyloxy-1,2,3,4-tetrahydro-naphthalene-1-ol.

Example 30

Hydrochloride, (RS)-1-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol

To (RS)-1-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl) piperidine-4-Olu (500 mg, of 1.36 mmol) in tO (4 ml) at 4oWith added ethanol solution model HC1 (1.1 EQ.). After evaporation tO got mentioned in the title compound as white foam (530 mg, 1,32 mmol, 97%), MS: m/e=366,2 (M+N+).

Example 31

(RS)-1-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl) piperidine-4-ol

To (RS)-1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-Olu (843 mg, 2.22 mmol) in CH2Cl2(20 ml) was added over 15 min at -78oWith 1M VVG3/CH2CL2(4,88 ml, 4,88 mmol, 2.2 equiv.) and then the mixture was allowed to warm to room temperature over 40 minutes was Added Meon (3 ml), N2O (20 ml) and Panso3(20 ml)SUB>2
SO4), filtered and evaporated, obtaining the crude product as yellow foam. After chromatography was carried out on SiO2(Merck, 230-400 mesh mesh), elwira CH2Cl2-MeOH (97: 3), was obtained (RS)-1-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol in the form of a white foam (500 mg, 13,68 mmol, 61%), MS: m/e=366,2 (M+H+).

Example 32

Hydrochloride, (RS)-N-[6-(4-benzyl-4-hydroxypiperidine-1-ylmethyl)-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl]ndimethylacetamide

N-(5,6,7,8-tetrahydro-5-oxo-2-naphthyl)ndimethylacetamide (1.0 g, to 4.92 mmol), hydrochloride of 4-(benzyl)piperidine-4-ol (1.12 g, to 4.92 mmol) and paraformaldehyde (148 mg, to 4.92 mmol) stood together in DMF (50 ml) at 80oC for 4 h and Then DMF is evaporated, the residue was dissolved in CH2CL2(50 ml) and washed with 10% solution Panso3(25 ml), and then the aqueous phase was extracted with CH2CL2(50 ml) and the combined CH2CL2the extracts were dried (Na2SO4), filtered and evaporated. The crude product was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira CH2Cl2-MeOH-NH4OH (110: 10:1) and receiving 0,79 g of yellow foam. This product was dissolved in EtOH, cooled to 0-4oWith, and was added to the ethanol solution model HC1 (1.1 equiv.) sediment in view of the Sabbath.)-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl] ndimethylacetamide (639 mg, 1.44 mmol, 29%), tPL123-126oC, MS: m/e=of 407.5 (M+N+).

N-(5,6,7,8-tetrahydro-5-oxo-2-naphthyl)ndimethylacetamide received in accordance with the method described in the literature: Biggs D. F., and others, J. Med. Chem., 19, 1976, 472-475; Allinger N. L., Jones, E. S., J. Org. Chem., 27, 1962, 70-76.

The production of intermediate products

A common way to obtain benzylpiperidine intermediate products

Example 33

(RS)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl) piperidine-4-ol

(RS)-5-benzyloxy-2-methyl bromide-2,3-dihydrobenzofuran (840 mg, 2,63 mmol) and 4-(4-methylbenzyl)piperidine-4-ol (1.08 g, 5,26 mmol) suspended in toluene (20 ml) and heated to 110oC for 17 h the Mixture was filtered and evaporated, getting an orange oil, which was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira MeOH-CH2Cl2(3:97) and receiving (RS)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol as yellow oil (1,03 g, 2.32 mmol, 88%), MS: m/e=445,5 (M+H+).

Obtaining intermediates for examples 2-12

As described in example 33 was obtained compounds of examples 34-43.

Example 34

1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methoxybenzyl) piperidine-4-ol

Specified-(RS)-methyl bromide-2,3-dihydrobenzofuran.

Example 35

(RS)-4-benzyl-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl) piperidine-4-ol

Specified in the title compound [MS: m/e=430,6 (M+H+)] was obtained from 4-(benzyl)piperidine-4-ol and 5-benzyloxy-2-(RS)-methyl bromide-2,3-dihydrobenzofuran.

Example 36

(RS)-4-(4-terbisil)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl) piperidine-4-ol

Specified in the title compound [MS: m/e=448,6 (M+H+)] was obtained from 4-(4-terbisil)piperidine-4-ol and 5-benzyloxy-2-(RS)-methyl bromide-2,3-dihydrobenzofuran.

Example 37

(RS)-4-(3,4-dimethylbenzyl)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol

Specified in the title compound [MS: m/e=458,6 (M+N+)] was obtained from 4-(3,4-dimethylbenzyl)piperidine-4-ol and 5-benzyloxy-2-(RS)-methyl bromide-2,3-dihydrobenzofuran.

Example 38

(RS)-4-(4-active compounds)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl) piperidine-4-ol

Specified in the title compound [MS: m/e=458,6 (M+H+)] was obtained from 4-(4-active compounds)piperidine-4-ol and 5-benzyloxy-2-(RS)-methyl bromide-2,

3-dihydrobenzofuran.

Example 39

(RS)-4-(4-isopropylbenzyl)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl) piperidine-4-ol

Specified in the title compound [MS: m/e=472,6 (M+N+)] received the 40

(RS)-4-(2-methylbenzyl)-1-(5-ensiacet-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol

Specified in the title compound [MS: m/e=444,6 (M+H+)] was obtained from 4-(2-methylbenzyl)piperidine-4-ol and 5-benzyloxy-2-(RS)-methyl bromide-2,3-dihydrobenzofuran.

Example 41

(RS)-4-(2,4-diferensial)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol

Specified in the title compound [MS: m/e=466,6 (M+H+)] was obtained from 4-(2,4-diferensial)piperidine-4-ol and 5-benzyloxy-2-(RS)-methyl bromide-2,3-dihydrobenzofuran.

Example 42

(RS)-4-(4-cryptomaterial)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol

Specified in the title compound [MS: m/e=514,6 (M+H+)] was obtained from 4-(4-cryptomaterial)piperidine-4-ol and 5-benzyloxy-2-(RS)-methyl bromide-2,3-dihydrobenzofuran.

Example 43

(RS)-4-(3-trifloromethyl)-1-(5-benzyloxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol

Specified in the title compound [MS: m/e=498,6 (M+H+)] was obtained from 4-(3-trifloromethyl)piperidine-4-ol and 5-benzyloxy-2-(RS)-methyl bromide-2,3-dihydrobenzofuran.

Example 44

(RS)-5-benzyloxy-2-(methyl bromide)-2,3-dihydrobenzofuran

4-benzyloxy-2-(2,3-dibromopropyl)phenyl ether (RS)-acetic acid (of 5.05 is s 2 h at ambient temperature. Then added distilled N2O (100 ml) and CH2Cl2(100 ml) and the separated organic phase. The aqueous phase was extracted with CH2Cl2(100 ml) and the combined organic extracts were washed with saturated NaCl solution (100 ml). The yellow oil obtained after drying over Na2SO4, filtration and evaporation was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira CH2Cl2and receiving (RS)-5-benzyloxy-2- (methyl bromide)-2,3-dihydrobenzofuran in the form of a yellow oil (3.0 g, 9,39 mmol, 83%), MS: m/e= 318,0 (M+).

Example 45

4-benzyloxy-2-(2,3-dibromopropyl)phenyl ether (RS)-acetic acid

To a solution of 2-allyl-4-benzyloxyphenyl ether acetic acid (3,30 g, 11.7 mmol) in CCL4(30 ml) at 0-5oC for 10 min was added bromine (0.6 ml, 11.7 mmol) and the resulting mixture was stirred for 1 h at 5-10oC. To terminate the reaction solution was added PA2CO3(10%, 4 ml) and distilled H2About (10 ml). The organic phase was separated, dried over Na2SO4and then was evaporated, obtaining a colorless oil, which after recrystallization when standing was obtained 4-benzyloxy-2-(2,3-dibromopropyl)phenyl ether (RS)-acetic acid (of 5.05 g of 11.4 mmol, who kusnoy acid

2-allyl-4-benzyloxyphenol (2,87 g, 12 mmol) was dissolved in acetic anhydride (40 ml) was added NaOAc (150 mg, 1.8 mmol) and the mixture was stirred at 80oC for 18 hours After cooling, the reaction mixture was evaporated, getting an oil, which was distributed between EtOAc and H2O (100 ml), the aqueous phase was extracted with EtOAc (100 ml) and the combined organic phases were dried over MgSO4, was filtered and was evaporated, obtaining 2-allyl-4-benzyloxyphenyl ether acetic acid as a pale yellow oil (3,30 g, 11.7 mmol, 97%), MS: m/e=282,1 (M+).

Example 47

2-allyl-4-benzyloxyphenol

1-benzyloxy-4-allyloxymethyl (20.4 g, 84,9 mmol) dissolved in mesitylene (150 ml), kept at 165oC for 48 h in an argon atmosphere. After cooling to ambient temperature the resulting brown oil was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira EtOAc-n-hexane (1: 9) and receiving 2-allyl-4-benzyloxyphenol in the form of a light yellow oil (17,45 g, to 72.6 mmol, 85%), MS: m/e=240,l (M+).

Example 48

1-benzyloxy-4-allyloxymethyl

4-benzyloxyphenol (20 g, 100 mmol), K2CO3(20,8 g, 150 mmol) and allylbromide (12,7 ml, 150 mmol) was boiled under reflux in acetone (200 ml) for 18 hours Polenovo color (23,8 g, 99 mmol, 99%), tPL56-57oC, MS: m/e=240,1 (M+).

Obtaining an intermediate product for examples 13 and 14

Example 49

(S)-1-(5-methoxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl) piperidine-4-ol

5-methoxy-2,3-dihydrobenzofuran-2-ymetray ether (S)-toluensulfonate acid (2.30 g, to 6.88 mmol), 4-(4-methylbenzyl)piperidine-4-ol (1,62 g, 7.9 mmol) and Na2CO3(1.10 g, or 10.3 mmol) suspended in DMF and kept at 110oC for 1 h After cooling to ambient temperature was added distilled N2O and EtOAc (100 ml), the mixture was shaken, the organic phase was separated and the aqueous phase was extracted with EtOAc (10 ml). Then the combined organic extracts were washed with saturated NaCl solution (100 ml) and the organic phase was dried over Na2SO4, was filtered and was evaporated, receiving a yellow oil. The product was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira CH2Cl2and then CH2Cl2-MeOH (97:3) and obtaining (S)-1-(5-methoxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol as yellow oil (2.20 g, 6.0 mmol, yield 87%), MS: m/e=368,2 (M+N+); []20D=+45,8o(C=1,0, SMS3).

As described in EAN-2-ylmethyl)-4-(4-Chlorobenzyl)piperidine-4-ol

Specified in the title compound [MS: m/e=387,9 (M+N+)] was obtained from 4-(4-Chlorobenzyl)piperidine-4-ol and 5-methoxy-2,3-dihydrobenzofuran-2-Eletropaulo ether (S)-toluensulfonate acid.

Example 51

5-methoxy-2,3-dihydrobenzofuran-2-ymetray ether (S)-toluensulfonate acid

A solution of (S)-5-methoxy-2,3-dihydrobenzofuran-2-carboxylic acid (2.4 g, 12.4 mmol) in THF (30 ml) was added dropwise over 15 min while cooling to a suspension of LiA1H4 (0.71 g, 18.5 mmol) in THF (20 ml). The mixture is then boiled under reflux for 1 h, after cooling, were added distilled N2About (0.7 ml), and then 4 N. NaOH (1.4 ml) and distilled H2Of (2.1 ml). The whole mixture was dried over Na2SO4, was filtered and was evaporated, getting the oil light yellow (2.20 g, 12.2 mmol, 100%). This oil was dissolved in pyridine (22 ml) was added para-toluensulfonate (3,48 g, and 18.3 mmol) and the mixture was stirred at ambient temperature for 1 h Then the crude mixture was added N2Oh and intensively stirred for 10 min, was extracted with EtOAc (2100 ml) and washed organic phase is 2 N. model HC1 (150 ml) and then saturated NaCl solution (100 ml), dried over Na2SO4and evaporated, receiving a yellow oil. hydroventure-2-ymetray ether (S)-toluensulfonate acid in a solid white color (2.4 g, 7.2 mmol, 57%), tPL82-84oC, MS: m/e=334,1 (M+); []20D=+75,1o(C=1,0, SMS3).

Example 52

(S)-5-methoxy-2,3-dihydrobenzofuran-2-carboxylic acid

To a solution of R(+)-1-(1-naphthyl)ethylamine (3.80 g, of 22.2 mmol) in acetone (40 ml) was added (RS)-5-methoxy-2,3-dihydrobenzofuran-2-carboxylic acid (4.1 g, 21.1 mmol) in acetone (80 ml), and after keeping under stirring for 2-3 minutes at ambient temperature was deposited solid beige color, after which the mixture was cooled to 0-5oC and stirred for another 30 minutes, the Solid product was filtered and washed with cold (4o(C) acetone (320 ml) to give 6 g of white crystals, tPL183-190oC. This solid product is twice recrystallized from hot EtOH (60 ml) to give 4.0 g of white crystals, tPL190-194oC. This product is suspended in EtOAc (100 ml) and washed with 1 N. model HC1 (50 ml), the acidic aqueous phase was extracted with EtOAc (50 ml) then the combined organic extracts were washed with distilled H2About (50 ml), then dried over Na2SO4and evaporated, obtaining (S)-5-methoxy-2,3-dihydrobenzofuran-2-carboxylic acid as a pale yellow crystalline solid (2.3 g, the EP 53

(RS)-5-methoxy-2,3-dihydrobenzofuran-2-carboxylic acid

To a suspension of 5-methoxybenzophenone-2-carboxylic acid (14 g, for 72.8 mmol) in Meon (600 ml) was added magnesium turnings (10.6 g, 437 mmol) and the mixture was intensively stirred with a mechanical stirrer for 2 h, keeping the temperature below 30oC. After 2 h was additionally added magnesium (10.6 g, 437 mmol) and the mixture was stirred for 4 h, again maintaining the temperature below 30oC. After 6 h the mixture was concentrated to ~100 ml) was added distilled N2O (600 ml) and the pH value was brought to 1-2 with 1 N. sulfuric acid. The crude product was extracted with EtOAc (2300 ml) and the combined organic extracts were washed N2O (200 ml). The combined organic phase was dried over Na2SO4, was filtered and was evaporated, getting a yellowish solid, which was recrystallized from hot toluene (100 ml) to give white crystals (9.2 grams, with 47.4 mmol, 65%), tPL98-100oC, MS: m/e=194,1 (M+).

As described in example 49 was obtained compound from example 54.

Example 54

(R)-1-(5-methoxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol

Specified in the header connection (2,40 g, 6,53 mmol, and 5-methoxy-2,3-dihydrobenzofuran-2-Eletropaulo ether (R)-toluensulfonate acid.

As described in example 51 was obtained compound of example 55.

Example 55

5-methoxy-2,3-dihydrobenzofuran-2-ymetray ether (R)-toluensulfonate acid

Specified in the title compound (3.0 g, 9.0 mmol, 67%) as a solid white color [tPL82-84oC, MS: m/e=334,l (M+); []20D=-74,9o(c=l, O, SNS3)]>99% E. E. was obtained from (R)-5-methoxy-2,3-dihydrobenzofuran-2-carboxylic acid using GHUR with chiral phase.

Example 56

(R)-5-methoxy-2,3-dihydrobenzofuran-2-carboxylic acid

To a solution of S(-)-1-(1-naphthyl)ethylamine (7,21 g of 41.6 mmol) in acetone (80 ml) was added (RS)-5-methoxy-2,3-dihydrobenzofuran-2-carboxylic acid (of 7.70 g, to 39.6 mmol) in acetone (150 ml), and after keeping under stirring for 2-3 minutes at ambient temperature was deposited solid beige color, after which the mixture was cooled to 0-5oC and stirred for another 30 minutes, the Solid product was filtered and washed with cold (4o(C) acetone (320 ml), getting to 9.90 g of white crystals, tPL145-160oC. This solid product is twice recrystallized from hot EtOH (125 ml), receiving of 4.75 g of white crystals, tPL185-194oC. This combined organic extracts were washed with distilled H2About (50 ml), then dried over Na2SO4and evaporated, obtaining (R)-5-methoxy-2,3-dihydrobenzofuran-2-carboxylic acid as a pale yellow crystalline solid (2.5 g, 12.9 mmol, 65%), tPL85-87oC, MS: m/e=194,1 (M+); []20D=+9,8o(C=1,0, EtOH).

Example 57

A mixture of (1RS, 2RS) and (1RS,2SR)-2-[4-benzyloxy-4-(4-methylbenzyl) piperidine-1-ylmethyl] indan-1,5-diol

5-benzyloxyindole-1-he (2.38 g, 10 mmol), hydrochloride of 4-(4-methylbenzyl) piperidine-4-ol (2,41 g, 10 mmol) and paraformaldehyde (0.3 g, 10 mmol) in DMF (20 ml) kept at 70oC for 20 h, After cooling, was added EtOAc (150 ml), distilled H2O (200 ml) and 25% NH4OH (4 ml) and the mixture was shaken. Then the aqueous phase was extracted with EtOAc (150 ml), the combined organic extracts were washed with saturated solution of NaCl (2100 ml) and dried over PA2SO4getting after evaporation a yellow oil. This oil was dissolved in THF (40 ml) was added within 30 min to a suspension of LiAlH4(1,87 g, 50 mmol, 5 EQ.) in THF (50 ml) while cooling on ice (5-15oC). Then the mixture was allowed to mix for a further 2 h at room temperature, the reaction was stopped by adding distilled H2About (2 ml), 4 N. NH4HE (4 m that was filtered, washed with THF and evaporated, receiving a viscous oil. The crude product was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira CH2CL2-Meon (97:3), and then CH2Cl2-MeOH (9:1) and receiving a white foam, which can be recrystallized from EtOAc-Et2O obtaining (1RS, 2RS) and (1RS,2SR)-2-[4-benzyloxy-4-(4-methylbenzyl) piperidine-1-ylmethyl] indan-1,5-diol as white crystals (1.89 g, 4,13 mmol, 41%), tPL131-132oC, MS: m/e=458,4 (M+N+).

Example 58

5-benzyloxyindole-1-he

A mixture of 5-hydroxyine-1-it (5.3g, to 35.7 mmol), KI (0.6 g, 3.6 mmol), K2CO3(6,17 g and 44.6 mmol) and benzylbromide (of 4.66 ml, or 39.3 mmol) in DMF (50 ml) kept at 100oC for 1 h After addition of N2O (150 ml) and extraction with EtOAc (350 ml), washing the organic phase with saturated NaCl solution (100 ml), drying over MgSO4and evaporation was obtained a solid brown color. This product is twice recrystallized from EtOH, receiving 5-benzyloxyindole-1-it is in the form of yellow crystals (6 g, 25,17 mmol. 70%), tPL105-106oC, MS: m/e= 238,1 (M+).

Example 59

5-hydroxyine-1-he

5-methoxyindol-1-he (8 g, to 49.3 mmol) and sodium salt of 4-tert-butyl-2-methylbenzamide (11,92 g, 5 the s was added water (80 ml), and then 1 ad model HC1 (80 ml) and EtOAc (120 ml). The mixture was shaken and the aqueous phase was extracted with EtOAc (100 ml), the combined organic extracts were washed with saturated NaCl solution (100 ml) and dried over Na2SO4, was filtered and was evaporated. The residue was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira tO-n-hexane (2:3) and receiving 5-hydroxyine-1-it is in the form of orange crystals (3.55 g, and 22.6 mmol, 45.9 per cent), tPL185-187oC, MS: m/e= 148,2 (M+).

Example 60

(RS)-1-(5-methoxy-2,3-dihydro-1H-indole-2-ylmethyl)-4-(4-methylbenzyl) piperidine-4-ol

To a solution of (RS)-1-[5-methoxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indole-2-ylmethyl-4-(4-methylbenzyl) piperidine-4-ol (300 mg, 0,576 mmol) in toluene (15 ml) was added bis(2-methoxyethoxy)alumoweld sodium (3.5 M in THF) (0,66 ml, 2,31 mmol) and the mixture is boiled under reflux for 18 hours, After cooling, was added 2 N. NaOH to pH 14, the mixture was extracted with EtOAc (325 ml) and the combined extracts were washed with saturated NaCl solution (25 ml), dried (Na2SO4), then filtered and evaporated. The residue was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira a mixture of EtOAc-cyclohexane-Et3N (9: 10: 1) and receiving (RS)-1-(5-methoxy-2,3-dihydro-1H-indole-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol as a viscous is l-4-sulfonyl)-2,3-dihydro-1H-indole-2-ylmethyl] -4-(4-methylbenzyl)piperidine-4-ol

5-methoxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indole-2-ymetray ether (RS)-toluene-4-sulfonic acid (200 mg, 0.41 mmol) and 4-(4-methylbenzyl)piperidine-4-ol (337 mg, of 1.64 mmol) was kept in mesitylene (10 ml) for 20 h at 140oC. After cooling, was added 4 N. model HC1 to pH 1 and the mixture was extracted with EtOAc (325 ml), the extracts were dried (PA2SO4), filtered and evaporated. After purification of the crude product on SiO2(Merck, 230-400 mesh mesh), elwira a mixture of EtOAc-cyclohexane-Et3N (9:10:1) were specified in the title compound as yellow oil (155,9 mg, 0.3 mmol, 73%), MS: m/e=521,4 (M+N+).

Example 62

5-methoxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indole-2-ymetray ether (RS)-toluene-4-sulfonic acid

(RS)-(5-methoxy-2,3-dihydro-1-H-indol-2-yl)methanol (100 mg, 0.46 mmol), para-toluensulfonate (177 mg, of 0.93 mmol), triethylamine (of 0.21 ml, 1.48 mmol) and N,N-dimethylaminopyridine (2 mg) was stirred for 18 h at room temperature in CH2CL2(5 ml). Added 1 N. model HC1 (10 ml), the mixture was extracted with CH2CL2(225 ml), the extracts washed with saturated solution of NaCl (20 ml) and dried (Na2SO4). The crude product was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira a mixture of EtOAc-cyclohex: m/e=488,0 (M+N+).

Example 63

(RS)-(5-methoxy-2,3-dihydro-1-H-indol-2-yl)methanol

Methyl ester of (RS)-5-methoxy-2,3-dihydro-1H-indole-2-carboxylic acid (2.5 g, 12,06 mmol) in THF (130 ml) was added dropwise to a suspension of LiAlH4in THF (80 ml) at 4oC and the mixture was allowed to mix at room temperature overnight, and then kept at 65oC for 4 h, After cooling, was carefully added N2O (20 ml) and the mixture was stirred for 20 min, then filtered and the filtrate was extracted with EtOAc (350 ml), the extracts washed with saturated NaCl solution (50 ml), dried (Na2SO4), filtered and evaporated. The crude oil was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira CH2Cl2-MeOH (9: 1) and receiving (RS)-(5-methoxy-2,3-dihydro-1-H-indol-2-yl)methanol in the form of a yellow oil (1,41 g, 7,86 mmol, 65%), MS: m/e= 179,l (M+).

Example 64

Methyl ester of (RS)-5-methoxy-2,3-dihydro-1H-indole-2-carboxylic acid

To ethyl ether, 5-methoxy-1H-indole-2-carboxylic acid (5 g, of 22.8 mmol) in Meon (150 ml) was added magnesium turnings (2.2 g, to 91.6 mmol, 4 EQ. ) and the mixture was intensively stirred with a mechanical stirrer (10-30oC) for 2 hours was Added 4 N. model HC1 (to pH 1-2), and then 25% NH4OH (to pH 7) and the (Na2SO4), filtered and evaporated. Crude oil green colors chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira EtOAc-n-hexane (1:3), obtaining specified in the connection header in a solid yellow color (3,21 g, a 15.5 mmol, 68%).PL59-61oC, MS: m/e=207,l (M+).

Example 65

Ethyl ester of 5-methoxy-1H-indole-2-carboxylic acid

5-methoxy-1H-indole-2-carboxylic acid (10 g, 52,3 mmol) in tO (400 ml) containing 36% H2SO4(7 ml) was boiled under reflux for 18 hours, After cooling the mixture was neutralized 2 N. NaOH (to pH 7) and was extracted with EtOAc (3150 ml), the combined extracts washed with 10% NaHCO3(225 ml), dried (MgSO4), filtered and evaporated, obtaining the ethyl ester of 5-methoxy-1H-indole-2-carboxylic acid in the form of a solid brown color (9,52 g, 43,3 mmol, 82%), tPL154-155oC, MS: m/e=219,1 (M+).

The intermediate products of examples 22 and 23

Example 66

(RS)-N-(2-methyl bromide-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

(RS)-2-methyl bromide-2,3-dihydrobenzofuran-5-ylamine (410 mg, of 1.80 mmol), methanesulfonamide (206 mg, 1.8 mmol), Et3N (182 mg, of 1.80 mmol) was dissolved in CH2Cl2(50 ml) and stirred the SUB>2(Merck, 230-400 mesh mesh), elwira CH2CL2-Meon (95:5) and receiving (RS)-N-(2-methyl bromide-2,3-dihydrobenzofuran-5-yl)methanesulfonamide (516 mg, 94%) as an oil, MS: m/e=305,9 (M-N+).

(RS)-2-methyl bromide-2,3-dihydrobenzofuran-5-ylamine was obtained according to the method described in example 44.

The intermediate products of examples 24 and 25

Example 67

(RS)-1-(6-methoxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol

6-methoxy-2,3-dihydrobenzofuran-2-ymetray ether (RS)-toluene-4-sulfonic acid (110 mg, 0.33 mmol) and 4-(4-methylbenzyl)piperidine-4-ol (148 mg, to 0.72 mmol) was dissolved in DMF (3 ml) and kept at 130oC for 1 h and Then DMF is evaporated, the residue was dissolved in CH2Cl2(5 ml) and washed with H2O (5 ml). The organic phase was dried over Na2SO4and concentrated. The residue was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira CH2Cl2-MeOH (19:1) and receiving (RS)-1-(6-methoxy-2,3-dihydrobenzo-furan-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol as yellow oil (80 mg, 66%), MS: m/e=368,4 (M+H+).

Example 68

6-methoxy-2,3-dihydrobenzofuran-2-ymetray ether (RS)-toluene-4-sulfonic acid

To a solution of (RS)-(6-methoxy-2,3-dihydrobenzofuran-2-yl)methanol (0 is ri 0oWith was added dropwise a solution of para-toluensulfonate (115 mg, 0.6 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 4 h before the addition of N2About (2 ml). The aqueous phase was extracted with CH2Cl2(25 ml). The combined organic phases were dried over Na2SO4and concentrated. The residue was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira n-hexane-EtOAc (4:1) and receiving 6-methoxy-2,3-dihydrobenzofuran-2-ymetray ether (RS)-toluene-4-sulfonic acid as a colourless oil (120 mg, 72%). MS: m/e=334 (M+).

Example 69

1-(6-methoxybenzophenone-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol

To a solution of 6-methoxy-2-benzofuranyl (89 mg, 0.5 mmol) in dioxane (3 ml) at room temperature was added dropwise SOCl2(of 0.11 ml, 1.5 mmol). After 1.5 h the reaction mixture was concentrated at room temperature in high vacuum. The residue was dissolved in dioxane (3 ml) and was treated with 4-(4-methylbenzyl)piperidine-4-I (225 mg, 1.1 mmol). After stirring for 17 h at room temperature the solvent is evaporated. The residue was dissolved in N2O (4 ml) and was extracted with CH2Cl2(64 ml). The combined organic phases were dried over PA2SO+).

Example 70

(RS)-(6-methoxy-2,3-dihydrobenzofuran-2-yl)methanol

A solution of (RS)-6-methoxy-2,3-dihydrobenzofuran-2-carboxylic acid (158 mg, 0,813 mmol) in THF (2 ml) was added dropwise at 0oWith the suspension of LiAlH4(31 mg, 0,813 mmol) in THF (2 ml). After stirring for 30 min at 0oWith the reaction mixture is boiled under reflux for 30 minutes Then the reaction mixture was cooled to 0oWith and consistently processed N2About (0.05 ml), 5 N. NaOH (0.05 ml), N2About (0.15 ml). After stirring for 20 min at room temperature was added EtOAc, and then Na2SO4. The thus obtained solid product was filtered and the filtrate was evaporated. The residue was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira n-hexane-tO (4: 1) and receiving (RS)-(6-methoxy-2,3-dihydrobenzofuran-2-yl)methanol as a colorless oil (102 mg, 70%), MS: m/e=180 (M+).

By way of example 70 was obtained the compound of example 71.

Example 71

6-methoxy-2-benzofuranyl

Specified in the title compound [MS: m/e=178 (M+)] was obtained from 6-methoxy-2-benzofuranol acid.

By way of example 53 was obtained the compound of example 72.

PL108-110oC, MS: m/e=194 (M+)] was obtained from 6-methoxy-2-benzofuranol acid.

6-methoxy-2-benzofuranol acid was obtained in accordance with the method described in the literature: S. Tanaka, J. Am. Chem. Soc. 73, 1951, 872.

Example 73

(RS)-4-benzyl-1-(6-benzyloxyindole-2-ylmethyl)piperidine-4-ol

(RS)-6-benzyloxy-2-bromethalin (0.52 g, 1.56 mmol) and 4-(benzyl) piperidine-4-ol (0.66 g, of 3.43 mmol) in toluene (20 ml) was boiled under reflux for 18 h in an argon atmosphere. After removal of solvent the crude mixture was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira CH2Cl2-MeOH-NH4HE (100: 5:0,25) and getting listed in the title compound, (RS)-4-benzyl-1-(6-benzyloxyindole-2-ylmethyl) piperidine-4-ol as yellow oil (0.6 g, 1.35 mmol, 86%), MS: m/e= 445,5 (M+N+).

Example 74

(RS)-6-benzyloxy-2-bromethalin

(RS)-6-benzyloxy(chroman-2-yl)methanol (0.97 g, 3.58 mmol) and 1,1'-carbonyldiimidazole (0,58 g, 3.58 mmol) and allylbromide (to 19.9 mmol) was kept in acetonitrile at 80oC for 4 h and Then the crude mixture was evaporated to dryness and chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira CH2Cl2. The way it was obtained (RS)-6-benzyloxy-2-bromethalin in Example 75

(RS)-6-benzyloxy (chroman-2-yl) methanol

To a suspension of LiAlH4(0,352 g, 9,26 mmol) in THF for 15 min under stirring at 10oC was added a solution of (RS)-6-hydroxypropan-2-carboxylic acid (1.2 g, 6,18 mmol) in THF (25 ml). The mixture was allowed to warm to ambient temperature, was added 4 N. model HC1 (25 ml) and EtOAc (100 ml) and the mixture was shaken. The aqueous phase was extracted with EtOAc (100 ml) and the combined organic extracts were washed with saturated NaCl solution (50 ml), dried over Na2SO4and was evaporated. The formed solid product was dissolved in acetone (50 ml), then added TO a2CO3(0,94 g, 6.8 mmol) and benzylbromide (0,81 ml, 6.8 mmol) and the mixture is boiled under reflux for 18 hours, the Reaction mixture was filtered, evaporated to dryness and chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira EtOAc-cyclohexane (3:7) and receiving (RS)-6-benzyloxy(chroman-2-yl)methanol in the form of a solid white color (1.0 g, 3.7 mmol, 60%), tPL80-82oC, MS: m/e=270,1 (M+).

Example 76

(RS)-6-hydroxypropan-2-carboxylic acid

(RS)-6-methoxypropan-2-carboxylic acid (1.12 g, 5.37 mmol) and pyridinethione (11.2 g, to 96.6 mmol) was kept together under stirring at 80oC for 2 h in the atmosphere and is one phase was extracted with EtOAc (50 ml) and the combined organic extracts were washed with saturated NaCl solution (50 ml), and then was dried over Na2SO4and evaporated, receiving (RS)-6-hydroxypropan-2-carboxylic acid as white crystals (0,94 g, 4,84 mmol, 90%), tPL175-177oC, MS: m/e=194,1 (M+).

Example 77

(RS)-6-methoxypropan-2-carboxylic acid

A mixture of 6-methoxyamino-2-carboxylic acid (2.20 g, 10 mmol) and Pd/C (10%) (300 mg) in acetic acid (200 ml) with vigorous stirring and kept at 60oC for 5 h in an atmosphere of hydrogen. The catalyst was removed and the solution was evaporated, receiving (RS)-6-methoxypropan-2-carboxylic acid in the form of yellowish crystals (2,04 g, 9.8 mmol, 98%), tPL131-135oC, MS: m/e=208,1 (M+).

Literature: N. Cohen and others, J. Med. Chem., 1989, 32, 1842-1860; and D. T. Witaik etc., J. Med. Chem., 1971, 14, 758-766.

Example 78

(1RS, 2RS)-1-(6-benzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol

(RS)-6-benzyloxy-2-[4-hydroxy-4-(4-methylbenzyl)piperidine-1-ylmethyl] -3,4-dihydro-2H-naphthalene-1-he (1,30 g, 2.77 mmol) in THF (15 ml) was added dropwise within 15 min (5 to 10o(C) to a suspension of LiAlH4(0.6 g, a 15.5 mmol) in THF (20 ml) and then stirred at room temperature for 2.5 hours To terminate the reaction was added distilled N2O (1 ml), and 4 N. Na2SO4, was filtered and was evaporated. The resulting crude liquid was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira CH2Cl2-MeOH-NH4OH (100:5:0,25) and getting listed in the title compound as white foam (0.75 g, 1.6 mmol, 57%), MS: m/e=472,4 (M+H+).

By way of example 78 was obtained the compound of example 79.

Example 79

(1RS, 2RS)-1-(6-benzyloxy-1-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-benzylpiperidine-4-ol

Specified in the title compound as a colourless oil [MS: m/e=458,6 (M+N+)] was obtained from (RS)-2-(4-benzyl-4-hydroxypiperidine-1-ylmethyl)-(6-benzyloxy-3,4-dihydro-2H-naphthalene-1-it.

Example 80

(RS)-6-benzyloxy-2-[4-hydroxy-4-(4-methylbenzyl)piperidine-1-ylmethyl] -3,4-dihydro-2H-naphthalene-1-he

6-benzyloxy-1-tetralone (1.26 g, 5 mmol), hydrochloride of 4-(4-methylbenzyl) piperidine-4-ol (1.20 g, 5 mmol) and paraformaldehyde (150 mg, 5 mmol) in DMF (10 ml) kept at 70oC for 17 h, the Crude mixture was distributed between distilled H2O (150 ml), 25% NH4HE (2 ml) and EtOAc (100 ml). Then the aqueous phase was extracted with EtOAc (100 ml) and the combined organic extracts washed twice with saturated NaCl solution (100 ml), dried over Na2SO3N (19:1), was obtained (RS)-6-benzyloxy-2-[4-hydroxy-4-(4-methylbenzyl) piperidine-1-ylmethyl]-3,4-dihydro-2H-naphthalene-1-it is in the form of oil of amber (1,34 g, 2,85 ml, 57%), MS: m/e=470,3 (M+H+).

By way of example 80 was obtained the compound of example 81.

Example 81

(RS)-2-(4-benzyl-4-hydroxypiperidine-1-ylmethyl)-6-benzyloxy-3,4-dihydro-2H-naphthalene-1-he

Specified in the title compound in the form of a yellow oil [MS: m/e= 456,6 (M+N+)] was obtained from 6-benzyloxy-1-tetralone, hydrochloride 4-benzyl-4-hydroxypiperidine and paraformaldehyde.

Example 82

6-benzyloxy-1-tetralone

6-hydroxy-1-tetralone (10 g, 61,65 mmol), benzylbromide (8.1 ml, 67,82 mmol) and K2CO3(21,3 g, 154 mmol) in acetone (40 ml) was boiled under reflux for 2.5 hours After filtration and evaporation of the solvent the crude product was acidified with 1 ad model HC1 to pH 1 and distributed between H2O (150 ml) and EtOAc (150 ml). Then the aqueous phase was extracted with EtOAc (100 ml) and the extracts were dried (Na2SO4), filtered and evaporated, getting 6-benzyloxy-1-tetralone in the form of a solid orange color (12,37 g, to 49.3 mmol, 80%), tPL97-100oC, MS: m/e=252,1 (M+).

Example 83

6-Ki is amasyali at ambient temperature for 4 hours When cooled to 4oWith added distilled N2O (1 l) and the precipitated solid was filtered, primeval H2Oh and twice recrystallized from tO-N2Oh (4: 1) to give 6-hydroxy-1-tetralone in a solid beige color (59,7 g, 368 mmol, 81%), tPL153 to 155oC. MS: m/e=162,1 (M+).

Example 84

(RS)-1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl) piperidine-4-ol

6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ymetray ether (RS)-toluene-4-sulfonic acid (1,32 g, 3,81 mmol) and 4-(methylbenzyl)piperidine-4-ol (3.13 g, 15,24 mmol) in mesitylene (100 ml) kept at 140oWith over 20 hours After evaporation of the solvent the crude product was distributed between CH2Cl2(50 ml) and 5% Panso3(30 ml) and the aqueous phase was extracted with CH2Cl2(2100 ml), washed with saturated NaCl solution (50 ml), dried (Na2SO4), filtered and evaporated. The crude product was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira a mixture of EtOAc-n-hexane (1:3), and then (1:1) and receiving (RS)-1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol in the form of a solid white color (972 mg, 2.56 mmol, 67.3 per cent), tPL91-94oC, MS: m/e=380,3 (M+H+what you

(RS)-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)methanol (939 mg, 4,88 mmol), para-toluensulfonate (934 mg, 4.9 mmol), triethylamine (1,12 ml, 7,88 mmol) and N,N-dimethylaminopyridine (10 mg) in CH2Cl2(10 ml) was stirred together at ambient temperature within 24 hours After acidification 1 N. model HC1 (pH 1-2), extraction of the aqueous phase CH2Cl2(220 ml), drying (PA2SO4), filtration and evaporation was obtained the crude product, which was chromatographically on SiO2(Merck, 230-400 mesh mesh), elwira EtOAc-n-hexane (1:3) and getting listed in the title compound as a colourless oil (1,37 g, 3.95 mmol, 81%), MS: m/e=346,l (M+).

Example 86

(RS)-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl) methanol

Ethyl ester of (RS)-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid (1.39 mg, to 5.93 mmol) in THF (20 ml) was added dropwise at 0 to 10oWith over 15 min to a suspension of LiAlH4(473 mg, 12,46 mmol). The reaction mixture was stirred for 1 h at room temperature, and then the reaction was stopped by adding 4 N. NaOH (15 ml) and water (20 ml). After intensive stirring for 15 min the mixture was extracted with EtOAc (25 ml), then aqueous phase was extracted with EtOAc (225 ml), the combined organic extracts were washed nasishennokrasnie oil. After chromatographic purification on SiO2(Merck, 230-400 mesh mesh), elwira EtOAc-n-hexane (1: 3), was obtained (RS)-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl) methanol as a colorless oil (989 mg, 5,14 mmol, 86%). MS: m/e=USD 192.1 (M+).

Example 87

Ethyl ester of (RS)-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid

Ethyl ester of (RS)-6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid (2.0 g, with 8.05 mmol) in Meon (20 ml) and Pd/C (10%) (200 mg) was intensively stirred in hydrogen atmosphere for 3 h at ambient temperature. The catalyst was removed and the solvent evaporated to obtain an oil, which was purified by chromatography on SiO2(Merck, 230-400 mesh mesh), elwira EtOAc-n-hexane (1: 9) and receiving ethyl ester of (RS)-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid as a colourless oil (1.88 g, 6,14 mmol, 76%), MS: m/e=234,1 (M+).

Example 88

Ethyl ester of (RS)-6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid

6-methoxytyramine (10 g, 56,75 mmol), diethylmalonate (20,6 ml, 170, 2 mmol) and sodium hydride (of 5.06 g, 210,8 mmol) stood together at 65oWith in THF (400 ml) for 18 hours, After cooling, was carefully added glacial acetic acid (15 ml, 250 mmol), and then toluene (2200 ml), which somayajulu, the aqueous phase was extracted with EtOAc (2100 ml) and the combined organic extracts were washed with saturated NaCl solution (100 ml), dried (Na2SO4), was filtered and washed. The crude product was led from EtOAc-n-hexane, obtaining mentioned in the title compound in the form of a solid yellow (8,3 g, 33.4 mmol, 58%), MS: m/e=248,1 (M+).

In table. 2 and 3 shows examples of pharmaceutical preparations.

1. Derivatives of piperidine derivatives of the formula I

< / BR>
where X represents-O-, -NH-, -CH2-, -CH= , -SNON - or-CO-;

R1- R4independently from each other denote hydrogen, a hydroxy-group, (lower) alkylsulfonyl or acetaminoph;

R5- R8independently from each other denote hydrogen, a hydroxy-group, (lower)alkyl, halogen, (lower)alkoxygroup, trifluoromethyl or cryptometrics;

a and b can denote a double bond, provided that when a represents a double bond, b is unable to designate a double bond;

n = 0-2;

m = 1-3;

p is 0 or 1,

and their pharmaceutically acceptable additive salt.

2. Connection on p. 1, where X denotes-O-.

3. Connection on p. 2, selected from the group including:

(RS)-1-(5-benzofuran-2-ylmethyl)piperidine-4-ol,

(RS)-4-(4-terbisil)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol,

(RS)-4-(4-active compounds)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)piperidine-4-ol,

(S)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol,

(S)-1-(5-hydroxy-2,3-dihydrobenzofuran-2-ylmethyl)-4-(4-Chlorobenzyl)piperidine-4-ol,

(RS)-N-[2-{ 4-chloro-4-(4-methylbenzyl)piperidine-1-ylmethyl} -2,3-dihydrobenzofuran-5-yl] methanesulfonamide and

(RS)-N-[2-{ 4-hydroxy-4-(4-methylbenzyl)piperidine-1-ylmethyl} -2,3-dihydrobenzofuran-5-yl] methanesulfonamide.

4. Connection on p. 1, where X denotes NON-.

5. Connection on p. 4, selected from the group including:

(1RS, 2RS) and (1RS, 2SR)-2-[4-hydroxy-4-(4-methylbenzyl)piperidine-1-ylmethyl] indan-1,5-diol,

(1RS, 2RS)-1-(1,6-dihydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol and

(1RS, 2RS)-2-(4-benzyl-4-hydroxypiperidine-1-ylmethyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-ol.

6. Connection on p. 1, where X denotes-CH2- or-CH= .

7. Connection under item 6, selected from the group including:

(RS)-1-(5-hydroxyine-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol and

(RS)-1-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)-4-(4-methylbenzyl)piperidine-4-ol.

10. Connection on p. 1, where X denotes-CO-.

11. Pharmaceutical drug, possessing inhibiting NMDA-receptor activity, containing one or more compounds of formula I on PP. 1-10 or their pharmaceutically acceptable salt.

 

Same patents:

The invention relates to new piperidine derivative of the formula I, where R1means sensational, benzofuranyl, naphthyl which may be substituted with halogen, C1-C6-alkyl, C1-C6-alkoxygroup, substituted thienyl or substituted furanyl, which is substituted by halogen, C1-C6-alkyl, C3-C6-cycloalkyl or1-C6-alkenyl, R2means halogen and R3means1-C6-alkyl or C3-C6-cycloalkenyl, or their pharmaceutically acceptable salt, or solvate

The invention relates to new derivatives of 2- (iminomethyl) aminobenzoyl General formula (I) where a represents either a radical represented by the formula of the invention in which R1and R2denote, independently, a hydrogen atom, a group HE, a linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, R3means a hydrogen atom, a linear or branched alkyl with 1-6 carbon atoms or the radical COR4, R4means a linear or branched alkyl with 1-6 carbon atoms, or radicals represented by the formula of the invention, R5means a hydrogen atom, a group HE or linear or branched alkyl or alkoxy with 1-6 carbon atoms, means thienyl, X means Z1-, -Z1-CO-, -Z1-NR3-CO, -CH=CH-CO - or a simple bond, Y represents a radical chosen from the radicals Z2-Q, piperazinil, homopiperazine, -NR3-CO-Z2-Q-, -NR3-O-Z2-, -O-Z2Q-in which Q means a simple bond, -O-Z3and-N(R3)-Z3-, Z1, Z2and Z3means independently a simple link or a linear or branched alkylene with 1-6 carbon atoms, preferably Z1, Z2and Z3means -(CH2)m-, and m is an integer, R

The invention relates to new derivatives benzoylpyridine General formula (I), where R1means alkyl with 1-8 carbon atoms, a represents a group represented by the formula of the invention, means (-CH2-)aor (-CO-)band means an integer of 0 to 8, preferably 1, 2, 3 or 4, b means of 0,1 or 2, preferably 1, R2means unsubstituted or substituted alkyl with 1-8 carbon atoms, unsubstituted phenyl, NR3R4or preferably the five-membered heterocycle represented in the claims, in which U, V, W, X and Z can mean CH, NH, O or S, R3and R4denote alkyl with 1-8 carbon atoms

The invention relates to new Bermatingen compounds, the United propylenebis communication, General formula I where Ar represents a radical of formula (a) or (b), R1is-OR6or-COR7, R2represents a polyether radical, comprising 1 to 6 carbon atoms and 1 to 3 atoms of oxygen or sulfur, and if in the latter case, R4represents a linear or branched C1-C20alkyl, he is in ortho - or meta-position relative to X-Ar connection, R3represents lower alkyl, or R2or R3taken together form a 6-membered ring, optionally substituted by at least one of the stands and/or optional split the atom of oxygen or sulfur, R4represents H, linear or branched C1-C20alkyl or aryl, R5represents H or-OR8, R6represents H, R7represents H, -OR10or-N(r)r (r) r are H, lower alkyl or taken together with the nitrogen atom form a ring of morpholino, R8represents H or lower alkyl, R10represents H, linear or branched C1-C20alkyl, X represents a divalent radical, which is from right to left or Vice versa has the formula (d), R11Fri carboxylic acid and the optical and geometrical isomers of the above compounds of formula (I)

-(5'-nitro-2'-furyl)vinyl]-6,7,8,9 - tetrahydropyrimido[4,5-b] quinoline-4-one and 1-metalorganic-2- [-(5'-nitro-2'-furyl)vinyl]-7,8-dihydro-6n-pyrimido[4 ,5-b] -pyrindine-4-one, exhibiting antimicrobial activity" target="_blank">

The invention relates to the field of organic chemistry, a class pyrimido[4,5-b] quinoline, pyrimido[4,5 - b]pyrindine, namely to new biologically active 1-phenyl-2- [-(5'-nitro-2'-furyl)vinyl]-6,7,8,9-tetrahydropyrimido[4,5-b]quinoline-4-ONU(I)I1-metalorganic-2-[-(5'-nitro-2'-furyl)vinyl]-7,8-dihydro-6H-pyrimido[4,5-b]pyrindine-4-ONU (II), formula

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which can find use as a drug of antimicrobials

The invention relates to new derivatives of 1-[2-(substituted vinyl)]-5H-2,3-benzodiazepine, method of production thereof, pharmaceutical composition, method thereof and method of treating diseases of the Central nervous system

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, in particular fungicidal activity, and more particularly to a derivative triazolyl, the way they are received and fungicidal tool

The invention relates to methods of reducing the level of TNFin mammals and connections that are applicable for this purpose

The invention relates to new derivatives of chloropyridinyl formula I where Het is a group of formula a, b, C, d or e, R1is hydrogen, unsubstituted or substituted C1- C6alkyl, and the substituents selected from the group comprising halogen, phenyl, cyano, C1- C4alkoxy, C1- C4alkylthio,1- C4alkylsulphonyl; C2- C4alkenyl, unsubstituted or substituted C1- C4alkoxygroup; phenyl or unsubstituted or substituted 1 or 21- C4alkoxygroup, n = 1 or 2, and their acid additive salts

The invention relates to new tetrahydropyridine - or 4-hydroxypiperidine-alkylation formula I, where R1, R2, R3and R6denote hydrogen, halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, C1-C6-alkoxyl or two adjacent radicals can form precondensation benzene ring, And denotes the carbon atom, and the dotted line denotes an optional bond, or a denotes a carbon atom that is associated with a hydroxyl group (C-OH), and the dotted line indicates the absence of coupling, n = 2 to 6, Z1, Z2and Z3represent a nitrogen atom or a substituted carbon atom, or a physiologically favourable salts, which possess antipsychotic or anxiolytic activity

The invention relates to novel triazole compounds of the General formula (1), where a denotes a linear or branched C1-C18-alkylenes group which may comprise at least one group which is selected from O, S, CONH, COO,3-C6-cycloalkene or double or triple bond; In denotes the radical of formula (a), (b) or (C); R1denotes H, NH2WITH3-C6-cycloalkyl or1-C8-alkyl, which is not substituted or substituted OS1-C8-alkyl; R2denotes H, HE, C1-C8-alkyl, C3-6-cycloalkyl, CF3, CN, NR3R4, SR3or CO2R3where R3denotes N or C1-C8-alkyl, a R4denotes H, C1-C8-alkyl, or COR3where R3stands WITH1-C8-alkyl; Ar represents naphthyl, phenyl with 1-2 substituent selected from C1-C8-alkyl, CF3, CHF2, NO2, SR3, SO2R3where R3means1-C8-alkyl; and pyridyl, pyrimidyl or triazinyl, which have from 1 to 3 substituents selected from C1-C8-alkyl, C2-C6-alkenyl, C2-C6-quinil, halogen, CN, CF3, OR4where R43-C6-lalouche possibly condensed, phenylalkylamine or 5-membered aromatic heterocycle with 1 to 2 nitrogen atoms, which may be condensed with a benzene ring

The invention relates to new N-substituted azaheterocyclic carboxylic acids f-crystals (I) or their salts, in which R1and R2independently represent a hydrogen atom, halogen atom, trifluoromethyl, C1-C6-alkyl or C1-C6-alkoxy: Y is the grouporin which only the underlined atom participates in the cyclic system; X is a group-O-, -S-, -CR7R8, -CH2-CH2-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2CH2CH2-, -CH=CH-, -NR9-(C= O)-, -O-CH2-, -(C= O)- or -(S=O)-, where R7, R8and R9independently represent a hydrogen atom or a C1-C6-alkyl; z = 1, 2, or 3; m = 1 or 2, n = 1 when m = 1 and n = 0 when m = 2; R4and R5each represents a hydrogen atom or, when m = 2, can both work together to develop a bond; R6is hydroxyl or C1-C8-alkoxygroup, or its pharmaceutically acceptable salt, provided that is not included compound 10-(3-(3-carbomethoxy-1-piperidyl) propyl) phenothiazines and 10-(3-(3-carborexics-1-piperidyl) propyl) phenothiazines

The invention relates to Hinayana and hinokitiol, compositions containing them, and methods of producing these compounds

The invention relates to the derivatives of diphenylbutylpiperidine formula I where n is 1 or 2, or pharmaceutically acceptable salts

The invention relates to aromatic amedieval derivatives and their salts, which have the ability to strong antikoaguliruyuschee action through reversible inhibition of activated coagulation factor, factor X (hereinafter referred to "FXA"), and which can be administered orally
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