Derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine and pharmaceutical agent

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

 

The present invention relates to derivatives of 1-arenesulfonyl-2-arylpyrimidine and piperidine derivatives of General formula

where

R1means hydrogen or lower alkyl;

R2means furyl, thienyl, pyridyl or phenyl, which is optionally substituted by 1-3 substituents selected from lower alkyl, alkoxygroup, where the alkyl residue refers to the lower alcelam, halogen, langroup, CF3or-N(R4)2,

R3means naphthyl or phenyl, which is optionally substituted by 1-3 substituents selected from lower alkyl, alkoxygroup, where the alkyl residue refers to the lower alcelam, halogen, acetyl, langroup, hydroxyalkyl, where the alkyl residue refers to the lower alcelam, -CH2-morpholine-4-yl, alkyloxyalkyl (where both alkyl residue belong to the lower alnilam), alkyl-N(R4)2where the alkyl residue refers to the lower alcelam, or CF3;

R4means independently from each other hydrogen or lower alkyl, and their pharmaceutically acceptable salts.

The compounds of formula I are new, with the exception of (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpropan, N-tosyl-CIS-3-methyl-2-phenyl-pyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidin-2-yl]pyridine and N-tosyl-2-(3,4-acid)pyrrole is on. Obtaining these compounds is described in J.Org.Chem., 51, (1986) 4089-4090. In addition, obtain (RS)-2-phenyl-1-(toluene-4-sulfonyl)-pyrrolidine described in Liebigs Ann. Chem., 762, (1972) 93-105.

The aim of the invention was to provide a connection with the properties of agonist or antagonist in respect of metabotropic glutamate receptors Group I. These compounds may be suitable for the production of medicines for the treatment or prevention of neurological disorders.

It has been unexpectedly found that compounds of General formula I are antagonists and/or agonists of metabotropic glutamate receptors. The compounds of formula I differ valuable therapeutic properties.

The transmission of stimuli in the Central nervous system (CNS) occurs when the interaction of the neurotransmitter, upravlyaemogo nerve cell, with neuroreceptors.

L-Glutamic acid, the most common neurotransmitter in the Central nervous system, plays a crucial role in a large number of physiological processes. Glutamate-dependent receptors of stimuli are divided into two main groups. The first main group forms a controlled ligand ion channels. Metabotropic glutamate receptors (mGluR) are the second main group and, in addition, belong to the family of receptors associated with G-protein.

Currently, WPI is STN eight different members of these mGluR, and some of them even have subtypes. On the basis of the structural parameters of various influences on the synthesis of secondary metabolites and different affinity for compounds with low molecular weight of these eight receptors can be subdivided into three subgroups:

mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II, and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

The ligands of metabotropic glutamate receptors belonging to the first group, can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer's disease, disorders of learning and memory loss, and chronic and acute pain.

In this regard, other treatable symptoms are restricted brain function caused by operations bypass surgery or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycemia. Other treatable indications are Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, a disease of unknown origin or parkinsonism caused by drugs, as well as conditions that lead to reactions, due the lack of glutamate, as, for example, muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, the addiction to opium, anxiety, vomiting, dyskinesia and depression.

The objects of this invention are the compounds of formula I and their pharmaceutically acceptable salts by themselves and as pharmaceutically active substances, their getting medicines on the basis of the connection in accordance with the invention and their manufacture, as well as the use of compounds according to the invention for the control or prevention of diseases of the aforementioned type and, respectively, for the manufacture of the drugs.

Preferred compounds of formula I of the present invention are those where R is hydrogen or methyl; R2means phenyl, optionally substituted with halogen, lower alkyl, CF3or-N(CH3)2with the exception of (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpropan, N-tosyl-CIS-3-methyl-2-phenyl-pyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidin-2-yl]pyridine and N-tosyl-2-(3,4-acid)pyrrolidine and their salts. The following are examples of such compounds are:

(RS)-2-(3-forfinal)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-1-(4-chlorobenzenesulfonyl)-2-(3-forfinal)pyrrolidin,

(RS)-1-(4-chlorobenzenesulfonyl)-2-phenylpyrrolidine,

(RS)-2-(4-chlorophenyl)-1-(olwal-4-sulfonyl)pyrrolidin,

(RS)-1-(4-chlorobenzenesulfonyl)-2-(4-forfinal)pyrrolidin,

(RS)-2-(4-forfinal)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-1-benzazolyl-2-(4-chlorophenyl)pyrrolidin,

(RS)-1-(4-permentantly)-2-(4-forfinal)pyrrolidin,

(RS)-2-(4-forfinal)-1-(toluene-2-sulfonyl)pyrrolidin,

(RS)-1-(4-chlorobenzenesulfonyl)-2-p-tolylpropan,

(RS)-1-(4-ethylbenzonitrile)-2-(4-forfinal)pyrrolidin,

(RS)-1-(toluene-4-sulfonyl)-2-m-tolylpropan,

(RS)-2-(3-chlorophenyl)-1-(toluene-4-sulfonyl) pyrrolidin,

(RS)-2-(3,4-differenl)-1-(toluene-4-sulfonyl) pyrrolidin,

(RS)-2-(3-chloro-4-forfinal)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-1-(4-permentantly)-2-(4-dimethylamino-3-chlorophenyl)-pyrrolidin,

(RS)-1-(toluene-4-sulfonyl)-2-(4-tri-formationl)pyrrolidin,

(RS)-2-(4-chloro-3-were)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-2-(4-forfinal)-1-(4-trifloromethyl)-pyrrolidin,

(RS)-2-(N,N-dimethylaminophenyl)-1-(4-permentantly)-pyrrolidin,

(R)-1-(4-chlorobenzenesulfonyl)-2-(4-forfinal)pyrrolidin,

(S)-1-(4-chlorobenzenesulfonyl)-2-(4-forfinal)pyrrolidin,

(RS)-2-(4-ethylphenyl)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-2-(4-ethylphenyl)-1-(4-permentantly)pyrrolidin,

(S)-2-(4-forfinal)-1-(toluene-4-sulfonyl)pyrrolidin,

(R)-2-(4-forfinal)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-2-(4-forfinal)-1-(4-ethoxymethylenemalonic)-pyrrole is in and

(2RS,3RS)-2-(4-forfinal)-3-methyl-1-(toluene-4-sulfonyl)-pyrrolidin

The compounds of formula I, where

R1means hydrogen; and

R2means furyl, thienyl or pyridyl,

also preferred.

Examples of such compounds are the following:

(RS)-1-(4-chlorobenzenesulfonyl)-2-Tien-2-iparralde,

(RS)-2-Tien-2-yl-1-(toluene-4-sulfonyl)pyrrolidin and

(RS)-2-Tien-3-yl-1-(toluene-4-sulfonyl)pyrrolidin.

The invention includes all stereoisomeric forms in addition to the racemate.

The term "lower alkyl", as used herein, means a saturated hydrocarbon residues with a straight or branched chain with 1 to 7 carbon atoms, preferably 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and the like.

The term "alkoxygroup with related to the lower alcelam alkyl residue" means the residue of lower alkyl terms of the above definitions, linked through an oxygen atom.

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

Compounds of General formula I and their pharmaceutically acceptable salts can be obtained by reaction of compounds of formula

with the compound of the formula

and, if desirable,

during the transformation of a functional group in the compound of formula I in drughulpverlening group and if it is desirable, when the conversion of the compounds of formula I in a pharmaceutically acceptable salt.

In accordance with the invention suitably substituted compound of formula II, for example (RS)-2-(3-fluoro-phenyl)pyrrolidin, is subjected to reaction with the appropriate compound of formula III, for example toluene-4-sulfochloride. The reaction according to known methods is held at room temperature for 16 hours in an inert solvent, such as dichloromethane. After evaporation of the solvent the mixture is dissolved in water and extracted with a suitable solvent, such as ethyl acetate, and purified using known methods.

In particular, langroup can be provideruri in amino groups, or halogen atoms in galijasevic lower alkyl groups can be substituted amines or converted into ethers.

The hydrogenation is preferably carried out using a Nickel catalyst Raney at room temperature under normal pressure, and the amino group may be proaccelerin by known methods.

The formation of ester derivatives benzylchloride can be conveniently carried out as follows: the compound of General formula I, which contains alojamiento lower alkyl group, for example (RS)-2-(4-forfinal)-1-(4-chlorodibenzo-sulfonyl)pyrrolidin, is subjected to reaction with methylate NAT the Oia in methanol for 80 h at 50° C and purified using known methods.

Replacement of the halogen atom in halogenosilanes the remainder of the lower alkyl-amine can be suitably carried out as follows: the compound of General formula I, which contains alojamiento lower alkyl group, for example (RS)-2-(4-forfinal)-1-(4-chloromethanesulfonyl) pyrrolidin, is subjected to reaction with morpholine in dimethylformamide for 17 h at 80° and purified using known methods.

Pharmaceutically acceptable salts can be easily obtained according to known methods, by itself, and taking into account the nature of the connection that turned into salt. Inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate, p-toluensulfonate and the like, are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds that contain alkali metals or alkaline earth metals, for example sodium, potassium, calcium, magnesium or the like, primary amines or basic amino acids, are suitable for the formation of pharmaceutically acceptable salts kislotno the x connections.

Scheme 1 gives an overview of how to obtain compounds of the formula I in terms of the known compounds. The substituents R, present in the compounds of formula I, are entered in accordance with known to the person skilled in the art ways. Obtaining typical representatives of compounds of the formula I is described in detail in the examples 1-91.

Scheme 2 and scheme 3 provides an overview of the transformations of functional groups in the compounds of formula I, described in detail in the examples 85-87.

Scheme 1

R1means hydrogen or lower alkyl and the other substituents have the meanings given previously.

Scheme 2

Scheme 3

The compounds of formula I and their pharmaceutically acceptable salts are, as mentioned above, agonists and/or antagonists of metabotropic glutamate receptors and can be used for the treatment or prevention of acute and/or chronic neurological disorders, such as psychosis, schizophrenia, Alzheimer's disease, disorders of learning and memory disorders, and chronic and acute pain. The other is they are treatable symptoms are limited brain function, caused by operations bypass surgery or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycemia. Other treatable indications are Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, a disease of unknown origin or parkinsonism caused by medicaments as well as States, which lead to reactions related to the lack of glutamate, such as muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, the addiction to opium, anxiety, vomiting, dyskinesia and depression. Compounds of the present invention are agonists and/or antagonists of receptors mGlu group I. it Was shown that the compounds of examples 1-4, 6, 8, 9, 11-14, 16, 19, 21, 25, 26, 28, 29, 31, 38, 39, 40, 42, 48, 55, 56, 58, 60, 69, 72, 76, 77, 78, 81, 82, 83, 84, 85, 88, 89 and 90 exhibit agonistic activity, the compounds of the other special examples have antagonistic activity to the mGlu receptor. The compounds exhibit activity as measured in the following analysis, 50 μm or below, usually 3 μm or less, and ideally from 0.5 μm or below.

The table below shows some data specific activity:

Example No.agonist/antagonistIC50(µm)
3agonistby 8.22
4agonist0,23
88agonist0,62
7antagonist8,00
18antagonist1,37
36antagonist0,56

cDNA encoding the receptor of rat mGlu la, obtained from Prof. S.Nakanishi (Kyoto, Japan), was temporarily artificially introduced into EBNA cells using the method described by Schlaeger et al., New Dev. New Appl. Anim. Cell Techn., Proc. ESACT Meet., 15th(1998), 105-112 and 117-120. Measuring ion concentration [CA2+] was performed on transfected mGlu la EBNA cells after incubation of the cells with Fluo-3 AM (final concentration 0.5 µm) for 1 hour at 37°C, followed by 4 washes with buffer for analysis (modified Dulbecco Wednesday Needle (DMEM), supplemented with salt Hanks and 20 mm N-2-hydroxyethylpiperazine-N'-2-econsultation (HEPES)). Measuring ion concentration [CA2+] was performed using fluorometric device that reads the image from the plate (FLIPR, Molecular Devices Corporation, La JOLLA, California, USA). When compounds were evaluated as antagonists, they were tested against 10 ám CH is tamata as agonist.

Curves of inhibition (antagonists) or activate (agonists) were close four-parameter logistic equation, which determined the effective concentration causing 50%effect (EC50), the concentration leading to 50%inhibition (IC50), and the coefficient of the hill through the use of iterative procedures for the approximation of nonlinear dependencies in the software package Origin (Microcal Software Inc., Northampton, mA, USA).

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example in the form of tablets, coated tablets, pills, hard or soft gelatin capsules, solutions, emulsions or suspensions. However, administration can also be carried out through the rectum, for example, in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and their pharmaceutically acceptable salts can be processed using an inert inorganic or organic carriers for pharmaceutical drugs. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and similar compounds may be used, for example, as the e of such carriers for tablets, the coated tablets, dragées and hard gelatin capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like compounds; depending on the nature of the active substance carriers, however, are not usually required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like compounds. Adjuvants, such as alcohols, polyols, glycerine, vegetable oils and the like, can be used for aqueous injection solutions of water-soluble salts of compounds of the formula I, but usually not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like compounds.

In addition, the pharmaceutical preparations can contain preservatives, promote solubilization tools, stabilizers, wetting means, emulsifiers, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffers, masking means or antioxidants. They may also contain other therapeutically valuable substances.

As mentioned above, the drug with the holding compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert filler, are also the object of the present invention, as a method of obtaining such medicines, which involves combining one or more compounds of the formula I or their pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable compounds in herbal dosage form together with one or more therapeutically inert carriers.

The dosage may vary within wide limits and, of course, selected in accordance with the individual requirements in each particular case. Typically, the effective dose for oral or parenteral administration is between 0.01-20 mg/kg/day, the preferred dosage for these indications is 0.1-10 mg/kg/day. Daily dose for an adult weighing 70 kg is respectively between 0.7 to 1400 mg per day, preferably between 7 and 700 mg per day.

Finally, as noted earlier, the use of compounds of the formula I and their pharmaceutically acceptable salts for the preparation of drugs in particular for the treatment or prevention of acute and/or chronic neurological disorders of the above mentioned type, the object of the invention.

Example 1

(RS)-2-(3-Forfinal)-1-(toluene-4-sulfonyl)pyrrolidin

a) Hydrochloride of 3-dimethylamino-1-(3-forfinal)propane-1-it (1:1)

Stir SMEs-fortetienne (10.5 g, to 75.7 mmole), paraformaldehyde (3,79 g, 126 mmol), dimethylamine hydrochloride (6,17 g, to 75.7 mmole), concentrated hydrochloric acid (0.2 ml) and ethanol (17 ml) was boiled under reflux for 1.5 hours the Clear solution was cooled to 0°and was added diethyl ether (100 ml). The resulting solid white collected, washed with diethyl ether and recrystallized from ethanol/diethyl ether, there was obtained the product (10.2 g, 58%) as a solid white color, tPL152°and mass spectrum (MS):m/e=195 (M+).

b) 4-(3-Forfinal)-4-oxobutyrate

Stir a mixture of the hydrochloride of 3-dimethylamino-1-(3-forfinal) propane-1-it (5.20 g, 22.4 mmole) and potassium cyanide (2,19 g, a 33.6 mmole) was heated under reflux for 17 h, evaporated, dissolved in water (150 ml) and was extracted with ethyl acetate (2×120 ml). The combined organic layers were washed with water (120 ml), with brine (120 ml), 3 N. sulfuric acid (100 ml) and with brine (100 ml), dried (magnesium sulfate) and was evaporated, the obtained orange oil (2.15 g), which was then purified by column chromatography on silica gel (ethyl acetate/hexane 1:3), received the product (1.68 g, 42%) as a solid pale yellow color, tPL46°and MS: m/e=177 (M+).

C) 5-(3-Forfinal)-3,4-dihydro-2H-pyrrol

4-(3-Forfinal)-4-oxobutyrate (1.60 g, 9,03 mmole), attoreny in methyl alcohol (45 ml) and 3,5 N. Meon-NH3(45 ml), was first made over Ra-Ni at room temperature for 16 hours, the Catalyst was filtered, the filtrate was evaporated and the technical product was purified with column chromatography on silica gel (ethyl acetate/toluene 1:2), received the product (1,16 g, 79%) as a colourless oil, MS: m/e=163 (M+).

g) (RS)-2-(3-Forfinal)pyrrolidin

To a stirred solution of 5-(3-forfinal)-3,4-dihydro-2H-pyrrole (1.10 g, 6,74 mmole) in methanol (40 ml) was added at 0°With sodium borohydride (0.51 g, a 13.4 mmole) and the reaction mixture was stirred at room temperature for 1 h Then was added an additional amount of sodium borohydride (0.25 g, 6,61 mmole) and continued stirring for 1 h the Mixture was evaporated, dissolved in saturated sodium bicarbonate solution (70 ml) and was extracted with dichloromethane (2×70 ml). The combined organic layers were washed with brine (70 ml), dried (magnesium sulfate) and was evaporated. Technical product was purified with column chromatography on silica gel (dichloromethane/methanol/ammonium hydroxide 15:1:0,1), received the product (0,77 g, 69%) as a colourless oil, MS: m/e=165 (M+).

d) (RS)-2-(3-Forfinal)-1-(toluene-4-sulfonyl)pyrrolidin

To a stirred solution of (RS)-2-(3-forfinal)pyrrolidine (0.24 g, a 1.45 mmole) and triethylamine (and 0.40 ml, 2,87 mmole) in dichloromethane (40 ml) was added at 0°With toluene-4-sulfochloride (0,42 g of 2.20 mmol who). The mixture was stirred at room temperature for 16 h, evaporated, dissolved in water (40 ml) and was extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with water (40 ml), with brine (40 ml), dried (magnesium sulfate) and was evaporated. Technical product was purified by crystallization from ethyl acetate/hexane, received the product (0,38 g, 83%) as a solid white color, tPL116°and MS: m/e=319 (M+).

Example 2

(RS)-1-(4-Chlorobenzenesulfonyl)-2-(3-forfinal)pyrrolidin

Specified in the title compound, solid white, tPL126°and MS: m/e=339 (M+), was obtained from (RS)-2-(3-forfinal)pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 3

(RS)-4- [1-(Toluene-4-sulfonyl)pyrrolidin-2-yl]pyridine

Specified in the title compound, solid pale brown, tPL158° and MS: m/e=302 (M+), was obtained from (RS)-4-(2-pyrrolidinyl)pyridine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 4

(RS)-2-Phenyl-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL109°and MS: m/e=301 (M+), was obtained from (RS)-2-phenyl-pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example the 1 day

Example 5

(RS)-1-Benzazolyl-2-phenylpyrrolidine

Specified in the title compound, solid light pink color, tPL116°and MS: m/e=287 (M+), was obtained from (RS)-2-phenylpyrrolidine and benzosulfimide in accordance with generally accepted way of example, 1 day

Example 6

(RS)-1-(4-Chlorobenzenesulfonyl)-2-phenylpyrrolidine

Specified in the title compound, a solid pale pink color, tPL119°and MS: m/e=321 (M+), was obtained from (RS)-2-phenylpyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 7

(RS)-1-Benzazolyl-2-(4-forfinal)pyrrolidin

Specified in the title compound, solid white, tPL100°and MS: m/e=305 (M+), was obtained from (RS)-2-(4-forfinal)-pyrrolidine and benzosulfimide in accordance with generally accepted way of example, 1 day

Example 8

(RS)-2-(4-Chlorophenyl)-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL121°and MS: m/e=335 (M+), was obtained from (RS)-2-(4-chlorophenyl)-pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 9

(RS)-1-(4-Chlorobenzenesulfonyl)-2-(4-chlorophenyl)pyrrolidin

Specified in the title compound, solid white, tPL159 And MS: m/e=355 (M+), was obtained from (RS)-2-(4-chlorophenyl)-pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 10

(RS)-2-(4-Forfinal)-1-(4-methoxybenzenesulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL134°and MS: m/e=335 (M+), was obtained from (RS)-2-(4-forfinal)-pyrrolidine and 4-methoxybenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 11

(RS)-1-(4-Chlorobenzenesulfonyl)-2-(4-forfinal)pyrrolidin

Specified in the title compound, solid white, tPL118°and MS: m/e=339 (M+), was obtained from (RS)-2-(4-forfinal)-pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 12

(RS)-2-(4-Forfinal)-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, not quite white solid, tPL128°and MS: m/e=319 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 13

(RS)-1-Benzazolyl-2-(4-chlorophenyl)pyrrolidin

Specified in the title compound, solid white, tPL122°and MS: m/e=321 (M+), was obtained from (RS)-2-(4-chlorophenyl)-pyrrolidine and benzosulfimide in accordance with generally accepted is m by way of example, 1 day

Example 14

(RS)-4-[1-(4-Chlorobenzenesulfonyl)pyrrolidin-2-yl]pyridine

Specified in the title compound, solid white, tPL177°and MS: m/e=322 (M+), was obtained from (RS)-4-(pyrrolidin-2-yl) pyridine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 15

(RS)-1-Benzazolyl-2-(3-forfinal)pyrrolidin

Specified in the title compound, solid white, tPL96°and MS: m/e=305 (M+), was obtained from (RS)-2-(3-forfinal)-pyrrolidine and benzosulfimide in accordance with generally accepted way of example, 1 day

Example 16

(RS)-1-(4-Permentantly)-2-(4-forfinal)pyrrolidin

Specified in the title compound, solid, light brown, tPL121°and MS: m/e=324,2 (M+N+), was obtained from (RS)-2-(4-forfinal) pyrrolidine and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 17

(RS)-2-(4-Forfinal)-1-(toluene-3-sulfonyl)pyrrolidin

Specified in the title compound, solid, light brown, tPL102°and MS: m/e=319 (M+), was obtained from (RS)-2-(4-forfinal) pyrrolidine and toluene-3-sulfochloride in accordance with generally accepted way of example, 1 day

Example 18

(RS)-2-(4-Forfinal)-1-(toluene-2-sulfonyl)pyrrolidin

Specified in the title of the link is, colorless oil, MS: m/e=319 (M+), was obtained from (RS)-2-(4-forfinal) pyrrolidine and toluene-2-sulfochloride in accordance with generally accepted way of example, 1 day

Example 19

(RS)-1-(Toluene-4-sulfonyl)-2-p-tolylpropan

Specified in the title compound, solid white, tPL124°and MS: m/e=315 (M+), was obtained from (RS)-2-p-tolyl-pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 20

(RS)-1-(4-Chlorobenzenesulfonyl)-2-p-tolylpropan

Specified in the title compound, solid white, tPL129°and MS: m/e=335 (M+), was obtained from (RS)-2-p-tolyl-pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 21

(RS)-1-(4-Ethylbenzonitrile)-2-(4-forfinal)pyrrolidin

Specified in the title compound, solid white, tPL78°and MS: m/e=333 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 4-ethylbenzaldehyde in accordance with generally accepted way of example 1D.

Example 22

(RS)-2-(4-Forfinal)-1-(4-isopropylbenzenesulfonyl)-pyrrolidin

Specified in the title compound, solid white, tPL77°and MS: m/e=347 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 4-isopropylbenzaldehyde in accordance with generally accepted is m by way of example, 1 day

Example 23

(RS)-1-(4-Permentantly)-2-p-tolylpropan

Specified in the title compound, solid white, tPL112°and MS: m/e=319 (M+), was obtained from (RS)-2-p-tolyl-pyrrolidine and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 24

(RS)-1-(4-Chlorobenzenesulfonyl)-2-(4-methoxyphenyl)pyrrolidin

Specified in the title compound, solid white, tPL133°and MS: m/e=352 (M+N+), was obtained from (RS)-2-(4-methoxyphenyl)pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 25

(RS)-2-(4-Methoxyphenyl)-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL122°and MS: m/e=332 (M+N+), was obtained from (RS)-2-(4-methoxyphenyl)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 26

(RS)-1-(4-Brabanthallen)-2-(4-forfinal)pyrrolidin

Specified in the title compound, not quite white solid, tPL131°and MS: m/e=383 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 4-bromobenzaldehyde in accordance with generally accepted way of example, 1 day

Example 27

(RS)-1-{4-[2-(4-Forfinal)pyrrolidin-1-sulfonyl]phenyl}-alanon

Specified in the title compound, the solid substance is pale brown, tPL148°and MS: m/e=348 (M+N+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 4-acetylbenzenesulfonyl in accordance with generally accepted way of example, 1 day

Example 28

(RS)-1-(Toluene-4-sulfonyl)-2-m-tolylpropan

Specified in the title compound, not quite white solid, tPL79°and MS: m/e=315 (M+), was obtained from (RS)-2-m-tolylpropan and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 29

(RS)-1-(4-Chlorobenzenesulfonyl)-2-m-tolylpropan

Specified in the title compound, not quite white solid, tPL78°and MS: m/e=335 (M+), was obtained from (RS)-2-m-tolylpropan and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 30

(RS)-1-(4-Permentantly)-2-m-tolylpropan

Specified in the title compound, not quite white solid, tPL80°and MS: m/e=319 (M+), was obtained from (RS)-2-m-tolylpropan and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 31

(RS)-2-(3-Chlorophenyl)-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, not quite white solid, tPL107°and MS: m/e=335 (M+), was obtained from (RS)-2-(3-chlorophenyl)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted method is m example 1 D.

Example 32

(RS)-1-(4-Chlorobenzenesulfonyl)-2-(3-chlorophenyl)pyrrolidin

Specified in the title compound, solid, light brown, tPL99°and MS: m/e=355 (M+), was obtained from (RS)-2-(3-chlorophenyl)pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 33

(RS)-2-(4-Forfinal)-1-(4-siebenthaler)pyrrolidin

Specified in the title compound, not quite white solid, tPL147°and MS: m/e=330 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 4-siebentischwald in accordance with generally accepted way of example, 1 day

Example 34

(RS)-1-(4-Chlorobenzenesulfonyl)-2-(3-methoxyphenyl)pyrrolidin

Specified in the title compound, solid white, tPL95°and MS: m/e=351 (M+), was obtained from (RS)-2-(3-methoxyphenyl)pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 35

(RS)-1-(4-Permentantly)-2-Tien-2-iparralde

Specified in the title compound, solid white, tPL97°and MS: m/e=312,1 (M+N+), was obtained from (RS)-2-Tien-2-yl-pyrrolidine and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 36

(RS)-1-(4-Chlorobenzenesulfonyl)-2-Tien-2-iparralde

Specified in the title compounds is s, solid white, tPL84°and MS: m/e=328,1 (M+N+), was obtained from (RS)-2-Tien-2-yl-pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 37

(RS)-2-Tien-2-yl-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL108°and MS: m/e=308,2 (M+N+), was obtained from (RS)-2-Tien-2-yl-pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 38

(RS)-2-(3,4-Differenl)-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL127°and MS: m/e=338,2 (M+N+), was obtained from (RS)-2-(3,4-differenl) pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 39

(RS)-1-(4-Chlorobenzenesulfonyl)-2-(3,4-differenl)-pyrrolidin

Specified in the title compound, solid white, tPL121°and MS: m/e=358,1 (M+H+), was obtained from (RS)-2-(3,4-differenl) pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 40

(RS)-1-(4-Chlorobenzenesulfonyl)-2-(4-dimethylamino-3-forfinal)pyrrolidin

Specified in the title compound, solid white, tPL99°and MS: m/e=383,2 (M+N+), was obtained from (RS)-2-(4-dimethyl what Mino-3-forfinal)pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 41

(RS)-1-(p-Toluensulfonyl)-2-(4-dimethylamino-3-forfinal)-pyrrolidin

Specified in the title compound, solid white, tPL66°and MS: m/e= 363,1 (M+N+), was obtained from (RS)-2-(4-dimethylamino-3-forfinal)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 42

(RS)-2-(3-Chloro-4-forfinal)-1-(toluene-4-sulfonyl)-pyrrolidin

Specified in the title compound, not quite white solid, tPL96°and MS: m/e=354,2 (M+N+), was obtained from (RS)-2-(3-chloro-4-forfinal)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 43

(RS)-1-(4-Chlorobenzenesulfonyl)-2-(3-chloro-4-forfinal)-pyrrolidin

Specified in the title compound, not quite white solid, tPL119°and MS: m/e=374,2 (M+N+), was obtained from (RS)-2-(3-chloro-4-forfinal)pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 44

(RS)-2-(3-Chloro-4-forfinal)-1-(4-permentantly)-pyrrolidin

Specified in the title compound, solid white, tPL116°and MS: m/e=358,1 (M+), was obtained from (RS)-2-(3-chloro-4-forfinal)pyrrolidine and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 45

(RS)-1-(4-Chlorobenzenesulfonyl)-2-(-dimethylamino-3-chloro-phenyl)pyrrolidin

Specified in the title compound, solid white, tPL103°and MS: m/e=398 (M+), was obtained from (RS)-2-(4-dimethylamino-3-chlorophenyl)pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 46

(RS)-1-(4-Permentantly)-2-(4-dimethylamino-3-chloro-phenyl)pyrrolidin

Specified in the title compound, not quite white solid, tPL119°and MS: m/e=382 (M+), was obtained from (RS)-2-(4-dimethylamino-3-chlorophenyl)pyrrolidine and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 47

(RS)-2-(3,4-Dichlorophenyl)-1-(toluene-4-sulfonyl) pyrrolidin

Specified in the title compound, not quite white solid, tPL136°and MS: m/e=369 (M+), was obtained from (RS)-2-(3,4-dichlorophenyl)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 48

(RS)-1-(Toluene-4-sulfonyl)-2-(4-triptoreline)-pyrrolidin

Specified in the title compound, solid white, tPL99°and MS: m/e=369 (M+), was obtained from (RS)-2-(4-triptoreline)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 49

(RS)-1-(4-Chlorobenzenesulfonyl)-2-(4-triptoreline)-pyrrolidin

Specified in the title compound, a solid is e substance of white color, tPL107°and MS: m/e=3 (M+), was obtained from (RS)-2-(4-triptoreline)pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 50

(RS)-1-(4-Permentantly)-2-(4-triptoreline)-pyrrolidin

Specified in the title compound, solid white, tPL114°and MS: m/e=373 (M+), was obtained from (RS)-2-(4-triptoreline)pyrrolidine and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 51

(RS)-2-(2-Chlorophenyl)-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL149°and MS: m/e=336,2 (M+N+), was obtained from (RS)-2-(2-chlorophenyl)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 52

(RS)-2-(2-Forfinal)-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL143°and MS: m/e= 320,3 (M+N+), was obtained from (RS)-2-(2-forfinal)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 53

(RS)-1-(4-Chlorobenzenesulfonyl)-2-(2-forfinal)pyrrolidin

Specified in the title compound, solid white, tPL134°and MS: m/e=340,2 (M+N+), was obtained from (RS)-2-(2-forfinal)pyrrolidine and 4-chlorobenzene is elfoglalta in accordance with generally accepted way of example, 1 day

Example 54

(RS)-1-(4-Permentantly)-2-(2-forfinal)pyrrolidin

Specified in the title compound, solid white, tPL108°and MS: m/e=324,2 (M+N+), was obtained from (RS)-2-(2-forfinal)pyrrolidine and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 55

(RS)-2-Tien-3-yl-1-(toluene-4-sulfonyl)pyrrolidine

Specified in the title compound, solid white, tPL114°and MS: m/e=308,2 (M+H+), was obtained from (RS)-2-Tien-3-yl-pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 56

(RS)-1-(4-Chlorobenzenesulfonyl)-2-Tien-3-iparralde

Specified in the title compound, solid white, tPL120°and MS: m/e= 328,1 (M+N+), was obtained from (RS)-2-Tien-3-elparoladon and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 57

(RS)-1-(4-Permentantly)-2-Tien-3-iparralde

Specified in the title compound, solid white, tPL135°and MS: m/e= 312,1 (M+N+), was obtained from (RS)-2-Tien-3-elparoladon and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 58

(RS)-2-(4-Chloro-3-were)-1-(toluene-4-sulfonyl)-pyrrolidin

Specified in the title compound, solid white is the first color, tPL103°and MS: m/e=349 (M+), was obtained from (RS)-2-(4-chloro-3-were)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 59

(RS)-2-(4-Forfinal)-1-(4-propylbenzenesulfonyl)pyrrolidin

Specified in the title compound, colorless oil, MS: m/e=347 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 4-propyl-benzosulfimide in accordance with generally accepted way of example, 1 day

Example 60

(RS)-2-(4-Forfinal)-1-(4-trifloromethyl)-pyrrolidin

Specified in the title compound, solid white, tPL85°and MS: m/e=373 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 4-triftormetilfullerenov in accordance with generally accepted way of example, 1 day

Example 61

(RS)-2-(4-Forfinal)-1-(2,4,6-trimethylbenzenesulfonyl)-pyrrolidin

Specified in the title compound, solid white, tPL111°and MS: m/e=347 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 2,4,6-trimethylbenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 62

(RS)-1-(3-Chloro-4-methylbenzenesulfonyl)-2-(4-forfinal)-pyrrolidin

Specified in the title compound, not quite white solid, tPL134°and MS: m/e=353 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 3-chloro-4-methylb is solarpowered in accordance with generally accepted way of example, 1 day

Example 63

(RS)-1-(2-Permentantly)-2-(4-forfinal)pyrrolidin

Specified in the title compound, not quite white solid, tPL91°and MS: m/e=323 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 2-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 64

(RS)-1-(3-Permentantly)-2-(4-forfinal)pyrrolidin

Specified in the title compound, not quite white solid, tPL101°and MS: m/e=323 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 3-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 65

(RS)-1-(2-Siebenthaler)-2-(4-forfinal)pyrrolidin

Specified in the title compound, solid light green color, tPL101°and MS: m/e=330 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 2-siebentischwald in accordance with generally accepted way of example, 1 day

Example 66

(RS)-2-(4-Forfinal)-1-(naphthalene-2-sulfonyl)pyrrolidin

Specified in the title compound, not quite white solid, tPL166°and MS: m/e=355 (M+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and naphthalene-2-sulfochloride in accordance with generally accepted way of example, 1 day

Example 67

(RS)-2-(2,4-Dimetilfenil)-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title connect the tion, solid white, tPL130°and MS: m/e=329 (M+), was obtained from (RS)-2-(2,4-dimetilfenil)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 68

(RS)-2-(2,4-Dimetilfenil)-1-(4-permentantly)pyrrolidin

Specified in the title compound, solid white, tPL134°and MS: m/e=333 (M+), was obtained from (RS)-2-(2,4-dimetilfenil)pyrrolidine and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 69

(RS)-2-Furan-2-yl-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL58°and MS: m/e=291 (M+), was obtained from (RS)-2-furan-2-yl-pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 70

(RS)-1-(4-Permentantly)-2-furan-2-iparralde

Specified in the title compound, solid white, tPL69°and MS: m/e=295 (M+), was obtained from (RS)-2-furan-2-elparoladon and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 71

(RS)-1-(4-Chlorobenzenesulfonyl)-2-furan-2-iparralde

Specified in the title compound, yellow oil, MS: m/e=311 (M+), was obtained from (RS)-2-furan-2-elparoladon and 4-chlorobenzenesulfonamide in accordance with the General who inatum way of example, 1 day

Example 72

(RS)-2-(4-N,N-Dimethylaminophenyl)-1-(toluene-4-sulfonyl)-pyrrolidin

Specified in the title compound, solid white, tPL132°and MS: m/e= 345,3 (M+N+), was obtained from (RS)-2-(4-N,N-dimethylaminophenyl)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 73

(RS)-2-(4-N,N-Dimethylaminophenyl)-1-(4-permentantly)-pyrrolidin

Specified in the title compound, solid white, tPL109°and MS: m/e=349,4 (M+N+), was obtained from (RS)-2-(4-N,N-dimethylaminophenyl)pyrrolidine and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 74

(RS)-2-(4-N,N-Dimethylaminophenyl)-1-(4-chlorobenzenesulfonyl)-pyrrolidin

Specified in the title compound, solid white, tPL117°and MS: m/e=365,2 (M+N+), was obtained from (RS)-2-(4-N,N-dimethylaminophenyl)pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 75

(RS)-1-Benzazolyl-2-(4-triptoreline)pyrrolidin

Specified in the title compound, solid white, tPL95°and MS: m/e=355 (M+), was obtained from (RS)-2-(4-triptoreline)pyrrolidine and benzosulfimide in accordance with generally accepted way of example, 1 day

Example 76

(R)-1-(4-Chlorbenzyl the Nile)-2-(4-forfinal)pyrrolidin

Specified in the title compound, solid white, tPL119°and MS: m/e=339 (M+), was obtained from (R)-2-(4-forfinal)pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 77

(S)-1-(4-Chlorobenzenesulfonyl)-2-(4-forfinal)pyrrolidin

Specified in the title compound, solid white, tPL120°and MS: m/e=339 (M+), was obtained from (S)-2-(4-forfinal)pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 78

(RS)-2-(4-Ethylphenyl)-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL92°and MS: m/e=330,3 (M+N+), was obtained from (RS)-2-(4-ethylphenyl) pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 79

(RS)-2-(4-Ethylphenyl)-1-(4-chlorobenzenesulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL94°and MS: m/e=350,3 (M+), was obtained from (S)-2-(4-ethylphenyl)pyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 80

(RS)-2-(4-Ethylphenyl)-1-(4-permentantly)pyrrolidin

Specified in the title compound, solid white, tPL93°and MS: m/e=334,2 (M+N+), received the C (S)-2-(4-ethylphenyl)pyrrolidine and 4-forbindelsesteknologi in accordance with generally accepted way of example, 1 day

Example 81

(R)-2-(4-Forfinal)-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL136°,=+174° (C=0.1 in chloroform) and MS: m/e=319 (M+), was obtained from (R)-2-(4-forfinal)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 82

(S)-2-(4-Forfinal)-1-(toluene-4-sulfonyl)pyrrolidin

Specified in the title compound, solid white, tPL136°,=-172° (C=0.1 in chloroform) and MS: m/e=319 (M+), was obtained from (S)-2-(4-forfinal)pyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 83

(RS)-3-[1-(Toluene-4-sulfonyl)pyrrolidin-2-yl]pyridine

Specified in the title compound, solid white, tPL112°and MS: m/e=302 (M+), was obtained from 3-(pyrrolidin-2-yl)-pyridine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 84

(RS)-2-(4-Forfinal)-1-(4-hydroxymethanesulfinic)-pyrrolidin

Specified in the title compound, solid white, tPL107°and MS: m/e=336,2 (M+N+), was obtained from (RS)-2-(4-forfinal)pyrrolidine and 4-hydroxyethylmethylcellulose in accordance with generally accepted way of example, 1 day

When the EP 85

(RS)-2-(4-Forfinal)-1-(4-ethoxymethylenemalonic)-pyrrolidin

The reaction of (RS)-2-(4-forfinal)-1-(4-chloromethanesulfonyl)pyrrolidine (0.50 g, of 1.41 mmole), which was obtained in accordance with the generally accepted method of example 1 g from (RS)-2-(4-forfinal)pyrrolidine and 4-bromocinnamaldehyde, with sodium methylate in methanol for 80 h at 50°resulted after crystallization from diethyl ether/hexane to 0.28 g (52%) specified in the title compound in the form of a solid white color, tPL115°and MS: m/e=349 (M+).

Example 86

Fumarate (RS)-4-{4-[2-(4-forfinal)pyrrolidin-1-sulfonyl]-benzyl}of the research (1:1)

The reaction of (RS)-2-(4-forfinal)-1-(4-chloromethanesulfonyl)pyrrolidine (0.50 g, of 1.41 mmole), which was obtained in accordance with the generally accepted method of example 1 g from (RS)-2-(4-forfinal) pyrrolidine and 4-bromocinnamaldehyde, morpholine (potassium carbonate, dimethylformamide, 80°C, 17 h) and further education fumarata (methanol, diethyl ether) resulted specified in the title compound in the form of not quite white solids, tPL136°and MS: m/e=405,4 (M+H+).

Example 87

Fumarate (RS)-4-[2-(4-forfinal)pyrrolidin-1-sulfonyl]-benzylamine (1:0,5)

Hydrogenation of (RS)-2-(4-forfinal)-1-(4-siebenthaler) pyrrolidine (Ra-Ni, MeOH-NF3and further education fumarata (Meon, IER is silt ether) resulted specified in the title compound in the form of a solid white color, tPL207°and MS: m/e=335,2 (M+N+).

Example 88

A mixture of (2RS,3RS)- and (2RS,3SR)-2-(4-forfinal)-3-methyl-1-(toluene-4-sulfonyl)pyrrolidine

Specified in the title compound, not quite white solid, tPL94°and MS: m/e=333 (M+), was obtained from a mixture of (2RS,3RS) - and (2RS,3SR)-2-(4-forfinal)-3-methylpyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 89

A mixture of (2RS,3RS)- and (2RS,3SR)-1-(4-chlorobenzenesulfonyl)-2-(4-forfinal)-3-methylpyrrolidine

Specified in the title compound, not quite white solid, tPL87°and MS: m/e=354,2 (M+N+), was obtained from a mixture of (2RS,3RS)- and (2RS,3SR)-2-(4-forfinal)-3-methylpyrrolidine and 4-chlorobenzenesulfonamide in accordance with generally accepted way of example, 1 day

Example 90

(2RS,3RS)-2-(4-Forfinal)-3-methyl-1-(toluene-4-sulfonyl)-pyrrolidin

Specified in the title compound, not quite white solid, tPL112°and MS: m/e=333 (M+), was obtained from (2RS,3RS)-2-(4-forfinal)-3-methylpyrrolidine and toluene-4-sulfochloride in accordance with generally accepted way of example, 1 day

Example 91

(2RS,3RS)-[2-(4-forfinal)-1-(toluene-4-sulfonyl)-pyrrolidin-3-yl]methanol

Restore methyl ester (2RS,3RS)-2-(4-forfinal)-1-(toluene-4-sulfonyl)pyrrolidin-3-carboxylic acid was obtained from methyl ester (2RS,3RS)-2-(4-forfinal)-pyrrolidin-3-CT is about acid and toluene-4-sulfochloride in accordance with the generally accepted method of example 1 d, the sodium borohydride in methyl alcohol was brought after water treatment and purification using column chromatography on silica gel (ethyl acetate/hexane 1:1) to the specified in the title compound as a pale yellow oil, MS: m/e=348 (M-H+).

Example

Tablets of the following composition are produced in the usual way:

mg tablet

The active ingredient 100

Powdered lactose 95

White corn starch 35

Polyvinylpyrrolidone 8

Sodium carboximetilkrahmal 10

Magnesium stearate 2

Weight tablets 250

Example B

Tablets of the following composition are produced in the usual way:

mg tablet

The active ingredient 200

Powdered lactose 100

White corn starch 64

Polyvinylpyrrolidone 12

Sodium carboximetilkrahmal 20

Magnesium stearate 4

Weight tablets 400

The example In

Capsules of the following composition get:

mg/capsule

The active ingredient 50

Crystalline lactose 60

Microcrystalline cellulose 34

Talc 5

Magnesium stearate 1

The mass is placed in a capsule

content 150

The active ingredient with a suitable particle size, crystalline lactose and microcrystalline cellulose are mixed by homogenization with each other, sieved and then mixed into talc and magnesium stearate. The final mixture is placed is in hard gelatin capsules of suitable size.

1. Derivatives of 1-arenesulfonyl-2-arylpyrimidine and piperidine derivatives of General formula

where

R1means hydrogen or (C1-C7) alkyl;

R2means furyl, thienyl, pyridyl or phenyl, optionally substituted by 1-3 substituents selected from (C1-C7)alkyl, (C1-C7)alkoxygroup, halogen, langroup, CF3or-N(R4)2;

R3means naphthyl or phenyl, optionally substituted by 1-3 substituents selected from (C1-C7)alkyl, (C1-C7)alkoxygroup, halogen, acetyl, langroup, hydroxy(C1-C7)alkyl, -CH2-morpholine-4-yl, (C1-C7)alkyloxy(C1-C7)alkyl, (C1-C7)alkyl-N(R4)2or CF3;

R4means independently from each other hydrogen or (C1-C7)alkyl, with the exception of (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpropan, N-tosyl-CIS-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidin-2-yl] pyridine and N-tosyl-2-(3,4-acid)pyrrolidine,

and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, where

R1means hydrogen or methyl;

R2means phenyl, optionally substituted, halogeno is, (C1-C7)alkyl, CF3or-N(CH3)2;

and their pharmaceutically acceptable salts.

3. Compounds according to claims 1 and 2, which represent

(RS)-2-(3-forfinal)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-1-(4-chlorobenzenesulfonyl)-2-(3-forfinal)pyrrolidin,

(RS)-1-(4-chlorobenzenesulfonyl)-2-phenylpyrrolidine,

(RS)-2-(4-chlorophenyl)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-1-(4-chlorobenzenesulfonyl)-2-(4-forfinal)pyrrolidin,

(RS)-2-(4-forfinal)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-1-benzazolyl-2-(4-chlorophenyl)pyrrolidin,

(RS)-1-(4-permentantly)-2-(4-forfinal)pyrrolidin,

(RS)-2-(4-forfinal)-1-(toluene-2-sulfonyl)pyrrolidin,

(RS)-1-(4-chlorobenzenesulfonyl)-2-p-tolylpropan,

(RS)-1-(4-ethylbenzonitrile)-2-(4-forfinal)pyrrolidin,

(RS)-1-(toluene-4-sulfonyl)-2-m-tolylpropan,

(RS)-2-(3-chlorophenyl)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-2-(3,4-differenl)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-2-(3-chloro-4-forfinal)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-1-(4-permentantly)-2-(4-dimethylamino-3-chlorophenyl)-pyrrolidin,

(RS)-1-(toluene-4-sulfonyl)-2-(4-triptoreline)pyrrolidin,

(RS)-2-(4-chloro-3-were)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-2-(4-forfinal)-1-(4-triptorelin sulfonyl)pyrrolidin,

(RS)-2-(N,N-dimethylaminophenyl)-1-(4-permentantly)pyrrolidin,

(R)-1-(4-chlorobenzenesulfonyl)-2-(4-forfinal)pyrrolidin,

(S)-1-(4-chlorobenzenesulfonyl)-2-(4-forfinal)pyrrolidin,

(RS)-2-(4-ethylphenyl)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-2-(4-ethylphenyl)-1-(4-permentantly)pyrrolidin,

(S)-2-(4-forfinal)-1-(toluene-4-sulfonyl)pyrrolidin,

(R)-2-(4-forfinal)-1-(toluene-4-sulfonyl)pyrrolidin,

(RS)-2-(4-forfinal)-1-(4-ethoxymethylenemalonic)-pyrrolidin and

(2RS,3RS)-2-(4-forfinal)-3-methyl-1-(toluene-4-sulfonyl)-pyrrolidin.

4. Compounds according to claim 1, where R1means hydrogen and R2means furyl, thienyl or pyridyl.

5. Compounds according to claims 1 and 4, which represent

(RS)-1-(4-chlorobenzenesulfonyl)-2-Tien-2-iparralde,

(RS)-2-Tien-2-yl-1-(toluene-4-sulfonyl)pyrrolidin and

(RS)-2-Tien-3-yl-1-(toluene-4-sulfonyl)pyrrolidin.

6. Pharmaceutical drug intended for the treatment or prevention of acute and/or chronic neurological disorders, comprising a compound according to any one of claims 1 to 5, or (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpropan, N-tosyl-CIS-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidin-2-yl]pyridine or N-tosyl-2-(3,4-acid) pyrrolidin with the action of the ago is earnest or antagonists of metabotropic glutamate receptors and their pharmaceutically acceptable salts, and pharmaceutically acceptable excipients.

7. The pharmaceutical agent according to claim 6 for the prevention or treatment of acute and/or chronic neurological disorders, such as, for example, restricted brain function caused by operations bypass surgery or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest, hypoglycemia, Alzheimer's disease, Huntington's chorea, ALS, AIDS-dementia, eye injuries, retinopathy, impaired learning, memory disorders, and acute and chronic pain, schizophrenia, Parkinson's disease of unclear origin or parkinsonism caused by medicaments as well as States that lead to reactions related to the lack of glutamate, such as muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychosis, addiction to opium, anxiety, vomiting, dyskinesia and depression.

8. Compounds according to any one of claims 1 to 5, or (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpropan, N-tosyl-CIS-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidin-2-yl] pyridine or N-tosyl-2-(3,4-acid)pyrrolidine, as well as their pharmaceutically acceptable salts designed for cooking, in addition to the state funds for the treatment or prevention of acute and/or chronic neurological disorders.

9. Compounds according to claims 1-5, or (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolyl-pyrrolidine, N-tosyl-CIS-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidin-2-yl]pyridine or N-tosyl-2-(3,4-acid)pyrrolidin, as well as their pharmaceutically acceptable

salt for the prevention or treatment of acute and/or chronic neurological disorders.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

The invention relates to a method for producing a condensed 2-getreleasedate General formula

using the diamine of General formula

where A=

R=2-furyl, 2-thienyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, and aldehydes in the presence of acetate or copper sulfate, characterized in that the interaction takes place by boiling in 50% acetic acid, followed by decomposition of the copper salt, the effect on its suspension in 50% acetic acid sodium thiosulfate in 100With

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The invention relates to organic chemistry and pharmacology, namely a mixture of isomers of the potassium salt of 2-[5(6)-nitro-1-(titanyl-3)benzimidazolyl-2-thio] acetic acid in a molar ratio of 1:3, manifesting cardiotonic activity

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The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to new compounds of the mixture of isomers of 2-monoethanolamine-5(6)-nitro-1-(titanyl-3)benzimidazole of the formula I

The invention relates to tricyclic condensed heterocyclic compounds of the formula I, X is, for example, CH, CH2, СНR (where R means a lower alkyl group or a substituted lower alkyl group) or CRR' (where R and R' have the values specified above for R); Y means, for example, CH, CH2or C=O; z means, for example, S, S=O=; U denotes C; R1-R4independent means, for example, a hydrogen atom, SR (where R has the above values), phenyl group, substituted phenyl group, follow group, thienyl group, benzofuran or benzothiazyl at least one element of R5and R8means, for example, HE and the rest of the elements of R5and R8independent means, for example, a hydrogen atom; and their optical isomers, conjugates, and pharmaceutically acceptable salts

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

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using the diamine of General formula

where A=

R=2-furyl, 2-thienyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, and aldehydes in the presence of acetate or copper sulfate, characterized in that the interaction takes place by boiling in 50% acetic acid, followed by decomposition of the copper salt, the effect on its suspension in 50% acetic acid sodium thiosulfate in 100With

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

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The invention relates to tricyclic condensed heterocyclic compounds of the formula I, X is, for example, CH, CH2, СНR (where R means a lower alkyl group or a substituted lower alkyl group) or CRR' (where R and R' have the values specified above for R); Y means, for example, CH, CH2or C=O; z means, for example, S, S=O=; U denotes C; R1-R4independent means, for example, a hydrogen atom, SR (where R has the above values), phenyl group, substituted phenyl group, follow group, thienyl group, benzofuran or benzothiazyl at least one element of R5and R8means, for example, HE and the rest of the elements of R5and R8independent means, for example, a hydrogen atom; and their optical isomers, conjugates, and pharmaceutically acceptable salts

The invention relates to a new crystalline modification of 5-fluoro-1-(tetrahydro-2-furyl)uracil, as well as complex compounds of this form with 2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine or licorice root extract (Radices Glycyrrhzae)

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

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