Derivatives of carbamic acid esters, their preparing (variants) and their applying as ligands of metabotropic glutamate receptors


FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

22 cl, 1 tbl, 2 sch, 78 ex

 

The present invention relates to derivatives of esters carbamino acid of General formula

where R1means hydrogen or lower alkyl;

R2, R2'mean independently from each other hydrogen, (lower)alkyl, (lower)alkoxy, halogen or trifluoromethyl;

X represents O, S or two hydrogen atoms, not forming a bridge;

Al/A2means independently of each other phenyl or 6-membered heterocycle containing 1 or 2 nitrogen atom;

In means a group of the formula

where

R3means lower alkyl, (lower)alkenyl, (lower)quinil, benzyl, (lower)alkylsilane, (lower)ancillary, (lower)alkylphenyl, (lower)alkyl(lower)alkoxyphenyl, (lower)alkylphenyl, optionally substituted (lower)alkoxygroup, or phenyl, which is optionally substituted by (lower)alkoxygroup, or (lower)alkylaryl, cycloalkyl, (lower)alkyltrimethyl or (lower)alkylsulfonyl;

Y represents-O-, -S -, or a bond;

Z denotes-O - or-S-;

or is a 5-membered heterocyclic group of the formula

where

R4and R5mean hydrogen, (lower)alkyl, (lower)alkoxygroup, cyclohexyl, (lower)alkylcyclohexane or trifluoromethyl, provided that at m is re, one of R4or R5must be hydrogen;

and their pharmaceutically acceptable salts.

In particular, the invention relates to compounds having the following structures:

or

or

or

or

where the substituents are as indicated above.

These compounds and their salts are new and different valuable therapeutic properties.

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

In the Central nervous system (CNS) signaling stimuli occurs in the interaction of the neurotransmitter, sending neuron, with neuroreceptors.

L-Glutamic acid, the most common neurotransmitter in the Central nervous system, plays an important 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 ligands ion channels. Metabotropic glutamate receptors (mGluR) belong to the second major group, and, in addition, belong to the family of receptors associated with G-protein.

This is now known eight different members of such mGluR receptors and some of them even have subtypes. Based on the structural parameters of different signaling pathways of secondary messengers and different affinity for compounds with a low molecular weight of these eight receptors can be subdivided into three subgroups:

mGluR1 and mGluR5 belong to group I, mGluR2 and niGluR3 belong to the group II and mGluR4, mGluR6 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 cognition and memory disorders, and chronic and acute pain.

Other treatable indications in this regard are limited brain activity 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 SPID ohms, eye injuries, retinopathy, a disease of unknown origin or parkinsonism caused by medicaments, as well as the condition in which associated with deficiency of the m glutamate reactions as, for example, muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, ophiomyia, 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 compounds according to the invention and their preparation and the use of the compounds according to the invention for the treatment or prevention of the above diseases, respectively, to obtain the drugs.

Preferred compounds of formula I in this invention are those in which a represents phenyl, X represents two hydrogen atoms, not forming a bridge, and means In the group,

where Z means oxygen and R3and Y are as described above.

The following are examples of such compounds are:

butyl ether diphenylacetylene acid, ethyl ester diphenylacetylene acid or Penta-4-injuly ether diphenylacetylene acid.

Further preferred compounds of formula I, where a represents phenyl, X is-O - or-S - and means In the group,

where Z denotes O and R3and Y are as described to enter the.

Examples of such compounds are:

ethyl ether (N-xanthene-9-carbonyl)carbamino acid, butyl ester (N-xanthene-9-carbonyl)carbamino acid or butyl ether (N-thioxanthen-9-carbonyl)carbamino acid.

Preferred compounds of formula I of the present invention are those in which a represents phenyl, X represents 2 hydrogen atoms, not forming a bridge, and means heterocyclic group of the formula

where R4and R5have the above values.

Examples of such compounds are:

N-(5-ethyloxazole-2-yl)-2,2-diphenylacetamide,

N-(5-methoxazole-2-yl)-2,2-diphenylacetamide,

2,2-diphenyl-N-(5-propyl-[1,3,4]oxadiazol-2-yl)acetamide", she

N-[5-(2-methoxyethyl)-[1,3,4]oxadiazol-2-yl]-2,2-diphenylacetamide,

N-(3-methyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenylacetamide,

N-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenylacetamide or

N-(5-methyl-[1,2,4]oxadiazol-3-yl)-2,2-diphenylacetamide.

Further preferred compounds of formula I in which a represents phenyl, X is-O - or-S - and means heterocyclic group of the formula

for example, the following connections:

oxazol-2-alamid N-xanthene-9-carboxylic acid,

(5-propyl[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid,

(5-ethyloxazole-2-yl)and the ID N-xanthene-9-carboxylic acid,

(5-methoxazole-2-yl)amide N-xanthene-9-carboxylic acid,

(5-preprocessor-2-yl)amide N-xanthene-9-carboxylic acid,

(5-ethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid,

(5-cyclopropylmethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid,

(4-methoxazole-2-yl)amide N-xanthene-9-carboxylic acid,

(3-methyl-[1,2,4]oxadiazol-5-yl)amide N-xanthene-9-carboxylic acid,

(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid,

(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid,

(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)amide N-xanthene-9-carboxylic acid, or

(5-methyl-[1,2,4]oxadiazol-3-yl)amide N-xanthene-9-carboxylic acid.

The invention comprises in addition to the racemates all stereoisomeric forms.

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

The term "(lower)alkoxy" means the residue of lower alkyl, having in mind the above definition, linked through an oxygen atom.

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

Compounds of General formula I and their pharmaceutically acceptable salts may b the th received by way including

a) interaction of the compounds of formula

with the compound of the formula

with the formation of compounds of the formula

where the substituents have the above values, or

b) interaction of the compounds of formula

with the compound of the formula

with the formation of compounds of the formula

where G is a suitable leaving group, which can be, for example, chlorine, bromine or alloctype, or equivalent carbonylchloride, such as carbonylation, carbonyldiimidazole, carbonylation, carbamidomethylation, or the residue of an activated complex ester, such as p-nitrophenylamino ether, pentachlorphenol ether and the like compounds, and other substituents have the above values,

in) or the interaction of the compounds of formula

with the compound of the formula

with the formation of the compounds of formula

or

g) the interaction of the compounds of formula

with the compound of the formula

with the formation of compounds of the formula

where the substituents have the above values, or

d) the interaction of the compounds of formula

with a heterocyclic compound of the formula

with the formation of compounds of the formula

where means a 5-membered heterocycle of the formula

and where the remaining substituents have the above values,

and, if desirable, the transformation of a functional group in the compound of formula I into another functional group and, if desired, converting the compounds of formula I in a pharmaceutically acceptable salt.

In accordance with variant a) method to the compound of formula III, such as alcohol (butane-1-ol, benzyl alcohol, allyl alcohol, isopropyl alcohol), in dichloromethane is added a compound of the formula II, for example diphenyltetrazolium, and the mixture is stirred at room temperature.

The compounds of formula IA can be obtained in accordance with variant b) method. The compound of formula V, for example the corresponding urethane or alkilany ether of carbamino acid, reacts with the compound of the formula IV, for example with N-xanthene-9-carbonylchloride or N-xanthene-9-carbonlimited, or aloxiprin denim formula IV, or equivalent carbonylchloride compound of formula IV, such compounds contain carbonyliron group, carbonyldiimidazole group, carbonylmethyl group, carbonylcontaining group or activated ester such as p-nitrophenyloctyl ether, pentachlorphenol ether and the like. This reaction is carried out in a solvent, such as pyridine, at room temperature using methods known in this field.

In addition, the compounds of the formulae IA-1 and IA can be obtained in accordance with the variants C) and d) of the method, when the compound of formula VI is reacted with the compound of the formula VII or VIII. This reaction is carried out analogously to the reactions for variant b) method.

The compounds of formula IB can be obtained by reaction of the heterocyclic compounds of formula IX with the compound of the formula IV in the presence of N,N-dimethylaminopyridine at a temperature of 0°C. the Preferred solvent is methylene chloride.

Pharmaceutically acceptable salts can be easily obtained according to known methods, taking into account the nature of the turn in the Sol connection. Inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fu the steam 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 containing 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 of acidic compounds.

Scheme 1 gives an overview of the formation of compounds of formula IA. Getting the individual compounds of the formula I is described in detail in examples 1-30, 32, 34-43. Scheme 2 describes a method of obtaining compounds of formula IB, this method is more particularly described in examples 31, 33 and 44-69.

Scheme 1

The substituents have the above values.

Scheme 2

where means a 5-membered heterocyclic compound of the formula

and the rest of the definitions of the substituents listed above.

Source materials used in schemes 1 and 2 are known compounds and can be obtained using known methods.

Link the 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 cognition and memory disorders, and chronic and acute pain. Other treatable indications are limited brain activity 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 SPID ohms, eye injuries, retinopathy, a disease of unknown origin or parkinsonism caused by medicaments, as well as the condition in which associated with deficiency of glutamate reactions, such as muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, ophiomyia, anxiety, vomiting, dyskinesia and depression.

Compounds of the present invention are agonists and/or antagonists of receptors mGlu group I. for Example, it was shown that the compounds of note is the moat 1-22 and 30-69 show agonistic activity, and compounds of examples 23-29 are antagonists. The compounds exhibit activity as measured in the following experience, at a concentration of 50 μm or less, typically of 1 μm or less and, ideally, in a concentration of 0.5 μm or less.

The table below presents some data specific activity:

Example No.agonist/antagonistIC50(µm)
10agonist0,22
32agonist0,14
65agonist0,4
23antagonistof 6.31
24antagonist2,79
25antagonist1,38

Description of the test

cDNA encoding the receptor of rat mGlu 1a, 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, 15, (1998), 105-112 and 117-120. Measuring ion concentration [CA2+] was performed on transfected mGlu 1A 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 of the (modified Dulbecco Wednesday Needle (DMEM), supplemented 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 μm glutamate as an agonist.

Curves of inhibition (antagonists) or activate (agonists) were close four-parameter logistic equation, which was determined by causing 50%effect concentration, EC50and the hill coefficient using the iterative procedure 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, for example in the form of injection solutions.

The compounds of formula I and their pharmaceutically acceptable the salts can be processed with pharmaceutically 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 such carriers for tablets, 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 osmotic the ski pressure, buffers, masking means or antioxidants. They may also contain other therapeutically valuable substances.

As mentioned earlier, drugs, containing a compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert excipient are also an 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, particularly for the treatment or prevention of acute and/or chronic neurological disorders of the above type, the object of the invention.

Example 1

Butyl ether diphenylacetylene acid

To a stirred solution of butane-1-ol (0,32 ml, 3,49 mmole) in dichloromethane (4 ml) was added a solution of diphenylacetonitrile (2,33 ml, 0.5 M in dichloromethane, 1.16 mmole) and the mixture was stirred at room temperature for 1 h After removal of the solvent in vacuo received a yellow oil, which was purified with column chromatography on silica gel (ethyl acetate/hexane 1:2)were specified in the title compound (0.3 g, 83%) as a solid light-yellow, tPL82-84°and mass spectrum (MS): m/e=334 (M+Na+).

Example 2

Benzyl ether diphenylacetylene acid

Specified in the title compound, solid white, tPL100-101°and MS: m/e=345 (M+), was obtained in accordance with the General method of example 1 from diphenylacetylene and benzyl alcohol.

Example 3

Allyl ether diphenylacetylene acid

Specified in the title compound, solid white, tPL118-120°and MS: m/e=295 (M+), was obtained in accordance with the General method of example 1 from diphenylacetylene and allyl alcohol.

Example 4

Isopropyl ether diphenylacetylene acid

Specified in the title compound, firmly the substance of white color, tPL122-124°and MS: m/e=297 (M+), was obtained in accordance with the General method of example 1 from diphenylacetylene and isopropyl alcohol.

Example 5

tert-Butyl ether diphenylacetylene acid

Specified in the title compound, a solid light-yellow, tPL160-162°and MS: m/e=334 (M+Na+), was obtained in accordance with the General method of example 1 from diphenylacetylene and tert-butyl alcohol.

Example 6

Etilogy ether (N-xanthene-9-carbonyl)carbamino acid

To a stirred solution of urethane (0,82 g of 9.21 mmole) and 4-dimethylaminopyridine /DMAP/ (0.05 g, 0,41 mmole) in pyridine (10 ml) was added at 0°N-xanthene-9-carbonylchloride (1.50 g, 6,13 mmole). Stirring was continued at room temperature for 17 h, the reaction mixture was evaporated and water was added (50 ml)/ saturated solution of NaHCO3(20 ml). The solid was filtered and was led out of the water and then from ethanol/hexane, received the product (1.22 g, 67%) as a solid white color, tPL228°C (decomp.) and MS: m/e=298,2 (M+H+).

Example 7

Ethyl ester of (RS)-(2-bromo-N-xanthene-9-carbonyl)carbamino acid

Specified in the title compound, solid, light brown, tPL203°C and MS: m/e=375 (M+), was obtained in accordance with the General method of PR is a measure 6 of urethane and 2-bromo-N-xanthene-9-carbonylchloride.

Example 8

Butyl ether (N-xanthene-9-carbonyl)carbamino acid

Specified in the title compound, solid white, tPL180-183°C, MS: m/e=325,4 (M+H+), was obtained in accordance with the General method of example 6 from N-xanthene-9-carbonylchloride and butyl ether of carbamino acid.

Example 9

Ethyl ester diphenylacetylene acid

Specified in the title compound, solid white, tPL133°and MS: m/e=284,2 (M+N+), was obtained in accordance with the General method of example 1 from diphenylacetylene and ethanol.

Example 10

Cyclopropylmethoxy ether diphenylacetylene acid

Specified in the title compound, solid white, tPL108°S, MS: m/e=309,4 (M+N+), was obtained in accordance with the General method of example 1 from diphenylacetylene and cyclopropylmethanol.

Example 11

The Penta-4-injuly ether diphenylacetylene acid

Specified in the title compound, solid white, tPL109°and MS: m/e=321,4 (M+N+), was obtained in accordance with the General method of example 1 from diphenylacetylene and Penta-4-in-1-ol.

Example 12

2-Tionately ether diphenylacetylene acid

Specified in the title compound, solid white, tPL113#x000B0; And MS: m/e=308,3 (M+H+), was obtained in accordance with the General method of example 1 from diphenylacetylene and 3-hydroxypropionitrile.

Example 13

3-Pyridin-4-ylpropionic ether diphenylacetylene acid

Specified in the title compound, solid brown, tPL147-50°and MS: m/e=374,4 (M+N+), was obtained in accordance with the General method of example 1 from diphenylacetylene and 3-pyridine-4-improper-1-ol.

Example 14

3-Benzyloxypropionic ether diphenylacetylene acid

Specified in the title compound, colorless oil, MS: m/e=403,5 (M+N+), was obtained in accordance with the General method of example 1 from diphenylacetylene and 3-benzyloxypropionic-1-ol.

Example 15

2-(3,4-Acid)ethyl ester diphenylacetylene acid

Specified in the title compound, solid white, tPL144°and MS: m/e=419,5 (M+H+), was obtained in accordance with the General method of example 1 from diphenylacetylene and 2-(3,4-acid)ethanol.

Example 16

(RS)-2-Phenylpropionyl ether diphenylacetylene acid

Specified in the title compound, solid white, tPL131°and MS: m/e=373,5 (M+N+), was obtained in accordance with the General method of example 1 from diphenylacetylene and (RS)-2-phenylpropane-1-on the A.

Example 17

Tien-2-ymetray ether diphenylacetylene acid

Specified in the title compound, solid white, tPL116°and MS: m/e=351,4 (M+N+), was obtained in accordance with the General method of example 1 from diphenylacetylene and Tien-2-ylmethanol.

Example 18

Cyclopentyloxy ether diphenylacetylene acid

Specified in the title compound, solid white, tPL120-123°C and MS: m/e=323,4 (M+N+), was obtained in accordance with the General method of example 1 from diphenylacetylene and Cyclopentanol.

Example 19

Cyclohexyloxy ether diphenylacetylene acid

Specified in the title compound, solid white, tPL117-119°and MS: m/e=337,4 (M+N+), was obtained in accordance with the General method of example 1 from diphenylacetylene and cyclohexanol.

Example 20

4-Privately ether diphenylacetylene acid

Specified in the title compound, a solid light-yellow, tPL118°and MS: m/e=387,5 (M+N+), was obtained in accordance with the General method of example 1 from diphenylacetylene and 4-phenylbutane-1-ol.

Example 21

3,5-Dimethoxyphenyl ether diphenylacetylene acid

Specified in the title compound, solid white, t PL150-152°C and MS: m/e=391,4 (M+H+), was obtained in accordance with the General method of example 1 from diphenylacetylene and 3.5-dimethoxyphenol.

Example 22

2,2,2-Triptoreline ether diphenylacetylene acid

Specified in the title compound, solid white, tPL125-127°and MS: m/e=337,3 (M+N+), was obtained in accordance with the General method of example 1 from diphenylacetylene and 2,2,2-triptoreline.

Example 23

Methyl ester (2,2-diphenylpropionic)carbamino acid

Specified in the title compound, colorless gum, MS: m/e=297,4 (M+N+), was obtained in accordance with the General method of example 1 from crude 2,2-diphenylmethanediisocyanate and methanol.

Example 24

Allyl ether (2,2-diphenylpropionic)carbamino acid

Specified in the title compound, solid white, tPL89°and MS: m/e=309,4 (M+N+), was obtained in accordance with the General method of example 1 from 2,2-diphenylmethanediisocyanate and prop-2-EN-1-ol.

Example 25

Butyl ether (2,2-diphenylpropionic)carbamino acid

Specified in the title compound, solid white, tPL83°and MS: m/e=325,4 (M+N+), was obtained in accordance with the General method of example 1 from 2,2-diphenylmethanediisocyanate and butane-1-ol.

Example 26

Cyclopropyl levy ether (2,2-diphenylpropionic)carbamino acid

Specified in the title compound, solid white, tPL125°and MS: m/e=323,4 (M+H+), was obtained in accordance with the General method of example 1 from 2,2-diphenylmethanediisocyanate and cyclopropylmethanol.

Example 27

Cyclohexyloxy ether (2,2-diphenylpropionic)carbamino acid

Specified in the title compound, solid white, tPL126°C and MS: m/e=351,4 (M+N+), was obtained in accordance with the General method of example 1 from 2,2-diphenylmethanediisocyanate and cyclohexanol.

Example 28

4-Privately ether (2,2-diphenylpropionic)carbamino acid

Specified in the title compound, yellow oil, MS: m/e=is 401.5 (M+N+), was obtained in accordance with the General method of example 1 from 2,2-diphenylmethanediisocyanate and 4-phenylbutane-1-ol.

Example 29

2,2,2-Triptoreline ether (2,2-diphenylpropionic)carbamino acid

Specified in the title compound, solid white, tPL143-145°S, MS: m/e=to 351.3 (M+H+), was obtained in accordance with the General method of example 1 from 2,2-diphenylmethanediisocyanate and 2,2,2-triptoreline.

Example 30

Ethyl ether (N-thioxanthen-9-carbonyl)carbamino acid

Specified in the title compound, solid white, tPL179-182°S, MS: m/e=314,2 (M+N+), was obtained in accordance with the General the method of example 6 from N-thioxanthen-9-carbonylchloride (U.S. patent 3284449) and urethane.

Example 31

Oxazol-2-alamid N-thioxanthen-9-carboxylic acid

To mix the solution (0,048 g, 0,575 mmol) of 2-aminoanisole [Cockerill & al. Synthesis 591 (1976)], DMAP (0.003 g, 0.03 mmole) in pyridine (2 ml) was added at 0°N-thioxanthen-9-carbonylchloride (0,100 g, 0,384 mmole). Stirring was continued at room temperature for 16 h, the reaction mixture was evaporated and water was added (5 ml)/ saturated solution of NaHCO3(2 ml). The solid precipitate was filtered, dissolved in dichloromethane, dried over MgSO4and concentrated in vacuum. Technical product was purified by column chromatography on silica gel (methylene chloride/methanol 40:1), has received the product (0,022 g, 18%) as a solid white color, tPL188-191°and MS: m/e=309,1 (M+N+).

Example 32

Butyl ether (N-thioxanthen-9-carbonyl)carbamino acid

Specified in the title compound, solid white, tPL151-154°S, MS: m/e=342,2 (M+N+), was obtained in accordance with the General method of example 6 from N-thioxanthen-9-carbonylchloride and butyl ether of carbamino acid.

Example 33

Oxazol-2-alamid N-xanthene-9-carboxylic acid

Specified in the title compound, solid white, tPL232-235°S, MS: m/e=292 (M+), was obtained in accordance with the General method of example 31 from N-xanthene-9-is carbonylchloride and 2-aminoanisole.

Example 34

2-Morpholine-4-jatiluwih ether diphenylacetylene acid

Specified in the title compound, solid white, tPL135-137°and MS: m/e=369,3 (M+H+), was obtained in accordance with the General method of example 1 from diphenylacetylene and 2-morpholine-4-retinol.

Example 35

S-Butyl ether diphenylethylenediamine acid

Specified in the title compound, solid white, tPL99°and MS: m/e=327 (M+), was obtained in accordance with the General method of example 1 from diphenylacetylene and potential.

Example 36

Ethyl ester [(3-chloro-5-triptorelin-2-yl)-m-tolylacetic]-carbamino acid

Was dissolved with 97 μl (95 mg, 0,80 mmole) of diethylmalonate and 38 μl (30 mg, and 0.50 mmole) of ISO-propanol in 2 ml of anhydrous tetrahydrofuran (THF). The solution was cooled to 0°and was added 29 mg (0.67 mmole) of a dispersion of sodium hydride (55% in mineral oil). Then added in portions 164 mg (0,50 mmole) of 3-chloro-5-trifluoromethyl-2-pyridyl-3-methylphenylacetic at 0°C. After stirring for 1 h at 0°the reaction mixture was allowed to warm to room temperature and was stirred overnight. Processing in the usual way with a solution of ammonium chloride and ethyl acetate gave the product as yellow oil, which was purified using flash chrome is adopted on silica gel, using a mixture (5:1) of hexane and ethyl acetate as eluent. Get a 14.1 mg (0.035 mmole, 7%) ethyl ester [(3-chloro-5-triptorelin-2-yl)-m-tolylacetic]carbamino acid in a solid white color, tPL146-147°S, MS: m/e=401,3 (M+N+).

Example 37

Cyclopropylmethoxy ether (N-xanthene-9-carbonyl)carbamino acid

Specified in the title compound, solid white, tPL183-185°C, MS: m/e=323 (M+H+), was obtained in accordance with the General method of example 36 from N-xanthene-9-carbonylchloride and cyclopropylmethanol ether carbamino acid.

Example 38

Ethyl ester (4-trifluoromethyl-N-xanthene-9-carbonyl)carbamino acid

Specified in the title compound, solid white, tPL196-198°C, MS: m/e=365 (M+), was obtained in accordance with the General method of example 36 4-trifluoromethyl-N-xanthene-9-carbonylchloride and ethyl ether of carbamino acid.

Example 39

Diphenylacetylene cyclopropanecarbonyl acid

To a stirred and cooled (0° (C) to a solution of 2,2-diphenylacetamide (500 mg, a 2.36 mmole) in THF (20 ml) was added sodium hydride (95 mg, a 2.36 mmole; 60%) and the mixture was stirred at room temperature for 0.5 h and Then was added dropwise at room temperature the acid chloride cyclopropanecarbonyl acid (247 mg, 236 mmole), dissolved in THF (5 ml)and the solution was stirred at room temperature for 20 hours the Reaction mixture was poured into a saturated solution of NaHCO3(50 ml) and was extracted with ethyl acetate (2×70 ml). The combined organic layers were washed brine (50 ml), dried over MgSO4and was evaporated. Further purification using column chromatography (toluene/ethyl acetate 19:1) gave a product which was recrystallized from ethyl acetate/hexane, received solid white (133 mg, 20%), tPL178°C and MS: m/e=279 (M+).

Example 40

Butyramide N-xanthene-9-carboxylic acid

Specified in the title compound, solid white, tPL222°and MS: m/e=295 (M+), was obtained in accordance with the General method of example 39 from amide N-xanthene-9-carboxylic acid and carboxylic propenylboronic acid.

Example 41

N-Diphenylacetylene

Specified in the title compound, solid white, tPL205°and MS: m/e=281 (M+), was obtained in accordance with the General method of example 39 from 2,2-diphenylacetamide and acid chloride propenylboronic acid.

Example 42

Diphenylacetylene PENTACARBONYL acid

Specified in the title compound, solid white, tPL87°and MS: m/e=309 (M+), was obtained according to the method of example 39 from 2,2-diphenylacetamide and acid chloride PENTACARBONYL acid.

Example 43

Diphenylacetylene pentanol acid

Specified in the title compound, solid white, tPL83°and MS: m/e=296,3 (M+N+), was obtained in accordance with the General method of example 39 from 2,2-diphenylacetamide and acid chloride balancebalance acid.

Example 44

(5-Propyl-[ 1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid

44a) To a solution of 76 mg (0.60 mmole, 1.2 EQ.) 5-propyl-[1,3,4]oxadiazol-2-ylamine and 6 mg (0.05 mmole, 0.1 EQ.) N,N-dimethylaminopyridine in 2 ml of anhydrous pyridine was added dropwise at 0°With a solution of 122 mg (0.5 mmole) of the acid chloride 9-cantankerous acid 1,22 ml of methylene chloride. The mixture was stirred for 3-4 h at 0°and then overnight at room temperature. The mixture was poured into a well stirred mixture of 50 ml of ethyl acetate and 50 ml of water. The organic phase was separated. The aqueous phase was twice extracted with 25 ml ethyl acetate. The combined organic phases are washed twice with 25 ml water and concentrated. The residue was dissolved in approximately 25 ml of ethyl acetate and evaporated to dryness. Technical product (167 mg, solid light yellow) after recrystallization from ethanol received 62 mg (0,185 mmole, 37%) (5-propyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid as white crystals, tPL215-216°and MS: m/e=335 (M+).

B) 5-Propyl-[1,3,4]ACS is diazol-2-ylamine, used in the above reaction was prepared as follows:

To a solution of 5.0 g (47,0 mmol) of CYANOGEN bromide in 50 ml of methanol was added dropwise over 30 min a solution 4,80 g (47,0 mmol) of butyric acid hydrazide in 50 ml of methanol. The mixture is then boiled under reflux for 15 min and then concentrated in vacuo to start crystallization. Crystals (9 g) was filtered, dissolved in 60 ml of ethanol. Then there was added 5 g of finely ground potassium carbonate, and the suspension was stirred 5 min at room temperature. The resulting orange suspension was filtered and the filtrate was concentrated in vacuum. The resulting powder orange (5.5 g) was purified using flash chromatography on silica gel using a mixture (80:10:1) methylene chloride/ methanol/ 28%ammonia as eluent, got 3,95 g (31,1 mmole, 66%) of 5-propyl-[1,3,4]oxadiazol-2-ylamine in the form of white crystals, MS: m/e=127 (M+).

Example 45

2,2-Diphenyl-N-(5-propyl-[1,3,4]oxadiazol-2-yl)ndimethylacetamide

Specified in the title compound, a viscous oil, MS: m/e=322,4 (M+N+), was obtained in accordance with the General method of example 44a from 5-propyl-[1,3,4]-oxadiazol-2-ylamine and acid chloride of 2,2-diphenyloxazole acid.

Example 46

[1,3,4]Oxadiazol-2-alamid N-xanthene-9-carboxylic acid.

Specified in SAP the following connection solid white, tPL239-240°and MS: m/e=293 (M+), was obtained in accordance with the General method of example 44a from [1,3,4]oxadiazol-2-ylamine and the acid chloride 9-xanthene-carboxylic acid.

[1,3,4]Oxadiazol-2-ylamine, solid white, MS: m/e=85 (M+)used in the above reaction, was obtained in accordance with the General method of example b of the hydrazide of formic acid and CYANOGEN bromide.

Example 47

N-[1,3,4]Oxadiazol-2-yl-2,2-diphenylacetamide.

Specified in the title compound, a solid light-yellow, tPL131-132°and MS: m/e=279,2 (M+), was obtained in accordance with the General method of example 44a from [1,3,4]oxadiazol-2-ylamine and acid chloride of 2,2-diphenyloxazole acid.

Example 48

(5-Ethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid.

48A) Suspended 500,5 mg (1,64 mmole) of (3,5-dimethylpyrazol-1-yl)-(N-xanthene-9-yl)methanone and 186,8 g (1,64 mmole) of 5-ethyl-[1,3,4]oxadiazol-2-ylamine in 1.5 ml DMF and stirred 6 h at 130°C. the Reaction mixture was left to cool to room temperature and was added 5 ml of acetone. After stirring for 5 minutes, the product was filtered, washed with acetone and dried in vacuo, got to 219.5 mg of (5-ethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid in the form of solids in white, tPL256-257° And MS: m/e=321,2 (M+).

B) Used in the above reaction of 5-ethyl-[1,3,4]oxadiazol-2-ylamine was prepared as follows:

To a solution of 6.3 g of propionic acid hydrazide (72 mmole) in 50 ml of water was added 34 g of saturated solution of potassium bicarbonate (75 mmol) and a solution of 7.7 g (72 mmole) of CYANOGEN bromide in 60 ml of water. The temperature rose from 22°to 32°and stood out carbon dioxide. After 30 min began to appear white crystals. The white suspension was stirred 3 h and left to stand over night. The reaction mixture was evaporated to dryness in vacuum. Technical product was recrystallized from 20 ml of water. The product was filtered off, washed with a small amount of cooling to the temperature of ice water and dried in vacuum. Get 6,1 g (54 mmole, 75%) of 5-ethyl-[1,3,4]oxadiazol-2-yl-amine in the form of solids in white, tPL174-175°C and MS: m/e=113,1 (M+).

48V) Used in the above reaction (3,5-dimethylpyrazol-1-yl)-(N-xanthene-9-yl)methanon received as follows: 2.6 g (11 mmol) of hydrazide 9-cantankerous acid suspended in 2.5 ml of water. Was added 10 ml of 2n. hydrochloric acid solution. To the thick white suspension was added 30 ml of ethanol and the suspension was heated to 65°and then the suspension was left to cool to room temperature. To the resulting solution light yellow the CSOs color was added with vigorous stirring, 1.1 g (11 mmol) of acetylacetone. The temperature rises to 30°and formed white crystals after about 2 minutes the Stirring was continued for 15 min at room temperature and then a further 15 min at 0°C. the Product was filtered and washed with ethanol temperature -20°C. Technical product was recrystallized from 15 ml of ethanol, got 2,80 g (9.2 mmole, 84%) of (3,5-dimethylpyrazol-1-yl)-(N-xanthene-9-yl)methanone in the form of white crystals, tPL114-115°and MS: m/e=304,1 (M+).

Example 49

N-(5-Ethyl-[1,3,4]oxadiazol-2-yl)-2,2-diphenylacetamide.

Specified in the title compound, solid white, tPL123-125°and MS: m/e=308,2 (M+H+), was obtained in accordance with the General method of example 48A of 1-(3,5-dimethylpyrazol-1-yl)-2,2-diphenylethanone and 5-ethyl-[1,3,4]oxadiazol-2-ylamine.

Used in the above reaction, 1-(3,5-dimethylpyrazol-1-yl)-2,2-diphenylethane, solid white, tPL91-92°C and MS: m/e=291,2 (M+H+), was obtained in accordance with the General method of example 48V from hydrazide 2,2-diphenyloxazole acid [Chem. Zentralblatt. 100, 2414 (1929)] and acetylacetone.

Example 50

(5-Methyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid.

Specified in the title compound, solid white, tPL261-263°C and MS: m/e=to 307.1 (M+), was obtained in accordance with the General method of example 44a from 5-methyl-[1,3,4]oxadiazol-ylamine acid chloride 9-xanthene-carboxylic acid.

Used in the above reaction of 5-methyl-[1,3,4]oxadiazol-2-ylamine, solid white, MS: m/e=99 (M+), was obtained in accordance with the General method of example b of the hydrazide of acetic acid and methyl cyanide.

Example 51

N-(5-Methyl-[1,3,4]oxadiazol-2-yl)-2,2-diphenylacetamide.

Specified in the title compound, solid white, tPL160-161°and MS: m/e=293,1 (M+), was obtained in accordance with the General method of example 44a from 5-methyl-[1,3,4]oxadiazol-2-ylamine and acid chloride of 2,2-diphenyloxazole acid.

Example 52

(5-Methoxymethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid.

Specified in the title compound, solid white, tPL233-234°and MS: m/e=sauce 337,1 (M+N+), was obtained in accordance with the General method of example 48A (3,5-dimethylpyrazol-1-yl)-(N-xanthene-9-yl)methanone and 5-methoxymethyl-[1,3,4]oxadiazol-2-ylamine.

Used in the above reaction 5-methoxymethyl-[1,3,4]oxadiazol-2-ylamine, solid white, tPL113-114°and MS: m/e=to 129.2 (M+), was obtained in accordance with the General method of example b of hydrazide methoxybutanol acid [Journal of organic chemistry, USSR, 6(1), 93(1970)] and CYANOGEN bromide.

Example 53

N-(5-Ethyl-[1,3,4]oxadiazol-2-yl)-2,2-diphenylacetamide.

Specified in the title compound, solid prophetic the creation of white, tPL138-140°and MS: m/e=324,3 (M+N+), was obtained in accordance with the General method of example 44a from the acid chloride of 2,2-diphenyloxazole acid and 5-methoxymethyl-[1,3,4]oxadiazol-2-ylamine.

Example 54

[5-(2-Methoxyethyl)-[1,3,4]oxadiazol-2-yl]amide N-xanthene-9-carboxylic acid.

Specified in the title compound, solid white, tPL204°C and MS: m/e=351,1 (M+N+), was obtained in accordance with the General method of example 44a from (3,5-dimethylpyrazol-1-yl)-(N-xanthene-9-yl)methanone and [5-(2-methoxyethyl)-[1,3,4]oxadiazol-2-yl]amine.

Used in the above reaction [5-(2-methoxyethyl-[1,3,4]oxadiazol-2-yl]amine, solid white, tPL105-106°and MS: m/e=143,1 (M+), was obtained in accordance with the General method of example b of hydrazide 3-methoxypropionate acid [US patent No. 3441606] and methyl cyanide.

Example 55

N-[5-(2-Methoxyethyl)-[1,3,4]oxadiazol-2-yl]-2,2-diphenylacetamide.

Specified in the title compound, solid white, tPL114-115°and MS: m/e=338,2 (M+N+), was obtained in accordance with the General method of example 44a from the acid chloride of 2,2-diphenyloxazole acid [5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl] amine.

Example 56

(5-Cyclopropyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid.

Specified in the title compound, solid white t PL246-248°C and MS: m/e=333,1 (M+H+), was obtained in accordance with the General method of example 48A (3,5-dimethylpyrazol-1-yl)-(N-xanthene-9-yl)methanone and 5-cyclopropyl-[1,3,4]oxadiazol-2-ylamine [J. Med. Pharm. Chem. 5, 617 (1962)].

Example 57

N-(5-Cyclopropyl-[1,3,4]oxadiazol-2-yl)-2,2-diphenylacetamide.

Specified in the title compound, solid white, tPL159-160°and MS: m/e=320,3 (M+H+), was obtained in accordance with the General method of example 44a from the acid chloride of 2,2-diphenyloxazole acid and 5-cyclopropyl-[1,3,4]oxadiazol-2-ylamine.

Example 58

(5-Cyclopropylmethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid.

Specified in the title compound, solid white, tPL234-236°and MS: m/e=347,1 (M+H+), was obtained in accordance with the General method of example 48A (3,5-dimethylpyrazol-1-yl)-(N-xanthene-9-yl)methanone and 5-cyclopropylmethyl-[1,3,4]oxadiazol-2-ylamine.

Used in the above reaction 5-cyclopropylmethyl-[1,3,4]oxadiazol-2-ylamine, solid white, tPL140-141°and MS: m/e=139 (M+), was obtained in accordance with the General method of example b of hydrazide cyclopropanecarbonyl acid [J. Chem. Soc. Perkin Trans. 2, 1844 (1974)] and methyl cyanide.

Example 59

N-(5-Cyclopropylmethyl-[1,3,4]oxadiazol-2-yl)-2,2-diphenylacetamide.

Specified in the title compound, solid is emesto white, tPL158-159°and MS: m/e=334,3 (M+N+), was obtained in accordance with the General method of example 44a from the acid chloride of 2,2-diphenyloxazole acid and 5-cyclopropylmethyl-[1,3,4]oxadiazol-2-ylamine.

Example 60

(5-Trifluoromethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid.

Specified in the title compound, solid white, tPL220-223°C (decomp.) and MS: m/e=362,2 (M+H+), was obtained in accordance with the General method of example 48A (3,5-dimethylpyrazol-1-yl)-(N-xanthene-9-yl)methanone and 5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamine [U.S. patent No. 2883391].

Example 61

N-(5-Trifluoromethyl-[1,3,4]oxadiazol-2-yl)-2,2-diphenylacetamide.

Specified in the title compound, solid white, tPL149-150°C and MS: m/e=347,2 (M+), was obtained in accordance with the General method of example 44a from 5-trifluoromethyl-[1,3,4]oxadiazol-2-ylamine and acid chloride of 2,2-diphenyloxazole acid.

Example 62

(5-Ethyloxazole-2-yl)amide N-xanthene-9-carboxylic acid.

Specified in the title compound, solid white, tPL212-213°and MS: m/e=320,1 (M+), was obtained in accordance with the General method of example 44a from 5-ethyloxazole-2-ylamine [Weg. 95, 2419 (1962)] and the acid chloride 9-cantankerous acid.

Example 63

N-(5-Ethyloxazole-2-yl)-2,2-diphenylacetamide.

Specified in the title compound, tortoiseshell white, tPL148-149°and MS: m/e=307,3 (M+H+), was obtained in accordance with the General method of example 44a from 5-ethyloxazole-2-ylamine and acid chloride of 2,2-diphenyloxazole acid.

Example 64

(5-Methoxazole-2-yl)amide N-xanthene-9-carboxylic acid.

Specified in the title compound, solid white, tPL217 to 220°and MS: m/e=306,1 (M+), was obtained in accordance with the General method of example 44a from 5-methoxazole-2-ylamine [Weg. 95. 2419 (1962)] and the acid chloride 9-cantankerous acid.

Example 65

N-(5-Methoxazole-2-yl)-2,2-diphenylacetamide

Specified in the title compound, not quite white solid, tPL166-168°and MS: m/e=292,2 (M+), was obtained in accordance with the General method of example 44a from 5-methoxazole-2-ylamine and acid chloride of 2,2-diphenyloxazole acid.

Example 66

(5-Preprocessor-2-yl)amide N-xanthene-9-carboxylic acid.

66A) Specified in the title compound, solid white, tPL203-205°and MS: m/e=334,1 (M+), was obtained in accordance with the General method of example 44a from 5-preprocessor-2-ylamine [Weg. 95, 2419 (1962)] and the acid chloride 9-cantankerous acid.

B) Used in the above reaction of 5-preprocessor-2-ylamine was prepared as follows:

dissolved 21.8 g (0,132 mole) 2-bromacleanse aldehyde [Chem. Weg., 70, 1898 (1937)] of 67.5 ml of a mixture (4:3) DM is a and water. Under stirring was added 8,77 g (0,145 mole) of urea. Clear colorless solution was stirred 16 h at 105°C. the resulting light yellow solution was cooled to 0°and there was added 10 ml of 45%sodium hydroxide solution. The solution becomes dark yellow (pH 12). Add 100 ml of brine and the solution is extracted five times with 100 ml of a mixture (9:1) methylene chloride and methanol. The combined organic phases were concentrated, received 15.62 wide g of a reddish-brown oil, which was purified using flash chromatography on silica gel using a mixture (9:1) methylene chloride and methanol as eluent. Obtain 6.2 g (0,049 mol, 37%) 5-preprocessor-2-ylamine in the form of a yellow oil, which was used directly without further purification; MS: m/e=126,1 (M+).

Example 67

2,2-Diphenyl-N-(5-preprocessor-2-yl)ndimethylacetamide

Specified in the title compound, solid white, tPL122°and MS: m/e=320,2 (M+), was obtained in accordance with the General method of example 44a from 5-preprocessor-2-ylamine and acid chloride of 2,2-diphenyloxazole acid.

Example 68

(4-Methoxazole-2-yl)amide N-xanthene-9-carboxylic acid

Specified in the title compound, a solid light-yellow, tPL219-222°C and MS: m/e=306,1 (M+), was obtained in accordance with the General method of example is 48A of (3,5-dimethylpyrazol-1-yl)-(N-xanthene-9-yl)methanone and 5-methoxazole-2-ylamine [German patent DE 2459380].

Example 69

N-(4-Methoxazole-2-yl)-2,2-diphenylacetamide

Specified in the title compound, solid white, tPL209-211°and MS: m/e=306,1 (M+), was obtained in accordance with the General method of example 44a from the acid chloride of 2,2-diphenyloxazole acid and 4-methoxazole-2-ylamine.

Example 70

N-(3-Methyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenylacetamide

Specified in the title compound, solid white, tPL215°and MS: m/e=293 (M+), was obtained in accordance with the General method of example 44a from 3-methyl-[1,2,4]oxadiazol-5-ylamine (Helv. Chim. Acta, 49(1966), 1430-1432) and the acid chloride of 2,2-diphenyloxazole acid.

Example 71

(3-Methyl-[1,2,4]oxadiazol-5-yl)amide N-xanthene-9-carboxylic acid

Specified in the title compound, solid white, tPL208°and MS: m/e=307 (M+), was obtained in accordance with the General method of example 44a from 3-methyl-[1,2,4]oxadiazol-5-ylamine and acid chloride N-cantankerous acid.

Example 72

N-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenylacetamide

Specified in the title compound, solid white, tPL163°and MS: m/e=219 (M+), was obtained in accordance with the General method of example 44a from 3-cyclopropyl-[1,2,4]oxadiazol-5-ylamine (Helv. Chim. Acta, 49(1966), 1430-1432) and the acid chloride of 2,2-diphenyloxazole acid.

Example 73

(3-Cyclo is ropyl-[1,2,4]oxadiazol-5-yl)amide N-xanthene-9-carboxylic acid

Specified in the title compound, solid white, tPL275°C and MS: m/e=333 (M+), was obtained in accordance with the General method of example 44a from 3-cyclopropyl-[1,2,4]oxadiazol-5-ylamine and acid chloride N-xanthene-carboxylic acid.

Example 74

N-(5-Methyl-[1,2,4]oxadiazol-3-yl)-2,2-diphenylacetamide

Specified in the title compound, solid white, tPL153°and MS: m/e=293 (M+), was obtained in accordance with the General method of example 44a from 5-methyl-[1,2,4]oxadiazol-3-ylamine (European patent EP 413545) and the acid chloride of 2,2-diphenyloxazole acid.

Example 75

(5-Methyl-[1,2,4]oxadiazol-3-yl)amide N-xanthene-9-carboxylic acid

Specified in the title compound, solid white, tPL186°and MS: m/e=307 (M+), was obtained in accordance with the General method of example 44a from 5-methyl-[1,2,4]oxadiazol-3-ylamine and acid chloride N-cantankerous acid.

Example

Tablets of the following composition are produced in a standard way, mg/tablet:

The active ingredient 100

Powdered lactose 95

White corn starch 35

Polyvinylpyrrolidone 8

Na-carboximetilkrahmal 10

Magnesium stearate 2

Weight tablets 250

Example B

Tablets of the following composition are produced in a standard way, mg/tablet:

The active ingredient 200

<> Powdered lactose 100

White corn starch 64

Polyvinylpyrrolidone 12

Na-carboximetilkrahmal 20

Magnesium stearate 4

Weight tablets 400

The example In

Produce capsules of the following composition (mg/capsule:

The active ingredient 50

Crystalline lactose 60

Microcrystalline cellulose 34

Talc 5

Magnesium stearate 1

The weight of the contents of the capsule 150

The active ingredient with a suitable particle size, crystalline lactose and microcrystalline cellulose are mixed with each other to obtain a homogeneous mixture, sift and then mix talc and magnesium stearate. The final mixture is placed in a hard gelatin capsule of appropriate size.

1. Derivatives of esters carbamino acid of General formula:

where R1means hydrogen or (C1-C7)alkyl;

R2, R2’mean independently from each other hydrogen, (C1-C7)alkyl, (C1-C7)alkoxygroup, halogen or trifluoromethyl;

X represents O, S or two hydrogen atoms, not forming a bridge;

And1/A2means independently of each other phenyl or 6-membered heterocycle containing 1 or 2 nitrogen atom;

In is a group of the formula

where

R3means (C1-C7)alkyl, (C2-C7)alkenyl, (C2-C7)quinil, benzyl, (C1-C7)alkylsilane, (C1-C7)alkilirovaniya, (C1-C7)alkylpyridine, (C1-C7)alkyl-(C1-C7)alkoxyphenyl, (C1-C7)alkylphenyl, optionally substituted (C1-C7)alkoxygroup, or phenyl, optionally substituted (C1-C7)alkoxygroup, or (C1-C7)alkylthiol, cycloalkyl, (C1-C7)alkyltrimethyl or (C1-C7)alkylsulphonyl,

Y represents-O-, -S -, or a bond;

Z denotes-O - or-S-;

or means a 5-membered heterocyclic group of the formula

where

R4and R5mean hydrogen, (C1-C7)alkyl, (C1-C7)alkoxygroup, cyclohexyl, (C1-C7)alkylcyclohexane or trifluoromethyl, provided that at least one of R4or R5must be hydrogen; and their pharmaceutically acceptable salts, with the exception of N-(diphenylacetyl)thiobenzamide, N-benzylpiperazine, N-phenoxycarbonyl-α,α-diphenylacetamide and N-phenoxycarbonyl-α-2-pyridylacetate.

2. The compounds of formula IA according to claim 1,

where is a group of the formula

and the other substituents are as defined in claim 1.

3. The compounds of formula IB according to claim 1,

where b is a 5-membered heterocyclic group of the formula

and the other substituents are as defined in paragraph 1.

4. The compounds of formula IA according to claim 2, where a represents phenyl, X stands for 2 hydrogen atoms, not forming a bridge, and Z denotes-O-.

5. Compounds according to claim 4, which represent butyl ether diphenylacetylene acid, ethyl ester diphenylacetylene acid or Penta-4-injuly ether diphenylacetylene acid.

6. The compounds of formula IA according to claim 2, in which a represents phenyl, X is-O - or-S -, and Z denotes-O-.

7. The compounds of formula IA according to claim 6, which represent

ethyl ether (N-xanthene-9-carbonyl)carbamino acid,

butyl ether (N-xanthene-9-carbonyl)carbamino acid or

butyl ether (N-thioxanthen-9-carbonyl)carbamino acid.

8. The compounds of formula IB according to claim 3, in which a represents phenyl, X stands for 2 hydrogen atoms, not forming a bridge, and Z denotes-O-.

9. The compounds of formula IB according to claim 8, which represent

N-(5-this is oxazol-2-yl)-2,2-diphenylacetamide,

N-(5-methoxazole-2-yl)-2,2-diphenylacetamide,

2,2-diphenyl-N-(5-propyl-[1,3,4]oxadiazol-2-yl)acetamide", she

N-[5-(2-methoxyethyl)-[1,3,4]oxadiazol-2-yl]-2,2-diphenylacetamide,

N-(3-methyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenylacetamide,

N-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenylacetamide or

N-(5-methyl-[1,2,4]oxadiazol-3-yl)-2,2-diphenylacetamide.

10. The compounds of formula 1B according to claim 3, in which a represents phenyl, X is-O - and Z denotes-O-.

11. The compounds of formula IB according to claim 10, which represent oxazol-2-alamid N-xanthene-9-carboxylic acid,

(5-propyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid,

(5-ethyloxazole-2-yl)amide N-xanthene-9-carboxylic acid,

(5-methoxazole-2-yl)amide N-xanthene-9-carboxylic acid,

(5-preprocessor-2-yl)amide N-xanthene-9-carboxylic acid,

(5-ethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid,

(5-cyclopropylmethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid,

(4-methoxazole-2-yl)amide N-xanthene-9-carboxylic acid,

(3-methyl-[1,2,4]oxadiazol-5-yl)amide N-xanthene-9-carboxylic acid,

(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid,

(5-methoxymethyl-[1,3,4]oxadiazol-2-yl)amide N-xanthene-9-carboxylic acid,

(3-cycloprop the yl-[1,2,4]oxadiazol-5-yl)amide N-xanthene-9-carboxylic acid, or

(5-methyl-[1,2,4]oxadiazol-3-yl)amide N-xanthene-9-carboxylic acid.

12. Drug with activity against metabotropic glutamate receptor group I mGlu comprising the compound according to any one of claims 1 to 11, as well as their pharmaceutically acceptable salts, and pharmaceutically acceptable excipients.

13. The drug is indicated in paragraph 12 for the treatment or prevention of acute and /or chronic neurological disorders, limited activity of the brain, caused by operations bypass surgery or transplants, poor blood supply to the brain, spinal injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest, hypoglycemia, Alzheimer's disease, horii's chorea, amyotrophic lateral sclerosis (ALS), dementia caused SPID ohms, eye injuries, retinopathy, disorders, cognitive abilities, memory disorders, schizophrenia, Parkinson's disease of unclear origin or parkinsonism caused by medicaments, as well as the conditions that trigger associated with deficiency of glutamate reactions, muscle spasms, convulsions, migraine, urinary incontinence, addiction to nicotine, psychoses, opiomania, anxiety, vomiting, acute and chronic pain, dyskinesia and depression.

14. Compounds according to any one of claims 1 to 11, as well as their pharmaceutically acceptable salts, about daysie activity against metabotropic glutamate receptor group I mGlu, intended for obtaining a medicinal product for the treatment or prevention of acute and /or chronic neurological disorders.

15. Method of producing compounds of the formula I according to claim 1, and their pharmaceutically acceptable salts, including the interaction of the compounds of formula

with the compound of the formula

with the formation of compounds of the formula

where the substituents are listed in claim 1 values, and, if necessary, the transformation of the functional groups in the resulting compound of the formula I into other functional groups, and, if necessary, conversion of the compounds of formula I in a pharmaceutically acceptable salt.

16. Method of producing compounds of the formula I according to claim 1, and their pharmaceutically acceptable salts, including the interaction of the compounds of formula

with the compound of the formula

with the formation of compounds of the formula

where G denotes a suitable leaving group and the other substituents are listed in claim 1 values, and, if necessary, the transformation of the functional groups in the resulting compound of the formula is I in other functional groups, and, if necessary, conversion of the compounds of formula I in a pharmaceutically acceptable salt.

17. Method of producing compounds of the formula I according to claim 1, and their pharmaceutically acceptable salts, including the interaction of the compounds of formula

with the compound of the formula

with the formation of the compounds of formula

where the substituents are listed in claim 1 values, and, if necessary, the transformation of the functional groups in the resulting compound of the formula I into other functional groups, and, if necessary, conversion of the compounds of formula I in a pharmaceutically acceptable salt.

18. Method of producing compounds of the formula I according to claim 1, and their pharmaceutically acceptable salts, including the interaction of the compounds of formula

with the compound of the formula

with the formation of compounds of the formula

where the substituents have shown earlier in claim 1 values, and, if necessary, the transformation of the functional groups in the resulting compound of the formula I into other functional groups, and, if necessary, the conversion of compounds of formulas is I in pharmaceutically acceptable salt.

19. Method of producing compounds of the formula I according to claim 1, and their pharmaceutically acceptable salts, including the interaction of the compounds of formula

with a heterocyclic compound of the formula

B-NH2IX

with the formation of compounds of the formula

where means a 5-membered heterocycle of the formula

and where G is a leaving group and the other substituents are listed in paragraph 1 values, and, if necessary, the transformation of the functional groups in the resulting compound of the formula I into other functional groups, and, if necessary, conversion of the compounds of formula I in a pharmaceutically acceptable salt.

20. The compounds of formula IA according to claim 2, where Z denotes-O-, obtained by any method according to PP or 17.

21. The compounds of formula IA according to claim 2, obtained by any method according to item 16 or 18.

22. The compounds of formula IB(a-d) according to claim 3, obtained by the method according to claim 19.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to new compounds of the formula (I)

in which Ar1means pyrazole which may be substituted by one or more groups R1, R2or R3; Ar2means naphthyl, tetrahydronaphthyl, each of which is optionally substituted by 0-1 groups R2; X means5-C8cycloalkenyl, phenyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, furan, pyridinoyl, pyrazolyl, pyridinyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, piperidinyl; Y represents a bond or a saturated branched or unbranched1-C4the carbon chain, with one methylene group is optionally replaced with NH, or and Y is optionally independently substituted by oxopropoxy; Z means morpholine, group, pyridinyl, furanyl, tetrahydrofuranyl, thiomorpholine, pentamethylbenzene, pentamethylbenzene, secondary or tertiary amine, the nitrogen atom of the amino group covalently linked to the following groups selected from a range that includes the C1-C3alkyl and C1-C5alkoxyalkyl; R1means31-C6alkyl which is optionally partially or fully galogenidov, halogen; R3means phenyl, pyrimidinyl, pyrazolyl, which is substituted by one branched or unbranched1-C6the alkyl, and pyridinyl, optionally substituted C1-C3alkoxygroup or amino group, W denotes O and its pharmaceutically acceptable salts

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to organic chemistry and can find application in medicine

The invention relates to pharmaceutically acceptable salts of the compounds of formula (I) or solvate specified salts in which the compound of formula (I) is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to a method for producing compounds of formula I:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid, R1means phenyl or a straight or branched alkyl or alkenyl and R2means hydrogen or acetyl, which comprises: (a) simultaneous protection of the hydroxyl groups in positions 7 and 10 10-deacetylbaccatin III trichloroethylene derivatives with obtaining the compounds of formula III:

b) subsequent etherification of the hydroxyl group of the compounds of formula III in position 13 interaction with the compound of the formula VII:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid and R1means phenyl or a straight or branched alkyl or alkenyl, obtaining the compounds of formula IV:

(C) removing trichloroethylene protective groups of the compounds of formula IV with connection inflectional acetylation of the hydroxyl group in position 10 of the compounds of formula V to obtain the compounds of formula VI:

e) acid hydrolysis oxazolidinone ring compounds of the formula VI to obtain the compounds of formula I

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to compounds of General formula (I)

in which R1means a hydrogen atom, a radical, CH3or the radical (CH2HE; R2means the radical (CH2HE; X-Y represents a relationshiporZ indicates cycle selected among the cycles of the following formulas:

; R3means alkyl chain with 4 to 8 carbon atoms, substituted by one or more hydroxyl groups and, in addition, possibly substituted by one or more lower alkyl groups and/or substituted by one or more halogen atoms and/or substituted by one or more groups of CF3and/or in which one or a few simple links of the chain may be substituted with one or more double bonds, and R3is a cycle in the para - or meta-position relative to the link X-Y, as well as optical and geometrical isomers of the above compounds of formula (I)

The invention relates to new derivatives of balkanov General formula (A)

< / BR>
where Ar is phenyl which may be unsubstituted or substituted one, two or three substituents independently chosen among Cl, Br, F, -OMe, NO2, CF3C1-4lower alkyl, -NMe2, -NEt2, -SCH3, -NHCOCH3; 2-thienyl, 2-furyl; 3-pyridyl; 4-pyridyl or 3-indolyl; R-OCH2R1where R1choose from a number of-CH= CME2The CME=CH2-The CCH; provided that when Ar is a phenyl,4-alkylphenyl, 4-methoxyphenyl or 3,4-acid, R can be any except 3-methyl-2-butenyloxy

-diketones and ketoesters" target="_blank">

The invention relates to the chemistry of adamantane derivatives, and in particular to a new method of obtaining-dicarbonyl derivatives of adamantane General formula

< / BR>
where R=CH3:R1=CH3OC2H5; R=C6H5: R1=OC2H5C6H5, CF2H

R=CF3:R1=C6H5n-C6H4C1

< / BR>
< / BR>
which are the products for the synthesis of biologically active substances

The invention relates to a new therapeutic drug for diabetes and includes the compound of the formula I: R1-C(O)-C(R2')(R2)-X-C(O)-R3where X represents a group of formula-C(R4)(R5)-, -N(R6)-, -O-; where R4is a hydrogen atom, a C1-C5alkyl, carboxy, phenyl, C2-C5acyl, C2-C5alkoxycarbonyl, R5is a hydrogen atom, a C1-C5alkyl; R6is hydrogen; R1is phenyl, optionally substituted C1-C5by alkyl, hydroxy, hydroxyalkyl, C2-C6alkenyl, acyl, carboxy, teinila, C3-C7cycloalkyl; biphenyl, optionally substituted C1-C5the alkyl or hydroxy; naphthyl; terphenyl; C3-C7cycloalkyl, optionally substituted C1-C5the alkyl or phenyl; optionally substituted C1-C5alkyl; pyridyl; sensational; substituted; indanyl; fluorenyl or group; R2is hydrogen, C1-C5alkyl, optionally substituted by carboxy; R2'is hydrogen; R3- C1-C5alkyl, optionally substituted by phenyl or C1-C4alkoxy, C1-C4alkoxy; hydroxy; phenyl; C3-C72)2-; R2and R5taken together, form a simple bond or-CH2-, - (CH2)3-, -(CH2)4-; R2, R2', R4and R5taken together form =CH-CH=CH-CH=; R2' and R3taken together form a-CH(R8)-OH, -CH(R8)-CH(R9)-, -CH(R8)NH; R8and R9is hydrogen, and pharmaceutically acceptable salts

The invention relates to compounds of dehalogenation, insecticide/acaricidal agents containing these compounds as active ingredients and intermediates for their production

Iodinated esters // 2088579

The invention relates to 1-alkyl, 1-alkenyl, and 1-alkynylaryl-2-amino-1,3-propandiol formula 1:

< / BR>
where R is

< / BR>
< / BR>
R5represents a group of the formula:

CH3(CH2)mCC-, CH3(CH2)mCH CH-,

CH3(CH2)mCH2-CH2-,< / BR>
,< / BR>
m is from 3 to 15 and n is from 0 to 12

The invention relates to the field of organic chemistry, namely the chemistry of azo compounds which are used as acid-base indicators

The invention relates to 1-alkyl, 1-alkenyl or 1-alkynylaryl-2-amino-1,3-propandiol formula I

RCH (OR1)CHN(R2R3)P4whereOSO

R5-CH3(CH2)mCC,

CH3(CH2)mCH=CH-, CH3(CH2)mCH2-CH2-,-CH2(CH2)nCC-,

-CH2(CH2)nCH= CH or-CH2(CH2)nCH2-CH2-, where m = 3-15; n = 0-12;

R1is hydrogen orR6where R6is hydrogen, alkyl, alkoxy, or OCH2-;

R2is hydrogen or alkyl;

R3is hydrogen, alkyl orOR7where R7is hydrogen or alkyl, or CH2OR8where R8is hydrogen orR6where R6is defined above,

R1and R8taken together with the oxygen atom to which they are attached, form a group of the formula

where R9and R10independently are hydrogen or alkyl
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