Derived indole

 

(57) Abstract:

Derived indole of the formula I

< / BR>
where R1- lower alkyl, possibly substituted by hydroxyl, mono - or di-(lower alkyl) aminosulfonyl, -X-Ra, -[O(CH2)m-CHRb]nRbb, -O(CH2)p-Rc, Rais lower alkyl, X Is O, Rb- H, lower alkyl, Rbb- alkoxycarbonyl or carboxyl group, m=0, n=0 or 1, Rclowest alkanoyl or phenyl, R=1, R2, R3-H, halogen, lower alkyl, W is a group of formula II, which connects to the indole ring in position 2 or 3, R4- halogen, R5- lower alkyl, or its salt have strong activity, stimulating 3-adrenergic receptor, with excellent adrenoreceptor selectivity. 6 C. and 9 C.p. f-crystals, 9 PL.

This invention relates to a new derivative of indole with strong activity, stimulating3-adrenergic receptor, with excellent adrenoreceptor selectivity.

Background of the invention

It was known that the receptor of the sympathetic nerve has two subtypes, i.e. 1-receptor and2the receptor. Currently, funds, stimulating 1-adrenergicheskikh, as a means of stimulating2-adrenergic receptor, used as a bronchodilator, respectively.

Recently was found and identified as the third subtype of adrenergic receptor3-adrenergic receptor, which differs from the above two subtypes [Emorine, L. J. et al; Science, 245, 1118-1121 (1989)] .3-Adrenergic receptor exists in brown fat cells and it is found that manifests termodinamicheskuyu activity by decomposition of lipids white fat cells, adherent to the subcutaneous tissues or internal organs, and therefore, it was hypothesized that3-adrenergic receptor is associated with one of the cases of obesity. In addition, it was reported that the crisis insulin-independent diabetes may also be associated with a3-adrenergic receptor.

When stimulant3-adrenergic receptor, acts on the subtypes,1-adrenergic receptor and2-adrenergic receptor. There may be some side effects, such as hyperactivity of the heart, trembling hands and feet, etc. Thus, it was desirable to develop a drug that has strong activity, stimulating2-adrenergic receptor, or with weak activity, stimulating1and2-adrenergic receptors. In this description and the claims connection with such properties, referred to as a "compound having excellent adrenoreceptor selectivity".

As a means of stimulating3-adrenergic receptor, were BRL35135{(R*,R*)-(3-adrenergic receptor.

It is known that these compounds have a chemical structure that is closer to the compounds of the present invention than the compounds listed in table. 1.

For example, in J. Pharm.Pharmacol., 17, 742-746 (1965), describes the following compound A

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Acta Polon.Pharm., 38, 407-410 (1981) (Chem. Abstr., 96, 142543k (1982)) describes the following compound B

< / BR>
The above compounds A and B differ in chemical structure from the compounds of the present invention that does not have a Deputy on the benzene nucleus and do not have a Deputy, corresponding to the substituent R5specify the following compounds of the present invention. In addition, these literary sources are never reported or even speculated about pharmacological activity soedineniya the following formula [VIII]:

< / BR>
where R represents a phenyl group, m - or n-nitrophenyl group, etc., and R1represents a hydrogen atom or methyl group.

The above compound has a chemical structure that is different from the compounds of the present invention that the substituents on the benzene ring is a nitro-group, and the fact that he does not have a Deputy on the indole nucleus. Compounds of the above formula [VIII] particularly include the following compound C

< / BR>
The compound of the present invention is superior as a means of stimulating3-adrenergic receptor, the compounds A, B and C, as shown in pharmacological experiments mentioned below.

Thus, the purpose of this invention is the introduction of a new derivative of indole with strong activity, stimulating3/-adrenergic receptor, with excellent adrenoreceptor selectivity, or salt.

Description of the invention

This invention relates to a derivative of indole following formula [I] :

< / BR>
where R1represents a lower alkyl group, optionally substituted hydroxy-group, phenylcarbonylamino, lower alkylsulfonamides, mo/SUB> in combination with R2forms methylendioxy, and this methylendioxy optionally substituted by carboxypropyl or lower alkoxycarbonyl group;

(a) a group of the formula-X-Ra (where, X represents O, S or NH, Ra represents a hydrogen atom or a lower alkyl group, provided that when X represents S, then Ra is a lower alkyl group);

(b) a group of the formula

< / BR>
(where Rb represents a hydrogen atom, a lower alkyl group, lower alkoxycarbonyl group or carboxypropyl, Rbb is lower alkoxycarbonyl group or carboxypropyl, m represents an integer from 0 to 3 and n represents 0 or 1);

(C) a group of the formula-O(CH2)p-Rc (where Rc represents lower alkanoyloxy group, a hydroxy-group, cyano, phenyl group, mono - or di-(lower alkyl)aminocarbonyl group or a group of the formula

< / BR>
(where RArepresents a hydrogen atom or a lower alkyl group and p represents an integer from 1 to 4);

d) a group of the formula-Y-(CH2)q-Rd (where Y represents NH or S, Rd represents a carboxyl group or a lower alkoxycarbonyl group, q represents an integer from 1 to 4);

R2represents the atom of water is th alkoxygroup or the above group (b) or (C) or R2in combination with R1form methylenedioxy, and this methylendioxy optionally substituted carboxyl group or a lower alkoxycarbonyl group;

R3represents a hydrogen atom or a lower alkyl group;

W represents a group of the formula [II], which is connected to position 2 or 3 of the indole nucleus:

< / BR>
where R4represents a halogen atom or triptorelin group, and R5represents a lower alkyl group,

or salt.

Structural characteristics of the compounds [I] of this invention are:

(1) the presence of a specific atom or group in position 3 of the nucleus of the benzene Deputy W;

(2) the substituent R5that represents a lower alkyl group;

(3) the presence of certain substituents R1and R2in positions 4-7 the indole nucleus;

(4) the presence of the substituent W in position 2 or 3 of the indole nucleus.

Strong activity, stimulating3-adrenergic receptor, and excellent adrenoretseptory selectivity of the compounds of the present invention based on the above structural characteristic features of these compounds or their combinations.

The term is presumed to define "lower", means the group having 1-4 carbon atoms. "Lower alkyl group" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and so on , but methyl, ethyl, propyl and isopropyl more preferable. "Lower alkyl group substituted by a hydroxy-group" includes, for example, hydroxymethyl, 2-hydroxyethyl, etc. "Inferior alkylsulfonamides" includes, for example, methylsulfonylamino, ethylsulfonyl etc., "Mono - or di-lower alkylaminocarbonyl group" includes, for example, monomethylmercury, dimethylaminomethyl, monoethanesulfonate, diethylaminosulfur etc. "Lower alkoxycarbonyl group" includes, for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl etc. "Lower alcoolica group" includes, for example, acetyl, propionyl etc., "Mono - or di-lower alkylaminocarbonyl group" includes, for example, methylaminomethyl, dimethylaminoethyl, methylaminomethyl etc., "halogen Atom" means fluorine, chlorine, bromine, iodine, the preferred halogen is fluorine, chlorine, bromine and the most preferred halogen is fluorine and chlorine. "The lowest alkoxygroup" includes, for example, methoxy, ethoxy, propoxy, isopropoxy the em for example, ethoxycarbonylmethoxy, 1 ethoxycarbonylmethoxy, 2-ethoxycarbonylmethoxy, 1 methoxycarbonylpropionyl, 3 methoxycarbonylpropionyl etc., "Carboxy-lower alkoxygroup" includes, for example, carboxymethoxy, 1 carboxymethoxy, 2-carboxymethoxy, 1 carboxyphenoxy, 3 carboxypropyl etc., "Phenyl-lower alkoxygroup" includes, for example, benzyloxy, penetrate etc.

Salt of these compounds of the formula [I] is, for example, an acid additive salt is particularly preferred pharmaceutically acceptable acid additive salt. An acid additive salt includes, for example, salts with inorganic acid such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, phosphoric acid, and salts with organic acid such as oxalic acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, methanesulfonate, etc. in Addition, the compounds of this invention having a carboxyl group in the definition for substituent R1or R2can exist in the form of alkali metal salt or a salt with an organic base, for example salt sibutramin, diisopropylethylamine, N-methylmorpholine, dicyclohexylamine etc.

These acid additive salts, alkali metal salts or salts with organic base may exist in the form of its hydrate or MES, the invention also includes, in addition, these hydrate and solvate.

The compound of this invention of the formula [I] have two asymmetric carbon atom. That is, in the formula [II] the carbon atom to which is connected a hydroxy-group, and the carbon atom to which is attached R5are asymmetric carbon atoms. Thus, the compound of this invention has four stereoisomer this invention also includes these optically active compounds, racemic compounds, and mixtures thereof.

The preferred compound of this invention is the compound of formula [I] , in which the Deputy W is attached to the indole nucleus at position 3, i.e., the compound of the formula [I-a]

< / BR>
in which R1, R2, R3, R4and R5such as defined above, or salt. Among other preferred compound of this invention is the compound of the formula [I-a] , where R1attached in position 5, 6 or 7 of the indole ring and R1and R2attached to the indole ring in position 6, and the other is in position 7, or its salt.

Another preferred compound of this invention is derived indole of the formula [I-a] in which R1represents a lower alkyl group substituted by a hydroxy-group, phenylcarbonylamino, lower alkylsulfonyl, di-lower alkylaminocarbonyl group or a group of the following groups (a), (b-1), (s-1) or (d);

(a) a group of the formula-X-Ra (where X and Ra are the same as defined above);

(b-1) a group of the formula

< / BR>
(where Rb-1 represents a hydrogen atom or a lower alkyl group, Rbb, m and n are the same as defined above);

(1) a group of the formula-O(CH2)p-Rc-1 (where Rc-1 is the lowest alkanoyloxy group, phenyl group, mono-lower alkylaminocarbonyl group, and p is the same as defined above);

(d) a group of the formula-Y-(CH2)q-Rd (where Y, Rd and q are the same as defined above);

R2represents a hydrogen atom, halogen atom, lower alkyl group, optionally substituted hydroxy-group, a hydroxy-group, the lower alkoxygroup or group from the above group (b-1) or (C-1), or salt. Among UCU R1is lower alkoxygroup, a lower alkyl group, lower alkoxycarbonyl group, a lower alkoxycarbonyl-lower alkoxygroup, carboxy-lower alkoxygroup, phenyl-lower alkoxygroup or di-lower alkylaminocarbonyl group, R2represents a hydrogen atom, halogen atom, lower alkoxygroup, a lower alkyl group, lower alkoxycarbonyl group, a lower alkoxycarbonyl-lower alkoxygroup, carboxy-lower alkoxygroup or phenyl-lower alkoxygroup, R3represents a hydrogen atom, R4represents a halogen atom and R5represents a methyl group, or salt.

Especially preferred compound is a derivative of indole of the formula [I-a], where R1represents a methoxy group, ethoxypropan, propoxylate, isopropoxy, methyl group, methoxycarbonyl group, ethoxycarbonylmethoxy, carboxymethoxy, benzyloxy or dimethylaminomethylene group, R2represents a hydrogen atom or a methoxy group, R3represents a hydrogen atom, R4represents a chlorine atom, R5represents a methyl group, or salt.

Most predpochtitelnye, ethoxypropan, methoxycarbonyl group, ethoxycarbonylmethoxy or carboxymethoxy, which is attached at position 6 or 7 of the indole ring, R2and R3represent a hydrogen atom, R4represents a chlorine atom, R5represents a methyl group, or salt.

The most preferred compounds are:

(1) 2-[3-(7-Methoxyindol-3-yl)-2-propylamino]-1-(3 - chlorophenyl)ethanol,

(2) 2-[3-(7-Taxiing-3-yl)-2-propylamino]-1-(3 - chlorophenyl)ethanol,

(3) 2-[3-(7-Ethoxycarbonylmethoxy-3-yl)-2 - propylamino] -1-(3-chlorophenyl)ethanol,

(4) 2-[3-(7-Carboxymethoxy-3-yl)-2-propylamino] -1- (3-chlorophenyl)ethanol

and their optical isomers or their salts.

Representatives included in this invention are the compounds listed in the table. 2, 3 and 4, and their salts.

The compound of this invention can be obtained in the following ways:

Method (a):

The compound of the formula [I] of this invention can be obtained by reaction of the compound of the formula [III]

< / BR>
where R4the same as defined above, with a compound of the formula [IV]

< / BR>
where R1, R2, R4and R5are the same as defined above, or who should be selected in accordance with types of the parent compounds, they include, for example alcohols (e.g. methanol, ethanol, isopropanol and so on), ketones (e.g. acetone, methyl ethyl ketone, and so on), halogenated hydrocarbons (e.g. methylene chloride, chloroform, and so on), ethers (e.g. diethyl ether, tetrahydrofuran, dioxane and so on), aromatic hydrocarbons (e.g. benzene, toluene and so on), ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide and the like, and these solvents can be used individually or in combination of two or more of them. In addition, when the compound [IV] is in the form of an acid additive salts, for example salts with inorganic acid such as hydrochloride, hydrobromide, etc. or salts with organic acids, such as oxalate, maleate, fumarata and so on , the reaction is carried out in the presence of a base. The base includes, for example, bicarbonate of an alkali metal such as sodium bicarbonate, potassium bicarbonate, and so on, a carbonate of an alkali metal such as sodium carbonate, potassium carbonate, etc. or organic base, such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, etc. in Addition, when the substituent R1or R2included carboxyl group, the reaction is carried out in the presence of a base, upominanii, but usually it is in the range from room temperature to about 150oC, preferably in the range of from about 25oC to about 100oC.

In method (a) both the parent compound [III] and [IV] are asymmetric carbon atom and the reaction takes place with retention of stereoconfiguration asymmetric carbon atom, giving the target compound [I] having the same stereoconfiguration. That is, for example, the target compound [I] with (R,R)-configuration, is obtained from the starting compound [III] with R-configuration, and the starting compound [IV] with R-configuration.

Optically active compound of the formula [III] can be obtained, for example, by a method similar to the method described in Bloom, J. D. et.al., J. Med. Chem. 35, 3081-3084 (1992) or in E. L. Eliel and Delmonte, D. W. J. Orq.Chem., 21, 596-697 (1956). Optically active compound of the formula [IV] can be obtained, for example, by a method similar to the method described in Repke, D. B. and Ferquson, W. J., J. Heterocycl., Chem., 13, 775-778 (1976).

The original compound of the formula [IV] can be obtained, for example, by the method described in J. Orq.Chem., 25, 1548-1558 (1960).

Among the compounds of the formula [IV] a compound of the formula [IV], in which the residue has the following structure:

< / BR>
where R5the same as defined above, is connected with the floor of the procedure (b):

The compound of the formula [I] of the present invention, where the substituent R1is more limited group R'1, i.e. the compound of the formula [I-b]:

< / BR>
where R'1represents lower alkyl, optionally substituted by a hydroxy-group, phenylcarbonylamino, lower alkylsulfonyl, mono - or di-lower alkylaminocarbonyl group or a group selected from the following groups (a)', (b), (C) and (d)', or R'1in combination with R2forms methylendioxy, and this methylendioxy optionally substituted carboxyl group or a lower alkoxycarbonyl group

(a)' group of the formula-X'-Ra (where X' represents O or S, Ra is the same as defined above, provided that when X' is S, then Ra is a lower alkyl group);

(b) a group of the formula

< / BR>
(where Rb, Rbb, m and n are the same as defined above);

(C) a group of the formula-O(CH2)p-Rc (where Rc and p are the same as defined above);

d)' group of the formula Y'-(CH2)q-Rd (where Y' is S, Rd and q are the same as defined above);

can be obtained by reaction of the compound of the formula [V]

< / BR>
where R4the same as defined above, with a compound of the formula [VI]

< / BR>
where R'1the context of recovery" in this invention means the reaction of the compound [V] and the compound [VI] in the presence of a reducing agent or catalyst, which can only be recovered by aminogroup formed in the reaction, but does not affect the carbonyl group.

The reducing agent includes, for example, cyanoborohydride sodium and catalyst includes, for example, palladium, platinum oxide, etc.

The reaction is carried out in the presence of a reducing agent or catalyst in a suitable solvent. The solvent is preferably alcohols, such as methanol, ethanol and so on, the Reaction is usually carried out at a temperature of from about 20oC to about 80oC when using a reducing agent, and when using a catalyst, it is usually carried out at a temperature from about 10oC to about 25oC.

Method (c)

The compound of the formula [I] where substituent R1or R2not included carbonyl group, or cyano, i.e. the compound of the formula [I-c]

< / BR>
where R1represents lower alkyl, optionally substituted by a hydroxy-group, phenylcarbonylamino, lower alkylsulfonyl, mono - or di-lower alkylaminocarbonyl group or a group selected from the following group (a) or (C), or R1together with R2form methylenedioxy,

(a) a group of the formula-X-Ra (where X and Ra the UCCI, phenyl group, or a group of the formula

< / BR>
(where RArepresents a hydrogen atom or a lower alkyl group, and p is the same as defined above), R2represents a hydrogen atom, halogen atom, lower alkyl group which is optionally substituted by a hydroxy-group, a hydroxy-group, the lower alkoxygroup defined above or group (s)" or R2together with R1form methylenedioxy and R3, R4and R5are the same as defined above, can be obtained by reduction of compound of the formula [VII]

< / BR>
where R1, R2, R3, R4and R5the same as above.

The reaction is carried out in the presence of a reducing agent in a suitable solvent. The reducing agent includes, for example, DIBORANE, sociallyengaged or alkoxyamines, its salt of the transition metal, borohydride sodium, which added aluminium chloride, boron TRIFLUORIDE, phosphorus oxychloride or carboxylic acid (e.g. acetic acid, triperoxonane acid) etc., the Solvent includes, for example, ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, diglyme etc., the reaction Temperature varies according to the type of use asanam above method stereoconfiguration asymmetric carbon atom of the parent compound [VII] remains in the final product.

The original compound [VII] is a new connection, it is obtained, for example, by reaction of the compound of the formula [IX]

< / BR>
where R4the same as defined above, with a compound of the formula [X]

< / BR>
where R1, R2, R3and R5same as above, or its salt.

The reaction of the compound [IX] and the compound [X] is carried out in the presence of a condensing means, for example N,N'-dicyclohexylcarbodiimide, the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, N,N'-carbonyldiimidazole, N, N'-carbonylchloride, 1-etoxycarbonyl-2-ethoxy - 1,2-dihydroquinoline, diphenylphosphinite, papapostolou anhydride (anhydride papapostolou acid), etc. When the condensing means use N,N'-dicyclohexylcarbodiimide or hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, the reaction can be performed by adding N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc.

The reaction is usually carried out in a suitable solvent. The solvent includes, for example, the same solvents that are mentioned for the method (a). In addition, compound [X] can be used in the form of its acid salt additive, as mentioned in method (a), and when using acid the amine, tributylamine, diisopropylethylamine, N-methylmorpholine and so on, the Reaction is usually carried out at a temperature of from about 20oC to about 50oC.

Stereoconfiguration compound [IX] and the compound [X] remains in the target compound [VII].

Optically active compound [IX] get, for example, by a method similar to the method described in Collet, A. and Jacques. J., Bull.Soc.Chim.France, 3330-3334 (1973).

Optically active compound [X] get, for example, by a method similar to the method described in the first publication of the Japan patent (Kokai) - 22559/1988.

The products obtained in the above ways, you can select and clear in the usual way, for example by chromatography, recrystallization, presidenial etc.

The products obtained by the above methods, you can get in the form of an acid additive salt or free base according to the used reaction conditions. These products can be converted into an acid additive salt or free base in the usual way.

In each of the above methods, when the substituent R1or R2represents an amino group or a lower alkoxygroup substituted group of the formula

< / BR>
or when the substituent R1or R2

When the compounds of this invention obtained by the above methods, or original compounds are the racemic compound or in the form of a mixture of diastereoisomers, each stereoisomer is separated in the usual way, for example by the method described in the publication N 455006 European patent.

The best way of carrying out the invention

Pharmacological experiments:

The following experiments were performed to assess the activity of representative compounds of this invention in the form of:

(1) Activities that stimulate3and2- adrenergic receptors of the person;

(2) Activities that reduce the glucose content in the blood;

(3) Activity against obesity.

First, due to the creation of cell lines highly expressing 3and2- adrenergic receptors of the man, and then gives examples of experiments with their use.

The creation of cell lines strongly expressing3-adrenergic receptor person:

(1) the Design of expressing what endonuclease SalI and was a small mistake with a set for blunting DNA (Takara Shuzo Co., Ltd). Separately, another expressing vector for animal cells pSV2-neo [Southern and Berq, J. Mol. Appl.Genet. 1:327-341 (1982)] was digested with restriction endonuclease AccI and AatII and a small mistake with the set to break the DNA. These DNA ligated by means of a set for ligating DNA (Takara Shuzo Co. , Ltd.) and inserted into E. Coli HB 101 accepted way, obtaining transformants. Plasmid DNA was obtained from transformants and digested with restriction endonuclease > PST. Was selected clone, which was produced fragments with around 3.8 T. p. N. (thousand base pairs), 2,2 T. p. N., 1,4, etc. n and 0.9, etc., n, to obtain plasmid, named pKCNO. Plasmid pKCNO were digested with restriction endonuclease HindIII and ligated with the following synthetic adapter 1, represented by SEQ ID N:1, with a set of ligation of DNA.

5'-AGCTCCTGCAGGCGCGCCGATA TCTCGAGCGGCCGCGGTACCA-3'

3'-GACGTCCGCGCGGCTATAGAG CTCGCCGGCGCCATGGTTCGA-5'

The reaction mixture was used to transform E. coli HB101 and selected transformants were obtained plasmid DNA. Plasmid DNA was digested with restriction endonucleases DraI and HindIII and was selected clone, which has produced a fragment with approximately 430 p. N., to obtain plasmid, named pKCNl, as expressing vector.

(2) Konica SK-N-MC (ATSS NTV 10) and cDNA was synthesized using the SuperScript system (Life Technologies), cDNA amplified set for polymerase reaction synthesis circuit GeneAmp (Perkin-Elmer) using as primers the following oligonucleotides 1 and 2 represented by SeQ ID No. 2 and No. 3, respectively. In the reaction mixture polymerase reaction synthesis circuit was added 10% dimethyl sulfoxide.

5'-CCACCTGCAGGTGATTTGGGAGACCCC-3' --- oligonucleotide 1

5'-TTCTCGAGCCGGGGAATCCCATGGGAC-3' --- oligonucleotide 2

After the cleavage reaction mixture restriction endonucleases Sse 83871 and StuI electrophoresis was selected fragment having about 1.3, etc., N. This fragment ligated expressing vector pKCNl, which was cleaved with restriction endonucleases Sse83871 and EcoRV, and the ligation product was inserted into E. coli HB101 accepted way. Plasmid DNA was obtained from the selected transformant and determined the nucleotide sequence of the fragment with approximately 1.3 T. p. N., obtained by cleavage of plasmid DNA restriction endonucleases, Sse83871 and XhoI. The sequence was identical to sequence cDNA3-adrenergic receptor person reported Leilas et al. [FEBS Lett. 324:127-130 (1994)]. This plasmid for expression3-adrenergic receptor human, was named pKREX10.

(3) B is transformed by the plasmid, expressing3-adrenergic receptor human, the method of calcium phosphate and transformants were selected using 600 μg/ml G-418 (Life Technologies) in a minimal supportive environment Dulbecco (ICN Biochemicals), supplemented with 10% fetal bovine serum and 11.5 μg/ml Proline. In cultures 69 G-418-resistant clones of these cells were separated by incubation with phosphate buffered salt solution containing 0.5 mm ethylenediaminetetraacetate (EDTA), at 37owithin 10 minutes after removal of the medium. The cells were collected by centrifugation and suspended in 10 mm Tris-HCl buffer (pH 7.5) containing 1 mm EDTA, at a concentration of 5106cells/ml of This suspension (20 μl) and (-)-3-[125I] itsinitial (1.5 nm) (Amsterdam) were mixed in the medium RPMI-1640 (200 ml) (ICN Biomedicals) containing 1% bovine serum albumin, 0.1% of NaN3and 20 mm HEPES buffer (pH 7,4), and the mixture incubated at 4oC for 2 hours. The reaction mixture was filtered through a glass filter GF/C (Whatman) pre-soaked with 0.3% polyethylenimine and washed using devices BIO-DOT (Bio-Rad Laboratories) and the radioactivity on the filter was counted by the count of gamma-rays. One clone, named CHO/pKREX10-36, which showed the highest radioactivity was used as the first line, strongly expressing3-adrenergic receptor human.

cDNA was synthesized using Poly (A)+-RNA derived from human brain (Clontech: trading room; CL6516-1), using SuperScrip-systems (Life Technologies). This amplified cDNA kit for polymerase reactions of synthesis target GeneAmp (Perkin-Elmer) using as primers the following oligonucleotides represented by SEQ ID No. 4 and No. 5, respectively

5'-ACACCTGCAGGTGAGGCTTCCAGGCGTCC-3' --- oligonucleotide 3

5'-TGTAAGCTTCTGCTTTACAGCAGTGAGTC-3' --- oligonucleotide 4

After the cleavage reaction mixture restriction endonucleases Sse83871 and HindIII electrophoresis was isolated fragment having about 1.4 T. p. N. This fragment ligated expression vector pKCNl cleaved with restriction endonucleases Sse83871 and HindIII, and inserted into E. coli HB101 accepted way. Plasmid DNA was obtained from the selected transformant and determined the nucleotide sequence of the fragment with approximately 1.4 T. p. N. , obtained by splitting this plasmid DNA restriction endonucleases, Sse83871 and HindIII. The sequence was identical to sequence cDNA2-adrenergic receptor person reported Kobilka B. K. ical receptor human it was introduced into CHO-K1 in the same manner as in the method of creating a cell line expressing 3-adrenergic receptor of human rights. One clone, named CHO/pKREX21-8, which showed the highest radioactivity was used for cell lines expressing2-adrenergic receptor human.

Experiment 1: Active, stimulating-adrenergic receptor person:

Cell line CHO/pKREX10-36, strongly expressing 3-adrenergic receptor human, were cultured for 3 days with minimal supportive environment Dulbecco, supplemented with 10% fetal bovine serum, and 11.5 μg/ml Proline and 200 μg/ml G-418. The cells were separated by incubation with phosphate buffered saline containing 0.5 mm EDTA, at 37oC for 10 minutes after removing the above environment. Cells CHO/pKREX10-36 was collected by centrifugation and suspended in balanced salt Khanka (ICN Biomedicals) containing 1 mm L-ascorbic acid and 1 mm 3-isobutyl-1-of methylxanthines, to a concentration of 2106cells/ml of This suspension (100 μl) and the test compound was mixed in the same balanced salt (500 μl) and incubated at 37oC for 30 minutes followed by boiling decentrali using camp ElA (Amsterdam).

Similarly, the amount of camp was measured using CHO/pKREX21-8 as strongly expressing2-adrenergic receptor with CHO/pKREX10-36 as strongly expressing 3-adrenergic receptor human.

The number of camp, when added 10-5M (-)-isoproterenol in the reaction mixture or not added at all, taken as 100% and 0%, respectively, relative to the maximum response of each of the compounds of this invention were expressed as % of the intrinsic activity [I. A. (%)].

The value of EC50that is the concentration of test compound required to achieve the accumulation of 50% of camp, was calculated by regression of the least squares curve concentration-response of each connection.

The results are given in table. 5. The above-mentioned compounds A, B and C was used as reference compound.

It is believed that a compound with a low EC50and of high magnitude, I. A., has strong activity, stimulating3or2--adrenergic receptor human. Thus, as shown in table 5, it is proved that the compounds of the present invention, in particular compounds of example 1, 1-A, tiwest data connections, stimulating3-adrenergic receptor human, stronger than its activity, stimulating 2-adrenergic receptor of human rights. In particular, the compounds of example 1, 1-A, 1-A-b, 2, 2-A and 14 have excellent adrenoreceptor selectivity for3-adrenergic receptor human.

On the other hand, the reference compounds A, B and C indicated here earlier, show very weak activity, stimulating3-adrenergic receptor human, compared with the compounds of the present invention.

In addition, when studying the activity of the increase in the rate of spontaneous contractions in a dedicated right atrium of Guinea pigs, it was shown that the compounds of this invention hardly show activity, stimulating1-adrenergic receptor human.

As shown in the above results, the compounds of this invention can be a stimulant3-adrenergic receptor someone with excellent adrenoreceptor activity.

Experiment 2. Activity, reduce the content of glucose in the blood from the hungry mice:

The test compound suspended in 0.5% solution of tragakant, perigo compounds were selected blood samples. The level of glucose in the blood was determined by the method Kunst, A., et al. (method hexokinase/G6PDH) [Berqmeyer, H. U. (eds.). Methods in Enzymoloqy, vol. Yl, 3rd edition, Verlag Chemie Gmbh, Weinheim-Deerfield Beach, Florida-Basel, 163-172 (1984)] . The activity of the test compounds on reduction of blood glucose was expressed by the value of the ED25, which represents the concentration of test compound required to reduce the level of glucose in the blood before the introduction of the test compounds at 25%. As a reference compound used gliclazide, which is commercially available drug for the treatment of diabetes. The results are given in table. 6.

Experiment 3. Activity against obesity in mice suffering from diabetic obese.

The test compound suspended in 0.5% solution of tragakant, oral introduced suffering from diabetic obese mice (KK-Ay/Ta Jcl. females; 50-60 g, Clea Japan Inc.) at the dose of 0.3 mg/kg/day for three weeks and then took retroperitoneal adipose tissue and interscapular adipose tissue mass was measured as white adipose tissue and brown adipose tissue, respectively. The results are given in table. 7.

The compounds of this invention show low toxicity, such as a connection p. the acute toxicity using mice. Thus, if we take into account therapeutically effective dose of the compounds of this invention do not create problems for the security of the living organism.

The compounds of this invention are excellent means of stimulating 3-adrenergic receptor, with high adrenoreceptor selectivity, their use for prophylaxis or treatment of obesity and diabetes in mammals, including humans. In addition, the compounds of this invention can also be used in the treatment of irritable bowel syndrome, acute or chronic diarrhea or alleviate symptoms, such as abdominal pain, nausea, vomiting, abdominal discomfort, and so on, followed poeticheskoi ulcer, acute or chronic gastritis, dyskinesia, cholecystitis, etc.

The compound [I] of the present invention or its pharmaceutically admissions salt can be entered as a means of stimulating3-adrenergic receptor, oral, parenteral or rectal, but preferably by mouth. The dose of the compounds of the present invention varies in accordance with by introducing, conditions, age of the patients or concrete is in the range of 0.05-10 mg/kg/day.

The compounds of this invention are usually administered in the form of a pharmaceutical preparation, which is obtained by mixing it with a pharmaceutically acceptable carrier or diluent. Pharmaceutically acceptable carrier or diluent may be a common carrier or diluent, which is usually used in the pharmaceutical field and which does not react with the compounds of the present invention. Suitable examples of pharmaceutically acceptable carrier or diluent is, for example, lactose, glucose, mannitol, dextrin, starch, white sugar, metasilicate-magnesium aluminate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl, calcium carboxymethyl cellulose, ion exchange resin, methylcellulose, gelatin, gum Arabic, hydroxypropylcellulose, slabosolenaja hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, polyvinyl alcohol, loose anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, ester of fatty acid and sorbitan (anhydromannitol), sodium lauryl sulfate, glycerin, the ester of glycerol and fatty acids, purified lanolin, glycoregulation, water, etc.

The pharmaceutical preparation is, for example, tablets, capsules, granules, powders, syrups, suspensions, suppositories, gel-like preparations, injectable preparations, etc., These drugs can be obtained in the usual way. To obtain the fluid connection of the present invention prior to the introduction of dissolved or suspended in water or other suitable solvent. Tablets and granules may be coated in the usual way. In injectable preparations preferably the dissolution of the pharmaceutically acceptable acid additive salts of the compounds [1] of the present invention in water, but if necessary, it can be dissolved in isotonic medium and then added to a solution of the means for regulating the pH buffer agent or preservative.

These preparations may contain the compound of the present invention in a proportion of at least 0.01 percent, preferably in a proportion of 0.05-70%. These preparations can also contain other pharmaceutically effective compounds.

Examples

This invention is illustrated in more detail by the following reference examples and examples, but they should not be construed as limiting the invention.

Identification of compounds ososanya the present invention can use the following abbreviations.

Me: Methyl

Et: Ethyl

Ph: Phenyl

E: Ethanol

M: Methanol

H: n-Hexane

DE: Diethyl ether

CF: Chloroform

EA: ethyl Acetate

DMF: Dimethylformamide

s: Singlet

d: Doublet

dt: Double triplet

DD: Double doublet

t: Triplet

to: Quartet

MC: Mass spectrum

Reference example

Obtaining 3-(2-aminopropyl)-7-methoxyindole:

The title compound was obtained in the following ways in accordance with the method described in published UK patent N 974893.

(1) Dimethylformamide (DMF), 16 ml) cooled in an ice bath and added dropwise phosphorus oxychloride (5 ml) and the mixture is stirred for 10 minutes. A solution of 7-methoxyindole (6.5 g), which was obtained from 3-methyl-2-nitroanisole in accordance with the method described in Heterocycles, 16, 1119-1124 (1981), in DMF (16 ml) is added dropwise to this mixture and the mixture is stirred at room temperature for two hours. The mixture was added 30% aqueous solution of sodium hydroxide (30 ml) under ice cooling and the mixture is heated at about 80oC for five minutes in a hot bath and leave to cool. The precipitate is collected by filtration, washed with water and dried, obtaining the crude 7-methoxyindol-3-al is ewout under stirring at 50oC for 20 minutes and add the product (4.5 g) obtained in (1), acetic acid (19.2 ml) and nitroethane (16 ml). The mixture is heated to 100oC and to it was added sodium acetate (2.25 g). The mixture is refluxed for two hours while gradually adding dropwise acetic anhydride (3.2 ml). After cooling on standing, the mixture was added water and the precipitated solid product is collected by filtration, washed with water and dried, obtaining the crude 1-(7-methoxyindol-3-yl)-2-nitropropene (3,35 g).

(3) the Solution nitropropene compound (3.2 g) obtained in (2), in tetrahydrofuran (60 ml) is added dropwise to a suspension of aluminiumhydride lithium (3.2 g) in diethyl ether (60 ml) under ice cooling and the mixture is refluxed for 5.5 hours. To the mixture while cooling with ice, add saturated aqueous solution of mixed sodium tartrate and potassium and insoluble materials are removed by filtration and the filtrate is dried over anhydrous magnesium sulfate. This mixture is evaporated to remove solvent under reduced pressure, obtaining the crude target compound (3.2 g) as an oily product, which is used as starting compound in example 1.

MC (m/z): 205 (MH<1) 6-Hydroxyindole (2.9 g), methylchloride (2.7 g), potassium carbonate (5.5 g) and potassium iodide (0.2 g) is added to acetone (100 ml) and the mixture refluxed for 8 hours. The reaction mixture is cooled to room temperature and insoluble material removed by filtration. The filtrate is evaporated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: chloroform) to give 6-ethoxycarbonylmethoxy (2.83 g).

1H NMR spectrum (CDCl3): of 3.78 (3H, s, COOCH3), of 4.67 (2H, s, OCH2), of 6.49 (1H, m), 6,83 (1H, m), to 6.88 (1H, s), 7,11 (1H, m), 7,53 (1H, m), and 8.2 (1H, s, NH).

(2) In the solution of the above product (2,77 g) in benzene (50 ml) add a solution of 2-nitropropene (of 3.56 g) in benzene (17,8 ml) and the mixture is refluxed for 15 hours. The mixture is evaporated to remove solvent under reduced pressure and the residue purified column chromatography on silica gel (eluent: chloroform) to give 3-(2-nitropropyl)-6 - ethoxycarbonylmethoxy (2.15 g) as an oily product.

1H NMR spectrum (CDCl3): of 1.56 (3H, d, J=7 Hz, CHCH3), 3,10-of 3.48 (2H, m, CH2CHNO2), of 3.77 (3H, s, COOCH3), with 4.64 (2H, s, OCH2), to 4.92 (1H, m, CHNO2), 6,76-7,05 (3H, m), of 7.48 (1H, m), 8,08 (1H, s, NH).

(3) the above product (2,1 sphere pressure. After consumption of theoretical amount of hydrogen, the Raney Nickel is removed by filtration. The filtrate is evaporated to remove the solvent, obtaining the crude 3-(2-aminopropyl)-6 - ethoxycarbonylmethoxy (1.98 g) as an oily product, which is used as starting compound in example 7.

MC (m/z): 263 (MH+).

Reference examples 3-13

In the same manner as in reference example 1 or 2, get the source compounds listed in table 8.

Example 1

Getting 2-[3-(7-methoxyindol-3-yl)-2-propylamino] -1-(3 - chlorophenyl)atenol

Method (a):

In methanol (20 ml) is added (3-chlorophenyl)oxiran (0,77 g) and 3-(2-aminopropyl)-7-methoxyindole (2.16 g) and the mixture is stirred at room temperature for 64 hours. The mixture is evaporated to remove solvent under reduced pressure and the residue purified column chromatography on silica gel (eluent: chloroform/methanol = 12:1), fractions containing the desired product are pooled and concentrated under reduced pressure, obtaining an oily product (1.06 g).

1H NMR spectrum (CDCl3): of 1.12 (3H, d, J= 7 Hz, CHCH3), 2,61 (1H, m), 2,78-of 2.86 (2H, m), 2,88-of 3.12 (2H, m), of 3.95 (3H, s, OCH3), 4,56 (1H, m, CHOH), of 6.65 (1H, m), 6,93-to 7.09 (2H, m), 7,11-7,29 (4H, m), 7,33 (aluca fumarate target compound (0.15 g) (fumarate of the compound of example 1). So pl. 143-147oC (recrystallized from a mixture of ethanol/diethyl ether).

Method (b):

In methanol (10 ml) is added 7-methoxyindol-3-acetone (0.4 g), which was obtained by a method described in UK patent N 974893, and to the mixture under cooling with ice add the hydrochloride of 2-(3-chlorophenyl)ethanolamine (0.45 g) and cyanoborohydride sodium (0.2 g). The mixture is stirred for five minutes and then stirred at room temperature for 18 hours. The mixture is evaporated to remove solvent under reduced pressure and the residue is added saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate and the extract is washed successively with water and saturated aqueous sodium chloride and dried over magnesium sulfate. The resulting mixture is evaporated to remove solvent under reduced pressure and the resulting residue is purified column chromatography on silica gel (eluent: a mixture of chloroform/methanol = 15:1), obtaining the target compound (0,58 g) as an oily product.

Method (s):

(1) In a solution of DMF (80 ml) containing 3-(2-aminopropyl)-7 - methoxyindole (12,24 g) and 3-horninglow acid (7,46 g), add hexaphosphate benzotriazol-N-oxides(dimethylamino) phosphonium (17,68 g) and the operating mixture was added ethyl acetate. The mixture is washed successively with water, 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The mixture is evaporated to remove solvent under reduced pressure and the residue purified column chromatography on silica gel (eluent: a mixture of ethyl acetate/n-hexane = 1:1-->2:1) to give N-[3-(7-methoxyindol-3-yl)-2-propyl] -3-harmondale (14,02 g) as an oily product.

1The NMR spectrum (CDCl3): 1,12, of 1.18 (3H, d, J=7 Hz, CHCH3), 2,82-2,95 (2H, m, CH2CH), of 3.97 (3H, s, OCH3), to 4.33 (1H, m, CHCH3), is 4.85 (1H, s, CHOH), of 6.65 (1H, m), 6,86-7,37 (7H, m), compared to 8.26 (1H, d, J=13 Hz, CONH).

(2) Solution of the above amide compounds (a 13.4 g) in tetrahydrofuran (144 ml) is added dropwise a 1 M solution of the complex of borane-tetrahydrofuran (144 ml) at 20oC and the mixture is refluxed for four hours. In the mixture with ice cooling are added dropwise methanol (150 ml). The mixture is refluxed for one hour to decompose the excess borane. The mixture is evaporated to remove solvent under reduced pressure. To the residue add chloroform and the mixture is washed sequentially with saturated blockhead magnesium. The mixture is evaporated to remove solvent under reduced pressure and the residue purified column chromatography on silica gel (eluent: chloroform/methanol = 20: 1--->10: 1) to give the target compound (7,35 g) as an oily product.

Example 1-A

Getting 2-[3-(7-methoxyindol-3-yl)-2-propylamino]-(1R)-1- (3-chlorophenyl)ethanol

Using (R)-(3-chlorophenyl)oxiran (produced SEPRACO, Ltd.; optical purity: 99.2% of enantiomeric excess) instead of (3-chlorophenyl)oxirane in example 1, the target connection receive in the same manner as in example 1, method (a), in the form of an oily product.

MC (m/z): 359 (MH+).

Example 1-A-A and 1-A-b

Getting 2-[(2R or 2S)-3-(7-methoxyindol-3-yl)- 2-propylamino-(1R)-1-(3-chlorophenyl)ethanol and 2-[(2S or 2R)-3-(7 - methoxyindol-3-yl)-2-propylamino]-(1R)-1-(3-chlorophenyl)ethanol

2-[3-(7-Methoxyindol-3-yl])-2 - propylamino]-(1R)-1- (3-chlorophenyl) ethanol (3.0 g) obtained in example 1-A, which is a mixture of two diastereoisomers, divide column chromatography, obtaining the compound (1A-a) (0,82 g), elution of less polar solvent and the compound (1-A-b) (1.12 g) when more polar elution solvent.

The compound (1-A-A):

The retention time of it with their high separation for HPLC:

1. Column: CHIRALPAK AD (inner diameter 4.6 mm, length 250 mm, Daicel Chemical Industries, Ltd.).

2. Eluent: n-hexane/ethanol/diethylamine = 85:15:0.1 to.

3. Flow rate: 0.4 ml/min

4. Temperature: 40oC.

5. The wavelength for detection: 254 nm.

So pl. 129-130oC (recrystallized from a mixture of ethyl acetate/n-hexane).

1H NMR spectrum (CDCl3): of 1.12 (3H, t, J=7 Hz, CHCH3), to 2.57 (1H, DD, J=a 12.7 Hz), of 2.81 (2H, d, J=7 Hz, CH2CH), 2.91 in-to 3.09 (2H, m), of 3.95 (3H, s, JCH3), 4,59 (1H, DD, J=8,4 Hz, CHOH), only 6.64 (1H, d, J=8 Hz), to 6.95 (1H, d, J=2 Hz), 7,03 (1H, t, J=8 Hz), 7,10-7,24 (4H,m), 7,32 (1H, m), of 8.25 (1H, s, indole-NH).

The compound (1-A-b)

The retention time of it when HPLC: 24,5 min (optical purity: > 99% diastereomeric excess). Conditions for HPLC separation: the same as the conditions for the separation of compounds (1-A-A).

So pl. 86-87oC (recrystallized from a mixture of ethyl acetate/n-hexane).

1H NMR spectrum (CDCl3): of 1.12 (3H, d, J=7 Hz, CHCH3), 2,62 (1H, DD, J=12.9 Hz), 2,82 (2H, d, J=7 Hz, CH2CH), 2,87 (1H, DD, J=12,4 Hz), 3,05 (1H, m, CHCH3), of 3.96 (3H, s, OCH3), of 4.49 (1H, DD, J=9.4 Hz, CHOH), of 6.65 (1H, d, J=8 Hz), of 6.99 (1H, d, J=2 Hz),? 7.04 baby mortality (1H, t, J=8 Hz), 7,12-of 7.25 (4H, m), 7,33 (1H, m), compared to 8.26 (1H, s, indole-NH).

Example 2

Getting 2-[3-(7-taxiing-3-yl)-2-propylamino] -1-(3 - chlorp the Ohm, as in example 1, method (a), obtaining the target compound (1,16 g) as an oily product.

1H NMR spectrum (CDCl3): of 1.12 (3H, d, J=6 Hz, CHCH3), to 1.48 (3H, t, J=7 Hz, CH2CH3), 2,4 (2,4 (2H, Shir., NH, OH), 2,60 (1H, d, t, J=12,8 Hz), 2.77-to 2,96 (3H, m), 3.04 from (1H, m), 4,20 (2H, K, J=7 Hz, CH2CH3), 4,55 (1H, DD, J=9.4 Hz, CHOH), 6,63 (1H, d, J=7 Hz), 6,91-7,06 (2H, m), 7,10-of 7.25 (4H, m), 7,32 (1H, m), of 8.27 (1H, s, indole-NH).

Example 2-A

Getting 2-[3-(7-taxiing-3-yl)-2-propylamino]-(1R)-1- (3-chlorophenyl)ethanol

(R)-(3-Chlorophenyl)oxiran and 3-(2-aminopropyl)-7-taxiing obtained in the above referential example 3 is treated in the same manner as in example 1-A, obtaining the target compound in the form of an oily product.

MC (m/z): 373 (MH+).

Examples 3-12

Using the appropriate indole compounds obtained in reference examples 2 and 4-12, instead of 3-(2-aminopropyl)-7 - methoxyindole in example 1 was obtained in the same manner as in example 1, method (a), the compounds listed in table 9.

Example 13

Obtaining the sodium salt of 2-[3-(6-carboxymethoxy-3 - yl)-2-propylamino]-1-(3-chlorophenyl)ethanol

The compound of example 7 (0,42 g) and sodium hydroxide (0.3 g) is added to an aqueous solution of methanol (methanol/water=2:1.9 ml) and the mixture kipyatkov, the precipitated crystals are collected by filtration, obtaining the target compound (0.24 g) in the form 1/2-hydrate.

So pl. 236-242oC.

Example 14

Getting 2-[3-(7-ethoxycarbonylmethoxy-3-yl)-2 - propylamino] -(1R)-1-(3-chlorophenyl)ethanol

(R)-(3-Chlorophenyl)oxiran and 3-(2-aminopropyl)-7 - ethoxycarbonylmethoxy obtained in reference example 13, is treated in the same manner as in example 1-A, obtaining the target compound in the form of an oily product.

MC (m/z): 417 (MH+).

1H-NMR spectrum (CDCl3): of 1.13 (3H, d, J=6 Hz, CHCH3), 2,62 (1H, dt, J=12,8 Hz), 2.77-to of 3.13 (4H, m), 3,81 (3H, s, CO2CH3), 4,47-and 4.68 (1H, m, CHOH), and 4.75 (2H, s, OCH2), to 6.57 (1H, d, J=8 Hz), 6,92-7,06 (2H, m), 7,11 and 7.36 (5H, m), 8,77 (1H, s, indole-NH).

Example 15

Getting 2-[3-(7-carboxymethoxy-3-yl)-2-propylamino] - (1R)-1-(3-chlorophenyl)ethanol

The compound obtained in example 14, and sodium hydroxide added to an aqueous solution of methanol (methanol/water = 2:1) and the mixture is treated in the same manner as in example 13, receiving the target connection.

MC (m/z): 403 (MH+).

Example 16

(Getting tablets)

The following components are mixed and kneaded in the usual manner and the mixture granularit, the resulting product then press starch - 25 g

Lactose - 54 g

Crystalline cellulose - 11 g

Hydroxypropylcellulose 3 g

Loose anhydrous silicic acid 1 g

Magnesium stearate 1 g

Industrial application

The compounds of this invention are valuable as medicines for mammals, including humans, in particular as a means of stimulating3-adrenergic receptor, they can be used in the treatment of diabetes and obesity.

1. Derived indole of the formula I

< / BR>
where R1represents a lower alkyl group, optionally substituted hydroxy-group, mono - or di-(lower alkyl)aminosulfonyl group, or a group selected from the subsequent groups (a) - (C), where (a) a group of formula X-Ra, where X is O, Ra is a lower alkyl group; (b) a group of the formula

< / BR>
where Rbrepresents a hydrogen atom, a lower alkyl group, Rbb is lower alkoxycarbonyl group or carboxypropyl, m = 0, n = 0 or 1; (C) a group of the formula-O(CH2)p-Rcwhere Rcrepresents the lower alkanoyloxy group or phenyl group, and p = 1;

R2represents a hydrogen atom, halogen atom, lower alkyl group, for long dstanley a hydrogen atom or a lower alkyl group;

W represents a group of formula II, which connects to the indole ring in position 2 or 3

< / BR>
where R4represents a halogen atom and R5represents a lower alkyl group, or salt.

2. A derivative of indole under item 1, represented by formula I-a

< / BR>
where R1, R2, R3, R4and R5are the same as defined in paragraph 1, or salt.

3. A derivative of indole under item 2, where R1attached in position 5, 6 or 7 of the indole nucleus and R2represents a hydrogen atom, or its salt.

4. A derivative of indole under item 2, where R2represents a group other than hydrogen, one of R1and R2located in the 6 position of the indole nucleus and the other in position 7 of its, or its salt.

5. A derivative of indole under item 2, where R1represents a lower alkyl group substituted by a hydroxy-group, di-(lower alkyl)aminosulfonyl group or a group selected from the subsequent groups (a), (b) or (c), R2, R3, R4and R5same as specified in paragraph 1, or salt.

6. A derivative of indole under item 2, where R1is lower alkoxygroup, a lower alkyl group, lower alkoxycarbonyl group, a lower alkoxycarbonyl-ness the ilen group, R2represents a hydrogen atom, halogen atom, lower alkoxygroup, a lower alkyl group, lower alkoxycarbonyl group, a lower alkoxycarbonyl-lower alkoxygroup, carboxy-lower alkoxygroup or phenyl-lower alkoxygroup, R3represents a hydrogen atom, R4represents a halogen atom and R5represents methyl, or its salt.

7. A derivative of indole under item 6, where R1represents a methoxy group, ethoxypropan, methyl group, methoxycarbonyl group, ethoxycarbonylmethoxy, carboxymethoxy, benzyloxy or dimethylaminomethylene group, R2represents a hydrogen atom or a methoxy group, R3represents a hydrogen atom, R4represents a halogen atom and R5represents a methyl group, or its salt.

8. A derivative of indole under item 7, where R1represents a methoxy group, ethoxypropan, methoxycarbonyl group, ethoxycarbonylmethoxy or carboxymethoxy that is attached to the indole ring in position 6 or 7, R2and R3represent a hydrogen atom, R4represents a chlorine atom and R5represents a methyl group or its salt.

9. Connect the ol; optical isomer of 2-[3-(7-methoxyindol-3-yl)-2-propylamino]-1-(3-chlorophenyl)ethanol or its salt; 2-[3-(7-Taxiing-3-yl)-2-propylamino]-1-(3-chlorophenyl)ethanol or a salt, optical isomer of 2-[3-(7-taxiing-3-yl)-2-propylamino]-1-(3-chlorophenyl)ethanol or its salt; 2-[3-(7-Ethoxycarbonylmethoxy-3-yl)-2-propylamino] -1-(3-chlorophenyl)ethanol or a salt, optical isomer of 2-[3-(7-ethoxycarbonylmethoxy-3-yl)-2-propylamino]-1-(3-chlorophenyl)ethanol or its salt.

10. 2-[3-(7-carboxymethoxy-3-yl)-2-propylamino] -(1R)-1-(3-chlorophenyl)ethanol or its salt.

11. The pharmaceutical composition exhibiting stimulating3-adrenergic receptor activity, containing the active ingredient and pharmaceutically acceptable carrier or diluent, characterized in that it contains as active ingredient an effective amount of a derivative of indole, as proposed in paragraph 1, or its pharmaceutically acceptable salt.

12. The pharmaceutical composition according to p. 11, manifesting stimulating 3-adrenergic receptor activity, used to treat diabetes and obesity.

13. The method of obtaining the derivative of the indole of the formula [I], as proposed in paragraph 1, or its salt, lagena with the compound of the formula IV

< / BR>
where R1represents a lower alkyl group, optionally substituted hydroxy-group, mono - or di-(lower alkyl)aminosulfonyl group or a group selected from the subsequent groups (a) - (c), where (a) a group of the formula: -X-Ra, where X is O, Ra is a lower alkyl group; (b) a group of the formula

< / BR>
where Rb represents a hydrogen atom, a lower alkyl group, Rbb is lower alkoxycarbonyl group or carboxypropyl, m = 0 and n = 0 or 1; (C) a group of the formula: -O(CH2)p-Rcwhere Rcrepresents the lower alkanoyloxy group, or phenyl group, and p = 1;

R2represents a hydrogen atom, halogen atom, lower alkyl group, optionally substituted hydroxy-group, the lower alkoxygroup or the above group (b) or (c);

R3represents a hydrogen atom or a lower alkyl group;

R5represents a lower alkyl group,

or its salt.

14. The method of obtaining the compounds of formula I-b

< / BR>
where R1' represents a lower alkyl group, optionally substituted hydroxy-group, mono - or di-lower alkylaminocarbonyl group or a group selected from the following groups (a)', (b) and (c) where (a)' GRU is Rb represents a hydrogen atom, lower alkyl group, Rbb is lower alkoxycarbonyl group or carboxypropyl, m = 0 and n = 0 or 1; (C) a group of the formula: -O(CH2)p-Rcwhere Rcrepresents the lower alkanoyloxy group, or phenyl group, and p = 1;

R2represents a hydrogen atom, halogen atom, lower alkyl group, optionally substituted hydroxy-group, the lower alkoxygroup or the above group (b) or (c),

R3represents a hydrogen atom or a lower alkyl group;

R4represents a halogen atom;

R5- lower alkyl group,

or its salts, characterized in that carry out the reaction of the compound of formula V

< / BR>
where R4the same as defined above, with a compound of formula VI

< / BR>
where R1', R2, R3and R5are the same as defined above, in terms of recovery.

15. The method of obtaining the compounds of formula I-c:

< / BR>
where R1" represents a lower alkyl group which is optionally substituted by a hydroxy-group, mono - or di-lower alkylaminocarbonyl group or a group selected from the following group (a) or (c) where (a) a group of formula X-Ra, where X is O, Ra is lower alkylene the
R2" represents a hydrogen atom, halogen atom, lower alkyl group which is optionally substituted by a hydroxy-group, the lower alkoxygroup or the above group (c)";

R3represents a hydrogen atom or a lower alkyl group, R4represents a halogen atom, R5represents a lower alkyl group,

or its salt,

characterized in that the restoring compound of the formula VII

< / BR>
where R1and R2", R3, R4and R5are the same as defined above.

 

Same patents:

The invention relates to medicine, namely to the use of Tris(2-hydroxyethyl) ammonium salt of 3-IntelliTouch acid having the following formula

< / BR>
as a highly effective protective means in cardiogenic shock and toxic stress

The invention relates to new indole derivative of General formula

RQ-X-Y-Z-R3where R1carboxy or pharmaceutically acceptable protected carboxypropyl;

R2hydrogen, lower alkyl or halogen;

R3phenyl or mono-, di - or tri phenyl(lower)alkyl; each of which may have a Deputy or deputies, selected from lower alkyl, halogen, cyanocorax, lower alkoxycarbonyl, mono-, di - or triphenyl(lower)alkoxycarbonyl, mono - or di(lower)allylcarbamate, phenylcarbamoyl and (lower) alkylresorcinol,

or a group of the formula

-(CO)n- Nwhere Nmeans phenoxazines, phenothiazines or 10,11-dihydro - 5H-dibenzazepine,

n is 0 or 1,

And lower alkylene, which may be substituted by oxo group, or a lower albaniles;

Q is carbonyl or lower alkylene;

X means a group of the formula

orwhere R1hydrogen or lower alkyl;

R5hydrogen, lower alkyl /19954/003.dwl/2045518-11t.gif" ALIGN="ABSMIDDLE">where R6hydrogen, lower alkyl, mono-, di - or triphenyl(lower)alkyl which may have a Deputy or deputies, selected from lower alkyl, carboxy, lower alkoxycarbonyl, mono-, di - or triphenyl(lower)allylcarbamate, phenylcarbamoyl and (lower)alkylresorcinol, or pharmaceutically acceptable aminosidine group,

or their pharmaceutically acceptable salts, having inhibitory activity on testosterone 5-reductase

The invention relates to new compounds of General formula I, where R1-R4is hydrogen, halogen, lower alkyl or trifluoromethyl, R5and R6is hydrogen, halogen, lower alkyl, trifluoromethyl or lower alkoxy and R7- lower alkyl, and pharmaceutically acceptable additive salts of acid compounds of the formula I

The invention relates to new salts of 3-[2-(dimethylamino)ethyl]-N-methyl-1H-indol-5-methanesulfonamide, pharmaceutical compositions containing it, in particular to compositions intended for intranasal and their use in medicine

The invention relates to a method, vkluchaysya decarboxylation of 2-carboxy-3 [2-(dimethylamino)ethyl] N-methyl-1H-indol-5 methanesulfonamide (formula II) in the presence of a suitable solvent and a suitable catalyst in an inert atmosphere and at a temperature in the range from 189 to 250oWith, allowing to obtain 3-[2-(dimethylamino)ethyl] N-methyl-1H-indol-5-methanesulfonamide (formula I), its salt and a solvate, which is effective in the treatment of migraine

The invention relates to new chemical compounds, particularly to derivatives of 2-aminoindole that exhibit hepatoprotective activity and can find application in medical practice

The invention relates to certain polyamines, which are present in the venom of the spider Agelenopsis aperta

Antihypoxic complex // 2137478
The invention relates to medicine, specifically to pharmacology

The invention relates to certain derivatives of tetrahydrocarbazole for use in the treatment of disorders characterized by excessive expansion of the lumen of blood vessels, in particular the treatment of migraine
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