The hydrazides 1h-indole-3-acetic acid as inhibitors spla2

 

(57) Abstract:

The hydrazides 1H-indole-3-acetic acid formula I, where X is 0; R1- C4-C20-alkyl, where Y = 1 to 8; R74- independently - H, C1-C10-alkyl; R75-aryl, possibly substituted with halogen, HE, NO2, phenyl, C1-C10-alkylthio,1-C10-alkoxy, C1-C10-alkyl, NH2; R2- halogen, C1-C3-alkyl, C1-C2-alkylthio,1-C2-alkoxy; R3- independently - H, C1-C3-alkyl; R4, R5, R6, R7- independently - H, C1-C10-alkyl, C1-C10-alkoxy, C4-C8-cycloalkane, halogen, HE, COOH, hydrazino, hydrazido, its pharmaceutically acceptable salt. Use for the preparation of a pharmaceutical composition inhibiting secretory phospholipase sPLA2 in an effective amount. 6 S. p. f-crystals, 2 PL.

The invention relates to new hydrazides IH-indole-3-acetic acid, which can be used for inhibition of sPLA2-mediated release of arachidonic acid for the treatment of conditions such as septic shock.

Prior art

Structure and UB>") are described in detail in two articles, namely, "Cloning and Recombinant Expression of Phospalipase A2Present in Rheumatoid Artritic Synoval Fluid" (Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Peter Vadas; Plant. Shelley; Miller, Judy A.; Kloss, Jean; & Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, ed. 5 APR., page 5335 - 5338, 1989); and "Structure and Properties of Human Nonpancreatic Phospholipase A2" (Kramer, Ruth m.; Hession, Catherine; Johansen, Berit; Gretchen Hayes; McGray, Paula; Chow E. Pingchang; Richard; Penisky, R. Blake; The Journal of Biological Chemistry, vol. 264, No. 10, ed. 5 APR., page 5768 - 5775, 1990); however, disclosure of these works is introduced in the present description by reference.

Obviously, sPLA2represents the degree of limiting enzyme in arachidonic acid metabolism, gidrolizuemye phospholipids of the membrane. Thus, it would be desirable to obtain compounds that inhibit sPLA2- mediated release of fatty acids (e.g. arachidonic acid). Such compounds could be successfully used for the treatment of disorders induced and/or maintained by sverginate sPLA2; for example, such as septic shock; respiratory distress syndrome in adults; injuries; asthma; allergic rhinitis; rheumatoid arthritis, etc.

In U.S. patent 2825734 describes indolyl-3-substituted compounds is s 3-(2-amino-1-peroxyacyl)indoles.

In U.S. patent 3271416 describes indolylmethane acid used as agents that protect against exposure to sunlight, as well as intermediate compounds. These acids can be NH2-substituted (see the definition of M in paragraph 1 of the claims), and a 5 - or 6-position, they must be replaced by nitrogen or sulfur functional groups.

In U.S. patent 2890223 and in the article "The Synthesis of Tryptamines Related to serotonin" (Elliott Shaw, J. Am. Chem. Soc., Vol. 77, 1955, pp. 4319 - 4324) describes some amide derivatives of 3-indeloxazine acids. These connections are used to obtain 5-(lower alkoxy)tryptamines, and it was found that they can be used for impact on serotonin-associated brain function.

The literature also describes some connection type indole, which can be used to treat arthritis. For example, in U.S. patent N 3196162; 3242162; 3242163, 3242193 (see, example 56, column 3, lines 55 to 60) described indolylmethane acids and their salts, esters and amides. These compounds, their structure, close to that of indomethacin compounds; substituted benzyl group at the 1-position; and, in all likelihood, the e indolique. VI sur tryptamines substituces" (Marc Julia, Jean Igolen and Hanne Igolen, Bull. Soc. Chim. France, 1962, pp. 1060 - 1068) describes some of the hydrazides of indole-3-acetic acid, and their transformation into tryptamine derivatives.

It would be desirable to obtain new compounds that could be used for the treatment of sPLA2-induced diseases.

Brief description of the invention

The present invention relates to a new use class of compounds known as hydrazides IH-indole-3-acetic acid, namely, to their use as inhibitors of the release of arachidonic acid-mediated secretory phospholipase A2person (persons sPLA2).

The present invention also relates to a new class of hydrazides IH-indole-3-acetic acid, with a strong and selective activity as inhibitors people. sPLA2.

The present invention also relates to pharmaceutical compositions containing hydrazide IH-indole-3-acetic acid of the present invention.

The present invention also relates to a method of prevention in the treatment of septic shock, involving the use of hydrazides IH-indole-3-acetic acid this izaberete the awn to inhibit sPLA2- mediated release of arachidonic acid, selected from the "IH-indol-3-hydrazines" the General formula (A):

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where Z is an organic divalent radical having the formula:

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and unsubstituted position on indoline core are independently saturated with hydrogen or a non-reactive organic radical.

Some hydrazides IH-indole-3-acetic acid of the present invention represented by formula (A) are preferred, and for determining these compounds are used the following terms. In particular, the term "alkyl" as such or as part of another substituent means, unless otherwise specified particularly, a straight or branched monovalent hydrocarbon radical, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl and n-hexyl. The term "alkenyl", used alone or in combination with other terms, means a straight or branched monovalent hydrocarbon group having the specified number of carbon atoms and includes such groups as vinyl, propenyl, crotonyl, isopentenyl and various isomers butenyl. The term "halogen" means fluorine, chlorine, bromine, or iodine. The term "samesung pyrrole, furan, thiophene, pyridine, piperidine, azepine, indole, quinoline, imidazole, oxazole, thiazole, pyrazin and pyrimidine. The term "carbocyclic ring" means an organic nucleus, where the atoms forming the ring are the only carbon atoms, for example, the kernel, passing from benzene, naphthalene, cyclopentane, cyclohexane or bicycloheptadiene. The term "acidic group" means an organic group, which upon binding with the indole nucleus by means of respective connecting atoms (for example, alkylidene circuit) acts as a proton donor, is able to bind hydrogen. Examples of the "acid groups" are the following placeholders:

5-tetrazolyl

-SO3H,

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where R89is alkyl.

The preferred compounds used in the present invention are hydrazides IH-indole-3-acetic acid, substituted in the 2-position with groups that are not hydrogen, and is represented by the formula (I) and their pharmaceutically acceptable salts:

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where X is oxygen or sulfur;

R1selected from group (I), (II) and (III), where

(I) represents a C4-C20-alkyl, C4-C20alkenyl, C4- the second aryl or aryl, substituted with halogen, -CN, -CHO, -OH, -SH, C1-C10-alkylthio, C1-C10-alkoxy, C1-C10by alkyl, carboxy, amino, or hydroxyamino;

(III) is a

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where "Y" is an integer from 1 to 8, R74independently represents hydrogen or C1-C10-alkyl, R75represents aryl or aryl substituted by halogen, -CN, -CHO, -OH, nitro, phenyl, -SH, C1-C10-alkylthio, C1-C10-alkoxy, C1-C10-alkyl, amino, hydroxyamino, or substituted or unsubstituted heterocyclic ring with 5 to 8 members.

R2represents halogen, C1-C3-alkyl, ethynyl, C1-C2-alkylthio, C1-C2-alkoxy, -CHO, -CN;

each R3independently represents hydrogen, C1-C3-alkyl, or halogen;

R4, R5, R6and R7each independently represents hydrogen, C1-C10-alkyl, C1-C10alkenyl, C1-C10-quinil, C3-C8-cycloalkyl, aryl, aralkyl; or any two adjacent gidrolabilna group in a series of R4, R5, R6and R7taken together with the ring carbon atoms to which they are linked, form a replacement is -C10-alkoxy, C1-C10-halogenoalkane, C4-C8- cycloalkane, phenoxy, halogen, hydroxy, carboxyl, -SN, -CN, -S (C1-C10-alkyl), arieti, thioacetal, -C(O)O(C1-C10-alkyl), hydrazino, hydrazido, -NH2, -NO2, -C(O)NR82R83where R82and R83independently are hydrogen, C1-C10-alkyl, C1-C10-hydroxyalkyl, or taken together with N, R82and R83form a heterocyclic ring with 5 to 8 members; or a group of the formula:

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where each R76independently selected from hydrogen, C1-C10-alkyl, hydroxy, or both R76taken together represent = 0;

p is a number from 1 to 8;

Z represents a bond, -O-, -N(C1-C10-alkyl)-, -NH, or-S-; and

Q represents-CON (R82R83), -5-tetrazolyl, -SO3H,

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where R86independently selected from hydrogen, metal, or C1-C10-alkyl.

Other preferred compounds used in the implementation of the present invention are acetic acid hydrazides, substituted in 1-position with groups that are not benzyl, such as alkyl and the E. salt;

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where X is oxygen or measure;

R11selected from group (I), (II) and (III), where

(I) represents a C4-C20-alkyl, C4-C20alkenyl, C4-C20-quinil, C4-C20-halogenated, C4-C12-cycloalkyl, or

(II) is an aryl or aryl substituted by halogen, -CN, -CHO, -OH, -SH, C1-C10-alkyl, C1-C10-alkylthio, C1-C10-alkoxy, carboxy, amino or hydroxyamino; and

(III) is -(NH) - (R81), where R81is a group defined for (I) or (II);

R12represents hydrogen, halogen, C1-C3-alkyl, ethynyl, C1-C2-alkylthio, C1-C2-alkoxy, -CHO, -CN;

each R13independently represents hydrogen, C1-C3-alkyl, or halogen;

R14, R15, R16and R17each independently represent hydrogen, C1-C10-alkyl, C1-C10alkenyl, C1-C10-quinil, C3-C8-cycloalkyl, aryl, aralkyl; or any two adjacent gidrolabilna group in a series of R14, R15, R16and R17taken together with the ring carbon atoms to which they are linked, form Samusenko the 0-alkoxy, C1-C10-halogenoalkane, C4-C8-cycloalkane, phenoxy, halogen, hydroxy, carboxyl, -SH, -CN, -S(C1-C10-alkyl), arieti, thioacetal, -C(O)O(C1-C10-alkyl), hydrazino, hydrazido-, -NH2, -NO2, -NR82R83and-C(O)NR82R83where R82and R83independently are hydrogen, C1-C10-alkyl, C1-C10-hydroxyalkyl, or R82and R83taken together with N form a heterocyclic ring with 5 to 8 members; or a group of the formula:

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where each R76independently selected from hydrogen, C1-C10-alkyl, hydroxy, or both R76taken together represent = O;

p is a number from 1 to 8;

Z represents a bond, -O-, -N(C1-C10-alkyl), -NH-, or-S-; and

Q represents-CON(R82R83), -5-tetrazolyl, SO3H

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where R86independently represents hydrogen, a metal, or C1-C10-alkyl.

Other preferred compounds used in the present invention are acetic acid hydrazides, substituted 5-or 6-position with groups that are not methoxy, aprilaugust the compounds of formula (III) and their pharmaceutically acceptable salts:

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where X is oxygen or sulfur;

R21selected from group (I), (II) and (III), where

(I) represents a C4-C20-alkyl, C4-C20alkenyl, C4-C20-quinil, C4-C20-halogenated, C4-C12-cycloalkyl, or

(II) is an aryl or aryl substituted by halogen, -CN, -CHO, -OH, -SH, C1-C10-alkylthio, C1-C10-alkoxy, C1-C10by alkyl, carboxy, amino, or hydroxyamino;

(III) is:

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where "Y" is an integer from 1 to 8, R74independently represents hydrogen or C1-C10-alkyl, and R75represents aryl or aryl substituted by halogen, -CN, -CHO, -OH, nitro, phenyl, -SH, C1-C10-alkylthio, C1-C10-alkoxy, C1-C10-alkyl, amino, hydroxyamino, or substituted or unsubstituted heterocyclic ring with 5 to 8 members;

R82represents hydrogen, halogen, C1-C3-alkyl, ethynyl, C1-C2-alkylthio, C1-C2-alkoxy, -CHO, -CN;

each R23independently represents hydrogen, C1-C3-alkyl, or halogen;

R24, R25, R26and R27each independently of t8-cycloalkyl, aryl, aralkyl; or any two adjacent gidrolabilna group in a series of R24, R25, R26and R27taken together with the ring carbon atoms to which they are linked, form a substituted or unsubstituted carbocyclic ring; or C1-C10-halogenated, C2-C10-alkoxy, C1-C10-halogenoalkane, C4-C8-cycloalkane, phenoxy, halogen, hydroxy, carboxyl, -SH, -CN, -S(C1-C10-alkyl), alkylthio, thioacetal, -C(O)O(C1-C10-alkyl), hydrazino, hydrazido, -NH2, -NO2, -NR82R83and-C(O)NR82R83where R82and R83independently represent hydrogen, C1-C10-alkyl, C1-C10-hydroxyalkyl, or R82and R83taken together with N form a heterocyclic ring with 5 to 8 members; or a group of the formula:

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where each R76independently selected from hydrogen, C1-C10-alkyl, hydroxy, or both R76taken together represent = O;

p is a number from 1 to 8;

Z represents a bond, -O-, -N(C1-C10-alkyl)-, -NH, or-S-; and

Q represents-CON(R82R83), -5-tetrazolyl, -SO3H.

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< / BR>P> The most preferred compounds are acetic acid hydrazides of the formula (V) and their pharmaceutically acceptable salts:

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where X is oxygen;

R51is a 6

where R84represents hydrogen or C1-C10-alkyl, and

R87represents aryl or aryl substituted by halogen, -CN, -CHO, -OH, nitro, phenyl, -SH, C1-C10-alkylthio, C1-C10-alkyl, C1-C10-alkoxyl, carboxyla, amino, hydroxyamino, or substituted or unsubstituted heterocyclic ring with 5 to 8 members;

R52represents halogen, methylthio, or C1-C3-alkyl;

each R53represents hydrogen or halogen;

R54, R55, R56and R57each independently represent hydrogen, C1-C10-alkyl, C1-C10alkenyl, C1-C10-quinil, C3-C8-cycloalkyl, aryl, aralkyl; or any two adjacent gidrolabilna group in a series of R54, R55, R56and R57taken together with the ring carbon atoms to which they are linked, form a substituted or unsubstituted carbocyclic ring; or C1-C10-halogenated, C21-C10-alkyl), arieti, thioacetal, -C(O)O(C1-C10-alkyl), hydrazino, hydrazido, -NH2-NO2, -NR82R83and-C(O)NR82R83where R82and R83independently represent hydrogen, C1-C10-alkyl, C1-C10-hydroxyalkyl, or R82and R83taken together with N form a heterocyclic ring with 5 to 8 members,

or a group of the formula:

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where each R76independently selected from hydrogen, C1-C10-alkyl, hydroxy or both R76taken together represent = O;

p is a number from 1 to 8;

Z represents a bond, -O- -N(C1-C10-alkyl)-, -NH-or-S-; and

Q represents-CON(R82R83), -5-tetrazolyl, -SO3H,

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where R86independently represents hydrogen, a metal or a C1-C10-alkyl.

Examples of new compounds that can be used for the purposes of the present invention are the following compounds:

5-cyclopentyloxy-2-ethyl-1-(phenylmethyl)-IH-indole-3-acetic acid hydrazide;

2-ethyl-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid hydrazide;

2-ethyl-5-methyl-1-(phenylmethyl)->/BR>1-[(3-course)methyl] -5-methoxy-2-methyl-IH-indole-3-acetic acid hydrazide;

2-chloro-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid hydrazide;

2-bromo-5-methoxy - 1-(phenylmethyl)-IH-indole-3-acetic acid hydrazide;

5-methoxy-2-(methylthio)-1-(phenylmethyl)-IH-indole-3-acetic acid hydrazide;

5-chloro-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid hydrazide;

5-carboxy-1-[(3-course)-methyl] -2-methyl-IH-indole-3-acetic acid hydrazide,

and mixtures thereof.

In another embodiment, the present invention relates to layers above hydrazides IH-indole-3-acetic acid, having the formula I, II, III, V, or salts of the above compounds. Many of these salts (obtained from the corresponding functional parent compound indolylacetic acid or a complex ester) are mostly water-soluble and physiologically absorbable than the original compounds. Examples of salts included in the scope of the present invention are salts of alkali metals such as sodium, potassium and calcium, and organic amines originating from glucosamine, research, choline or diethylamine.

Methods of synthesis of

Synthesis of hydrazides IH-indole-3-acetic acid, is subramania conducted in accordance with the following reaction schemes:

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In the first scheme, esters IH-indole-3-acetic acid, II, can be easily alkylated using alkylhalides or arylalkylamine in a solvent such as N, N-dimethylformamide (DMF) in the presence of a base (method a), the result can be obtained intermediate esters of 1-alkyl-IH-indole-3-acetic acid, III. Especially preferred bases are t-piperonyl potassium and sodium hydride. Moreover, it is preferable to first perform the reaction of indole II with a base, which forms a salt of the compound (II), and then adding an alkylating agent. The alkylation reaction is preferably carried out at room temperature. As a result of processing of esters of 1-alkyl-IH-indole - 3-acetic acid, III, hydrazine or hydrazinehydrate in ethanol (method b) get (1-alkyl-IH-indole-3-acetic acid, I. Specified condensation with formation of compound I is usually carried out at a temperature distillation of the solvent over a period of time from 1 to 24 hours.

Intermediate esters IH-indole-3-acetic acid II can be synthesized in several ways, for example, as illustrated below.

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IH-indol-3-uksunay to the), such as sulfuric acid, to obtain the compound (II). Substituted phenylhydrazine V can be subjected to reaction with derivatives of levulinate acid, VI, in accordance with well-known synthesis Fisher (method d) (see, R. B. Carlin and E. E. Fisher, J. Am. Chem. Soc., 1948, 70, 3421) c direct receipt of indole II. In this reaction, the solvent used ethanol (at a temperature of distillation), and as the acid catalyst used hydrogen chloride. Indoles, which are unsubstituted in the 3-position, VII, can be first alkylated with obtaining zinc salts of the compounds VII, and then these salts can be treated with alkyl 2-bromooctanoate (method e) to give II (see, Joshihiko Ito, Hideaki Sato, Mashiro Marakami, J. Org. Chem. 1991, 56, 4864-4867). Zinc salts of the compounds VII can be obtained by using the reaction of indoles VII first called. butyllithium using tetrahydrofuran as a solvent, and then with zinc chloride in a simple ether. For this reaction, a solvent is usually replaced by toluene by simple removal of the ether and THF under reduced pressure and addition of toluene.

Many intermediate indoles VII are commercially available compounds. For more substituted derivatives of indolo the id B. Repke, Michel Souchet, Synthesis, 1991, 871-878.

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Derivatives of ortho-nitrotoluene, VIII, is subjected to catalytic recovery, using as a catalyst, palladium carbon, and get ortho-methylaniline, IX, which is treated with di-tert.BUTYLCARBAMATE in THF at a temperature distillation (method g), resulting in a gain of N-tert. butoxycarbonylamino, X. Dianion compound X obtained in THF by treatment with two equivalents of Deut.utility, is subjected to reaction with one equivalent of amide N-methoxy-N-methylalkanes acid, resulting in a gain (method h) arylketones, XI. By processing triperoxonane acid (method i), these ketones are subjected to cyclization and unlocking the nitrogen atom, and receive indoles, VII.

The indoles of type VII, which are substituted in the 5-positions of the nitrogroup, receive (see Wayland E. Noland, Lowell R, Smith u Donald C. Johnson, J. Med. Chem. , 1963, 28, 2262-2266) by adding sodium nitrate to the corresponding indole, pre-dissolved in sulfuric acid (method j).

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Derivatives, where R4represents 1-(hydroxyphenyl)-methyl-, is obtained by hydrogenolysis of the corresponding 1-(benzyloxyphenyl)methyl derivatives (method k). Proizvedenii (method l).

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For the synthesis of compounds where R1as the Deputy is hydroxy, methoxy-substituted indole-3-acetic acid, XII (obtained by hydrolysis of compound III), is subjected to demethylation using reaction with BBr3(method m), resulting in a receive connection XIII, which (see Tsung-Jing & Charles A. Winter, Adv. Drug. Res., 1977, 12, 176) is subjected to esterification method c, and get a connection XIV. Hydroxy-derivative XIV can be alkylated by treatment with arylalkylamines in the presence of potassium carbonate (method n) to obtain the intermediate ester III, where R1is animetake.

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Methoxy-substituted hydrazides 1H-indole-3-acetic acid can be subjected to demethylation with direct obtaining a hydroxy-substituted hydrazines acetic acid (in the terms of use BBr3method o). These compounds can be subjected to alkylation with the help of ester bromoalkanes acid (method w) and using sodium hydrate as a base and DMCO as a solvent, which may be obtained hydrazide acid ester. This hydrazide acid ester hydrolyzing method M and get the carboxylic hydrazide(see N. Miyura, J. Eshiyama, H. Sasaki, M. Ishikawa, M. Satoh u A. Suzuki, J. A. Chem. Soc., 1989, III, 3124) intermediate compounds, where R1is Br (method p). This familyromagna can be carried out on the basis of the corresponding complex bromo-ether or bromo-hydrazide.

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Intermediate esters IH-indole-3-acetic acid, III, where R3is chlorine, obtained by reaction of ester IH-indole-3-acetic acid, III, where R3is hydrogen, N-chlorosuccinimide (method q).

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Similarly, in the treatment with N-bromosuccinimide (method r) or methanesulfonanilide (method s) received 2-bromo - and 2-petitioner, respectively. 2-Methylthio-indole may be subjected to oxidation using m-chloroperbenzoic acid and obtaining 2-methylsulfonylbenzoyl (method t).

Intermediate connection, namely, ester IH-indole-3-acetic acid, III, where R1is a carboxy group, obtained by selective esterification derived dicarboxylic acid (synthesized via hydrolysis of ester of the dibasic acid method u), resulting in a derived complex monoether IH-indole-3-acetic acid.

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However, every expert obviously, these examples should not be construed as a limitation of the scope of the present invention.

Examples

Example 1

Getting hydrazide 5-ethoxy-2-methyl-1-(phenylmethyl)-IH - indole-3-acetic acid

A. 4-Ethoxy-2-1-nitrobenzene

A solution of 15.3 g (0.1 M) of 3-methyl-4-NITROPHENOL, and 23.4 g (0.15 M) iodomethane and 27.6 g (0.2 M) K2CO3in 250 ml of methyl ethyl ketone was heated under reflux for 16 hours. After cooling, the reaction mixture was poured into water and was extracted with ethyl acetate. After this EtOAc solution was washed with water, 1 N. NaOH solution, then with water and dried with sodium sulfate. After removal of dissolved under reduced pressure, was received with 16.8 g (yield 93%) of 4-ethoxy-2-methyl-1-nitrobenzene (so pl. 41 - 43oC).

Elemental analysis for C9H11NO3:

Calculated: C 59,66, 6,12 H, N 7,73,

Found: C 59,58, H 6,28, N 7,79.

B. 4-Ethoxy-2-methylalanine

4 Ethoxy-2-methyl-1-nitrobenzene (16.5 g 0,091 M) was hydrogenosomal for 4 hours under hydrogen pressure of 60 lb/sq (4218 g/cm2) in 135 ml of ethanol, using as catalyst 1.6 g of Pd/C Catalyst was filtered, and the obtained product was subjected to distillation at 54 - 55oC/0.08 mm RT. Art., resulting in perfectly is: C 71,49, H 8,67, N 9,26,

Found: C 72,07, H 8,95, N 10,42.

C. N-tert-butoxycarbonyl-4-ethoxy-2-methylaniline

A solution of 4-ethoxy-2-methylaniline (10.5 g, 0,0695 M) and 15.5 g (0,071 M) di-tert. BUTYLCARBAMATE in 200 ml of tetrahydrofuran slowly to a temperature of distillation and the mixture is maintained at this temperature for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc. The EtOAc solution washed with 1 N. citric acid solution, dried with sodium sulfate and concentrated under reduced pressure. As a result of crystallization of the resulting residue from hexane, got 10,26 g (yield 59%) of N-tert.butoxycarbonyl-4-ethoxy-2-methylaniline (so pl. 55-56oC).

Elemental analysis for C14H21NO3:

Calculated: C 66,91, H 8,42, N 5,57

Found: C 66,69, H 8,23, N 5,52

D. 5-Ethoxy-2-methyl-1H-indol

A solution of 1.3 M sec.utility/cyclohexane (105,7 ml, 0,137 M) was slowly added to 17.25 g (0,0687 M) N-tert.-butoxycarbonyl-4 - ethoxy-2-methylaniline in 250 ml of THF, maintaining the temperature below -40oC in a bath of dry ice/ethanol. At 0.25 hours drop was added 7,21 g (0,07 M) N-methoxy - N-methylacetamide in an equal volume of THF. After the reaction mixture was stirred for 1 hour, Oh ml of 1 N. HCl solution. then the organic layer was separated, washed with water and dried with sodium sulfate. After solvent removal, was received with 17.7 g of the crude 1-(2-tert. butoxycarbonylamino-5-ethoxyphenyl)-2-propanol. This resulting material and 25 g triperoxonane acid in 400 ml of CH2Cl2was stirred at room temperature for 16 hours. The resulting mixture was twice washed with water, saturated solution of sodium sulfate and drained Na2CO3. After removal of solvent, the product was chromatographically on silicon dioxide, elwira toluene, resulting in received of 4.95 g (yield 41%) 5-ethoxy-2-methyl-1H-indole (so pl. 76-77oC).

Elemental analysis for C11H13NO:

Calculated: C 75,40, H of 7.48, N 7,99

Found: C 77,07, H 7,83, N 8,09.

E. Methyl ester 5-ethoxy-2-methyl-1H-indole-3-acetic acid

To the cooled solution is 4.85 g (0,0277 M) 5-ethoxy-2-methyl-1H - indole in 40 ml of THF was added to 17.3 ml (0,0277 M), a 1.6 M solution of n-utility in hexane, maintaining the temperature below -10oC in a bath of ice/ethanol. At 0.25 hours, to the mixture was added to 27.7 ml (0,0277 M) 1M solution of ZnCl2in the ether. Then the cooling bath was removed, and the mixture was stirred for 2 hours and concentrated pratem to this solution was added 2,62 ml (0,0277 M) of methyl 2-bromoacetate, the mixture was stirred for 24 hours and poured into 100 ml of 1 n HCl and 100 ml EtOAc. The organic layer was washed twice with water, dried with sodium sulfate and concentrated under reduced pressure. The obtained residue was chromatographically on silicon dioxide and suirable 5% EtOAc/toluene, resulting in a received 5.0 g (73%) 5-ethoxy-2-methyl-IH-indole-3-acetic acid methyl ether complex in the form of an oily substance.

Elemental analysis for C14H17NO3:

Calculated: C 68,00, H 6,93, N 5,66

Found: C 68,04, H 7,07, N 5,77.

F. 5-Ethoxy-2-methyl-1-(Phenylmethyl)-IH-indole-3-acetic acid methyl ester

A suspension of 80 mg (2 mm) of 60% NaH/mineral oil was washed with hexane and placed in a solution of 8 ml of DMF. After cooling in an ice bath, was added 494 mg (2 mm) 5-ethoxy-2-methyl-IH-indole-3-acetic acid methyl ether complex and the resulting mixture was stirred 1 hour and then added to 0.24 ml benzylbromide and the mixture was stirred for 1.5 hours. After that, the mixture was diluted with water, was extracted with EtOAc, then EtOAc solution was washed with water/NaCl and was dried with magnesium sulfate. The resulting solution was concentrated under reduced pressure and the product was chromatographically on silicon dioxide, elsey acid methyl ether complex, which was utverjdali when defending (dot square 82 - 85oC).

Elemental analysis for C21H23NO3:

Calculated: C 74,75, H 6,87, N 4,15

Found: C 75,60, H? 7.04 Baby Mortality, N Is 4.03.

G. Hydrazide 5-ethoxy-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

A solution of 323 mg (0,95 mm) 5-ethoxy-2-methyl-1-(phenylmethyl)-IH - indole-3-acetic acid methyl of ester and 1.5 ml of 98% hydrazine in 5 ml of ethanol was heated under reflux for 16 hours. The mixture was cooled, diluted with water and was extracted with EtOAc. The EtOAc solution was washed with a mixture of water and NaCl, dried with magnesium sulfate and concentrated under reduced pressure. The obtained residue was led from MeOH, resulting in received 77 mg (yield 23%) of the hydrazide 5-ethoxy-2-methyl-1-(phenylmethyl)- IH-indole-3-acetic acid (so pl. 145 - 148oC).

Elemental analysis for C20H23N3O2:

Calculated: C 71,19, H 6,87, N 12,45

Found: C 71,49, H 6,94, N 12,38.

Example 2

Getting hydrazide 5-cyclopentyloxy-2-ethyl-1-(phenylmethyl)-IH - indole-3-acetic acid

A. 4-cyclopentyloxy-2-methyl-1-nitrobenzene

Using the procedure described in example 1 (part a). 15.3 g (0.1 M) of 3-methyl-4-NITROPHENOL was subjected to reaction from 16.1 ml (0.15 M) b-1-nitrobenzene in the form of an oily substance.

B. 4-cyclopentyloxy-2-methylaniline

4 cyclopentane-2-methyl-1-nitrobenzene (17.5 g, 0,0792 M) was hydrogenosomal in accordance with the procedure described in example 1 (part B), and obtained 10.3 g (yield 68%) of 4-cyclopentyloxy-2-methylaniline (so Kip. 100 - 100oC/0.07 mm RT.cent.).

Elemental analysis for C12H17NO:

Calculated: C 75,35, H 8,96, N 7,32

Found: C 75,50, H, 9,10, N EUR 7.57

G. of N-tert-butoxycarbonyl-4-cyclopentene-2-methylaniline

In accordance with the procedure described in example 1 (part C), 10.3 g (0.54 M) 4 cyclopentane-2-methylaniline was subjected to reaction from 12.24 g (0,056 M) di-tert. BUTYLCARBAMATE, resulting, after crystallization from toluene/hexane, obtained 6.3 g (yield 40%) of N-tert.butoxycarbonyl-4-cyclopentene-2-methylaniline (so pl. 75 - 77oC).

Elemental analysis for C17H25NO3:

Calculated: C 70,07, H 8,65, N 4,81

Found: C 69,79, H 8,67, N 4,60.

D. 1-[2-(tert.butoxycarbonylamino)-5-cyclopentadienyl]-2 - butanone

A solution of 1.3 M sec.utility/cyclohexane (33.3 ml, 0,0433 M) was slowly added to 6.3 g (0,0216 M) N-tert.butoxycarbonyl-4-cyclopentene-2-methylaniline in 80 ml of THF, maintaining the temperature below -40oC in a bath of dry ice/acetone. Bath was removed, the temperature increases is 7 g (0,022 M) N-methoxy-N-methylpropanamide in an equal volume of THF. The resulting reaction mixture was stirred for 1 hour, the cooling bath was removed, and then the stirring was continued for 1 hour. The resulting solution was poured into a mixture of 200 ml of ether and 200 ml of 1 n HCl solution. The organic layer was separated, washed with water and dried with sodium sulfate. After removal of solvent, the residue was led from the hexane and received 3.58 g (yield 48%) of 1-(2-(tert. butoxycarbonylamino)-5-cyclopentadienyl)-2-butanone (so pl. 71 - 73oC).

Elemental analysis for C20H29NO4:

Calculated: C 69,14, H to 8.41, N 4,03

Found: C 69,17, H 8,42, N 4,14.

E. 5-cyclopentyloxy-2-ethyl-IH-indole

1-[2-(tert. butoxycarbonylamino)-5-cyclopentadienyl]-2 - butanone (6,45 g, 0,0186 M) in 120 ml of methylene chloride and 20 ml triperoxonane acid was stirred for 20 hours, washed with water, a solution of NaHCO3and the product was chromatographically on silica (eluent: 4% EtOAc/toluene), which was obtained 2.35 g (yield 50%) 5-cyclopentyloxy-2-ethyl-IH-indole in the form of an oily substance.

Elemental analysis for C15H19NO:

Calculated: C 78,56, H 8,35, N 6,11

Found: C 78,84, H To 8.41, N Is 6.19.

F. 5-cyclopentyloxy-2-ethyl-IH-indole-3-acetic acid methyl clonil-IH-indole was treated with 6.4 milliliters (0,0102 M) 1.6 M solution of N-utility in hexane, 10,2 milliliters (0,0102 M) 1M solution of ZnCl2in the air, and 0.97 milliliters (0,0102 M) of methyl 2-bromoacetate, resulting, after chromatography on silica (eluent: 5% EtOAc/toluene) were obtained 1.8 g (59%) 5-cyclopentyloxy-2-methyl-IH-indole-3-acetic acid methyl ether complex in the form of an oily substance.

Elemental analysis for C18H23NO3:

Calculated: C 71,74, H of 7.69, N 4,65

Found: C 71,64, H 7,89, N 4,70.

G. 5-cyclopentyloxy-2-ethyl-(phenylmethyl)-IH-indole-3-acetic acid methyl ester

In accordance with the procedure described in example 1 (part F), 602 g (2 mm) 5-cyclopentyloxy-2-ethyl-IH-indole-3-acetic acid methyl ether complex was turned into a 427 mg (yield 55%, an oily substance) 5-cyclopentyloxy-2-ethyl-1-(phenylmethyl)- 1H-indole-3-acetic acid methyl ether complex, purified by chromatography on silica (eluent: a mixture of 33% EtOAc/hexane).

Elemental analysis for C25H29NO3:

Calculated: C 76,78, H 7,47, N TO 3.58

Found: C 76,68, H A 7.62, N 3,62.

H. Hydrazide 5-cyclopentyloxy-2-ethyl-1-(phenylmethyl)-IH-indole-3 - acetic acid

In accordance with the procedure described in example 1 (part G), 417 mg (1,07 mm) 5-cyclopentyloxy-2-ethyl-1-(f the Tata which received 163 mg (yield 39%) 5-cyclopentyloxy-2-ethyl-1-(phenylmethyl)-IH-indole-3-acetic acid hydrazide (after crystallization from MeOH, so pl. 117 - 118oC).

Elemental analysis for C24H29N3O2:

Calculated: C 73,62, H 7,47, N OF 10.73

Found: C 73,52, H To 7.61, N 10,55.

Example 3

Getting hydrazide 2-ethyl-5-methoxy-1-(phenylmethyl)-IH-indole - 3-acetic acid

A. N-tert-butoxycarbonyl-4-methoxy-2-methylaniline

In accordance with the procedure described in example 1 (part C) of 13.7 g (0.1 M) 4-methoxy-2-methylaniline was subjected to reaction with 25 g (0,1145 M) di-tert. BUTYLCARBAMATE, after crystallization from hexane got to 17.25 g (yield (73%) of N-tert-butoxycarbonyl-4-methoxy-2-methylaniline (so pl. 80 - 82oC).

Elemental analysis for C13H19NO3:

Calculated: C 65,80, H 8,07, N 5,90

Found: C 65,86, H 8,15, N 5,61.

B. 1-[2-(tert.butoxycarbonylamino)-5-methoxyphenyl]- 2-butanone

In accordance with the procedure described in example 2 (part I), 11.85 g (0.05 M) of N-tert. butoxycarbonyl-4-methoxy-2-methylaniline was treated with 1.3 moles of a mixture of W. utility/cyclohexane (81 ml, 0,105 M) and 6.1 grams (0,052 M) N-methoxy-N-methylpropanamide, resulting in received of 10.9 g (yield 74%) of 1-[2-(tert. butoxycarbonylamino)-5-methoxyphenyl] -2-butanone (after chromatography on silica using as eluent the R> Calculated: C 65,51, H of 7.90, N 4,77

Found: C 65,69, H 7,89, N 4,90

C. 2-Ethyl-5-methoxy-IH-indole

In accordance with the procedure described in example 2 (part E), 1-[2-(tert. butoxycarbonyl)-5-methoxyphenyl] -2-butanone (7,33 g, 0.025 M) was treated with 20 milliliters triperoxonane acid and the product was chromatographically on silicon dioxide, elwira a mixture of 20% EtOAc/hexane, resulting in received of 2.54 g (yield (58%) of 2-ethyl-5-methoxy-1H-indole as a white solid (so pl. 49 - 50oC).

Elemental analysis for C11H13NO:

Calculated: C 75,40, H of 7.48, N 7,99

Found: C 75,64, H to 7.61, N 8,04

D. 2-ethyl-5-methoxy-1H-indole-3-acetic acid methyl ester

In accordance with the procedure described in example 1 (part E), 3.5 g (0.02 M) of 5-methoxy-2-ethyl-IH-indole was treated with 12.5 milliliters (0.02 M) Of 1.6 M solution of n-utility in hexane, 20 ml (0.02 M) 1M solution of ZnCl2in the air and 1,89 milliliters (0.02 M) of methyl 2-bromoacetate, resulting, after chromatography on silica (toluene _ 10% EtOAc/toluene) were of 3.32 g (59%) 2-ethyl-5-methoxy-1H-indole-3-acetic acid methyl ether complex in the form of oily substance

Elemental analysis for C14H17NO3:

Calculated: C 67,99, H 6,9 iny ether

The solution 2,47 g (0.01 M) 2-ethyl-5-methoxy-1H-indole-3-acetic acid methyl complex ester in 25 ml of DMF was treated to 1.12 grams (0.01 M) t-butoxide potassium was stirred for 0.5 hour and then was added to 1.15 ml (0.01 M) benzylchloride. After 72 hours, the reaction mixture was diluted with water, was extracted with EtOAc and the EtOAc solution was washed 4 times with water and then dried with sodium sulfate. After concentration under reduced pressure, the obtained product was purified by chromatography on silica, elwira gradient mixture of toluene and 10% EtOAc/toluene, resulting in a received 1.5 g (yield 44%) of 2-ethyl-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid methyl ether complex in the form of an oily substance.

Elemental analysis for C21H23NO3:

Calculated: C 74,75, H 6,87, N 4,15

Found: C 75,00, H 6,99, N 4,28

F. Hydrazide 2-ethyl-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 748 mg (2.2 mm) of 2-ethyl-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid methyl ether complex was subjected to reaction with 2.2 ml of hydrazine, resulting received 552 mg ( yield 74%) of hydrazide 2-ethyl-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid (so-PZ for C20H23N3O2:

Calculated: C 71,19, H 6,87, N 12,45

Found: C 71,13, H 6,86, N Of 12.33.

Example 4

Getting hydrazide 1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-5-methoxy-IH-indole-3-acetic acid

A. 1-([1,1'-Biphenyl] -2-ylmethyl)-2-ethyl-5-methoxy-IH-indole - 3-acetic acid methyl ester

In accordance with the procedure described in example 1 (part F), 483 mg (2 mm) 2-ethyl-5-methoxy-IH-indole-3-acetic acid methyl ester was treated with 48 milligrams (2 mm) of 60% NaH/mineral oil and 0.37 milliliters (2 mm) of 2-(bromomethyl)-biphenyl, resulting, after chromatography on silica (eluent: 20% EtOAc/hexane), was obtained 362 mg(44%) 1-/[1,1'-the biphenyl] -2-ylmethyl)-2-ethyl-5-methoxy - IH-indole-3-acetic acid methyl ether complex in the form of an oily substance.

Elemental analysis for C22H27NO3:

Calculated: C 78,42, H to 6.58, N 3,39

Found: C 78,70, H 6,59, N 3,43.

B. Hydrazide 1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-5-methoxy-IH - indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 859 mg (2,15 mg (2,15 mm) 1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl - 5-methoxy-IH-indole-3-acetic acid methyl ether complex was subjected to reaction with 2.5 ml of hydrazine, as a result, acetic acid (so pl. 123-125oC).

Elemental analysis for C26H27N3O2:

Calculated: C 75,52, H to 6.58, N 10,16

Found: C 75,29, H Of 6.65, N 9,95.

Example 5

Getting hydrazide 5-methoxy-1-(phenylmethyl)-2-propyl-IH-3 - acetic acid

A. 1-[2-(tert-butoxycarbonylamino)-5-methoxyphenyl]-2-pentanon

In accordance with the procedure described in example 2 (part D), 15,17 g (0,964 M) N-tert-butoxycarbonyl-4-methoxy-2-methylaniline was treated with a solution of 1.3 M sec-utility/cyclohexane (100 ml of 0.13 M) and 8.4 grams (0,064 M) N-methoxy-N-methylethanamine, resulting, after chromatography on silica (eluent: 5% EtOAc/toluene) were 14,31 g (yield 73)% 1-(tert-butoxycarbonylamino-5-methoxyphenyl)-2-pentanone (so pl. 77-78oC).

Elemental analysis for C17H25NO4:

Calculated: C 66,43, H 8,20, N 4,56

Found: C 66,42, H 8,09, N 4,71

B. 5-methoxy-2-propyl-IH-indole

In accordance with the procedure described in example 2 (part E), 1-[2-(tert-butoxycarbonylamino)-5-methoxyphenyl] -2-pentanon (14,27 g, 0,0465 M) was treated with 20 milliliters triperoxonane acid and the product was led from the hexane, which was obtained 5.5 g (yield 58%) of 5-methoxy-2-propyl-IH-indole in the form of a white firmly the N 7,40

Found: C 76,36, H 8,07, N 7,52.

C. 5-Methoxy-2-propyl-IH-indole-3-acetic acid methyl ester

In accordance with the procedure described in example 1 (part E), the 5.125 g (0,0271 M) 5-methoxy-2-propyl-IH-indole was treated 16,9 milliliters (0,0271 M) 1.6 M solution of n-utility in hexane, 27,1 milliliters (0,0271 M) 1M solution of zinc chloride in ether and 2.7 milliliters (0,0271 M) of methyl 2-bromoacetate, after chromatography on silica (eluent: 20% EtOAc/hexane), was obtained with 4.65 g (66%) 5-methoxy-2-propyl-IH-indole-3-acetic acid methyl ether complex in the form of an oily substance.

Elemental analysis for C15H19NO3:

Calculated: C 68,94, H 7,33, N ARE 5.36

Found: C 68,69, H Of 7.36, N 5,63.

D. 5-Methoxy-1-(phenylmethyl)-2-propyl-IH-indole-3-acetic acid methyl ester

In accordance with the procedure described in example 1 (part F), 522 mg (2 mm) 5-methoxy-2-propyl-1-indole-3-acetic acid methyl ether complex was subjected to reaction with 48 mg (2 mm) of a mixture of 60% NaH mineral oil and 0.24 ml (2 mm) benzylbromide, resulting, after chromatography on silica (eluent; 25% EtOAc/hexane), was obtained 501 mg (71%) of 5-methoxy-12(phenylmethyl)-2-propyl-IH-indole - 3-acetic acid methyl 3-acetic acid

In accordance with the procedure described in example 1 (part G), 480 mg (1,37 mm) 5-methoxy-1-(phenylmethyl)-2-propyl-IH-indole-3-acetic acid methyl ether complex was subjected to reaction with 1.4 ml of hydrazine, resulting, after crystallization from MeOH received 56 mg (yield 74%) of 5-methoxy-1-(phenylmethyl)-2-propyl-IH-indole-3-acetic acid hydrazide (so pl. 140-141oC).

Elemental analysis for C21H25N3O2:

calculated: C 71,77, H 7,17, N 11,96

found: C 71,98, H 7,12, N 11,98.

Example 6

Getting hydrazide 2-ethyl-5-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

A. N-tert-butoxycarbonyl-2,4-dimethylaniline

In accordance with the procedure described in example 1 (part C), 27.4 g (0.2 M) of 2,4-dimethylaniline was subjected to reaction with 50 g (0,229 M) di-tert-BUTYLCARBAMATE, resulting, after crystallization from hexane, got 18,42 g (yield 76%) of N-tert-butoxycarbonyl-2,4-dimethylaniline (so pl. 90-91oC).

Elemental analysis for C13H19NO2:

Calculated: 70,56, H 8,65, N 6,33

Found: C 67,18, H 8,90, N 5,39

B. 2-Ethyl-5-methyl-IH-indole

In accordance with the procedure described in example 1 (part D) 11,05 (0.05 M) of N-tert-butoxycarbonyl-2,4-dimethylaniline was subjected to reaction with 81 ml of 1 is oxycarbonyl)-5-were]-2-pentanon. This resulting material was treated triperoxonane acid and was led from EtOAc/hexane resulting in a received 1,82 g (yield 13%) of 2-ethyl-5-methyl-IH-indole (so pl. 77-78oC).

Elemental analysis for C11H13N:

Calculated: C 82,97, H 8,23, N 8,80

Found: C 83,19, H 8,35, N 8,89

C. 2-Ethyl-5-methyl-IH-indole-3-acetic acid methyl ester

In accordance with the procedure described in example 1 (part E), 3,18 g (0.02 M) 2-ethyl-5-methyl-IH-indole was treated with 12.5 milliliters (0.02 M) Of 1.6 M solution of n-utility in hexane, 20 ml (0.02 M) 1M solution of zinc chloride in ether and 1,89 milliliters (0.02 M) of methyl 2-bromoacetate, resulting, after chromatography on silica (toluene _ 20% EtOAc/hexane) received 3,23 g (yield 70%) 2-ethyl-5-methyl-IH-indole-3-acetic acid methyl ester as an oily substance.

Elemental analysis for C14H17NO2:

Calculated: C 72,70, H 7,41 N 6,06

Found: C 70,76, H 7,29, N 5,85.

D. 2-ethyl-5-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid methyl ester

In accordance with the procedure described in example 1 (part E), 1.73 g (0,0075 M) 2-ethyl-5-methyl-IH-indole-3-acetic acid methyl ether complex was subjected to reaction with 0.84 g (0,00 who (eluent: 2% EtOAc/toluene), received 1,74 g (71%) of 2-ethyl-5-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid methyl ester as an oily substance.

Elemental analysis for C12H23NO2:

Calculated: C of 78.47, H 7,21, N 4,36

Found: C 78,68, H 7,30, N 4,42

E. Hydrazide 2-ethyl-5-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G) 1.4 g (0,0044 M) 2-ethyl-5-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid methyl ether complex was subjected to reaction with 2 ml of hydrazine, resulting, after crystallization from MeOH, received of 0.77 g (yield 55%) of hydrazide 2-ethyl-5-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid (so pl. 115-125oC).

Elemental analysis for C20H23N3O:

Calculated: C 74,74, H 7,21, N 13,07

Found: C 74,73, H 7.23 Percent, N 13,00.

Example 7

Getting hydrazide 2-ethyl-5-fluorescent-1-(phenylmethyl)-IH-indole - 3-acetic acid

A. N-tert-butoxycarbonyl-4-fluorescent-2-methylaniline

In accordance with the procedure described in example 1 (part C), 44 g (0,352 M) 4-fluorescent-2-methylaniline was subjected to reaction with 80 - 75 g (0,37 M) di-tert-BUTYLCARBAMATE, resulting, after crystallization from hexane, got 60.1 g (yield 76%) of N-tert-butoxycarbonyl-4-fluorescent is prohibited: C 63,98, H 7,16, N 6,22

Found: C 63,84, H 7,32, N 6,26.

B. 1-[2-(tert.Butoxycarbonylamino)-5-forefeel]-2-pentanon

In accordance with the procedure described in example 2 (part D), 14.4 g (0,064 M) N-tert-butoxycarbonyl-4-fluorescent-2-methylaniline was subjected to reaction with 100 ml of 1.3 M sec.-utility and 7.5 g (0,064 M) N-methoxy-N-methylpropanamide, resulting, after crystallization from hexane, obtained 11.2 g (yield(62%) 1-[2-(tert.-butoxycarbonylamino)-5-forefeel]-2-pentanone (so pl. 110 - 112oC).

Elemental analysis for C15H20FNO3:

Calculated: C 64,04, H 7,17, N TO 4.98

Found: C 63,02, H 7,29, N 4,93

C. 2-Ethyl-5-fluorescent-IH-indole

In accordance with the procedure described in example 2 (part E), 1-[2-tert. -butoxycarbonylamino)-5-forefeel] -2-pentanon (19,0 g, 0,0676 M) was treated with 25 milliliters triperoxonane acid and the product was chromatographically on silica (eluent : toluene), resulting in a received 8,89 g (yield 81%) of 2-ethyl-5-fluorescent-IH-indole as a white solid (so pl. 41 - 42oC).

Elemental analysis for C10H10FN:

Calculated: C 73,60, H 6,18, N 8,58,

Found: C 73,37, H 6,39, N 8,31.

D. 2-Ethyl-5-fluorescent-IH-indole-3-acetic acid methyl ester

In accordance with the laws of the Sabbath. 055 M) 1.6 M solution of n-utility in hexane 55 milliliters (0,055 M) 1 M solution of zinc chloride in ether, and to 5.21 milliliters (0,055 M) of methyl 2-bromoacetate, resulting after chromatography on silicon dioxide (eluent: 5% EtOAc/toluene) were of 6.9 g (54%) of 2-ethyl-5-fluorescent-IH-indole-3-acetic acid methyl ether complex in the form of an oily substance.

Elemental analysis for C13H14FNO2:

Calculated: C 66,37, H 6,00, N 5,95

Found: C 66,47, H X 6.15, N 5,97.

E. 2-Ethyl-5-fluorescent-1-(phenylmethyl)-IH-indole-3-acetic acid methyl ester

In accordance with the procedure described in example 3 (part E), 3,17 g (0,0135 M) 2-ethyl-5-fluorescent-IH-indole-3-acetic acid methyl ether complex was subjected to reaction with 1.5 grams (0,0135 M) so-butoxide potassium and 1.55 milliliters (0,0135 M) benzylbromide, resulting, after chromatography on silica (eluent: 5% EtOAc/toluene) were 3,76 g (71%) of 2-ethyl-5-fluorescent-1-(phenylmethyl)-IH-indole-3-acetic acid methyl ether complex in the form of an oily substance.

Elemental analysis for C20H20FNO2:

Calculated: C 73,83, H 6,20, N 4,30

Found: C 74,41, H 6,35, N 4,19

F. Hydrazide 2-ethyl-5-fluorescent-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 3.7 g (0,0114 M) 2-ethyl-5-fluorescent-1-(phenylmethyl)-IH-indol-3-is lisali from a mixture of MeOH and water, received 1.63 g (yield 44%) of hydrazide 2-ethyl-5-fluorescent-1-(phenylmethyl)-IH-indole-3-acetic acid (so pl. 127 - 128oC).

Elemental analysis for C19H20FNO3:

Calculated: C 70,13, H is 6.19, N 12,91

Found: C 70,26,, H 6,17, N 12,71.

Example 8

Obtaining 6-Chloro-2-methyl-1-(phenylmethyl)-IH-indole - 3-acetic acid

A. N-tert-Butoxycarbonyl-4-chloro-2-methylaniline

In accordance with the procedure described in example 1 (part C), and 28.3 g (0.2 M) 5-chloro-2-methylaniline was subjected to reaction from 48.1 g (0.22 M) of di-tert-BUTYLCARBAMATE, resulting, after crystallization from hexane, got 37,1 g (yield 77%) of N-tert-butoxycarbonyl-5-chloro-2-methylaniline (so pl. 100 - 102oC).

Elemental analysis for C12H16FNO2:

Calculated: C 59,63, H 6,67, N 5,79,

Found: C 59,75, H 6,83, N 5,74.

B. 1-[2-(tert.-Butoxycarbonylamino)-4-course]-2-butanone

In accordance with the procedure described in example 2 (part D), 7,73 g (0,032 M) N-tert-butoxycarbonyl-4-chloro-2-methylaniline was subjected to reaction with 50 ml (0,065 M) 1.3 M sec.-utility and 3.3 g (0,032 M) N-methoxy-N-methylacetamide, resulting, after crystallization from hexane, got 3,49 g (yield 38%) of 1-[2-(tert.-butoxycarbonylamino)-4-course]-2-butanone (so PL
Found: C 59,14, H 6,30, N 5,16.

C. 6-Chloro-2-methyl-IH-indole

In accordance with the procedure described in example 2 (part E), 1-[2-(tert. -butoxycarbonylamino)-4-course] -2-butanone (3,49 g, 0,123 M) was treated with 10 milliliters triperoxonane acid and the product was chromatographically on silica (eluent: gradient of a mixture of toluene and 5% EiOAc/toluene), which was obtained 1,2 (yield 59%) of 6-chloro-2-methyl-IH-indole as a white solid (so pl. 120 - 122oC).

Elemental analysis for C9H8ClN:

Calculated: C 65,23, H 4,87, N 8,46.

Found: C 65,09, H 5,07, N 8,24.

D. 6-Chloro-2-methyl-IH-indole-3-acetic acid methyl ester

In accordance with the procedure described in example 1 (part E), 2.2 g (0,0133 M) 6-chloro-2-methyl-IH-indole was treated to 8.3 milliliters (0,0133 M) 1.6 M solution of n-utility in hexane, 14 ml (0,014 M) 1 M solution of zinc chloride in ether and 1.26 milliliters (0,0133 M) of methyl 2-bromoacetate, which was obtained 2.1 g (66%) 6-chloro-2-methyl-IH-indole-3-acetic acid methyl ether complex in the form of oily substance (after chromatography on silica, elwira gradient mixture of toluene and 10% EiOAc/toluene).

Elemental analysis for C12
In accordance with the procedure described in example 3 (part E), 1.0 g (0,00421 M) 6-chloro-2-methyl-IH-indole-3 - acetic acid methyl ether complex was subjected to reaction with 0,472 grams (0,00421 M) so-butoxide potassium and 0,48 milliliters (0,00421 M) benzylchloride, resulting, after chromatography on silica (eluent: toluene ---> 10% EiOAc/toluene) received 0.97 g (yield 70%) 6-chloro-2-methyl-1- (phenylmethyl)-IH-indole-3-acetic acid methyl ether complex (so pl. 92 - 93oC).

Elemental analysis for C19H18ClNO2:

Calculated: C 69,62, H 5,54, N 4,27

Found: C 69,84, H 5,49, N 4,55.

F. Hydrazide 6-chloro-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 0.97 g (2,96 mm) 6-chloro-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid methyl ether complex was subjected to reaction with 3 ml of hydrazine, resulting, after crystallization from MeOH, received 0.4 g (yield 41%) of 6-chloro-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid hydrazide (so pl. 179 - 181oC).

Elemental analysis for C18H18ClNO3:

Calculated: C 65,95, H 5,54, N 12,82

Found: C 65,54, H 5,47, N 12,21.

Example 9

Getting hydrazide 5-benzyloxy-1-(Fe) - Rev. In accordance with the procedure described in example 1 (part E), 80 g (0,358 M) 5-benzyloxy-IH-indole was treated with 222 ml of 1.6 M solution of n-utility in hexane, 360 ml of 1 M solution of zinc chloride in ether and 39,92 milliliters of ethyl 2-bromoacetate, resulting, after chromatography on silica (elwira gradient of toluene and 5% EiOAc/toluene), received 30 g (yield 27%) 5-benzyloxy-IH-indole-3-acetic acid ethyl ether complex (so pl. 57 - 59oC).

Elemental analysis for C19H19NO3:

Calculated: C 73,77, H is 6.19, N 5,43,

Found: C 73,75, H 6,34, N 4,50

B. 5-Benzyloxy-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 3 (part E), 6,18 g (0.02 M) of 5-benzyloxy - IH-indole-3-acetic acid ethyl ether complex was subjected to the reaction of 2.24 grams (0.02 M) t-butoxide potassium and 2.3 milliliters (0.02 M) benzylchloride, resulting, after chromatography on silica (eluent: toluene _ 6% EiOAc/toluene) was obtained 5.0 g (63%) of 5-benzyloxy-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex (so pl. 107 - 109oC).

Elemental analysis for C26H25NO3:

Calculated: C 78,17, H of 6.31, N 3,51

Found: C 78,46, H 6,60, N 3,59.

C. G is the iMER 1 (part G), 2.0 g (5 mm) of 5-benzyloxy-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 3 ml of hydrazine, resulting, after crystallization from MeOH, received a 1.25 g (yield 62%) of the hydrazide 5-benzyloxy-1-(phenylmethyl) -IH-indole-3-acetic acid (so pl. 149 - 150oC).

Elemental analysis for C24H23N3O2:

Calculated: C 74,78, H 6,01, N 10,90

Found: C 74,91, H 6,04, N 10,97.

Example 10

Getting hydrazide 2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

A. 2-Methyl-IH-indole-3-acetic acid methyl ester

To a solution of 25 g (0,132 M) 2-methyl-IH-indole-3-acetic acid in 500 ml of matinale was added 10 ml methanesulfonic acid and the resulting mixture was stirred for 24 hours. Then the reaction mixture was diluted with water, was extracted with EtOAc, the EtOAc solution washed with water, a solution of Na2CO3and then again washed with water. After drying with sodium sulfate, the solvent was removed under reduced pressure, resulting in a received 26,62 g (yield 97%) of 2-methyl-IH-indole-3-acetic acid methyl ether complex in the form of an oily substance.

Elemental analysis for C12H13NO2:

Calculated: C 7th ester

In accordance with the procedure described in example 3 (part E), 6,09 g (0.03 M) 2-methyl-IH-indole-3-acetic acid methyl ether complex was subjected to reaction with 3,36 g (0.03 M) so-butoxide potassium and 3.45 ml (0.03 M) benzylchloride, after chromatography on silica (eluent gradient: toluene _ 5% EtOAc/toluene) was obtained 6.0 g (yield (68%) of 2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid methyl ether complex (so pl. 71 - 73oC).

Elemental analysis for C19H19NO2:

Calculated: C 77,79, H 6,53, N 4,77

Found: C 78,00, H 6,51, N Is 5.06.

C. Hydrazide-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G) 2.0 g (6,83 mm) of 2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 5 ml of hydrazine, which was obtained 1.2 g (yield 60%) of 2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid hydrazide (after crystallization from MeOH) (so pl. 140 - 143oC).

Elemental analysis for C18H19N3O:

Calculated: C 73,70, H 6,53, N 14,32

Found: C 73,95, H 6,76, N 14,60

Example 11

Getting hydrazide 1-(2-methoxy-1-naphthalenyloxy)-2-methyl-IH-indole-3-acetic acid

A. 1-(2-Methoxy-1-naphthalenyl the example 3 (part E), 4,06 g (0.02 M) 2-methyl-IH-indole-3-acetic acid methyl ether complex was subjected to reaction with 2.24 g (0.03 M) t-butoxide potassium and 4.13 g (0.02 M) 1-chloromethyl-2-methoxynaphthalene, resulting, after chromatography on silica (eluent gradient: toluene _ 5% EtOAc/toluene) were of 4.95 g (66%) of 1-(2-methoxy-1-naphthaleneacetic)-2-methyl-H-indol-3-acetic acid methyl ether complex (so pl. 120 - 123oC).

Elemental analysis for C24H23NO3:

Calculated: C 77,19, H 6,21, N 3,75

Found: C 77,45, H 6,27, N 3,69.

B. Hydrazide-1-(2-methoxy-1-naphthalenyloxy)-2-methyl-IH-indole - 3-acetic acid

In accordance with the procedure described in example 1 (part G), 4.9 g (0,0131 M) 2-methyl-1-(2-methoxy-1-naphthalenyloxy)-IH-indole-3 - acetic acid methyl ether complex was subjected to reaction with 10 ml of hydrazine, resulting, after crystallization from MeOH/CH2Cl2got to 3.02 g (yield 62%) of hydrazide 2-methyl-1-(2-methoxy-1-naphthalenyloxy)-IH-indole-3 - acetic acid (so pl. 201 - 203oC).

Elemental analysis for C23H23N3O2:

Calculated: C 73,97, H 6,21, N TO 11.52

Found: C 74,24, H 6,28, N 11,51.

Example 12

Getting hydrazide 1-([1,1'-biphenyl]-2-ylmethyl)-5-methoxy-IH - indol-3-the UKS the accordance with the procedure described in example 1 (part F), 1.2 g (5 mm) of 5-methoxy-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 200 mg (5 mm) of 60% NaH/mineral oil and 0.9 ml (5 mm) 2-chloromethylpyridine, resulting, after chromatography on silica (eluent: 20% EtOAc/hexane), was obtained 1,15 g(58%) 1-([1,1'-the biphenyl]-2-ylmethyl)-5-methoxy-IH-indole - 3-acetic acid ethyl ether complex in the form of an oily substance.

Elemental analysis for C26H25NO3:

Calculated: C 78,17, H of 6.31, N 3,51

Found: C Unchanged At 78.81, H 6,28, N 3,47.

B. Hydrazide 1-([1,1'-biphenyl]-2-ylmethyl)-5-methoxy-IH-indole - 3-acetic acid

In accordance with the procedure described in example 1 (part G), 859 mg (2,15 mm) 1-([1,1'-biphenyl]-2-ylmethyl)-5-methoxy-IH-indole - 3-acetic acid ethyl ether complex was subjected to reaction with 2.5 ml of hydrazine, resulting, after crystallization from MeOH/hexane, received 300 mg (36%) hydrazide 1-([1,1'-biphenyl] -2-ylmethyl)-5-methoxy-IH-indole-3-acetic acid (so pl. 123 - 125oC).

Elemental analysis for C24H23N3O2:

Calculated: C 74,78, H 6,01, N 10,90

Found: C 75,01, H 6,27, N 10,87.

Example 13

Getting hydrazide 5-methoxy-2-methyl-1-(2-methyl-1-propyl)-IH - indole-3-acetic kistwar 27,95 g (0.16 M) of the hydrochloride of 4-methoxyphenylhydrazine and of 19.72 g (0.17 M) levulinate acid in 500 milliliters of ethanol, was barbotirovany dry hydrogen chloride, using a cooling bath of ice and water. Then the bath was removed, and the reaction mixture was slowly heated under reflux for 20 hours. After cooling, the mixture was poured into water and was extracted with EtOAc. The EtOAc solution was washed with sodium bicarbonate solution and was dried with sodium sulfate. After removal of the solvent under reduced pressure, the obtained residue was chromatographically on silicon dioxide, elwira a mixture of 5% EtOAc and toluene, which was obtained 14.2 g (yield 36%) 5 methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex (so pl. 38 - 40oC).

Elemental analysis for C14H17NO3:

Calculated: C 67,99, H 6,93, N 5,6

Found: C 68,24, H 6,88, N 5,75

B. 5-Methoxy-2-methyl-1-(2-methyl-1-propyl)-IH-indole-3-acetic acid ethyl ester

A solution of 2.06 g (8.34 per mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex, 3 g of potassium carbonate and 3 ml of 2-methyl-1-propyliodide, was heated at 65oC for 96 hours and then the mixture was poured into water. The resulting product was extracted with EtOAc and then EtOAc four times washed with water and dried with sodium sulfate. After chromatography was carried out on dioxide cream is ol-3-acetic acid ethyl ether complex in the form of an oily substance.

C. Hydrazide 5-methoxy-2-methyl-1-(2-methyl-1-propyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 230 mg (0.76 mm) of 5-methoxy-2-methyl-1-(2-methyl-1-propyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 1 ml of hydrazine, resulting, after recrystallization from Meon, received 10 mg (yield of 4.5%) hydrazide 5-methoxy-2-methyl-1-(2-methyl-1-propyl)-IH-indole-3-acetic acid (so pl. 113 - 116oC).

Elemental analysis for C16H23N3O2:

Calculated: C 66,41, H 8,01, N 14,52

Found: C 65,79, H 8,10, N 14,16.

Example 14

Getting hydrazide 1-decyl-5-methoxy-2-methyl-IH-indole-3-acetic acid

A. 1-Decyl-5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 3 (part E), 2,47 g (0.01 M) of 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.12 g (0.01 M) t-butoxide potassium and from 2.07 ml (0.01 M) of decembered, resulting, after chromatography on silica (eluent gradient: toluene _ 5% EtOAc/toluene) were 2.16 g (yield 56%) 1-decyl-5-methoxy-2-methyl-IH-indole-3-acetic acetic acid ethyl ether complex in the form of oily substances is 74,53, H 9,38, N 3,57.

B. Hydrazide 1-decyl-5-methoxy-2-methyl-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 2.1 g (0,00545 M) 1-decyl-5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 5 ml of hydrazine, resulting, after recrystallization from MeOH, was obtained 0.65 g (yield 32%) of 1-decyl-5-methoxy-2-methyl-IH-indole-3-acetic acid hydrazide (so pl. 129 - 131oC).

Elemental analysis for C22H35N3O2:

Calculated: C 70,74, H 9,44, N 11,25

Found: C 70,79, H 9,60, N 11,13.

Example 15

Getting hydrazide 5-methoxy-2-methyl-1-octadecyl-IH-indole-3-acetic acid

A. 5-Methoxy-2-methyl-1-octadecyl-IH-indole-3-acetic acid methyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of 60% NaH/mineral oil and 667 mg (2 mm) octadecylamide, resulting, after crystallization from MeOH, received 648 mg (65%) 5-methoxy-2-methyl-1-octadecyl-IH-indole-3-acetic acid methyl ether complex (so pl. 68 - 69oC).

Elemental analysis for C32H53NO3:

VL-3-acetic acid

In accordance with the procedure described in example 1 (part G), 250 mg (0.5 mm) of 5-methoxy-2-methyl-1-octadecyl-IH-indole-3-acetic acid methyl ether complex was subjected to reaction with 0.5 ml of hydrazine, resulting, after crystallization from the reaction mixture, was obtained 130 mg (yield 54%) of the hydrazide 5-methoxy-2-methyl-1-octanediol-IH-indole-3-acetic acid (so pl. 121 - 123oC).

Elemental analysis for C30H51N3O2:

Calculated: C 74,18, of 10.58 H, N 8,65

Found: C 74,45, At 10.64 H, N 8,63.

Example 16

Getting hydrazide 5-methoxy-2-methyl-1-(phenylmethyl)-IH-indole-3 - acetic acid

A. 5-Methoxy-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 3 (part E), 4,07 g (0,0165 M) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ester was subjected to reaction with 1.85 g (0,0165 M) t-butoxide potassium and from 1.96 ml (0,0165 M) benzylchloride, resulting, after chromatography on silica (eluent gradient: toluene _ 10% EtOAc/toluene) were of 3.78 g (yield 68%) 5-methoxy-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex (so pl. 63 - 64oC).

Elemental analysis for C21H23NO3:

Calc is ssnoi acid

A solution of 1.0 g (2,96 mm) 5-methoxy-2-methyl-1-(phenylmethyl)- IH-indole-3-acetic acid ethyl complex ether and 5 ml of hydrazine in 50 ml of MeOH was heated under reflux for 8 hours, cooled, diluted with water and was extracted with EtOAc. After that, the EtOAc solution washed with saturated NaCl solution and dried with sodium sulfate. The solvent is evaporated under reduced pressure and the obtained residue was pereirae with ether, the resulting received 920 mg (yield 96%) of the hydrazide 5-methoxy-2-methyl-1-(phenyl-methyl)- IH-indole-3-acetic acid (so pl. 161 - 162oC).

Elemental analysis for C19H21N3O2:

Calculated: C 70,53, H is 6.54, N 12,99

Found: C 70,41 H To 6.58, N 12,93.

Example 17

Getting hydrazide 1-(2-chlorophenylacetyl)-5-methoxy-2-methyl - IH-indole-3-acetic acid

A. 1-(2-Chlorophenylacetyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex were subjected to reccie with 80 mg (2 mm) of 60% NaH/mineral oil and 0.25 ml (2 mm) ortho-chlorobenzylchloride, resulting, after chromatography on silica (eluent: 30% EtOAc/hexane) and Cristallago ether (so pl. 74 - 77oC).

Elemental analysis for C21H22NO3:

Calculated: C 67,83, H 5,95, N OF 3.77

Found: C 67,88, H 6,09, N 3,84.

B. Hydrazide-1-(2-chlorophenylacetyl)-5-methoxy-2-methyl-IH-indole-3 - acetic acid

In accordance with the procedure described in example 1 (part G), 395 mg (1,06 mm) 1-(2-chlorophenylacetyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.0 ml of hydrazine, resulting, after crystallization from MeOH received 200 mg (yield 53%) hydrazide 1-(2-chlorophenylacetyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid (so pl. 99 - 100,5oC).

Elemental analysis for C19H20N3O2:

Calculated: C 63,77, H 5,63, N 11,74

Found: C 63,51, H 5,77, N Of 11.45.

Example 18

Getting hydrazide 1-(3-chlorophenylacetyl)-5-methoxy-2-methyl - IH-indole-3-acetic acid

A. 1-(2-Chlorophenylacetyl)-5-methoxy-2-methyl - IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of 60% NaH/mineral oil and 0.25 ml (2 mm) meta-chlorobenzylchloride, resulting, after chromatography on toxi-2-methyl-IH-indole-3-acetic acid ethyl ether complex (so pl. 79 - 81oC).

Elemental analysis for C21H22NO3:

Calculated: C 67,83, H 5,95, N OF 3.77

Found: C 67,55, H 5,95, N 3,76.

B. Hydrazide 1-(3-chlorophenylacetyl)-5-methoxy-2-methyl-IH - indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 395 mg (1,06 mm) 1-(3-chlorophenylacetyl)-5-methoxy-2 - methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.0 ml of hydrazine, resulting, after crystallization from MeOH, received 257 mg (yield 68%) hydrazide 1-(3-chlorophenylacetyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid (So pl. 139 - 140oC).

Elemental analysis for C19H20N3O3:

Calculated: C 63,77, H 5,63, N 11,74

Found: C 63,79, H 5,69, N 11,67.

Example 19

Getting hydrazide 1-(4-chlorophenylacetyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid

A. 1-(4-Chlorophenylacetyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of 60% NaH/mineral oil and 322 mg (2 mm) para-chlorobenzylchloride, resulting, after chromatography on dmutil-IH-indole-3-acetic acid ethyl ether complex (so pl. 98 - 100oC).

Elemental analysis for C21H22ClNO2:

Calculated: C 67,83, H 5,95, N OF 3.77

Found: C 67,98, H Of 5.92, N 3,69.

B. Hydrazide 1-(4-chlorophenylacetyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 333 mg (0.9 mm) of 1-(4-chlorophenylacetyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.0 milliliters of hydrazine, resulting, after crystallization from MeOH, received 251 mg (yield 78%) hydrazide 1-(4-chlorophenylacetyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid (so pl. 177 - 180oC).

Elemental analysis for C19H20ClN3O2:

Calculated: C 63,77, H 5,63, N 11,74

Found: C 64,02, H 5,77, N Of 11.45.

Example 20

Getting hydrazide 1-(2,5-dichlorophenylethyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid

A. 1-(2,5-Dichlorophenylethyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of 60% NaH/mineral oil and 391 mg (2 mm) (2.5-dichlorophenyl)of methyl chloride, as a result, p-(2-5-dichlorophenylethyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex (so pl. 146 - 148oC).

Elemental analysis for C21H21Cl2NO3:

Calculated: C 62,08, H to 5.21, N 3,45

Found: C 62,34, H 5,23, N 3,72.

B. Hydrazide 1-(2,5-dichlorophenylethyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 221 mg (0,54 mm) 1-(2,5-dichlorophenylethyl)-5-methoxy-2-methyl-IH - indole-3-acetic ethyl ether complex was subjected to reaction with 0.6 ml of hydrazine, resulting after crystallization from MeOH received 135 mg (yield 64%) hydrazide 1-(2,5-dichlorophenylethyl)-5-methoxy-2-methyl-IH-indole-3-acetic acid (so pl. 168 - 170oC).

Elemental analysis for C19H19Cl2N3O2:

Calculated: C 58,17, H 4,88, N 10,71,

Found: C 58,46, H 4,94, N Of 10.73.

Example 21

Getting hydrazide 1-(2,6-dichlorophenylamino)-5-methoxy-2-methyl-IH-indole-3-acetic acid

A. 1-(2,6-Dichlorophenylamino)-5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of 60% NaH/mineral oil and 391 mg (2 mm) (2,6-dichlorophenyl) of methyl chloride, the h is methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex (so pl. 131 - 132oC).

Elemental analysis for C21H21Cl2NO3:

Calculated: C 62,08, H to 5.21, N 3,45

Found: C 61,79, H 5,23, N 3,751.

B. Hydrazide-1-(2,6-dichlorophenylamino)-5-methoxy-2-methyl-IH - indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 533 mg (1.3 mm) of 1-(2,6-dichlorophenylamino)-5-methoxy-2-methyl-IH-indole - 3-acetic acid ethyl ether complex was subjected to reaction with 1.3 ml of hydrazine, resulting, after crystallization from MeOH, received 250 mg (yield 61%) hydrazide 1-(2,6-dichlorophenylethyl)- 5-methoxy-2-methyl-IH-indole-3-acetic acid (so pl. 194 - 196oC).

Elemental analysis for C19H19Cl2N3O2:

Calculated: C 58,17, H 4,88, N 10,71

Found: C 58,65, H 4,98 N IS 10.68

Example 22

Getting hydrazide 5-methoxy-1-[(3-phenylphenyl)methyl]-2-methyl-IH-indole-3-acetic acid

A. 5-Methoxy-1-[(3-were)-methyl] -2-methyl-IH-indole-3 - acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of 60% NaH/mineral oil and from 0.26 ml (2 mm) metamotivational, cut-methoxy-1-[(3-were)- methyl-phenyl)methyl] -2-methyl-IH-indole-3-acetic acid ethyl ether complex in the form of an oily substance.

Elemental analysis for C22H25NO3:

Calculated: C 75,19, H 7,17, N 3,99

Found: C 75,46, H 7,29, N 3,97

B. Hydrazide-5-methoxy-1-[(3-were)-methyl]-2-methyl-IH-indole - 3-acetic acid

In accordance with the procedure described in example 1 (part G), 409 mg (1,17 mm) 5-methoxy-1-[(3-were)-methyl] -2-methyl-IH-indole - 3-acetic acid ethyl ether complex was subjected to reaction with 1.2 ml of hydrazine, resulting, after crystallization from MeOH, got 157 mg (yield 40%) of the hydrazide 5-methoxy-1-[(3-feelfeel) methyl]-2-methyl-IH-indole-3-acetic acid (so pl. 133 - 135oC).

Elemental analysis for C20H23N3O2;

Calculated: C 71,19, H 6,87, N 12,45,

Found: C 71,42, H 6,97, N 12,66.

Example 23

Getting 5-methoxy-2-methyl-1-[(3-trifluromethyl-phenyl)] -methyl]- IH-indole-3-acetic acid hydrazide

A. 5-Methoxy-2-methyl-1-[(3-trifluromethyl)-methyl] -IH-indole - 3-acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of 60% NaH/mineral oil and 389 mg (2 mm) meta-trifluromethanesulfonate, resulting, after the chromatograph[(3-trifluromethyl)methyl]-IH-indole-3-acetic acid ethyl ether complex (so pl. 95 - 97oC).

Elemental analysis for C22H22F3NO3:

Calculated: C 65,18, H 5,47, N OF 3.46

Found: C 65,41, H of 5.53, N 3,60

B. Hydrazide 5-methoxy-2-methyl-1-[(3-trifluromethyl)methyl]- IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 390 mg (0.96 mm) 5-methoxy-2-methyl-1-[(3-trifluromethyl)methyl]- IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.2 ml of hydrazine, resulting, after crystallization from MeOH, received 166 mg (yield 44%) of the hydrazide 5-methoxy-2-methyl-1-[( 3-triptoreline) methyl]-IH-indole-3-acetic acid (so pl. 162 - 165oC).

Elemental analysis for C20H20F3N3O2:

Calculated: C 61,38, H 5,15, N A 10.74

Found: C 61,58, H 5,24, N 10,95.

Example 24

Getting hydrazide 1-([1,1'-biphenyl] -2-ylmethyl)-5-methoxy-2 - methyl-IH-indole-3-acetic acid

A. 1-([1,1'-Biphenyl] -2-ylmethyl)-5-methoxy-2-methyl-IH-indole-3 - acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 483 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid methyl ether complex was treated with 80 milligrams (2 mm) of 60% NaH/mineral oil and 0.37 milliliters (2 mm) of 2-(bra mg (yield 69%) 1-([1,1'-the biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-IH-indole-3 - acetic acid ethyl ether complex as a yellow oily substance.

Elemental analysis for C27H27NO3:

Calculated: C 78,42, H to 6.58, N 3,39

Found: C 78,12, H 6,47, N 3,03.

B. Hydrazide 1-([1,1'-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-IH - indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 552 mg (1,34 mm) 1-([1,1'-biphenyl] -2-ylmethyl)-5 - methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 2.0 ml of hydrazine, resulting, after chromatography on silica (eluent: EtOAc) received 150 mg (yield 28%) hydrazide 1-([1,1'-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl - IH-indole-3-acetic acid.

Elemental analysis for C25H25N3O2:

Calculated: C 75,16, H of 6.31, N 10,52,

Found: C 75,01, H 6,34, N 10,26.

Example 25

Getting hydrazide 1-([1,1'-biphenyl] -3-ylmethyl)-5-methoxy-2 - methyl-IH-indole-3-acetic acid

A. Ethyl ester 1-([1,1'-biphenyl]-3-ylmethyl)-5-methoxy - 2-methyl-IH-indole-3-acetic acid

In accordance with the procedures described in example 1 (part F), 483 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid methyl ether complex was treated with 80 milligrams (2 mm) of a mixture of 60% NaH/mineral oil and 405 milligrams (2 mm) 3-(chloromethyl) biphenyl, as a result, the settlement of the toxi-2-methyl-IH-indole-3-acetic acid ethyl ether complex as a yellow oily substance.

B. Hydrazide 1-([1,1'-biphenyl]-3-ylmethyl)-5-methoxy-2-methyl-IH - indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 490 mg (1.2 mm) of 1-([1,1'-biphenyl]-3-ylmethyl)-5-methoxy-2-methyl-IH - indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.2 ml of hydrazine, resulting, after crystallization from MeOH, got 316 mg (yield 66%) hydrazide 1-([1,1'-biphenyl] -3-ylmethyl)-5 - methoxy-2-methyl-IH-indole-3-acetic acid.

Elemental analysis of C25H25N3O2:

Calculated: C 75,16, H of 6.31, N 10,52

Found: C 74,96, H 6,32, N 10,28.

Example 26

Getting hydrazide 5-methoxy-1-[(2-methoxyphenyl)methyl]-2-methyl - IH-indole-3-acetic acid

A. 5-Methoxy-1-[(2-methoxyphenyl)methyl]-2-methyl-IH-indole-3 - acetic acid

In accordance with the procedure described in example 1 (part F), 2.0 g (8,12 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 325 mg (8,12 mm) mixture of 60% NaH/mineral oil and 1,272 g (8,12 mm) ortho-methoxybenzylamine, resulting, after chromatography on silica (eluent: 25% EtOAc/hexane), was obtained of 1.74 g (yield 52%) 5-methoxy-1[(2-methoxyphenyl)methyl]-2-methyl-IH-indole-3-acetic acid ethyl ether complex in the form of mA is adalnikam for 20 hours. Then the mixture was diluted with water, and was extracted with EtOAc, then EtOAc solution was dried with sodium sulfate, the solvent was removed under reduced pressure and the obtained residue was led from MeOH, which was obtained 1.1 g (yield 68%) of 5-methoxy-1-[(2-methoxyphenyl)-methyl] -2-methyl-IH-indole-3-acetic acid (so pl. 176 - 180oC).

Elemental analysis for C22H21NO4:

Calculated: C 70,78; H 6,24; N 4,13

Found: C 70,98, H 6.42 per, N 4,19

B. 5-Methoxy-1- (2-methoxyphenyl)methyl-2-methyl-IH-indole-3 - acetic acid methyl ester

In accordance with the procedure described in example 10 (part A), 848 mg (2.5 mm), 5-methoxy-1-[(2-methoxyphenyl)-methyl]-2-methyl-IH - indole-3-acetic acid was treated with 0.2 milliliters methanesulfonic acid in 20 ml of MeOH, resulting, after chromatography n silica (eluent: 20% EtOAc/hexane), was obtained 655 mg (yield 74%) of 5-methoxy-1-[(2-methoxyphenyl)-methyl] -2-methyl-IH - indole-3-acetic acid methyl ether complex (so pl. 98 - 100oC).

Elemental analysis for C21H23NO4:

Calculated: C 71,37, H 6,56, N 3,96

Found: C 71,59, H 6,74, N 3,81

C. Hydrazide 5-methoxy-1-[(2-methoxyphenyl)methyl] -2-methyl-IH - indole-3-acetic acid

Under the Noah acid methyl ether complex was subjected to reaction with 2.0 ml of hydrazine, as a result, after crystallization from MeOH, got 358 mg (yield 56%) of the hydrazide 5-methoxy-1-[(2-methoxy-phenyl)- methyl]-IH-indole-3-acetic acid (so pl. 140 - 143oC).

Elemental analysis for C20H23N3O3:

Calculated: C 67,97; H 6,56, N 11,89

Found: C 68,84, H 6,67, N 11,84

Example 27

Getting hydrazide 5-methoxy-1-[(3-methoxyphenyl)-methyl]-IH - indole-3-acetic acid

A. 5-Methoxy-1-[(3-methoxyphenyl)methyl]-2-methyl-IH-indole-3 - acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and 313 mg (2 mm) meta-methoxybenzylamine, resulting, after chromatography on silica (eluent: 20% EtOAc/hexane) and crystallization from MeOH, received 424 mg (yield 58%) 5-methoxy-1-[(3-methoxyphenyl)methyl]-2-methyl-IH-indole-3-acetic acid ethyl ether complex (so pl. 88 - 90oC).

Elemental analysis for C22H25NO4:

Calculated: C 71,91, H 6,86, N 3,81

Found: C 72,05, H 6,99, N 4,07

B. Hydrazide 5-methoxy-1-[(3-methoxyphenyl)methyl] -2-methyl-IH - indole-3-acetic acid

In accordance with the por acid ethyl ether complex was subjected to reaction with 1.0 ml hydrazide, as a result, after crystallization from MeOH, received 240 mg (yield 62%) of the hydrazide 5-methoxy-1-[(3-methoxyphenyl)- methyl]-2-methyl-IH-indole-3-acetic acid (so pl. 161 - 163oC).

Elemental analysis for C20H23N3O3:

Calculated: C 67,97, H 6,56, N 11,89

Found: C 68,00; H Is 6.61, N 12,02.

Example 28

Getting hydrazide 5-methoxy-1-[(4-methoxyphenyl)methyl] -2 - methyl-IH-indole-3-acetic acid

A. Ethyl ester 5-methoxy-1-[(4-methoxyphenyl)-methyl]- 2-methyl-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/ mineral oil and 0.3 ml (2 mm) para-methoxybenzylamine, resulting, after chromatography on silica (eluent: 25% EtOAc/hexane), was obtained 341 mg (yield 46%) 5-methoxy-1-[(4-methoxy-phenyl)methyl] - 2-methyl-IH-indole-3-acetic acid ethyl ether complex in the form of an oily substance.

Elemental analysis for C22H25NO4:

Calculated: C 71,91; H 6,86; N 3,81

Found: C 72,62, H is 6.75, N 3,41

B. Hydrazide 5-methoxy-1[(4-methoxyphenyl)methyl]-2-methyl-IH-indole - 3-acetic acid

In Sohotel-3-acetic acid ethyl ether complex was subjected to reaction with 1.0 ml of hydrazine, the result was obtained after crystallization from MeOH, 124 mg (yield 41%) of the hydrazide 5-methoxy-1-[(4-methoxy-phenyl) methyl]-2-methyl-IH-indole-3-acetic acid (so pl. 161 - 163oC).

Elemental analysis for C20H23N3O3:

Calculated: C 67,97, H 6,56, N 11,89

Found: C 68,21, H Of 6.65, N 11,95.

Example 29

Getting hydrazide 1-[(3-disiloxane)methyl]-5-methoxy-2 - methyl-IH-indole-3-acetic acid

A. 1-[(3-Disiloxane)methyl] -5-methoxy-2-methyl-IH-indole-3 - acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and 565 mg (2 mm) meta-decyloxybenzoate, resulting, after chromatography on silica (eluent: 20% EtOAc/hexane), was obtained 590 mg (yield 60%) 1-[(3-disiloxane) methyl]-5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex in the form of an oily substance.

Elemental analysis for C31H43NO4:

Calculated: C 75,42, H 8,78, N 2,84

Found: C 75,21, H 9,00, N 2,78

B. Hydrazide 1-[(3->decalcifier)-methyl]-5-methoxy-2-methyl-IH - indole-3-acetic acid
2-methyl-IH - indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.5 ml of hydrazine, as a result, after crystallization from MeOH, received 188 mg (yield 34%) hydrazide 1-[(3-disiloxane)methyl]-5 - methoxy-2-methyl-IH-indole-3-acetic acid (so pl. 66 - 76oC).

Elemental analysis for C29H41N3O3:

Calculated: C 72,62, H 8,62, N 8,76

Found: C 72,92, H 8,66, N 6,99

Example 30

Getting hydrazide 1-[(3-benzyloxyphenyl)-methyl]-5-methoxy - 2-methyl-IH-indole-3-acetic acid

A. 1-[(3-benzyloxyphenyl)-methyl]-5-methoxy-2-methyl-IH-indole - 3-acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and 465 mg (2 mm) meta - benzyloxybenzaldehyde, resulting, after chromatography on silica (eluent: 20% EtOAc/hexane) and after crystallization from MeOH, received 376 mg (yield 42) 1-[(3-benzyloxyphenyl)methyl]-5 - methoxy-2-methyl-IH-indole-3-acetic acid (so pl. 60 - 70oC).

Elemental analysis for C28H29NO4:

Calculated: C 75,82, H 6,59, N 3,16

Found: C 76,06, H 6,56, N 3,35.

B. Hydrazide-1-[(3-benzyloxyphenyl)methyl] -5-methoxy-2-methyl-IH - indole-3-acetic acid

In the Il-IH - indole-3-acetic acid ethyl ether complex was subjected to reaction from 0.83 ml of hydrazine, as a result, after crystallization from MeOH, received 180 mg (51% yield) of 1-[(3-benzyloxyphenyl)methyl]-5-methoxy-2 - methyl-IH-indole-3-acetic acid hydrazide (so pl. 130 - 132oC).

Elemental analysis for C26H27N3O3:

Calculated: C 72,71, H 6,34, N 9,78

Found: C 72,92, H 6,50, N 9,99

Example 31

Getting hydrazide 1-[(3-hydroxyphenyl)-methyl]-5-methoxy-2 - methyl-IH-indole-3-acetic acid

A. 1-[(3-hydroxyphenyl)methyl]-5-methoxy-2-methyl-IH-indole-3 - acetic acid ethyl ester

A solution of 357 mg (0.8 mm) of 1-[(3-benzyloxyphenyl)-methyl]-5 - methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex (example 31, part a) in 30 milliliters of a mixture of tetrahydrofuran and EtOH (1:1), for 16 hours was hydrogenosomal under hydrogen pressure of 60 pounds per square inch (4218 g/cm2), using 90 mg Pb/BaSO4as the catalyst. Thereafter, the catalyst was filtered and the resulting filtrate was concentrated under reduced pressure. The obtained residue was dissolved in EtOAc and washed with water and then saturated NaCl solution. After drying with magnesium sulfate, the product was chromatographically on silicon dioxide, elwira a mixture of EtOAc/hexane and EtOAc (1: 1), resulting, after crystallization can ether (so pl. 114 - 116oC).

Elemental analysis for C21H23NO4:

Calculated: C 71,37, H 6,56, N 3,96

Found: C 71,63, H Of 6.49, N 4,14.

B. Hydrazide 1-[(3-hydroxyphenyl)-methyl]-5-methoxy-2-methyl - IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 76 mg (0.22 mm) 1-[(3-hydroxyphenyl)methyl]-5-methoxy-2-methyl - IH-indole-3-acetic acid ethyl ether complex was subjected to reaction from 0.22 ml of hydrazine, resulting, after crystallization from MeOH, received 35 mg (yield 47%) hydrazide 1-[(3-hydroxyphenyl)- methyl]-5-methoxy-2-methyl-IH-indole-3-acetic acid (so pl. 201 - 203oC)

Elemental analysis for C19H21N3O3:

Calculated: C 67,24, H 6,24, N 12,38

Found: C 67,46, H 6,36, N Of 12.33.

Example 32

Getting hydrazide 1-[(4-benzyloxyphenyl)methyl] -5-methoxy - 2-methyl-IH-indole-3-acetic acid

A. 1-[(4-Benzyloxyphenyl)methyl] -5-methoxy-2-methyl-IH-indole-3 - acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and 465 mg (2 mm) para-benzyloxybenzaldehyde, as a result� (39%) 1-[(4-benzyloxyphenyl)-methyl]-5-methoxy - 2-methyl-IH-indole-3-acetic acid ethyl ether complex (so pl. 118 - 119oC).

Elemental analysis for C28H29NO4:

Calculated: C 75,82, H 6,59, N 3,16

Found: C 75,94, H 6,60, N 2,96

B. Hydrazide-1-[(4-benzyloxyphenyl)methyl] -5-methoxy-2-methoxy - IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 315 mg (0.7 mm) 1-[(4-benzyloxyphenyl/methyl] -5-methoxy-2-IH-indole-3 - acetic acid ethyl ether complex was subjected to reaction with 1.0 ml of hydrazine, resulting, after crystallization from MeOH, got 246 mg (yield 82%) hydrazide 1-[(4-benzyloxyphenyl)methyl]- 5-methoxy-IH-indole-3-acetic acid (so pl. 179 - 180oC).

Elemental analysis for C26H27N3O3:

Calculated: C 72,71, H 6,34, N 9,78

Found: C 72,76, H To 6.43, N 10,01.

Example 33

Getting hydrazide 1-[(4-hydroxyphenyl)methyl]-5-methoxy-2 - methyl-IH-indole-3-acetic acid

A. 1-[(4-Hydroxyphenyl)methyl]-5-methoxy-2-methyl-IH-indole-3 - acetic acid ethyl ester

In accordance with the procedure described in example 32 (part A), 357 mg (0.8 mm) of 1-[(4-benzyloxyphenyl)methyl]-5-methoxy-2-methyl-IH - indole-3 - acetic acid ethyl ether complex (example 33, part a) was hydrogenosomal and chromatographically on Dukakis silica (eluent: 25% EtOAc/hexane) the l-IH-indole-3-acetic acid ethyl ether complex (so pl. 113 - 115oC).

Elemental analysis for C21H23NO4:

Calculated: C 71,37, H 6,56, N 3,96

Found: C 71,08, H 6,57, N 4,18

B. Hydrazide-1-[(4-hydroxyphenyl)methyl] -5-methoxy-2-methoxy - IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 182 mg (0.5 mm) of 1-[(4-hydroxyphenyl)-methyl]-5-methoxy-2-IH-indole-3 - acetic acid ethyl ether complex was subjected to reaction with 1.0 ml of hydrazine, resulting, after crystallization from MeOH, received 110 mg (yield 65%) hydrazide 1-[(4-hydroxyphenyl)methyl] - 5-methoxy-IH-indole-3-acetic acid (so pl. 211 - 214oC).

Elemental analysis for C19H21N3O3:

Calculated: C 67,24, H 6,24, N 12,38

Found: C 67,74, H 6,32, N 11,83.

Example 34

Getting hydrazide 5-methoxy-2-methyl-1-[(3-nitrophenyl)-methyl]- IH-indole-3-acetic acid

A. 5-Methoxy-2-methyl-1-[(3-nitrophenyl)-methyl] -IH-indole-3 - acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 484 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and 432 mg (2 mm) metatarsalgia, resulting, after chromatography-nitrophenyl)methyl]-IH-indole-3-acetic acid ethyl ether complex (so pl. 105 - 106oC).

Elemental analysis for C21H22N2O5:

Calculated: C 65,96, H 5,80, N 7,33

Found: C 65,84, H 5,86, N Of 7.36.

B. Hydrazide-5-methoxy-2-methyl-1-[(3-nitrophenyl)methyl] - IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 115 mg (0.3 mm) of 5-methoxy-2-methyl-1-[(3-nitrophenyl)methyl]-IH-indole-3 - acetic acid ethyl ether complex was subjected to reaction with 0.3 ml of hydrazine, resulting, after crystallization from MeOH, received 42 mg (yield 38%) of the hydrazide 5-methoxy-2-methyl- [(3-nitrophenyl)methyl]-IH-3-acetic acid (so pl. 177 - 179oC).

Elemental analysis for C19H20N4O4:

Calculated: C of 61.95, H 5,47, N 15,21

Found: C 62,53, H 5.56mm, N 14,96.

Example 35

Getting hydrazide 1-[(3-AMINOPHENYL)methyl] -5-methoxy - 2-methyl-IH-indole-3-acetic acid

A. 1-[(3-AMINOPHENYL)-methyl]-5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ester

A solution of 500 mg (1.3 mm) 5-methoxy-2-methyl-1-[(3-nitrophenyl)- methyl]-IH-indole-3-acetic acid ethyl ether complex in 50 ml of EtOH was hydrogenosomal for 16 hours at room temperature under hydrogen pressure of 60 pounds per square inch (4218 g/cm2using as produce the NII. The obtained residue was chromatographically on silicon dioxide, elwira a mixture of 25% EtOAc and hexane, resulting in received 234 mg (51% yield) of 1-[(3-AMINOPHENYL)methyl]-5-methoxy-2 - methyl-IH-indole-3-acetic acid ethyl ether complex as an oily substance.

Elemental analysis for C21H24N2O3:

Calculated: C 71,57, H 6,86, N OF 7.95

Found: C 71,18, H Is 6.75, N 7,52.

B. Hydrazide 1-[(3-AMINOPHENYL)methyl] -5-methoxy-2-methyl-IH-indole - 3-acetic acid

In accordance with the procedure described in example 1 (part G), 192 mg (0,54 mm) of ester ethyl 1-[(3-AMINOPHENYL)-methyl]- 5-methoxy-2-methyl-IH-indole-3-acetic acid is subjected to reaction with 1.0 milliliters of hydrazine, resulting after crystallization from MeOH received 78 mg (yield 40%) of the hydrazide 1-[(3-AMINOPHENYL)methyl]-5 - methoxy-2-methyl-IH-indole-3-acetic acid (so pl. 154 - 156oC).

Elemental analysis for C19H22N4O2:

Calculated: C 67,44, H 6,55, N 16,56

Found: C 67,47, H Of 6.49, N 16,46.

Example 36

Getting hydrazide 5-methoxy-2-methoxy-1-(1-phenylethyl)- IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-memela and from 0.27 ml (2 mm) (1-bromoethyl)-benzene, as a result, after chromatography on silica (eluent: 25% EtOAc/hexane), was obtained 160 mg (yield 22%) of 5-methoxy-2-methyl-1-(1-phenylethyl)-IH-indole-3-acetic acid ethyl ether complex in the form of an oily substance.

Elemental analysis for C22H25NO3:

Calculated: C 75,19, H 7,17, N 3,99

Found: C 75,45, H 7,45, N 4,40.

B. Hydrazide 5-methoxy-2-methyl-1-(1-phenylethyl)-1H-indole - 3-acetic acid

In accordance with the procedure described in example 1 (part G), 143 mg (0.4 mm) 5-methoxy-2-methyl-1-(1-phenylethyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 0.5 ml of hydrazine, resulting, after chromatography on silica (eluent: EtOAc) received 80 mg (yield 59%) of the hydrazide 5-methoxy-2-methyl-1-(1-phenylethyl)-IH-indole-3-acetic acid as a white foamy substance.

Elemental analysis for C20H23N3O2:

Calculated: C 71,19 H 6,87, N 12,45

Found: C 7,41 H 7,07 N 12,53.

Example 37

Getting hydrazide 5-methoxy-2-methyl-1-[(2-pyridyl)methyl]-IH-indole-3-acetic acid

A. 5-Methoxy-2-methyl-1-[(2-pyridyl)methyl] -IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), thmei 60% NaH/mineral oil and 328 mg (2 mm) of the hydrochloride of 2-picolylamine, as a result, after chromatography on silica (eluent: 50% EtOAc/hexane), received 510 mg (75% yield) of 5-methoxy-2-methyl-1-[(2-pyridyl)-methyl]-IH-indole-3-acetic acid ethyl ether complex in the form of an oily substance.

Elemental analysis for C20H22N2O3:

Calculated: C 70,99 H 6,55 N 8,28

Found: C 71,28 H 6,84 N 8,44

B. Hydrazide 5-methoxy-2-methyl-1-[(2-pyridyl)methyl]-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 480 mg (1.4 mm) 5-metoki-2-methyl-1-[(2-pyridyl)-methyl]-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.4 ml of hydrazine, resulting, after crystallization from MeOH, received 304 mg (yield 67%) of the hydrazide 5-methoxy-2-methyl-1[(2-pyridyl)methyl] -IH-indole-3-acetic acid so pl. 147-148oC).

Elemental analysis for C18H20N4O2:

Calculated C 66,65 H 6,22 N 17,27

Found: C 66,40 H 6,21 N 17,34.

Example 38

Getting hydrazide 5-methoxy-2-methyl-1-[(3-pyridyl)methyl]-IH-indole-3-acetic acid

A. 5-Methoxy-2-methyl-1-[(3-pyridyl)methyl] -IH-indole-3-acetic acid ethyl ester

To a solution of 247 mg (1 mm) of 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl complex aali 164 mg (1 mm) of the hydrochloride of 3-picolylamine. Then the cooling bath was removed, and the mixture was stirred for 4 hours. Then the mixture was diluted with water, the resulting product was extracted with EtOAc, and the EtOAc solution was washed with saturated solution of NaCl. After drying with magnesium sulfate, the product was chromatographically on silicon dioxide, elwira a mixture of 50% EtOAc/hexane, resulting, after crystallization from MeOH, received 75 mg (yield 22%) of 5-methoxy--2-methyl-1-[(3-pyridyl)methyl] -IH-indole-3-acetic acid ethyl ether complex (so pl. 109-111oC/.

Elemental analysis for C20H22N2O3:

Calculated: C 70,99 H 6,55 N 8,28

Found: C 71,05 H 6,66 N 8,20

B. Hydrazide 5-methoxy-2-methyl-1-[(3-pyridyl)methyl]-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 340 mg (1.0 mm) of 5-methoxy-2-methyl-1-[(3-pyridyl)methyl]-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.0 ml of hydrazine, resulting after crystallization from MeOH, received 54 mg (yield 17%) of the hydrazide 5-methoxy-2-metyl-1-[(3-pyridyl)-methyl] -IH-indole-3-acetic acid (so pl. 153-154,5oC).

Elemental analysis for C218H20N4O2:

Calculated: C 66,65 H 6,22 N 17,27

Found: C 66,84 H 6,36 N 17,17

Example 39
In accordance with the procedure described in example 1 (part F), 494 mg (2 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 160 mg (4 mm) of a mixture of 60% NaH/mineral oil and 328 mg (2 mm) of the hydrochloride of 4-picolylamine, resulting, after chromatography on silica (eluent: 50% EtOAc/hexane), was obtained 480 mg (yield 71%) 5-methoxy-2-methyl-1-[(4-pyridyl)methyl]-IH-indole-3-acetic acid ethyl ether complex in the form of an oily substance, which was utverjdali when peeling.

B. Hydrazide 5-methoxy-2-methyl-1-[(4-pyridyl)methyl]-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 410 mg (1.2 mm) 5-methoxy-2-methyl-1-[(4-pyridyl)methyl]-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.2 ml of hydrazine, resulting, after crystallization from Meon, got 148 mg (yield 38%) of the hydrazide 5-methoxy-2-methyl-1-[(4-pyridyl)methyl] -IH-indole-3-acetic acid (so pl. 192-193,5oC).

Elemental analysis for C18H20N4O2:

Calculated: C 66,6, H 6,22, N 17,27

Found: C 66,54, H 27, N 17,10

Example 40

Getting hydrazide 5-methoxy-2-methyl-1-[(2-chinolin)-methyl]-IH-indole-3-acetic acid

A. 5-Methoxy-2-miannay in example 1 (part F), 525 mg (2.1 mm) of 5-methoxy-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 168 mg (4.2 mm) mixture of 60% NaH/mineral oil and 450 mg (2.1 mm) of the hydrochloride of 2-chloromethyl-quinoline, as a result, after chromatography on silica (eluent: 25% EtOAc/hexane), was obtained 466 mg (yield 57%) of 5-methoxy-2-methyl-1-[(2-chinolin)methyl]-IH-indole-3-acetic acid ethyl ether complex in the form of an oily substance.

B. Hydrazide-5-methoxy-2-methyl-1-[(2-chinolin)methyl] -IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 446 mg (1.15 mm) of 5-methoxy-2-methyl-1-[(2-chinolin)-methyl]-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.0 ml of hydrazine, resulting, after crystallization from Meon, received 238 mg (yield 55%) of the hydrazide 5-methoxy-2-methyl-1-[(2-chinolin)methyl] -IH-indole-3-acetic acid (so pl. 173-175oC).

Elemental analysis for C22H22N4O2:

Calculated: C 70,57, H of 5.92, N 14,96

Found: C 70,37, Of 6.02 H, N 14,93.

Example 41

Getting hydrazide 5-methoxy-2-methyl-1-(3-phenylpropyl)-IH-indole-3-acetic acid

A. Ethyl ester 5-methoxy-2-methyl-1-(3-phenylpropyl)-IH-indole-3-acetic acid

The fit is about the complex ester was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and 0.3 ml (2 mm) of 1-bromo-3-phenylpropane, as a result, after chromatography on silica (eluent: 25% EtOAc/hexane), was obtained 424 mg (yield 58%) of 5-methoxy-2-methyl-1-(3-phenylpropyl)-IH-indole-3-acetic acid ethyl ether complex in the form of an oily substance.

Elemental analysis for C23H27NO3:

Calculated: C 75,59, H 7,45, N 3,83

Found: C 75,71, H of 7.70, N 3,90

Century Hydrazide 5-methoxy-2-methyl-1-(3-phenylpropyl)-IH-indole-acetic acid

In accordance with the procedure described in example 1 (part G), 308 mg (0.84 mm) 5 methoxy - 2-methyl-1-(3-phenylpropyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 0.9 ml of hydrazine, resulting, after crystallization from MeOH, received 93 mg (yield 31%) of the hydrazide 5-methoxy-2-methyl-1-(3-phenylpropyl)-IH-indole-3-acetic acid (so pl. 133-135oC).

so pl. 133-135oC)

Elemental analysis for C21H25N3O2:

Calculated: C 71,77, H 7,17, N 11,96

Found: C 72,02, H 7,38, N 11,98

Example 42

Receiving hydrazine 5-methoxy-2-methyl-1-(4-phenylbutyl)-IH-indole-3-acetic acid

A. Ethyl ester 5-methoxy-2-methyl-1-(4-phenylbutyl)-IH-indole-3-acetic acid.

In accordance with the procedure described in example 1 ( part F), 494 mg (2 mm) 5-methoxy-2-the oil and 337 mg (2 mm) 4-chloromethylbenzene, as a result, after chromatography on silica (eluent: 20% EtOAv/hexane), was obtained 234 mg (yield 15%) of 5-methoxy-2-methyl-1-(4-phenylbutyl)-IH-indole-3-acetic acid ethyl ether complex in the form of an oily substance.

Elemental analysis for C24H29NO3:

Calculated: C 75,96, H of 7.70, N 3,69

Found: C 76,18, H 7,73, N 3,76

B. Hydrazide 5-methoxy-2-methyl-1-(4-phenylbutyl)-IH-indol-3-ukrasni acid

In accordance with the procedure described in example 1 (part G), 215 mg (0,57 mm) 5-methoxy-2-methyl-1-(4-phenyl-butyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 0.6 milliliters of hydrazine, in resultatet which, after crystallization from MeOH, received 62 mg (yield 30%) of the hydrazide 5-methoxy-2-methyl-1-(4-phenylbutyl)-IH-indole-3-acetic acid (so pl. 133 - 135oC).

Elemental analysis for C22H27N3O2:

Calculated: C 72,30, H 7,45, N 11,50

Found: C 72,32, H 7,45, N 11,35.

Example 43

Getting hydrazide 2-chloro-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid

A. 5-Methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid fenilmetilovy ester

A solution of 2.0 g (10 mm) 5-methoxy-IH-indole-3-acetic acid in 100 ml of DMF portions was treated with 1.0 grams of the obtained mixture was diluted with water and was extracted with EtOAc, and then EtOAcc-the solution was washed with water, saturated NaCl solution and then dried with sodium sulfate. After concentration under reduced pressure, the obtained residue was chromatographically on silicon dioxide, elwira with methylene chloride, which was obtained 3.7 g (yield 96%) of 5-methoxy-1-(phenyl-methyl)-IH-indole-3-acetic acid phenylmethylene of ester in the form of oily substance (structure of the compounds is confirmed by NMR analysis)

B. 2-Chloro-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid fenilmetilovy ester

To a solution of 770 mg (2 mm) 5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid phenylmethylene of ester in 100 ml of CH2Cl2cooling at -5oC, was added 0.6 ml (4.9 mm) of etherate of boron TRIFLUORIDE, and then added to 0.24 ml (3 mm) SO2Cl2. After 10 minutes, to the mixture was added an aqueous solution of NaHCO3and then methylenchloride layer was separated, dried with sodium sulfate and concentrated under reduced pressure. The obtained residue was chromatographically on silicon dioxide, elwira gradient mixture of 15% ether/hexane and 100% ether, resulting in received 100 mg (yield 12%) of 2-chloro-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid phenylmethylene complex e is-(phenylmethyl)-IH-indole-3-acetic acid

A solution of 100 mg (0,238 mm) 2-chloro-5-methoxy-IH-indole-3-acetic acid phenylmethylene of ester and 5 ml of hydrazinehydrate in 40 ml of EtOH was heated under reflux for 1.5 hours. Then the reaction mixture was cooled and was extracted with EtOac, and then EtAOc the solution was washed with saturated NaCl solution and dried with sodium sulfate. After concentration under reduced pressure, the obtained residue was pereirae with ether, and dried, resulting in a received 90 mg (yield 100%) of the hydrazide 2-chloro-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid (so pl. 186 - 187oC).

Elemental analysis for C18H18ClN3O2< / BR>
Calculated: C 62,88, H 5,28, Cl 10,31, N 12,22

Found: C 62,31, H 5,62, Cl 10,63, N 11,30.

Example 44

Getting hydrazide 2-bromo-5-methoxi-1-(phenylmethyl)-IH-indole-3-acetic acid

A. 2-Bromo-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid fenilmetilovy ester

To a solution of 910 mg (2.4 mm) 5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid phenylmethylene of ester (example 44, part a), in 75 ml of CCl4, with stirring, was added 450 mg (2.5 mm) N-bromosuccinimide. After 15 minutes, the reaction mixture was washed with an aqueous solution of Na2S2O4, water and then nasy the obtained residue was chromatographically on silicon dioxide, elwira with methylene chloride, which after crystallization from ether/hexane, received 420 mg (yield 69%) of 2-bromo-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid phenylmethylene of ester (so pl. 89 - 90oC).

Elemental analysis for C25H22BrNO3:

Calculated: 64,66, N 4,78, N 3,02

Found: C 64,43, H 4,75, N 2,96

B. Hydrazide-2-bromo-5-methoxy-1-(phenylmethyl)-IH-indol-3 - ukrasni acid

A solution of 340 mg (0,732 mm) 2-bromo-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid phenylmethylene of ester and 5 ml of hydrazinehydrate in 50 ml of EtOH was heated under reflux for 2.75 hours. The resulting reaction mixture was cooled and was extracted with EtOAc and then EtOac-solution was washed with saturated NaCl solution and dried with sodium sulfate. After concentration under reduced pressure, the obtained residue was chromatographically on silicon dioxide, elwira ether, and then EtOAc, resulting in the received 200 mg (71% yield) of hydrazide 2-bromo-5-methoxy-1-(phenylmethyl)-IH-indole-3-acetic acid (so pl. 178 - 180oC).

Elemental analysis for C18H18BrN3O2:

Calculated: C 55,68, H 4,67, Br 20,58, N 10,82

Found: C 54,02, to 4.52 H, Br 23,17, N 10,69

Example 45

Getting hydrosilylation-1-(phenylmethyl)-IH-indole-3-acetic acid

A solution of 1.0 ml (11 mm) of dimethyl disulfide in 25 ml of methylene chloride was cooled to -25oC, was added 0.8 ml (10 mm), and then the cooling bath was removed and the resulting mixture was stirred and warmed up to room temperature. Then 3 ml of this solution was added 770 mg (2 mm) 5-methoxy-1-)phenylmethyl)-IH-indole-3-acetic acid phenylmethylene of ester (example 44, part a) in 100 ml of methylene chloride. After 0.5 hours, the reaction mixture was washed with an aqueous solution of Na2CO3saturated NaCl solution and dried with sodium sulfate. After concentration under reduced pressure, the obtained residue was chromatographically, elwira gradient mixture of 20% ether/Genkina and 30% ether/hexane, resulting after crystallization from ether/hexane received 600 mg (yield 70%) of 5-methoxy-2-methylthio-1-(phenylmethyl)-IH-indole-3-acetic acid phenylmethylene of ester (so pl. 89 - 90oC).

Elemental analysis for C26H25NO3S:

Calculated: C 72,36, H of 5.84, N 3,25, S 7,75

Found: C 72,43, H by 5.87, N 3,30, S 7,60

B. Hydrazide 5-methoxy-2-methylthio-1-(phenylmethyl)-1H-indole-3-acetic acid

In accordance with the procedure described in example 45 (part B), 240 mg (0,555 mm) 5-methoxy-2-methylthio-1-(phenylmethyl)-1H-indole-3-acetic acid is 5-methoxy-2-methylthio-1-(phenylmethyl)-1H-indole-3-acetic acid (so pl. 181 - 182oC).

Elemental analysis for C19H21N3O2S:

Calculated: C 64,20, H 5,95, N 11,82, S 9,02

Found: C 64,05, H of 5.99, N 11,53, S 8,75

Example 46

Getting hydrazide 5-methoxy-2-methylsulfinyl-1-(phenylmethyl)-1H-indole-3-acetic acid

A. 5-Methoxy-2-methylsulfinyl-1-(phenylmethyl)-1H-indole-3-acetic acid fenilmetilovy ester.

To a solution of 460 mg (1 mm) of 5-methoxy-2-methylthio-1-(phenylmethyl)-1H-indole-3-acetic acid phenylmethylene of ester in 50 ml of methylene chloride was added 200 mg (1.0 mm) N-chloroperbenzoic acid (80 - 85% purity), and then the resulting mixture was stirred for 0.75 hour. After the reaction mixture was washed with a solution of Na2CO3was dried with sodium sulfate and concentrated under reduced pressure, resulting, after chromatography on silica (eluent: methylene chloride, and then ether and crystallization from EtOH, received 424 mg (yield 95%) of 5-methoxy-2-methylsulfinyl-1-(phenylmethyl)-IH-indole-3-acetic acid phenylmethylene of ester in the form of a solid substance.

Elemental analysis for C26H25NO4S:

Calculated: C 69,78, H 5,63, 3,13 N, S 7,16

Found: C 69,99, H 5,76, N 3,24, S 7,11.

B. Hydrazide 5-methoxy-2-m is 45, (part B), 380 mg (0.85 mm) 5-methoxy-2-methylsulfinyl-1-(phenylmethyl)-IH-indole-3-acetic acid phenylmethylene of ester and 3 ml of hydrazine hydrate is added in 30 ml of EtOH was subjected to the reaction, resulting in a received desired product, which was led from EtOAc and then received 270 mg (yield 85%) of the hydrazide 5-methoxy-2-methylsulfinyl-1-(phenylmethyl)-IH-indole-acetic acid (so pl. 172 and 174oC).

Elemental analysis for C19H21N3O3S:

Calculated: 61,44, N 5,70, N 11,31, S 8,42

Found: C 61,34, H 5,67, N 11,20, S 8,63

Example 47

Getting hydrazide 5-fluoro-2-methyl-1-(phenylmethyl)-IH-and ndol-3-acetic acid

A. 5-Fluorescent-2-methyl-IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 14, (part A)., 27,95 g (0.16 M) of the hydrochloride of 4-forevergreen and of 19.72 g (0.17 M) levulinate acid was subjected to reaction and chromatographically on silica (eluent: 5% EtOAc/toluene), resulting in received a 5-fluorescent-2-methyl-IH-indole-3-acetic acid ethyl ester as an oily substance.

Elemental analysis for C13H14FNO2:

Calculated: C 66,37, H 6,00, N 5,95,

Found: C 66,12, H Between 6.08, N By 5.87.

B. 5-Fluorescent-1-(phenylmethyl)-IH-indole-3-acetic acid e is-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and from 0.24 ml (2 mm) benzylbromide, as a result, after chromatography on silica (eluent: 25% EtOAc/hexane) and crystallization from MeOH, got 499 mg (yield 77%) of 5-fluorescent-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex (so pl. 79 - 81oC).

Elementary analysis for C20H20NO2:

Calculated: C 73,83, H 6,20, N 4,30

Found: C 74,12, H 6,30, N OR 4.31

C. Hydrazyl 5-fluorescent-2-methyl-1-(phenylmethyl)-1H-3-acetic acid

In accordance with the procedure described in example 1 ( part G), 450 mg (1.4 mm) 5-fluorescent-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ether complex was subjected to reaction with 2.0 ml of hydrazine, resulting, after crystallization from MEOH, received 170 mg (yield 39%) of the hydrazide 5-fluorescent-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (so pl. 167 - 169oC).

Elemental analysis for C18H18FNO3:

Calculated: C 69,44, H of 5.83, N 13,50

Found: C 69,70, H by 5.87, N 13,67

Example 48

Getting hydrazide 5-chloro-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid

A. 5-Chloro-2-methyl-1H-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 14 (part A), 16,01 g (0,089 M) of the hydrochloride of 4-chlorophenylhydrazone and 10,65 g (0,092 M) levulinate acid abraman), received of 11.5 g (yield 51%) of 5-chloro-2-methyl-IH-indole-3-acetic acid ethyl ether complex in the form of an oily substance.

Elemental analysis for C13H14ClNO2:

Calculated: C 62,03, H 5,61, N 5,57

Found: C 61,97, H 5,58, N 5,85

B. 5-Chloro-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ester.

In accordance with the procedure described in example 1 (part F), 503 mg (2 mm) 5-chloro-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and c of 0.24 ml (2 mm) benzylbromide, after chromatography on silica (eluent: 25% EtOAc/hexane) received 357 mg (yield 52%) 5-chloro-2-methyl-1-(2-phenylethyl)-IH-3-acetic acid ethyl ether complex in the form of an oily substance.

Elemental analysis for C20H20ClNO2:

Calculated: C 70,27, H 5,90, N 4,10

Found: C 70,48, H 5,80, N 3,99

C. Hydrazide 5-chloro-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 324 mg (0,95 mm) 5-chloro-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 2.0 ml of hydrazine, resulting, after crystallization from C).

Elemental analysis for C18H18ClN3O:

Calculated: C 66,95, H of 5.53, N 12,82

Found: C 66,25, H 5,59, N 12,79.

Example 49

Getting hydrazide 5-chloro-(3-course)methyl)-2-methyl-1H-indole-3-acetic acid

A. 5-Chloro-[(3-course)methyl] -2-methyl-1H-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 503 mg (2 mm) 5-chloro-2-methyl-1H-indole-3-acetic acid ethyl ether complex (example 48, part a) was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and 0.25 ml (2 mm) of N-chlorobenzylchloride, resulting, after chromatography on silica (eluent: 20% EtOAc/hexane) and crystallization from MeOH, received 325 mg (yield 43%) of 5-chloro-[(3-course)-methyl] -2-methyl-1-1H-indole-3-acetic acid ethyl ether complex (so pl. 97 - 106oC).

Elemental analysis for C20H19Cl2NO2:

Calculated: C 63,84, H 5,09, N 3,72

Found: C 64,07, H 5,10, N 3,63

B. Hydrazide-5-chloro[(3-chlorophenyl)methyl] -2-methyl-1H-indole-3 - acetic acid

In accordance with the procedure described in example 1 (part G), 315 mg (0,83 mm) 5-chloro-[(3-course)methyl]-2-methyl-1-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 0.9 ml guide the Teal]-2-methyl-1-IH-indole-3-acetic acid (so pl. 168 - 170oC).

Elemental analysis for C18H17Cl2N3O:

Calculated: C 59,68, H 4,73, N 11,60

Found: C 59,79, H a 4.86, N 11,83

Example 50

Getting hydrazide 5-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

A. Ethyl ester 5-bromo-2-methyl-IH-indole-3-acetic acid

In accordance with the procedure described in example 14 (part A), 32,3 n (0,144 M) 4-bromophenylacetonitrile and 15,36 ml (0.15 M) levulinate acid was treated with dry HCl solution in 300 ml of EtOH, resulting, after chromatography on silica (eluent: 5% EtOAc/toluene) were 35,72 g (yield 83%) of 5-bromo-2-methyl-IH-indole-3-acetic acid ethyl ether complex (so pl. 65 - 68oC), which was utverjdali when defending.

Elemental analysis for C13H14BrNO2:

Calculated: C 52,72, H 4,77, N 4,73

Found: C 52,94, H 4,77, N 4,95

B. Ethyl ester 5-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part F), 592 mg (2 mm) 5-bromo-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and from 0.24 ml (2 mm) benzylbromide, resulting, after chromatography NN-indole-3-acetic acid ethyl ether complex (so pl. 83 - 84oC).

Elemental analysis for C20H20BrNO2:

Calculated: C 62,19, H 5,22, N 3,63

Found: C 62,44, H of 5.29, N 3,59

C. Hydrazyl 5-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 312 mg (0.81 mm) 5-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 0,81 milliliters of hydrazine, and after crystallization from MeOH, was obtained 130 mg (yield 43%) of the hydrazide 5-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid (so pl. 181 - 182oC).

Elemental analysis for C18H18BrN3O:

Calculated: C 58,08, H 4,87, N 11,29

Found: C 58,37, H 4,87, N 11,27

Example 51

Getting hydrazide 1-([1,1'-biphenyl]-3-ileti)-5-bromo-2-methyl-IH-indole-3-acetic acid

A. Ethyl ester 1-([1,1'-biphenyl]-3-ylmethyl)-5-bromo-2-methyl-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part F), 592 mg (2 mm) 5-bromo-2-methyl-IH-indole-3-acetic acid ethyl ether complex (example 51, part a) was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and 405 mg (2 mm) 3-chloromethylpyridine. After the reaction mixture was treated and was chromatographically on dioxide to the H-indole-3-acetic acid ethyl ether complex as a yellow oily substance.

Elemental analysis for C26H24BrNO2:

Calculated: C 67,54, H 5,23, N 3,03

Found: C 67,73, N 5,46, N 2,74

B. Hydrazide-1-([1,1'-biphenyl] -3-ylmethyl)-5-bromo-2-methyl-IH - indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 550 mg (1.2 mm) of 1-([1,1'-biphenyl] -3-ylmethyl)-5-bromo-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.2 milliliters of hydrazine, resulting, after crystallization from MeOH, got 290 mg (yield 54%) hydrazide 1-([1,1'-biphenyl]-3-ylmethyl)-5-bromo-2-methyl-IH-indole-3-acetic acid (so pl. 162-164oC).

Elemental analysis for C24H22BrN3O:

Calculated: C 64,29, H 4,94, N 9,37

Found: C 64,52, H Of 5.05, N 9,16.

Example 52

Getting hydrazide 1-[(3-benzyloxyphenyl)methyl] -5-bromo-2-methyl-IH-indole-3-acetic acid

A. 1-[(3-Benzyloxyphenyl)-methyl]-5-bromo-2-methyl-1-IH-indole - 3-acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 592 mg (2 mm) 5-bromo-2-methyl-IH-indole-3-acetic acid ethyl ether complex (example 51, part a) was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and 465 mg (2 mm) 3-benzyloxybenzaldehyde. After the reaction mixture abroad 60%) 1-[(3-benzyloxyphenyl)-methyl]-5-bromo-2-methyl-IH-indole-3-acetic acid ethyl ether complex in the form of an oily substance.

B. Hydrazide 1-[(3-benzyloxyphenyl)methyl] -5-bromo-2-methyl-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 565 mg (1.15 mm) 1-[(3-benzyloxyphenyl)methyl]-5-bromo - 2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 1.2 ml of hydrazine, resulting, after crystallization from MeOH, got 318 mg (yield 60%) of the hydrazide 1-[(3-benzyloxyphenyl)-methyl]-5-bromo-2-methyl-IH-indole-3 - acetic acid (so pl. 163-164oC).

Elemental analysis for C23H24BrN3O2:

Calculated: C 62,77, H is 5.06, N 8,78

Found: C 62,69, H to 5.21, N 8,75

Example 53

Getting hydrazide of 4-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

A. 6-Bromo-2-methyl-IH-indole-3-acetic acid ethyl ester and

6-bromo-2-methyl-IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 14 (part A), 25,0 g (0,112 M) of the hydrochloride of 3-bromophenethylamine and to 12.28 ml (0.12 M) levulinate acid was treated with dry HCl solution in 30 ml of EtOH, and then the reaction mixture is again processed and received an oily substance. After chromatography on silica (eluent% 15 EtOAc/toluene) received an early fraction (11,84 g, yield 36%) of 6-bromo-2-IU.

Elemental analysis for C13H14BrNO2:

Calculated: C 52,72, H 4,77, N 4,73

Found: C 53,59, H 4,89, N OR 4.31

In the chromatography described above, the later fractions in the form of oily substance was pereirae with cyclohexane and received 1.8 g (yield of 5.5%) 4-bromo-2-methyl-IH-indole-3-acetic acid ethyl ether complex (so pl. 74-84oC).

Elemental analysis for C13H14BrNO2:

Calculated: C 52,72, H 4,77, N 4,73

Found: C 52,97, H 4,78, N 4,66.

B. Ethyl ester 4-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part F), 1.18 g (4 mm) 4-bromo-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 160 mg (2 mm) of a mixture of 60% NaH/mineral oil and of 0.48 ml (4 mm) benzylbromide, resulting, after chromatography on silica (eluent: 25% EtOAc/hexane) and crystallization from MeOH, got 1,2 (yield 78%) 4-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex (so pl. 133-135oC).

Elemental analysis for C20H20BrNO2:

Calculated: C 62,19, H 5,22, N 3,63

Found: C 62,46, H 5,31, N 3,64

C. Hydrazide-4-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic Kikinda-3-acetic acid ethyl ether complex was subjected to reaction with 1.0 ml of hydrazine, after crystallization from MeOH, received 214 mg (yield 58%) of the hydrazide of 4-bromo-2-methyl-1-(phenylmethyl)-IH-indole - 3-acetic acid (so pl. 182-183oC).

Elemental analysis for C18H18BrN3O:

Calculated: C 58,08; H to 4.87; N 11,29

Found: C 58,11, H 4,90, N 11,49.

Example 54

Getting hydrazide 6-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

A. Ethyl ester of 6-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part F), 1.18 g (4 mm) 6-bromo-2-methyl-IH-indole-3-acetic acid ethyl ether complex (example 54, part a) was subjected to reaction with 160 mg (2 mm) of a mixture of 60% NaH/mineral oil and of 0.48 ml (4 mm) benzylbromide. After the reaction mixture was chromatographically on silica (eluent: 25% EtOAc/hexane) and was led from MeOH, resulting in received 776 mg (yield 50%) of 6-bromo-2-methyl-1-(2-phenylethyl)-IH-indole-3-acetic acid ethyl ether complex (so pl. 99-100oC).

Elemental analysis for C20H20BrNO2:

Calculated: C 62,19, H 5,22, N 3,63

Found: C 62,18, H Of 5.29, N 3,59.

B. Hydrazide 6-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure, the author ether was subjected to reaction with 1.0 ml of hydrazine, as a result, after crystallization from MeOH, received 178 mg (yield 51%) of the hydrazide 6-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid (so pl. 183-184oC).

Elemental analysis for C18H18Br3O:

Calculated: C 58,08, H 4,87, N 11,29

Found: C with 58.33, H 4,96, N 11,28

Example 55

Getting hydrazide 2-methyl-4-phenyl-1-(phenylmethyl)-IH-indole-3-acetic acid

A. 2-Methyl-4-phenyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ester

To 25 ml of EtOH was added 386 mg (1.0 mm) 4-bromo-2 - methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex (example 54, part B), 139 mg (0.12 mmol) of Pd[P(C6H5)3]4and 4.5 ml of 2M solution of Na2CO3. Then to this solution was added 281 mg (2.8 mm) phenylboric acid in 5 ml of EtOH and the reaction mixture was heated under reflux for 16 hours. After cooling, the mixture was diluted with EtOAc and filtered through celite. The obtained filtrate was washed with water and saturated NaCl solution and then dried with magnesium sulfate and concentrated under reduced pressure. The obtained residue was chromatographically on silicon dioxide, elwira a mixture of 25% EtOAc and hexane, and then recrystallized twice from MeOH, resulting in received 142 ).

Elemental analysis for C26H25NO2:

Calculated: C 81,43, H 6,57, N 3,65

Found: C 81,15, H 6,70, N 3,71.

B. Hydrazide 2-methyl-4-phenyl-1-(phenylmethyl)-IH-indole-3-acetic acid.

In accordance with the procedure described in example 1 (part G), 127 mg (0.33 mm) of 2-methyl-4-phenyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 0.35 ml of hydrazine and after crystallization from MeOH/hexane, received 40 mg (yield 32%) of 2-methyl-4-phenyl-1-(phenylmethyl)-IH-indole-3-acetic acid hydrazide (so pl. 73-77oC).

Elemental analysis for C24H23N3O:

Calculated: C 78,02, H 6,27, N 11,37

Found: C 78,10, H 6,35, N 11,44.

Example 56

Getting hydrazide 2-methyl-5-phenyl-1-(phenylmethyl)-IH-indole-3-acetic acid

A. Ethyl ester of 2-methyl-5-phenyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 56 (part A), 266 mg (0.7 mm) 5-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex (example 51, part B), 194 mg (has 0.168 mm) of Pd[P(C6H5)3]4, 3.2 ml of 2M solution of Na2CO3and 196 mg (1.6 mm) phenylboric acid was subjected to the reaction, and then the resulting reaction mixture chromatographia ylmethyl)-IH-indole-3-acetic acid ethyl ether complex (so pl. 116-119oC).

Elemental analysis for C26H25NO2:

Calculated: C 81,43, H 6,57, N 3,65

Found: C 81,41, H 6,64, N 3,85

B. Hydrazide 2-methyl-5-phenyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 80 mg (0.2 mm) of 2-methyl-5-phenyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 0.5 ml of hydrazine, resulting, after crystallization from MeOH, received 26 mg (yield 35%) of hydrazide 2-methyl-5-phenyl-1-(phenylmethyl)-IH-indole-3-acetic acid (so pl. 154-156oC).

Elemental analysis for C24H23N3O:

Calculated: C 78,02, H 6,27, N 11,37

Found: C 78,26, H 6,28, N 11,34

Example 57

Getting hydrazide 2-methyl-6-phenyl-1-(phenylmethyl)-IH-indole-3 - acetic acid

A. Ethyl ester of 2-methyl-6-phenyl-1-(phenylmethyl)-IH - indole-3-acetic acid

In accordance with the procedure described in example 56 (part A), 386 mg (1.0 mm) of 6-bromo-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex (example 55, part a), 139 mg (0.12 mmol) of Pd[P(C6H5)3]4, and 4.5 ml of 2M solution of Na2CO3and 281 mg (2.3 mm) phenylboric acid was subjected to the reaction and then the reaction mixture is 52%) 2-methyl-6-phenyl-1- (phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex (so pl. 90-93oC).

Elemental analysis for C26H25NO2:

Calculated: C 81,43, H 6,57, N 3,65

Found: C 81,20, H 6.73 X, N 3,70.

B. Hydrazide 2-methyl-6-phenyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 170 mg (0.2 mm) of 2-methyl-6-phenyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 0.45 ml of hydrazine, resulting, after crystallization from MeOH, received 66 mg (yield 41%) of hydrazide 2-methyl-6-phenyl-1-(phenylmethyl)- IH-indole-3-acetic acid (so pl. 146-147oC).

Elemental analysis for C24H23N3O:

Calculated: C 78,02, H 6,27, N 11,37

Found: C 78,24, H 6,26, N 11,27.

Example 58

Getting hydrazide 1-[(3-benzyloxyphenyl)methyl]-2-methyl-5 - phenyl-IH-indole-3-acetic acid

In accordance with the procedure described in example 56 (part A), 95,6 mg (0.02 mm) 1-[(3-benzyloxyphenyl)methyl]-5-bromo-2-methyl-IH - indole-3-acetic acid hydrazide (example 53, part B), 28 mg (0.024 mm) of Pd[P(C6H5)3]4, 0.9 ml of 2M solution of Na2CO3and 56,12 mg (0.46 mm) phenylboric acid was subjected to the reaction, and then the resulting reaction mixture was subjected to chromatography on silica, elwira mixture is hydrazide 1-[(3-benzyloxyphenyl)-methyl]-2-methyl-5-phenyl-IH-indole-3-acetic acid (so pl. 114-121oC).

Elemental analysis for C31H29N3O2:

Calculated: C 78,29, H x 6.15, N 8,84

Found: C 78,37, H 6,20, N 9,06

Example 59

Getting hydrazide 2,5-dimethyl-1-(phenylmethyl)-IH-indole-3 - acetic acid

A. Ethyl ester of 2,5-dimethyl-IH-indole-3-acetic acid

In accordance with the procedure described in example 14 (part A), 25 g (0,158 M) 4-methylphenylacetonitrile and 18.3 g (0,158 M) levulinate acid was treated with dry hydrochloric acid in 500 ml of EtOH and after chromatography on silica (eluent: 5% EtOAc/toluene) were of 30.3 g (yield 77%) of 2,5-dimethyl-IH-indole-3-acetic acid ethyl ether complex, which was then utverjdali when stevenii (so pl. 40-42oC).

Elemental analysis for C14H17NO2:

Calculated: C 72,70, H 7,41, N 6,06

Found: C 72,53, H rate of 7.54, N 6,00

B. Ethyl ester of 2,5-dimethyl-1-(phenylmethyl)-IH-indole-3 - acetic acid

In accordance with the procedure described in example 1 (part F), 464 mg (2 mm) of 2,5-dimethyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaN/mineral oil and from 0.24 ml (2 mm) benzylbromide. After the reaction mixture was chromatographically on the silicon dioxide is false ether (so pl. 66-69oC).

Elemental analysis for C21H23NO2:

Calculated: C of 78.47, H 7,21, N 4,36

Found: C 78,27, H 7,13, N 4,36

C. Hydrazide 2,5-dimethyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 375 mg (1.2 mm), 2,5-dimethyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 2.0 ml of hydrazine, resulting, after crystallization from MeOH, got 144 mg (yield 39%) of the hydrazide of 2,5-dimethyl-1-(phenylmethyl)-IH-indole-3 - acetic acid (so pl. 165-166oC).

Elemental analysis for C19H21N3O:

Calculated: C 74,24, H 6,89, N 13,67

Found: C 74,49, H For 6.81, N 13,77.

Example 60

Getting hydrazide 5-tert-butyl-2-methyl-1-(phenylmethyl)-IH - indole-3-acetic acid

A. 5-tert-Butyl-2-methyl-IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 14 (part A), 10 g (0.05 M) of 4-tert-butterfingered and 5.8 g (0.05 M) levulinate acid was treated with dry hydrochloric acid in 200 ml of EtOH. The resulting mixture was chromatographically on silica (eluent: 5% EtOAc/toluene) and received 5-tert-butyl-2 - methyl-IH-indole-3-acetic acid ethyl with the/BR> Calculated: C 74,69, H 8,48, N 5,12

Found: C 72,95, H at 8.36, N 6,29

B. 5-tert-butyl-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ester

In accordance with the procedure described in example 1 (part F), 546 mg (2 mm) 5-tert-butyl-2-methyl-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and from 0.24 ml (2 mm) benzylbromide. After that, the obtained reaction mixture was chromatographically on silicon dioxide, elwira a mixture of 33% EtOAc/hexane, and received 448 mg (yield 62%) of 5-tert-butyl-2-methyl-1-(2-phenylethyl)-IH-indole-3-acetic acid ethyl ether complex (so pl. 102-105oC).

Elemental analysis for C24H29NO2:

Calculated: C 79,30, H 8,04, N 3,85

Found: C 79,40, H 8,14, N Of 4.04.

C. Hydrazide 5-tert-butyl-2-methyl-1-(phenylmethyl)-IH-indole-3 - acetic acid

In accordance with the procedure described in example 1 (part G), 396 mg (1.1 mm) 5-tert-butyl-2-methyl-1-(phenylmethyl)-IH-indole-3 - acetic acid ethyl ether complex was subjected to the reaction, 2.0 ml of hydrazine, resulting, after crystallization from MeOH, received 89 mg (yield 23%) of 5-tert-butyl-2-methyl-1-(phenylmethyl)-IH-indole-3 - acetic acid hydrazide (so pl. 149-151oC).

Element as the example 61

Getting hydrazide 5-hydroxy-2-methyl-1-(phenylmethyl)-IH-indole - 3-acetic acid

To a solution of 165 mg (0.51 mm) hydrazide 5-methoxy-2-methyl-1- (phenylmethyl)-IH-indole-3-acetic acid (example 16, part B) in 30 ml of CH2Cl2was added 1.0 ml of 1M solution of BBr3in CH2Cl2and the resulting mixture was stirred for 1.5 hours, and then to this mixture was added 0.5 ml of a solution of BBr3. After 1.5 hours the reaction mixture was washed with sodium carbonate solution, dried with sodium sulfate and concentrated under reduced pressure. The obtained residue was chromatographically on silicon dioxide, elwira a mixture of 2% MeOH/CH2Cl2and 5% MeOH/CH2Cl2and received 60 mg (yield 39%) of the hydrazide 5-hydroxy-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid (so on. 216-219oC).

Elemental analysis for C18H19N3O2:

Calculated: C 69,88, H is 6.19, N OF 13.58

Found: C 69,65, H 6,25, N 13,46.

Example 62

Getting hydrazide 2-methyl-1-(phenylmethyl)-5-[(2-chinolin)- methoxy]-IH-indole-3-acetic acid

A. 5-Methoxy-2-methyl-IH-indole-3-acetic acid methyl ester.

A solution of 12.2 g (0,0557 M) 5-methoxy-2-methyl-IH-indole-3-acetic acid in 150 ml of MeOH and 1 ml of sulfuric acid agravante sodium and was extracted with EtOAc. Then EtOAc solution was washed with saturated NaCl solution and dried with sodium sulfate. After that, the solvent was removed under reduced pressure and obtained 13 g of crude methyl ether complex 5-methoxy-2-methyl-IH-indole-3-acetic acid.

B. 5-Methoxy-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

The crude methyl ester 5-methoxy-2-methyl-IH-indole-3 - acetic acid (example 62, part A) (56 mm) was dissolved in 250 ml of DMF and approximately 10 ml of THF, and then added 2.5 g (62 mm) mixture of 60% NaH/mineral oil. After 0.5 hour, to the mixture was added 8 ml (67 mm) benzylbromide, and the resulting mixture was stirred for 0.75 hour, diluted with water and extracted with ethyl acetate. The product was chromatographically on silica (eluent: 20% ether, hexane and 50% ether/hexane) and got to 10.1 g of a mixture of methyl and ethyl esters of 5-methoxy-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid. Then the resulting mixture was dissolved in 200 ml EtOH and 20 ml of 5 n NaOH solution, after which the mixture was heated under reflux for 20,75 hours. After cooling, this mixture was acidified 5 N. hydrochloric acid and was extracted with ethyl acetate. EtOAc solution was washed with NaCl, dried with sodium sulfate and to whom-(phenylmethyl)-IH-indole-3-acetic acid.

C. 5-Hydroxy-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid methyl ester

To 3.1 g (10 mm) 5-methoxy-2-methyl-1-(phenylmethyl)-IH-indole-3 - acetic acid in 250 ml of methylene chloride was added 3 ml (30 mm) BBr3and then the mixture was stirred for 17 hours. After stirring, to the mixture was added 1 n hydrochloric acid and a certain amount of EtOH. The obtained organic layer was separated, washed with saturated NaCl solution, dried and concentrated under reduced pressure, resulting in a received 2,95 g (yield 100%) of crude 5-hydroxy-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid. In accordance with the procedure described in example 62 (part A), 1.7 g of a methanol solution was treated with sulfuric acid and after chromatography on silica gel (eluent: 30% ether/hexane ---> 60% ether/hexane) received 1.5 g of 5-hydroxy-2-methyl-1-(phenylmethyl)-IH - indole-3-acetic acid methyl ether complex.

D. 2-Methyl-1-(phenylmethyl)-5-[(2-chinolin)methoxy] -IH-indole-3 - acetic acid methyl ester

In accordance with the procedure described in example 1 (part F), 750 mg (2.4 mm) 5-hydroxy-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid methyl oil and 500 mg (2.8 mm) 2-chloromethylpyridine was subjected to reaction, and receiving the UB>2
) and was obtained 1.1 g (yield 65%) of 2-methyl-1-(phenylmethyl)-5-[(2-chinolin)methoxy] -IH - indole-3-acetic acid methyl ether complex, if so pl. 113-114oC.

Elemental analysis for C29H26N2O3:

Calculated: C 77,31, H of 5.82, N 6,22

Found: C 77,41 H of 5.89, N 6,09

E. Hydrazide 2-methyl-1-(phenylmethyl)-5-[(2-chinolin)methoxy]-IH - indole-3-acetic acid

In accordance with the procedure described in example 1 part G), 700 mg (1,55 mm) of 2-methyl-1-(phenylmethyl)-5-[(2-chinolin)methoxy]-IH-indole - 3-acetic acid methyl of ester and 3 ml of hydrazine was subjected to reaction and then the reaction mixture was cooled and filtered, resulting in a received 450 mg (yield 64%) of hydrazide 2-methyl-1-(phenylmethyl)-5-[(2-chinolin)methoxy]-IH-indole-3-acetic acid (so pl. 195-197oC).

Elemental analysis for C28H26N4O2:

Calculated: C 74,65, H of 5.82, N 12,43

Found: C 74,69, H of 5.82, N OF 12.33

Example 63

Getting hydrazide 1-[(4-chlorophenyl)-methyl] -2-methyl-5-[(2 - chinolin)methoxy]-IH-indole-3-acetic acid

A. 1-[(4-chlorophenyl)methyl]-5-methoxy-2-methyl-IH-indole-3-acetic acid

In accordance with the procedure described in example 63 (part B), 1.35 g (5.5 mm) 5-methoxy-2-methyl-IH-indole-3-acetic acid this is chloride, the result that was obtained 1.4 g of 1-[(4-chlorophenyl)-methyl] -2-methyl-5-methoxy-IH-indole-3-acetic acid ethyl ether complex, which was subjected to chromatography on silica (eluent: 20% ether/hexane ---> 35% ether, hexane). Then the obtained ester hydrolyzed with 3 ml of 5 n NaOH solution and got to 1.23 g of the crude 1-[(4-chlorophenyl)methyl]-5-methoxy - 2-methyl-IH-indole-3-acetic acid.

B. 1-[(4-Chlorophenyl)methyl]-5-hydroxy-2-methyl-IH-indole-3 - acetic acid methyl ester

In accordance with the procedure described in example 63 (part C), 1.2 g (3.5 mm) 1-[(4-course)-methyl-5-methoxy-2-methyl-IH-indole-3 - acetic acid was treated with 15 ml of 1M solution of BBr3in CH2Cl2and obtained crude 1-[(4-chlorophenyl)-methyl]-5-hydroxy-2-methyl-IH-indole-3-acetic acid. Then the obtained acid was treated with sulfuric acid in MeOH and received 1.2 g of 1-[(4-chlorophenyl)methyl]-5-hydroxy-2-methyl-IH - indole-3-acetic acid methyl ether complex.

C. 1[(4-chlorophenyl)methyl]-2-methyl-5-[(2-chinolin)-methoxy]-IH - indole-3-acetic acid methyl ester

In accordance with the procedure described in example 1 (part F), 750 mg (2.1 mm) of 1-[(4-chlorophenyl)methyl]-5-hydroxy-2-methyl-IH-indole-3-acetic kislali reaction, and the resulting reaction mixture was chromatographically on silica (eluent: CH2Cl2_ 2% MeOH/CH2Cl2) and was led from ether/hexane, resulting in received 565 mg (yield 57%) of 1-[(4-chlorophenyl)methyl]-2-methyl-5-[(2-chinolin)-methoxy] -IH - indole-3-acetic acid methyl ether complex (so pl. 101-103oC).

Elemental analysis for C29H25ClN2O3:

Calculated: C 71,82, H 5,20, N 5,78, Cl 7,31

Found: C 72,03, H of 5.29, N 5,65, Cl to 7.59

D. Hydrazide 1-[(4-chlorophenyl)metal] -2-methyl-5-[(2-chinolin)- methoxy]-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 680 mg (1.4 mm) of 1-[(4-course)-methyl] -2-methyl-5-[(2-chinolin)- methoxy]-IH-indole-3-acetic acid methyl of ester and 3 ml of hydrazine was subjected to reaction and then the reaction mixture was led from EtOH, resulting received 440 mg (yield 65%) hydrazide 1-[(4-course)methyl] -2-methyl-5-[(2-chinolin)methoxy] - IH-indole-3-acetic acid (so pl. 191-193oC).

Elemental analysis for C28H25ClN4O2:

Calculated: C 69,34, H 5,20, N 11,55, Cl 7,31

Found: C 68,77, H 5,20, N 11,42, Cl 7,87.

Example 64

Getting hydrazide 5-methoxy-1-(phenylmethyl)-IH-indol-3 - disappear is a procedure, described in example 1 (part E), 8,83 g (0,06 M) 5-methoxy-IH-indole was treated to 37.5 milliliters (0,06 M) of 1.6 M solution of n-utility in hexane, 60 ml (0,06 M) 1M solution of zinc chloride in ether and 6.7 milliliters (0,06 M) of methyl 2-bromopropionate, resulting, after chromatography on silica (eluent: 10% EtOAc/hexane), was obtained 7.0 g (yield 50%) 5-methoxy-IH-indol-3-propanoate acid methyl ether complex in the form of an oily substance.

Elemental analysis for C13H15NO3:

Calculated: C 66,94, H 6,48, N 6,00

Found: C 67,20, H 6,69, N Between 6.08.

B. 5-Methoxy-1-(phenylmethyl)-IH-indole-3-propanoic acid methyl ester

In accordance with the procedure described in example 1 (part F), 466 mg (2 mm) 5-methoxy-IH-indole-3-propanoic acid methyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and 0.24 ml (2 mm) benzylbromide, after chromatography on silica (eluent: 25% EtOAc/hexane), was obtained 469 mg (yield 73%) of 5-methoxy-1-(phenylmethyl)-IH-indole-3-propanoic acid methyl ether complex in the form of an oily substance.

Elemental analysis for C20H21NO3:

Calculated: C 74,28, H is 6.54, N 4,33

Found: C 74,49, H 6,80, N 4,32
< / the example 1 (part G), 444 mg (1.4 mm) of 5-methoxy-(1-phenylmethyl)-IH-indole-3-propanoic acid methyl ether complex was subjected to reaction with 1.4 ml of hydrazine, resulting, after crystallization from MeOH, received 279 mg (yield 62%) of the hydrazide 5-methoxy-1-(1-phenylmethyl)-IH-indole-3 - propanoic acid (so pl. 152 - 156oC).

Elemental analysis for C19H21N3O2:

Calculated: C 70,57, H 6,55, N 12,99

Found: C 70,41, H 6,62, N 13,11.

Example 65

Getting hydrazide 2-methoxy-2-methyl-1-(phenylmethyl)-IH-indole - 3-propanoic acid

A. 5-Methoxy-2-methyl-IH-indole-3-propanoic acid methyl ester

In accordance with the procedure described in example 1 (part E), 9,67 g (0,06 M) 5-methoxy-2-methyl-IH-indole was treated to 37.5 milliliters (0,06 M) 1.6 M solution of n-utility in hexane, 60 ml (0,06 M) 1M solution of zinc chloride in ether, and 6.7 milliliters (0,06 M) of methyl 2-bromopropionate, resulting, after chromatography on silica (eluent: 10% EtOAc/hexane), was obtained 8.7 g (yield 59%) 5-methoxy-2-methyl-IH-indole-3-propanoic acid methyl ether complex in the form of an oily substance.

Elemental analysis for C14H17NO3:

Calculated: C 68,00, H 6,93, N the ceiling of 5.60

Found: C 67,73, H 6,92, N 5,72

B. 5-Unit-2-methyl-IH-indole-3-propanoic acid methyl complex ester in 40 ml of DMF was treated to 1.12 grams (0.01 M) t-butoxide potassium and was stirred for half an hour, and then added to 1.15 ml (0.01 M) benzylchloride. After 72 hours the reaction mixture was diluted with water and was extracted with EtOAc, then EtOAc solution four times washed with water and dried with sodium sulfate. After concentration under reduced pressure, the product was chromatographically on silicon dioxide, elwira gradient mixture of toluene and 10% EtOAc/toluene, resulting in a received 2,03 g (yield 61%) of 5-methoxy-2-methyl-1-(phenylmethyl)-IH - indole-3-propanoic acid methyl ether complex in the form of an oily substance.

Elemental analysis for C21H23NO3:

Calculated: C 74,75, H 6,87, N 4,15

Found: C 74,69, H 7,05, N 4,29.

C. Hydrazide 5-methoxy-2-methyl-1-(phenylmethyl)-IH-indole-3 - propanoic acid

In accordance with the procedure described in example 1 (part G), 2.0 g (0,054 M) 5-methoxy-2-methyl-1-(phenylmethyl)-IH-indole-3-propanoic acid methyl ether complex was subjected to reaction with 5 ml of hydrazine. After that, the obtained reaction mixture was subjected to chromatography on silica, elwira a mixture of CH2Cl2_ 10% MeOH/CH2Cl2, and obtained 0.8 g (yield 40%) of 5-methoxy-2-methyl-1-(phenylmethyl)-IH-indole-3-propanoic acid hydrazide in the form of a waxy substance.

Element the
Example 66

Getting hydrazide 5-methoxy-1-(phenylmethyl)-IH-indol-3 - butane acid

A. Ethyl ester 5-methoxy-IH-indol-3-butane acid

In accordance with the procedure described in example 1 (part E), 8,83 g (0,06 M) 5-methoxy-IH-indole was treated to 37.5 milliliters (0,06 M) 1.6 M solution of n-utility in hexane, 60 ml (0,06 M) 1M solution of zinc chloride in ether and 8,86 milliliters (0,06 M) ethyl-2-bromobutyrate, resulting, after chromatography on silica (eluent gradient: toluene _ 10% EtOAc/hexane), was obtained 7.8 g (yield 50%) 5-methoxy-2-IH-indol-3-butane acid ethyl ether complex in the form of oily substance:

Elemental analysis for C15H19NO3:

Calculated: C 68,94, H 7,33, N ARE 5.36

Found: C 66,84, H 7,50, N 5,50

B. 5-Methoxy-1-(phenylmethyl)-IH-indol-3-butane acid ethyl ester

In accordance with the procedure described in example 1 (part F), 496 mg (1.9 mm) of 5-methoxy-IH-indol-3-butane acid ethyl ether complex was subjected to reaction with 80 ml (2 mm) of a mixture of 60% NaH/mineral oil and from 0.24 ml (2 mm) benzylbromide. After that, the obtained reaction mixture was subjected to chromatography on silica, elwira 25% EtOAc/hexane, and received 526 mg (yield 79%) of 5-methoxy> Elemental analysis for C22H25NO3:

Calculated: C 75,19, H 7,17, N 3,99

Found: C 74,99, H 7,13, N 4,28.

C. Hydrazide 5-methoxy-1-(phenylmethyl)-IH-indol-3-butane acid

In accordance with the procedure described in example 1 (part G), 525 mg (1.4 M) 5-methoxy-1-(phenylmethyl)-IH-indol-3-butane acid ethyl ether complex was subjected to reaction with 1.4 ml of hydrazine, resulting, after crystallization from MeOH, received 232 mg (yield 51%) of the hydrazide 5-methoxy-1-(phenylmethyl)-IH-indol-3 - butane acid (so pl. 140 - 141oC).

Elemental analysis for C20H23N3O2:

Calculated: C 71,19, H 6,87, N 12,45

Found: C 70,95, H 6,82 N 12,46.

Example 67

Getting hydrazide 5-methoxy-2-methyl-1-(phenylmethyl)-IH-indol - 3-butane acid

A. 5-Methoxy-2-methyl-IH-indol-3-butane acid ethyl ester

In accordance with the procedure described in example 1 (part H), 9,67 g (0,06 M) 5-methoxy-2-methyl-IH-indole was treated to 37.5 milliliters (0,06 M) 1.6 M solution of n-utility in hexane, 60 ml (0,06 M) 1M solution of zinc chloride in ether and 8,86 milliliters (0,06 M) ethyl-2-bromobutyrate. The resulting mixture was chromatographically on silica (eluent gradient: toluene _ 10% EtOAc/hexane) and the floor of the substance.

Elemental analysis for C16H21NO3:

Calculated: C 69,79, H of 7.69, N 5,09

Found: C 69,51, H 7,71, N 5,39.

B. 5-Methoxy-2-methyl-1-(phenylmethyl)-IH-indol-3-butane acid ethyl ester

In accordance with the procedure described in example 1 (part F), 522 mg (1.9 mm) of 5-methoxy-2-methyl-IH-indol-3-butane acid ethyl ether complex was subjected to reaction with 80 mg (2 mm) of a mixture of 60% NaH/mineral oil and from 0.24 ml (2 mm) benzylbromide, after chromatography on silica (eluent: 25% EtOAc/hexane) received 550 mg (yield 79%) 5-methoxy-2-methyl-1-(phenylmethyl)-IH-indol-3-butane acid ethyl ether complex in the form of an oily substance.

Elemental analysis for C23H27NO3:

Calculated: C 75,59, H 7,45, N 3,83

Found: C 75,72, H of 7.68, N 3,82

C. Hydrazide 5-methoxy-2-methyl-1-(phenylmethyl)-IH-indol-3 - butane acid

In accordance with the procedure described in example 1 (part G), 525 mg (1.4 mm) of 5-methoxy-2-methyl-1-(phenylmethyl)-IH-indol-3 - butane acid ethyl ether complex was subjected to reaction with 1.4 mg of hydrazine, resulting, after chromatography on silica (eluent: 50% EtOAc/hexane _ EtAOc), received 172 mg (yield 35%) 5-hydrazide 5-methoxy-2-methyl-1-(phenylmethyl)-IB>N3O2:

Calculated: C 71,77, H 7,17, N 11,96

Found: C 71,99, H 7,44, N 12,16

Example 68

Getting hydrazide 5-carboxy-[(3-course)methyl] -2 - methyl-IH-indole-3-acetic acid

A. 5-Etoxycarbonyl-2-methyl-IH-indole-3-acetic acid ethyl ester

Within half an hour through a solution of 25 g (0,1643 M) 4-hydrazinobenzene acid and 20.5 ml (0.2 M) levulinate acid was barbotirovany dry hydrogen chloride, and then the resulting reaction mixture was heated under reflux for 20 hours. After cooling, the mixture was concentrated under reduced pressure, adding water and then was extracted with a mixture of EtOAc/ether. After drying with sodium sulfate, the solution was concentrated, and the obtained residue was chromatographically on silicon dioxide, elwira gradient mixture of toluene and > 20% EtOAC/toluene, which was received late fractions 12 g of a mixture of 5-etoxycarbonyl-2-methyl-IH-indole-3 - acetic acid ethyl ether complex and the intermediate hydrazone. Then the mixture was again treated with dry hydrochloric acid in 250 ml of EtOH and heated under reflux for 16 hours. After cooling, the mixture was poured into water and was extracted with EtOAc, then EtOAc solution was washed with a solution of Na is mnia (eluent: toluene _ 20% EtOAc/toluene) was obtained 3.6 g (yield of 7.6%) 5-etoxycarbonyl-2-methyl-IH-indole-3-acetic acid ethyl ether complex (so pl. 74-76oC).

Elemental analysis for C16H19NO4:

Calculated: C 66,42, H 6,62, N 4,84

Found: C 66,54, H 5,00, N accounted for 10.39

B. 1-[(3-Course)-methyl]-5-etoxycarbonyl-2-methyl-IH-indole - 3-acetic acid ethyl ester

In accordance with the procedure described in example 3 (part E), 1.1 g (0,0038 M) 5-etoxycarbonyl-2-methyl-IH-indol-3-uksusnoi acid ethyl ether complex was subjected to reaction from 0.43 ml (0,0038 M) t-butoxide potassium and 0,482 ml (0,0038 M) 3-chlorobenzylchloride, resulting, after chromatography on silica (eluent: gradient of a mixture of toluene and 20% EtOAc/toluene) were of 0.54 g (yield 34%) 1-[(3-course)methyl]-5-etoxycarbonyl-2-methyl-IH-indole-3 - acetic acid ethyl ether complex (so pl. 100-102oC).

Elemental analysis for C23H24ClNO4:

Calculated: C 66,74, H 5,85, N 3,38

Found: C 66,68, H 5,93, N 3,20

C. 5-Carboxy-1-[(3-course)methyl]-2-methyl-IH-indole-3 - acetic acid methyl ester

A solution of 0.27 g (0.65 mm) 1-[(3-course)methyl]-5 - etoxycarbonyl-2-methyl-IH-indole-3-acetic acid ethyl of ester and 2 ml of a 5 n solution of NaOH in 40 ml of EtOH was heated under reflux for 4 hours. After cooling, the mixture was diluted with water and extragere and the resulting residue was led from MeOH, as a result, we received 100 mg (yield 43%) of 5-carboxy-1-[(3-course)- methyl]-2-methyl-IH-indole-3-acetic acid methyl ether complex (so pl. 216-217oC).

Elemental analysis for C20H18ClNO4:

Calculated: C 64,60, H 4,88, N 3,99

Found: C 64,49, H 5,00, N 3,10.

D. Hydrazide-5-carboxy-1-[(3-course)methyl]-2-methyl-IH - indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 660 mg (1.6 mm) 5-carboxy-1-[(3-course)-methyl] -IH-indole-3 - acetic acid methyl ether complex was subjected to reaction with 1.0 ml of hydrazine. After that, the obtained reaction mixture was led from EtOH and received 10 mg (yield 10%) of the hydrazide 5-carboxy-1-(3-course)-methyl-2-methyl-IH-indole-3-acetic acid, with so pl. 216-217oC.

Elemental analysis for C19H18ClN3O3< / BR>
Calculated: C 61,37, H 4,88, N 11,30

Found: C 61,16, H 5,07, N 11,54.

Example 69

Getting hydrazide 1-[(3-course)methyl] -5-hydrazinophenyl-2-methyl-1H-indole-3 - acetic acid

In accordance with the procedure described in example 1 (part G), 270 mg (0.65 mm) 1-[(3-course)methyl]-5-etoxycarbonyl-2-methyl-1H-indole-3 - acetic acid ethyl ether complex (example 71, part B) were subjected to loropeni)methyl]-5-hydrazinophenyl-2-methyl-1H-indole-3 - acetic acid (so pl. 245-246oC).

Elemental analysis for C19H20ClN5O2:

Calculated: C 59,14, H 5,23, N 18,15

Found: C $ 59.13 USD, 5,30 H, N 17,93

Example 70

Getting hydrazide 5-hydrazinophenyl-2-methyl-1H-(phenyl-methyl)-1H-indole-3-acetic acid

A. 5-Etoxycarbonyl - 2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid ethyl ester.

In accordance with the procedure described in example 1 (part F), 2,18 g (7.5 mm) 5-etoxycarbonyl - 2-methyl-1H-indole-3-acetic acid ethyl ether complex was subjected to reaction with 320 mg (8 mm) mixture of 60% NaH/mineral oil and 1.0 ml (8.4 mm) benzylbromide. After that, the obtained reaction mixture was chromatographically on silica (eluent: 25% ether, hexane ---> 50% ether/hexane) and was obtained 1.6 g (yield 56%) 5-etoxycarbonyl-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex.

B. 5-Carboxy-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ester

A solution of 1.6 g (4.2 mm) 5-etoxycarbonyl-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex and 4.2 ml of 1 n solution of NaOH in 75 ml EtOH was stirred for 2.25 hours, was added 10 ml of 1 n NaOH solution, and then stirred another 18.5 hours. After that, the obtained reactionary sodium sulfate and concentrated under reduced pressure. The obtained residue was heated for 4.5 hours in 150 ml of EtOH, and then left at room temperature for 96 hours. After concentration under reduced pressure, the obtained residue was chromatographically on silica (eluent: 25% ether/hexane ---> 50% ether/hexane) and received 110 mg (yield of 7.5%) 5-carboxy-2-methyl-1-(phenyl)-IH-indole-3-acetic acid ethyl ether complex.

C. Hydrazide 5-hydrazinophenyl-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid

In accordance with the procedure described in example 1 (part G), 110 mg (0,31 mm) 5-carboxy-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid ethyl ether complex was subjected to reaction with 3 ml of hydrazine (total time of heating under reflux with 78 hours) and after cooling, the reaction mixture was obtained 40 mg (38%) of the hydrazide 5-hydrazino-carbonyl-2-methyl-1-(phenylmethyl)-IH-indole-3-acetic acid (so pl. > 255oC).

Elemental analysis for C19H21N5O2:

Calculated: C 64,94, of 6.02 H, N 19.93 PER

Found: C 65, 15, H 6,14, N RECEIVED 19.82

Example 71

Getting 4-[[3-(2 - hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-IH-indol-5-yl]-oxy] butane acid

A solution of 310 mg (1 mm) of 5-hydroxy-2-methyl-1-(phenylmethyl)-IH - indole-3-acetic acid hydrazide (the mm) of ethyl 4-bromobutyrate. The resulting mixture was stirred for 4 hours, diluted with water and was extracted with EtOAc solution was washed with NaCl solution, dried with sodium sulfate and concentrated under reduced pressure. The obtained residue was chromatographically on silica (eluent: CH2Cl2---> 4% MeOH/CH2Cl2) and received 290 mg (yield 68%) 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)- IH-indol-5-yl] -oxy]-butane acid ethyl ether complex. After that, the obtained ester (0,685 mm) and 2 ml of 2 n NaOH in 25 ml EtOH and 5 ml THF was stirred for 22.5 hours. Then the mixture was diluted with water, acidified to pH 6 solution 1 N. HCl and was extracted with EtOAc, then EtOAc solution was dried with sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in EtOH and precipitated with ether, the resulting received 50 mg (yield 47%) 4-[[3-(2-hydrazino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-IH - indol-5-yl] -oxy]butane acid so pl. 160oC(decomposition).

Elemental analysis for C22H25N3O4:

Calculated: C 66,82, H 6,37, N 10,63,

Found: C 66,19, H 6,23, N To 9.32.

Therapeutic use of hydrazides IH-indole-3-acetic acid

The experiments conducted on the test Rossiskoi action of these compounds, mainly due to the direct inhibition of secretory phospholipase A2(sPLA2), and not antagonistic action on the arachidonic acid, or in respect of active precursors arachidonoyl acid in its path of metabolism, such as 5-lipoxygenase, cyclooxygenase, etc.

In accordance with the present invention, a method of inhibiting sPLA2- mediated release of arachidonic acid is that sPLA2were subjected to interaction with a therapeutic amount of hydrazide - IH-indole-3-acetic acid and its pharmaceutically acceptable salts.

The preferred method of inhibition of sPLA2-mediated release of fatty acids is in the interaction sPLA2with a therapeutically effective amount of hydrazide IH-3-acetic acid, where the specified hydrazide is substituted in the 1-position of the benzyl or substituted benzyl group, and its pharmaceutically acceptable salts.

In General, sPLA2- mediated release of arachidonic acid can be ingibirovalo method, which consists in the interaction sPLA2with a therapeutically effective amount of Hydra is R> where X represents oxygen or sulfur;

R61selected from groups (I), (II) and (III), where:

(I) represents a C4-C20-alkyl, C4-C20alkenyl, C4-C20-quinil, C4-C20- halogenated, C4-C12-cycloalkyl; or

(II) is an aryl or aryl substituted by halogen, -CN, -Cho, -OH, -SH, C1-C10-alkylthio, C1-C10-alkoxide, carboxyla, amino or hydroxyamino;

(III) is:

< / BR>
where "Y" is a number from 1 to 8;

R74independently represents hydrogen or C1-C10-alkyl;

R75represents aryl or aryl substituted by halogen, -CN, -CHO, -OH, nitro, phenyl, -SH, C1-C10-alkylthio, C1-C10-alkoxyl, C1-C10-alkyl, amino, hydroxyamino, or substituted or unsubstituted heterocyclic ring with 5 to 8 members, or both R74taken together represent = 0;

R62represents hydrogen, halogen, C1-C3-alkyl, ethynyl, C1-C2-alkylthio, C1-C2-alkoxy, -CHO, -CN;

each R63independently represents hydrogen or halogen;

R64, R65, R66and R67each nesail, C3-C8-cycloalkyl, aryl, aralkyl, or any two adjacent gidrolabilna group in a series of R64, R65, R66and R67taken together with the ring carbon atoms to which they are linked, form a substituted or unsubstituted carbocyclic ring with 5 or 6 members; or C1-C10-halogenated, C1-C10-alkoxy, C1-C10-halogenoalkane, C4-C8-cycloalkane, phenoxy, halogen, hydroxy, carboxyl, -SH, -CN, -S(C1-C10-alkyl), arieti, thioacetal, -C(O)O(C1-C10-alkyl), hydrazide, hydrazino, hydrazido, -NH2, -NO2, -NR82R83and-CNR82R83where R82and R83independently represents hydrogen, C1-C10-alkyl, C1-C10-hydroxy-alkyl, or R82and R83taken together with N form a heterocyclic ring with 5 to 8 members; or a group of the formula:

< / BR>
where each R76independently selected from hydrogen, C1-C10-alkyl, hydroxy, or both R76taken together represent = 0;

p = 1-5;

Z represents a bond, -O-, -N(C1-C10-alkyl)-, -NH, or-S-; and

Q represents-CON (R82R83), -5-tetrazolyl, -SO3H,

< / BR>
< / BR>
< / BR>
2- mediated release of arachidonic acid is intended, in particular, for the treatment of septic shock in humans. For example, according to this method, septic shock in humans treated by introducing this person a therapeutically effective dose of hydrazide IH-indole-3-acetic acid and its pharmaceutically acceptable salts. In a preferred embodiment, the treatment of septic shock in humans is the introduction to that person a therapeutically effective dose of hydrazide IH-indole-3-acetic acid, substituted in the 1-position of the benzyl or substituted benzyl group, and its pharmaceutically acceptable salts. In another preferred embodiment, the treatment of septic shock in humans is that this person is administered a therapeutically effective dose of hydrazide IH-indole-3-acetic acid, substituted in the 2 position by a group containing halogen, oxygen, nitrogen or sulfur, and its pharmaceutically acceptable salts.

Pharmaceutical compositions

As mentioned above, the compounds of the present invention can be used for inhibition of sPLA2-mediated release of fatty acids such as arachidonic acid 2-initiated release of fatty acids through the use of the compounds of the present invention.

The specific dose of a compound of the present invention, the input in order to obtain an appropriate therapeutic or prophylactic effect, depends on many factors, such as the type of connection, the route of administration, and the particular disease to which directed this treatment. However, in General, the daily dose includes non-toxic amount of the active compounds of the present invention, comprising from about 0.01 mg/kg to about 50 mg/kg body weight.

The compound of the present invention can be introduced in various ways, for example, using aerosols, oral: rectally, transdermally, subcutaneously, intravenously, intramuscularly, and through the nose. The pharmaceutical compositions of the present invention is obtained by combining (e.g., by mixing) a therapeutically effective amount of hydrazides IH-indole-3-acetic acid with a pharmaceutically acceptable carrier or diluent. Preferably, if the composition of the present invention are prepared prior to their introduction.

These drugs are active incredibility or filler, which is compatible with other ingredients of the composition and do not adversely affect the recipient.

The pharmaceutical compositions of the present invention obtain by conventional methods well known in the art, and using easily available ingredients. In the manufacture of the compositions of the present invention, the active ingredient is usually mixed with a carrier, or diluted by a carrier, or injected inside the carrier, which may take the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material that acts as a filler, and the drug can be manufactured in the form of tablets, pills, pills, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid and in liquid medium), or ointments containing, for example, up to 10 wt.% active compounds.

Tablets for oral administration can include suitable fillers such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and dezintegriruetsja agents such as corn starch, alginic acid, and/or binding agents, such as same the

The following examples of compositions are given only for illustrative purposes and should not be construed as a limitation of the scope of the present invention. The term "active ingredient" means a compound of hydrazine IH-indole-3-acetic acid of the present invention or its pharmaceutically acceptable salt.

Composition 1

Tablets were obtained using the following ingredients: - Quantity (mg/capsule)

Active ingredient: 250

Microcrystalline cellulose - 400

Colloidal silicon dioxide - 10

Stearic acid - 5

These components were mixed and compressed into tablets. The weight of each tablet was 665 mg

Composition 2

Spray the solution was obtained using the following components: - Weight

Active ingredient - 0,25

Ethanol - 25,75

Chlorodifluoromethane (propellant) - 70,00

The active ingredient was mixed with ethanol and the resulting mixture was added to part of the propellant cooled to -30oC, and then transferred to a pouring device. After that, the required number was introduced into a vessel made of stainless steel and kept the remaining amount of propellant. The filled container supplied cleanance inhibitors of recombinant secretory phospholipase A2conducted the following procedure chromogenic assay. The following analysis was adapted for screening large volumes using 96-well plates for micrometrology. Meta description of this analysis can be found in the article "Analysis of Human Synovial Fluid Phospholipase A2on Short Chain Phosphatidylcholine-Mixed Micelles. Development of a Spectrophotometric Assay suitable for a Microtiterplate Reader", by Laure J. Reynolds, Lori L. Hughes, and Edward A Dennis, Analytical Biochemistry, 204, pp. 001-008, 1992. Used reagents, the disclosure of which is introduced into the present description by reference.

Reaction buffer:

CaCl22H2O (1,46 g/l)

KCl (7,455 g/l)

Bovine serum albumin (containing fatty acids) (1 g/l) (Sigma A-7030, product of Sigma Chemical Co. St. Louis MO, USA)

Tris-HCl (3.94 g/l)

pH 7.5 (adjusted with NaOH)

Enzyme buffer:

0,05 NaOAc3H2O, pH 4.5

0,2 NaCl

the pH was brought to 4.5 with acetic acid

The racemic mixture of diheptanoate - PC

Racemic 1,2-bis(heptanoyl)-1,2-dideoxy-sn-glycero - 3-phosphorylcholine

Triton X-100TMreceived at concentrations 6,249 mg/ml in reaction buffer (10 µm)

The reaction mixture is:

The measured volume of racemic diheptanoate PC was poured into chloroform at a concentration of 100 mg/ml, autogo to the solution was added to the reaction buffer, and then DNB, resulting in the obtained reaction mixture. Thus obtained reaction mixture contained 1 mm diheptanoate-PC-substrate, 0,29 mm detergent Triton-X-100TMand 0.12 mm DTNB in buffer aqueous solution at pH 7.5.

Test procedure:

1. To all wells add 0.2 ml of the reaction mixture;

2. In appropriate wells add 10 μl of the test compounds (or, in the case of the control holes, solvent) and 20 with stir;

3. In appropriate wells add 50 nanograms sPLA2(10 microliters);

4. Tablets incubated at 40oC for 30 minutes;

5. Using automatic tablet reader take readings of the optical density at 405 nm.

All test compounds were carried out with triple redundancy. In General, the compounds were tested at a final concentration of 5 μl/ml At the same time, it was believed that these compounds are active when compared to eingeborenen control, they discover a 40% inhibition or more at 405 nm. The inhibition indicates no staining at 404 nm. Connection, which was originally found their activity, were again analyzed to confirm this activity, and eclaring twofold dilution of the test compound, so that the final concentration in the ongoing reaction was in the range of 45 μg/ml to 0.35 µg/ml For stronger inhibitors was required significantly more breeding. In all cases, the measured % inhibition (at 405 nm) due to enzymatic reactions containing inhibitors, compared with reactions neighborhoo control. Each sample was subjected to titration with triple redundancy; the results were averaged for plotting and calculated IC50-values. IC50-values were determined using the curves of the dependences of the logarithm of concentration from the logarithm of the index of inhibition in the range from 10% to 90% inhibition. For each of the test compounds IC50-values were determined at least three times. The average values obtained for these measurements are presented in the following table 1.

Example analysis 2

Method. Male Guinea pigs (500-700 g) Hartlwy were killed by their necks, and their heart and lungs entirely removed and placed in aerated Krebs buffer (95% O2: 5% CO2). From the whole parenchymal segments (HH mm), cut parallel to the outer edge of the lower lobes of the lung, cut strips dorsal pleura (HH the m end and independently attached to the metal rod-holder. One terminal connected to the sensor force-displacement grass (Grass) (model FTD3C, product Grass Medical Instrument Co., Quincy, MA, USA). Changes in isometric tension were observed using the monitor and thermograph (product Modular Instrumrnt, Malvern, PA). All tissues were placed in 10 mm bath tissue, fitted shirts and maintained at 37oC. the tissue bath, which was maintained at a constant aeration, contained a modified Krebs solution with the following composition (mm): NaCl-118,2, KCl - 4,6, CaCl22H2O - 2,5, MgSO47H2O - 1,2, NaHCO3- 24,8, KH2PO4- 1.0 and dextrose to 10.0. Strips pleura, cut from the opposite lobes of the lung, was used for paired experiments. Preliminary data obtained from curves "tension/response showed that the residual tension of 800 mg is optimal. Tissue was left for equilibration for 45 minutes, while the liquid bath is periodically changed.

Curves "cumulative concentration - response

First, the fabric was subjected to provocative stimulation using KCl (h mm) in order to test their viability and receive an appropriate answer. After it was recorded the maximum averted following inflammatory stimulation. Curves "cumulative concentration - response built for strips of the pleura by increasing the concentration of agonist (sPLA2in bath increments of 1/2 (Ioo10), while the previous concentration was left in contact with the tissues [1] . The concentration of agonist increased after reaching the plateau of the curve, which corresponds to a reduction identified by the previous concentration. To minimize variablenode among tissues obtained from different animals, a reduction in the response expressed as a percentage of the maximum response obtained at the end-KCl-stimulatie. To study the effect of various drugs on reducing action sPLA2for 30 minutes before the curve "concentration sPLA2- the answer to the tissues was added compounds and their respective fillers.

Statistical analyses

Data obtained in different experiments were combined and expressed as a percentage of the maximal KCl responses (mean average square Osh.). To assess shifts to the right on the curve "concentration-response" induced by the drug, these curves were analyzed simultaneously using a static nonlinear modeling methods similar to the methods described Waud (197 is alagaesia, is the same for each curve; ED50for the control curve, the steepness of the curves; and pF2, the concentration of antagonist that requires a twofold increase in the concentration of agonist to achieve an equivalent response. As determined using nonlinear statistical modeling methods similar to the methods described Waud (1976) Fguation 27, page 164 [2], the angular coefficient of the Plate (Schild) was equal to 1. The fact that the angular coefficient of the Plate is equal to 1, indicates that this model is in accordance with the proposed specific to the antagonist; and therefore, pA2 can be interpreted as moving the dissociation constant, KB, inhibitor.

To evaluate the suppression induced drug maximum responses SPLA2replies (10 μg/ml) was measured both in the absence and in the presence of drugs, and for each pair of tissues was calculated the percentage of suppression. The following table 2 presents typical examples of inhibitory activities.

Although the present invention described above, some specific examples of its implementation, however, these examples should not be construed as a limitation of the amount of es in isolated organs and the evaluation of drug parameters. Arch. Int. Pharmacodyn. Ther. 143:299-330, 1963.

2. Waud, D. Analusis of dose-response relationship. in Advances in General and Celliar Pharmacology eds Narashi, Bianchi 1:145-178, 1976.

1. Hydrazide 1H-indole-3-acetic acid formula I

< / BR>
where X is oxygen;

R1selected from group (I) and (III) where (I) represents a C4-C20-alkyl; (III) is a

< / BR>
where y = 1 - 8;

R74independently represents hydrogen or C1-C10-alkyl;

R75represents aryl or aryl substituted by halogen, -HE, nitro, phenyl, C1-C10-alkylthio,1-C10-alkoxy, C1-C10-alkyl, amino;

R2represents a halogen, WITH1-C3-alkyl, C1-C2-alkylthio,1-C2-alkoxy;

each R3independently represents hydrogen, C1-C3-alkyl;

R4, R5, R6and R7each independently represents hydrogen, C1-C10-alkyl, C3-C8-cycloalkyl, aryl, aralkyl,1-C10-alkoxy, C4-C8-cycloalkane, halogen, hydroxy, carboxyl, hydrazino, hydrazido;

or its pharmaceutically acceptable salt.

2. Hydrazide 1H-indole-3-acetic acid form>-C20-alkyl;

R12represents hydrogen, halogen, C1-C3-alkyl, C1-C2-alkylthio,1-C2-alkoxy;

each R13independently represents hydrogen, C1-C3-alkyl;

R14, R15, R16and R17each independently represents hydrogen, C1-C10-alkyl, C3-C8-cycloalkyl, aryl, aralkyl,1-C10-alkoxy, C4-C8-cycloalkane, halogen, hydroxy, carboxyl, hydrazino, hydrazido;

or its pharmaceutically acceptable salt.

3. Hydrazide 1H-indole-3-acetic acid of formula III

< / BR>
where X is oxygen;

R21selected from group (I) and (III) where (I) represents a C4-C20-alkyl; (III) is:

< / BR>
where y = 1 - 8;

R74independently represents hydrogen or C1-C10-alkyl;

R75represents aryl or aryl substituted by halogen, -HE, nitro, phenyl, C1-C10-alkoxy, C1-C10-alkyl, amino;

R22represents hydrogen, halogen, C1-C3-alkyl, C1-C2-alkylthio,1-C2-alkoxy;

each R23the independent is y independently represents hydrogen, WITH1-C10-alkyl, C3-C8-cycloalkyl, aryl, aralkyl,1-C10-alkoxy, C4-C8-cycloalkane, halogen, hydroxy, carboxyl, hydrazino, hydrazido;

or its pharmaceutically acceptable salt.

4. Hydrazide 1H-indole-3-acetic acid of formula V

< / BR>
where X is oxygen;

R51represents the formula

< / BR>
where R84represents hydrogen or C1-C10-alkyl;

R87represents aryl or aryl substituted by halogen, -HE, nitro, phenyl, C1-C10-alkyl, C1-C10-alkoxy, carboxyla, amino;

R52represents halogen, methylthio, or1-C3-alkyl;

each R53represents hydrogen;

R54, R55, R56and R57independently selected from groups (a), where (a) represents hydrogen;

or its pharmaceutically acceptable salt.

5. The pharmaceutical composition inhibiting secretory phospholipase sPLA2, including an active ingredient and a pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains a compound according to any one of paragraphs.1 to 4 in an effective amount.

4-C20-alkyl; (III) is a

< / BR>
where y = 1 - 8;

R74independently represents hydrogen or C1-C10-alkyl;

R75represents aryl or aryl substituted by halogen, -HE, nitro, phenyl, C1-C10-alkoxyl,1-C10-alkyl, amine;

R62represents hydrogen, halogen, C1-C3-alkyl, C1-C2-alkylthio,1-C2-alkoxy;

each R63independently represents hydrogen, C1-C3-alkyl;

R64, R65, R66and R67each independently represents hydrogen, C1-C10-alkyl, C3-C8-cycloalkyl, aryl, aralkyl,1-C10-alkoxy, C4-C8-cycloalkane, halogen, hydroxy, carboxyl, hydrazino, hydrazido,

or its pharmaceutically acceptable salt, inhibitory sPLA2 - mediated release of arachidonic acid.

 

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 medicine, in particular to rheumatology, and for the treatment of arthritis

Anti-inflammatory // 2086239
The invention relates to medicine, namely to the use of new anti-inflammatory drugs from the class alkanolammonium salts hetarylthioacyl acids, specifically to indolyl-3-diacetate Tris/2-hydroxyethyl/ammonium

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 medicine, namely to psychiatry

FIELD: medicine.

SUBSTANCE: it is suggested to apply tris-(2-hydroxyethyl)ammonium salt of 1-benzylindolyl-3-thioacetic acid earlier known as a stabilizer of cell membrane as preparation to treat autoimmune diseases. The property of the above-mentioned salt to inhibit T-dependent activation of B-lymphocytes, under conditions of decreased medullary function and body leukopenia should enable to develop new pharmacological preparation for treating autoimmune diseases, such as, for example, systemic lupus, rheumatoid polyarthritis, transplant's detachment at transplanting either organs or bony marrow.

EFFECT: higher efficiency of application.

4 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: medicine, arthrology, pharmacy.

SUBSTANCE: agent comprises glucosamine salt as saccharide, dimethylsulfoxide, ointment base and ibuprofen or nimesulide, or piroxicam, or meloxicam, or diclofenac salt, or indometacin, or ketoprofen as a nonsteroid anti-inflammatory agent. Glucosamine hydrochloride, glucosamine sulfate sodium, potassium or calcium salt is used as glucosamine, and diclofenac potassium or sodium salt is used as diclofenac salt. New ointment shows high perfusion rate of active substances to the articulation zone and enhanced effectiveness. Invention expands assortment of agents used in treatment of articulations.

EFFECT: improved, enhanced and valuable medicinal properties of agent.

2 cl, 14 ex

FIELD: medicine, arthrology, pharmacy.

SUBSTANCE: invention relates to agents of topical applying used in treatment of articulation diseases. Proposed agent comprises mixture of chondroitin sulfate and glucosamine salts as a saccharide, the compound taken among the group nonsteroid anti-inflammatory agents, in particular, ibuprofen or nimesulid, or piroxicam, or meloxicam, or diclofenac salt, or indometacin, or ketoprofen, dimethylsulfoxide and an ointment base taken in the definite ratio of components. Invention provides enhancing effectiveness due to the content a mixture of low-molecular and high-molecular saccharides in it that results to increasing diffusion rate of active component to the articulation zone and also the compound taken among the group of nonsteroid anti-inflammatory agents. The combined using these agents provides the curative synergetic effect.

EFFECT: improved and valuable medicinal properties of agent.

2 cl, 14 ex

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