Derivatives of indole, the method of production thereof and pharmaceutical composition for treatment of mental disorders based on them
(57) Abstract:Usage: as biologically active compounds in pharmaceutical compositions suitable for the treatment of mental disorders. The inventive product: indole derivatives of General formula (I) described in the text of the description, where R1- (C1- C4)alkyl, R2- (C1- C7)alkyl, in free form or in salt form. Reagent 1: 7 - (C1- C4)-alkoxy-1H-indol-3-yl carboxylic acid. Reagent 2: propane alkaloid General formula II, where R2- (C1- C7) alkyl. Reaction conditions: inert solvent at 20 - 70oC. Pharmaceutical composition comprises a pharmaceutically acceptable carrier and an active substance 1 in the amount of 2.5 μg to 2.5 mg 3 S. and 1 C. p. F. - ly. The invention relates to new 3,7-disubstituted indole derivatives, method for their production and pharmaceutical compositions based on them.The following derivative indole:
(1H, 5H-8-methyl-8-Aza-bicyclo(3.2.1) Oct-3-ilen ether 7-hydroxy-1H-indole-3-carboxylic acid, which is described as a possible additional product conversion;
(1H, 5H)-8-methyl-8-Aza-bicyclo (3,2,1) Oct-ilen epitomy (in vitro (Mol.Foxicol, 1,341-350, 1987);
1,2,3,9-tetrahydro-8-hydroxy-9-methyl-3-/ (2-methyl-1H-imidazol-1-yl)methyl/-4H-CT - basal-4-it, which is described as the product of the transformation 1,2,3,9-tetrahydro-9-methyl-3/(2-methyl-1H-imidazol-1-yl)methyl/-4H - carbazole-4-it (Eur.J. Cancer Clin.Oncol. 25, suppl.a 1.75-77, 1989).The invention relates to compounds of the formula
(I) where R1(C1-C4) alkyl;
R2(C1-C7) alkyl.These compounds can exist in free form or in salt form. These compounds possess valuable pharmacological properties.Indole compounds of General formula I is obtained by condensation of compounds of formula
OH(II) where R1have the above significance, with a compound of General formula
HON-R2(III) where R2have the above meaning.The process is carried out at a temperature from room temperature up to 70aboutIn the presence of an inert solvent, for example, ethyl acetate. You can also use alcohol, in particular, in the form of a salt of an alkali metal, preferably lithium salts. Such salts receive by known methods, for example, in the reaction of n-utility with alcohol in tetrahydrofuran. If desired, the reaction is carried out in the presence of heterocycling or tertiary is aboutC. In an inert organic solvents Pets also use ether or dimethoxyethane.Isolation and purification of the compounds of formula (I) also carry out the conventional methods.The compounds of formula (I) in free base form may be converted into a salt with one or another acid, in particular hydrochloric acid, malonic acid, hydrobromide, maleic, malic, fumaric, Sheveleva or tartaric acids. Partial ammonium salt compounds of formula (I) are obtained by conventional means, for example, in the reaction with methylated iodine.P R I m e R 1. (1 N, 5 N)-8-methyl-8-Aza-bicyclo (3.2.1)Oct-3 - silt ester of 7-methoxy-1H-indole-3-carboxylic acid.to 19.1 g of 7-methoxy 1H-indol-3-yl carboxylic acid suspension in 300 ml of ethyl acetate. 10 ml oxalyl-chloride added to the mixture for 30 min at room temperature. The resulting solution of red-mud color is stirred for 3 h at room temperature and then concentrated to 2/3 of the original volume. Then, the condensate is added dropwise 14 g of tropine in 50 ml of ethyl acetate at a temperature of about 50aboutC. the Resulting mixture is stirred for another 2 h at 50aboutAfter what lacerata (three times) and then washed 2NHCl. Acid phase is then alkalinized potassium carbonate, extracted three times CH2CL2and evaporated to obtain the desired compound with a melting point 298-299aboutWith in which it occurs decomposition.18,8 g of the thus obtained base is dissolved in 200 ml of ethanol and add 1 equivalent 4NHCl (15 ml). The solution is concentrated to 2/3 of the original volume.After crystallization from ethanol the product is filtered and washed. Obtain 19 g of the desired product as hydrochloride. So pl. 298-299aboutC (decomposition).In the literature it is not known use as pharmaceutical compounds of the formula (I) in free form or in the form suitable for pharmaceutical purposes of salts and complexes, which are referred to as the "compounds according to the invention". These compounds possess valuable pharmaceutical properties and can be recommended for clinical use.In particular, the compounds according to the invention have azeotropes activity (A. K. Dixon etal.Adv. Study Behav, 1990, 19, 171-204), as shown when tested on mice by a known method (A. K. Dixon et al. Triangle, 1982, 21, 95-105). This study found that these compounds e manifested in dosages from 0.01 to 100 µg/kg after oral or parenteral administration and impact on socio-search behavior of mice, encourage and ambivalent protective reaction, which was oppressed.The action of the compounds according to the invention on social behavior is also shown in the study (K. A. Dixon et al. Adv. Study Behav. 19, 171, 1990), in which pairs contained in the individual cells of the males were transferred into one big, shared cage, unfamiliar animals, then registered their behavioral reactions and poses. One member of each pair received either the test compound or the solvent in the form of intraperitoneal injection for 45 min prior to transplantation in a common cell. Set the action of the test compounds on the social behavior of mice (increased search activity) after intraperitoneal administration at doses of 0.01-100 μg/kgCompounds according to the invention inhibit the increase in the concentration of corticosterone in the blood plasma of mice in the form of aggressive, but isolated male. When administered orally in doses of 0.1-10 mg/kg / day for 14 days they restore the concentration of corticosterone in the blood to normal size.In addition, the compounds according to the invention are antagonists NT3. This is confirmed by the following.They are characterized by active jt (Mol.Pharm. 33, 303-309). Figure RKaboutfor described in example connection is 8,870,01.They have a stimulating effect on gastric emptying in rats, as shown in the standard tests in vivo after intraperitoneal injection in doses of from 0.01 to about 1 mg/kg of the Tested compounds injected 15 min prior to the introduction of animals 25 glass beads, and removing the last of the gastrointestinal tract recorded after 5, 10, 15 and 30 minutes Index ED50for described in the above example, the compound is 0.2 mg/kg in the case intraperitoneal injection.They cause the blockade of reflex Benzalde-Arish, as shown, for example, in the study by the method of I. R. Fojard (Naunyn-Schmiedeberg Arch. Fharm. 326, 36-44, 1984). When the test compounds described in the above example, the value of U50is 70 ág/kgIn connection with the foregoing, the compounds according to the invention can be recommended for the treatment of mental disorders, in particular anxiety of various origins and disorders caused by stress exposure. They can also be used in the treatment of disorders such as depressive and manic-depressive States, antisocialist, E. panic, fear of space, compulsive phenomena.Recommended daily doses ranging from 0.01 to 5 mg, you can enter fractional, for example, 4 times a day.Preferably used for therapeutic purposes, the compounds described in the above example.Compounds according to the invention can be entered in free form or in a form suitable for pharmaceutical use salts or compositions. Of activity similar to the activity of free connections.These indole derivatives can be used in pharmaceutical compositions, which include the connection according to the invention and suitable for pharmaceutical purposes solvents or carriers. These compounds can be entered in the usual ways, for example, parenterally, in the form of injectable solutions or suspensions), and oral (for example, in the form of tablets or capsules), or intranasal or use for their introduction of the candle. A single dosage of the free compounds or their suitable for pharmaceutical applications salts may be 2.5 mg to 2.5 mgSample preparation of pharmaceutical compositions.Ingredient Weight (mg)
The active ingredient of 0.5 Stearate Mg 2,0
Ingredient connect easily and fill 80 mg capsules. 1. Derivatives of indole of General formula I
< / BR>where R1WITH1WITH4-alkyl;
in free form or in salt form.2. Derivatives under item 1, wherein R1R2- CH3.3. The method of obtaining derivatives of indole of General formula I
< / BR>where R1WITH1WITH4-alkyl;
in free form or in salt form, wherein conducting the condensation of compounds of General formula II
< / BR>where R1has the specified value,
with a compound of General formula III
< / BR>where R2has the specified value,
with the release of the product in free form or in salt form.4. Pharmaceutical composition for treatment of mental disorders, comprising an active substance and a pharmaceutically acceptable carrier, characterized in that the active substance composition comprises the compounds of General formula I on PP. 1 and 2 in the amount of 2.5 μg to 2.5 mg
SUBSTANCE: invention relates to compounds of formula: U1-M-U2, where U1 and U2 have general formula (I), where: G stands for: IVb IVd ive, and values M, X1, X2, R2, R3, R3', R4, R4', R5, R5', R6, R6', R7, Z7, Z2, Z3, Z4, Q2 are given in item 1 of the formula.
EFFECT: compounds can be applied for induction of apoptosis in cell.
37 cl, 13 dwg, 43 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,
(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.
EFFECT: valuable medicinal properties of compounds.
10 cl, 2 tbl, 39 ex
FIELD: organic chemistry, chemical technology, medicine.
SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):
wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.
EFFECT: improved preparing method, valuable medicinal properties of compounds.
11 cl, 7 tbl, 353 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to a method for preparing compounds of the formula (I): wherein R means halogen atom; R1 means hydrogen atom (H); R2 means cyano-group (CN); X means oxygen atom (O) or H, H; n = 2, 3, 4, and their acid-additive salts. If X means oxygen atom (O) then the method involves interaction of compound of the formula (II): with compound of the formula (III): R-(CH2)n-CO-L (III) wherein L means halogen atom or others in the process of Friedel-Crafts acylation reaction in the presence of Lewis metalhalides of type R'-Al(Cl)2 as a catalyst wherein R' means (C1-C6)-alkyl. Prepared compound of the formula (I) is isolated as a base or its acid-additive salts followed by reduction by using complex hydrides and activation with Lewis metalhalides of type R'-Al(Cl)2. Method provides preparing compounds with the yield 87-89%.
EFFECT: improved preparing method.
3 cl, 4 ex
FIELD: organic chemistry, medicine, hematology.
SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.
EFFECT: valuable medicinal properties of compounds.
13 cl, 1 tbl, 195 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to a method for synthesis of novel compounds of formulas (Ia-g): wherein: (a) R means -OCH3; R1 means phenyl (Ph); (b) R means -OCH3; R1 means 4-bromophenyl (4-Br-Ph); (c) R means -OCH3; R1 means CH3; (d) R means -OCH3; R1 means 4-CH3-Ph; (e) R means -OCH3; R1 means C2H5; (f) R means -OCH3; R1 means hydrogen atom (H); (g) R means -O-CH2-CH2-O-; R1 means CH3. Method involves interaction of benzhydrol of formulas (IIa-g): wherein values R and R1 are given above with N-furan-2-yl-methyl-4-methylbenzenesulfonamide of the formula: in acetic acid medium in boiling for 0.2-20 h in the presence of phosphoric acid as a catalyst wherein 3 ml of phosphoric acid are added per 0.01 mole of benzhydrol of formulas (IIa-g). Compounds of formulas (Ia-g) can be used in synthesis of novel analogs of anti-tumor preparations.
EFFECT: improved method of synthesis, valuable medicinal property of preparations.
2 tbl, 5 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention relates to methods (variants) for synthesis of stable form of indole-3-carbonol hydrate. Indole-3-carbonol hydrate is a known compound and used in pharmaceutical industry. Method for synthesis of indole-3-carbinol hydrate involves the reduction reaction of indole-3-carboxaldehyde with sodium boron hydride in (C1-C3)-alkyl alcohol medium, Water is added to a prepared reaction mass and kept at decreased temperature up to its complete precipitation followed by drying at environment temperature. Alternative method involves isolation of the reaction product after reaction mass obtained after carrying out the reduction reaction and crystallization from water or aqueous (C1-C3)-alkyl alcohol at weak heating, the following cooling and keeping the prepared solution at temperature about zero and its drying at environment temperature. If necessary, synthesized indole-3-carbinol hydrate is re-crystallized additionally from water or aqueous (C1-C3)-alkyl alcohol and keeping the prepared solution at temperature from +3°C to -18°C and its drying at environment temperature. Proposed methods provide preparing product showing enhanced stability and without undesirable impurities of by-side conversion substances and solvents used in re-crystallization.
EFFECT: improved method of synthesis.
3 cl, 7 dwg, 7 ex
FIELD: organic chemistry, medicine, biochemistry.
SUBSTANCE: invention relates to novel compounds of indoline of the formula (I): , wherein R1 and R3 are similar or different and each means hydrogen atom (H), lower alkyl group or lower alkoxy-group; R2 means -NO2, -NHSO2R6 [wherein R means (C1-C20)-alkyl group, aryl group or -NHR7 (wherein R7 means H, -COR13 (wherein R13 means H, lower alkyl group) or lower alkoxycarbonyl group)], -NHCONH2 or lower alkyl group substituted with -NHSO2R6 [wherein R6 means (C1-C20)-alkyl group, aryl group or -NHR7 (wherein R7 means H, -COR13 (wherein R13 means H, lower alkyl group) or lower alkoxycarbonyl group)]; R4 means H, (C1-C20)-alkyl group optionally substituted with hydroxy-group, -COR13 (wherein R13 means H, lower alkyl group), lower alkenyl group, lower alkoxy-lower alkyl group, lower alkylthio-lower alkyl group, (C3-C8)-cycloalkyl group or (C3-C8)-cycloalkyl-(C1-C3)-alkyl group; R5 means (C1-C20)-alkyl group, (C3-C8)-cycloalkyl group or aryl group; R12 means H, lower alkyl group, lower alkoxy-lower alkyl group or lower alkylthio-lower alkyl group wherein aryl represents phenyl or naphthyl, or its pharmaceutically acceptable salt. Compounds possesses the strong inhibitory effect on activity of acyl-coenzyme A:cholesterol acyltransferase and the strong inhibitory effect on lipid peroxidation processes that allows its using as a component of pharmaceutical compositions.
EFFECT: valuable medicinal and biochemical properties of compound and pharmaceutical compositions.
31 cl, 5 tbl, 68 ex
SUBSTANCE: invention relates to the novel indole derivatives with the common formula I: or its pharmaceutically acceptable salt, where R1 is (a) -X-aryl-Y-Z and (b) -X-heteroaryl-Y-Z, where aryl and heteroaryl are unsubstituted or substituted with 1-3 groups, chosen independently from A; aryl means phenyl or naphthyl; heteroaryl means the monocyclic or condensed bicyclic aromatic ring structure containing one heteroatom chosen independently from N or O, where the monocyclic ring or each ring of the bicyclic ring structure means the penta- or hexamerous ring; X means the bond CH2, CH(CH3) and C(CH3)2; Y means -CH=CH-, -CH(OH)CH(OH)-, -OCR7R8-, -SCR7R8- and -CH2CR5R6-; Z means -CO2H, tetrazole; A means C1-4alkyl, -OC1-4alkyl and halogen, where alkyl, and -Oalkyl, each not necessarily substituted with 1-5 halogens; R5, R6, R7 and R8 , each independently means H, C1-C5alkyl, -OC1-C5alkyl, C3-6cycloalkyl and phenyl, where C1-C5alkyl, -OC1-C5alkyl, C3-6cycloalkyl and phenyl are not necessarily substituted with 1-5 halogens; and C3-6cycloalkyl and phenyl are additionally not necessarily substituted with 1-3 groups, independently chosen from C1-C3alkyl and -OC1-C3alkyl, at that, the said C1-C3alkyl and -OC1-C3alkyl are not necessarily substituted with 1-3 halogens; or alternatively, R7 and R8 together can form the C3-C6cycloalkyl group; or alternatively, when R1 means -X-phenyl-Y-Z, Y means -OCR7R8 and R7 are chosen from group containing H, C1-C5alkyl, -OC1-C5alkyl, then R8 can, not necessarily , mean the 1-2-hydrocarbon bridge, bound to the phenylic ring by the orthoposition relative to Y, and generating in this way the 5- or 6-membered heterocyclic ring, condensated with the phenylic ring; R2 means C1-C4alkyl, which is not necessarily substituted with 1-5 halogens; R3 means (a) bensoxazolil, (d) aryl, (e) -C(=O)aryl, (f) -C(=O)heteroaryl, (g) -Oaryl, (i) -S(O)naryl and where R3 is not necessarily substituted with 1-3 substituting groups, independently chosen from halogen, C1-3alkyl, -OC1-3alkyl and -SC1-3alkyl, where C1-3alkyl, -OC1-3alkyl and -SC1-3alkyl are not necessarily substituted with 1-5 halogens; each R4 means from H, halogen, C1-C5alkyl and -OC1-C5alkyl, where C1-C5alkyl and -OC1-C5alkyl are not necessarily substituted with 1-5 halogens; n is the even number 0-2 and p is the even number 1-3.
EFFECT: composition I reveals agonistic activity considering PPAR, that allows to use them in pharmaceutical composition, in means to fix PPAR and production of medication to fix PPAR.
33 cl, 8 tbl, 32 ex