Purgative agent composition

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a purgative agent composition comprising bicyclic compound of the formula (1) and a method providing the purgative effect and using compounds of the formula (1). He composition possesses the enhanced effectiveness.

EFFECT: valuable medicinal properties of composition.

42 cl, 3 tbl, 2 ex

 

The technical field to which the invention relates.

The present invention relates to a new composition laxative agent, which is used for the relief and prevention of constipation in patients suffering from constipation and for bowel cleansing.

The level of technology

Prostaglandins (in the following denoted PG) are a group of fatty acids, which possess a wide spectrum of physiological activity and are contained in the tissues and organs of humans and animals. PG contain the frame postanowi acid of the following formula:

some synthetic products may contain the above framework with some modifications. Prostaglandins are classified into several types according to the structure and substituents in the five-membered ring, for example:

Prostaglandins series A (PGA),

Prostaglandins series (PGB),

Prostaglandins series (PGC),

Prostaglandins series D (PGD),

Prostaglandin E series (PGE),

The F-series prostaglandins (PGF);

etc. they can also be classified on PG1containing the 13,14-double bond; PG2containing 5,6 - and 13,14-double bond;and PG 3containing 5,6-, 13,14 - and 17,18-double bond.

Prostaglandins depicted as follows. The carbon atoms constituting the PG αchain ω-chain and five-membered ring are numbered in accordance with the main frame:

That is, the carbon atoms constituting the main skeleton are numbered in such a way that the carbon atom in the carboxyl group is denoted by s-1, and αchain contains carbon atoms from C-2 to C-7, and the numbers increase towards the ring, five-membered ring contains carbon atoms from C-8 to C-12 and ωchain contains carbon atoms from C-13 to C-20. In the case of a smaller number of carbon atoms in α-chain numbering of carbon atoms, the subsequent p-2 must be shifted appropriately, and when the number of carbon atoms is greater than 1, this connection is provided that the carbon atom at position C-2 has a Deputy, instead of the carboxylic group in position C-1). In the case of a smaller number of carbon atoms in ω-chain numbering should be less than 20, and when the number of carbon atoms up to 8, carbon atoms in position 21 and the following should be considered as a Deputy.

As for the configuration, it is treated in accordance with the above configuration of the main frame, unless otherwise noted. For example, the R, PGD, PGE and PGF mean compounds which have a hydroxyl group at positions C-9 and/or C-11. In this PG invention also includes the prostaglandins, in which there is a different group instead of the hydroxyl group at positions C-9 and/or C-11, and they are called 9-dihydroxy-9-substituted or 11 dihydroxy-11-substituted prostaglandin compounds.

In addition, prostaglandins may include isomers such as bicyclic tautomers, optical isomers; the geometrical isomers, or the like.

It is known that PG have various kinds of pharmacological and physiological activity, such as the expansion of blood vessels, inducing inflammation, induction of platelet aggregation, stimulation of the muscles of the uterus, antiulcer activity, etc. Found that PGE or PGF have a high ability to reduce bowel, caused by stimulation of the intestine, while the effect of intestinal clusters is weak. Accordingly, the application of PGE or PGF as a laxative agent is impossible due to side effects such as pain in the stomach, caused by contractions of the intestine.

On the other hand, found that PG with simple 13,14-link and C-15 carbonyl group, and the PG, which have double-13,14-link and C-15 carbonyl group, are products of metabolism of the human is ka or animal. These 13,14-dihydro-15-keto-prostaglandins and 15-keto-prostaglandin (in the following referred to as 15-keto-RS) known as metabolites produced naturally through enzymatic metabolism relevant PG in vivo. It was reported that for the 15-keto-PG hardly manifest various kinds of physiological activity, typical for PG and that they are pharmacologically and physiologically inactive metabolites (see Acta Physiologica Scandinavica, t, s-(1966)).

In U.S. patent 5317032 (Ueno and others) described prostaglandin laxatives, including bicyclic tautomers. However, for bicyclic tautomers are still unknown specific activity as agents for treatment and prevention of constipation.

The invention

However, when assessing the physiological activity of analogues of 15-keto-PG the authors of the present invention have found that the corresponding bicyclic compounds, for example bicyclic tautomers, substituted by one or more halogen atoms, can be used in small doses to relieve constipation. If desired, you can use the increased dosage, in order to cause a strong laxative effect, although the main purpose of the present invention is the restoration of normal bowel function (stool from 3 to 7 times per week).

The task is altoadige invention is the provision of a composition laxative agent, devoid of side effects on the intestine, which includes an effective amount of the bicyclic compound represented by formula (I):

where V1and V2represent atoms of carbon or oxygen;

W1when V1is a carbon atom, and W2when V2is a carbon atom, is a

R3and R4represent a hydrogen atom, or one of these substituents is a group of IT;

X1and X2represent a hydrogen atom, lower alkyl or halogen, and at least one of them is a halogen;

Z represents a carbon atom, oxygen, sulfur or nitrogen;

R2represent a hydrogen atom or alkyl;

Y represents a saturated or unsaturated With2-10hydrocarbon, substituted or not substituted by oxo, halogen, alkyl, hydroxyl, aryl or heterocyclic group;

A represents a-CH2OH, -COCH2OH, -COOH or a functional derivative; and

R1represents a saturated or unsaturated lower hydrocarbon residue, having an unbranched or branched chain, which is not substituted or substituted by a halogen atom, oxo group, hydroxy group, lower Alcock and group, lower alkanoyloxy group, a lower cycloalkyl group, a lower cycloalkane group, aryl group, aryloxy group, a heterocyclic group or a heterocyclic oxy group; lower cycloalkyl group; a lower cycloalkane group; aryl group; aryloxy group; heterocyclic group; heterocyclic oxy group.

the bond between C-13 and C-14 are double or simple communication and

C-15 has a spatial configuration R, S or a mixture.

The present invention also provides the use of compounds of formula (I) to obtain composition a laxative agent.

The present invention also provides a method of providing a laxative effect for the needy in this patient, which includes the introduction of the compounds of formula (I).

Although bicyclic halogenated compound of formula (I) provides an excellent laxative effect, the specified connection does not cause significant side effects such as pain in the stomach, caused by contractions of the intestine. Therefore, the connection of the present invention can be applied not only for the treatment of chronic or intermittent constipation, but also for the treatment or prevention of constipation (as well as to induce bowel movements, when this is desirable in patients, suffering the x from constipation, associated with, for example, hernia or disease of the cardiovascular system, in order not to strain at stool and do not suffer from protogenic diseases. Moreover, this composition can be applied to ensure the normal peristalsis of the bowel to flush the harmful substances from the intestines in the case of drug or food poisoning. In addition, bicyclic halogenated compounds of the present invention can be used as an agent, bowel cleansing, used for bowel preparation for preventive, diagnostic or surgical procedures.

DETAILED description of the INVENTION

The present invention provides a composition of a laxative agent, which includes effective as a laxative number of bicyclic compounds of the formula (I).

Laxatives function by combining one or more of the four mechanisms described below, results in increased water content in the feces and makes it easier to move the content in the intestine:

i). Water and electrolytes may persist in the intestine due to hydrophilicity or osmotic effects of drugs, resulting in an increasing amount of content inside the intestines, which indirectly leads to a more rapid movement to the keep.

ii). The medication may affect the intestinal mucosa, thus reducing the magnitude of the normal absorption of electrolytes and water and increasing the amount of water, which indirectly leads to a more rapid movement of intestinal contents.

iii). The medication may affect the intestinal mucosa, increasing the overall value of the normal secretion of electrolytes and water and increasing the amount of water that directly and/or indirectly leads to more rapid movement of intestinal contents.

iv). Medicine first affects peristalsis, accelerating the move, which indirectly leads to a decrease in the total absorption of water and electrolytes, reducing the time during which they can be absorbed.

Used in the present invention the test intestinal accumulations is intended for research mainly mechanisms (ii) and/or (iii)that determine the drug effect on the accumulation of water inside the bowel by measuring the amount of content inside the intestines. For bicyclic halogenated compounds of the present invention may be a very strong effect on these clusters. Moreover, they cause a weak or mild contractions of the intestine that is one of the indices for evaluating the mechanism of iv). In accordance with this, it is considered that bizik the practical halogenated compounds of formula (I) of the present invention facilitate constipation mainly through direct and/or indirect effects on the intestinal mucosa, to affect the movement of water and electrolytes from the intestinal wall into the blood vessels and/or blood vessels in the intestines, which reduces water absorption and/or increase the secretion of water through the intestines, increased accumulation of water in the intestine and facilitate the movement of intestinal contents.

In the definitions of formula (I), the term "unsaturated" refers to the inclusion of at least one or more double bonds and/or triple bonds that in isolation, separately or serially present between carbon atoms in the main and/or side chains. Unsaturated bond between two successive positions indicated by bringing the smaller number of the two provisions, and the unsaturated bond between two remote positions indicated by specifying both positions. Preferred unsaturated bonds represent a double bond in position 2 and double or triple bond in position 5.

The term "lower" includes a group having from 1 to 8 carbon atoms, unless otherwise indicated.

The term "halogen atom" includes fluorine atoms, chlorine, bromine or iodine. Particularly preferred is a fluorine atom.

The term "lower alkoxy" refers to the group of lower alkyl-O-, in which the lower alkyl is a branched or non-branched chain saturated hydrocarbon groups which, containing from 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.

The term "lower hydroxyalkyl group" refers to lower alkyl groups defined above, substituted by at least one hydroxy group such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-1-hydroxyethyl.

The term "lower alkanoyloxy group" refers to a group represented by the formula RCO-O-, in which RCO is an acyl group, formed by oxidation of the previously described lower alkyl groups, such as acetyl.

The term "lower cycloalkyl" refers to a cyclic group formed by cyclization of the above mentioned lower alkyl groups, but containing three or more carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "lower cycloalkane" refers to the lowest cycloalkyl-O-group in which the lower cycloalkyl group is the same as defined above.

The term "aryl" may include substituted or unsubstituted aromatic carbocyclic group (preferably monocyclic group, for example phenyl, naphthyl, tolyl and xylyl. Examples of the substituents are a halogen atom and a lower haloalkyl, in which the halogen atom and a lower alkyl such as defined enter the.

The term "aryloxy" refers to a group represented by the formula ArO-, in which Ar represents an aryl, such as defined above.

The term "heterocyclic group" may include monocyclic heterocyclic group, in a cycle which has from 5 to 14 atoms, preferably from 5 to 10 atoms, containing as constituent atoms optionally substituted carbon atoms and from 1 to 4, preferably from 1 to 3 heteroatoms of one or two types selected from oxygen atom, nitrogen atom and sulfur atom, and a condensed heterocyclic group containing up to 3 cyclic functional groups, at least one of which represents the above-mentioned monocyclic group. Examples of heterocyclic groups include follow group, thienyl group, pyrrolyl, oxazolyl, isoxazolyl, thiazolium group, isothiazolinone group, imidazolium group, pyrazolinone group, foratenolol group, pyranyloxy group, pyridyl, pyridil, pyrimidyl, perilou group, 2-pyrrolyl, pyrrolidinyl, 2-imidazolyl, imidazolidinyl group, 2-pyrazolinone group, pyrazolidinone group, piperidino group, piperazinyl group, morpholino group, indolenine group, benzothiazoline group, pinolillo group, izohinolinove group, peril, khinazolinov group carbazolyl group, acridines, phenanthridines, benzimidazolyl, benzimidazolinyl, phenothiazinyl group. Examples of substituents in this case include a halogen atom and a halogen-substituted lower alkyl, in which the halogen atom and lower alkyl are as described above.

The term "heterocyclic oxy group" means a group represented by the formula Na-O-, where Na is a heterocyclic group as described above.

Used in the present invention bicyclic-16-halogenated compounds may be salts or these compounds include esterified carboxyl group, or a group of simple ether. Such salts include pharmaceutically acceptable salts, for example alkali metal salts, such as sodium and potassium; salts of alkaline earth metals such as calcium and magnesium; and pharmaceutically acceptable ammonium salts such as ammonium salts, methylamine, dimethylamine, cyclopentylamine, cyclohexylamine, benzylamine, piperidine, Ethylenediamine, monoethanolamine, diethanolamine, triethanolamine, monomethylethanolamine, tromethamine, lysine, procaine, caffeine, arginine salt of tetraalkylammonium, and the like. These salts can be prepared in the traditional way, for example, from the corresponding acids and bases or substitution reaction of salts.

Examples of such complex and simple afireplace alkalemia simple and complex esters with unbranched or branched chain, which may contain one or more unsaturated bonds, such as methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, tert-butyl esters, pentalonia esters and 2-ethylhexylamine ethers; esters, which are alicyclic group, such as cyclopropyl, cyclopentyl or cyclohexyloxy group; esters containing an aromatic group such as phenyl or benzyl group in which the aromatic group may contain one or more substituents); lower alkenyl, such as vinyl and allyl and lower quinil, such as ethinyl and PROPYNYL; hydroxyalkyl or alkoxyalkyl, such as hydroxyethyl, hydroxyisopropyl, polyhydroxyethyl, polyhydroxyethyl, methoxyethyl, ethoxyethyl or methoxyestradiol simple or complex ester; optionally substituted arily, such as phenyl, tosyl, simple tert-butylphenyl, salicyl, 3,4-acid and benzamidophenyl; alkylsilane, such as trimethylsilyl or triethylsilyl; or a simple or complex tetrahydropyranyloxy ether.

Preferably simple and complex esters include, for example, simple and complex esters of the lower Akilov with unbranched or branched chain, such as methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl; benzyl; or hydroxyalkyl, such as hydroxyethyl or hydroxyisopropyl.

Preferably a is a group -- COOH or its pharmaceutically acceptable salt or ester.

Preferably both X1and X2represent halogen atoms, and more preferably fluorine atoms.

Preferably W1represents a group =O.

Preferably W2representsorwhen both R3and R4represent hydrogen atoms.

Preferably Z represents an oxygen atom.

Preferably Y is an unsubstituted saturated or unsaturated hydrocarbon chain containing from 6-8 carbon atoms.

Preferably R1represents unsubstituted saturated or unsaturated hydrocarbon chain containing 4 to 8 carbon atoms.

Preferably R2represents a hydrogen atom.

The composition of the present invention may include the isomers of the above compounds. Examples of such isomers include monocyclic the tautomers having a keto group in position C-15 and the halogen atom at position C-16; optical isomers, geometrical isomers, etc.

Tautomerism between the oxygen atom at position C-11 and a keto group in position C-15, shown above, is especially significant in the case of the of dinani, having 13,14-simple connection and two fluorine atom at position C-16.

It was found that in the absence of water, the compounds represented by formula (I), exist mainly in the form of bicyclic compounds. I believe that in water the hydrogen bond is formed, for example, between the ketone group in position C-15, thus impeding the formation of the bicyclic system. In addition, it is believed that the atom (atoms) halogen at position C-16 facilitate the formation of the bicyclic system. For example, monocyclic/bicyclic structure may be present in a ratio of 1:6 in D2O; 1:10 in CD3OD-D2O; and 4:96 in CDCl3. Accordingly, the preferred embodiment of the present invention is a composition in which the bicyclic compound is present in a ratio of bicyclic/monocyclic equal to at least 1/1, and preferably 20/1 or even more, including almost all of the bicyclic compound; 100% of the bicyclic compound is included in the scope of protection of this invention.

The above bicyclic 16-halogenated compounds of formula (I) can be obtained in accordance with the General method, which is described below.

Getting isopropyl ester of 7-[(1S,3S,6S,7R)-3-heptyl-3-hydroxybutyl[4,3,0]-nonan-8-one-7-yl]hept-5-ene acid and isopropyl ether 7-[(1S,3R,6S,7R)-3-heptyl-3-guide oxabicyclo[4,3,0]-nonan-8-one-7-yl]hept-5-ene acid.

1. Getting isopropyl ether (Z) 7-[(1R,2R,3R,5S)-2-(3,3-ethyleneoxide-5-hydroxy-3-(p-toluensulfonyl)cyclopentyl]hept-5-ene acid (2)

Add to the mixture of pyridine (0,77 g) and of 4.05 g of isopropyl ether (Z) 7-[(1R,2R,3R,5S) - for 3,5-dihydroxy-2-(3,3-ethyleneoxide)cyclopentyl]hept-5-ene acid (1) in dichloromethane a solution of 1.86 g of chloride Totila in dichloromethane at 0°and the mixture is stirred for 2 hours at this temperature. During the reaction the three portions add separately to 5.58 g of chloride Totila and 2,31 g of pyridine. After normal processing of the crude product highlight chromatography on silica gel, receiving of 3.45 g of isopropyl ether (Z) 7-[(1R,2R,3R,5S)-2-(3,3-ethyleneoxide)-5-hydroxy-3-(p-toluensulfonyl)cyclopentyl]hept-5-ene acid (2) with the release of 64.1 percent.

2. Getting isopropyl ether (Z) 7-[(1R,2S)-2-(3,3-ethyleneoxide)-5-oxo-cyclopent-3-enyl]hept-5-ene acid (3)

Isopropyl ether (Z) 7-[(1R,2R,3R,5S)-2-(3,3-ethyleneoxide)-5-hydroxy-3-(p-toluensulfonyl)cyclopentyl]-hept-5-ene acid (2) (1,72 g) oxidized in acetone at a temperature of from -40 to -20°With Jones reagent within 4 hours After normal processing of the crude product is passed through a layer of silica gel with a mixture of n-hexane/ethyl acetate (3,5/1). The product is then optionally purified chromatographically n the silica gel with a mixture of n-hexane/ethyl acetate (4/1). Get 0,81 g of isopropyl ether (Z) 7-[(1R,2S)-2-(3,3-ethyleneoxide)-5-oxo-cyclopent-3-enyl]hept-5-ene acid (3) with access to 64.6%.

3. Getting isopropyl ester of 7-[(1R,2S,3R)-2-(3,3-ethyleneoxide)-3-hydroxymethyl-5-oxocyclopent]hept-5-ene acid (4)

Dissolve in methanol 0,81 g of isopropyl ether (Z) 7-[(1R,2S)-2-(3,3-ethylene-deoxidizer)-5-oxo-cyclopent-3-enyl]hept-5-ene acid (3) and benzophenone. In argon atmosphere, this solution was irradiated with a mercury lamp high pressure (300 W) for 4 h and 40 min After evaporation of the solvent the crude product is purified chromatographically on silica gel with a mixture of n-hexane/ethyl acetate (3/2). Get 0,41 g of isopropyl ester of 7-[(1R,2S,3R)-2-(3,3-ethyleneoxide)-3-hydroxymethyl-5-oxocyclopent]hept-5-ene acid (4) with a yield of 47%.

4. Getting isopropyl ester of 7-[(1R,2S,3R)-2-(3,3-ethyleneoxide)-5-oxo-3-(p-toluensulfonyl) cyclopentyl]-hept-5-ene acid (5)

Dissolving 0.21 g of isopropyl ester of 7-[(1R,2S,3R)-2-(3,3-ethyleneoxide)-3-hydroxymethyl-5-oxocyclopent]hept-5-ene acid (4) and 0.07 g of pyridine in dichloromethane. To this solution was added 0.17 g of chloride Totila at 0°and the mixture is stirred for 72 hours After normal processing of the crude product highlight chromatography is as silica gel, receiving 0.25 g of isopropyl ester of 7-[(1R,2R,3R)-2-(3,3-ethyleneoxide)-5-oxo-3-(p-toluensulfonyl)methylcyclopentene]hept-5-ene acid (5) with a yield of 89%.

5. Getting isopropyl ester of 7-[(1R,2R,3R)-2-(3,3-ethyleneoxide)-3-iodomethyl-5-oxocyclopent]hept-5-ene acid (6)

Dissolve 0.25 g of isopropyl ester of 7-[(1R,2S,3R)-2-(3,3-ethyleneoxide)-5-oxo-3-(p-toluensulfonyl)methylcyclopentene]-hept-5-ene acid (5) in acetone and add 0.12 g of sodium iodide. The mixture is refluxed for 3 hours To the mixture 0,097 g of sodium iodide and the mixture is refluxed for an additional 80 minutes. After normal processing of the crude product is purified chromatographically on silica gel with a mixture of n-hexane/ethyl acetate (5/1). Obtain 0.16 g of isopropyl ester of 7-[(1R,2R,3R)-2-(3,3-ethyleneoxide)-3-iodomethyl-5-oxocyclopent]hept-5-ene acid (6) with a yield of 68%.

6. Getting isopropyl ester of 7-[(1R,2R,3R)-3-iodomethyl-5-oxo-2-(3-octadecyl)-cyclopentyl]hept-5-ene acid (7)

Dissolving 0.16 g of isopropyl ester of 7-[(1R,2R,3R)-2-(3,3-ethyleneoxide)-3-iodomethyl-5-oxocyclopent]hept-5-ene acid (6) in a mixed solvent of acetic acid/water/tetrahydrofuran (3/1/1). The mixture is stirred for 20 h at room temperature and 2.5 h at 50°C. After evaporation of the races is vorites the resulting residue is purified chromatographically on silica gel with a mixture of n-hexane/ethyl acetate (1/1). Gain of 0.13 g of isopropyl ester of 7-[(1R,2R,3R)-3-iodomethyl-5-oxo-2-(3-octadecyl)-cyclopentyl]hept-5-ene acid (7) with the release of 86%.

7. Getting isopropyl ester of 7-[(1S,3S,6S,7R)-3-heptyl-3-hydroxybutyl-[4,3,0]-nonan-8-one-7-yl]hept-5-ene acid (8A) and isopropyl ether 7-[(1S,3R,6S,7R)-3-heptyl-3-hydroxybutyl[4,3,0]-nonan-8-one-7-yl]hept-5-ene acid (8b)

Dissolved in tetrahydrofuran 0,0574 g of isopropyl ester of 7-[(1R,2R,3R)-3-iodomethyl-2-(3-octadecyl)-5-oxo-cyclopentyl]hept-5-ene acid (7) and dichloride zirconocene. The mixture is treated with sound in a stream of argon, to blow air out of the mixture. To this mixture is added dropwise 0.1 M solution of samarium iodide in tetrahydrofuran (2.1 ml). The mixture is stirred for 30 min at room temperature and then add 1 ml of 0.1 M hydrochloric acid. After normal processing of the crude product is purified chromatographically on silica gel with a mixture of n-hexane/ethyl acetate (5/1). Get two bicyclic product, the more polar (8A) and its less polar epimer (8b) and source material (7) as follows:

Isopropyl ester of 7-[(1S,3S,6S,7R)-3-heptyl-3-hydroxybutyl-[4,3,0]-nonan-8-one-7-yl]hept-5-ene acid (8A) and isopropyl ether 7-[(1S,3R,6S,7R)-3-heptyl-3-hydroxy-bicyclo[4,3,0]-nonan-8-one-7-yl]hept-5-ene acid (8b). Output (8A) of 5.1 mg Output (8b) 7.2 mg; dedicated to 26.7 mg source material is (7).

The scheme for synthesis of compounds represented by formula (I)in which Z is a sulfur atom and W1represents a group-IT below:

The scheme for synthesis of compounds represented by formula (I)in which Z is a sulfur atom and W1is a keto-group, to the following:

The scheme for synthesis of compounds represented by formula (I)in which Z is a sulfur atom, W1is a keto-group

The scheme for synthesis of compounds represented by formula (I)in which Z is a nitrogen atom, the following:

Another scheme of the synthesis of compounds represented by formula (I)in which Z is a nitrogen atom, the following:

One should not assume that the preparations of the present invention limited to the above, and when you receive them may apply appropriate means to protect, oxidation, recovery, etc.

In bicyclic 16-halogenated compounds used in the present invention, greatly enhanced activity against intestinal accumulations, when it is in position C-16 there are two atoms of halogen substituent, especially two atoms of fluorine, regardless of structure and substituents in the five-membered ring or the presence of double bonds or other substituents. Particularly preferred bicyclic halogenated compounds are those tautomers, which are formed from monocyclic compounds having a keto group in position C-9 hydroxyl group in position C-11 in the five-membered ring. Another preferred group is bicyclic halogenated compounds containing 5,6-simple link, 5,6-double bond, or those in which the number of carbon atoms is from 20 to 22, and R1contains 4 to 6 carbon atoms, preferably an unbranched chain.

Example monocyclic/bicyclic 16-halogenated compounds containing 5,6-double bond, the following:

Another variant of the embodiment of the present invention includes the composition of the present invention and the triglyceride fatty acids with medium chain. Acid triglycerides may be saturated or unsaturated, containing 6-14 carbon atoms, which may form a branched chain. Preferred fatty acid is a saturated fatty acid with unbranched chain, for example Caproic acid, Caprylic acid, lauric acid and myristic acid. Can the be used as a mixture of two (or more) of the triglyceride fatty acids with medium chain length.

The composition of the present invention can be obtained by dissolving or mixing the bicyclic compounds of formula (I) in the triglyceride fatty acids with medium chain. The amount of triglyceride fatty acids with medium chain is not limited. However, usually you can use from 1 to 1,000,000 parts by weight of the triglyceride fatty acids with medium chain per one weight part of the bicyclic compounds, preferably from 5 to 500,000 weight parts and more preferably from 10 to 200,000 weight parts.

Examples of triglyceride fatty acids with medium chain used in the present invention include the triglyceride of saturated or unsaturated fatty acids containing 6-14 carbon atoms, which may form a branched chain. Preferred fatty acid is a saturated fatty acid with unbranched chain, for example, hexanoic acid (C6), Caprylic acid (C8), lauric acid (C12) and myristic acid (C14). You can also use a mixture of two or more triglycerides of fatty acids with medium chain.

To increase the ratio of monocyclic/bicyclic compounds can be used more non-polar solvent, such as industrial available Miglyol.

To illustrate the formulation of a draft of this image is etenia and demonstrate the strong influence of steric below is an example of

Example

The following compounds 1 and 2 dissolved in a mixture of triglycerides of fatty acids with medium chain MCT (MCT - a mixture of triglycerides of Caprylic acid and Caproic acid triglyceride in the ratio 85:15) in the amount indicated in the table below

Each solution is placed in a container made of strong glass, and stored at 40°C. change the content of compounds 1 and 2 in solution in time is determined by liquid chromatography high pressure (ghvd). At the same time each of the compounds 1 and 2 are placed in a container separately (not diluting them with a solvent as described above, and stored at 40°With, in order to ensure control study.

In the absence of a solvent, the content of the compounds is determined by the method jhud as follows. Persistent connections 1 and 2 and standard connections 1 and 2 accurately weighed (weight of about 0.025 g) and add an aliquot (exactly 5 ml of the internal standard solution to the corresponding external and internal connections. Preparations for the test and standard preparations obtained by adding acetonitrile (for liquid chromatography), to get the total amount of each drug exactly 10 ml liquid chromatograph injected sample, 10 µl of the preparation for tests and the standard preparation, and determine the content of the substance by the method of internal standard point on the calibration curve:

WS- the number of connections in the standard drug mg

WT- the number of connections 1 and 2 in preparation for tests, mg

QSthe peak area of the compound in the standard preparation relative to the peak area of internal standard.

QTthe peak area of compounds in drug test relative to the peak area of internal standard.

Measurement conditions

Detector: ultraviolet spectrophotometer (UV) absorption at a wavelength of 294 nm.

Column: stainless steel tube having an inner diameter of approximately 5 mm and a length of about 250 mm, filled octadecylsilyl-silica gel for liquid chromatography (particles of 5 microns).

The column temperature: a constant, approximately 35°C.

Mobile phase: mixed solution of acetonitrile (for liquid chromatography)/aqueous solution of sodium acetate (0.01 mol/l)/glacial acetic acid(800:200:1).

In the presence of a solvent determine the connection method jhud as follows.

Based on the values shown in the table below, accurately weigh the sample solution corresponding to 36 μg of compounds 1 and 2. Add exactly 1.0 ml of the internal standard solution and then add ethyl acetate (liquid chromatography), receiving in each case a total volume of 10 ml of Each sample 0.1 m is this solution was concentrated in vacuo to dryness, getting a drug test.

Accurately weighed 18 mg of each standard compound and mixed with ethyl acetate (liquid chromatography), receiving in each case the total amount of exactly 50 ml. Accurately measure 1.0 ml of this solution and 10 ml of solution of standard compounds and mixed with ethyl acetate (liquid chromatography), receiving in each case, the total exactly 100 ml of Each sample of 0.1 ml of this solution was concentrated in vacuo to dryness, obtaining the drug test.

Add in the test and standard preparations of 0.1 ml of the reagent is a fluorescent label and 0,85 ml catalyst for fluorescent labels, respectively, and the mixture is stirred, conducting the reaction at room temperature for more than 30 minutes. The reaction mixture was added an aliquot (0.05 ml) of acetonitrile (for liquid chromatography)containing 2% acetic acid, respectively, the mixture is stirred and incubated for 30 minutes to get the test and standard solutions.

In the liquid chromatograph is injected sample 10 ál of the solution for test and standard solution and determine the content of the substance by the method of internal standard point on the calibration curve:

Ws- the number of connections in the standard drug mg

Qs- the square of the peak area of the compound in the standard preparation relative to the peak area of internal standard.

Qtthe peak area of compounds in drug test relative to the peak area of internal standard.

Measurement conditions

Detector: fluorescence spectrometer (wavelength excitation radiation 259 nm; wavelength fluorescence 394 nm).

Column: stainless steel tube having an inner diameter of approximately 5 mm and a length of about 250 mm, filled with phase - octadecylsilyl-silica gel for liquid chromatography (particles of 5 microns).

The column temperature: a constant, approximately 35°C.

Mobile phase: mixed solution of acetonitrile (for liquid chromatography)/methanol (for liquid chromatography)/aqueous solution of ammonium acetate (0.05 mol/l) (4:11:5).

Table
Connection 1Connection 2
CrystalsMCT1CrystalsMCT2
Source100100100100
6 days84,5
7 days97,2
14 days94,1 101,475,099,6
28 days87,453,4the 98.9
38 days102,1
90 days100,9
191 days99,6
1Connection 1/solvent: 0.36 mg/g

2Connection 2/solvent: 0,12 mg/g

The composition of the present invention causes a very strong effect in respect of the clusters inside the intestines, inhibiting water absorption in the intestine. In addition, for compounds of the present invention is absent or strongly reduced the effect of reducing the intestine, which is possible for prostaglandins PGE or PGF. Therefore, the composition of the present invention cure constipation without discomfort in the stomach due to the contractions of the intestine, causing complaints of pain. In addition, the compound of the present invention allows ease constipation, leading to the normal functioning of the intestine. Moreover, it takes a bit of time to recovery of bowel from symptoms of diarrhea, if it is caused by compounds of the present invention, which have greatly the m promoting effect in relation to movements in the intestine. Therefore they are very effective as a laxative agent.

The composition of the present invention can be used as a laxative agent for the treatment and prevention of constipation in humans and animals, and usually it is used for systemic or local destination by entering through the mouth or in the form of suppositories, enemas, etc. In some cases these tools can be applied in the form of intravenous or subcutaneous injection. Dosage varies depending on the kind of patient (people, animals), its age, weight, condition, therapeutic effect, method of appointment, the treatment time and the like, Preferred is a dose of 0.001-1000 μg/kg and more preferably from 0.01 to 100 µg/kg

The composition of the present invention can also be used to provide agent, cleansing the bowel to bowel preparation for diagnostic or surgical procedure, such as endoscopy, colonoscopy (examination of the colon), x-ray, fluoroscopy with double contrast barium enema and intravenous pyelography; and for the case of emergency, such as the removal of toxic substances or food poisoning.

The solid composition of the present invention for oral administration includes tablets, drugs, granules, etc. In such solid compositions one or N. the many active ingredients can be mixed, at least one inactive diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminate and metasilicates magnesium, etc. in accordance with the usual procedure, the composition may contain other additives in addition to the inactive diluent, for example a lubricating substance, such as magnesium stearate; a shredder, such as fibrous calcium gluconate; stabilizer, such as a cyclodextrin, for example, α-, βor γ-cyclodextrin; etherified cyclodextrin, such as dimethyl-α, dimethyl-β-, trimethyl-β- or hydroxypropyl-β-cyclodextrin; a branched cyclodextrin, such as glucosyl-, maltose-cyclodextrin; formirovanii cyclodextrin, cyclodextrin containing sulfur; a phospholipid, etc. In the case of using the above cyclodextrins sometimes can form compounds include with the cyclodextrin to improve stability. An alternative may be used phospholipid with the formation of liposomes, which leads to increased stability.

If necessary, tablets or pills may be coated with a film soluble in the stomach or intestines, such as sugar, gelatin, hydroxypropyl-cellulose phthalate of hydroxypropylmethylcellulose. In addition to the, they can be shaped in the form of capsules of substances that can be absorbed, such as gelatin.

Liquid composition for oral administration may contain pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir, as well as commonly used inactive diluent. Such a composition may contain in addition to the inactive diluent excipients, such as suspendresume agents, sweeteners, fragrances, preservatives, antioxidants, etc. the details about the additives can be selected from those described in any General reference on pharmaceuticals. Such liquid compositions may be contained directly in soft capsules. However, the choice of diluent, different from those mentioned above, which can be dissolved or mixed monocyclic/bicyclic compound must be thoroughly grounded in order not to influence the attitude of bicyclic/monocyclic connection.

Solutions for parenteral administration, such as suppositories, enemas, etc. according to the present invention, include, for example, distilled water, saline solution and ringer's solution.

Non-aqueous solution and suspension include, for example, propylene glycol, polyethylene glycol, a triglyceride of a fatty acid, a vegetable oil, such as olive oil, alcohols such the AK ethanol, Polysorbate and the like, the composition may contain auxiliary substances such as preservatives, wetting agent, emulsifier, suspendisse agent, antioxidants, etc.

The present invention will be illustrated in the following examples, which are given only for illustration and are not intended to limit the scope of the present invention.

Correlation monocyclic/a bicyclic structure and biological activity.

To illustrate the influence of atoms of halogen in position C-16 bicyclic halogenated compounds in the compositions of the present invention were prepared and tested compounds in the following examples.

Example 1

The biological activity of the composition of the present invention depending on the ratio of monocyclic/a bicyclic structure, when in the General formula (I), Z represents an oxygen atom, and the keto group is present at position C-9 can be seen from the following examples. The number of fluorine atoms in position C-16 and the ratio of monocyclic/bicyclic structure is shown in table 1.

Trials were conducted intestinal accumulations and tests of diarrhea, the results are presented in table 1. The dosage at which the content inside of the intestine is increased by 50%, called the ED50.

Table 1
Example aThe example InComparative example a
The number of fluorine atoms in position C-16210
The ratio of monocyclic/bicyclic structure*4:961:1Not detected a signal from a bicyclic structure
The activity of intestinal accumulations, ED500.6 ág/kg2 ág/kg320 ág/kg
Diarrhea in mice+: when 3 mg/kg1+: at 0.3 mg/kg, PC±: at 0.3

mg/kg / PC2
-: 10 mg/kg IN: 1 mg/kg, PC
* Determined from measurements by NMR in CDCl solution3< / br>
lIN the dose by mouth

2PC - subcutaneous administration

Example 2

The dependence of the biological activity of the composition of the present invention the ratio of monocyclic/a bicyclic structure, when in the General formula (I), Z represents an oxygen atom, and the keto group is present at position C-9 and has a double bond between carbon atoms 5 to 6 shown below.

Were n is Evegeny tests of intestinal accumulations and tests diarrhea, the results are presented below in table 2. The dosage at which the content inside of the intestine is increased by 50%, called the ED50.

Table 2
ExampleExample DComparative example
The number of fluorine atoms in position C-16210
The ratio of monocyclic/bicyclic structure*4:961:1Not detected a signal from a bicyclic structure
The activity of intestinal accumulations, ED500.3 ug/kg3 mcg/kg220 ág/kg
Diarrhea in mice+: 1

mg/kg1
-: 1 mg/kg) + : at 5 mg/kg-: 10 mg/kg
* Determined from measurements by NMR in CDCl solution3< / br>
1IN the dose by mouth

The effect of the compounds of the present invention dissolved in triglyceride fatty acids with medium chain on peristalsis after a single oral administration to healthy male volunteers.

Healthy male volunteers (n=3 to 9) introducing a composition comprising the following monocyclic/bicyclic structure (CDCl solution 3) in the ratio of 4:96.

The test substance (R1and R2are fluorine atoms) dissolved in reagent Panacet 800 (triglyceride fatty acids with medium chain, the product of the company Nippon Oil &Fat Co., Ltd., Amagasaki, Japan) and filled with a solution of a capsule (each capsule contains 200 ál of the mixture). Each subject is administered one capsule with 100 ml of water.

Table 3 shows the number of subjects who have a loose stool or diarrhea.

Table 3
Dose, mcgThe number of subjects
Normal stoolLoose stools or diarrhea
51/32/3
105/72/7
201/32/3
302/97/9

Although this invention is described in detail and with reference to its specific variants of the embodiment for qualified professionals in this area of technology will be evident that various modifications and variations of the invention without deviating from the intent and scope of the invention.

1. The composition of a laxative agent, which includes effective as sleutels the th, the amount of the bicyclic compound represented by formula (I)

where V1and V2represent carbon atoms;

W1and W2are

R3and R4represent a hydrogen atom or one of these substituents is an OH group;

X1and X2represent a hydrogen atom, lower alkyl or halogen atom, and at least one of them is a halogen atom;

Z represents an oxygen atom;

R2represent a hydrogen atom or alkyl;

Y represents a saturated or unsaturated With2-10hydrocarbon chain;

A represents a-CH2OH, -COCH2HE, -COOH or a functional derivative;

R1represents a saturated or unsaturated lower hydrocarbon residue, having an unbranched or branched chain;

the relationship between the provisions of C-13 and C-14) is a double or a simple bond;

C-15 has a spatial configuration R, S or a mixture.

2. The composition according to claim 1, which additionally includes the connection, which is a monocyclic tautomer formula (I), in an amount to provide a ratio of bicyclic the structure to a monocyclic, at least equal to 1:1.

3. The composition according to claim 1, which additionally includes the connection, which is a monocyclic tautomer formula (I), in an amount to provide a ratio of the bicyclic structure to a monocyclic, at least equal to 20:1.

4. The composition according to claim 1, in which a is the group-COOH, W1is a keto-group, R2is a hydrogen atom and X1and X2represent fluorine atoms.

5. The composition according to claim 1, in which a is the group-COOH, Y is (CH2)6, W1is Oh, R3and R4represent hydrogen atoms, X1and X2represent fluorine atoms and R1represents -(CH2)3CH3.

6. The composition according to claim 1, in which the bicyclic compound is a

7. The composition according to any one of claims 1 to 6, which additionally includes the triglyceride fatty acids with medium chain.

8. The composition according to claim 7, in which the triglyceride fatty acids with medium chain is present in an amount of from 1 to 1000000 weight. hours per weight part of the bicyclic compounds of the formula (I).

9. The composition according to claim 8, in which the triglyceride fatty acids with medium chain is present in an amount of from 5 to 500,000 weight. o'clock in the calculation of the well, the weight portion of the bicyclic compounds of the formula (I).

10. The composition according to claim 9, in which the triglyceride fatty acids with medium chain is present in an amount of from 10 to 200,000 weight. hours per weight part of the bicyclic compounds of the formula (I).

11. The composition according to claim 7, in which the triglyceride fatty acids with medium chain is a triglyceride of a fatty acid containing 6-14 carbon atoms.

12. The composition according to claim 11, in which the triglyceride fatty acids with medium chain is a triglyceride of Caprylic acid and/or capric acid.

13. The composition according to any one of claims 1 to 12 for the relief and prevention of constipation in patients suffering from constipation.

14. The composition according to any one of claims 1 to 12, which is used for bowel cleansing.

15. The method provides a laxative effect for the needy in this patient, which comprises administration to the patient of a composition containing effective as a laxative, the number of bicyclic compounds of the formula (I)

where V1and V2represent carbon atoms;

W1and W2are

R3and R4represent a hydrogen atom or one of these substituents is a group of IT;

X1and X2before the represent a hydrogen atom, lower alkyl or halogen atom, and at least one of them is a halogen atom;

Z represents an oxygen atom;

R2represent a hydrogen atom or alkyl;

Y represents a saturated or unsaturated With2-10hydrocarbon chain;

A represents a-CH2OH, -COCH2OH, -COOH or a functional derivative;

R1represents a saturated or unsaturated lower hydrocarbon residue, having an unbranched or branched chain; lower cycloalkane group; aryl group; alloctype; heterocyclic group; the heterocyclic oxygraph;

the relationship between the provisions of C-13 and C-14) is a double or a simple bond;

C-15 has a spatial configuration R, S or a mixture.

16. The method according to item 15, in which the composition additionally includes the connection, which is a monocyclic tautomer formula (I), in an amount to provide a ratio of the bicyclic structure to a monocyclic, at least, equal to 1:1.

17. The method according to clause 16, in which the ratio of the bicyclic structure to a monocyclic, at least equal to 20:1.

18. The method according to item 15, in which a is the group-COOH, W1is a keto-group, R2is a hydrogen atom and X1and X2PR is astavliaut a fluorine atoms.

19. The method according to item 15, in which a is the group-COOH, Y is (CH2)6, W1is Oh, R3and R4represent hydrogen atoms, X1and X2represent fluorine atoms and R1represents -(CH2)3CH3.

20. The method according to item 15, in which the bicyclic compound is a

21. The method according to any of PP-20, in which the composition additionally comprises a triglyceride of fatty acids with medium chain.

22. The method according to item 21, in which the triglyceride fatty acids with medium chain is present in an amount of from 1 to 1000000 weight. hours per weight part of the bicyclic compounds of the formula (I).

23. The method according to item 22, in which the triglyceride fatty acids with medium chain is present in an amount of from 5 to 500,000 weight. hours per weight part of the bicyclic compounds of the formula (I).

24. The method according to item 23, in which the triglyceride fatty acids with medium chain is present in an amount of from 10 to 200,000 weight. hours per weight part of the bicyclic compounds of the formula (I).

25. The method according to item 21, in which the triglyceride fatty acids with medium chain is a triglyceride of a fatty acid containing 6-14 carbon atoms.

26. The method according A.25, in which the triglyceride of IRN the th acids with medium chain is a triglyceride of Caprylic acid and/or capric acid.

27. The method according to any of p-26, for the relief and prevention of constipation in patients-people.

28. The method according to any of p-26, which is used for bowel cleansing.

29. The use of bicyclic compounds of the formula (I)

where V1and V2represent carbon atoms;

W1and W2are

R3and R4represent a hydrogen atom or one of these substituents is a group of IT;

X1and X2represent a hydrogen atom, lower alkyl or halogen atom, and at least one of them is a halogen atom;

Z represents an oxygen atom;

R2represent a hydrogen atom or alkyl;

Y represents a saturated or unsaturated With2-10hydrocarbon chain;

A represents a-CH2OH, -COCH2OH, -COOH or a functional derivative; and

R1represents a saturated or unsaturated lower hydrocarbon residue, having an unbranched or branched chain;

the relationship between the provisions of C-13 and C-14) is a double or a simple bond, and

C-15 has a spatial configuration R, S or a mixture thereof,

for manufacturing is oppozitsii a laxative agent.

30. The application of clause 29, in which the composition additionally includes the connection, which is a monocyclic tautomer formula (I), in an amount to provide a ratio of the bicyclic structure to a monocyclic, at least equal to 1:1.

31. The application of article 30, in which the ratio of the bicyclic structure to a monocyclic, at least 20:1.

32. The application of clause 29, in which a is a group-COOH, W1is a keto-group, R2is a hydrogen atom and X1and X2represent fluorine atoms.

33. The application of clause 29, in which a is a group-COOH, Y represents a group (CH2)6, W1is a group =O, R3and R4represent hydrogen atoms, X1and X2represent fluorine atoms and R1represents -(CH2)3CH3.

34. The application of clause 29, in which the bicyclic compound is a

35. The use according to any one of p-34, in which the composition additionally comprises a triglyceride of fatty acids with medium chain.

36. Use p, in which the triglyceride fatty acids with medium chain is present in an amount of from 1 to 1000000 weight. hours per weight part of the bicyclic compounds of the formula (I).

37. the label on p, in which the triglyceride fatty acids with medium chain is present in an amount of from 5 to 500,000 weight. hours per weight part of the bicyclic compounds of the formula (I).

38. The application of clause 37, in which the triglyceride fatty acids with medium chain is present in an amount of from 10 to 200,000 weight. hours per weight part of the bicyclic compounds of the formula (I).

39. Use p, in which the triglyceride fatty acids with medium chain is a triglyceride of a fatty acid containing 6-14 carbon atoms.

40. The application of § 39, in which the triglyceride fatty acids with medium chain is a triglyceride of Caprylic acid and/or capric acid.

41. The use according to any one of p-40 for the relief and prevention of constipation in patients-people.

42. The use according to any one of p-40 to clean the intestines.



 

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