Complex 17-deoxy-corticoid-21-ether carboxylic acids, the methods of its production, drug

 

(57) Abstract:

Describes complex 17-deoxy-corticoid-21 - esters of carboxylic acids of the formula I, where denotes CHOH - position, Y represents hydrogen, fluorine, single or double bond, Z represents hydrogen, fluorine or methyl, R(1) denotes a phenyl, thienyl, pyridyl, indolyl, naphthyl, each of which is unsubstituted or substituted by one or two substituents selected from the group comprising lower alkoxygroup, methylendioxy, [(C1-C4) - alkyl] is busy or starting with C2once the unsaturated starting with C3- multiply unsaturated, or cyclic, branched at the expense of other alkyl groups, R(2) denotes hydrogen, or methyl. Can be used for the treatment of dermatoses and to have antitumor and anti-inflammatory action. Describe the methods for their preparation and medicinal products based on them. 4 S. and 2 C.p. f-crystals, 5 PL.

The invention relates to complex 17-deoxy-corticoid-21 - esters of carboxylic acids of the formula (I):

< / BR>
where:

A represents CHOH and CHCl at any spatial location, CH2C=O or 9(11) - double bond;

Y denotes hydrogen, fluorine or chlorine;

Z about the;

[(C1-C4)-alkyl] is saturated, since C2also once the unsaturated starting with C3also multiply unsaturated, or cyclic, branched at the expense of other alkyl groups, enabled by the heteroatoms O, S, N or substituted; and provisions 1,2 are saturated or unsaturated (1,2 - double bond);

R (2) denotes hydrogen, or methyl.

Preferred complex 17-deoxy-corticoid-21-esters of carboxylic acids of the formula (I), in which;

R (1) has the above meaning;

A represents CHOH (configuration),

Y represents fluorine;

Z denotes hydrogen;

R (2) denotes-methyl.

The invention relates also to a method for obtaining compounds of formula (I), wherein

a) compound of formula (II);

< / BR>
in which R (4) denotes OH, and the other substituents have the above values,

enter into interaction

1) with an activated carboxylic acid of formula (III), preferably halogenerator or anhydride or asoleda:

R (5)-CO-[(C1-C4)-alkyl] - R (1) (III),

and [(C1-C4)-alkyl] and R (1) have the above significance, and R (5) denotes Cl, Br - O/CO-(C1-C4)-alkyl/ - R (1), -O-C(O)CF is (III), in which R (5) denotes OH, and the other substituents mentioned in the case of the formula (III), in the presence of a chip off the water reagents (DCCl and so on);

or

b) the compounds of formula (II):

< / BR>
in which R (4) denotes Br, Y is the group of complex aryl or alkylboron ether sulfonic acids, and the other substituents are specified in the case of the formula (I) is: enter into interaction with the salt, preferably with K - or Na-salt or dialkylammonium salt of carboxylic acid of the formula (III):

R (5)-CO-[(C1-C4)-alkyl] - R (1) (III),

in which R (5) refers to -[O-Me+], and the other substituents have the above in the case of the formula (III) values, and Me+denotes preferably a cation of the salt of an alkali metal or salt of trialkylamine.

The dotted line between C-atoms 1 and 2 indicates that this relationship may be single (simple) bond or an unsaturated bond.

As the aryl and heteroaryl groups are used preferably include phenyl, naphthyl, biphenylyl, phenyloxy group, phenylthiourea, benzoyl, thienyl, furyl, thiazolyl, pyrrolyl, imidazolyl, pyridyl, indolyl, xanthone-oxy group, flavonol. These aryl and heteroaryl groups unsubstituted or substituted by 1-3-me substituent is 1-C8) - alkoxyl (saturated or unsaturated, two adjacent groups may also form methylenedioxy-group), NO2, (C1-C4) - alkylthio group, phenoxy group, benzoyl; NR (6) R (7) R (6) R (7), identical or different, denoting hydrogen, (C1-C4)-alkyl, (C1-C4)-acyl, tert.-butyl-oxycarbonyl, (CH2)-CH2-Cl; in addition, the aromatic rings in the aryl substituents and heteroaryl groups can be unsubstituted or substituted by 1-3 two substituents selected from the group consisting of (C1-C4)-alkyl, (C1-C4)- alkoxyl, F, Cl, Br and j

Required as starting substances 17-deoxy-steroids with a free 21-hydroxyl group of formula (II) [R (4)=OH] generally known from the literature.

17-Deoxy-steroids c R (4) denoting Br, J,-OSO2- aryl, - OSO2the alkyl in the formula (II) receive, by analogy with the U.S. patent 4 377 575 (HOE 78/F 082). While taking into account, for example, the following 17-deoxy - corticosteroids: corticosterone (11-21-dihydroxy-pregn-4-he-3, 20-dione);

the hypertension (11-hypertension);

16-methyl-1(2)-degidro-corticosterone;

6 - fluoro-16-methyl-1(2)-degidro-corticosteroidal;

16-methyl-1(2), 9(11)-di dehydro-corticosterone;

6 , 9-debtor-corticosterone; 9-fluoro - corticosterone;

6-methyl-corticosterone, 6 '-fluoro-corticosterone;

11-hydroxy-1(2)-degidro-11-deoxy - corticosterone;

6 , 16-dimethyl-corticosterone; 11 dehydro-desoximetasone.

Used as components of the reactions of carboxylic acids of the formula (III), where R (5) is equal to OH, respectively, and their activated derivatives, as galodamadruga /R (5) = Cl, Br, J/ or their anhydrides or their azalide /R (5) = imidazole, triazole/ or their salts [R (5) = /Me+O-/ preferably /K+O-/, /Na+O-/ ] as a rule, well-known and you can get them if necessary preparative methods. The examples used according to the invention the carboxylic acid of formula (III), where R (5) denotes OH, are listed at the end of the text, before the claims.

All falling under this definition carboxylic acid in its acid residue containing substituted if necessary by halogen, alkyl, alkoxyl, acyl, tilkian or diazelam, a nitro group, an amine, aminoalkyl, amido, cyano, oxazolam, oxiella and so on, or if necessary anilinophenol acyl ilvaite in pharmacological part, in particular, complex 17-deoxy-corticoid-21 esters of carboxylic acids of this type (= complex type 21-aryl, respectively, 21 - heteroaryl ether), compared to the similar structure of the complex corticoid-21-esters of carboxylic acids that do not contain any aryl, respectively, heteroaryl group in 21 - acid residue, respectively, compared with a 17-deoxy - corticoide with neeterificirovannah ester to the free hydroxyl group in position 21 often have a distinctly better efficiency in relation to the ratio of local/systemic anti-inflammatory effect.

A more detailed description of the individual options response retrieval method is proposed according to the invention the products of formula (I) below:

To the variant of the method a):

To obtain a challenging 21-esters of carboxylic acids of the above type are preferably used either galodamadruga or azalide carboxylic acids of the formula (IV): R (5)-CO-/(C1- C4)-alkyl /R (1), (IV),

in which

R (5) denotes Cl, Br, J ; ;

and

R (1) and (C1-C4) - alkyl are indicated for formula (III) value:

or anhydrides of carboxylic acids of the formula (V):

O{-OC/(C1

R (5) in the formula (IV) can also cover other, activating the etherification to complex ester carboxyl group in the carboxylic acid group, for example,- O-CO-CF3; or you can use derived from anhydrides of phosphonic or phosphinic acids (for example, as the anhydride papapostolou acid or anhydride and polyphosphoric acid (PPA), activated carboxylic acids.

Other phosphorus-containing reagents that can cause mild esterification of an organic carboxylic acid with the alcohol group in position 21 corticoid-17-alkyl carbonate, indicated, respectively, described in the literature as Synth. Commun. 13, 471 and subsequent (1983) and Synth. Commun 14, 515 and subsequent (1984).

For the esterification to complex ester with galodamadruga or anhydride of the acid, steroid component is dissolved in an inert solvent, for example, in a simple ether as dioxane, tetrahydrofuran, diglyme, or, if necessary, in halogenated hydrocarbons as benzene, toluene, CEC is about the reaction time of the halogen acids add 1 to 1,000 mol-equivalents of a tertiary base, as pyridine, quinoline, triethylamine, dimethylaniline, dimethylaminopyridine, etc. However, it is also possible to use inorganic base like sodium bicarbonate or calcium carbonate, to remove the acid. Then added dropwise 1 - 200 mole equivalents, preferably 1-3 mol-equivalent, one of the above alleluya funds, if necessary dissolved in one of the foregoing solvents, at temperatures from -40oC to the boiling point of the used solvent, preferably at 0-25oC. After the reaction, the mixture is left to stand for 1-120 hours at a temperature of from -40oC to the boiling point of the solvent, preferably at 0-25oC.

When using anhydrides of carboxylic acids as Alliluyeva means sometimes preferable to work without the addition of solvents. As a rule, it is enough to add only organic base, preferably pyridine, to be used if necessary in excess of the anhydride of the acid.

Especially in the case of sensitive (and sometimes unstable) derivatives of carboxylic acids of the above type, particularly when using phenylacetylcarbinol, - anhydrides, heteroaryl introduction to interoperability 17 - desoxycortisol with a free 21 - hydroxyl group with 1-4 mol-equivalents of the acid chloride, accordingly, anhydride, with (-10) - (+6)oC (maximum 20oC) in chlorinated hydrocarbons, preferably as dichloromethane, as well as with 1-4 mol-equivalents of pyridine bases, preferably of dimethylaminopyridine.

You get the reaction products of the formula (I) of high purity, without appreciable impurities, by-products, in particular 11-acylated products (reaction monitored by thin layer chromatography (TLC), i.e., reactions in relation to the interaction of the hydroxyl group in position 21 flow vasoconstrictive.

When the reaction with carboxylic acid anhydrides, preferably to the reaction mixture often add absolute dioxane or tetrahydrofuran, for example, in the case of benzoyl chloride, and the ratio of dioxane / pyridine is about 1:1, and for acceleration of the reaction, the reaction mixture, in particular in the case of spatial difficult or less reactive acid chlorides of the acids or anhydrides of acids, often heated approximately at 60oC (TSK - controlling reaction).

Okharakterizovanie reaction products can be done by thin-layer chromatography (TLC); rinse with mass spectra molecular weight MS = m/Z = .... (M+H+(as a rule, FAB spectra); depending on the circumstances, covered monoisotopic molecular masses. (M+H+) - Values, if necessary rounded. Also for features to attract IR,1H-NMR - UV spectra.

For processing, the reaction mixture was poured into water, which, if necessary, mixed with sodium chloride and sodium bicarbonate, and the reaction products, often only after long standing, usually comes in the form of crystals. The remaining oily or waxy products of the reaction are concentrated by shaking with a suitable extracting agent and evaporation. The reaction products, if you want, you can separate or purify by recrystallization or by chromatography. Often also quite intensive infusion and little or no solvent the reaction product of an organic solvent like diethyl ether or cyclohexane, or a mixture of these components, for further purification of the reaction products.

When applying azalidov carboxylic acids substantial to esters suitable exercise in the form of a one-step reaction. Thus, for example, aryl - or heteroepitaxy coltellino equimolar amount of N,N-carbonyl-diimidazole or/1H - 1,2,4 - triazole/, and when 0-20oC are formed corresponding azalide acids. After the addition of approximately equimolar quantities of corticoid-17-alkalicarbonate formula (II) /R (5) = IT/ and a catalytic amount of base, preferably sodium hydride or imidazoline sodium, stirred in pyridine at 0-40oC, preferably at 20oC, and processed as usual.

However, you can also pre-obtained from equimolar amounts of N,N'-carbonylated and carboxylic acid in absolute tetrahydrofuran and the selected azole carboxylic acid add in solvents such as pyridine, dimethylformamide, tetrahydrofuran, dissolved steroid continue to do as described (see also Chem. Ber. , 95, S. 1284 and subsequent, (1962)).

When the esterification to complex ester using phosphonic anhydrides, respectively, phosphinic acid, the preferred type of equimolar amounts of carboxylic acids and corticoid-21-alcohol in absolute pyridine together with 50% anhydride propriospinal acid in methylene chloride at 20 to 60oC, with the addition of 4-dimethylaminopyridine as acid acceptor and process as usual (poured into ice water, extracted with ethyl acetate, p is also possible to use the anhydride and polyphosphoric acid (PPA).

Another preferred method of esterification to complex ether, which is applicable to the proposed according to the formula (III) /R (5) = HE / or specified in the list of carboxylic acids, is the direct conversion of 17-deoxy-corticoids formula (II) /R (4) = HE/ using dehydrating means, as carbodiimide, preferably, N, N'-dicyclohexylcarbodiimide (DCCl). Instead of DCCl in some cases, you can also work with a "molecular sieve" as dehydrating means.

Thanks to the addition of acid, for example sulfuric acid, phosphoric acid, hydrochloric acid, diphenylphosphinic acid, p-toluenesulfonic acid, respectively, pyridinium salts, or organic bases, such as, for example, dimethylaminopyridine (= especially preferably in a halogenated solvent, such as methylene chloride, or dimethylformamide) can catalytically to accelerate, respectively, to optimize the etherification to sophisticated broadcast that features very preferably using hard reacting, respectively, sensitive carboxylic acids, for example, type indolylacetic acid, terracarbon acid, aryl-and heteroarylboronic acid. This was unexpected, cloudmobile not tarifitsiruetsya to complex ester, as is often observed when the esterification to esters using appropriate golodnikov acids.

In a special embodiment of the method, to the solution of 1 mol equivalent 17-deoxy-corticoid-21-alcohol [formula (II), R (4) = HE] and 1-4 - x mol-equivalents of a carboxylic acid of formula (III) [R (5) = HE], preferably 2 equivalents, in absolute pyridine, add a catalytic amount of pyridinium salts of sulfuric acid, and after about 20 minutes, 1-4 mol-equivalent dicyclohexylcarbodiimide, preferably 1-2 mol equivalent. Then stirred at 0-50oC, preferably at 20oC until analyzed using TLC test will not show any of the original carboxylic acid, and will show the presence of only the target complex 17-deoxy-corticoid-21-ether carboxylic acids of the formula (I). Filtered from the formed dicyclohexylamine, the filtrate is advisable to pour in water, filtered (in the formation of crystals) or to decant (in the case of oil, respectively, waxy products), washed with additional water (if necessary also be extracted by using the extracting means, particularly dichloromethane), dried, n is preferably on silica gel.

Instead of pyridine in some cases it is also possible to use other inert solvents, such as tetrahydrofuran, dioxane, methylene chloride, dimethylformamide, appropriate with the addition of tertiary bases, such as pyridine, 4 - dimethylaminopyridine. When the use of molecular sieves as a dehydrating you need to prefer these latter solvents.

For the esterification to complex ester with sensitive aryl - and heteroarylboronic acids, then, is a useful one the following option: 1 equivalent of the carboxylic acid at 0oC dissolved in absolute dichloromethane, and this solution was sequentially mixed with 1 equivalent of DCCl, 0.2 equivalent of 4-N,N'-dimethylaminopyridine and a solution of 1 equivalent of 17 - deoxy-corticosteroid-21-spirit in absolute dichloromethane, and then stirred for 18-48 hours at 20oC. After normal processing of the target ester of the formula (I) can be obtained in a pure state. Instead of DCCl can also be applied molecular sieve.

According to another method of esterification to complex ether, 21-deoxy-corticoid-21-/tert. -butyldimethylsilyl - (O)-simple ether/ in absolute tetrahydrofuran is mixed with 1 mol is emiliania at 20oC is treated as usual.

However, it is also directly carboxylic acid, 17 - deoxy-corticoid-21-alcohol (free form), you can enter into interaction with the anhydride triperoxonane acid to obtain the target 21 is a complex ester of carboxylic acid (= formation of a mixed anhydride of carboxylic acid and triperoxonane acid, which then reacts with the 21-alcohol to obtain 21 - ether complex).

Option method b):

The following preferred variant of the method, which leads to a proposed according to the invention corticoids, is that 17-deoxy-corticoid-21-halide, preferably 21 - iodide or 21-bromide or 21-sulfonate, preferably 21 - ester and p-chlorobenzenesulfonate or a 21-ester of methansulfonate, together with metal salts, preferably salts of alkali metals or dialkylammonium salts specified in list 2 carboxylic acid in an inert organic solvent, preferably dimethylsulfoxide, dimethylformamide, butane-2-Ohe, acetone, acetonitrile for 1 to 16 hours, preferably 1-10 hours, heated at a temperature of 20oC up to the boiling point of the used solvents is, filtering or separation by decanting sludge and regular cleaning allocate the target connection.

To receive according to the options method a) and b) compounds of formula (I) is the value that the hydroxyl group at position 11 in case of need it is possible to oxidize the usual ways to ketogroup. It is preferable that the oxidation is carried out in an acidic medium and in an inert organic solvent. Available in corticoides part 9 (11)-double bond, if necessary, by attaching halogen acids or chlorine according to conventional methods can be translated into the corresponding proposed according to the invention of complex 17 - deoxy-corticoid-21-ester of 11-Oh-9-halide group (9 F, Cl) or 11 - 9-dichloro-group.

The products obtained by the proposed method have valuable pharmacological properties. In particular have a high anti-inflammatory effectiveness in local or topical application and have partly unexpectedly very good ratio of local to systemic anti-inflammatory action, which is often clearly outperforms similar in structure to the complex corticoid-21-esters in which the ester ocuppy 21-alkyl group, accordingly, similar to the 17-deoxy - corticoide with neeterificirovannah to ester, therefore, a free 21-hydroxyl group, as can be concluded from pharmacological trials. Accordingly, the subject invention is also effective for treatment of inflammatory dermatoses, consisting of the compounds of formula (I).

Obtained by the method according to the invention the compounds may find use in therapy and veterinary medicine for the treatment of inflammatory dermatoses of the different Genesis in the form of suspensions, ointments, creams, respecively drugs, etc. at the same time as particularly preferred for local and topical forms of therapy must be emphasized that the products of the method on the basis of its extremely favorable ratio of local to systemic anti-inflammatory action when therapy with high dosages and over a long period of time can actually cause only minor side effects. In the case of external treatment using ointments, creams, suspensions, etc. with a concentration of 0.01 to 2 wt.%. In particular, the products obtained according to the method of the invention, in pharmacological tests show partly significantly nucleosides 21-hydroxyl group, accordingly, with the 21-ester group, in which the ester portion containing no aryl, respectively, heteroaryl parts, as in the case of proposed according to the invention compounds. Next, obtained according to the method of the invention compounds also exhibit stronger local anti-inflammatory effect than the last similar drugs. Moreover, it is proposed according to the invention 17-deoxy-corticoid-21-esters compared to the same specified last corticoide derivatives, are often even less atrovaginata against the skin, which is a further advantage for dermatological therapeutic treatment.

17-Deoxy-corticoid-21-cinnamate, in particular substituted in position 4 in the aromatic part methoxy-, methylenedioxy or ethoxy group, and 17-deoxy - corticoid-21-[4-(dimethylamino)-benzoate] , beyond its anti-inflammatory action, may have additional light shielding effect against sunlight, particularly UV-B and UV-A radiation.

In addition, proposed according to the invention, the products by itself in a known manner by ventiliation, for example, the type of Gentamicin, Neomycin, Erythromycin, Tetracycline or guidikova acid and others. Such combinations obtained according to the method of the invention of products with locally applicable antibiotics can be used to treat primary bacterial or superinfection bacterial inflammatory dermatoses.

Pharmacological tests

For example, desoximetasone-21-cinnamate (compound of formula (I) exhibits strong local anti-inflammatory effect in clearly reduced systemic effects compared with desoximetasone, as is clear from the following examples pharmacological effectiveness.

1. Local anti-inflammatory effect in the case caused by oxazolone ear oedema in mice after nadyojnogo application

Apply described Evans D. P. and other Br.J. Pharmacol., 43, 403 (1971) method. 4 - Ethoxymethylene-2-phenyl-2 - oxazoline (oxazole) in mice causes allergic inflammation prolonged type, which is suppressed by corticosteroids. Animals are males NMR 1 mice weighing 25 g in groups of 10 animals. Animals sensibiliser by applying 0.1 ml of 2% aqueous solution of oxazolone in acetone to the skin of spalanie fact, 10 μl of a 2% aqueous solution of oxazolone in acetone applied on the internal side of the right ear (control group). In the case of the treated groups tested preparations contained in the above solution. After 24 hours after application of the solutions of animals killed with CO2. From treated right and left untreated ears cut one round, size 8 mm, sample. Samples immediately weighed, and the difference between the weight of the right and left samples is a measure of the degree of inflammation. It is inflammatory and edematous swelling, in mg, in the case of the control group is taken for 100% and overwhelming inflammation effects of drugs indicated as suppression in percentage compared with the control. Next, see table. 1.

Graphical estimation in semi-logarithmic system in both cases gives 50% the amount of suppression at 0.05 mg/ml, therefore, the equality of action.

2 (a). Test the system action after subcutaneous injection caused by carrageenan swelling of the paws of rats

The method described in Winter C. A., and others, in Proc. Soc. exp. Biol (N. Y.). III, 544 (1962). Male Spraque-Dawley - rats weighing approximately 200 g and using groups of 5 animals (n=5), receive subcutaneously westvalley hind paw injected with 0.1 ml of 0.5% solution carragenin. Before and after 3 and 6 hours, measure the volume of the paw (ml) to determine the increase in swelling compared with the previous value. Numbers represent mean values and standard deviation (x S).

Statistical demonstration test is performed using test Donato (see tab. 2).

The result: a Significant effect (*= p<0.05) in the case of desoximetasone begins with 0.1 mg/kg, however, this is not the case of the compounds of formula I. after 0.3 mg/kg compound of formula I is almost inactive, while desoximetasone almost completely suppresses inflammation.

2 b). The test system action: gluconeogenesis in rats

Male Spraque-Dawley - rats weighing about 140 g adrenalectomized. They get a 0.9% solution of sodium chloride in drinking water. After 48 hours the animals within 24 hours do not give food. On the day of testing (3 days after adrenalectomy and 1 day of fasting) subcutaneously injected tested preparations (2 ml/kg in sesame oil, control animals receive only excipient). After 6 hours decapitate animals and extract 1 g of the liver. The sample treated with 5 ml of 0.6 M perchloric acid. After homogenization and centrio aminoglycosides translate in soluble form and also determine its content of glucose (set for testing with hexokinase, Boehringer Mannheim).

Get the results, shown in table. 3.

From the result it is necessary that the compound of formula I at a dose of 0.3 mg/kg no effect gluconeogenesis, while desoximetasone already at the dose of 0.1 mg/kg shows this undesirable effect (*= p < 0.05, the test Dumato). In the case of the compounds of formula (I), this effect occurs only with doses of 1 mg/kg, so the advantage of the compounds of formula (I) can be installed by a factor of 3-10.

In General, example 1-2 (b). pharmacological tests can be amazing minimizing undesirable systemic effects due to the compound of formula (I) when the local intensity of activity compared with desoximetasone.

Examples

Regarding the below examples should make the following General comments:

The melting temperature is determined in the device Tottoli (firm Buchi) or on the device with Kofler hot bar company Reichert (Austria), type 7841, and are without amendment.

IR spectra (in KBr) removed on the diffraction spectrophotometer Perkin-Elmer 521. If necessary, specify only characteristicsa strip. Removing the UV spectra (in methanol) sushestvenno when using a mass spectrometer MS 9 (firm AEI). The data of mass spectra (peak molecular weight) predominantly are: MS = m/Z = . . . (M+H+) (measurement using pure isotopes), i.e., as the case may be, covered by a monoisotopic molecular mass. As a rule, shoot FAB - mass spectra.

For thin-layer chromatography (TLC) are prepared plates of silica gel F254(from Merck). Unless nothing else, then as solvent a mixture of methylene chloride with methanol in the ratio of 19:1 (distance 7 cm). Demonstrate, if necessary, twice. Spots or detected using a UV lamp at 254 nm, or manifest by spraying on by using 10% methanol solution of sulfuric acid, and by heating at 100oC. RfValues need to understand is always only relative. For column chromatography used silica gel 60, a grain size 0,063 - 0.2 mm (Merck).

When reactions with anhydrides of carboxylic acids preferably are often added to the reaction mixture of absolute dioxane, for example, in the case of benzoyl chloride, and the ratio of dioxane/pyridine is about 1:1, and to accelerate the reaction, the reaction mixture often, especially in the case of spatial C is from, heated approximately at 60oC (TLC monitoring of the reaction course).

Okharakterizovanie reaction products can be done by thin-layer chromatography (TLC); the reaction products have Rf- a value of about 0,65 - 0,75. Typically, the reaction products characterized using mass spectra with MS= m/Z =... (M+H+(as a rule, FAB spectra); if necessary, covered by a monoisotopic molecular mass. (M+ H+) - Values, if necessary, rounded. Also IR,1H-NMR and UV spectra can be attracted to the characteristics of the products.

Example 1

Desoximetasone-21-(3-phenyl) propionate

a). To a solution of 3 g of desoximetasone (~0,008 mol) in 20 ml of absolute pyridine at 0oWith and with stirring was added dropwise a solution of 1.8 g of acid chloride of 3-phenylpropionic acid (~to 0.011 mol) in 10 ml of absolute dioxane. After stirring for 5-6 hours at 0oC (TLC shows complete formation of the desired product of the reaction) was poured into 500 ml Polynesians aqueous solution of sodium chloride, separating the precipitate (oily or waxy) by filtration through a folded filter, treated him with methylene chloride or ethyl acetate), the solution of a new ether or diisopropyl ether or petroleum ether, filtered and, if necessary, recrystallized from a mixture of ethanol with diethyl ether (if necessary with the addition of diisopropyl ether or petroleum ether). Gain of 3.9 g (96,0%) above target connection so pl. = 161oC.

MS : m/Z = 509 (M+H+); TLC : Rf0,6.

b). If in example 1 (a) instead of 3-phenylpropionylamino using 3.1 g of the anhydride of 3-phenylpropionic acid and reaction, as well as processing and cleaning carried out in the same manner as described in example 1 (a), we get the same reaction product with the same characteristics as described in example 1 (a).

in). To a solution of 3 g (0,008 mol) desoximetasone in 25 ml of absolute acetone and 10 ml of absolute pyridine, at 0oC and under stirring, in portions added dropwise 1.8 g of 3 - phenylpropionylamino. Stirred for 20 hours at room temperature (21oC); heat up, if the thin chromatogram find another educt, even within a few hours (about 5 hours) at 40-50oC, allowed to cool, poured into 60 ml Polynesians aqueous solution of sodium chloride, the aqueous phase is removed by decantation from the released oil or wax (if precipitated crystallized, at, for example, with sodium sulfate and the solvent is distilled off. The remaining balance will recrystallized from ethanol, methylene chloride (solvent) with the addition of diethyl ether, respectively, diisopropyl ether, and obtain 3.2 g of the above target compound So pl. 158 - 160oC.

In TLC (solvent: CH2Cl2:CH3OH = 19:1) target connection, as well as above the selected weight, along with the principal spot at the Rf= 0,6 there are also another side spots. For purification (TLC) fractional chromatographic on silica gel [size grains 0,063 - 0,2000 mm (Merck), column size 20 x 3 cm] using a mixture of methylene chloride with methanol in the ratio 998: 2 (fractions of 50 ml). Fractions that TLC then show one of Rf- value of about 0.6, unite. After distillation, eluting means get kristalltherme of diethyl ether and/or ethanol, methylene chloride, diethyl ether or diisopropyl ether, in the amount of 2.0 g (at best reproduction mixture of 2.8 g) target connection so pl. 160oC. MS: m/Z = 509 (M+H+)

TLC: Rf0,6 (AP = 0,4) (AP = the original product). Also oily, respectively, waxy oily aforementioned spin-off weight after the zoom, as described in example 1 (a), 8 g of desoximetasone enter into interaction with 1.8 g of the acid chloride phenoxyalkanoic acid instead of 3-phenylpropionylamino, process, allocate and target connection get in a pure crystalline state (if necessary also in amorphous form). Get 3,82 g of the above-mentioned target compound. So pl. 147oC MS: m/Z = 511 (M+H+); TLC: Rf0,7

Example 3:

Desoximetasone-21-phenylacetate

a). In the same manner as described in example 1 (a), 8 g of desoximetasone enter into interaction with a 1.75 g phenylacetylide instead of 3 phenylpropionylamino, process, allocate and target connection get clean crystal (crystallized, if necessary also in amorphous form). Obtain 2.7 g of the above target compound, So pl. 151 - 153oC.

MS: m/Z = 495 (M+H+); TLC: Rf0,7

b). To a solution of 6.3 g of desoximetasone in 8.65 g of phenylacetic acid (dried for 5 hours in vacuum over P2O5about 50-60oC) in 44 ml of absolute pyridine, with stirring and at 20oC add a freshly prepared mixture of 250 ml of concentrated sulfuric acid in 4 ml of absolute pyridine (suspensionalcohol transparent solution soon falls crystalline precipitate formed N,N'- dicyclohexylmethane. Mix until until TLC will not find any of the educt and the reaction product detects when Rf= 07 (as a rule, the reaction time is 16 hours; longer reaction time, for example, standing, respectively, stirring until the end of the week, does not adversely affect the reaction). After that add 2.2 ml of acetic acid or acetic anhydride and the mixture is left to stand for 1 hour at 20oC, then within 24-48 hours in a low temperature refrigerator (about -15oC). Filtered from osadovskaya N,N'- dicyclohexylmethane, washed it with cooled to approximately -15oC pyridine and the filtrate contribute with stirring at approximately 500 ml Polynesians aqueous NaCl solution, add approximately 5 ml of ethanol, filtered off oily-crystalline mass, washed it repeatedly with water and treated with about 100 ml of methylene chloride. After drying the resulting solution over sodium sulfate, the solvent is distilled off and the residue is crystallized by adding diethyl ether. Get desoximetasone-21-phenylacetate with so pl. 132-145oC, which can be recrystallized from a mixture of tert.-butanol from duct 0,4).

in). Do the same and using the same quantities of reagents as described in example 3 (b): however, without the use of acid catalyst is concentrated sulfuric acid in pyridine. After the reaction time, which is 5 times more than that indicated in example 3 b), this sample does not show any educt. After similar treatment and purification as described in example 3 b), receive desoximetasone-21 - phenylacetate with the same characteristics as described in example 3 b).

If instead of pyridine as a solvent used absolute dimethylformamide, then get the target connection also with the same characteristics.

g). Do the same and using the same quantities of reagents as described in example 3 b). However, instead of sulfuric acid added 250 mg of p-toluenesulfonic acid. After similar treatment and purification as described in example 3 b), receive desoximetasone-21-phenylacetate with the same characteristics as described in example 3 b).

Example 4:

Desoximetasone-21-(indole-3-acetate)

To a solution of 1.92 g of desoximetasone and 3.1 g of 3-indole - acetic acid (dried) in 15 ml of absolute pyridine, with stirring and at 20othe example 2 (b)). After stirring for 30 minutes (20oC) add 1.55 g of N,N'- dicyclohexylcarbodiimide. After stirring for 48 hours at 20oC mass spectrum shows m/Z = 534,2 (M+H+and shows no m/Z = 377 (M+H+for the source of the steroid. After a similar further processing and processing according to example 3 b), after pouring about 500 ml Polynesians of NaCl, get oily precipitate, which turns into wax. The wax is separated by decantation, respectively, filtration, washed with water and dried in a vacuum desiccator over P2O5. After trituration with petroleum ether obtain 1.35 g of the target compound in the form of an amorphous product.

MS (wax, respectively, of the amorphous material): m/Z = 534 (M+H+) TLC 0,75 (basic spot [Hf] + a small amount of mild side spots). For cleaning chromatographic using a mixture of methylene chloride/ methanol = of 99.5: 0.5 on silica gel (column: diameter = 5 cm; height = 20 cm). Obtained with Rf0.75 of the fractions of the eluate are combined and the solvents removed by distillation. The residue is crystallized from diethyl ether. Obtain 1.0 g of the target compound with so pl. ~ 160oC with the same data on MS and TLC, and Rf0,75.

Example 5

Desoximetasone-21-cinnamate

To a solution of 6 g of desoximetasone in 40 ml of absolute pyridine, at 0oC and under stirring, was added dropwise a solution of 3.5 g of acid chloride of cinnamic acid in 20 ml of absolute dioxane. After stirring for 5 hours at 0oC (TLC shows complete formation of the desired product of the reaction), poured into 1 l Polynesians aqueous NaCl solution, the precipitate (wax) is separated by filtration through a folded filter, treated him with methylene chloride or ethyl acetate), the resulting solution was washed with water, dried over sodium sulfate, the solvent is distilled off in vacuum, the residue is crystallized from diethyl ether or diisopropyl ether or petroleum ether, filtered and, if necessary, recrystallized from a mixture of ethanol with diethyl ether (if necessary with the addition of diisopropyl ether or petroleum ether). Obtain 7.5 g of the above target compound with so pl. 161oC MS: m/Z = 507 (M+H+); TLC: Rf0,7

Example 6

Corticosterone-21-cinnamate

In the same manner as described in example 5, 580 mg of corticosterone in 4 ml of absolute pyridine enter into interaction with 350 mg loranger is up (pour 100 ml Polynesians NaCl solution, and so on) and was isolated by crystallization. Obtain 660 mg of the above-mentioned target compound with so pl. 154 - 157oC. MS:m/Z = 477 (M+H+), TLC: Rf0,7.

Example 7

11-Hypertension-21-cinnamate

In the same manner as described in example 6, 570 mg of 11 - hypertension instead of desoximetasone enter into interaction, then process the resulting reaction mixture and the product isolated. Obtain 520 mg of the above-mentioned target compound with so pl. 140-143oC. MS:m/Z = 461 (M+H+), TLC: Rf0,75.

Example 8

Forcertain-21-cinnamate

In the same manner as described in example 5, 600 mg of forcertain in 4 ml of absolute pyridine enter into interaction with 350 mg of cinnamic acid chloride acid in 2 ml of absolute dioxane (5 hours at 0oC), then process (pouring 100 ml Polynesians NaCl solution, and so on) and was isolated in crystalline form. Obtain 720 mg of the above-mentioned target compound with so pl. 154 - 159oC. MS: m/Z = 507 (M+H+), TLC: Rf0,8

Example 9

Deformation-21-cinnamate

In the same manner as described in example 8, instead of forcertain enter into interaction 610 mg of deformation; the resulting reaction mixture was treated and the product isolated. From diisopropyl ether (rasm+H+). TLC: Rf0,8.

Example 10

Harborton-21-cinnamate

In the same manner as described in example 8, in the interaction of the injected instead of forcertain 620 mg of harborton; then the obtained reaction mixture was treated and the product isolated. From diisopropyl ether (rubbing) obtain 590 mg of the above-mentioned target compound; in the form of an amorphous substance. MS: m/Z = 542 (M+H+). TLC: Rf0,8

Example 11

9-Fluoro-corticosterone-21-cinnamate

In the same manner as described in example 8, instead of forcertain interacting administered 600 mg of 9 - fluoro - corticosterone; the resulting reaction mixture was treated and the product isolated. From n-hexane (rubbing) obtain 630 mg of the above-mentioned target compound in amorphous form. MS: m/Z = 495 (M+H+); TLC: Rf0,8.

Example 12

Desoximetasone-21-(4-methoxy-cinnamate)

To a solution of 6 g of desoximetasone in 40 ml of absolute pyridine at 0oC and with stirring was added dropwise a solution of 4.2 g of acid chloride of 4-methoxy-cinnamic acid in 20 ml of absolute dioxane. After stirring for 5 hours at 0oC (TLC shows complete formation of the target product reactions) poured into 1 l Polynesians aqueous solution N by ethyl acetate), the resulting solution was washed with water, dried over sodium sulfate, the solvent is distilled off in vacuo, and crystallized from diethyl ether or diisopropyl ether or petroleum ether, filtered off and recrystallized, if necessary, from a mixture of ethanol with diethyl ether (if necessary with the addition of diisopropyl ether or petroleum ether). Obtain 9.4 g of the above target compound with so pl. 185oC. In the case of further processing of the reaction product gives so pl. 194oC. MS: m/Z = 537 (M+H+). TLC: Rf0,75.

In the case of further processing of the reaction product shows so pl. 194oC.

Example 13

Corticosterone-21-(4-methoxy-cinnamate)

In the same manner as described in example 12, 580 mg of corticosterone in 4 ml of absolute pyridine enter into interaction with 420 mg of the acid chloride of 4-methoxy-cinnamic acid in 2 ml of absolute dioxane, the reaction mixture after stirring for 5 hours at 0oC process (pouring 100 ml Polynesians NaCl solution, and so on) and the product produce by kristallizatsii. Obtain 620 mg of the above-mentioned target compound with so pl. = 160oC.

MS: m/Z = 507 (M+H+); TLC: Rf0,7

Example 14

Antiche enter into interaction 570 g of hypertension; the resulting reaction mixture was treated and the product isolated. Receive 500 mg of the above-mentioned target compound c so pl. 153oC. MS: m/Z = 491 (M+H+). TLC: Rf0,75

Example 15

Forcertain-21-(4 - methoxy-cinnamate)

In the same manner as described in example 12, 600 mg of forcertain in 4 ml of absolute pyridine enter into interaction with 420 mg of the acid chloride of 4-methoxy-cinnamic acid in 2 ml of absolute dioxane (5 hours at 0oC), the reaction mixture is treated (pouring 100 ml Polynesians NaCl solution, and so on) and the product isolated in crystalline form. Obtain 690 mg of the above-mentioned target compound with so pl. 164 - 176oC (ranging up to 150oC, sintering, amorphous substance).

MS:m/Z = 537 (M+H+); TLC: Rf0,75.

Example 16

Deformation-21-(4-methoxy-cinnamate)

In the same manner as described in example 15, instead of forcertain enter into interaction 610 mg of deformation; then process and the product isolated. From diisopropyl ether (rubbing) obtain 590 mg of the above-mentioned target compound (amorphous form).

MS: m/Z = 555 (M+H+); TLC: Rf0,8

Example 17

Harborton-21-(4-methoxy-cinnamate)

The same treatment is nnow mixture process and the product isolated. From diisopropyl ether (extension) obtain 620 mg of the above-mentioned target compound in amorphous form.

MS: m/Z = 572 (M+H+) TCX: Rf0,8

Example 18

9-Fluoro-corticosterone-21-(4-methoxy-cinnamate)

In the same manner as described in example 15, instead of forcertain interacting administered 600 mg of 9 - fluoro-corticosterone; then the obtained reaction mixture was treated and the product isolated. From diisopropyl ether (rubbing) get above 6.0 mg of target compound (amorphous form). MS: m/Z = 525 (M+H+); TLC: Rf0,8

Example 19

Desoximetasone-21-(4-phenyl) cinnamate

To a solution of 3.0 g of desoximetasone and 2.3 g of 4-phenyl-cinnamic acid in 60 ml of absolute methylene chloride, at 0oC and under stirring, added 96 mg of 4-dimethylaminopyridine and 2.0 g of dicyclohexylcarbodiimide.

The initially clear reaction solution soon becomes turbid. After stirring for 6 hours at room temperature TLC - test does not show any educt. Then aged 2 days at +4oC and 2 days at -15oC (low-temperature refrigerator), filtered osadovskaya dicyclohexylamine, washed it with a small amount of ohlord is in vacuum. The remaining residue is crystallized from boiling diethyl ether and, if necessary, recrystallized from a mixture of ethanol with diethyl ether. Obtain 4.1 g of the above-mentioned target compound with so pl. 142oC MS: m/Z = 583 (583,3) (M+H+). TLC: Rf0,75.

Example 20

Desoximetasone-21-(TRANS-3,4-methylendioxy)cinnamate

In the same manner as described in example 19, instead of 4 - phenylcarbinol acids in the interaction of the injected 2.0 g of TRANS-3,4 - methylendioxy - cinnamic acid with 3 g of desoximetasone; the reaction mixture is treated, the product is isolated and purified. Gain of 1.9 g of the above-mentioned target compound with so pl. 147-151oC MS: m/Z = 551 (M+H+). TLC Rf0,7

Example 21

Desoximetasone-21-(TRANS-3,4-dimethoxy)cinnamate

In the same manner as described in example 19, 3 g desoximetasone enter into interaction with 2.0 g of TRANS-3,4-dimethoxy-cinnamic acid instead of 4-phenylcarbinol acid, the reaction mixture is treated, the product is isolated and purified. Obtain 2.4 g of the above target compound with so pl. 189 - 144oC. MS: m/Z = 567 (M+H+) TCX: Rf0,75.

If in example 21 instead of 2.0 g of TRANS-3,4-dimethoxy - cinnamic acid in the interaction enter equivalents-cinnamic acid or TRANS-3,5-dimethoxy-cinnamic acid, after a similar reaction, processing and selection receive appropriate desoximetasone-21-TRANS-2,3 (or 2,4 - or 2,5 - or 3,5-)-dimethoxy-cinnamate, all with MS: m/Z = 567 (M+H+).

Example 22

("p" denotes 4): Desoximetasone-21-(n-methyl-cinnamate)

In the same manner as described in example 19, 3 g desoximetasone enter into interaction with 1.9 g of n-methyl-cinnamic acid instead of 4-phenyl-cinnamic acid, then the reaction mixture is treated, the product is isolated and purified. Obtain 2.1 g of the above target compound with so pl. 171oC. MS = m/Z = 521 (M+H+); TLC: Rf0,7

Example 23

If in example 22 instead of p-, respectively, 4-methyl-cinnamic acid, interacting enter 1,9 g-methyl-cinnamic acid

(= C6H5CH=C(CH3)CO2H), after a similar reaction, processing and selection, get isomeric desoximetasone-21- -methylcinnamic) (amorphous crystallized after precipitation with diethyl ether), MS: m/Z = 521 (M+H+); TLC: Rf0,75

If in example 22 instead of-methylcatechol acid in the interaction enter the appropriate number (1,9 g) -methyl-cinnamic acid (for example, TRANS-), then get desoximetasone is isano in example 19, 3 g desoximetasone enter into interaction with 1.9 g phenylpropionic acid instead of 4-phenyl-cinnamic acid (reaction time 24 hours); the resulting reaction mixture was treated and the product isolated. From the obtained dark oil (2.2 g) a few days later slowly crystallizes above the target connection that only bad can be purified. Analysis oily-crystalline crude product: MS: m/Z = 505 (M+H+); TLC: Rf0,8

Example 25

Desoximetasone-21-ester 5-finalmente-2,4 - diene acid

In the same manner as described in example 19, 3 g desoximetasone enter into interaction with 1.6 g of 5-phenyl-Penta-2,4 - diene acid (= cinnamaldehyde acid) instead of 4-phenyl - cinnamic acid, after which the reaction mixture is treated, the substance is isolated and purified. Obtain 3.1 g of the above target compound with so pl. 140-146oC (vaguely) MS: m/Z = 533 (M+H+), TLC: Rf0,75.

Example 26

Desoximetasone-21-[4-(4-(N,N)-(bis-(2-chloro-ethyl) - amino)-phenyl)-butyrate]

To a solution of 8.0 g of desoximetasone and 7.2 g of 4-(4-(N,N- (bis-(2-chloroethyl)-amino) phenyl) butyric acid (=chlorambucil) in 50 ml of absolute pyridine, with stirring and at 20oC add Piri is in 2 (b)). After stirring for 20 minutes at 20oC add 5,77 g of N,N-dicyclohexylcarbodiimide. After stirring for 48 hours at 20oC add 2 ml of glacial acetic acid and the mixture is left to stand for 48 hours in a low temperature refrigerator (-15oC). Filtered from osadovskaya N, N'-dicyclohexylmethane (6,1 g) and the filtrate is mixed with about 300 ml Polynesians aqueous NaCl, and stands out the oil. The oil is filtered through a folded filter, mixed with 400 ml of water, and within 48 hours it turns into wax. The wax is filtered off, washed with water and dried, in the end - in a vacuum desiccator. Then it is dissolved in boiling isopropanol under conditions of boiling under reflux and allowed to cool to 20oC, and soon deposited a dense crystallized. It is filtered off and washed with cooled to 0oC isopropanol. After drying obtain 6.2 g of the above-mentioned target compound.

So pl. = 142 - 145oC (another sample) shows so pl. 160-163o(the drug is often two, respectively, several melting /polymorphic!/)

MS: m/Z = 662 (M+H+); TLC: Rf0,8.

Example 27

is at 0oWith and with stirring was added dropwise a solution of 254 mg of the acid chloride 3-furyl acrylic acid (1.6 mmol) in 2 ml of absolute dioxane. After stirring for 4 hours at 0oC and standing within 62 hours in the refrigerator at +4oC (TLC shows complete formation of the desired product of the reaction; Rf0,8 /desoximetasone has Rf0,6/), filtered at +4oC from loose sediment (= pyridinethione). The solvent from the resulting filtrate is then distilled off in high vacuum. The resulting residue triturated with diethyl ether, and the resulting crystallized filtered off and repeatedly washed with diethyl ether. If desirable, the resulting crystallized can precrystallization from a mixture of ethanol with diethyl ether (if necessary with the addition of dichloromethane for complete dissolution). Obtain 580 mg of the above-mentioned target compound with so pl. 216oC. MS: m/Z = 497 (M+H+)

TLC: Rf0,8

For the synthesis of isomeric compounds - desoximetasone-21- -/3-(2-thienyl) acrylate/, respectively, desoximetasone- -21-/3-(2-furyl) acrylate/ - it is better to proceed from the free acid - 2-tanyakrylova acid, respectively, 2 - ferracioli acid instead of 4-phenyl-coachnet/

In the same manner as described in example 27, 0.5 g desoximetasone enter into interaction with a 2.75 mg of the acid chloride of 3 - tanyakrylova acid instead of the specified in example 27 of the acid chloride; the reaction mixture is treated in a similar manner, and the product is crystallized and purified. From diethyl ether to obtain 580 mg of the above-mentioned target compound with so pl. 219oC MS: m/Z = 513 (M+H+); TLC: Rf0,8.

Similarly, these examples provide examples of tables 4 and 5, and R (1)' represents the entire side chain of 21-CH2O - group.

To characterize the products of the synthesis, depending on the circumstances, assess only obtained according to the mass spectra peaks of molecular weight (m/Z =.. .(M+H+) (in the form of oil or wax or in amorphous or crystalline form), and as a rule, do not carry any purification by crystallization (recrystallization), respectively, chromatography.

The following carboxylic acids of the formula (III) /R (5) = OH/, respectively, and their activated derivatives, used, for example, as starting compounds (aryl, respectively, heteroaryl groups in them correspond to the substituents R (1)):

a) Panellinia acid:

penisular - or 3-chloro or 4-chloro-phenylacetic acid; 2,6 - dichloro - or 3,4-dichloro-phenylacetic acid; 2-fluoro - or 4-fluoro-phenylacetic acid; 2,6-debtor-phenylacetic acid; 2-nitro -, or 3-nitro or 4-nitro-phenylacetic acid; 2,4 - dinitro-phenylacetic acid, 2 methoxy - or 3-methoxy - or 4-methoxy-phenylacetic acid; 4-benzyloxy-, phenylacetic acid; 3-chloro-4-methoxy-phenylacetic acid; 3-bromo-4 - methoxy-phenylacetic acid; 3-nitro-4-methoxy-phenylacetic acid; 3,4-dimethoxy-phenylacetic acid; 2,3,4 - trimetoksi-phenylacetic acid; 3,4-methylendioxy - phenylacetic acid; 3,4-diethoxy-phenylacetic acid; 4 - biphenyl acetic acid; 3-phenoxy-phenylacetic acid; 2 - atsetamino - or 3-atsetamino - or 4-atsetamino-phenylacetic acid; 3-(N)-BOC-amino-phenylacetic acid; 4 formylamino-phenylacetic acid; 4-N,N-dimethylamino - phenylacetic acid; 4-benzyloxy-phenylacetic acid; 4- /2-methoxybenzyloxy/-phenylacetic acid; 4-(4 - forbindelse)-phenylacetic acid;

2-(thiazol-4-yl)-acetic acid; 2-(thiazol-4-yl)-2 - methoxyimino acid;

3-phenyl-propionic acid; D,L-2-phenyl-propionic acid;

3-(4-methyl-phenyl)-propionic acid; 3-(4-chloro or 4-fluoro or 4-methoxy-phenyl)-propionic acid; (S)- ()-2-FeNi is osvitnye (the substituents in the phenyl portion); CIS - or (preferably) TRANS-cinnamic acid; 2-, 3 - or 4-methoxy - cinnamic acid; 4-ethoxy-cinnamic acid; 3,4-dimethoxy - cinnamic acid; 3,4,5-trimetoksi-cinnamic acid; 4-fluoro - cinnamic acid; 3 - or 4-chloro-cinnamic acid; 3-bromo - cinnamic acid; 2 - or 3-nitro-cinnamic acid; 4-cyan - cinnamic acid; 4-isopropyl-cinnamic acid; 4-(tert.- butyl)-cinnamic acid; 2 - or 4-trifluoromethyl-cinnamic acid; D,L - or (S)- or (R)-2-(4-isobutylphenyl)- propionic acid (Ibuprofen);

4-(isobutylphenyl)-acetic acid (Ibufenac); phenylmercapturic acid; phenylpropiolate acid; 2 - methyl-3-(4-tetradecylphosphonic)-2-Papanova acid (MTPA); 3-(4-crotononitrile) propionic acid; 4 - dodecylbenzyl-acetic acid (DBAA); benzoylacrylate acid; chlorambucil; 3,4,5-trimetoksi-benzoylacrylic acid; 2-/4-(thiazol-2-yl) phenyl/ propionic acid; 2- (Cantonese) acetic acid; 2-phenyl-cyclopropane-carboxylic acid (TRANS);

3-(phenylmercaptan) acrylic acid; (4-phenyl) butyric acid;

2-trilocana acid; 3-trilocana acid; 1 - or 2-prilocaine acid; 2-, 3 - or 4-pyridyl-acetic acid; 2-mercaptomethyl-nicotinic acid;

3-(2 - or 3-furyl) acrylic acid; 3-(2-tail)-propionic acid; 3-(2-furyl) propionic acid;

3-(4-imidazolyl) acrylic acid; (N-methylpyrrole-2-yl) acetic acid;

B) Kannelirovannye acid

3-indolyl-acetic acid, 2-indolyl-acetic acid; (N-methyl)-2 - or 3-indolyl-acetic acid; 3-(3-indolyl)- propionic acid; 3 - or 2-indolyl acrylic acid /N-methyl/); (2-methyl-3-indolyl)-acetic acid; 3,4- (methylendioxy)-phenylacetic acid; 3,4-(methylendioxy) - cinnamic acid; indole-3-butyric acid;< / BR>
(5-methoxyindol-3-yl) acetic acid; naphthyl-1 - or 2 - acetic acid, flavone-8 - acetic acid; 5,6-dimethoxyethan - 4-acetic acid (derived from them corticoid -21 esters of carboxylic acids) can be also antitumor activity:

(L. L. Thomsen and other Cancer Chemother Pharmacol. 31, 151 and subsequent (1992), similarly as above chlorambucil).

1. Complex 17-deoxy-corticoid-21-ether carboxylic acids of General formula I

< / BR>
where And denotes SNON in-position;

Y is hydrogen, fluorine;

Z is hydrogen, fluorine, methyl;

- single or double bond,

R(1) - phenyl, thienyl, pyridyl, indolyl, naphthyl, each of which may be substituted by one or two substituents, selected from the group consisting of Nissho the>
once unsaturated, starting from s3-multiply unsaturated, or cyclic, branched at the expense of other alkyl groups;

R(2) denotes hydrogen, or methyl.

2. Complex 17-deoxy-corticoid-21-ether carboxylic acids of General formula I on p. 1, wherein R(1) is specified in paragraph 1 is, As is mentioned in paragraph (1 value, Y denotes fluorine, Z denotes hydrogen, R(2) denotes-methyl.

3. Complex 17-deoxy-corticoid-21-ether carboxylic acids of General formula I under item 1, with a local anti-inflammatory effect.

4. The method of obtaining compounds of General formula I on p. 1, characterized in that a) a compound of General formula II

< / BR>
where R(4) refers to IT;

And, Y, Z, and R(2) have the values listed in paragraph 1,

enter into interaction 1) with an activated carboxylic acid of General formula III, preferably a halide or anhydride

R(5)-CO-[(C1-C4)-alkyl]-R(1),

where [(C1-C4)-alkyl] and R(1) have the values listed in paragraph 1;

R(5) denotes Cl, [CO-[(C1-C4)-alkyl]-R(1)]1,

or 2) directly from a carboxylic acid of General formula III in which R(5) IT means, in the presence of vodoteplolichil Rea formula II

< / BR>
where R(4) denotes Br, J, aryl or alkyl ether group, sulfonic acids;

And, Y, Z, and R(2) have the values listed in paragraph 1,

enter into interaction with the salt, preferably a salt of sodium or potassium or salt of trialkylamine carboxylic acid of the formula III

R(5)-CO-[(C1-C4)-alkyl]-R(1),

where R(5) indicates [ON-Me+] Me+preferably denotes a cation of an alkali metal or trialkylamine.

6. Drug with anti-inflammatory action, characterized in that it contains as active substance a compound of the formula I on p. 1 in an effective amount.

 

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The invention relates to the field of organic synthesis

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The invention relates to a derivative 11,21-bisphenyl-19-norpregnane formula I, in which R1selected from H, halogen, NR5R6and R5and R6independently are hydrogen or C1-6-alkyl; R2represents hydrogen; R1and R2together are C1-3-alkylenedioxy, optionally substituted by one or more halogen atoms; R3represents methyl; R4choosing among C(O)-NR5R6, SOnC1-6-alkyl, optionally substituted by one or more halogen atoms, SOnC3-6-cycloalkyl, SO2-NR5R6, 2-oxopyrrolidin or NR5R6where R5and R6independently are hydrogen, C1-6-alkyl, or R5and R6together form a C3-6-alkylen, n = 1 or 2, R7represents N or C1-7-alkyl; R8represents H; X is chosen among the (H, HE, O and MO; or their pharmaceutically acceptable salts

The invention relates to organic synthesis

The invention relates to the field of chemical processing of birch bark (outer layer of birch bark)

The invention relates to extraction of valuable chemicals from waste timber, namely the allocation method betulin formula I from birch bark

The invention relates to medicine, specifically to Hematology, and can be used for pharmacological correction of disorders in the blood system under cytostatic mielodepressii

The invention relates to the field of medicine and is suitable for the treatment of rheumatism, rheumatic inflammatory diseases, diseases of Edison, acute insufficiency of the adrenal cortex, bronchial asthma, acute and chronic allergic diseases, hepatitis, hepatic coma, hypoglycemic conditions, diseases of the kidneys, the blood, skin and eye diseases, systemic diseases of connective tissue

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of chronic lympholeukosis. Method involves intravenous drop and jet administration of antitumor chemopreparations and carrying out the autochemotherapy. At the 1-st and 8-th day of treatment cyclophosphan in the dose 750 mg/m2, vincristine in the dose 1.4 mg/m2 and doxorubicin in the dose 30 mg/m2 incubated with 200 ml of autoblood are administrated to patients. From the 1-st to 14-th day of treatment prednisolone is used every day in the therapeutic dose. The treatment course is repeated in 30-35 days depending on blood indices and patient state. The total treatment of courses is 4-5. Method provides reducing cardiotoxicity of doxorubicin and cumulative toxicity of chemopreparations that allows carrying out administration of antitumor chemopreparations in the full volume to patients of elderly age groups.

EFFECT: improved method for treatment.

1 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: medicine, neurology.

SUBSTANCE: method involves intravenous administration of autolymphocytes treated with an immunomodulating agent by extracorporal method using cycloferon (250 mg) as an immunomodulating agent. Simultaneously, the following medicinal mixture comprising lidocaine, 100 mg; lidazum, 32 U; dexamethasone, 4 mg; leukinferon, 10 000 U; 40% glucose solution, 4 ml is administrated into interspinal ligaments of spinal column at levels corresponding to thoracal and lumbar enlargements of the spinal cord. The procedure is repeated three times with interval for 48-72 h. Method provides enhancing the effectiveness of lymphostimulation and immunomodulation in cerebrospinal sclerosis. Invention can be used for lymphostimulation and immunomodulation in cerebrospinal sclerosis.

EFFECT: improved method for treatment.

1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: method involves applying napkin impregnated with medicament to an injured articulation area. The medicament contains hydrocortisone acetate in the amount of 0.4mg/cm2, dimexide - 1.4 mg/cm2 and sodium alginate - 4.1 mg/cm2. The napkins are applied to internal and external side of the articulation for 6 days, changing them in three days.

EFFECT: accelerated treatment course.

FIELD: medicine, otorhinolaryngology.

SUBSTANCE: one should treat deformation in laryngeal and tracheal lumen due to excessive growth of granulation tissue in the sites of their lesions. One should introduce hormonal preparations, moreover, one should apply Diprosan as a hormonal preparation injected once intramucosally at 0.1 ml/sq. cm of granulation tissue, but not more than 0.3 ml.

EFFECT: higher efficiency of therapy.

3 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: method involves probing and rinsing lacrimal canaliculus. Working nozzle of YAG laser is additionally introduced into lacrimal canaliculus to reach medial wall of the lacrimal sac. The working nozzle of laser is taken away from the medial lacrimal sac wall in the reverse direction by 2 mm. Laser radiation treatment is applied in constant wave mode (CW) with power of 2.5 W during 5 s in smoothly moving laser working end from the lacrimal canaliculus. The lacrimal canaliculus is washed with corticosteroids.

EFFECT: enhanced effectiveness of treatment.

FIELD: medicine.

SUBSTANCE: the present innovation includes polychemotherapy and radiation therapy. Moreover, polychemotherapy should be carried out by the following scheme: on the 1st and the 8th d of the first and the third courses it is necessary to introduce doxorubicin, cyclophosphan, vincristine, and since the 1st to the 14th d - procarbazine and prednisolone; moreover, on the 1st and the 8th d of the second and the fourth courses one should introduce doxorubicin, bleomycin, vinblastine, dacarbazine. The method enables to decrease the quantity of late therapeutic complications, improves the results of relapse-free, total tumor-specific survival rate and decreases the number of polychemotherapeutic cycles.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, dermatology.

SUBSTANCE: it is suggested to apply quingamin in combination with prednisolone. The latter should be prescribed at its average daily dosages, and quingamin daily dosage should be increased for 120-130 mg every 9-11 d beginning from 120-130 mg to reach 450-500 mg/d. Moreover, course dosage of quingamin corresponds to 15-18 mg. The method decreases toxic reactions to quingamin introduction.

EFFECT: higher efficiency of therapy.

1 cl, 1 ex

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