Derivatives pregnana, unsubstituted 17-position the retrieval method, industrial products, pharmaceutical composition

 

(57) Abstract:

Describes compounds of formula I, in which either R1means halogen, hydroxyl, or R1and R2form together a second connection and R2means halogen or hydrogen, Z is selected from ancilliary with 1-8 carbon atoms, optionally substituted, aristocraty, optionally substituted HE or SLA, alkyloxyaryl with 1-8 carbon atoms, halogen, cyano, and a dashed line indicates a second possible link with the exception of 9-fluoro-11-hydroxy-16-methyl-21-chloro-pregna-1,4-diene-3,20-dione and provided that if R1and R2form together a double bond, Z is a halogen atom, and their additive salt. Describes the retrieval method, the intermediate products of this method and pharmaceutical composition based on them, have anti-inflammatory and immunosuppressive activity. 5 S. and 3 C. p. F.-ly, 4 PL.

The invention relates to steroids, their use as medicines, methods of their preparation, intermediates of this method and pharmaceutical compositions of their content.

The invention concerns compounds of General formula I

< / BR>
where either R2means a halogen atom or a hydrogen atom, or R1and R2form together a second bond, Z is chosen from alkyloxyaryl with 1-8 carbon atoms, ancilliary with 1-8 carbon atoms, unsubstituted or substituted, aristocraty with 6-12 carbon atoms, unsubstituted or substituted, halogen, cyano, mercapto, thiocyanate, CO2A and CH2CO2A, and a represents a hydrogen atom or alkyl group with 1-8 carbon atoms, Y represents a hydrogen atom or methyl, and the dotted line in position 1-2 or 5-6 means possible second link, as well as their additive salts with acids or bases, with the exception of 9-fluoro-11-hydroxy-16-methyl-21-chloro-pregna-1,4-diene-3,20-dione and when R1and R2together form a double bond, Z is not a halogen atom.

Under the halogen atom are fluorine atoms, bromine, chlorine and iodine.

Under alkyloxyalkyl and alkylthiomethyl containing from 1 to 8 carbon atoms, are understood to be preferably methoxy, ethoxy, propoxy and butylacetoacetate, and the corresponding sulfur-containing radicals.

Under acyloxyacyl with 1-12 carbon atoms are understood to be preferably the atomic charges, propionyloxy, butyryloxy and benzoi the filing, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-etylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-ethylphenyl, n-octyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 3-methyl-3-acylindrical. In particular, we are talking about methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butylthiacalix.

Under Artiodactyla refers mainly thiophenyl.

If Z denotes substituted alkylthiomethyl or keltiradigan, you are aware of the following substituents: fluorine, chlorine, bromine, iodine, alkyl radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, alkoxyalkyl, such as methoxy, ethoxy, propyloxy, isopropoxy, butylacetoacetate, alkylthiomethyl, such as methylthio, ethylthio, propylthio, isopropylthiazole, butylthioethyl, aminoacyl, acylaminoalkyl, such as methylamino or acylaminoalkyl, dialkylaminoalkyl, such as dimethylamino, diethylamino, methylaminomethyl, hydroxyl radical, optionally acylated, for example acetoxy, or a radical of the formula-O-CO-(CH2)nCO2N, where n = 2-5, the acyl radical with 2-8 carbon atoms, such as acetyl, propionyl, butyryl, benzoyl, free carbonyl or etoxycarbonyl, cyano, trifluoromethyl or phenyl. The alkyl radical contains from 1 to 12 carbon atoms.

The expression "optionally substituted" means that there may be one or more identical or different substituents.

The substitution on the aryl may occur in the ortho-, meta - or paraprotein.

If Z means alkylthiomethyl, which is optionally substituted, in this case means mostly group S-CH2-CH2-A' where A' denotes a hydroxyl, a halogen atom or acetyloxy.

If the cycle is saturated, then Y is preferably in the alpha position.

The invention relates to salts of compounds of formula (I) in the case where these compounds contain aminopentyl, in particular with hydrochloric acid, Hydrobromic acid, nitric, sulfuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, Glyoxylic, aspartic acids, alkanesulfonyl, such as methane - and ethane-sulfonic acids, arylsulfonate, such as benzene and paratroop-sulfonic acids, and arylcarbamoyl acids, and, when the compounds of formula (I) contain an acid function,what their concerns, in particular, compounds of formula (I) described above, where R1means hydroxyl radical, R2a fluorine atom, as well as their additive salts with acids or bases.

Of the compounds according to the invention can be specified mainly in the compounds of formula (I), in which the cycle is saturated, Y means a hydrogen atom, as well as their additive salts with acids or bases.

The invention concerns, in particular, compounds of formula (I) described above, in which Z means ceanorhaditis or alkylthiols with 1-8 carbon atoms.

Of the preferred compounds according to the invention it is possible to specify the following:

- 9-fluoro-11-hydroxy-16-methyl-pregn-4-ene-3,20-dioxo-21 - carbonitril,

- 3,20-dioxo-11-hydroxy-16-methyl-21-norolean-1,4-Dien-24-methylate,

- 21-fluoro-11-hydroxy-16-methyl-pregna-1,4-diene-3,20-dione,

- 21-thio-(2-hydroxyethylene)-9, 11-dichloro-16-methyl-pregna-1,4-diene-3,20-dione,

- 21-thio-(2-acetylacetone)-9, 11-dichloro-16-methyl-pregna-1,4-diene-3,20-dione,

- 9, 11-dichloro-21-fluoro-16-methyl-pregna-1,4-diene-3,20-dione and especially

- 9-fluoro-11-hydroxy-16-methyl-pregna-1,4-diene-3,20-dioxo-21-carbonitril,

- 9-fluoro-11-hydroxy-16-methyl-21-thiomethyl-pregna-1,4-diene-3,20-dione.

The invention concerning the Messiah. < / BR>
where either R'1means hydroxyl, R'2is halogen or hydrogen, or R'1means halogen, R'2is halogen or hydrogen, or R'1and R'2form together a second connection, Y has the above meaning, is exposed to reagent activation of the alcohol of formula Ha1-SO2In, and Hal denotes bromine atom or chlorine, means an alkyl radical with 1-6 carbon atoms, unsubstituted or substituted by 1-5 halogen atoms, or phenyl or naftalina group, unsubstituted or substituted 1-5 alkyl groups with 1-6 carbon atoms, with the aim of obtaining compounds of General formula (III)

< / BR>
and the resulting compound of formula (III) optionally subjected to one or more of the following reactions carried out in an arbitrary order with the aim of obtaining compounds of General formula (I):

the influence of reagent chlorination, iodination, synthesized or fluorination,

the impact alkylthiol or arylthiol, which are optionally substituted,

the impact thioamide or thiourea followed by hydrolysis,

- the effects of KCN,

- hydrolysis of ceanography in an acidic medium, and then, if necessary, the esterification or salt formation,

- consistently sleduyushei reaction of esterification,

the effect of KSCN or NaSCN,

influence of alcohol or alcoholate,

reaction of acylation in position 11,

reactions of alkylation in position 11,

- restoration of the double bond in position 1-2,

- the formation of a double bond in position 1-2,

reaction of dehydration to form a double bond in position 9-11,

the salt formation.

Preferably, In the meant radicals-CH3, -CF3, -Ph-Me.

Mesilate, toilet, triplet formula (III) are formed as a result of the interaction at low temperature of methanesulfonanilide, taillored or triflate anhydride with the appropriate alcohol of formula (II) in the presence of a base, such as pyridine.

Getting 21-chlorinated based on the nelfinavir of the formula (III) is well known to the average expert methods, in particular the influence of lithium chloride or potassium.

Getting 21-bromo derivatives from the corresponding nelfinavir formula (III) is well known to the average expert methods, in particular the influence of lithium bromide or potassium. You can also directly get the 21-bromo derivatives from the corresponding alcohols by exposure bromodiolone (III) is well known to the average expert methods in particular the influence of sodium iodide or potassium.

Getting 21-porpoising from the corresponding 21-chloro-21-bromo - or improsoned is, in particular, by treatment with potassium fluoride in the environment glycol under reflux or by using the crown ether phase transfer or through ion-exchange resin. Getting 21-porpoising of appropriate nelfinavir formula (III) is carried out using well known to the average expert methods, in particular by treatment with potassium fluoride.

Getting 21 alkylthio or artioposthia from the corresponding 21-chlorinated is mainly the influence of alkylthiol or artiola in the presence of a base such as triethylamine in tetrahydrofuran.

The receipt of an appropriate thiol is carried out mainly by indirect method, i.e. the influence of thioamide or thiourea followed by hydrolysis.

Getting 21-cyanoderivatives is held by the action of potassium cyanide in ethanol medium at the corresponding 21-chloro-, bromo - or improsoned.

Hydrolysis of the 21-cyano groups is carried out preferably in the presence of hydrochloric or sulphuric acid.

Getting 21-thiocyanatopropyl the water.

The impact of ethylmalonate 21-chlorinated order to obtain the corresponding compound 21-CH(COOEt)2carried out preferably in the presence of a strong base such as sodium hydride, in an environment dipolar aprotic solvent, such as triamide hexamethylphosphoric acid (NMRT).

The saponification reaction is carried out with known methods, for example in the presence of sodium hydroxide in ethanol medium.

The decarboxylation reaction is also well known to the average expert methods, in particular thermal way.

The esterification reaction is well known to the average expert methods, in particular the influence of diazomethane. You can also pre-prepare the acid chloride of the acid and then exposing it to aliphatic alcohol.

Education 21-alkyloxyalkyl derivatives occurs mainly when exposed to aliphatic alcohol, such as CH3HE or nvin, 21-chlorinated in a dipolar aprotic solvent such as dimethyl sulfoxide, in the presence of a base such as sodium hydroxide.

The salt formation reaction can be conducted under normal conditions, for example in Prov or bicarbonate of sodium or potassium.

The dehydration reaction of compounds of General formula (I), (II) or (III), where R1means hydroxyl, R2- the hydrogen atom is carried out with the purpose of obtaining compounds of formula (I) with a double bond in position 9-11, is carried out by conventional methods from which you can specify, for example, the processing methylthiourea or triflate anhydride followed by thermoreactive.

The compounds of formula (I) having a second connection position 1-2, can be restored to compounds of formula (I) with a saturated bond in position 1-2 by the hydrogenation reaction carried out the usual, well known to the average expert methods.

The formation of double bond in position 1-2 may occur when using conventional methods, enzymatic or chemical, in particular under the action of 2,3-dichloro-5,6-disinsertion (DDQ) in dioxane.

The reaction of acylation of the hydroxyl in position 11 flows under the action of a carboxylic acid or its anhydride.

The reaction of alkylation of the hydroxyl in position 11 flows, for example, under the action of alkylated in the presence of a base, such as tert-butyl potassium in solution, such as tetrahydrofuran.

The invention relates, furthermore, compounds of the General forms of the hydroxy)-16-methylpregna-1,4,9(11)-triene-3,20-dione,

- 21-(methanesulfonate)-11-hydroxy-16-methyl-pregna-1,4-diene-3,20-dione,

- 21 -(4-methylphenylsulfonyl)-16-methyl-pregna-1,4,9(11)-triene-3,20-dione.

The products of formula (II) used as the source in the way to obtain are in General well known. In particular, this refers to desoximetasone (USA 3232839), 9-, 11-dichloro-16-methyl-21-hydroxypregn-1,4-diene-3,20-dione (application 2381065 on the issuance of additional patent), 16-methyl-1,4-pregnadien-11, 21-diol-3,20-dione (USA 3354186), 6, 16-dimethyl-1,4-pregnadien-11, 21-diol-3,20-dione (USA 3232839) or 6-fluoro, 16-methyl-1,4-pregnadien-11, 21-diol-3,20-dione (USA 3232839).

From anti-inflammatory and immunosuppressive molecules, known at the present time, one of the most therapeutically strong classes are glucocorticoid.

However, their use is limited because of their numerous side effects, among which you can specify the following:

the impact in the direction of the hypothalamus-pituitary-adrenal;

- intolerance to glucose that can cause diabetes;

- muscle atrophy;

- delay scarring;

- atrophy of the skin;

- osteoporosis;

- increased susceptibility to infections;

- neurological disorders;

- hype is ASTA steroid receptors. These receptors are transcription factor "ligand-induction", is able to modulate positive or negative transcription of target genes (Evans, R. M. , 1988 Science, 240, pp. 889-895), (Green, S. , Kumar, V. , Theulaz, I. , Wahli, W. , Chambon, P. , 1988, J. EMBO, 7 p. 3037-3044), (Beato, M. , 1989, Cell 56, pp. 335-344), (Jonat, C. , Rahmansdorf, H. J. , Park, K. K. , Cato, A. C, Gebel, S. , Ponta, H. , Herrlich, P. , 1990, Cell 62, pp. 1189-1204), (Pfahl, M. , 1993, Endocrine Reviews, 14, pp. 651-658).

The use of mutant receptors glucocorticoids allowed to make a conclusion about what the different parts of these receptors are involved in TRANS-activation functions or transrepression and that, therefore, both theoretically inseparable to each other (Heck, S. , Kullmann, M. , Gast, A. , Ponta, H. , Rahmansdorf, H. J. , Herrlich, P. , Cato, A. C. C. , 1994, J. EMBO, 13 p. 4087-4095).

Getting ligands of the glucocorticoid receptor with in vivo anti-inflammatory properties and deprived of the functions of development, would create a more tolerant molecules.

Compounds of General formula (I) have the following interesting pharmacological properties:

1) Glucocorticoid activity

The applicant showed in fact a new class of glucocorticoids. Different types of animals (rats, mice) helped found the things is superb locally manifested glucocorticoid activity (see testing on the ear edema induced by Croton oil in mice, the activity in vivo is similar to or exceeds the activity of prednisolone or dexamethasone).

2) Divisive activity

The products according to the invention is affected by the following mechanism: these molecules allow in fact to separate the functions of development and transrepression receptor. They have so-called "divisive" activity against the transcription of target genes.

Molecules according to the invention was tested on models of HELA cells that have undergone transfection under the action of plasmid GRE-tk-CAT (transactivation) or plasmid pColl-CAT (transrepression) (see TEST 1).

These molecules, like dexamethasone, can slow down the transcription of the collagenase promoter, on the contrary, they do not activate or activate very slightly transcription promoter GRE-tk.

Since such products have anti-inflammatory and immunosuppressive properties to the same extent as prednisolone, the types of application for therapeutic purposes are classically described for medicines prepared on asagidaki, digestive, endocrine, infectious, neoplastic, renal, neurological, ophthalmological, respiratory and rheumatic disorders or diseases, disorders and diseases of the blood and tumors. They are of particular interest in organ transplantation to prevent rejection of transplanted organs, as well as for the treatment of local inflammatory reactions, such as swelling, dermatitis, itching, various forms of eczema, solar erythema, tendonitis and istorii. They are also of particular interest in the treatment of inflammatory ophthalmic disorders.

Their divisive activity gives the compounds according to the invention of particular interest in the treatment of the above diseases, which reduces some side effects.

The invention relates, therefore, the products of formula (I), as well as their additive salts with pharmaceutically compatible acids or bases are used as medicines.

The invention concerns in particular the products of formula (I), as well as their additive salts with pharmaceutically compatible acids or bases used as medicines with glucocorticoid farmatsevticheskii compatible acids or bases, used as medicines with dissociative glucocorticoid activity, and this separation can reduce or eliminate side effects.

Of medicines according to the invention can in particular include the following:

- 9-fluoro-11-hydroxy-16-methyl-pregna-1,4-diene-3,20-dioxo-21-carbonitril,

- 9-fluoro-11-hydroxy-16-methyl-3,20-dioxo-pregn-4-ene-21-carbonitril,

- 9-fluoro-11-hydroxy-16-methyl-21-thiomethyl-pregna-1,4-diene-3,20-dione,

- 3,20-dioxo-11-hydroxy-16-methyl-21-nor-Holan-1,4-Dien-24-methylate,

- 21-fluoro-11-hydroxy-16-methyl-pregna-1,4-diene-3,20-dione.

Medication according to the invention may in particular specify the following:

- 9-fluoro-11-hydroxy-16-methyl-pregna-1,4-diene-3,20-dione-21-carbonitril,

- 9-fluoro-11-hydroxy-16-methyl-21-thiomethyl-pregna-1,4-diene-3,20-dione.

Useful dosage varies depending on subject to treatment and method of reception of medicines. The dosage may be, for example, from 1 to 1000 mg per day for an adult with oral administration.

The invention relates to pharmaceutical compositions containing as active principle at least one of the drugs, such as indicated above.

Active or active agent can be introduced into them with eccipienti commonly used in pharmaceutical compositions, such as talc, Arabic gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or nonaqueous carriers, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

Useful dosage varies, in particular, depending on the patient and the disease. It may consist of, for example, from 1-4 single daily application of ointment containing 0.1-5% of the product of example 1.

The invention concerns, in particular, pharmaceutical compositions intended for local application and containing as a drug (active agent) compounds such as those listed above.

Examples

The compounds of formula (I)

Preparation 1: 9-fluoro-11-hydroxy-16-methyl-21-chloro-pregna-1,4-diene-3,20-dione (see the 6 g of lithium chloride and 6 ml of acid chloride of methansulfonate, keeping the temperature below the 50oWith, then was stirred for 2 hours at room temperature. Was poured into water, centrifuged, washed and dried, the crude product was then purified by chromatography on silica, elwira a mixture of chloroform : ethyl acetate in a ratio of 2: 8 and received 1.86 g of pure desired product.

So pl. = 185oC.

The infrared spectrum

C= About 1726 and 1707 cm-1.

Example 1: 9-fluoro-11-hydroxy-16-methyl-21-thiomethyl-pregna-1,4-diene-3,20-dione.

After dissolution of 1.86 g of the product obtained in Preparation 1, in 20 ml of tetrahydrofuran (THF) and 2 ml of triethylamine (TEA) was barbotirovany for 1 hour at 0oWith METERTOOL and was shaken for 48 hours at room temperature. Was poured into water, centrifuged, washed and dried crude product was purified by recrystallization in a mixture of methylene chloride (CH2Cl2) : isopropyl ether and received 1,477 g of pure desired product.

So pl. = 166oC.

Infrared spectrum (CHCl3)

HE 3620 cm-1+ associate;

C= O 1715 (protruding portion), 1694, 1666 cm-1;

C= C 1627, 1611 cm-1.

Example 2: 9-fluoro-11-hydroxy-16-methyl-pregna-1,4-diene-3,20-dione-21-carbonic,9 g of compound, obtained in Preparation 1, 39 ml of ethanol, 1,080 g of potassium cyanide (90%) and 1.6 ml of water. After cooling in an ice bath and brought to pH 4 by adding acetic acid was obtained after centrifugation mineral salts, evaporated under reduced pressure to obtain 4.7 g of crude product which was then purified by chromatography on silica, elwira a mixture of ethyl acetate : benzene in the ratio of 4: 6. Obtained 2.7 g of pure desired product.

So pl. = 250oC.

Infrared spectrum (SNSC)

HE 3615 cm-1+ associate;

C= O 1723, 1664 cm-1;

1-4 1627, 1608 cm-1;

CN 2260 cm-1.

Example 3: 21-chloro-9-fluoro-11-hydroxy-16-methyl-pregn-4-ene-3,20-dione.

Acted in a manner similar to that described in Preparation 1, but using 8 g 16-methyl-9'-fluoro-pregn-4-ene-11, 21-diol-3,20-dione (application France 1315629). After recrystallization in 2,2-dimethoxy-propane was obtained of 4.95 g of pure desired product.

So pl. = 196oC.

Infrared spectrum (CHCl3).

HE 3616 cm-1+ associate;

C= O 1725, 1706 cm-1;

4 1663, 1624 cm-1.

Example 4: 9-fluoro-11-hydroxy-16-methyl-3,20-dioxo-pregn-4-ene-21-carbon is Received at 2.36 g of pure desired product.

So pl. = 224oC.

Infrared spectrum (CHCl3)

HE 3610 cm-1+ associate;

C= O 1722 cm-1;

4 1667, 1625 cm-1;

CN 2260 cm-1.

Example 5: 3,20-dioxo-11-hydroxy-16-methyl-21-norolean-1,4-Dien-24-methylate.

Stage A: 21-chloro-16-methyl-pregna-1,4,9 (11)-triene-3,20-dione.

In the atmosphere of inert gas in a mixture of 15 g 16-methyl-21-hydroxy-pregna-1,4,9(11)-triene-3,20-dione and 40 ml of the stands-ethyl pyridine was injected with 10oWith 8.8 ml of the acid chloride of methanesulfonic acid and stirred at room temperature for 5 hours. Was poured into a mixture of ice water, acidified by addition of hydrochloric acid, filtered, washed and dried. Received 16.2 g of crude desired product, which was purified by chromatography, elwira a mixture of benzene: ethyl acetate in a ratio of 8: 2. Got a 13.4 g of pure desired product.

So pl. = 154oC.

Stage: 3,20-dioxo-23-etoxycarbonyl-16-methyl-21-Nichola -1,4,9(11)-triene-24-ethylate.

In the atmosphere of inert gas in a mixture of 1,860 g of 50% sodium hydride in 50 ml of triamide hexamethylphosphoric acid and 6 ml of ethylmalonate added to 13.9 g of chlorine-containing product obtained in the previous phase, in 80 ml of triamide hexamethylphosphoramide, was dried and evaporated under reduced pressure. Got a 21.5 g of crude product, which was purified by chromatography, elwira a mixture of benzene: ethyl acetate in a ratio of 9: 1. Got to 16.4 g of pure desired product.

Stage C: 23-carboxy-3,20-dioxo-16'-methyl-21-Nichola-1,4,9(11)-trien-24-OIC acid.

Mixed 16,4 g complex diapir obtained in the previous phase, 200 ml ethanol and 100 ml of 2N sodium hydroxide solution and was shaken at room temperature for 3 hours. After evaporation of the ethanol under reduced pressure, the mixture was diluted with ice water (1 l) and acidified with hydrochloric acid. After filtering, washing and drying the obtained 14.6 g of the target product.

So pl. = 170oC.

Stage D: 3,20-dioxo-16-methyl-21-Nichola-1,4,9(11)-triene-24-Wai acid.

Was heated for 4 min on a metal bath preheated to 180oWith a mixture of 14.6 g of decollate obtained at the previous stage, and 250 ml of triamide hexamethylphosphoric acid, was poured into 1500 ml of a mixture of ice water. Fallen in sediment monobasic acid was filtered, washed and dried. Received 11.9 g of the target product.

So pl. = 208oC.

Stage E: 3,20-dioxo-16-methyl-21-Nichola-1,4,9(11)-triene-24-in, solution was added to diazomethane at a concentration of 13 g/l in dichloromethane, evaporated under reduced pressure. Received 12.3 g of the target product.

So pl. = 98oC.

Stage F: 9-bromo-3,20-dioxo-11-hydroxy-16-methyl-21-Nichola-1,4-Dien-24-methylate.

In an inert atmosphere to a mixture of 10.8 g of complex methyl ester and 150 ml of acetone was added to 7.3 g of N-bromo-succinimide, then at a temperature of from 0 to 10oWith 7.3 ml of perchloric acid and 35 ml of water. Was stirred for 2 hours at 0-5oC, then poured into 500 ml of water, filtered and the precipitate dried. Received 12.8 g of the target product.

So pl. = 230oC.

Stage G: 3,20-dioxo-11-hydroxy-16-methyl-21-Nichola-1,4-Dien-24-methylate.

18 g of chromium acetate in an inert atmosphere was added to a mixture of 12.8 g of bromohydrin prepared in the previous step, in 50 ml of dimethyl sulfoxide and 6 ml of thiophenol, mixed for 1 hour at room temperature. Then the reaction mixture was poured into 1 l of water, was extracted with ethyl acetate, washed and dried organic phase was then evaporated under reduced pressure and obtained 16 g of crude desired product, which was purified by chromatography, elwira a mixture of benzene: ethyl acetate in a ratio of 7: 3, and peracre regreny spectrum (CHCl3)

C= O 1735 cm-1(ester), 1709 cm-1(20-keto);

C= 1609 cm-1, 1626 cm-1, 1664 cm-1;

HE 3615 cm-1.

Example 6: an example of a pharmaceutical composition comprising a compound of formula (I).

Were manufactured tablets containing 50 mg of the product as the active substance obtained in example 1.

The product of example 1 50 mg

Excipient (talc, starch, magnesium stearate).

Pharmacological study of the products according to the invention

1) Study the regulation of transcription in Hela cells that have undergone transfection

Hela cells (ATCS: CCL-2) were distributed in 6-hole tablet in a nutrient medium at a density of 4105cells/ml for 24 hours before transfection and incubated at 37oC. Transient transfection caused by precipitation of calcium phosphate. When investigating the development of transfection cells were transliterowany 1 µg plasmid GRE-tk-CAT, 1 μg plasmid polyII-CAL and KS plasmid (Stratagene) in sufficient quantity to 5 micrograms. In the study of transrepression transfection in cells caused 3 µg plasmid Coll (-517/+63) CAT, 250 ng of plasmid pSV-cjun, 1 μg plasmid polyII-GAL and plasmid S (Stratagen), destati them a nutrient medium, containing different concentrations of dexamethasone or investigational products (10-9M, 10-8M, 10-7M, 10-6M). 24 hours after the addition products of the cells were literally in 250 ál buffer MOPS NaCl Triton X-100. Dosing CAT (chloramphenicol-acetyltransferase) in cell extracts were made using an ELISA kit (F. Boehringer, D. Mannheim). Classical glucocorticoids, such as dexamethasone, activate transcription promoter GRE-tk and inhibit transcription of the collagenase promoter (see tab. 1).

Conclusion: the Products obtained in examples 1 and 2, are good inhibitors of collagenase, but weak activators of transcription.

2) anti-Inflammatory activity

Test granuloma. Demolitions activity

Anti-inflammatory activity was studied classical test of the granuloma. The methodology used is a modification of the method of Mayer and Call (Meier, Coll). (Experentia, 1950 , N 6, page 469). Rats female Wistar weighing from 90 to 100 g subcutaneously in the thoracic part of the implanted two cotton swab weighing 10 mg Immediately orally introduced products based: once a day for four days. After that, the animals were killed. Tampons, cloth surrounded education is the weight of the granuloma received less initial weight cotton.

Removed also the thymus gland and weighed them to determine demolitions activity products (see tab. 2).

Conclusion: the Products obtained in examples 1 and 2, have anti-inflammatory activity similar to the activity of prednisolone.

The sample is a tumor of the ear caused by Croton oil.

The products were also tested on the model of the tumor mouse ear caused by Croton oil, according to the method described Tonelli al. (Endocrinology, 1965 , 77, pp. 625-634). The tumor ear provoked in mice-males weighing from 18 to 22 g Croton oil (2 volume. %) in a solution of the pyridine-water-ether in the proportions 4: 1: 14,6 (by volume). After 6 hours the animals were killed, removed the ears and weighed them. The difference between the weight of the ear treated with Croton oil, and the weight of the other ear (not processed) has identified 100% of the tumor. The tested products were dissolved in Croton oil and applied to the ear (see tab. 3).

Conclusion: the Product obtained in example 2 in this test showed anti-inflammatory activity, the average between the activity of prednisolone and dexamethasone.

3) Immunosuppressive activity

Immunosuppressive activity was investigated in the test for hypersensitivity zamedlennogo the catfish from 150 to 160 g were senzibilizirani day 0 suspension of Mycobacterium Tuberculosis in the amount of 4 mg/ml paraffin oil, introduced subcutaneously at the base of the tail (0.1 ml/animal).

The products were administered orally with 4-th and 7-th day.

On the seventh day, one hour after the last injection, the animals took an injection fraction of the antigen that causes a reaction of hypersensitivity delayed-type: 0.4 mg/rat in 0.2 ml pomodorino in a rear leg, the second introduced the same amount of solvent.

Measurement of the tumor was made after 24 hours using plethysmometer UGO BASTIL F. APELEX.

The activity of the products was determined in percent, which decreased edema inyecciones paws compared with control animals paws (see tab. 4).

Conclusion: Prednisolone retains a high effective dose ED 50 in the range of 5-20 mg/kg with a maximum inhibition of 50%, the products obtained in examples 1 and 2, have effective dose ED 50, respectively, 2.3 and 1.5 mg/kg of Their activity depends on the dose, with maximum suppression is 82% (example 1) and 90% (example 2) at 10 mg/kg

1. Derivatives Pregnana, unsubstituted 17-position of General formula I

< / BR>
in which either R1means a hydroxyl radical, a halogen atom and R2means a halogen atom or a hydrogen atom, or R1and R21and R2form together a double bond, Z is not a halogen atom.

2. The compounds of formula I under item 1, in which R1means hydroxyl radical, R2a fluorine atom, or an additive salts with acids or bases.

3. The compounds of formula I according to one of paragraphs. 1 and 2, in which Z is selected from ceanography and ancilliary having 1-8 carbon atoms.

4. The compounds of formula I under item 1, with the following names:

9-fluoro-11-hydroxy-16-methyl-pregna-1,4-diene-3,20-dioxo-21-carbonitril,

9-fluoro-11-hydroxy-16-methyl-pregn-4-ene-3,20-dioxo-21-carbonitrile;

9-fluoro-11-hydroxy-16-methyl-21-thiomethyl-pregna-1,4-diene-3,20-dione,

3,20-dioxo-11-hydroxy-16-methyl-21-norolean-1,4-Dien-24-methylate,

21-fluoro-11-hydroxy-16-methyl-pregna-1,4-diene-3,20-dione,

21-thio-(2-hydroxyethylene)-9, 11-dichloro-16-pregna-1,4-diene-3,20-dione,

21-thio-(2-acetylacetone)-9, 11-dichloro-16-methyl-pregna-1,4-diene-3,20-dione,

9, 11-dichloro-21-fluoro-16-methyl-pregna-1,4-diene-3,20-dione.

5. The method of obtaining compounds of formula I, p is/SUB>'is halogen or hydrogen, or R1' means halogen and R2'is halogen or hydrogen, or R1' and R2' together form a second bond,

expose agent activation of the alcohol of General formula

Hal-SO2IN,

where Hal denotes bromine atom or chlorine;

In the mean alkyl residue with 1-6 carbon atoms,

to obtain compounds of General formula III

< / BR>
where has the specified values,

and the compound of formula III is subjected to one or more of the following reactions in the appropriate sequence to obtain compounds of General formula I: effects of agent chlorination, iodination or fluorination, the impact alkylthiol, the impact N sequentially effects the connection of CH2(t)2the saponification reaction, then the reaction decarboxylation optionally followed by reaction of esterification, the effects of alcohol and salt formation.

6. The compounds of formula I on PP. 1-4, which has anti-inflammatory and immunosuppressive activity.

7. Pharmaceutical composition having anti-inflammatory and immunosuppressive activity containing compound on the PP. 1-4, 6.

8. Compounds of General formula III-methyl-pregna-1,4-diene-3,20-dione,

9-fluoro-21-(methanesulfonate)11-hydroxy-16-methyl-pregna-1,4-diene-3,20-dione,

21-(methanesulfonate)-16-alpha-methylpregna-1,4,9(11)-triene-3,20-dione.

 

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