Retinoids and pharmaceutical composition containing them

 

(57) Abstract:

Describes new connections - retinoids General formula I, where X denotes oxoprop or group or SIG1in position 4 or 5, R1denotes hydrogen and R2denotes hydrogen or alkyl, communication, indicated by the dotted line are optional and 3,4-double bond can be present only when X is in position 5, and pharmaceutically acceptable salts of carboxylic acids of formula I. also Describes a pharmaceutical composition containing them. Retinoids and pharmaceutical composition based on them can be used for the treatment and prevention of skin diseases involving pathological changes of the epithelium, for example, for the treatment of acne and psoriasis, as well as malignant and precancerous lesions of the epithelium, tumor and precancerous changes in the mucous membrane of the mouth, tongue, larynx, esophagus, bladder, cervix and colon. 2 C. and 15 C.p. f-crystals, 3 PL.

The present invention relates to new retinoids General formula

< / BR>
where X denotes oxoprop or group OR1in position 4, or 5;

R1denotes hydrogen, alkyl or ACE, and 3,4-double bond can be present only when X is in position 5;

and to pharmaceutically acceptable salts of carboxylic acids of formula I.

In addition, the invention relates to a method for producing these retinoids and their salts, pharmaceutical compositions containing these retinoids or their salts, as well as the application of these retinoids and their salts as medicaments or for the preparation of medicines.

In the compounds of General formula I, the alkyl groups preferably represent lower alkyl groups (under "lower" understand group with 1-7 carbon atoms), which may be straight or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and heptyl. The term "acyl" preferably refers to the lower alkanoyl groups such as acetyl, propionyl, butyryl and pivaloyl; aromatic acyl groups such as benzoyl and toluyl; and to alifaticheskimi acyl groups such as phenylacetyl.

The compounds of formula I, in which X denotes a group OR1can represent as R - or S-enantiomers, and racemates.

A preferred group of compounds of formula I includes connection the/SUP> and R2have the above values.

In addition, the subgroups of compounds of formula I include compounds of formula ID, IE, IF, IG and IH

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< / BR>
< / BR>
< / BR>
Examples of compounds of formula I are:

(2Z, 4E, 6E, 8E)-(R)-9-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-3,7 - dimethylene-2,4,6,8-terraenovae acid,

(2Z, 4E, 6E)-(R)-9-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-3,7-dimethylene-2,4,6-tetraen-8-andnew acid,

2Z, 4E, 6E)-(R)-9-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-3,7 - dimethylene-2,4,6-trien-8-andnew acid,

ethyl(2Z,4E,6E,8E)-(R)-9-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-3,7 - dimethylene-2,4,6,8-tetraenoic

(2Z, 4E,6E,8E)-9-(5-oxo-2,6,6-trimethylcyclohexa-1,3-dienyl)-3,7 - dimethylene-2,4,6,8-terraenovae acid,

(2Z, 4E, 6E, 8E)-(R)-9-(4-acetoxy-2,6,6-trimethylcyclohex-1-enyl)-3,7 - dimethylene-2,4,6,8-terraenovae acid,

(2Z, 4E,6E,8E)-(R)-9-(4-methoxy-2,6,6-trimethylcyclohex-1-enyl)-3,7 - dimethylene-2,4,6,8-terraenovae acid,

(2Z, 4E, 6E, 8E)-(RS)-9-(5-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-3,7 - dimethylene-2,4,6,8-terraenovae acid,

(2Z, 4E, 6E,8E)-(RS)-9-(5-hydroxy-2,6,6-trimethylcyclohex-1,3-dienyl)-3,7 - dimethylene-2,4,6,8-terraenovae acid,

(2Z, 4E, 6E, 8E)-9-(5-oxo-2,6,6-trimethylcyclohex-1-enyl)-3,7 - dimethylene-2,4,6,8-terraenovae acid,

(2Z,4E,6E,8E)trimethylcyclohex-1-enyl)-3,7 - dimethylene-2,4,6,8-terraenovae acid and

(2Z, 4E, 6E, 8E)-(RS)-9-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-3,7 - dimethylene-2,4,6,8-terraenovae acid.

The compounds of formula I and their salts can be obtained in accordance with the invention by the interaction of the compounds of General formula

< / BR>
where A denotes a phenyl or substituted phenyl and Y-denotes an anion, and X and communications, indicated by the dotted line have the above significance, with 5-hydroxy-4-methyl-5H-furan-2-one in the presence of a base, present in the isomerization reaction product isomers, which formed as a result of the interaction of the double bond C = C has isconfiguration, TRANS-isomers and, if necessary, processing of the received product of the interaction of formula I according to one or more of the following reactions:

a) esterification of carboxyl or hydroxyl group in esters;

b) esterification of hydroxyl groups in a simple ether;

C) oxidation of the hydroxyl group to the carbonyl group;

g) recovering the carbonyl group to a hydroxyl group;

d) steric conversion of the hydroxyl group; and

e) converting the carboxyl group into salt.

The above reaction can be carried out in accordance with known for time methods by the reaction of Wittig. When the reaction components are interacting with each other in the presence of an acid binding agent, for example, in the presence of a strong base, such as KOH, in an aqueous solvent; or hydride of sodium, of potassium tert-butylate or ethylate sodium in anhydrous solvent such as dimethylformamide or methylene chloride, in a temperature range from approximately -30oC to room. Preferably used compounds of the formula II in which X represents oxo - or hydroxy-group. In the Wittig reaction in the operating mixture is formed a mixture of CIS/TRANS-isomers relative to the double bond C=C. This mixture 4E/Z-isomers can be selectively samaritana to 4E-isomers are well known manner, for example by treatment with palladium catalyst, such as nitrate Pd(II).

Of the anions Y-inorganic acids are preferred ions of chlorine and bromine, and anions of organic acids is preferred, tosyloxy-ion. Group And preferably represents a phenyl group.

The esterification of the carboxyl group in the compound of the formula I can be carried out, for example, by interacting with haloalkyl in the presence of a base, so the Noah group can be accomplished through interaction with galization in the presence of a base, such as pyridine. A hydroxyl group can be oxidized to the carbonyl group, for example, in accordance with the methods Swarna (dimethylsulfoxide/oxalicacid) or Dess-Martin (periodic). The recovery of the carbonyl group to a hydroxyl group can be carried out hydride reducing agent such as NaBH4. Steric configuration of the hydroxyl group may be converted in accordance with the method Mitsunobu (interaction with triphenylphosphine, para-nitrobenzoic acid and diethylazodicarboxylate and subsequent saponification).

Examples of salts that can be converted into carboxylic acids of formula I are salts of alkali metals such as Na and K salts of alkaline-earth metals, such as salts of Ca and Mg, and ammonium salts, e.g. salts with bonds alkylamines and hydroxyethylamine or with other organic bases such as dimethylamine, diethanolamine and piperidine.

The compounds of formula II can be obtained by the method described in Pure and Appl. Chem. 57, 741 (1985) or other presents in this publication literary references.

Compounds according to the invention can be used for the treatment and prevention of skin diseases, which are accompanied by pathological iesca changes of the epithelium, tumor and precancerous changes in the mucous membrane of the mouth, tongue, larynx, esophagus, bladder, cervix and colon.

Therefore, the compounds of formula I and their salts can be used in the form of pharmaceutical compositions.

Compositions which are used for systemic injections, can be obtained, for example, by adding the compounds of formula I or salts thereof as an active ingredient to a non-toxic, inert solid or liquid carriers which are usually used in such compositions.

The composition may be introduced enterline, parenterally or locally. Compositions in the form of tablets, capsules, pills, syrups, suspensions, solutions and suppositories suitable for enteral administration. Compositions in the form of solutions for infusion or injection is suitable for parenteral administration.

When enteral and parenteral administration the compounds of formula I can be administered to adults in doses of approximately 10-400 mg/day, preferably 20-200 mg/day.

For local application of the active ingredients usually used in the form of ointments, tinctures, creams, solutions, lotions, sprays, suspensions, etc., the Preferred ointments and creams, as well as the LLC as an active ingredient with non-toxic, inert solid or liquid carriers, suitable for local processing and are usually used in such compositions.

Usually for local application apply approximately 0.1-5%, preferably 0.3 to 2% solutions, and about 0.1-5%, preferably 0.3 to 2% ointment or creams.

Optionally, the compositions may be added an antioxidant, such as tocopherol, N-methyl - N-tokovinin, and bottled hydroxyanisol or bottled hydroxytrol.

The active compounds according to the invention for the treatment of acne can be confirmed using the following methods.

1. The inhibition of proliferation of sebocyti human (in vitro)

Literature: Methods in Enzymology 190, 334 (1990), T. Doran, and S. Shapiro

2. Changes in the differentiation of sebocyti pigs in vitro, induction of keratin 7

Culture of sebocyti pig is prepared from selected sebaceous glands located in the minds of the pigs. The sebocyti responsive to treatment by retinoids, expressive keratin 7, which also corresponds to the process in vivo. Keratin 7 is considered as a marker for evaluation of altered differentiation sebocyti. The resulting phenotype can no longer form the secretion of sebaceous glands. Measurement in keratin-7.

3. Model using pigs (in vivo)

The skin of pigs has similar anatomical structure with human skin. In particular the secretion of sebaceous glands similar to the one used in patients suffering from acne. When processed by retinoids sebaceous glands show similar histological changes which occur in humans. Piglets receive a daily oral dose of the compounds within 8 weeks. Every 2 weeks do a biopsy and performed histological examination.

In this test the compound obtained according to example 1, in amounts of 10 mg/kg in 3-4 weeks leads to a pronounced decrease in the secretion of sebaceous glands, which almost completely disappears after 8 weeks. In contrast to isotretinoin no side effects on the skin or mucous membrane was not detected at the dose of 50 mg/kg

Teratogenic effects are the most serious adverse manifestations of all retinoids. Compounds of the present invention have significantly lower teratogenicity compared to, for example, with isotretinoin or tretinoin. To assess the potential teratogenic effects were applied the method using the cell culture of embryo vo is very good.

The compound of example N - IC50(nm)

1 - > 1000

3 - > 1000

4 - > 1000

Isotretinoin - 200

Tretinoin - 80

Below the invention is illustrated in more detail by the following examples.

Example 1

50 g [(2E, 4E)-(R)-5-(4-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3 - methyl-2,4-pentadienyl]triphenylmethylchloride was dissolved in 500 ml of isopropanol and treated with 11 g of 5-hydroxy-4-methyl-5H-furan-2-it. After cooling the reaction mixture to -30oC was added dropwise to 120 ml of aqueous 2 n solution of KOH and the mixture was stirred for 1 h at -30oC in argon atmosphere. Then the reaction mixture was poured into 1.3 l of ice water, six were extracted using each time with 500 ml of a mixture (2:1) hexane/ethyl acetate, the aqueous alkaline solution was acidified by adding chilled on ice 3 N. sulfuric acid, continuing the cooling on ice, and then was extracted three times with ethyl acetate. The organic phase was washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated. A viscous yellow residue was again dissolved in 800 ml of ethyl acetate, and treated with 100 g of silica gel (Merck, 0,063-0.2 mm), slightly heated in a steam bath for 5 minutes with vigorous stirring and after filetransit product was treated with 500 ml of acetonitrile and heated to 50oC in argon atmosphere. After a La carte add approximately 700 ml of acetonitrile was obtained a transparent yellow solution. After adding 1.1 g of triphenylphosphine and 118 ml of a 0.125% aqueous solution of palladium nitrate (II) in acetonitrile, the reaction mixture was stirred at 50oC for 3 hours, the Final product was led from the reaction solution was cooled to -10oC. It was filtered, washed with hexane and dried at 40oC in high vacuum. By recrystallization from hexane/ethyl acetate received 15 g of (2Z,4E,6E,8E)-(R)-9- (4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-3,7-dimethylene-2,4,6,8 - terraenovae acid, tPL180-182oC (decomp.), []20D= -49,7 (C = 1, dioxane).

Example 2

3 g of carboxylic acid, obtained in accordance with example 1 was sequentially treated with 120 ml of methyl ethyl ketone, and 5.2 g of finely ground potassium carbonate and 7.4 g of ethyliodide and boiled under reflux in an argon atmosphere with vigorous stirring for 2.5 hours the Reaction mixture was poured into a mixture of ice/1 N. hydrochloric acid, was extracted with simple ether, washed with water, dried and evaporated. The oily crude product was filtered through silica gel (eluent hexane/ethyl acetate 2:1) and re is-dimethylene-2,4,6,8-tetraenoic in the form of yellow crystals, tPL93-95oC []20D/= -45,5 (C = 1, dioxane).

Example 3

Analogously to example 1 by the interaction of 10 g of [(E)-(R)- 5-(4-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2-penten - 4-inyl] triphenylmethylchloride with 2.3 g of 5-hydroxy-4-methyl-5H - furan-2-she followed catalyzed by palladium isomerization of the crude product and recrystallization from hexane/ethyl acetate was obtained 3.1 g (2Z,4E,6E)-(R)-9-(4-hydroxy - 2,6,6-trimethylcyclohex-1-enyl)-3,7-dimethylene-2,4,6-trien-8 - invoi acid as yellow crystals, tPL189-190oC (decomp.), []20D= -87,3 (C = 1, CHCl3).

Example 4

9 g [(2E, 4E)-3-methyl-5-(2,6,6-trimethyl-5-oxo-1,3 - cyclohexadiene-1-yl)-2,4-pentadienyl] triphenylphosphonium and 1.7 g of 5-hydroxy-4-methyl-5H-furan-2-it is suspended in 100 ml of isopropanol. After cooling the reaction mixture to -30oC was added dropwise 2 N. aqueous solution of potassium hydroxide. After stirring for 30 minutes at -30oC the reaction mixture was poured into ice water, was extracted three times with hexane, the aqueous alkaline phase was acidified by adding chilled on ice 3 N. sulfuric acid and was extracted several times with ethyl acetate. The organic phase is washed with water, dried and UPrev thus Obtained yellow oil (approximately 4 g) was dissolved in 100 ml of acetonitrile, was treated with 150 mg of triphenylphosphine and heated to 50oC, followed by dropwise it was added 10 ml of a 0.125% aqueous solution of palladium nitrate (II) in acetonitrile. After exposure at 50oC for 2 h, the reaction mixture was cooled to 0oC. After 2 h, the separated crystals were filtered off under vacuum and recrystallized from hexane/ethyl acetate. It was obtained 1.4 g (2Z,4E,6E, 8E)-9-(5-oxo-2,6,6-trimethylcyclohexa-1,3-dienyl)-3,7 - dimethylene-2,4,6,8-tetraenoic acid as yellow crystals, tPL188oC (decomp.).

Example 5

7 g [(2E, 4E)-3-methyl-5-(2,6,6-trimethyl-5-oxo-1-cyclohexen-1-yl)- 2,4-pentadienyl] triphenylphosphonium and 1.4 g of 5-hydroxy-4-methyl-5H-furan-2-it is suspended in 100 ml of isopropanol. After cooling the reaction mixture to -30oC it was added dropwise a solution containing of 1.76 g of potassium hydroxide in 30 ml of isopropanol. After stirring for 40 minutes at 30oC the reaction mixture was poured into 200 ml ice water, six were extracted with a mixture of hexane/ethyl acetate (2:1), the organic phase was washed with water, the combined aqueous phase was acidified 3 N. sulfuric acid and was extracted several times with ethyl acetate. The organic phase was washed (H2O), dried (Na2SO is actively stirred at 40oC in argon atmosphere. After cooling, the silica gel was filtered, thoroughly washed with ethyl acetate and the solution was evaporated. The residue was dissolved in 30 ml of acetonitrile and after adding 256 mg of triphenylphosphine were treated with 50oC introduced dropwise a solution containing 26 mg of palladium nitrate in 5 ml of acetonitrile. After stirring at 50oC for 1 h, the reaction mixture was cooled to 0oC and after 1 h was filtered the separated precipitate. After two recrystallization from hexane/ ethyl acetate was obtained 1.4 g (2Z,4E,6E,8E-3,7-dimethyl-9-(2,6,6 - trimethyl-5-oxocyclopent-1-enyl)Nona-2,4,6,8-tetraenoic acid as yellow crystals, tPL178-179oC.

Example 6

0.5 g of (2Z, 4E, 6E,8E-3,7-dimethyl-9-(2,6,6-trimethyl-5-oxocyclopent-1 - enyl)Nona-2,4,6,8-tetraenoic acid was dissolved in 25 ml of ethanol at low heat and was treated with 100 mg of sodium borohydride while cooling on ice. After stirring at 0oC for 1 h, the reaction mixture was poured into ice water, acidified 2 N. hydrochloric acid and was extracted with ethyl acetate. The organic phase was washed (H2O), dried (Na2SO4) and was evaporated. Through a small column (silica gel, hexane/ethyl acetate [1: 1] ) was filtered mortgagemerrimack-1-enyl)-3,7-dimethylene-2,4,6,8 - tetraenoic acid as yellow crystals, tPL152-154oC.

Example 7

2.5 g of ethyl ester obtained in accordance with example 2, was dissolved in 35 ml of absolute tetrahydrofuran and, at 0oC was sequentially treated with 3.8 g of triphenylphosphine, 2.4 g of para-nitrobenzoic acid and added dropwise a solution containing 2.5 g of diethylazodicarboxylate in 30 ml of tetrahydrofuran. After stirring for 2 h at room temperature the mixture was evaporated, the residue was dissolved in a simple ether and kept in the refrigerator for 3 hours separated was Removed when the sediment (triphenylphosphine), the filtrate was concentrated and the residue was purified by chromatography (silica gel, hexane/ethyl acetate 5%). Thus obtained yellow oil (0.68 g) was dissolved in 15 ml of ethanol and after addition of a solution containing 0,78 g of potassium hydroxide in 3 ml of water, 3 ml of ethanol and 3 ml of tetrahydrofuran, stirred at 45oC for 6 hours Then the reaction mixture was poured into ice water, acidified 1 N. hydrochloric acid and was extracted with ethyl acetate. The organic phase was washed (H2O), dried (Na2SO4) and was evaporated. The crystalline residue was filtered through a small column (silica gel, ethyl acetate) and after paracrystal the a-2,4,6,8-tetraenoic acid as yellow crystals, tPL178-180oC []20D= +48,2 (=0,66, dioxane).

Example 8

1 g of carboxylic acid, obtained in accordance with example 4, suspended in 50 ml of methyl ethyl ketone, was treated with 1.5 g of finely ground potassium carbonate and 1.3 ml of ethyliodide and kept at the temperature of reflux distilled for 1 h the Cooled reaction mixture was poured into ice water, neutralized 1 N. hydrochloric acid, was extracted with ethyl acetate, washed (H2O), dried (Na2SO4) and was evaporated. Thus obtained yellow oil was purified by chromatography (silica gel, hexane/ethyl acetate [2:1]), resulting in the 1.5 g of the corresponding ethyl ester as a yellow oil.

1.18 g of trichloride cerian2Oh was dissolved in 25 ml of methanol and sequentially treated with a solution of the above ethyl ester in 5 ml of methanol and 120 mg of sodium borohydride. Upon completion of gas (approximately 5 minutes) the mixture was evaporated and the organic residue was purified by chromatography (silica gel, hexane/ethyl acetate [4:1]). The way it was obtained 1.04 g of the corresponding hydroxyether in the form of a yellow oil. This oil was dissolved in 25 ml of ethanol was treated with a solution containing 1.6 g ginou mixture was poured into ice water, acidified to pH 3 1 N. hydrochloric acid and was extracted with ethyl acetate. The organic phase was washed (H2O), dried (Na2SO4) and was evaporated, receiving 0.95 g of amorphous residue is orange. By filtration through a small column (silica gel, hexane/ethyl acetate [1: 1] ) and crystallization from hexane/ethyl acetate was obtained (22,4 E, 6E, 8E)-9-(5-hydroxy-2,6,6-trimethylcyclohex-1,3-dienyl)-3,7-dimethylene-2,4,6,8-terraenovae acid as yellow-orange crystals, tPL108-110oC.

An example of a

Gelatin capsules with a hard coating can be prepared as follows.

Ingredient mg/capsule

Dried by spraying powder containing 75% of the compounds of formula I - 20

Dioctylsulfosuccinate sodium - 0,2

The sodium carboxymethyl cellulose is 4.8

Microcrystalline cellulose - 86,0

Talc - 8,0

Magnesium stearate - 1,0

Just - 120

Dried spray powder comprising the active ingredient, gelatin and microcrystalline cellulose and which has an average particle size of the active ingredient < 1 μm (measured using Avtomobilnaya spectroscopy), is moistened with an aqueous solution of sodium carboxymethyl cellulose and distils mesilat with microcrystalline cellulose, talc and magnesium stearate. Powder filled capsules of size 0.

Example B

Tablets can be prepared as follows.

Ingredients mg/tablet

The compound of formula I in the form of fine powder - 20

Powdered lactose - 100

White corn starch - 60

Povidone K - 8

White corn starch - 16

Talc - 16

Magnesium stearate - 4

Just - 320

The finely ground active ingredient is mixed with lactose and a portion of the corn starch. The mixture is moistened with an aqueous solution of povidone K and stirred, and the resulting mass granularit, dried and sieved. The granulate is mixed with the remaining quantity of starch, talc and magnesium stearate and pressed into tablets of appropriate size.

The example IN

The lotion can be prepared as follows.

Ingredients:

Micronized compound of formula I - 1,0

The carbopol 934 - 0,6

Sodium hydroxide - q.s. to pH 6

Ingredients:

Ethanol 94% - 50,0

Demineralized water up to 100.0

The active ingredient is introduced into a mixture of 94% ethanol/water, protecting from light. The carbopol 934 is stirred until completion of geleobrazovanie well known manner from the following ingredients.

Ingredient, wt.%:

The compound of formula I is 0.1 to 5

Cetyl alcohol - a 5.25 - 8,75

Arlacel 165 (glyceryl/stearate PEG-100) of 3.75 and 6.25

Miglyol 818 (triglyceride Caprylic/capric/linoleic acid) - 11,25 - 18,75

The sorbitol solution of 3.75 and 6.25

Na2ADD - 0,075 - 0,125

The carbopol R (carbomer R) - 0,15 - 0,25

Bottled hydroxyanisol - 0,0375 - 0,0625

Methylparaben - is 0.135 - 0,225

Propylparaben - 0,0375 - 0,0625

NaOH (10% solution) - 0,15 - 0,25

Water - q.s to 100.00

Example D

Ingredient, wt.%:

The compound of formula I is 0.1 to 5

Pluronic L 101 (poloxamer 331) - 10,00

Aerosil 200 (silicon dioxide) - 8,00

Liquid PCL (fatty acid ester) - 15,00

Cetiol V (decillia) - 20,00

The Neobee oil (triglyceride medium chain length) - 15,00

Eugenol G (octyldodecanol) - q.s. to 100.00

The physical properties of the composition can be changed by varying the ratio between the adjuvants in examples D and E.

Example 9

Pigs received daily oral dose of the compounds for 2 days. After 4 hours after taking the second dose was determined the levels of all-TRANS-isomeric analogue in the tissue (sebaceous glands) and in the plasma. The ratio of the content of the analyte Plasma
13-CIS-derivatives less teratogenic than the corresponding all-TRANS isomers. This is demonstrated by the results obtained in vivo in mice (see table. 2)

Example 11

13-CIS-4-oxo-retinoic acid (D) and 13-CIS-4-hydroxy-retinoic acid (E) are the major metabolites of 13-CIS-retinoic acid (prior art). 3-Hydroxy-derivatives according to the invention (a) and 13-CIS-retinoic acid (Roaccutan) was administered as a daily oral dose pigs for 8 weeks. Efficiency (decrease in sebum production is in accordance with standard histological studies) and the harmful side effects (skin-mucous phenomena studied in the process of introduction of the investigated compounds.

The activity of 13-CIS-3-hydroxy-retinoic acid was similar to the activity of known compounds Roaccutan, but the side skin and mucous phenomena (mainly conjunctivitis) appeared much later.

Example 12

The ratio of the teratogenicity/induction of keratin 7 (K7) for compounds according to the invention is considerably higher than that for Roaccutane. To assess teratogenic effects were applied the method using the cell culture Sania A-H are illustrated below.

1. Retinoids General formula

< / BR>
where X denotes oxoprop or group OR1in position 4, or 5;

R1denotes hydrogen;

R2denotes hydrogen or alkyl;

communication, indicated by the dotted line are optional and 3,4-double bond can be present only when X is in position 5,

as well as pharmaceutically acceptable salts of carboxylic acids of formula I.

2. Connection on p. 1 formula

< / BR>
where X and R2defined in paragraph 1.

3. Connection on p. 1 formula

< / BR>
where R1and R2defined in paragraph 1.

4. Connection on p. 1 formula

< / BR>
where R1and R2defined in paragraph 1.

5. Connection on p. 1, representing the (2Z, 4E, 6E, 8E)-(R)-9-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-3,7-dimethylene-2,4,6,8-terraenovae acid.

6. Connection on p. 1, representing the ethyl(2Z, 4E, 6E, 8E)-(R)-9-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-3,7-dimethylene-2,4,6,8-tetraenoic.

7. Connection on p. 1, representing the (2Z, 4E, 6E, 8E)-(S)-9-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-3,7-dimethylene-2,4,6,8-terraenovae acid.

8. Connection on p. 1 formula

< / BR>
where R1and R2defined Connection on p. 1, representing the (2Z, 4E, 6E, 8E)-9-(5-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-3,7-dimethylene-2,4,6,8-terraenovae acid.

11. Connection on p. 1 formula

< / BR>
where R2defined in paragraph 1.

12. Connection on p. 1, representing the (2Z, 4E, 6E, 8E)-9-(5-oxo-2,6,6-trimethylcyclohex-1,3-dienyl)-3,7-dimethylene-2,4,6,8-terraenovae acid.

13. Connection on p. 1, representing the (2Z, 4E, 6E, 8E-3,7-dimethyl-9-(2,6,6-trimethyl-5-oxocyclopent-1-enyl)Nona-2,4,6,8-terraenovae acid.

14. Connection on p. 1 formula

< / BR>
where R1and R2defined in paragraph 1.

15. Connection on p. 1, representing the (2Z, 4E, 6E)-(R)-9-(4-hydroxy-2,6,6-trimethylcyclohex-1-enyl)-3,7-dimethylene-2,4,6-trien-8-andnew acid.

16. Connection PP.1-15, with the ability to reduce the secretion of sebaceous glands and intended in particular for the treatment and prevention of acne.

17. Pharmaceutical composition having the ability to reduce the secretion of sebaceous glands, intended in particular for the treatment and prevention of acne and contains the connection PP.1-15 and conventional pharmaceutical carriers.

 

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The invention relates to medicine, namely to dermatology, and concerns the use of at least one-adrenergic agonist in cosmetic compositions as an antagonist of substance P for the treatment of diseases associated with excessive synthesis and/or release of substance P

The invention relates to chemical-pharmaceutical industry, refers to a stable solution palmitate, treatment of skin diseases and reducing the side effects of chemotherapy for cancer patients
The invention relates to the field of animal husbandry
The invention relates to medicine, namely to the pharmaceutical industry, to create vitamin complex and method of its production
The invention relates to a process for the preparation of powder, granular, water-dispersed preparations of fat-soluble vitamins and can be used in food, pharmaceutical industry and fodder production

The invention relates to the field of medicine and relates to means for the treatment of wounds, burns, ulcers, radiation skin lesions, pressure sores

The invention relates to medicine, namely to dermatology, and is intended for the treatment of atopic dermatitis

The invention relates to medicine, in particular, neurology, and for the treatment of cerebral ischemic stroke
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