Using sip receptor modulators in ophthalmology

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, particularly to ophthalmology. One of the objects is using 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diole (compound A), its separate isomers and a mixture of the same isomers, or pharmaceutically acceptable salts, solvates and hydrates thereof for preparing an agent for treating keratoplasty or refractive keratoplasty consequences. The second object is a method of treating the keratoplasty or refractive keratoplasty consequences in an individual in need thereof that involves administering a therapeutically effective amount of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diole (compound A), its separate isomers and mixtures of the same, pharmaceutically acceptable salts, solvates and hydrates thereof into the above individual.

EFFECT: invention provides treating the eye disorder consequences.

2 cl

 

The present invention relates to the use of agonist of S1P receptor to obtain drugs for the treatment of eye diseases.

Eye diseases to be treated according to the present invention, typically include eye diseases or disorders that are directly or indirectly associated with degeneration of the cells of the retina or the cornea, especially with apoptosis. Eye diseases, as specified in this context include mainly ischemic retinopathy, ischemic neuropathy anterior optic nerve, all forms of optic neuritis, age-related macular degeneration (AMD), dry form (dry AMD) and weeping form (wet AMD), diabetic retinopathy, diabetic edema yellow spots (DME), proliferative diabetic retinopathy (PDR), a cystic swelling yellow spots (CME), retinal detachment, retinitis pigmentosa (RP), the syndrome Stargardt, baby macular degeneration (a disease of the best), Leber's congenital amaurosis and other hereditary retinal degeneration, pathologic myopia, retrolateral fibroplasia, hereditary neuropathy of the optic nerve's, the effects of transplantation of corneal or refractive surgery on the cornea, keratoconjunctivitis sicca (KCS) or dry keratitis and herpes keratitis.

These eye diseases preferably is selected from the group including; dry AMD, wet AMD, diabetic retinopathy, diabetic edema yellow spots (DME), proliferative diabetic retinopathy (PDR), retinitis pigmentosa (RP) and keratoconjunctivitis sicca (KCS), more preferably these eye diseases are selected from the group including: dry AMD, wet AMD, DME and PDR.

Preferably specified eye disease also means PDR.

Preferably specified eye disease also means DME.

Preferably specified eye disease also means keratoconjunctivitis sicca (KCS).

Most preferably specified eye disease selected from dry AMD and wet AMD.

In the present description, the terms "treatment" or "treat" refers to prophylactic treatment and healing effect or to the effect of weakening the intensity of the disease, including treatment of high-risk patients predisposed to this disease or suspected risk, and treatment of those suffering from disease patients or patients who have the proper diagnosis.

Agonist of S1P receptors are compounds that exert an agonistic effect on one or more phosphate receptors of sphingosine-1, such as S1P1-S1P8. Binding of agonist to the receptor S1P may cause, for example, dissociation outside the gunning of heterotrimeric G-proteins with the formation of Gα-GTP and Gβγ-GTP, and/or to increase the degree of phosphorylation is associated with an agonist of the receptor and subsequent activation of signal transduction pathways/kinases.

Agonists of the receptor S1P usually are analogues of sphingosine, such as 2-substituted 2-aminopropan-1,3-diol or derivatives of 2-aminopropanol, for example, a compound containing a group of formula X

where Z denotes H, C1-With6alkyl, C2-With6alkenyl,2-C6quinil, phenyl, phenyl substituted by a group of HE, C1-C6alkyl, substituted by 1-3 substituents selected from the group comprising halogen, C3-C8cycloalkyl, phenyl and phenyl substituted by a group HE or CH2-R4z. where R4zIT means, acyloxy or a residue of formula (a)

where Z1means of a simple bond or O, preferably O,

each of R5zand R6zindependently denotes H or C1-C4alkyl, optionally substituted by 1, 2 or 3 halogen atoms,

R1zIT means, acyloxy or a residue of formula (a), and each of R2zand R3zindependently mean H, C1-C4alkyl or acyl.

A group of formula x is the functional group is attached as a terminal group to the main fragment, which is hydrophilic or lipophilic, and includes forefront of the crystals of one or more aliphatic, alicyclic, aromatic and/or heterocyclic residue, forming a molecule, where at least one of the groups Z and R1zmeans or comprises a residue of formula (a), which acts as an agonist in relation to one or more receptors for sphingosine-1-phosphate.

Examples of preferred agonist of S1P receptor include, for example,

connections, claimed in EP 627406 A1, for example, the compound of formula I

where R1means12-C22alkyl straight or branched chain, which comprises a chemical bond or a heteroatom that is selected from a double bond, a triple bond, O, S, NR6where R6means H, alkyl, aralkyl, acyl or alkoxycarbonyl and carbonyl, and/or

which contains as a substituent alkoxy group, alkenylacyl, alkyloxy, aralkylated, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonyl, acyloxy, allylcarbamate, nitro, halogen, amino, hydroxyimino, hydroxy or carboxy, or

R1means

phenylalkyl, where the alkyl includes straight or branched chain, containing from 6 to 20 carbon atoms, or

phenylalkyl, where the alkyl means a straight or branched chain, containing from 1 to 30 carbon atoms, with the specified phenylalkyl is substituted glad the Kalami selected from the group including

- C6-C20alkyl straight or branched chain, optionally substituted with halogen,

- C6-C20alkoxy with a straight or branched chain, optionally substituted with halogen,

- C6-C20alkenylacyl straight or branched chain,

- funeralcare, halogenerators, generalkonsulat, phenoxyethoxy or phenoxyethyl,

- cycloalkenyl, substituted C6-C20the alkyl,

- heteroaromatic, substituted C6-C20the alkyl,

- heterocyclic6-C20alkyl or

- heterocyclic alkyl, substituted C3-C20the alkyl,

and where

alkyl contains carbon chain chemical bond or a heteroatom that is selected from a double bond, a triple bond. O, S, sulfinil, sulfonyl, or NR6where R6has the values listed above, and

contains as a substituent alkoxy, alkenylacyl, alkyloxy, aralkylated, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonyl, acyloxy, allylcarbamate, nitro, halogen, amino, hydroxy or carboxy, and

each R2, R3, R4and R5independently mean H, C1-C4alkyl or acyl, or their pharmaceutically acceptable salt, MES or hydrate

connections, claimed in EP 1002792 A1, nab is emer, the compound of the formula

where m is 1-9, and each R'2, R'3, R'4and R'5independently mean H, alkyl or acyl,

or their pharmaceutically acceptable salt, MES or hydrate

connection, as claimed in ER A1, for example, the compound of the formula

where W denotes H, C1-C6alkyl, C2-C6alkenyl or2-C6quinil, unsubstituted or substituted phenyl, R4O(CH2)nor C1-C6alkyl, substituted by 1-3 substituents selected from the group comprising halogen, C3-C8cycloalkyl, phenyl and phenyl substituted by a group HE,

X is H or unsubstituted or substituted alkyl straight chain,

containing p carbon atoms, or unsubstituted or substituted alkoxy, straight chain, containing (p-1) carbon atoms, e.g. substituted by 1-3 substituents selected from the group comprising From1-C6alkyl, HE1-C6alkoxy, acyloxy, amino, C1-C6alkylamino, acylamino, oxo, halogen(C1-C6)alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1-3 substituents selected from the group comprising From1-C6alkyl, HE, C1-C6alkoxy, acyl, acyloxy, amino, C1-C6alkylamino, acylamino, halogen(C1-C )alkyl and halogen,

Y represents H, C1-C6alkyl, HE, C1-C6alkoxy, acyl, acyloxy, amino, C1-C6alkylamino, acylamino, halogen(C1-C6)alkyl or halogen,

Z2means a simple link or alkylene straight chain containing q carbon atoms, each of p and q independently from each other equal to the whole number of from 1 to 20, provided that 6≤p+q≤23, m' is 1, 2 or 3, n is 2 or 3, each R ' 1, R2, R3and R4independently mean H, C1-C4alkyl or acyl, or their pharmaceutically acceptable salt, MES or hydrate

the compounds claimed in WO 02/18395, for example, the compound of formula IVa or IVb

or

where Xandmeans O, S, NR1sor a group -(CH2)nais unsubstituted or is substituted by 1-4 halogen atoms, PA is 1 or 2, R1smeans N or C1-C4alkyl, unsubstituted or substituted with halogen, R1ameans H, HE, C1-C4alkyl or O(C1-C4)alkyl, unsubstituted or substituted by 1-3 halogen atoms, R1bmeans N, HE or1-C4alkyl, unsubstituted or substituted with halogen, each R2aindependently selected from N or C1-C4the alkyl, unsubstituted or substituted with halogen, R3Ameans H, HE, halogen or O(C 1-C4)alkyl, unsubstituted or substituted with halogen, and P3bmeans H, HE, halogen, C1-C4alkyl, unsubstituted or substituted by hydroxy group, or O(C1-C4)alkyl, unsubstituted or substituted with halogen, Yameans-CH2-, -C(O)-, -CH(OH)-, -C(=NOH)-, O or S, a R4ameans4-C14alkyl or C4-C14alkenyl,

or their pharmaceutically acceptable salt, MES or hydrate

the compounds claimed in WO 02/076995, for example, the compound of formula V

where

mcis 1, 2 or 3,

Xcmeans On or a simple link,

R1cmeans H, C1-C6alkyl, optionally substituted groups HE, acyl, halogen, C3-C10cycloalkyl, phenyl or hydroxyphenyl; or means2-C6alkenyl,2-C6quinil or phenyl, optionally substituted by a group of HE, R2cmeans

where R5cmeans N or C1-C4alkyl, optionally substituted by 1, 2 or 3 halogen atoms, and R6cmeans N or C1-C4alkyl, optionally substituted with halogen,

each R3cand R4cindependently mean H, C1-C4alkyl, optionally substituted by halogen, or acyl, and

Rcmeans13-C20alkyl, which is first optionally contain in the chain an oxygen atom and which is optionally substituted by nitro group, halogen, amino, hydroxy or carboxy, or a residue of formula (a)

where R7cmeans H, C1-C4alkyl or C1-C4alkoxy, a R8cmeans substituted C1-C20alkanoyl, phenyl(C1-C14)alkyl, where C1-C14alkyl optionally substituted with halogen or the group HE; means cycloalkyl(C1-C14)alkoxy or phenyl(C1-C14)alkoxy, where cycloalkyl or phenyl optionally substituted with halogen groups, With1-C4alkyl and/or C1-C4alkoxy, phenyl(C1-C14)alkoxy(C1-C14)alkyl, phenoxy(C1-C14)alkoxy or phenoxy(C1-C14)alkyl,

Rcalso means the residue of formula (a), where R8cmeans1-C14alkoxy, if R1cmeans1-C4alkyl, C2-C6alkenyl or2-C6quinil,

or the compound of formula VI

where

nxis 2, 3 or 4,

R1xmeans H1-C6alkyl, optionally substituted groups HE, acyl, halogen, cycloalkyl, phenyl or hydroxyphenyl; means2-C6alkenyl,3-C6quinil or phenyl, optionally substituted by a group HE,

R2xmeans H, C1-C4alkyl or acyl,

each R3x and R4xindependently mean H, C1-C4alkyl, optionally substituted by a group halogen or acyl,

R5xmeans H, C1-C4alkyl or C1-C4alkoxy, and

R6xmeans C1-C20alkanoyl substituted group cycloalkyl; means cycloalkyl(C1-C14)alkoxy, where cycloalkyl optionally substituted with halogen groups, With1-C4alkyl and/or C1-C4alkoxy; means phenyl(C1-C14)alkoxy, where phenyl optionally substituted with halogen groups, With1-C4alkyl and/or C1-C4alkoxy,

R6xalso means4-C14alkoxy, if R1xmeans2-C4alkyl, substituted by a group HE or pentyloxy or hexyloxy, if R1xmeans1-C4alkyl,

provided that P6xdoes not mean phenylbutyrate, if R5x represents N or R1xmeans methyl,

or their pharmaceutically acceptable salt, MES or hydrate

the compounds claimed in WO 02/06268 A1, for example, the compound of formula VII

where each R1dand R2dindependently denotes H or aminosidine group, R3dmeans hydrogen, hydroxyamino group or a residue of the formula

R4dmeans (ness.)alkyl,

nd an integer 1-6,

Xdmeans ethylene, vinile, ethynylene, a group of formula-D-CH2(where D is carbonyl, -CH(OH)-, O, S or N), aryl or aryl substituted by one to three substituents selected from group a indicated below,

Ydmeans simple link1-C10alkylen,1-C10alkylene substituted with one to three substituents selected from groups a and b, C1-C10alkylen, containing in the middle or end fragment carbon chain atoms are O or S, or C1-C10alkylen, containing in the middle or end fragment carbon chain atoms are O or S, substituted by one to three substituents selected from groups a and b,

R5dmeans hydrogen, cycloalkyl, aryl, heterocycle, cycloalkyl substituted with one to three substituents selected from groups a and b, aryl, substituted by one to three substituents selected from groups a and b, or a heterocycle substituted with one to three substituents selected from groups a and b,

each R8dand R7dindependently denotes H or Deputy, selected from group a,

each R8dand R9dindependently denotes H or C1-C4alkyl, optionally substituted with halogen,

group a consists of halogen, (ness.)alkyl, halogen(ness.)alkyl,

(ness.)alkoxy, (ness.)alkylthio, carboxyl, (ness.)alkoxycarbonyl, hydroxy, (n is ZS.)aliphatic acyl, amino, mono(ness.)alkylamino, di(ness.)alkylamino, (ness.)aliphatic, acylamino, cyano or nitro, and

"group b" includes cycloalkyl, aryl, heterocycle, each of which is optionally substituted with one to three substituents selected from group a,

provided that if R5dmeans hydrogen, Ydmeans of a simple bond or a C1-C10alkylen straight chain,

or their pharmaceutically acceptable salt or ester,

connection stated in JP-14316985 (JP 2002316985), for example, the compound of formula VIII

where R1e, R2e, R3e, R4e, R5e, R6e, R7eneXeand Yehave the values listed in the JP-14316985,

or their pharmaceutically acceptable salt, MES, or a hydrate or ester,

the compounds claimed in WO 03/29184 and WO 03/29205, for example, the compounds of formula IX

where Xfmeans O or S, a R1f, R2f, R3fand nfhave the meanings as stated in WO 03/29184 and WO 03/29205, each R4fand R5findependently denotes H or a residue of the formula

where each R8fand R9findependently denotes H or C1-C4alkyl, optionally substituted with halogen,

for example, 2-amino-2-[4-(3-benzyloxyphenyl)-2-chlorophenyl]propyl-1,3-propandiol or 2 and the Ino-2-[4-(benzyloxyphenyl)-2-chlorophenyl]propyl-1,3-propandiol, or their pharmaceutically acceptable salt, MES or hydrate

the compounds claimed in WO 03/062252 A1, for example, the compound of formula X'

where

Ar denotes phenyl or naphthyl, each mgand ngindependently equal to 0 or 1, And is chosen from the group comprising COOH, RHO3H2, PO2H, SO3H, PO(C1-C3alkyl)and 1H-tetrazol-5-yl, each of R1gand R2gindependently denotes H, halogen, HE, COOH or C1-C4alkyl, optionally substituted with halogen, R3gmeans N or C1-C4alkyl, optionally substituted with halogen or a group, each R4gindependently denotes a halogen or optionally halogen(C1-C4)alkyl or halo(C1-C3)alkoxy, and each of Rgand M has one of the meanings specified for compounds b and C, respectively, in WO 03/062252 A1,

or their pharmaceutically acceptable salt, MES or hydrate

the compounds claimed in WO 03/062248 A2, for example, the compound of formula XI

where Ar denotes phenyl or naphthyl, n is 2, 3 or 4, And means COOH, 1H-tetrazol-5-yl, RHO3H2, RHO2H2, -SO3H or PO(R5h)OH, where R5hselected from the group including1-C4alkyl, hydroxy(C1-C4)alkyl, phenyl, -CO-(C1-C3)alkoxy is-CH(OH)-phenyl, where specified phenyl, or phenyl group optionally is substituted; each R1hand R2hindependently denotes H, halogen, HE, COOH, or optionally halogen(C1-C6)alkyl or halogenfree, P3hmeans N or C1-C4alkyl, optionally substituted with halogen and/or group of each R4hindependent means halogen, HE, COOH, C1-C4alkyl, S(O)0,1 or 2(C1-C3)alkyl, C1-C3alkoxy, C3-C6cycloalkene, aryl or Alcoxy, where the alkyl groups optionally substituted by 1-3 halogen atoms, and each Rgand M has one of the meanings specified for compounds b and C, respectively, in WO 03/062248 A2,

the compounds claimed in WO 04/026817 As, for example, the compounds of formula XII

where R1jmeans halogen, trihalomethyl,1-C4alkyl, C1-C4alkoxy, C1-C4alkylthio,1-C4alkylsulfonyl,1-C4alkylsulfonyl, aralkyl, optionally substituted, phenoxy or aralkylated,

R2jmeans H, halogen, trihalomethyl,1-C4alkyl, C1-C4alkoxy, aralkyl or aralkylated,

R3jmeans H, halogen, CF3With1-C4alkyl, C1-C4alkoxy, C1-C4alkylthio or benzyl is XI,

R4jmeans H, C1-C4alkyl, phenyl, optionally substituted benzyl or benzoyl, or aliphatic (ness.)With1-C5acyl,

R5jmeans N, monohalogenated,1-C4alkyl, C1-C4alkoxymethyl,1-C4alkylthiomethyl, hydroxyethyl, hydroxypropyl, phenyl, aralkyl,2-C4alkenyl or quinil,

each R6jand R7jthat means independently N or C1-C4alkyl, or R7jalso means the rest of the formula

where each R8 (jand R9jindependently denotes H or C1-C4alkyl, optionally substituted with halogen,

Xjmeans O, S, SO or SO2and

njan integer from 1 to 4, for example, 2-amino-4-[4-(3-benzyloxyphenyl)-2-chlorophenyl]-2-methylbutane-1-ol or 2-amino-4-[4-(3-benzyloxyphenyl)-2-chlorophenyl]-2-ethylbutane-1-ol,

the compounds claimed in WO 04/103306A, WO 05/000833, WO 05/103309 or WO 05/113330, for example, the compounds of formula XIIIa or XIIIb

where

Akmeans COOR5kOPO(OR5k)2, PO(OR5k)2, SO2OR5k, POR5kOR5kor 1H-tetrazol-5-yl, R5kmeans N or C1-C6alkyl,

Wkmeans a chemical bond, With1-C3alkylen or2-C3linelen,

Ykmeans6-C10aryl or3-C9heteroaryl, optionally substituted by 1-3 radicals selected from the group comprising halogen, HE, NO2With1-C6alkyl, C1-C6alkoxy; means halogen(C1-C6)alkyl and halogen(C1-C6)alkoxy,

Zkmeans heterocyclic group specified in WO 04/103306 A, for example, azetidine,

R1kmeans6-C10aryl or3-C9heteroaryl, optionally substituted C1-C6alkyl, C6-C10aryl, C6-C10aryl(C1-C4)alkyl, C3-C9heteroaryl,3-C9heteroaryl(C1-C4)alkyl, C3-C8cycloalkyl,3-C8cycloalkyl(C1-C4)alkyl, C3-C8heteroseksualci or3-C8heteroseksualci(C1-C4)alkyl and any aryl, heteroaryl, cycloalkyl or heteroseksualci of

R1ksubstituted by 1-5 groups selected from the group comprising halogen, C1-C6alkyl, C1-C6alkoxy and halogen(C1-C6)alkyl or halo(C1-C6)alkoxy,

R2kmeans And, C1-C6alkyl, halogen(C1-C6)alkyl, halogen(C2-C6)alkenyl or halogen(C2-C6)quinil, and

p> each R3kor R4kindependently denotes H, halogen, HE, C1-C6alkyl, C1-C6alkoxy or halo(C1-C6)alkyl or halo(C1-C6)alkoxy,

and their N-oxides or prodrugs,

or their pharmaceutically acceptable salt, MES or hydrate.

In another embodiment, the invention is an agonist of S1P receptor intended for use according to the invention is a selective S1P1 receptor, for example, a connection that is characterized at least 20 times higher selectivity for the S1P1 receptor in comparison with the S1P3 receptor, for example, 100, 500, 1000 or 2000 times higher selectivity, and indicated the selectivity is determined by the ratio EC50for the S1P1 receptor and EU50for the S1P3 receptor, which are calculated according to the analysis of binding35S-γS. The specified connection is characterized by a value ES for binding to the S1P1 receptor of 100 nm or less according to the analysis of binding to 35S-γS. Typical agonists of the S1P1 receptor include, for example, compounds listed in the application WO 03/061567, the contents of which are incorporated into this description by reference, for example, the compound of the formula XIV or XV

or

It should be understood that when compounds of formulas I-XV sod is rgit one or more asymmetric centers in the molecule, in the present invention also includes various optical isomers and racemates, diastereoisomers and mixtures thereof. If asymmetric carbon atom in the compounds of the formula III or IVb contains amino group, the carbon atom is preferably in the R-configuration.

Compounds of the above formulas exist in free form or in salt form. Examples of pharmaceutically acceptable salts of the compounds of the above formulas include inorganic salts such as hydrochloride, hydrobromide and sulfate, salts of organic acids such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and bansilalpet or, respectively, metal salts, such as sodium, potassium, calcium and aluminium, salts of amines, such as triethylamine and salts of dibasic amino acids, such as lysine. The compounds and salts according to the present invention include hydrates and solvate.

The above acyl means the residue Ry-CO-, where Rymeans1-C6alkyl, C3-C6cycloalkyl, phenyl or phenyl(C1-C4)alkyl. Unless otherwise specified, alkyl, alkoxy, alkenyl or quinil include straight or branched chain.

If the compounds of formula I contain substituted hydrocarbon chain R1the substituents preferably include halogen, nitro, amino, hydroxy or ka is Boxing. If the hydrocarbon chain is interrupted by optionally substituted phenylene, hydrocarbon chain preferably is unsubstituted. Substituted phenylene includes substituents, preferably halogen, nitro, amino, methoxy, hydroxy or carboxy.

Preferred compounds of formula I include compounds in which R1means13-C20alkyl, optionally substituted by nitro groups, halogen, amino, hydroxy or carboxy, and more preferably compounds in which R1means phenylalkyl substituted group6-C14alkyl, optionally substituted with halogen, and an alkyl group means With1-C6alkyl, optionally substituted by a hydroxy group. More preferably R1means finals1-C6alkyl substituted in the phenyl cycle straight or branched, preferably straight With6-C14alkyl chain. With6-C14alkyl is in the ortho-, meta - or para-position, preferably in the para-position.

Preferably each R2-R5means N.

A preferred compound of formula I is 2-amino-2-tetradecyl-1,3-propandiol. First of all preferred agonist of S1P receptor formula I is FTY720, i.e. the 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in the form of a pharmaceutically when mlemos salt (in this context, the compound (A), for example, in the form of the hydrochloride:

The preferred compound of formula II is a compound in which R'2-R'5 mean hydrogen, a m is equal to 4, i.e. 2-amino-2-{2-[4-(1-oxo-5-fenilpentil)phenyl]ethyl}propane-1,3-diol in free form or in the form of pharmaceutically acceptable salts (in this context, connection), for example, in the form of hydrochloride.

The preferred compound of formula III is a compound in which W stands for CH3each R1-R3means N, Z2means ethylene, X is heptyloxy and Y means hydrogen, i.e. the 2-amino-4-(4-heptyloxy)-2-methylbutanol, in free form or in the form of pharmaceutically acceptable salts (in this context, the connection With, for example, in the form of hydrochloride. First of all preferred the R-enantiomer.

The preferred compound of formula IVa is FTY720 phosphate (R2ameans N, R3aIT means, Xandmeans Of, R1aand R1bmean IT). The preferred compound of formula IVb phosphate compound With (R2ameans N, R3bIT means, Xandmeans Of, R1aand R1bmean IT, Yameans Of and R4ameans heptyl). The preferred compound of formula V is phosphate compounds Century

The preferred compound of formula V is mono[(R)-2-amino-2-IU the Il-4-(4-pentyloxide)butyl]ester of phosphoric acid.

The preferred compound of formula VIII is (2K)-2-amino-4-[3-(4-cyclohexylmethyl)benzo[b]Tien-6-yl]-2-methylbutane-1-ol.

The preferred compound of formula IX is a compound in which Xfmeans S or O, R1fmeans benzyloxy, R2f, R4fand R5fjevery means N, R3fmean Cl and nfequal to 2.

The preferred compound of formula XII is a compound in which Xjmeans S or O, R1jmeans benzyloxy, R2j, R4j, R6jand R7jevery means N, R3jmeans Cl, R5jmeans hydroxyethyl or hydroxypropyl, a njequal to 2.

The binding affinity of agonists of the receptor S1P individual S1P receptors man was determined using the following methods of analysis.

Transient transfection of cells NC S1P receptors person

The EDG receptors and Giproteins were cloned and mixed equal amounts of the four cDNA for the receptor EDG, Giα, Gi-β and Gi-γ and used for transfection of monolayers of cells NC by precipitation with calcium phosphate (.Wigler, etc.. Cell. 11;223 and (1977), DS Im and others, Mol. Pharmacol. 57;753 (2000). The mixture of DNA containing 25 μg DNA and 0.25 M CaCl2, was added to the HEPES buffer solution containing 2 mm Na2HPO4. Subconfluent monolayers of cells NEC added a 25 mm solution of chloroquine and C is the sediment DNA was added to cells. After 4 h, the monolayers were washed in phosphate-saline buffer solution was added to the medium (90% modified essential medium, Dabelko (DMEM) and F-12, 1:1+10% fetal calf serum). Cells were harvested 48-72 h after addition of the DNA in a buffer solution of NMA (20 mm HEPES, 5 mm MgCl2, 1 mm EDTA, pH 7.4), containing 10% sucrose in an ice bath and was destroyed in homogenization. After centrifugation at 800×g supernatant was diluted with buffer solution, NME in the absence of sucrose and centrifuged at 100000×g for 1 h the precipitate is again homogenized and centrifuged for a further 1 h at 100000×g. The precipitate of the crude membrane fraction again suspended in a buffer solution of NMA containing sucrose was divided into aliquot parts and rapidly frozen by immersion in liquid nitrogen, Membrane fraction was stored at -70°C. the protein Concentration was determined spectrophotometrically by the method of Bradford.

Analysis of the binding γS using membrane fractions of the S1P receptor/HEK293

Analysis of the binding γS were performed as described in article D.S. Im and others, Mol. Pharmacol. 57:753 (2000). Mediated by ligand binding γS with G-proteins was determined in buffer solution to bind GTP (50 mm HEPES, 100 mm Nad, 10 mm MgCl2, pH 7.5) with 25 μg of membrane fraction isolated from temporarily transfection cells NC IN membranes the th fraction was added to the ligand in the presence of 10 μm GDF and 0.1 nm [ 35S]γS (1200 CI/mmol) and incubated at 30°C for 30 minutes Associated γS was separated from the unbound to the collector cells Brandel (Gaitherburg, MD) and radioactivity was measured by liquid scintillation the counter.

The compounds of formula As described, for example, in applications WO 94/09010, WO 95/16691, WO 96/41807, USP 5362718 or WO 99/15530 included in this description as a reference. They can be obtained by known methods or analogous manner as described in the above applications.

A series of additional embodiments of the invention includes the following objects:

1.1. A method of treating ophthalmic diseases, which is that suffering from a disease to a subject is administered a therapeutically effective amount of an agonist of S1P receptor.

The preferred agonist of S1P receptor is a compound a, b or C, (2R)-2-amino-4-[3-(4-cyclohexylmethyl)benzo[b]Tien-6-yl]-2-methylbutane-1-ol, or a compound of formula IX, where Xfmeans S or O, R1fmeans benzyloxy, R2f, R4fand R3fjevery means N, R3fmean Cl and nfequal to 2.

The term "introduction"used in this context, means oral, rectal, parenteral and local introduction. The most preferred method of introduction is the local introduction.

Effectiveness in the treatment of these ophthalmolo the systematic diseases evaluated, for example, using the following models,

1) Genetic animal models with retinal degeneration, such as a mouse rd (as described in Li et al., Invest. Ophthalmol. Vis. Sci. 42: 2981-2989 (2001), mouse Rpe65 deficiency (Van Hooser and others, PNAS 97: 8623-8628 (2000)), RCS rats (Faktorovich et al., Nature 347:83-86 (1990)), mouse rds (Ali et al., Nature Genetics 25: 306-310 (2000)), dogs rcdl (Suber and others, PNAS 90: 3968-3972(1993)).

2) Experimental retinal degeneration induced by the following factors:

- light irradiation of mice (Wenzel and others, Invest. Ophthalmol. Vis. Sci, 42:1653-1659 (2001)) or rats (Faktorovich, etc., J. Neurosci: 12:3554-3567 (1992)),

introduction N-methyl-N-nitrosoanatabine (kiuchi's and others, Exp.Eye Res. 74; 383-392 (2002)) or sodium Iodate (Sorsby & Harding, Vision Res. 2:139-148 (1962)).

3) Experimental model of damage to the optic nerve (ON)

the destruction ON mice (Levkovitch-Verbin and others, Invest. Ophthalmol. Vis. Sci. 41:4169-4174 (2000)) and in rats (Yoles and Schwartz, Exp. Neurol. 153:1-7 (1998)),

- transverse incision ON rats (as described in Martin et al., Invest. Ophthalmol. Vis. Sci. 43: 2236-2243 (2002), Solomon and others, J. Neurosci. Methods 70:21-25 (1996)),

experimental temporary (acute) ischemia of the retina in rats after ligation of the eye of the vessel (as described in article Lafuente and others, Invest. Ophthalmol. Vis. Sci. 42:2074-2084 (2001)) or catheterization of the anterior chamber of the eyeball (Buchi, etc., Ophthalmologica 203:138-147 (1991)),

- intraocular injection of endothelin-1 in rats (Stokely and others, Invest. Ophthalmol. Vis. Sci. 43: 3223-3230 (2002)) or rabbits (Takei et al., Graefes Arch. Clin. Exp. Ophthalmol 231:476-481 (993)).

The pharmaceutical compositions according to the invention include, for example, in the case of forms for enteral or parenteral administration, from about 5% to about 90%, preferably from about 10% to about 80% active ingredient. The pharmaceutical compositions according to the invention receives, for example, in the case of forms for enteral or parenteral administration in the form of standard dosage forms, such as pills, tablets, capsules or suppositories, and also ampoules. Get them in a known manner, for example, a standard mixing, granulating, coating, dissolving or lyophilization. For example, pharmaceutical compositions for oral administration obtained when mixing the active ingredient with solid carriers, optionally granulating the resulting mixture and processing the mixture or granules, if necessary after addition of appropriate excipients in the core of tablets or pills.

Suitable carriers are primarily fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose derivatives and/or calcium phosphates, for example tricalcium phosphate or calcium phosphate, and also binders, such as starch pastes, obtained, for example, from corn, wheat, rice or potato starch, gelatin, shall ramakant, the methylcellulose and/or polyvinylpyrrolidone, and, if necessary, dezintegriruetsja agents, such as the abovementioned starches, and carboximetilkrahmal, crosslinked polyvinylpyrrolidone, agar, alginic acid or its salts, such as sodium alginate. The excipients are primarily agents that increase the fluidity, conditioners yield and oil, for example, silicic acid, stearic acid or their salts, such as magnesium stearate or calcium, and/or polyethylene glycol. The dragee cores suitable cover, not necessarily intersolubility shell, with use concentrated solutions of Sugars, including Arabian gum, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or solutions for coating in a suitable organic solvent or mixtures of solvents, or for applying intersolubility shells use solutions suitable preparations of cellulose such as cellulose acetate phthalate or phthalate of hydroxypropylmethylcellulose. In the coating of tablets or pills can also add dyes or pigments for the purpose of identification of various dosage forms and different doses of active ingredient.

Other oral pharmaceutical compositions include hard gelatin capsules, and also soft sealed capsules made of gelatin and PL is tificate, such as glycerol or sorbitol. Hard gelatin capsules may include the active ingredient in the form of granules, for example, in a mixture with fillers, such as lactose, binders, such as starches, and/or galantai, such as talc or magnesium stearate, and, if necessary, with stabilizers. In the case of soft gelatin capsules the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols, and if necessary to add stabilizers.

Suitable rectally pharmaceutical compositions are suppositories containing a combination of the active ingredient with a base material for suppositories. Suitable materials bases for suppositories include, for example, natural or synthetic triglycerides, hydrocarbons of the paraffin series, glycols or higher alcohols. It is possible to use gelatin rectal capsules comprising the combination of the active ingredient with a base material. Suitable core materials include, for example, liquid triglycerides, polyethylene glycols and hydrocarbons of the paraffin series.

For parenteral administration by infusion and/or injection can be used aqueous solutions of the active ingredient in water-soluble form, for example, in the form of water-soluble is th salt, and also suspensions of the active ingredient, can be used suitable lipophilic solvents or carriers, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example, etiloleat or triglycerides, or aqueous suspension comprising increasing the viscosity agents, for example, sodium carboxymethyl cellulose, sorbitol and/or dextran, and optionally stabilizers.

Connections can also wadati local way in the eye or eye area, for example, in the form of eye drops, ophthalmic suspensions or ointments, as subconjunctivally, peribulbar, retro-bulbar or vnutrepenialnyh of inyecci, and these compounds can be used for delayed delivery, such as conductively microcamera, microspheres or other devices for delayed delivery in periocularly or eye region.

The dose of active ingredient depends on the species of warm-blooded animal, age and individual condition, and on a way of introduction. Usually approximate daily dose for oral administration to a patient weighing approximately 75 kg is from about 10 mg to about 500 mg. In the case of the local introduction of suitable approximate daily dose varies from 0.001 to 10 mg depending on the method is doing. The amount of active ingredient in the composition for local injection is usually lower compared to oral or parenteral formulations. Typically, the concentration of active agent in the composition for local introduction of changes in the range of from 0.01% to 10%, based on the total weight of the composition.

1. The use of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (compound A), its individual isomers or mixtures of these isomers, or pharmaceutically acceptable salts, solvate and hydrate to obtain drugs for the treatment of the consequences of the transplant corneal or refractive surgery on the cornea.

2. The treatment effects of transplantation of corneal or refractive surgery on the cornea of a subject in need of such treatment, comprising the introduction of a specified subject a therapeutically effective amount of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (compound A), its individual isomers or mixtures of these isomers, or pharmaceutically acceptable salts, solvate and hydrate.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and may be used for treating septic wounds and burns. A composition possessing antibacterial action contains active metal biocomplexes with 5-nitroimidazole and β-pyridine carboxylic acid and a base providing a soft dosage form. As a gelling agent, there may be used modified cellulose derivatives, additionally comprising methyl monosilane hydrogel (enterosgel) and/or polyvinylpyrrolidone, or an alloy of polyethylene oxide-400 and polyethylene oxide-1500. As a mixture of hydrophilic substances, the base contains substances specified in a group of: polyethylene oxides, dimexide, glycerol and aerosol, may comprise at least one target additive of: anaesthetic - trimecaine, pyrromecaine, lidocaine, or a mixture thereof, a repair process stimulator - methyluracil, acemine, solcoseryl, Spirulina microalgae (Spirulina platensis), or a mixture thereof, antiseptic - miramistine, chlorhexidine digluconate, dioxidine or a mixture thereof. The composition is presented in the form of an ointment or gel.

EFFECT: invention provides the improved microcirculation in wound tissues, as well as anti-inflammatory action, repair process stimulation.

5 cl, 6 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to microencapsulation of drugs through the example of rivanol which can be used as an antimicrobial, antifungal topical preparation. A method for preparing microcaplues of rivanol in a water-soluble polymer representing polyvinyl alcohol or polyvinyl pyrrolidone is implemented by physical-chemical precipitation with a solvent wherein a precipitant is acetone. The process is carried out at 25°C with no special equipment required.

EFFECT: method for preparing the microcapsules of rivanol provides simplifying the process of microencapsulation.

13 dwg, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to surgery and can be used for prevention of postoperative wound suppuration. For this purpose perforated tube is placed on the bottom of wound surface and its ends are brought outside through formed on patient's skin counteropenings with further fixation of tube to skin and their hermetic closing. Starting from the following after operation day and further on 2-3 postoperative days, 100-150 ml of antiseptic solution are forced fractionally once daily into wound through one of tube ends, the second one being closed. Intra-wound hydraulic compression of antiseptic is created and increased to such a degree that partial leakage of solution between skin sutures takes place. After that, compressed second end of tube is opened and all antiseptic is drained from wound. Then, remaining wound and drainage tube content is aspirated completely. After that from 3-4 to 9-10 days washing of wound in flow manner without element of hydraulic compression is continued on the same daily single time basis.

EFFECT: method makes it possible to reduce number of postoperative wound suppurations, thus ensuring wound healing with primary intention.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new substituted phenoxyacetic acids of general formula 1 possessing the properties of a selective antagonist inhibiting A2a adenosine receptor activity. The compounds may be used in preventing and treating central nervous system diseases, such as cognitive disorders, Parkinson's disease, or depression, tumour diseases, inflammatory processes. The invention also refers to an agent for intensification of immune response or action of drug preparations in the combination treatment of the diseases. In general formula

, R1, R2 and R3, optionally simultaneously represent hydrogen. C1-C5alkyl, C3-C5alkenyl or C3-C5-alkynyl; R4 represents hydrogen, a halogen atom, hydroxyl, C1-C3alkyl, C1-C3alkyloxy; R5 represents hydrogen, C1-C3alkyl, the group -C(O)R6;R6 represents hydroxyl, C1-C5alkyloxy, C3-C5alkenyloxy, C3-C5alkynyloxy optionally substituted by an amino group wherein the substitutes optionally identical are specified in hydrogen, C1-C3alkyl optionally substituted by a mono- or dialkylaminogroup, an alkyloxygroup, 5-6-member saturated heterocyclyl containing 1-2 heteroatoms specified in nitrogen and oxygen: pyridyl, phenyl optionally substituted by 1-3 methoxygroups; or optionally substituted 6-member, optionally annulated with 5-member unsaturated heterocyclyl, saturated heterocyclyl containing 2 nitrogen atoms wherein the substitutes are specified in C1-C3alkyl optionally substituted by 5- member heteroaryl containing 1-3 heteroatoms specified in nitrogen and oxygen; or 6- member optionally saturated heterocyclyl containing 1-2 nitrogen atom optionally substituted by C1-C3alkyl, oxo, optionally substituted by phenyl; a dashed line with an accompanying continuous line represents a single, double or triple bond.

EFFECT: preparing new substituted phenoxyacetic acids of general formula 1 possessing the properties of the selective agonist inhibiting A2a adenosine receptor activity.

15 cl, 3 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely surgery, and may be used for treating abscesses, festered residual cavities and ganglions. The cavity contents are daily aspirated through a catheter in laboratory animals (male rabbits) suffering simulated hepatic abscesses of the diameter of 1.5 cm. Then the abscess cavity is filled with copper nanoparticle suspension in 0.9% physiologic saline of the concentration of 1 mcg/ml. A laser light guide provided with a diffuser is placed in the cavity centre to expose to laser light at wave length 630 nm in a continuous mode, output power 35 mWt for 3 minutes.

EFFECT: method enables intensifying antimicrobial action of copper nanoparticles under laser light, starting treating without specifying an agent, suppressing pathogenic microogranisms over a relatively short time, stimulating repair processes successfully, reducing toxic action of nanoparticles on macroorganism, considerably reducing a length of treating festered cavities.

2 dwg, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a sorption plate containing furacilin, differing by the fact that a process for making it involves using the additional excipient therapeutic powdered Kimmeridge clay (blue) Undorovskaya, chitosan solution, dimethylsulphoxide, glycerol, acetic acid and purified water in the following proportions (wt %): furacilin 0.75 - 1.5; dimethylsulphoxide 2.5 - 5.0; blue clay 7.5 - 8.5; 98% acetic acid 1.5 - 3.0; chitosan 2.5 - 4.5; glycerol (7.5 - 8.5); purified water up to 100.0.

EFFECT: invention provides making sorption plates for ensuring wound-healing, anti-inflammatory action in medical practice and higher sorption activity.

9 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely otorhinolaryngology and may be used for treating chronic tonsillitis. That is ensured by ultrasound sanation of tonsils with the use of 0.05% chlorhexidine followed by Lugol's solution phonophoresis. The ultrasound sanation involves exposure on each tonsil for 60 seconds. The phonophoresis procedure involves contact exposure on each tonsil for 20 seconds. The therapeutic course is 10 daily procedures.

EFFECT: method provides microbiocoenosis recovery, anti-inflammatory action, reduced cicatricle changes in tonsil tissues, as well as mediated action on immunological processes.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically dermatovenerology. Baneocin ointment is used as an agent for topical treatment of infiltrative-suppurant trichophytosis capitis for 48 hours with underlying conventional systemic antimycotic therapy. The agent shows manifested antimicrobial, anti-inflammatory, resolving and regenerative effect.

EFFECT: invention extends the range of topical products for treating infiltrative-suppurant trichophytosis capitis.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely surgery, and concerns skin and soft tissue wound and wound infection healing. That is ensured by using tissue coatings impregnated by a phytotherapeutic substrate in the following proportions: eucalyptus leave extract - 30.0 gram; pot marigold blossom extract - 10.0 gram; purple Echinacea herb extract - 10.0 gram; distilled water to 1000.0 ml.

EFFECT: method provides higher clinical effectiveness ensured by an ability of the phytotherapeutic substrate to clean the wounds fast from necrotic elements and providing a faster process of natural healing.

3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. A method involves daily abscess cavity sanitation, sanitation liquid evacuation. Then the abscess cavity is filled with a copper nanoparticle suspension in physiologic saline in the concentration of 100 mcg/ml, exposing for 30 min to be evacuated thereafter.

EFFECT: method provides fast and effective growth inhibition of pathogens in the abscess cavity, intensifies hepatic regeneration, normalises hepatic function.

3 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a pharmaceutical composition in the form of a spray for treating a damage by non-lethal irritants (e.g. pelargonic acid morpholide), containing pediphene in the following proportions, wt/volume %: pediphene hydrochloride 0.01-10.0; sodium chloride 0.1-10.0; water for injections up to 100 ml. What is shown is the efficacy of pediphene in compliance with the declared application ensured by the local anaesthetic effect of the drugs.

EFFECT: drug preparation has no allergenic and immunotoxic properties.

3 dwg, 40 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to ophthalmology and can be applied for treatment of traumatic and dystrophic injuries of eye cornea. For this purpose peptide fragments of protein S100b - SP2 and/or SP3 in concentrations 10-6 M are introduced in conjunctive cavity or in endonasal way. Introduction is realised daily two times per day during 10 days.

EFFECT: method ensures fast and high-quality restoration of injured zone of cornea due to stimulation of regenerative-reparative processes in cornea.

3 ex, 2 cl

FIELD: medicine.

SUBSTANCE: invention refers to ophthalmology and may be used for treating degenerative and dystrophic retinal diseases. That is ensured by subcutaneous introduction of the preparation Coenzyme compositum 0.5 ml within the mastoid process, the preparation Lymphomyosot - within the temporal fossa, as well as by parabulbar introduction of the preparation Placenta compositum. The course is 10 sessions every second day 1-2 days a year. The introductions are double-sided if the retina in both eyes is involved.

EFFECT: invention provides improving the peripheral circulation in the eyes, increasing visual acuity due to the integrated effect of the drugs administered.

2 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutical formulations and methods for preparing them of lipids for ophthalmological application containing a phospholipid ingredient containing natural zwitterion phospholipids, and an oil ingredient containing natural oil-in-water emulsions. The oil ingredient and phospholipid ingredient are preferentially related as 3:1; the phospholipid ingredient is found in the amount of 0.1%-5%, and the oil ingredient is found in the amount of 0.3%-15%.

EFFECT: group of inventions provides ocular drug delivery applicable for treating dry eye syndrome; it has an ability to recover the lipid lachrymal film layer, inhibits the inflammatory element observed.

37 cl, 19 tbl, 4 ex, 7 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to ophthalmology, and is intended for treatment of eye burns. For this purpose instillations of eye drops of 2% of mexidol solution in conjunctival cavity is carried out 2-4 times per day immediately after burn and during the following two weeks.

EFFECT: chosen concentration of mexidol and mode of introduction in claimed method ensure effective treatment of burns at early terms after trauma, including by normalisation of activity of enzymes and proteins, which take part in processes of reparation and regeneration, fast growth of vessels and recovery of microcirculation, as well as prevention of formation of deep ulcers of cornea.

9 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to ophthalmology, and can be applied for cell therapy in case of different ophthalmopathologies, accompanied by dystrophic and atrophic processes as well. Three-component complex for cell therapy contains mesenchymal stem cells, labeled by magnetic microparticles. Cells are translocated into biological or synthetic fine-pore material, which in its turn is strongly fastened with polymer magnetic material with induction of constant magnetic field 1.5 mT, with multipolar reverse magnetisation.

EFFECT: invention ensures directed supply of stem cells to pathological nidus and holding stem cells for specified time with creation of possibility of giving complex any form, size and space configuration, suitable for extrascleral implantation to any area of eyeball or visual.

2 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I): and pharmaceutically acceptable salts, diastereoisomers and enantiomers thereof, wherein D is specified in a group consisting of , and , M is ; Z is -O-; Ar is a 6-member aromatic ring system substituted by 0 to 4 R2 groups; and G is or ; the other radical values are presented in cl.1 of the patent claim, as well as to using them for inhibiting protein tyrosine kinase inhibition.

EFFECT: preparing the new compounds.

14 cl, 33 tbl, 191 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to ophthalmology, and can be used for treating luetic optic neuropathy. That is ensured by subconjunctival administration of Cefazolin 0.3-0.5 mg. That is combined with intramuscular injection of Gliatilin 2.0-4.9 ml, 1-3% Glutoxim 2.0 ml and Milgamma 1.0-2.0 ml. Dexazon 0.5 ml is introduced parabulbarly. The preparations are introduced once a day for 10 days. Additionally, starting with the first therapeutic day, 10 sessions of percutaneous transcranial magnetic stimulation of the optic nerves are conducted daily.

EFFECT: method provides improving the visual functions and eliminating the complications of the central nervous system due to the integrated treatment developed with the severity of the pathological process in these patients.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to ophthalmology, and may be used to treat viral ocular diseases. That is ensured by the interferon (INF) status assay, namely evaluating alpha-INF production, gamma-INF production, serum INF titre, spontaneous INF in the reaction in vitro. The derived data collection and the presence of clinical manifestations enable stating the viral diseases thereby choosing the therapeutic approach.

EFFECT: invention enables normalising the interferon status in the patients with the viral ophthalmic diseases.

4 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly ophthalmology, and may be used for treating corneal ulcer. That is ensured by the integrated treatment including the intake of Lymphomyosot 10 drops in 50-100 ml of water three times a day for three weeks; Traumel 1 tablet 3 times daily for three weeks sublingually; 10 subcutaneous 2.2 ml injections twice a week: Mucosa Compositum, Solidago Compositum, Coenzyme Compositum; 10 subcutaneous 2.2 ml injections of Traumeel every second day; eye instillations of Oculoheel, okulohelya, Mydriacyl and colloidal silver 2 drops 3 times a day for 10 days; sea buckthorn oil under the eyelid 3 times a day for 10 days; Solcoseryl ointment or gel in the conjunctival cavity until observing the complete epithelialisation, and also the radiotherapy course from the first day of treatment in a dose of 50 cGy daily, within 5 sessions. The severe corneal opacities require the additional 5 sessions of the repeated radiotherapy course in a dose of 500 cGy daily following the 5-session radiotherapy course in a dose of 50 cGy three months later.

EFFECT: method enables increasing or recovering the visual acuity ensured by ulcer epithelisation with no side effects.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to a sustained-release tapentadol composition also containing a second active agent, wherein the above second active agent is specified in tramadol, pregabalin, gabapentyl, or pharmaceutically acceptable salts thereof. The given composition may be used to prepare a therapeutic agent for pain management. Besides, the present invention refers to a method of managing pain and conditions related to pain, by administering the given composition. The given invention also refers to a kit including a sustained-release tapentadol formulation also containing the second active agent, wherein the above second active agent is specified in tramadol, pregabalin, gabapentyl or pharmaceutically acceptable salts thereof.

EFFECT: reducing side effects.

15 cl, 19 tbl, 16 ex, 6 dwg

Up!