Method and composition for treating macular degeneration

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely to ophthalmology, and aims at treating macular degeneration in a mammal. A pharmaceutical composition for treating macular degeneration in a mammal contains an effective amount of 13,14-dihydro-15-keto-20-ethyl-prostaglandin F isopropyl ester. The above ophthalmic composition is presented in the form of eye drops, which are sterile, preservative-free as a single-use dosage form. What is also provided is a method of treating macular degeneration in a mammal that involves administering an effective amount of 13,14-dihydro-15-keto-20-ethyl-prostaglandin F isopropyl ester into an individual in need thereof.

EFFECT: using declared group of inventions provides effective treatment of macular degeneration in a mammal.

11 cl, 1 tbl, 2 dwg, 2 ex

 

The technical field to which the invention relates

The present invention relates to a method and composition for the treatment of macular degeneration, particularly age-related macular degeneration, particularly the dry form of age-related macular degeneration.

The level of technology

Macular degeneration is caused by destruction of the Central part of the retina, the inside back layer of the eye that captures the images we see and sends them via the optic nerve from the eye to the brain. The Central part of the retina known as the macula, is responsible for focusing Central vision in the eye that controls our ability to read, drive, recognize faces or colors, and see objects in great detail.

Age-related macular degeneration (AMD) is the leading cause of legal blindness among people over 65. People suffering from AMD, lose the ability to see fine details. The patient is able to see the edges of the image, but the middle image is blank or appears as a dark spot called a scotoma. This condition can occur in one or both eyes.

There are two main forms of AMD, known as "wet AMD and dry AMD." Dry AMD is also called nonneovascular or nonexudative AMD. From about 85% to 90% of patients�s with AMD have dry AMD (atrophic) type. Patients with this form of AMD may have good Central vision (20/40 or better), but they have significant functional limitations. In dry AMD the destruction of the retina is associated with the formation of drusen under the yellow spot. Drusen are accumulations of acellular (small yellow deposits), amorphous residue, which lies beneath the basal membrane of the retinal pigment epithelium. This phenomenon leads to thinning and drying of the macula, causing the macula loses its function. Currently medicines against dry AMD is unknown, and there is no approved method for the treatment of this condition by pharmacological means. Consequently, there is an acute need for treatment that reduces or limits the macular degeneration.

Prostaglandins (below in this application, referred to as PG) are members of class of organic carboxylic acids, which are contained in tissues or organs of human or other mammals, and provide a physiological effect. PG found in nature (primary PG) have, as their common structural properties, carbon skeleton prostanoids acid of formula (A):

On the other hand, some of synthetic analogues of the primary PG have modified carbon skeletons. P�ruinae PG classified as PGA, PGB, PGC, PGD, PGE, PGF, PGG, PGH, PGI and PGJ in accordance with the structure of the five-membered ring, and further divided into the following three types by the number and position of unsaturated bonds in the carbon chain:

Subscript 1: 13,14-unsaturated-15-HE

Subscript 2: 5,6 - and 13,14-Dimensiona-15-HE

Subscript 3: 5,6-, 13,14 - and 17,18-trikanasana-15-HE.

Additionally, PGF subdivide, in accordance with the configuration of the hydroxyl group at 9-position, α-type (the hydroxyl group is in α-configuration) and β type (the hydroxyl group is in the β-configuration).

In addition, some 15-keto PG (i.e. those that have an oxo group at position 15 instead of the hydroxyl group) and 13,14-dihydro-15-keto-PG (i.e. those that have a single bond between positions 13 and 14) are known as substances produced in nature by the action of enzymes in the process of in vivo metabolism of the primary PG and have some therapeutic effect. For example, it is known that 15-keto-prostaglandins are used to treat elevated intraocular pressure and glaucoma (U.S. patents Nos. 5,001,153 and 5,151,444, these publications are incorporated in this application by reference).

However, it is unknown how 15-keto-prostaglandin effect on macular degeneration, especially for AMD, especially on dry AMD.

Disclosure of the invention

The purpose of the present invention zaklyuche�Xia in providing methods and compositions for the treatment of macular degeneration, especially age-related macular degeneration and, in particular, dry age-related macular degeneration in mammals, including humans.

The present invention relates to a method for treating macular degeneration in a mammal, which comprises administering to the needy in this subject an effective amount of 15-keto-prostaglandin.

Particularly the present invention relates to a method for the treatment of age-related macular degeneration in a mammal, which comprises administering to the needy in this subject an effective amount of 15-keto-prostaglandin.

In particular the present invention relates to a method for treating dry age-related macular degeneration in a mammal, which comprises administering to the needy in this subject an effective amount of 15-keto-prostaglandin.

In addition, the present invention relates to pharmaceutical compositions for the treatment of macular degeneration, particularly age-related macular degeneration and, in particular, dry age-related macular degeneration in a mammal, which comprises an effective amount of 15-keto-prostaglandin.

The present invention also relates to the use of 15-keto-prostaglandin for the manufacture of pharmaceutical compositions for the treatment of macular degeneration, particularly age-deg�neratzia yellow spots and, in particular, dry age-related macular degeneration in a mammal.

Brief description of the drawings

Figure 1 depicts a graph showing the effect of isopropylnaphthalene loss of transepithelial resistance (TER) of cells of the retinal pigment epithelium under the action of tert-butylhydroperoxide (tBH).

Figure 2 depicts a graph showing the effect of isopropylnaphthalene to degeneration of the cells of the retinal pigment epithelium under the action of tert-butylhydroperoxide (tBH).

The implementation of the invention

In the present invention are 15-keto-prostaglandin" (below in this application, referred to as "15-keto-PG") can include any derivatives or analogs (including substituted derivatives) of compounds having oxoprop 15-position of the carbon skeleton prostanoids acid is a hydroxyl group, regardless of the configuration of the five-membered ring, the number of double bonds, presence or absence of a Deputy, or any other modification in the α - or ω-chain.

The nomenclature of 15-keto-PG used in this application are based on the numbering system prostanoids acid represented in the above formula (A).

Formula (a) shows the basic carbon skeleton consisting of the C-20 carbon atoms, but the connection 15-keto-PG in the present invention is not limited to those�, which have the same number of carbon atoms. In the formula (A) numbering of carbon atoms which form the basic skeleton of the PG compounds starts at the carboxylic acid (numbered 1), and the carbon atoms in α-chain are numbered 2 to 7 towards the five-membered ring, the carbon atoms in the ring are numbered from 8 to 12 carbon atoms in the ω-chain are numbered from 13 to 20. If the number of carbon atoms in α-chain is reduced, the number is removed for the purpose of starting from position 2; and if the number of carbon atoms in α-chain increases, the connection is called a connection with the under having respective substituents at position 2 in place of carboxy group (C-1). Similarly, if the number of carbon atoms in the ω-chain is reduced, the number removed to begin with position 20; and when the number of carbon atoms in the ω-chain is increased, the carbon atoms at position 20 is called as substitutes. Stereochemistry of the compounds remains the same as in the connection by the above formula (A), unless otherwise indicated.

In General, each term, PGD, PGE and PGF represents a connection PG having a hydroxyl group at positions 9 and/or 11, but in the present description, these terms also include compounds having substituents different from the hydroxyl group at positions 9 and/or 11. Such compounds are referred to as 9-dihydroxy-9-Deputy�ers-PG or 11 dihydroxy-11-substituted-PG, PG connection that has a hydrogen instead of a hydroxyl group, just 9 - or 11-deoxy-PG.

As stated above, the nomenclature of compounds 15-keto-prostaglandin is based on the carbon skeleton prostanoids acid. However, in the case that the compound has in its structure the same constituent parts as prostaglandin, can be used the abbreviation "PG". Thus, a PG compound, α-chain which is elongated by two carbon atoms, namely having 9 carbon atoms in α-chain, called 2-decarboxy-2-(2-carboxyethyl)-15-keto-PG. Similarly, a PG compound having 11 carbon atoms in α-chain, called 2-decarboxy-2-(4-carboxybutyl)-15-keto-PGF. Additionally, PG-connection ω-chain which is elongated by two carbon atoms, namely having up to 10 carbon atoms in the ω-chain, referred to as 15-keto-20-ethyl-PG. These compounds, however, can also be named in accordance with IUPAC nomenclature.

15-keto-PG used in the present invention, can include any derivatives or analogues of PG, in cases where they are in the position for 15 oxoprop instead of the hydroxyl group. Accordingly, for example, 15-keto-PG type 1 has a double bond at 13-14 position, 15-keto-PG type 2 has two double bonds in the 13-14 and 5-6 positions, 15-keto-PG type 3 has three double bonds at 5-6, 13-14 and 17-18 provisions, 13,14-dihydro-15-keto-PG, in which the double bond at 13-14 position is with�fight single connection.

Typical examples of the compounds used in the present invention include 15-keto-PG type 1, 15-keto-PG type 2, 15-keto - PG type 3, 13,14-dihydro-15-keto-PG type 1, 13,14-dihydro-15-keto-PG type 2, 13,14-dihydro-15-keto-PG type 3 and their derivatives or analogues.

Examples of the analogs (including substituted derivatives) or derivatives include 15-keto-PG in which carboxypropyl at the end of α-chain etherification; a compound in which the α-chain is extended; physiologically acceptable salt; a compound having the double bond in position 2-3 or triple bond at position 5-6, a compound having a Deputy (deputies) in provisions 3, 5, 6, 16, 17, 18,19 and/or 20; and a connection having a lower alkyl group or lower hydroxyalkyloxy group at positions 9 and/or 11 instead of the hydroxyl group.

In accordance with the present invention, the preferred substituents in position 3, 17, 18 and/or 19 include alkyl having 1-4 carbon atoms, especially methyl and ethyl. Preferred substituents at position 16 include lower alkyl, such as methyl and ethyl, hydroxyl, halogen atoms such as chlorine and fluorine, and aryloxy group, such as triftormetilfullerenov group. Preferred substituents in position 17 include lower alkyl, such as methyl and ethyl, hydroxyl, halogen atoms such as chlorine and fluorine, aryloxy group, such as triftormetilfullerenov-GRU�PU. Preferred substituents at position 20 include saturated or unsaturated lower alkyl, such as C1-4-alkyl, lower-alkoxy-group, such as C1-4-alkoxy group and the lower alkoxy-alkyl, such as C1-4-alkoxy-C1-4-alkyl. Preferred substituents at position 5 include halogen atoms such as chlorine and fluoride. Preferred substituents at position 6 include oxoprop, forming a carbonyl group. Stereochemistry PG having as a substituent at positions 9 and 11 hydroxy group, lower alkyl or hydroxy lower-alkyl, can be α, β or a mixture thereof.

Further, the above analogs may represent compounds having alkoxy group, cycloalkyl, cycloalkane group, phenoxy group or phenyl group at the end of the ω chain, when the chain is shorter than in primary PG.

Particularly preferred compounds include compound 13,14-dihydro-15-keto-PG, which has a single bond at position 13-14; the connection in which ω-chain is elongated.

A preferred compound according to the present invention, represented by formula (I):

in which L, M and N represent hydrogen, hydroxyl, halogen, lower alkyl, hydroxy lower-alkyl or oxoprop, and five-membered ring may have at least one double bond;

But a -�N 3, -CH2HE, the PINES2HE, -COOH or its functional derivative;

In represents-CH2-CH2-, -CH=CH - or-C≡C-;

R1represents a saturated or unsaturated divalent residue of a lower aliphatic hydrocarbon or aliphatic hydrocarbon with a chain of medium length, which is not substituted or substituted by halogen, lower alkyl, hydroxyl, exography, aryl or heterocyclic group and at least one carbon atom in the aliphatic hydrocarbon optionally substituted with an oxygen atom, nitrogen or sulfur; and

Ra is a saturated or unsaturated group of a lower aliphatic hydrocarbon or aliphatic hydrocarbon with a chain of medium length, which is not substituted or substituted by halogen, exography, hydroxyl, lower alkyl, lower alkoxy-group, the lower alkanoyloxy group, a lower cycloalkyl, the lower cycloalkane-group, aryl, aryloxy group, heterocyclic group or heterocyclic-group; a lower alkoxy group, a lower alkanoyl a hydroxy group, a lower cycloalkyl; the lower cycloalkane-group; aryl; aryloxy group; heterocyclic group; heterocyclic group.

Of the above compounds is a group of especially preferred compounds represented by formula (II):

in which L and M represent hydrogen, hydroxyl, halogen, lower alkyl, hydroxy lower-alkyl, lower alkanoyloxy group or oxoprop, and five-membered ring may have at least one double bond;

A represents-CH3, -CH2HE, the PINES2HE, -COOH or its functional derivative;

In represents-CH2-CH2-, -CH=CH-, -C≡C-;

X1and X2represent hydrogen, lower alkyl or halogen;

R1represents a saturated or unsaturated divalent residue of a lower aliphatic hydrocarbon or aliphatic hydrocarbon with a chain of medium length, which is not substituted or substituted by halogen, lower alkyl, hydroxyl, exography, aryl or heterocyclic group and at least one carbon atom in the aliphatic hydrocarbon optionally substituted with an oxygen atom, nitrogen or sulfur;

R2represents a single bond or a lower alkylene; and

R3represents a lower alkyl, a lower alkoxy group, lower alkanoyloxy group, a lower cycloalkyl, the lower cycloalkane group, aryl, aryloxy group, heterocyclic group or heterocyclic-Grupo.

In the above formula, the term "unsaturated" in the definitions for R1and Ra is intended to include, at less� least one or more double bonds and/or triple bonds that apart, separately or serially present between carbon atoms of the main and/or side chains. In accordance with conventional nomenclature of unsaturated bond two consecutive provisions represented, indicating a smaller number of the two positions, and an unsaturated bond between two distal provisions pose, pointing both provisions.

The term "lower aliphatic hydrocarbon or aliphatic hydrocarbon with a chain of medium length" means a hydrocarbon group with unbranched or branched chain having 1 to 14 carbon atoms (for a side chain, preferably 1-3 carbon atoms) and preferably 1-10, in particular 1-8 carbon atoms.

The term "halogen atom" includes fluorine, chlorine, bromine and iodine.

The term "lower" throughout the description is intended to enable the group which has 1-6 carbon atoms, unless otherwise indicated.

The term "lower alkyl" means a group of saturated hydrocarbons with straight or branched chain containing 1-6 carbon atoms, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.

The term "low alkylene" means a divalent saturated hydrocarbon with unbranched or branched chain, contain�asuu 1-6 carbon atoms, and includes, for example, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, tert-butylene, pentile and exile.

The term "lower alkoxy group" means a group representing a lower alkyl-O-, in which lower alkyl such as defined above.

The term "hydroxy lower-alkyl" means lower alkyl as defined above which is substituted by at least one hydroxyl group, such as gidroximetil, 1-hydroxyethyl, 2-hydroxyethyl and 1-methyl-1-hydroxyethyl.

The term "lower alkanoyloxy group" means a group represented by the formula RCO-O-, in which RCO represents an acyl group obtained by oxidation of the group of lower alkyl, as defined above, such as acetyl.

The term "low cycloalkyl" means a cyclic group obtained by cyclization of the group of lower alkyl, as defined above, but containing three or more carbon atoms, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "lower cycloalkane-group" means a group of low cycloalkyl-O-, in which the lower cycloalkyl such as defined above.

The term "aryl" may include unsubstituted or substituted aromatic hydrocarbon rings (preferably monocyclic groups), for example phenyl, tolyl, xylyl. Examples of the substituents represent the atom g�lagena and low halogenated, in which a halogen atom and a lower alkyl such as defined above.

The term "aryloxy group" means a group represented by the formula ArO-, where Ar represents aryl, as defined above.

The term "heterocyclic group" may include mono - to tricyclic group, preferably monocyclic heterocyclic group which represents a 5 to 14-, preferably 5 to 10 membered ring having optionally substituted carbon atom and 1-4, preferably 1-3 heteroatoms 1st or 2nd type, which is selected from nitrogen atom, oxygen atom and sulfur atom. Examples of heterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, furutani, pyranyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 2-pyrrolyl, pyrrolidinyl, 2-imidazolyl, imidazolidinyl ureido, 2-pyrazoline, pyrazolidine, piperidine, piperazinyl, morpholino, indole, benzothiazyl, hinely, ethanolic, hypernil, chinazoline, carbazolyl, acridines, phenanthridines, benzimidazolyl, benzimidazolinyl, benzothiazolyl, phenothiazinyl. Examples of the substituent in this case include halogen, and halogen-substituted lower alkyl group in which a halogen atom and a group of lower alkyl such as described above.

The term "heterocyclic group" means a group, �reported by the formula HcO-, in which Hc is a heterocyclic group as described above.

The term "functional derivative" includes salts (preferably pharmaceutically acceptable salts), ethers, esters and amides.

Suitable "pharmaceutically acceptable salts" include conventionally used non-toxic salts, for example, salt with inorganic base, such as alkali metal salt (such as sodium salt and potassium salt), alkaline earth metal salt such as calcium salt and magnesium salt), ammonium salt; or a salt with an organic base, such as amine salt (such as melaminovaya salt, dietilamina salt, cyclohexylamine salt, benzylamine salt, piperidino salt, ethylendiamine salt, secondary water ethanolamine salt, diethanolamine salt, triethanolamine salt, Tris(hydroxymethylamino)ethane salt, the mono-monoethanolamine salt, procinema salt and Katayeva salt), salt of the basic amino acids (such as arginine salt and lysine salt), tetraalkylammonium salt and the like. These salts can be obtained by using a conventional method, for example, from the corresponding acid and base or by exchange reactions of salts.

Examples of the ethers include alkyl ethers, for example esters of lower Akilov, such as methyl ether, ethyl ether, propyl ether, and�profilemy ether, butyl ether, isobutyl ether, tert-butyl ether, pentyl ether and 1-cyclopropyl-ethyl ester; and esters of Akilov with a chain of medium length or longer chain, such as octyl ether, diethylhexyl ether, lauryl ether and cetyl ether; unsaturated ethers such as alerby ether and linalilovy ether; esters of lower alkenyl, such as vinyl ether, allyl ether; esters of lower alkinyl, such as atinlay ether and propenyloxy ether; esters of lower hydroxyalkyl, such as gidroksiètilovyh ether and hydroxyisopropyl ether; lower alkoxy-(lower)alkyl esters, such as methoxymethyl ether and 1-methoxyethylamine ether; optionally substituted aryl ethers such as phenyl ether, docelowy ether, tert-BUTYLPEROXY ether, salicyl ether, 3,4-di-methoxybenzyloxy ether and benzamidophenyl ether; and esters of lower aryl-Akilov, such as benzyl ether, trailovic ether and benzhydrylamine the air.

Examples of the esters include aliphatic esters, for example esters of lower Akilov, such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, tert-butyl ether, pentyl ether and 1-cyclopropylethyl ether; esters of lower alkenyl, such as vinyl ester and allyl ester; esters of lower alkinyl, such kakainlove ether and propenyloxy ether; esters of lower hydroxyalkyl, such as gidroksiètilovyh ether; esters of lower alkoxyalkyl, such as methoxymethyl ether and 1-methoxyethylamine ester; and optionally substituted aryl esters such as, for example, phenyl ester, tallowy ether, tert-BUTYLPEROXY ether, salicyl ether, 3,4-di-methoxybenzyloxy ether and benzamidophenyl ether; and esters of the lower arylalkyl, such as benzyl ether, trailovic ether and benzhydrylamine the air.

Amide group A means a group represented by the formula-CONR'R", in which each of R' and R" represents hydrogen, lower alkyl, aryl, alkyl - or aryl-sulfonyl, lower alkenyl and lower alkynyl, and includes, for example, amides of lower Akilov, such as methylamide, ethylamide, dimethylamide and diethylamide; arylamide, such as anilide and toluidin; and alkyl - or aryl-sulfanilamide, such as methylsulfonylamino, ethylsulfonyl-amide and tolilsulfonil.

Preferred examples of groups L and M are a combination in which both are a hydroxyl group which has the structure of 5-membered rings, so called, PGF type; a combination in which L is a hydroxyl group, and M represents oxoprop, which has the structure of 5-membered rings, so called, PGE type, and combination in �otoroy L is oxoprop, and M represents hydrogen, which has the structure of 5-membered rings, the so-called 11-deoxy-PG-type.

A preferred example And represents-COOH, its pharmaceutically acceptable salt, ester or amide.

A preferred example is a-CH2-CH2- that provides a structure of, so called, 13,14-dihydro type.

A preferred example of X1and X2represents hydrogen or halogen, preferably, at least one of them is a halogen, more preferably they both represented the Halogens, especially fluorine, which provides a structure so called 16,16-debtor type.

Preferred R1is a hydrocarbon containing 1-10 carbon atoms, preferably 6-10 carbon atoms. In addition, at least one carbon atom in the aliphatic hydrocarbon optionally substituted with an oxygen atom, nitrogen or sulfur.

Examples of R1include, for example, the following groups:

-CH2-CH2-CH2-CH2-CH2-CH2-,

-CH2-CH=CH-CH2-CH2-CH2-,

-CH2-CH2-CH2-CH2-CH=CH-,

-CH2-C≡C-CH2-CH2-CH2-,

-CH2-CH2-CH2-CH2-O-CH2-,

-CH2-CH=CH-CH2-O-CH2-,

-CH2C≡C-CH 2-O-CH2-,

-CH2-CH2-CH2-CH2-CH2-CH2-CH2-,

-CH2-CH=CH-CH2-CH2-CH2-CH2-,

-CH2-CH2-CH2-CH2-CH2-CH=CH-,

-CH2-C≡C-CH2-CH2-CH2-CH2-,

-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-,

-CH2-CH2-CH2-CH2-CH(CH3)-CH2-,

-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-,

-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2-,

-CH2-CH2-CH2-CH2-CH2-CH2-CH=CH-,

-CH2-C≡C-CH2-CH2-CH2-CH2-CH2- and

-CH2-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-.

Preferred Ra is a hydrocarbon containing 1-10 carbon atoms, more preferably 1-8 carbon atoms. Ra may have one or two side chain having one carbon atom.

The ring configuration and the α - and/or ω chains in the above formula (I) and (II) may be the same as in the primary PG, or different from that of the primary PG. However, the present invention also includes a mixture of compounds having the configuration of a primary type and connection configuration, from�base of the primary type.

The compound 13,14-dihydro-15-keto-20-ethyl PG and its derivatives or analogues represents typical examples of the compounds in the invention. An example of the most preferred compounds in the invention is a 13,14-dihydro-15-keto-20-ethyl Fisopropyl ether (below in this application also referred to as "isopropylparaben").

In the present invention the connection of PG, which is a dihydro-compound between positions 13 and 14, and keto-compound (=O) at position 15 may be in the keto-polyacetylene equilibrium through the formation of polyacetale between a hydroxyl group at position 11 and keto-group in position 15.

For example, it was found that if both X1and X2are atoms of Halogens, especially fluorine atoms, the compound contains a tautomeric isomer, bicyclic compound.

If there are tautomeric isomers as described above, the proportion of both tautomeric isomers varies with the structure of the remaining part of the molecule or type the presence of the Deputy. Sometimes one isomer may predominantly be present in comparison with others. However, one should take into account that the present invention includes both isomers.

Additionally, the compounds of the 15-keto-PG used in the invention include compounds with bicyclic� groups and their analogues or derivatives.

Coupling with bicyclic groups represented by the formula (III)

in which, a represents-CH3or-CH2HE, the PINES2HE, -COOH or its functional derivative;

X1'andX2'represent hydrogen, lower alkyl or halogen;

Y represents

,, or

whereR4'andR5'represent hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy group or a lower hydroxyalkyl in which, at the same time,R4'andR5'not represent hydroxyl and lower alkoxy group.

R1represents a saturated or unsaturated divalent residue of a lower aliphatic hydrocarbon or �the STATCOM aliphatic hydrocarbon with a chain of medium length, which is not substituted or substituted by halogen, alkyl, hydroxyl, exography, aryl or heterocyclic group and at least one carbon atom in the aliphatic hydrocarbon optionally substituted with an oxygen atom, nitrogen or sulfur; and

R2'represents a saturated or unsaturated residue of a lower aliphatic hydrocarbon or an aliphatic hydrocarbon residue with a chain of medium length, which is not substituted or substituted by halogen, exography, hydroxyl, lower alkyl, lower alkoxy-group, the lower alkanoyloxy group, a lower cycloalkyl, the lower cycloalkanes-group, aryl, aryloxy group, heterocyclic group or heterocyclic-a hydroxy group; a lower alkoxy group; lower alkanoyloxy group; a lower cycloalkyl; the lower cycloalkanes-group; aryl; aryloxy group; heterocyclic group; heterocyclic group.

R3'represents hydrogen, lower alkyl, lower cycloalkyl, aryl or heterocyclic group.

In addition, because the compounds used in the invention can be represented by the formula or named based on keto-type regardless of the presence�the third or absence of the isomers, it should be noted that such structure or name is not meant to exclude compounds polyacetylene type.

In the present invention for the same purpose can be applied to any of the isomers such as the individual tautomeric isomers, a mixture thereof, or optical isomers, a mixture thereof, a racemic mixture, and other steric isomers.

Some compounds used in the present invention can be obtained by the method disclosed in U.S. patents№№5,073,569, 5,166,174, 5,221,763, 5,212,324, 5,739,161 and 6,242,485 (these cited references are incorporated in this application by reference).

In accordance with the present invention the subject is a mammal can be treated using the present invention, by introducing the compounds used in the present invention. The subject can be any subject of a mammal, including humans. The connection can be applied systemically or topically. Typically, the compound can be administered by oral administration, intravenous injection (including infusion), local injection into the eye (e.g., periocular (e.g., by injection subtenon injections), subconjunctival, intraocular, intravitreal, intracameral, subretinal, suprachoroidal and retrobulbar injection) and the like.

The dose may vary depending on the breed of animal, age, mA�si body, symptoms that should be treated, desired therapeutic effect, the route of administration, duration of treatment, and the like. A satisfactory effect can be obtained by systemic administration 1-4 times per day or continuous administration at the amount of 0,00001-500 mg/kg / day, more preferably of 0.0001-100 mg/kg / day.

The connection is preferably made in the form of pharmaceutical compositions suited for administration in the traditional way. The composition may be suitable for oral administration, local injection into the eye, injection or perfusion, and it can represent an external agent.

The composition of the present invention may further contain physiologically acceptable additives. These additives may include the ingredients used with the compounds of the present invention, such as excipient, diluent, excipient, solvent, a moving substance, adjuvant, binder, dezintegriruetsja a means, a tool to shape the envelope, means for forming a shell capsules, ointment base, base for suppositories, the vehicle for creating aerosols, emulsifier, dispersing agent, fluidizer agent, a thickener, a substance that regulates the correct tonicity buffer substance, soothing agent, preservative, antioxidant prop�sident, corrective substance, flavoring, colorant, a functional material such as cyclodextrin and biodegradable polymer, stabilizer. These additives are well known in the art, and they can be additive, which is selected from those described in General reference books on the technology of medicinal forms.

The number of compounds described above the compositions of the invention may vary depending on the composition, and, in General, can be 0,000001-10,0%, more preferably 0,00001% and 5.0%, most preferably of 0.0001-1%.

Examples of solid compositions for oral administration include tablets, lozenges, sublingual tablets, capsules, pills, powders, granules and the like. The solid composition can be obtained by mixing one or more active ingredients at least one inactive diluent. The composition may further contain additives than the inactive diluents, for example a moving substance, dezintegriruetsja agent and stabilizer. Tablets and pills may be coated with soluble in the intestine or gastrointestinal tract film, if necessary.

They can be covered by two or more layers. They can also be adsorbed on the material for sustained release, or encapsulated in microcapsules. Furthermore, the compositions may be encapsulated with the aid of an easily destructible material, such gelatin. In addition, they can be dissolved in a suitable solvent, such as fatty acid or its mono-, di - or triglyceride, to obtain soft capsules. Sublingual tablet may be applied in the case when you need a fast acting drug form.

Examples of liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs and the like. Said composition may further contain conventionally used inactive diluents, such as distilled water or ethyl alcohol. The composition may contain additives than the inactive diluents such as assistive tools, such as wetting means and suspendida funds, sweeteners, flavorings, fragrances and preservatives.

The composition of the present invention can be in the form injectisome composition that contains one or more active ingredients and may be obtained in accordance with the known method.

Examples of compositions of the present invention for parenteral injection, administered by injection include sterile aqueous or nonaqueous solutions, suspensions and emulsions.

Diluents for the aqueous solution or suspension �might include, for example, distilled water for injection, physiological saline and ringer solution.

Non-aqueous diluents for solution and suspension may include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol and Polysorbate. The composition may further include additives such as preservatives, moisturizers, emulsifiers, dispersing funds, and the like. They may be sterilized by filtration through, for example, restraining bacteria filters built into the sterilizer, or by gas sterilization or sterilization with the use of radioisotopes.

The composition is introduced by injection, can be provided as a composition in the form of a sterile powder, which before use should be dissolved in a sterilized solvent for injection.

The compound of the present invention can also be in the form of ophthalmic compositions such as eye drops and eye ointments. Dosage form may include all ophthalmic compositions for local injection into the eye used in the field of ophthalmology.

Eye drops are prepared by dissolving the active ingredient in a sterile aqueous solution such as saline solution and buffer solution. Eye drops can be �nespecheny as composition in powder form, which should be dissolved before use, or by combining powder compositions to be dissolved before use. Eye ointment is prepared by mixing the active ingredient in an ointment base. Compositions prepared in accordance with conventional methods.

The osmolarity regulators include sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, boric acid, borax, sodium hydroxide, hydrochloric acid, mannitol, isosorbide, propylene glycol, glucose and glycerol, but not limited to, as they are traditionally used in the field of ophthalmology.

In addition, if desirable, the composition of the present invention can be added additives traditionally used in the field of ophthalmology. Such additives include, for example, buffer agent (e.g., boric acid, sodium monohydratefast and sodium dihydrogen phosphate), preservatives (e.g., benzalkonium chloride, benzene chloride and chlorobutanol), thickeners (e.g., saccharide such as lactose, mannitol and maltose; for example, hyaluronic acid or its salt, such as sodium hyaluronate and potassium hyaluronate; e.g., mucopolysaccharide such as chondroitin sulfate; e.g., sodium polyacrylate, carboxyvinyl p�the hotel search option and crosslinked polyacrylate).

Upon receipt of the compositions of the present invention in the form of eye ointments, than the ointment of the above additives, the composition may contain traditionally used as the basis for eye ointment. Such a basis for eye ointment includes, but is not limited to, oil-based, such as vaseline, liquid paraffin, polyethylene, selenium 50, plastibase, macrogol or a combination thereof; emulsion-based, with oil phase and water phase emulsified with a surface active compound; and water-soluble base, such as methylcellulose, carboxylmethylcellulose and polyethylene glycol.

In accordance with the present invention a preferred embodiment includes an ophthalmic composition which does not contain benzalkonium chloride in substantial amounts. The phrase "ophthalmic composition, which is not

contains benzalkonium chloride in substantial amounts" used in this application, means that the composition does not contain benzalkonium chloride or the composition contains benzalkonium chloride in as low amounts as possible. In the present invention is an ophthalmic composition that does not contain benzalkonium chloride in substantial amounts" may contain benzalkonium chloride in a concentration of less than 0.01%, preferably 0.005% or less, �more preferably of 0.003% or less.

Eye drops of the present invention can be in the form of a sterile composition type dose single dose (day type, or the type of metered-dose form for a single injection), does not contain preservatives such as benzalkonium chloride.

Ophthalmic composition further includes a dosage form with a slow release, such as gel composition, a liposomal composition, the composition is in the form of a lipid microemulsion, the composition with microspheres, the composition of the nanospheres and the composition with the implant for a long period of active connections the back of the eye.

The concentration and number of injections of the active ingredient of eye drops used in the present invention may vary in accordance with, for example, used by the connection, the type of the subject (such as animals or people), age, body weight, symptoms that must be treated, the desired effect of the treatment, methods of administration, enter the volume and duration of treatment. Accordingly, the appropriate concentration and the number of administrations can be selected as desired. Choosing as an example isopropylparaben, which represents one of the forms of the present invention, the composition containing 0.01 to 1.0%, preferably 0.05 to 0.5%, more preferably at least 0.12%, and 0.15% or 0.18% of isopropranolol�it, can be traditionally introduced adult 1-10 times a day.

The term "treatment" used in this application, includes any means of control such as prevention, medical care, relief of the condition, attenuation of the condition and delay the disease progression.

Pharmaceutical composition of the present invention may contain a single active ingredient or a combination of two or more active ingredients. In combination of multiple active ingredients in their relative content can be appropriately increased or decreased according to their therapeutic effect and security.

Additionally, the compositions of the present invention may appropriately contain other pharmacologically active ingredients, to the extent they do not conflict with the purposes of the present invention.

The present invention will be described in detail with reference to the following example which, however, is not intended to limit the scope of the present invention.

Example 1

Method

This study used cells of the retinal pigment epithelium (cells ARPE-19, obtained from the American type culture collection (of ATS)). Cells ARPE-19 grown on filters "Corning Transwell with a pore size of 0.4 µm (Corning Incorporated, NY, USA) in the medium Needle, modification�cireundeu by way of Dulbecco, containing 10% fetal calf serum. Transepithelial resistance (TER) of cultured cells was determined using voltammetry "EVOM". TER of cultured cells was determined by subtracting the value of resistance measured with only one filter, from values measured with cultured cells.

Cells grow until, until they reach the TER value of approximately 50 Ohms/1.2 cm2. They were then treated with 100 µm tert-butyl hydroperoxide (tBH) in 0.1% Dean, 100 nm compound A (isopropylnaphthalene, i.e. isopropyl ester of 13,14-dihydro-15-keto-20-ethyl-PGF) in DMSO (the final concentration of DMSO is 0.1%) or a combination tBH plus the connection A. TER determined after 0, 6, 18, 24 and 48 hours after treatment. The result is shown in figure 1.

Cells ARPE-19 grown until, until they reach the TER value, approximately equal to 50 Ohms/1.2 cm2, treated with 100 μm tBH in 0.1% Dean, 100 nm of the compound A in DMSO (final concentration of DMSO is 0.1%) or a combination tBH plus compound a (initial processing). After 20 hours after the initial treatment add 3000-daltonii FITC-labeled dextran in a concentration of 0.1 mg/ml on the apical surface of the cell culture and the culture further incubated. Then at the 44th hour measure the fluorescence of the medium, washing the bazo-lateral surface. Wavelengths d�I FITC 494 (excitation)/518 (issue). The result is shown in figure 2.

Results

tBH causes a rapid and large loss of TER. Connection And protects against the loss of TER caused by tBH (Fig.1). Connection And protects against the loss of barrier function caused by tBH, as measured by the leak 3000-altonaga fluorescent dextran from the apical to the basolateral medium (Fig.2). These results indicate that compound a protects the cells of the retinal pigment epithelium from damage caused by reactive oxygen species.

The result indicates that compound a is applicable for the treatment of macular degeneration, especially AMD.

Example 2

Connection And protects against light induced cell death in cells of the retinal pigment epithelium (RPE) containing pyridinium bis-retinoid (AE) Method

This study used cells of the retinal pigment epithelium (cells ARPE-19). Cells ARPE-19 was maintained in DMEM/F12 (supplemented with 10% FBS and a mixture of 1% among penicillin-streptomycin) in 25 cm2or 75 cm2culture vials. For the experiment, cells are seeded in multi-well glass slides. After confirming that the cells were attached to subject the glass, the medium replaced with culture medium containing pyridine bis-retinoid (AE) and cells are cultured for 5-14 days. Wednesday the Deputy�represent in phosphate-saline buffer solution (containing UE), and then cage light with blue light (430 nm) emanating from a halogen lamp for 20 min. compound a, dissolved in dimethylsulfoxide, were added over 1 hour to lighting (final concentration equal to 10 and 50 nm). After illumination, the cells are cultured in DMEM/F12 for 24 hours. Then cells were incubated in DMEM/F12 containing 10% WSTPET-8 (without A2Z) for 4 hours. Measure absorption at 450 nm. The increase in absorption is an indicator of cell viability.

Results

The connection And prevents cell death induced AE/lighting (table 1).

Table 1
ConnectionConcentrationStatusCell viability (%)
The carrier (DMSO)-AE + lighting55
Compound a50 nmAE + lighting89
Compound a10 nmAE + lighting90

Reza�the adds, shown in table 1, indicates that compound a is suitable for treatment of macular degeneration, especially AMD.

Example compositions 1

Ophthalmic solution is produced by dissolving in purified water the ingredients in the amounts listed below (% weight/volume), and they fill a sterilized container made of low density polyethylene (LDPE) under sterile conditions (1 drop: approximately 35 μl):

0.15% of isopropyl ester of 13,14-dihydro-15-keto-20-ethyl-PGF(isopropylmalate);

1.0% polyoxyethylenesorbitan;

1,0% mannitol;

1.9% of glycerin;

0.05% dintre edetate;

of 0.003% benzalkonium chloride.

Example composition 2

Sterile ophthalmic solution in the form for a single use are obtained by dissolving in purified water the ingredients in the amounts listed below (% weight/volume), and they fill the container for a single use in sterile conditions:

0.18% of isopropyl ester of 13,14-dihydro-15-keto-20-ethyl-PGF(isopropylmalate);

0.70 percent of polyoxyethylenesorbitan monooleate;

0,30% alerby broadcast polyoxyl-10;

4.7% mannitol;

0.01% dintre edetate.

Example composition 3

Sterile ophthalmic solution in the form for a single use are obtained by dissolving in purified water the ingredients in the quantity t�nom lower (% weight/volume), and placed in a disposable container for use in sterile conditions:

0,24% isopropyl ester of 13,14-dihydro-15-keto-20-ethyl-PGF(isopropylmalate);

0.95% of polyoxyethylenesorbitan monooleate;

0,42% alerby broadcast polyoxyl-10;

4.7% mannitol;

0.01% dintre edetate.

1. Pharmaceutical composition for treating macular degeneration in a mammal, which comprises an effective amount of 15-keto-prostaglandin where the specified 15-keto-prostaglandin is an isopropyl ester of 13,14-dihydro-15-keto-20-ethyl-prostaglandin F.

2. A composition according to claim 1, in which a specified macular degeneration is an age-related macular degeneration.

3. A composition according to claim 2, in which a specified age-related macular degeneration is dry age-related macular degeneration.

4. A composition according to any one of claims. 1-3, which is designed as a composition for local administration.

5. A composition according to claim 4, which is an ophthalmic composition for topical administration in the eye.

6. A composition according to claim 5, which is an ophthalmic composition made in the form of eye drops.

7. A composition according to claim 6, in which these eye drops are sterile eye drops, preservative-free, in the form �La single application.

8. A composition according to claim 5, where the specified ophthalmic composition does not contain or contains less than 0.01% benzalkonium chloride.

9. The use of 15-keto-prostaglandin for the manufacture of pharmaceutical compositions for treating macular degeneration in a mammal, where the specified 15-keto-prostaglandin is an isopropyl ester of 13,14-dihydro-15-keto-20-ethyl-prostaglandin F.

10. The use of 15-keto-prostaglandin for the treatment of macular degeneration in a mammal, where the specified 15-keto-prostaglandin is an isopropyl ester of 13,14-dihydro-15-keto-20-ethyl-prostaglandin F.

11. A method of treating macular degeneration in a mammal, which comprises administering to the needy in this subject an effective amount of 15-keto-prostaglandin where the specified 15-keto-prostaglandin is an isopropyl ester of 13,14-dihydro-15-keto-20-ethyl-prostaglandin F.



 

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12 cl, 3 tbl, 21 ex

FIELD: medicine, pharmaceutics.

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11 cl, 18 dwg, 7 ex

FIELD: medicine, pharmaceutics.

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19 cl, 35 tbl, 3 dwg, 13 ex

FIELD: medicine.

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2 ex

FIELD: medicine.

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1 ex

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13 cl, 7 dwg, 7 tbl, 4 ex

FIELD: medicine.

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5 ex

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1 ex, 1 tbl

FIELD: medicine.

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1 ex, 1 tbl

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12 cl, 9 ex, 10 dwg

FIELD: veterinary medicine.

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3 tbl, 3 ex

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10 cl, 1 tbl, 1 ex

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10 cl, 1 tbl, 1 ex

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1 tbl

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31 cl, 4 tbl, 2 ex

FIELD: medicine.

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FIELD: medicine, pharmaceutics.

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8 cl, 4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

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17 cl, 6 dwg

FIELD: chemistry.

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FIELD: veterinary science.

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EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

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