Composition for treating disorders of external secretion

FIELD: chemico-pharmaceutical industry.

SUBSTANCE: the suggested composition contains prostaglandin-like compound as an active component and it , also, deals with the method to treat disorders of external secretion that includes application of efficient quantity of prostaglandin-like compound for a person who needs such a treatment. The composition is of high efficiency at treating disorders inactivity of lacrimal and sudoriferous glands being of high bioavailability and nontoxic.

EFFECT: higher efficiency of therapy.

33 cl, 5 ex, 7 tbl

 

The technical field to which the invention relates.

The present invention relates to compositions for treating disorders of external secretion, particularly to compositions for the treatment of low slezootdelenia, including the syndrome of dry eye, and reduced salivation, including the syndrome of dryness in the mouth. The present invention also relates to a method for treating disorders of external secretion and to the use of certain compounds to obtain a pharmaceutical composition for treating disorders of external secretion.

The level of technology

External secrets are allocations that are allocated directly from exocrine glandular cells or through the excretory channels, or the like on the body surface or cavity. Tears and saliva are typical external secrets, and, in addition, it includes secrets from the nose or mucosa respiratory tract, the secrets of the stomach or intestines, vaginal secretions, perspiration and other conditions resulting from violations of external secretion, include dryness of body parts, such as "syndrome dry eyes (xerophthalmia), "the syndrome of dry mouth (xerostomia), "the syndrome of dryness of the nasal mucosa (ceramictile), "the syndrome of dry skin (xeroderma) and "a syndrome of a dry vagina" (the symptom of vaginal dryness); and chronic pancreatitis, chronic is th gastritis and chronic bronchitis, due to the reduction of external secretion.

"Sjogren syndrome", an autoimmune disease, is one of the many known and unknown etiological factors that may be responsible for violations of external secretion. Sjogren syndrome is characterized by a state of dryness due to infiltration of inflammatory cells in the acinus exocrine gland and around the excretory canal that leads to destruction and atrophy of acinus and epithelial cells of the channel. Typical symptoms include dry eyes and mouth, and dry skin, nasal mucosa, pharynx, bronchi, of the external female genitalia and vagina. For example, dryness of the respiratory tract can cause infection in the lungs and can sometimes cause serious illness, such as pneumonia, which can lead to death. The other main cause of the disease is aging. Despite the fact that violations of external secretion can cause serious diseases that are mentioned above, have so far been available only symptomatic treatments, such as artificial hydration. Therefore, the development of fundamental treatment method that improves the reduced external secretion, is desirable.

One of the diseases caused by disorders of external secretion, which is called at the present time what I'm keen interest in medicine and pharmacy, is reduced tearing, including the syndrome of dry eye.

The syndrome of dry eye is defined as a state of reduced or altered quantity of tears, regardless of the presence or absence of lesions of the cornea and conjunctiva (Yamal and others, GANKI, t, s-1293 (1992)). This syndrome includes the state of dryness of the eye surface, detected in patients with reduced tearing, alacrima, xerophthalmia, Sjogren syndrome, drying keratoconjunctivitis, the syndrome of malignant pericardial Eritrea, eye disease, blepharida marginal, diabetes and others; dry eyes after cataract surgery; dry eye associated with allergic conjunctivitis; and the syndrome of dry eye associated with aging. In addition, dry eye also includes a condition found in patients with reduced tearing caused by long-term work with visual display terminal (VDT), dry rooms with air conditioning, etc.

There are several causes of the syndrome of dry eye, including those listed above and those that are not identified. However, currently available to physicians have only palliative treatments for symptoms of dry eye, including the appointment of an artificial tear solution in order to increase the amount of tears that are held in the bag con is for, resulting in attenuated subjective symptoms or eyes are protected from dryness. It would be desirable to develop compositions that are able to provide satisfactory healing effect, including improved low slezootdelenia.

The secretion of tears is subdivided into the basal secretion of tears and reflex secretion of tears. The basal secretion of tears is a selection under normal conditions, open age, and it is considered that it is mainly associated with accessory lacrimal glands, such as the glands of Krause and gland Wolfring. On the other hand, the reflex secretion of tears is a secretion of tears in response to some stimulation surface keratoconjuctivitis, nasal mucosa or the like, or to stimulate, accompanied by mental changes, such as grief or joy. It is believed that this release is from the main lacrimal gland. Given the symptoms of the syndrome of dry eye, it is especially important to improve weak basal secretion of tears, that is, the allocation of tears under normal conditions, the open-century.

In addition, diseases associated with disorders of external secretion, also include decreased tearing, and sometimes it may be accompanied by symptoms of dry mouth (xerostomia). Patients suffering from dry mouth, ponies who built a number of eye-catching saliva leads to dryness of the lips and mouth and can cause a feeling of thirst, xerosis of the mucous membrane of the mouth, burning sensation, impaired mastication and dyspepsia. In addition, patients with the syndrome of dryness of the mouth, probably in the oral cavity remains foods that can cause tooth decay.

There are many etiological factors, which are responsible for the syndrome of dryness of the mouth. For example, the systemic factors include fever, dehydration, endocrinopathy (myxedema, graves ' disease, incipient diabetes, and others), metabolic disorders (diabetes, uremia, cirrhosis, and others), vitamin a deficiency, vitamin deficiency, autoimmune disease (Sjogren syndrome, progressive scleroderma and others), anemia, bleeding, aging, exposure to various drugs (sedatives, parasympatholytics medicines, antihistamines, and others). Local factors include inflammation of the salivary glands, atrophy of the salivary gland complications after radiotherapy and malignancy (ectodermal dysplasia, and others).

As described above, there are many known and unknown etiological factors responsible for the syndrome of dryness in the mouth. However, currently there are only palliative therapies syndrome of dryness in the mouth, such as continuous intake of small amounts of fluids during the day, the use of chewing the gum, or the like and the use of artificial saliva. It would be desirable to develop a composition that is able to provide fundamental treatment that improves attenuated the secretion of saliva.

Usually a healthy person is allocated an average of from 1 to 1.5 liters of saliva per day from a pair of (left and right) major salivary glands (including the parotid gland, submandibular gland and the sublingual gland and the minor salivary glands (including lip cancer, tongue cancer, Palatine glands and buccal glands). Saliva is secreted in response to a stimulant that may cause damage to the body, diluting the stimulator or maintaining a physiological pH value, as well as facilitating chewing and swallowing food. In addition, saliva dissolves food and thereby gives a taste sensation like no other man and provides him with smooth speech, keeping wet condition inside the mouth. There are two types of saliva: one is the saliva of the continuous type, which is continuously secreted in small quantities, in the absence of a specific promoter, and the other type is a saliva reflex type, which is released in response to stimulation by food, the movement of the jaws, taste, etc. In any case, the saliva is one of the essential physiological functions, and therefore improve weak reception is tion of saliva is especially important in the treatment of symptoms of dry mouth.

In the past it was found that certain fatty acids are essential, and with a food perspective, it is necessary to take a sufficient amount of these acids. Was recently investigated the biological activity of many fatty acids, and attracts the attention activity linoleinovoy acid, arachidonic acid, alpha-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In the body linoleinovoy acid, via di-Homo-gamma-linolenic acid is converted to arachidonic acid; alpha-linolenic acid, through eykozapentaenovuyu acid, is converted into docosahexaenoic acid; di-Homo-gamma-linolenic acid is converted into prostaglandin of the first type (PG1), arachidonic acid into prostaglandin of the second type (PG2or leukotrien fourth type (LT4) and eicosapentaenoic acid into prostaglandin third type (PG3or leukotrien fifth type (LT5), respectively.

Prostaglandins (in the following referred to as PG) are representatives of a class of organic carboxylic acids, which are contained in tissues or organs or most other mammals, and display a wide range of physiological activity. Found in nature, PG (primary PG) usually have skel is t postanowi acid, shown in the formula (A):

On the other hand, some synthetic analogs have modified the skeleton. The primary prostaglandins are classified as PGA, PGB, PGC, PGD, PGE, PGF, PGG, PGH, PGI and PGJ, in accordance with the structure of the functional group of five-membered rings, and additionally are classified into the following three types according to the number and position of unsaturated bonds with the functional group of the carbon chain:

subscript 1 - 13,14-unsaturated-15-HE;

subscript 2 - 5,6 - and 13,14-dimensionali-15-HE;

subscript 3 - 5,6-, 13,14 - and 17,18-trimensional-15-HE;

Moreover, prostaglandins F are classified in accordance with the configuration of the hydroxyl group in position 9 at the alpha-type (hydroxyl group is in the alpha configuration) and beta-type (hydroxyl group is in the beta configuration).

In addition, some 15-keto-prostaglandins and 13,14-dihydro-15-keto-prostaglandins (i.e. having in position 15 oxo group instead of a hydroxy-group) are known as substances which in nature are formed by enzymatic effects in the course of metabolism in vivo primary prostaglandins. 15-Keto-prostaglandins have been disclosed, for example, in documents EP-A-0281239 (corresponds to the application of Japan JP-A-104040/89), EP-A-0281480 (corresponds to the application of Japan JP-A-52753/8), EP-A-0289349 (corresponds to the application of Japan JP-A-151552/89), EP-A-0453127 (corresponds to the application of Japan JP-A-58992/95) and EP-A-0690049 (corresponds to the application of Japan JP-A-48665/96). These cited documents included in the description by reference.

For example, when the primary prostaglandins such as PGE2or alpha-PGF2that are derived fatty acids, the fluid in the eye in the stimulus number, which causes the blood (plethora) of conjunctiva, tearing occurs simultaneously with the flushing. However, the small amount of PG, which does not cause any redness of conjunctiva, not well-known effect of derivatives of fatty acids, including prostaglandins, nor on the secretion of tears, and on the basal secretion of tears is not affected by the stimulant, nor on the secretion of saliva.

The invention

The aim of the present invention to provide compositions and method of treatment of disorders of external secretion, especially the way that is used for treating at least one condition selected from the weakened slezootdelenia syndrome dry eyes, impaired salivation syndrome and dry mouth.

The authors of the present invention have found that, if the number of derived fatty acids so little that cause no hyperemia of conjunctiva, this derivative can improve basal before the July tears, which is not affected by the stimulant, and to improve the condition of dry eye. In addition, the authors present invention also found that the derived fatty acids also can improve weakened salivation and to improve the condition of dry mouth.

Therefore, the present invention provides a composition for treating disorders of external secretion, especially for the treatment of weakened slezootdelenia syndrome dry eyes, impaired salivation or syndrome of dryness in the mouth, which contains a derivative of a fatty acid as an active component.

In addition, the present invention provides a method of treatment of disorders of external secretion, which includes the introduction of an effective amount of a fatty acid to a subject who is in need of such treatment.

Additionally, the present invention provides the use of a derivative of a fatty acid to obtain a pharmaceutical composition for treating disorders of external secretion.

According to this invention, the term "fatty acid" includes not only the above-mentioned linoleinovoy acid, di-Homo-gamma-linoleinovoy acid, arachidonic acid, alpha-linolenic acid, eykozapentaenovuyu acid (EPA) and docosahexaenoic acid (DHA), but also a compound containing at least one functional group CT is about acid, regardless of the presence or absence of double bonds in the cyclic group, or a substitute group, the number of carbon atoms, the position or number of double bonds, or modification circuit. In addition, derivatives of fatty acids include not only the above fatty acids, but also compounds such prostaglandin, which include PG, obtained from the above fatty acids, compounds such leukotriene, thromboxanes, hydroxyeicosatetraenoic acid, hydroperoxidation acids or their derivatives.

Moreover, in the present invention derived fatty acids also include a compound that has at least a group-COOH or CH2HE or their functional derivatives (salts, esters, ethers, amides and the like) at a terminal carbon atom, regardless of the presence or absence of a double bond, a cyclic group or a replacement group, the number of carbon atoms, the position and number of double bonds or modification of the chain.

In accordance with the present invention, the term "connection, such prostaglandine" (in the following referred to as "connection, like PG") includes any derivatives or substituted derivatives of compounds having the basic structure of postanowi acid, regardless of the configuration of five-membered rings, number of double connection is in the alpha or beta chains the presence or absence of hydroxy - and oxo groups, or any other Deputy, or any other modification. Because the connection of the present invention, such prostaglandin may possess activity as agonists PG-receptor, such as EP, FP, IP, TP or DP receptor, "connection, like PG" of the present invention may include any compound having agonist activity PG-receptor, regardless of their structure.

Nomenclature of compounds, such prostaglandin and used in this invention based on the numbering system of postanowi acid, the formula (A) which is presented above.

In the formula (A) shows a basic skeleton With-20, but connections like prostaglandin, the present invention is not limited to compounds that have the same number of carbon atoms. In the formula (A) the numbering of the carbon atoms that make up the basic skeleton of the compounds of prostaglandin begins with carboxylic acids (has number 1), and the carbon atoms in the alpha-chain are numbered from 2 to 7 in the direction of five-membered ring, the carbon atoms in the ring are numbered from 8 to 12, carbon atoms in omega-chain are numbered from 13 to 20. When in the alpha chain, the number of carbon atoms decreases, the rooms are excluded in order, starting with position 2, and when in the alpha chain, the number of carbon atoms led is ensured, such compounds are referred to as substituted compounds having the appropriate substituents in position 2, instead of the carboxyl group (C-1). Similarly, when the number of carbon atoms in the omega chain is reduced, the rooms are excluded in the order starting from position 20, and when in omega chain, the number of carbon atoms increases, the carbon atoms after provisions-20 are referred to as deputies. The stereochemistry of the compounds is the same as in the case of the above formula (A), unless otherwise indicated.

In General, each of PGD, PGE and PGF represents a connection PG, having in position 9 and/or -11 substituents different from the hydroxyl group. Such compounds are referred to as 9-dihydroxy-9-substituted-PG compounds or 11 dihydroxy-11-substituted-PG compounds. Connection PG having a hydrogen atom instead of a hydroxyl group, referred to simply as 9 - or 11-dihydroxy connection.

As indicated above, the nomenclature of compounds, such prostaglandin based on the skeleton postanowi acid. However, in the case where the connection has a similar partial structure prostaglandin may use the abbreviation "PG". Thus, the connection PG, in which the alpha-chain is extended by two carbon atoms, that is, having 9 carbon atoms in the alpha-chain is called 2-decarboxy-2-(2-carboxyethyl)-PG compound. Similar is the rule, PG compound having 11 carbon atoms in the alpha-chain is called 2-decarboxy-2-(4-carboxybutyl)-PG compound, and PG compound having 10 carbon atoms in the omega chain, called 20-ethyl-PG compound. However, these compounds can also be named according to the IUPAC nomenclature.

Compounds, such prostaglandin and used in the present invention, can include any of the derivatives of PG. Accordingly, for example, the connection PG1has a double bond in position 13-14 and hydroxyl group in position 15, the connection PG2another double bond at position 5-6, connection RS3has an additional double bond in position 17-18, 15-keto-connection PG is in position-15 oxo group instead of a hydroxyl group, a 15-dihydroxy connection PG is in position 15 a hydrogen atom instead of a hydroxyl group, or any 13,14-dihydro-connection PG, in which the double bond in position 13-14 represents a simple bond or a 13,14-didehydro connection PG, in which the double bond in position 13-14 represents a triple bond. Moreover, examples of the substituted compounds and derivatives include a compound in which the terminal carboxyl group to the alpha chain of the above-described connection etherification, its physiologically acceptable salt, a compound in which the number of carbon atoms in Alf is-or omega chain is decreased or increased, the compound having a side chain (for example, from 1 to 3 carbon atoms) in the alpha or omega chain, the connection with the Deputy/deputies, such as hydroxy, halogen atom, the group of lower alkyl, hydroxy-(lower)alkyl, and oxo group or a double bond (connection) in the five-membered ring compound with the Deputy/deputies, such as halogen atom, oxo group, the aryl and heterocyclic group in the alpha-chain compound with substituents such as halogen atom, oxo group, a hydroxyl, a lower alkoxy group, a lower alkanoyloxy group, cyclo-(lower)alkyl, cyclo-(lower)alkyloxy group, aryl, aryloxy-, heterocyclic group and the heterocyclic oxy group in the omega chain, and a compound having a Deputy, such as lower alkoxy group, a lower alkanoyloxy group, cyclo-(lower)alkyl, cyclo-(lower)alkyloxy group, aryl, aryloxy-, heterocyclic group and the heterocyclic oxy group at the end of the omega chain which is shorter than the regular postanova acid.

The preferred compound used in the present invention, represented by formula (1):

where W1, W2and W3represent atoms of carbon or oxygen, L, M and N are hydrogen atom, hydroxy group, halogen atom, lower alkyl, hydroxy(n is SSI) alkyl or oxo group, in which at least one Deputy from L and M is a group that is different from a hydrogen atom, five-membered ring may have at least one double bond;

Rather it represents a group-CH2HE PINES2HE, -COOH or its functional derivative;

Represents a simple bond, a group-CH2CH2-,

-CH=CH-,-CH2CH2CH2-, -CH=CH-CH2-, -CH2-CH=CH-,

or

Z represents

where R4and R5are hydrogen atoms, hydroxy group, halogen atom, lower alkyl, lower alkoxy group or hydroxy(lower)alkyl, where R4and R5are not both hydroxy group and a lower alkoxy group;

R1is a divalent saturated or unsaturated residue of the lower-medium aliphatic hydrocarbon which is unsubstituted or substituted by a halogen atom, oxo group, hydroxy group, lower alkyl, aryl, or heterocyclic group;

Ra is a saturated or unsaturated residue of the lower-medium aliphatic hydrocarbon which is unsubstituted or substituted by a halogen atom, oxo group, hydroxy group, lower alkyl is m, lower alkoxy group, a lower alkanoyloxy group, a cyclo(lower) alkyl, aryl, aryloxy group, or heterocyclic hydroxy-heterocyclic group; cyclo(lower) alkyl, cyclo(lower) alkyloxy group; the aryl, aryloxy group, or heterocyclic hydroxy-heterocyclic group.

A group of especially preferred compounds among the above described compounds represented by the General formula (II):

where L and M represent hydrogen atom, hydroxy group, halogen atom, lower alkyl, hydroxy(lower) alkyl or oxo group, where at least one Deputy from L and M is a group that is different from a hydrogen atom, five-membered ring may have at least one double bond;

A represents a-CH2OH, -COCH2OH, -COOH or its functional derivative;

Represents a simple bond, -CH2CH2-, -CH=CH-,-CH2CH2CH2-, -CH=CH-CH2-, -CH2-CH=CH-,or,

Z represents

where R4and R5is hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy(lower) alkyl, where R4and R5are not both hydroxy and lower alkoxy-gr is ppoi;

X1and X2represent hydrogen, halogen or lower alkyl;

R1is a divalent saturated or unsaturated residue of the lower-medium aliphatic hydrocarbon which is unsubstituted or substituted by a halogen atom, oxo group, hydroxy group, lower alkyl, aryl or heterocyclic group;

R2represents a simple bond or a lower alkylene;

R3is lower alkyl, lower alkoxy group, a cyclo-(lower)alkyl, cyclo-(lower)alkyloxy group, aryl, aryloxy-, heterocyclic or heterocyclic oxy group.

Another preferred compound used in the present invention, represented by formula (III):

where Q1and Q2represent hydrogen or lower alkyl, or Q1and Q2associated with the formation of the group -(CH2)n-, in which n is 1, 2 or 0, with the six-membered ring may have at least one double bond;

A represents a-CH2HE, -COOH2HE, -COOH or its functional derivative;

Represents a simple bond, -CH2CH2-, -CH=CH-,

-CH2CH2CH2-, -CH=CH-CH2-, -CH2-CH=CH-,or

Z represents

where R4and R5are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy group or hydroxy(lower)alkyl, where R4and R5are not both hydroxy group and a lower alkoxy group;

R1is a divalent saturated or unsaturated residue of the lower-medium aliphatic hydrocarbon which is unsubstituted or substituted by a halogen atom, oxo group, hydroxy group, lower alkyl, aryl, or heterocyclic group;

Ra is a saturated or unsaturated residue of the lower-medium aliphatic hydrocarbon which is unsubstituted or substituted by a halogen atom, oxo group, hydroxy group, alkyl, lower alkoxy group, a lower alkanoyloxy group, a cyclo-(lower)alkyl, cyclo-(lower)alkyloxy group, aryl, aryloxy-, heterocyclic or heterocyclic oxy group; cyclo-(lower)alkyl, cyclo-(lower)alkyloxy group; aryl; aryloxy-; heterocyclic or heterocyclic oxy group; and six-membered ring may optionally to have one or more double bonds and may optionally contain conjugated system.

Among the above described compounds of formula (III) is preferred type connected to the th with the benzene ring cycle in the six-membered ring.

In the above formula assumes that the term "unsaturated" in the definitions for R1and Raincludes at least one or more double bonds and/or triple bonds that are located between the carbon atoms of the main and/or side chains as isolated, separate or sequential. In accordance with conventional nomenclature, the unsaturated linkage between two consecutive positions is represented by the designation of a small number to these two provisions, and the unsaturated bond between two distant positions represented by the designation of both provisions. Preferred unsaturated bonds represent a double bond in position 2 and double or triple bond in position 5.

The term "lower-medium aliphatic hydrocarbon" means a hydrocarbon having a linear or branched chain of carbon atoms is from 1 to 14, and a side chain preferably contains from 1 to 3 carbon atoms. Preferably, the substituent R1contains from 1 to 10, more preferably from 1 to 8 carbon atoms, and the preferred substituent Racontains from 1 to 10, more preferably from 1 to 8 carbon atoms.

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

The term "lower" means a group containing from 1 to 6 carbon atoms, unless otherwise indicated.

Ter is in the "lower alkyl" means a saturated hydrocarbon with a linear or branched chain, which contains from 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl.

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

The term "hydroxy(lower)alkyl" means the above-described alkyl, which is substituted by at least one hydroxyl group, such as hydroxymethyl, 1-hydro-xiety, 2-hydroxyethyl and 1-methyl-1-hydroxyethyl.

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

The term "lower cycloalkyl" means a group resulting from cyclization of the lower alkyl groups containing 3 or more carbon atoms, as described above, for example cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "cyclo(lower)alkyloxy" means a group represented by the formula cycloalkyl-O-, in which cycloalkyl described above.

The term "aryl" includes aromatic hydrocarbon rings (preferably monocyclic group), which may be substituted, for example, phenyl, talila and xilian. In this case, examples of the substituent include a halogen atom and a lower alkyl group substituted with halogen, where the halogen atom is a lower alkyl group are the same as explained above.

The term "aryloxy" means a group represented by the formula ArO-, in which Ar represents an aryl group described above.

The term "heterocyclic" includes groups from mono - to tricyclic, preferably monocyclic heterocyclic group, which is a ring containing from 5 to 14 carbon atoms, preferably from 5 to 10 carbon atoms, and optionally substituted with a carbon atom and from 1 to 4, preferably from 1 to 3 heteroatoms of one or two kinds selected from a nitrogen atom, oxygen atom and sulfur atom. Examples of heterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, furutani, pyranyl, pyridyl, pyridil, pyrimidyl, Persil, 2-pyrrolidyl, pyrrolidinyl, 2-imidazolyl, imidazolidinyl, 2-pyrazoline, pyrazolidine, piperidine, piperazinil, morpholino, indolyl, benzothiazyl, hinely, ethanolic, peril, chinadoll, carbazolyl, acridines, phenanthridines, benzimidazolyl, benzimidazolinyl, benzothiazolyl, phenothiazinyl. In this case, examples of the substituents include a halogen atom and a lower alkyl group substituted with halogen, where the halogen atom and a lower alkyl group are as described above.

The term "heterocyclic oxy group" Osnach the et group, represented by the formula HCO-where Hc represents a heterocyclic group described above.

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

Examples of suitable pharmaceutically acceptable salts include non-toxic salts, which are usually used, and salts with inorganic bases, for example alkali metal salts (sodium salt, potassium salt and the like), salts of alkaline earth metals (calcium salt, magnesium salt and the like); ammonium salts; salts with organic bases, for example salts of amines (such as salt of methylamine, dimethylamine salt, salt cyclohexylamine, salt benzylamine, salt, piperidine salt, Ethylenediamine, ethanolamine salt, diethanolamine salt, triethanolamine salt, salt of Tris(hydroxymethylamino)ethane, salt monomethylethanolamine, salt lysine salt of procaine salt and caffeine); salts of basic amino acids (such as arginine salt and lysine salt), salts of tetraalkylammonium and the like. These salts can be obtained, for example, from the corresponding acids and bases in accordance with a conventional method or a salt exchange.

Examples of ethers include alkalemia esters, for example esters of lower Akilov, such as methyl ether, ethyl ether, propyl ether, isop opravy ether, butyl ester, isobutyl ester, tert-butyl methyl ether, pentalogy ether and 1-cyclopropylethyl ether; and esters of secondary and higher Akilov, such as oktilovom ether, ethylhexyloxy ester, lauric 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 hydroxy(lower) Akilov, such as hydroxyethyloxy ether and hydroxyisopropyl ether; esters (lower)alkoxy(lower) alkyl such as methoxymethyl ether and 1-methoxyethylamine ether; optionally substituted dearlove ethers such as phenyl ether, tailby ether, tert-BUTYLPEROXY ester, salicylic ether, 3,4-dimethoxyphenyl ether and benzamidophenyl ester; and aryl(lower)alkalemia esters, such as benzyl ether, trailovic ether and benzhydrylamine ether.

Examples of 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 methyl ether, pentalogy ether and 1-cyclopropylethyl ether; esters of lower alkenyl, such as vinyl ether and allyl ether; esters of lower alkinyl, such as atinlay ether and propenyloxy ether;esters of hydroxy(lower) Akilov, such as hydroxyethyloxy ether; esters (lower)ALCO-XI(lower)alkyl such as methoxymethyl ester and 1-methoxyethylamine esters; and also, for example, optionally substituted akrilovye ethers such as phenyl ether, tailby ether, tert-BUTYLPEROXY ester, salicylic ether, 3,4-dimethoxyphenyl ether and benzamidophenyl ester; and aryl(lower)alkalemia esters, such as benzyl ether, trailovic ether and benzhydrylamine ether. Examples of amides include mono - or di-(lower)alkylamide, such as methylamide, ethylamide and dimethenamid; arylamide, such as anilide and toluidin; and alkyl or arylsulfonate, such as methylsulfonylamino, ethylsulfonyl and tolilsulfonil.

Preferred examples of M and L include hydroxy and oxo groups, and especially, when M represents a hydroxy-, a L - oxo-group, which provides the structure of five-membered rings of the so-called PGE-type.

Preferred examples of A-groups include-COOH and pharmaceutically acceptable salts, esters and amides.

In formulas (I) and (II) is preferably a group-CH2-CH2-that provides the structure of the so-called 13,14-dihydro-type.

In the formula (III) preferably represents a simple link.

In formulas (I) and (II) Z is preferably a group =O, which provides the structure so n is called keto-type.

In the formula (III) Z is preferably hydroxy group.

Preferred examples X1and X2such that at least one of them is a halogen atom, more preferably, both of the substituent are halogen atoms, especially fluorine, which provides the structure of the so-called 16,16-Diptera-type.

Preferably R1represents a hydrocarbon radical containing 2-10 carbon atoms, more preferably 4-8 carbon atoms.

Examples R1include, for example, the following groups:

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

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

-CH2-CC-CH2-CH2,-CH2-CH2-CH2-CH2-CH2-CH2-,

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

-CH2- C-CH2-CH2-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-CH2CH 2-CH2-CH2-CH2-CH=CH-, -CH2- C-CH2-CH2-CH2-CH2-CH2-,

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

Preferably Ra is a hydrocarbon radical containing 1-10 carbon atoms, more preferably 1 to 8 carbon atoms, and especially one that has one or two side chains with one carbon atom.

The configuration of the ring and the alpha and/or omega-chains in the above formula (I) may be the same as in the primary PG, or different from it. However, the present invention also includes mixtures of compounds having the configuration of the primary type, and compounds having a configuration is not the primary type.

Example of typical compounds according to the present invention is 13,14-dihydro-15-keto-16-mono - or di-fluoro-PGE compound or its derivatives.

When 15-keto-PG compound of the present invention has a saturated bond between positions 13 and 14, it can be in equilibrium keto-Polyacetal with the formation of Polyacetal with the participation of the hydroxy group at position 11 and keto-group in position 15.

If there are such tautomeric isomers, as indicated above, the share of both tautomeric isomers varies depending on the structure of the rest of the second part of the molecule or species present deputies. Sometimes the predominant presence of one isomer over the other isomer. However, it should be recognized that used in this invention compounds include both isomers. In addition, although used in this invention compounds can be represented by the structural formula or name-based keto-type, regardless of presence or absence.

The above-described derivatives of fatty acids of the present invention are effective in the treatment of disorders of external secretion, especially in the treatment of low slezootdelenia, including disorders of the basal secretion of tears, as well as at the improvement and treatment of conditions of dryness of the eyes (i.e. reduced secretion of tear fluid and related disorders of the cornea). Moreover, these compounds are also effective in improving low salivation, as well as at the improvement and treatment of symptoms of dry mouth. Therefore, the compound is effective for treating disorders of external secretion, especially low slezootdelenia, including disorders of the basal secretion of tears and/or symptoms of dry eye, or reduced salivation, and/or the syndrome of dryness in the mouth.

The term "treating" or "treatment"as used in this invention, refers to any means of control of the patient's condition, including prevention, the ear is, the weakening of the syndrome and the withdrawal or weakening of the development of the syndrome.

Patients who can be approved treatment by the method of the present invention, are those who suffer from disorders of external secretion, including xeroz, such as the syndrome of dry eyes (xerophthalmia), symptoms of dry mouth (xerostomia), a syndrome of dryness of the nasal mucosa (ceramictile)syndrome dry skin (xeroderma) and "a syndrome of a dry vagina" (the symptom of vaginal dryness); and chronic pancreatitis, chronic gastritis and chronic bronchitis caused by reduction of external secretion. This is especially true for patients whose condition apparently caused by the syndrome of dry eye, including decreased tearing, alacrima, xerophthalmia, Sjogren syndrome, drying keratoconjunctivitis syndrome malignant pericardial Eritrea, eye disease, blepharida marginal, diabetes, dry eye after cataract surgery and dry eye associated with allergic conjunctivitis. In addition, it refers to patients with the syndrome of dry eye, which can be caused by aging, long-term work with visual display terminal, dry rooms with air conditioning.

Systemic factors that can cause symptoms of dry mouth include a feverish state, both varovanie, the endocrinopathy (myxedema, graves ' disease, incipient diabetes, and others), metabolic disorders (diabetes, uremia, cirrhosis, and others), vitamin a deficiency or vitamin b, autoimmune diseases (Sjogren syndrome, progressive scleroderma and others), anemia, bleeding, aging, exposure to various drugs (sedatives, parasympatholytics medicines, antihistamines, and others). In addition, local factors may include inflammation of the salivary glands, atrophy of the salivary gland complications after radiotherapy and malignancy (ectodermal dysplasia and other), etc.

Violation of external secretion is a condition when there is an abnormal external secretion (i.e., the reduction or cessation of secretion), which may be caused by different etiology, especially the state with an abnormal secretion of the lacrimal fluid, including basal secretion of tears and abnormal secretion of saliva.

The method of the present invention can be carried out by injecting the patient with a composition containing as an active ingredient derived fatty acids, either oral or parenteral. Dosage form of the composition can be in the form of eye drops, ophthalmic ointments, sublingual tablets, lozenges, chewable tablets, mouthwash R is a, aerosol, ointment, powder, granules, tablets, capsules, suppositories and vaginal suppositories. Preferred are dosage forms for local use, such as eye drops, ophthalmic ointments, sublingual tablets and ointment. These dosage forms can be prepared according to any of the traditional methods.

The composition of the present invention may be mixed with a suitable pharmaceutically acceptable additive. This additive is a compound that can be used with unsaturated derivatives of fatty acids of this invention, and it may include environment for a drug, diluent, filler, solvent, grease, synergist, a binder, a shredder, a covering agent, encapsulating agent, the base of the ointment base of the candle, the base of the aerosol, emulsifier, dispersing agent, suspendisse agent, thickening agent, isotonic agent, buffer agent, an analgetic agent, preservative, antioxidant, pharmacological modifier, a flavoring, a colorant and a functional agent (for example, cyclodextrin and biodegradable polymer). The additive may be selected on the basis of any reference on pharmaceuticals.

The composition of the present invention can also be mixed with any pharmaceutically active agent, as specified AG the NT is compatible with the present invention.

In the present invention an "effective amount" is derived fatty acids may vary depending on the type of fatty acid, the condition of the patient, his age and weight, dosage form, duration of treatment, the desired therapeutic effect, etc. for Example, when the composition is to be used for treatment, is made in the form of eye drops, dosage form contains from 0.000001 to 10 wt. %, preferably from 0.00001 to 1/0 masses. % derived fatty acid and may be given a few drops in one eye, preferably 1-4 drops, several times a day, preferably 1-6 times a day. When the composition is made up in the form of sublingual tablets, dosage form containing from 0.000001 to 10 wt. %, preferably from 0.00001 to 1.0 mass. % derived fatty acids, may be injected into the cavity of the mouth several times, preferably 1 to 6 times a day. In addition, when the composition is made up in the form of ointments, local injection dosage forms containing from 0.000001 to 10 wt. %, preferably from 0.00001 to 1.0 mass. % derived fatty acids, several times, preferably 1 to 6 times a day can provide a sufficient effect.

Examples

The present invention will be illustrated in more detail using the following examples. These examples should not be used as any limitations this is the future of invention.

The test example 1. The impact on the overall secretion of tears healthy rabbits

1) the animals in the study

Use of male Japanese albino rabbits (Std: JW/CSK).

2) route of administration

Ophthalmic solution containing 0.001% is 13,14-dihydro-15-keto-16,16-debtor-PGE1as the active component of the present invention, is prepared and used as the test composition. As a control using the specified media solution without the active component.

Each composition separately buried in eight eyes in the amount of 30 μl/eye. After the introduction examine the change in the selection tears in time in accordance with the following method.

3) Survey, the total secretion of tears

Total secretion of tears determine prior to backfilling (0 h) and after backfilling, 0.5, 2, 4 and 6 hours

Without anesthesia each test animal in conjuctival pouch impose one edge of the strip Schirmer (Showa Yakuhin Kako Co., Ltd., no products 70080). After one minute, the strip is removed and record the length of the wetted part of the scale, which is marked on the strip in order to determine the total amount of released tears.

4) the test Result

The test results of the total secretion of tears is given in table 1. After introduction of the solution as the test animal and the control animal not zaregistrirovannykh stimulating reactions such as redness of the outer part of the eye. The obtained data are presented along with statistical analysis.

Table 1
Control

group
The number of eye testTime, hThe total secretion of tears, mm/min
8Before the introduction of the solution5,5±0,3
80,58,1±0,7
828,3±0,8
847,3±0,7
867,1±0,7
The tested group, 0,001%8Before the introduction of the solution5,3±0,2
80,517,0±0,5**
8214,1±0,5**
8411,7±0,6**
8610,5±1,0*
*The reliability of p< 0,05

**p<0,01: comparison with the value for the control group at the corresponding time (t-distribution the T-test)

In accordance with the above results in the test group treated with the compound of this is part II of the invention as an active ingredient, registered a significant increase in the total number of emitted tears at a dose that does not cause any stimulating reactions, such as redness of the outer part of the eye. Therefore, the connection of the present invention exhibits activity against increasing the total quantity of the allocated tears without any stimulating reactions.

The test example 2. The impact of connections on attenuated total secretion of tears, weak basal secretion of tears and keratoepithelin defeat rabbits in the model of the syndrome of dry eye, which is caused by denervation of the trigeminal nerve

1) the animals in the study

Use fifteen male Japanese albino rabbits (Std: JW/CSK).

2) generating a model of syndrome dryness of the eyes of rabbits by denervation of the trigeminal nerve.

i) the working methods

Rabbits who have shaved the hair on the nape of the neck, intraperitoneally injected urethane (company Aldrich) at a dose of 1G/kg

After disinfection shaved area make a cut in the skin in the midline from the anterior bone to the root of the ear, and separate the muscle tissue around the periosteum, the temporal bone and mandibular articular process. After separation of the tissue in the bones make a hole the size of 2 of 1.5 cm from the parietal to the middle region to the temporal bone using a bone drill (firm Urawa Kogyo Co. Ltd. Minitor C-130) under x the surgical microscope (Konan Camera R& I Inc., PMO-50). Then separate the cerebral membrane from cranial bones, while between the temporal bone and brain shell retain the insertion of a cotton swab. After the surgery Department to the base of the skull spend a further separation in the direction of the medial border of the petrous part of the temporal bone in the skull cavity in order to find the trigeminal nerve in this area. Then make an incision of brain shell of approximately 1-2 mm in the nasal side of the Crescent of the cyst. After dissection of both branches of the nerve bundle, i.e. the first branch (ophthalmic nerve) and the second branches of the maxillary nerve, the trigeminal nerve, lateral pull and cut with corneoscleral scissors. Immediately after surgery, marked narrowing of the pupil of the eye, located on the same side, and then remove the paste with a cotton swab and closed suture the skin on the head of a rabbit. After surgery intramuscularly administered antibiotic (Mycelia Sol® Meiji) at a dose of 0.1 ml/kg

The denervation of the trigeminal nerve carries out only on the side of the left eye, while on the side of the right eye, so it was denervation of the trigeminal nerve or its simulation.

After surgery the animals are in a stable condition, and they have discovered weakened the overall secretion of tears, and keratoepithelin defeat subjected to the following test.

3) With the persons introduction

As the active component of the present invention use 13,14-dihydro-15-keto-16,16-debtor-PGE1in order to prepare the subjects eye drops containing of 0.0001% and 0.001% of the compound. As a control, use the media eye drops without active component.

Each composition daily fluid in the eye in the amount of 30 μl/eye twice a day (at 10:00 and 18:00) in two weeks. Process five eyes in each of the test groups and the control group, and then examine the overall secretion of tears, basal secretion of tears and keratoepithelin defeat as follows.

3) Examination

(i) the overall secretion of tears (Schirmer test)

Total secretion of tears determine before backfilling (0 week) and after 1, 2 and 3 weeks after the start of the test, 2 hours after the first instillation on the day of the survey.

Without anesthesia each test animal in conjuctival pouch impose one edge of the strip Schirmer (Showa Yakuhin Kako Co., Ltd., no products 70080). After one minute, the strip is removed and record the length of the wetted part of the scale, which is marked on the strip in order to determine the total amount of released tears. ii) the basal secretion of tears

Basal secretion of tears determine before backfilling (0 week) and after 1, 2 and 3 weeks after the start of the test, after 2 h, after which, I can pay tithing backfilling, on the day of the survey.

Keratoconjuctivitis anaesthetize the instillation of 4% lidocaine (Xylocain®4% for ophthalmic solution; firm Fujisawa Pharmaceutical Co. Ltd.), after about 5 minutes wipe eye drops and tears around the eye of the century and register the loss of sensitivity esthesiometer type Cochet-Bonnet. Then in conjuctival pouch impose one edge of the strip Schirmer and incubated for 5 minutes this strip. The length of the wetted part of the register on the scale on the strip.

Basal secretion of tears is expressed as an average value over one minute, which is calculated from glands found within 4 minutes by subtracting the initial value (1 min) of the amount received during the 5-minute Schirmer test, to exclude spontaneous volume of tears, enclosed in conjuctive bag.

iii) keratoepithelin defeat

Keratoepithelin defeat determine before backfilling (0 week) and after 1, 2 and 3 weeks after the start of the test, 2 hours after the first instillation, the day of the survey.

Each animal is placed in the latch stainless steel and introduce him dropwise 50 μl of a mixture of 1% rose Bengal dye and 1% fluorescein to stain keratoconjuctivitis epithelium. The painted area, then there is an abnormal region of the epithelium, anywayt in accordance with the criteria are shown in table 2.

Table 2
ScoreThe colored area keratoconjuctivitis
0No
0,5Lightly painted only part of the field
1The area is less than 1/4
2The region is greater than 1/4 and less than 1/2
3The region is greater than 1/2 and less than 3/4
4The region is greater than 3/4

4) the results of the test

The test results of the total secretion of tears in table 3, the results of the basal secretion of tears is shown in table 4 and data keratoepithelin lesions are shown in table 5. The obtained data are presented along with statistical analysis.

In accordance with the above results in the test group treated with the compound of the present invention as an active ingredient, registered improvement attenuated total secretion of tears and basal secretion of tears, and keratoepithelin lesions, accompanied by a weakening of the secretion of tears that nabludaetsa the model's syndrome dry eye animals. Therefore, the connection of the present invention, apparently, is an effective treatment for low slezootdelenia, including disorders of the basal secretion of tears, and the syndrome of dry eye, i.e. hipoglucemia and associated keratoepithelin defeat.

The test example 3. Stimulation of salivation

To determine the effect of the composition of the present invention on the secretion of saliva.

1) the animals in the study

Use of male and female rats (line Crj: CD). In each test and control group contained 16 animals.

2) route of administration

As the active component of the present invention use 13,14-dihydro-15-keto-16,16-debtor-PGE1in order to prepare the test solution containing 0.2 mg/ml of the connection.

Forcibly injected 5 ml/kg of solution (1 mg/kg compound) 1 time per day. Animals of the control group once a day administered 5 ml/kg of media without the active ingredient. Introduction connection lasts 4 weeks.

3) Examination

The amount of saliva in animals of the control group and the test group visually appreciate every day.

4) the Result of

In the group of animals who enter derived fatty acids of the present invention, stimulation of salivation was observed in 8 rats of 16 on day 10 after the start of treatment, and then the number of rats is excited slyunovydelenie increased with time trials. After 22 days after the start of the experiment each of the 16 rats, which were injected composition, the detected excitation of salivation, while in the control group, all animals remained normal saliva during the entire test period.

The test example 4. Stimulation of salivation

To determine the effect of the composition of the present invention on the secretion of saliva.

1) the animals in the study

Use of male rats (line 3D). In each test and control group contained 8 animals.

2) route of administration

As the active component of the present invention use 13,14-dihydro-15-keto-16,16-debtor-PGE1in order to prepare the test solution containing 0.2 mg/ml of the connection.

Forcibly injected 5 ml/kg of solution (1.0 mg/kg compound) 1 time per day. Animals of the control group once a day administered 5 ml/kg of 1%solution of Polysorbate. Introduction connection lasts 10 days.

3) Examination

The amount of saliva in animals of the control group and the test group was measured after 1 h after injection on day 10. Enter the edge of the filter paper (the indicator strip Schirmer, Showa Yakuhin Kako Co., Ltd) between the lower lip and jaw. After three minutes the filter paper is removed and determine the weight of saliva according to the following formula:

The weight of the saliva = (weight of filter paper with saliva) - (weight circular is but a paper filter).

4) the Result of

The test results in the secretion of saliva are shown in table 6.

Table 6
The control groupThe number of animalsThe average weight of saliva, mg (±standard deviation)
84,6±0,9
The test group818,1±5,6*
**The reliability of p< 0.05 compared with the value for the control group (U-test Mann Whitney)

In the group of animals treated with a derivative of a fatty acid of the present invention, the saliva is significantly increased compared with the secretion of saliva in the control animals.

The test example 5. The impact on the overall secretion of tears healthy rabbits

1) the animals in the study

Use of male Japanese albino rabbits.

2) route of administration

Ophthalmic solution containing the active ingredient of the present invention, is prepared and used as the test composition.

Each composition separately the fluid in the eye in the amount of 30 μl/eye.

3) Survey of the number of emitted tears

Total secretion of tears determine prior to backfilling (0 h) and 2 h after instillation of the solution.

Without anesthesia to the each trained animal in conjuctival pouch impose one edge of the strip Schirmer (Showa Yakuhin Kako Co., Ltd.). After one minute, the strip is removed and record the length of the wetted part of the scale, which is marked on the strip in order to determine the total amount of released tears.

The degree (in%) increase in the total quantity of the allocated tears count after 2 h after instillation of the solution and compare with the original number (0 h).

4) the Result of

The test results of the total secretion of tears is given in table 7. In addition to the data shown in the table, after administration of the tested compounds in animals not registered any stimulating reactions, such as redness of the outer part of the eye.

Table 7
Test connectionThe concentration of the test compounds, mg/mlThe number of eye testThe relative increase in the total secretion, %
Connection 130440,7
Connection 210452,5
Connection 310452,0
Connection 43461,8
Connection 53443,5
Soy is inania 6 100444,0
Connection 72000456,9
Compound 81424,8

Connection 1: methyl ester 15-dihydroxy-13,14-dihydro-14,15-degidro-16-keto-17,17-debtor-PGE1

Connection 2: 13,14-dihydro-15-keto-16,16-debtor-20-ethyl-PGE1

Compound 3: 2-decarboxy-2-(2-carboxyethyl)-13,14-dihydro-15-keto-16,16-debtor-RFE1

Compound 4: methyl ester 13,14-dihydro-15-keto-16,16-debtor-PGF2A

Connection 5: 11 dihydroxy-13,14-dihydro-15-keto-16,16-debtor-PGE1

Compound 6: 13,14-dihydro-15-keto-PGE1

Compound 7: complex isopropyl ester 2-decarboxy-2-(2-carboxyethyl)-13,14-dihydro-15-keto-16,16-debtor-20-ethyl-PGE1

Compound 8: 13,14-dihydro-15-keto-16,16-debtor-PGE2.

1. Composition for treating disorders of external secretion, which contains as active ingredient a compound of General formula (I)

where L, M and N are hydrogen, hydroxy - or oxo-, where at least one of L and M is a group that is different from a hydrogen atom, five-membered ring may have at least one double bond;

And represents-COOH or its salt, ester or amide;

Predstavljaet a-CH 2CH2- or-CH2-CH=CH-;

Z represents

where R4and R5is hydrogen or halogen;

R1is a saturated or unsaturated residue C1-14aliphatic hydrocarbon;

Ra is a saturated or unsaturated residue C1-14aliphatic hydrocarbon which is unsubstituted or substituted by halogen or C1-6.

2. The composition according to claim 1, where Ra substituted with halogen.

3. The composition according to claim 1, in which the compound represented by the General formula (II)

where L and M is hydrogen, hydroxy or oxoprop, where at least one of L and M is a group that is different from a hydrogen atom, five-membered ring may have at least one double bond;

And represents-COOH, its salt, ester or amide;

Represents a-CH2CH2-or-CH=CH-CH2-;

Z represents

where R4and R5is hydrogen or halogen;

X1and X2represent hydrogen or halogen;

R1is a divalent saturated or unsaturated residue C1-14aliphatic hydrocarbon;

R2represents a simple bond or a C1-6kilen;

R3is1-6the alkyl.

4. The composition according to claim 3, where at least one of X1and X2is halogen.

5. Composition according to any one of claims 1 to 4, which is used for treatment of symptoms of dry eye.

6. Composition according to any one of claims 1 to 4, which is used for the treatment of hypoglacemia.

7. Composition according to any one of claims 1 to 4, which is used for treatment of symptoms of dry mouth.

8. Composition according to any one of claims 1 to 4, which is used to treat weakened salivation.

9. The composition according to claim 1, in which the connection such as prostaglandin, is an agonist PG-receptor.

10. The composition according to claim 1, which is in a unit dosage form for local use.

11. The composition of claim 10, dosage form which is convenient for ophthalmic use.

12. The composition according to claim 11, which is prepared in the form of eye drops.

13. The composition of claim 10, dosage form which is convenient for insertion into the oral cavity.

14. The composition according to item 13, which is prepared in the form of sublingual tablets.

15. The composition according to claim 1, in which the connection specified is (I) selected from the group consisting of

13,14-dihydro-15-keto-16,16-debtor-PGE1;

methyl ester 15-dihydroxy-13,14-dihydro-14,15-degidro-16-keto-17,17-debtor-PGE1;

13,14-dihydro-15-keto-16,16-debtor-20-ethyl-PGE1/sub> ;

2 decarboxy-2-(2-carboxyethyl)-13,14-dihydro-15-keto-16,16-debtor-PGE1;

methyl ester 13,14-dihydro-15-keto-16,16-debtor-PGF2A;

11 dihydroxy-13,14-dihydro-15-keto-16,16-debtor-PGE1;

13,14-dihydro-15-keto-PGE1;

complex isopropyl ester 2-decarboxy-2-(2-carboxyethyl)-13,14-dihydro-15-keto-16,tifton-20-ethyl-PGE1and

13,14-dihydro-15-keto-16,16-debtor-PGE2.

16. 11 dihydroxy-13,14-dihydro-15-keto-16,16-debtor-PGE.

17. 11 dihydroxy-13,14-dihydro-15-keto-16,16-debtor-PGE1.

18. A method of treatment of disorders of external secretion, which comprises the administration to a subject in need of such treatment, an effective amount of compounds of General form (I)

where L, M and N are hydrogen, hydroxy - or oxo-, where at least one of L and M is a group that is different from a hydrogen atom, five-membered ring may have at least one double bond;

And represents-COOH or its salt, ester or amide;

Represents a-CH2CH2- or-CH2-CH=CH-;

Z represents

where R4and R5is hydrogen or halogen;

R1is a saturated or unsaturated residue C1-14aliphatic is glendorado;

Ra is a saturated or unsaturated residue C1-14aliphatic hydrocarbon which is unsubstituted or substituted with halogen or1-6,

or of a composition according to claim 1.

19. The method according to p, where Ra substituted with halogen.

20. The method according to p, wherein the compound represented by the General formula (II)

where L and M is hydrogen, hydroxy or oxoprop, where at least one of L and M is a group that is different from a hydrogen atom, five-membered ring may have at least one double bond; And a represents-COOH, its salt, ester or amide; a represents a-CH2CH2- or-CH=CH-CH2-; Z represents a

where R4and R5is hydrogen or halogen;

X1and X2represent hydrogen or halogen;

R1is a divalent saturated or unsaturated residue C1-14aliphatic hydrocarbons:

R2represents a simple bond or a C1-6alkylen;

and R3is C1-6the alkyl.

21. The method according to claim 20, where at least one of X1and X2is halogen.

22. The method according to p, in which the indicated compound (I) selected from the group consisting of

13,14-dihydro-15-keto-16,16-debtor-PGE1;

difficult methyl ever-dihydroxy-13,14-dihydro-14,15-degidro-16-keto-17,17-debtor-PGE 1;

13,14-dihydro-15-keto-16,16-debtor-20-ethyl-PGE1;

2 decarboxy-2-(2-carboxyethyl)-13,14-dihydro-15-keto-16,16-debtor-PGE1;

methyl ester 13,14-dihydro-15-keto-16,16-debtor-PGE2A:

11 dihydroxy-13,14-dihydro-15-keto-16,16-debtor-PGE1;

13,14-dihydro-15-keto-PGE1;

complex isopropyl ester 2-decarboxy-2-(2-carboxyethyl)-13,14-dihydro-15-keto-16,16-debtor-20-ethyl-PGE1and

13,14-dihydro-15-keto-16,16-debtor-PGE2.

23. The method according to p in which the specified connection is an 11-dihydroxy-13,14-dihydro-15-keto-16,16-debtor-PGE.

24. The method according to p in which the specified connection is an 11-dihydroxy-13,14-dihydro-15-keto-16,16-debtor-PGE1.

25. The method according to any of PP-24, where the violation of external secretion is a syndrome of a dry eye.

26. The method according to any of PP-24, where the violation of external secretion represents hypoglacemia.

27. The method according to any of PP-24, where the violation of external secretion is a syndrome of dryness in the mouth.

28. The method according to any of PP-24, where the violation of external secretion is a weakened salivation.

29. The method according to p in which the specified connection is an agonist PG-receptor.

30. The method according to p, which includes a eye appointment to the position, containing the compound of General formula (I), dosage form which is convenient for ophthalmic use.

31. The method according to item 30, in which this composition is prepared in the form of eye drops.

32. The method according to p, which includes oral patient compositions containing compounds of General formula (I), dosage form which is convenient for insertion into the oral cavity.

33. The method according to p in which this composition is prepared in the form of sublingual tablets.



 

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2 ex

FIELD: medicine, surgery.

SUBSTANCE: one should sanitize a fistulous canal with antiseptic solution by introducing a medicinal substance of the following composition: homogenized placental tissue 30-35 ml; 5% ε-aminocaproic acid 6-10 ml; kanamycin sulfate 1.0-2.0 g; collagen 400-600 mg; omnipak-350 10-35 ml; patient's native plasma - up to 100 ml. The innovation suggested provides rapid healing in case of fistulas due to developing reticular structure along the whole fistulous route that contains components complexly affecting the process for fistula's healing.

EFFECT: higher efficiency of obturation.

3 dwg, 5 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: method involves applying physiologic saline with ozone concentration of 5-10 mcg/l that is introduced in rectal way in the amount of 40 ml at a rate of 30 drops/min with pause 1-2 times per week within 2 months on the background of antibacterial treatment.

EFFECT: enhanced effectiveness in closing disintegration cavities and stopping bacterioexcretion.

FIELD: medicine.

SUBSTANCE: method involves determining value of bronchial mucociliar clearance MCC of radiopharmaceutical preparation in % per 1 h, using radioaerosol method. Discriminant equation is to be solved D=-0.6* MCC. D being greater than -15.51, instable bronchial asthma clinical course is to be predicted.

EFFECT: high reliability of prognosis.

FIELD: medicine, pediatrics.

SUBSTANCE: the present innovation deals with antenatal prophylaxis of transitive myocardial dysfunction in neonatals before their birth. One should introduce limontar daily per 1 tablet for pregnant women at the period of 35-36 wk gestation additionally to conventional therapy. It is necessary to conduct one course of prophylaxis for 14 d. The innovation provides normalization of myocardial contractile function in neonatals and prophylaxis in development of side effects caused by the preparation introduced.

EFFECT: higher efficiency of prophylaxis.

3 ex, 1 tbl

FIELD: medicine, surgery, urology.

SUBSTANCE: method involves administration of hypochlorite sodium in the concentration 0.004% that is combined with its intra-bladder administration in the concentration 0.06% in pre-operative and post-operative periods. Invention promotes to complete sanitation of urinary ways for the shortest time after surgery of transurethral resection of prostate. Invention can be used in prophylaxis of suppurative-inflammatory complications in patients with benign prostate hyperplasia in post-operative period.

EFFECT: improved method for prophylaxis.

2 ex

FIELD: medicine, obstetrics.

SUBSTANCE: invention relates to a method for treatment of delivery activity weakness. Method involves simultaneous administration of prostaglandin F in the concentration 12.5 mcg/ml at the rate 8 mcg/min and adenosine triphosphate sodium in the concentration 0.25 mcg/ml at the rate 0.25 mcg/min. Infusion continues up to end of the second stage of delivery. Method provides enhancing the delivery activity, increasing rate of uterine orifice opening on the background of the reduced dose of prostaglandin.

EFFECT: improved treatment method.

3 ex

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: invention relates to new applying EP4 receptors agonist for treatment and/or prophylaxis of diseases associated with loss of osseous mass. Agonists of EP4 receptors show high effectiveness in treatment of diseases associated with loss of osseous mass, among the, as osteoporosis of different genesis. Agonists of EP4 receptors involve prostaglandin skeleton base.

EFFECT: valuable medicinal properties of pharmaceutical composition.

16 cl, 3 tbl, 5 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to 1-ethanolamide PGF of formula I useful in relaxation of mammalian intraocular pressure. Claimed substance unlike majority of ocular hypotensive prostaglandins doesn't effect through FP-receptor.

EFFECT: new effective compound for relaxation of mammalian intraocular pressure.

4 cl, 1 ex, 16 dwg, 16 tbl

FIELD: animals science.

SUBSTANCE: the present innovation deals with intramuscular injection of sodium salt preparation cloprostenol 30-45 min before placing at the dosage of 750 mcg/animal. The method provides increased reproductive function, enhances sexual reflex, increases the volume of ejaculate, concentration, activity and quality of spermatozoa.

EFFECT: higher efficiency of breeding.

2 ex, 3 tbl

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

The invention relates to medicine, in particular to obstetrics

The invention relates to medicine and pharmacy, namely, set for induction of labour

The invention relates to the field of medicine and organic chemistry and relates to new derivatives of prostaglandin F-type used as an ocular hypotensive drugs, as well as to a method of treatment of glaucoma with their help, ophthalmic solutions and kits comprising these solutions

The invention relates to medicine, namely to obstetrics, and can be used for labor induction in discharge of amniotic waters in women with full-term pregnancy on a background of immature and ripening of the cervix

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

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