Water-based liquid composition containing amide compound

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and described a water-based liquid composition for activation of intraocular penetration of a compound of formula (I) containing an amide compound, and an agent forming an ionic pair. What is also described is a method for activation of intraocular penetration of the compound presented by formula (I), and using the compound prepared by formula (I).

EFFECT: invention provides activation of penetration of the compound of formula (I), as well as maintaining the pre-set concentration of the drug preparation, even if a periodicity of the composition administration is reduced.

14 cl, 7 tbl, 2 dwg, 4 ex

 

The technical field

The present invention relates to liquid compositions are water-based, containing amide compound. More specifically, the present invention relates to ophthalmic compositions containing as active ingredient an amide compound which has the activity of inhibiting Rho kinase, which promotes the intraocular penetration of the active ingredient.

Prior art

The cause of glaucoma is abnormally high internal pressure of the eyeball, where abnormally high pressure weakens the eye and causes it to "blur" or causes pain in the eye, which in turn gradually weakens eyesight, possibly even leading to its loss. Usually intraocular fluid is continuously circulated in the eyeball and maintains a constant intraocular pressure (10-20 mm Hg). Pressure is maintained by the circulation of blood and lymphocytes, the elasticity of the wall of the eyeball, the functioning of control nerves and similar factors. Any violation leads to increased intraocular pressure, which can lead to the development of glaucoma.

In order to prevent cases of increased intraocular pressure or to reduce intraocular pressure, which increased for the prevention and treatment of glaucoma ISOE who was inovalis various drugs. Known eye drops to treat glaucoma include sympathetic agonists, such as epinephrine, dipivefrin and the like. In addition, widely used β-adrenaline blockers, such as timolol, pindolol and such, because they have a beneficial effect in reducing intraocular pressure by suppressing the production of intraocular fluid and have no effect on the pupil. The recent assumption of stimulating action of α1-adrenaline blockers on the outflow of intraocular fluid also suggests the potential application of benzosulphochloride and similar funds as a new drug for the treatment of glaucoma (non-patent reference document 1).

At the same time it was reported that the compounds having activity of inhibiting Rho kinase, demonstrated hypotensive effects in different models of hypertension in animals (non-patent reference document 2). It was confirmed that Rho kinase is present in the epithelial cells of the cornea (non-patent reference document 3).

As compounds having activity of inhibiting Rho kinase, has been reported compound of formula (I), which will be described later (patent reference document 1). It is known that the compound described in patent reference document 1 is useful as a tool for prevention and is ecene diseases of the circulatory system, such as coronary, cerebral, renal, peripheral artery and the like (for example, a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a therapeutic agent against renal and peripheral circulation, means of weakening the reduction of cerebral vessels, and the like), a therapeutic agent for the treatment of asthma, which are potent and have a lasting effect, and, in addition, in the field of ophthalmology it is useful for the treatment of retinopathy. In addition, patent reference document 2 discloses that the compound of formula (I) is useful for the prevention and treatment of glaucoma, patent reference document 3 discloses that the compound is useful for the treatment of visual impairment, and patent reference document 4 discloses that the compound is useful for restoring the sensitivity of the cornea.

As stated above, there are various components that are effective for prevention or treatment of glaucoma. It is important to strengthen their penetration into the ocular fluid in order to maintain their efficiency. For example, patent reference document 5 discloses the addition of a fatty acid with a straight chain containing from 6 to 10 carbon atoms, alkylsulfonate acid, phosphoric or what imoney acid, containing from 6 to 10 carbon atoms, or salts of such acids, to enhance penetration into the cornea bunazosin or prazosin. Patent reference document 6 discloses the use of C3-C7 fatty acid or its salt to enhance penetration into the cornea β-blockers (carteolol, timolol, and so on). Non-patent reference document 4 discloses the introduction of ion pairs of timolol and Caprylic acid rabbit by putting to increase the number of timolol, penetrating into the ocular fluid. Moreover, patent reference document 7 discloses an ophthalmic composition containing xanthan gum and inhibitor carbonatehydroxide for the treatment of glaucoma. Patent reference document 8 discloses an ophthalmic liquid composition, which becomes a gel upon instillation in the eye, has a total ion intensity of no more than 120 mm, contains specific xanthan gum and gum beans carob. As a drug that should be contained in the composition, this link describes the remedy for glaucoma (timolol, brimonidine, latanoprost and so on).

patent reference document 1: WO98/06433

patent reference document 2: WO00/09162

patent reference document 3: WO02/083175

patent reference document 4: WO2005/118582

patent reference document 5: JP-A-63-30122

patent reference document 6: WO99/22715

patent reference document 7: JP-A-2001-508035

patent reference document 8: JP-A-2002-510654

non-patent reference document 1: Folia Ophthalmologica Japonica, vol. 42, pp. 710 - 714, 1990

non-patent reference document 2: Masayoshi Uehata, et al., Nature 389, 990-994, 1997

non-patent reference document 3: Nirmala SundarRaj, et al., IOVS, 39(7) 1266-1272, 1998

non-patent reference document 4: J. Pharm. Biomed. Anal., Vol.7, No.4, pp. 433-439, 1989

Disclosure of invention

The problems solved by the present invention

The purpose of the present invention is to enable the penetration of compounds with activity, inhibition of Rho kinase, to the desired portion of its actions and to provide a liquid pharmaceutical composition is water-based, capable of maintaining the concentration of the drug even in the case when the reduced frequency of administration.

Means of solving problems

In light of the above challenges, the authors of the present invention were conducted thorough research and was discovered mixing component that activates the penetration of compounds with activity, inhibition of Rho kinase, which led to the creation of the present invention. Therefore, the present invention relates to the next.

(1) the Liquid composition is water-based, including amide is Obedinenie, represented by the following formula (I)

where

Ra represents a group of the formula

in formulas (a) and (b),

R represents hydrogen, alkyl or cycloalkyl, cycloalkenyl, phenyl or aralkyl, which optionally contains substituents on the ring, or a group of the formula

where R6represents hydrogen, alkyl or of the formula-NR8R9

where R8and R9are the same or different from each other and each represents hydrogen, alkyl, aralkyl or phenyl, R7represents hydrogen, alkyl, aralkyl, phenyl, nitro or cyano, or R6and R7in combination represent a group forming a heterocycle, optionally additionally containing in the ring oxygen atom, sulfur atom or optionally substituted nitrogen atom,

R1represents hydrogen, alkyl or cycloalkyl, cycloalkenyl, phenyl or aralkyl, which optionally contains substituents on the ring,

or R and R1in combination form, together with the adjacent nitrogen atom, a group forming a heterocycle, optionally additionally containing in the ring oxygen atom, sulfur atom or optionally substituted nitrogen atom,

R2is Soboh is hydrogen or alkyl,

R3and R4are the same or different from each other and each represents hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkylated, cyano, acyl, mercapto, alkylthio, Uralkali, carboxy, alkoxycarbonyl, carbamoyl, alkylaromatic or azide, and

A represents a group of the formula

where R10and R11are the same or different from each other and each represents hydrogen, alkyl, halogenated, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, or R10and R11in combination represent a group forming cycloalkyl, and l, m and n each represent 0 or an integer having a value of from 1 to 3,

in the formula (c)

L represents hydrogen, alkyl, aminoalkyl, mono - or dialkylaminoalkyl, tetrahydrofurfuryl, carbamoylethyl, phthalimidomethyl, amidino or a group of the formula

where B represents hydrogen, alkyl, alkoxy, aralkyl, aralkylated, aminoalkyl, hydroxyalkyl, alkanoyloxy, alkoxycarbonyl, α-aminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridine,

Q1represents hydrogen, halogen, hydroxy, aralkylated or thienylmethyl,

W is the Wallpaper alkylen,

Q2represents hydrogen, halogen, hydroxy or aralkylated,

X represents alkylene,

Q3represents hydrogen, halogen, hydroxy, alkoxy, nitro, amino, 2,3-dihydrofuran or 5-methyl-3-oxo-2,3,4,5-tetrahydropyridine-6-yl;

and Y represents a simple bond, alkylene or albaniles, and

in the formula (c)

the dotted line represents a simple bond or double bond, and

R5represents hydrogen, hydroxy, alkoxy, alkoxycarbonyl, alkanoyloxy or uralelectromontrage;

Rb represents hydrogen, alkyl, aralkyl, aminoalkyl or mono - or dialkylaminoalkyl; and

Rc represents an optionally substituted heterocycle containing nitrogen,

its isomer and/or its pharmaceutically acceptable additive salt (hereinafter sometimes referred to as the compound of the present invention and forming an ion pair reagent or water-soluble polymer.

(2) the Liquid composition is water-based, as described in the above item (1), where forming the ion pair reagent is a sorbic acid, octanoic acid or N-lauroyl-L-glutamic acid, or their pharmacologically acceptable salt.

(3) the Liquid composition is water-based, as described in the above item (1), where a water-soluble polymer present is the focus of a xanthan gum.

(4) the Liquid composition is water-based in accordance with any of the above paragraph (1)-(3)where the compound represented by formula (I)represents the (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)benzamide·monohydrochloride.

(5) the Liquid composition is water-based in accordance with any of the above paragraph (1)-(4), which represents the eye drops.

(6) the activation Method of the intraocular penetration of compounds represented by formula (I) according to above paragraph (1), its isomer and/or its pharmaceutically acceptable salt additive, which includes the addition of forming an ion pair reagent or water-soluble polymer in an aqueous solution comprising the compound represented by formula (I)or its isomer and/or its pharmaceutically acceptable additive salt.

(7) a Method for prevention or treatment of diseases selected from the group including glaucoma, asthenopia and pseudomyopia caused by prolonged excessive tension of the ciliary muscle, functional vision disorders caused by damage to or degeneration of the retinal nerve or optic nerve dysfunction of the sensitivity of the cornea, caused by damage to the corneal nerve, and dryness of the eyes, caused by dysfunction of the sensitivity of the cornea, which includes the century the decline in the effective number of connections, represented by formula (I) according to above paragraph (1), its isomer and/or its pharmaceutically acceptable salt additive to the subject, together with forming an ion pair reagent or a water-soluble polymer.

(8) the Method according to the above item (7), where forming the ion pair reagent is a sorbic acid, octanoic acid or N-lauroyl-L-glutamic acid or its pharmacologically acceptable salt.

(9) the Method according to the above item (7), where a water-soluble polymer is a xanthan gum.

(10) the Method according to any of the above paragraph (7)-(9), where the compound represented by formula (I)represents the (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)benzamide·monohydrochloride.

(11) the Method according to any of the above paragraph (7)-(10), which relates to eye drops.

(12) the Use of compounds represented by formula (I), in accordance with the above paragraph (1), its isomer and/or its pharmaceutically acceptable salt additive and forming an ion pair reagent or water-soluble polymer to obtain a water-soluble liquid composition for the prevention or treatment of a disease selected from the group including glaucoma, asthenopia and pseudomyopia you the bathroom prolonged excessive tension of the ciliary muscle, functional vision disorders caused by damage to or degeneration of the retinal nerve or optic nerve dysfunction of the sensitivity of the cornea, caused by damage to the corneal nerve, and dryness of the eyes, caused by dysfunction of the sensitivity of the cornea.

(13) the Use according to the above item (12), where forming the ion pair reagent is a sorbic acid, octanoic acid or N-lauroyl-L-glutamic acid or its pharmacologically acceptable salt.

(14) the Use according to the above item (12), where the water-soluble polymer is a xanthan gum.

(15) Application in accordance with any of the above item (12)-(14), where the compound represented by formula (I)represents the (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)benzamide·monohydrochloride.

(16) the Use according to any of the above item (12)-(15), which refers to the eye drops.

(17) a Commercial package comprising the liquid composition is water-based in accordance with any of the above paragraph (1)to(5) and a written statement, clearly indicating that the liquid composition is water-based can or should be used for prevention or treatment of a disease selected from the group comprising chap is who, asthenopia and pseudomyopia caused by prolonged excessive tension of the ciliary muscle, functional vision disorders caused by damage to or degeneration of the retinal nerve or optic nerve dysfunction of the sensitivity of the cornea, caused by damage to the corneal nerve, and dryness of the eyes, caused by dysfunction of the sensitivity of the cornea.

The effect of the present invention

In accordance with the liquid composition of water based on the present invention the intraocular penetration of compounds of the present invention, which is an active ingredient, is activated, the concentration of the active ingredient, is effective for treatment can be maintained for a long time in the intraocular tissue, and the frequency of injection can be reduced. In accordance with the present invention can be provided a composition having higher characteristics in regard to the ability to achieve the active ingredient to the site of its action, the effective use of the ingredient and reducing the frequency of injection compared with the known compositions containing the same concentration of active ingredient. Moreover, in accordance with the present invention even composition containing a low concentration of the active ingredient, m who can demonstrate effectiveness, equivalent to the efficiency of the known compositions, and to increase the interval between doses. Thus, it may be given less burdensome composition, especially for patients who need long-term introduction of such a composition.

Brief description of drawings

Figure 1 is a graph showing the concentration of compound A in aqueous humor after administration by instillation.

Figure 2 is a graph showing the concentration of compound A in the conjunctiva after administration by instillation.

The best way to embodiments of the present invention

In the present invention Rho kinase means serine/trionychinae activated along with the activation of Rho. For example, presents ROKα (ROCKII: Leung, T. et al, J. Biol. Chem., 270, 29051-29054, 1995), p160 ROCK (ROKβ, ROCK-I: Ishizaki, T. et al, The EMBO J., 15(8), 1885-1893, 1996) and other proteins having serine/trionychinae activity.

In the present invention one type of compound having the activity of inhibiting Rho kinase, can be used separately or, where this is necessary, you can use several types of such compounds.

In the description of the present invention, each symbol in the formula (I) are defined as specified below.

Alkyl for R and R1represents a linear or branched alkyl containing from 1 is about 10 carbon atoms, examples are: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, preferred is an alkyl containing from 1 to 4 carbon atoms.

Cycloalkyl for R and R1contains from 3 to 7 carbon atoms, and its examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

Cycloalkylation for R and R1represents a group in which cycloalkenyl fragment represents the above cycloalkyl containing from 3 to 7 carbon atoms, and the alkyl fragment is a linear or branched alkyl containing from 1 to 6 carbon atoms (methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and so on), and you can specify cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclohexylethyl, cycloheptylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl and the like.

Aralkyl for R and R1represents a group in which the alkyl fragment is an alkyl containing from 1 to 4 carbon atoms, and in which the quality of the examples, you can specify phenylalkyl, such as benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl and the like.

Deputy optionally substituted cycloalkyl, cycloalkenyl, phenyl and aralkyl on the ring R and R1represents a halogen (e.g. chlorine, bromine, fluorine and iodine), alkyl (such as alkyl defined for R and R1), alkoxy (linear or branched alkoxy containing from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like), aralkyl (same as aralkyl defined for R and R1or halogenated (alkyl defined for R and R1which is substituted by 1-5 halogen atoms, and examples of which are vermeil, deformity, trifluoromethyl, 2,2,2-triptorelin, 2,2,3,3,3-pentafluoropropyl and the like), nitro, amino, cyano, azide and the like.

The group formed by R and R1in combination with the adjacent nitrogen atom, which forms a heterocycle, optionally additionally containing in the ring oxygen atom, sulfur atom or optionally substituted nitrogen atom, represents, preferably, 5 - or 6-membered ring and its associated ring. Examples include 1-pyrrolidinyl, piperidino, 1-piperazinil, morpholino, thiomorpholine, 1-imidazolyl, 2,3-dihydrothiazolo-3-yl and the like. As Deputy it is certainly substituted nitrogen atom, you can specify alkyl, aralkyl, halogenated and the like. As used in this application, alkyl, aralkyl and halogenated have the meanings defined for R and R1.

Alkyl for R2has the meanings given for R and R1.

Halogen, alkyl, alkoxy and aralkyl for R3and R4have the meanings defined for R and R1.

The acyl for R3and R4is alkanoyl containing from 2 to 6 carbon atoms (e.g. acetyl, propionyl, butyryl, valeryl, pivaloyl and the like), benzoyl, or phenylalkanoic where alcoholly fragment contains from 2 to 4 carbon atoms (for example, phenylacetyl, phenylpropionyl, phenylbutyl and the like).

Alkylamino for R3and R4represents a group in which the alkyl fragment is a linear or branched alkyl containing from 1 to 6 carbon atoms. Examples include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamine, hexylamine and the like.

Acylamino for R3and R4represents a group in which the acyl fragment is alkanoyl containing from 2 to 6 carbon atoms, benzyl or alcoholly fragment is phenylalkanoic containing from 2 to 4 carbon atoms, and the like, and examples of yasat is acetylamino, propionamido, bucillamine, Valeriano, paulolino, benzoylamine, phenylacetylamino, phenylpropionylamino, phenylethylamine and the like.

Alkylthio for R3and R4represents a group in which the alkyl fragment is a linear or branched alkyl containing from 1 to 6 carbon atoms, as an example, which you can specify methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.

Aralkylated for R3and R4represents a group in which the alkyl fragment is an alkyl containing from 1 to 4 carbon atoms, as an example, which you can specify benzyloxy, 1-phenylethylene, 2-phenylethylene, 3 phenylpropoxy, 4-phenylbutyrate and the like.

Uralkali for R3and R4represents a group in which the alkyl fragment is an alkyl containing from 1 to 4 carbon atoms, as an example, where you can specify benzylthio, 1 feniletilic, 2-feniletilic, 3 phenylpropyl, 4-phenylbutyl and the like.

Alkoxycarbonyl for R3and R4represents a group in which the alkoxy fragment is a linear or branched alkoxy containing from 1 to 6 carbon atoms, as an example, which you can specify m is oxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, pentyloxybenzoyl, hexyloxybenzoyl and the like.

Alkylaromatic for R3and R4is carbamoyl, mono - or di-substituted by alkyl containing from 1 to 4 carbon atoms, as an example, which you can specify methylcarbamoyl, dimethylcarbamoyl, ethylcarbitol, diethylcarbamoyl, propylboronic, dipropylamino, butylcarbamoyl, dibutylamino and the like.

Alkoxy for R5has the meanings given for R and R1.

Alkoxycarbonyl for R5represents a group in which the alkoxy fragment is a linear or branched alkoxy containing from 1 to 6 carbon atoms, as an example, where you can specify methoxycarbonylamino, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxyethene, sec-butoxycarbonyl, tert-butoxycarbonylamino, ventilatsioonile, hexyloxyethoxy and the like.

Alkanoyloxy for R5represents a group in which alcoholly fragment is alkanoyl containing from 2 to 6 carbon atoms, as an example, where you can specify the atomic charges, propionyloxy, butyryl the XI, valeriote, pivaloyloxy and the like.

Uralelectromontrage for R5represents a group in which Uralkaliy fragment is aralkyl containing C1-C4alkyl, as an example, where you can specify benzyloxycarbonyloxy, 1 feniltiosemicarbazonele, 2-feniltiosemicarbazonele, 3 phenylpropionitrile, 4-PrivateAssemblies and the like.

Alkyl for R6has the meanings given for R and R1; alkyl for R8and R9has the meanings given for R and R1; and aralkyl for R8and R9has the meanings given for R and R1.

Alkyl for R7has the meanings given for R and R1and aralkyl for R7has the meanings given for R and R1.

As examples of the group formed by R6and R7in combination, which forms a heterocycle, optionally additionally containing in the ring oxygen atom, sulfur atom or optionally substituted nitrogen atom, you can specify a group imidazol-2-yl, thiazol-2-yl, oxazol-2-yl, imidazolin-2-yl, 3,4,5,6-tetrahydropyridine-2-yl, 3,4,5,6-tetrahydropyrimidin-2-yl, 1,3-oxazoline-2-yl, 1,3-thiazolin-2-yl or optionally substituted benzoimidazol-2-yl, benzothiazol-2-yl, benzoxazol-2-silt, etc. containing a Deputy, such as halogen, alkyl, alkoxy, halogenated, neither the ro amino, phenyl, aralkyl and the like. As used in this application, halogen, alkyl, alkoxy, halogenated and aralkyl have the meanings defined for R and R1.

As an example, the Deputy of the above optionally substituted nitrogen atom, you can specify alkyl, aralkyl, halogenated and the like. As used in this application, alkyl, aralkyl and halogenated have the meanings defined for R and R1.

Hydroxyalkyl for R10and R11represents a linear or branched alkyl containing from 1 to 6 carbon atoms, which is substituted by 1-3 hydroxy groups, and examples include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl and the like. Alkyl for R10and R11has the meanings given for R and R1; halogenated and alkoxycarbonyl for R10and R11have the meanings defined for R and R1; aralkyl for R10and R11has the meanings given for R and R1. Cycloalkyl formed R10and R11in combination, has the same value as cycloalkyl for R and R1.

Alkyl for L has the meanings given for R and R1.

Aminoalkyl for L is a linear or branched alkyl containing from 1 to 6 carbon atoms, which is substituted by an amino group, and p is the iMER, you can specify aminomethyl, 2-amino-ethyl, 1-amino-ethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl and the like.

Mono - or dialkylaminoalkyl for L is a mono - or di-substituted aminoalkyl with alkyl group containing from 1 to 4 carbon atoms, as an example, which you can specify methylaminomethyl, dimethylaminomethyl, ethylaminomethyl, diethylaminomethyl, propylaminoethyl, dipropylamine, butylaminoethyl, dibutylamine, 2-dimethylaminoethyl, 2-diethylaminoethyl and the like.

Carbamoylethyl for L is a linear or branched alkyl containing from 1 to 6 carbon atoms, substituted carbamoyl, as an example, which you can specify carbamoylmethyl, 2-carbamoylethyl, 1-carbamoylethyl, 3-carbamoylethyl, 4-carbamoylmethyl, 5-carbamoylmethyl, 6-carbamoylethyl and the like.

Phthalimidobutyl for L is a linear or branched alkyl containing from 1 to 6 carbon atoms, which is substituted by phthalimido. Examples of such groups include phthalimidomethyl, 2-phthalimidomethyl, 1-phthalimidomethyl, 3-phthalimidopropyl, 4-phthalimidobutyl, 5-phthalimidomethyl, 6-phthalimidomethyl and the like.

Alkyl for B has the meanings given for R and R1.

Alkoxy for B has the meanings given for R and R1.

Aralkyl for B has the meanings given for R and R1.

Aralkylated for B is the meet value, defined for R3and R4.

Aminoalkyl for B has the values defined for L.

Hydroxyalkyl for B has the meanings given for R10and R11.

Alkanoyloxy for B is a group in which a linear or branched alkyl containing from 1 to 6 carbon atoms, substituted alkanoyloxy, including alcoholly fragment containing from 2 to 6 carbon atoms, and as an example, you can specify acetoacetyl, propionylacetate, butyraldoxime, valerolactone, pivaloyloxymethyl, acetoacetyl, propionylacetate, butyrylacetate, valeriansee, pivaloyloxymethyl and the like.

Alkoxycarbonylmethyl for B is a group in which a linear or branched alkyl containing from 1 to 6 carbon atoms, substituted alkoxycarbonyl, including alkoxy fragment containing from 1 to 6 carbon atoms, and as an example, you can specify methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonylmethyl, isobutoxyethanol, second-butoxycarbonylmethyl, tert-butoxycarbonylmethyl, ventilatsioonile, hexyloxymethyl, methoxycarbonylethyl, ethoxycarbonylethyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxyethanol, sec-butoxy carbonylethyl, tert-butoxycarbonylmethyl, ventilatsioonile, hexyloxymethyl and the like.

Halogen for Q1, Q2and Q3has the meanings given for R and R1.

Aralkylated for Q1and Q2has the meanings given for R3and R4.

Alkoxy for Q3has the meanings given for R and R1.

Alkylen for W, X and Y represents a linear or branched alkylene containing from 1 to 6 carbon atoms, as an example, which you can specify the methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.

Albaniles Y represents a linear or branched albaniles containing from 2 to 6 carbon atoms, as an example, which you can specify vinile, propylen, butylen, penttinen and the like.

Alkyl for Rb has the meanings given for R and R1.

Aralkyl for Rb has the meanings given for R and R1.

Aminoalkyl for Rb has the meanings given for L.

Mono - or dialkylaminoalkyl for Rb has the meanings given for L.

As an example, nitrogen-containing heterocycle to Rc, when it represents a monocyclic ring, you can specify pyridine, pyrimidine, pyridazine, triazine, pyrazole, triazole and the like, and when it represents a condensed ring, the quality is TBE example, you can specify pyrrolopyridine (for example, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrrolo[3,4-b]pyridine and the like), pyrazolopyrimidine (e.g., 1H-pyrazolo[3,4-b]pyridine, 1H-pyrazolo[4,3-b]pyridine and the like), imidazopyridine (for example, 1H-imidazo[4,5-b]pyridine and the like), pyrrolopyrimidine (for example, 1H-pyrrolo[2,3-d]pyrimidine, 1H-pyrrolo[3,2-d]pyrimidine, 1H-pyrrolo[3,4-d]pyrimidine and the like), pyrazolopyrimidine (e.g., 1H-pyrazolo[3,4-d]pyrimidine, pyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[4,3-d]pyrimidine and the like), imidazopyridine (for example, imidazo[1,2-a]pyrimidine, 1H-imidazo[4,5-d]pyrimidine and the like), pyrrolotriazine (for example, pyrrolo[1,2-a]-1,3,5-triazine, pyrrolo[2,1-f]-1,2,4-triazine), pyrazoloacridine (for example, pyrazolo[1,5-a]-1,3,5-triazine and the like), triazolopyridine (for example, 1H-1,2,3-triazolo[4,5-b]pyridine and the like), triazolopyrimidine (for example, 1,2,4-triazolo[1,5-a]pyrimidine, 1,2,4-triazolo[4,3-a]pyrimidine, 1H-1,2,3-triazolo[4,5-d]pyrimidine and the like), cinnolin, hinzelin, quinoline, iridoviridae (e.g., pyrido[2,3-c]pyridazine and the like), pyridorin (e.g., pyrido[2,3-b]pyrazin and the like), pyridopyrimidines (e.g., pyrido[2,3-d]pyrimidine, pyrido[3,2-d]pyrimidine and the like), pyrimidopyrimidine (for example, pyrimido[4,5-d]pyrimidine, pyrimido[5,4-d]pyrimidine and the like), pyrazinamide (e.g., pyrazino[2,3-d]pyrimidine and the like), naphthiridine (for example, 1,8-naphthiridine and the like), tetrapropylene (in the example, tetrazolo[1,5-a]pyrimidine and the like), thienopyridine (e.g., thieno[2,3-b]pyridine and the like), thienopyrimidine (e.g., thieno[2,3-d]pyrimidine and the like), triazolopyridine (for example, thiazolo[4,5-b]pyridine, thiazolo[5,4-b]pyridine and the like), triazolopyrimidine (for example, thiazolo[4,5-d]pyrimidine, thiazolo[5,4-d]pyrimidine and the like), oxazolopyridine (for example, oxazolo[4,5-b]pyridine, oxazolo[5,4-b]pyridine and the like), oxazolopyridine (for example, oxazolo[4,5-d]pyrimidine, oxazolo[5,4-d]pyrimidine and the like), properidine (e.g., furo[2,3-b]pyridine, furo[3,2-b]pyridine and the like), foroperation (e.g., furo[2,3-d]pyrimidine, furo[3,2-d]pyrimidine and the like), 2,3-dihydropyrimidin (for example, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine and the like), 2,3-dihydropyrimidin (for example, 2,3-dihydro-1H-pyrrolo[2,3-d]pyrimidine, 2,3-dihydro-1H-pyrrolo[3,2-d]pyrimidine and the like), 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine, 5,6,7,8-tetrahydro-1,8-naphthiridine, 5,6,7,8-tetrahydroquinolin and the like. When these rings form gidrirovannoe aromatic ring carbon atom in the ring may be carbonyl, and examples include 2,3-dihydro-2-oxopyrrolidin, 2,3-dihydro-2,3-dioxopiperidin, 7,8-dihydro-7-oxo-1,8-naphthiridine, 5,6,7,8-tetrahydro-7-oxo-1,8-naphthiridine and the like. Preferred is pyridine, pyrrolopyridine.

Such rings can the be replaced by substituents, such as halogen, alkyl, alkoxy, aralkyl, halogenated, nitro, amino, alkylamino, cyano, formyl, acyl, aminoalkyl, mono - or dialkylaminoalkyl, azide, carboxy, alkoxycarbonyl, carbamoyl, alkylaromatic, alkoxyalkyl (for example, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropan and the like), optionally substituted, hydrazine and the like.

As used in this application, the Deputy optionally substituted, hydrazino includes alkyl, aralkyl, nitro, cyano and the like, where the alkyl and aralkyl have the meanings defined for R and R1and as an example, you can specify methylhydrazino, acylhydrazone, benzoylhydrazone and the like.

The compound of formula (I) represented by the following compounds and their salts.

(1) 4-(2-pyridylcarbonyl)piperidine

(2) 1-benzyloxycarbonyl-4-(4-pyridylcarbonyl)piperidine

(3) 1-benzoyl-4-(4-pyridylcarbonyl)piperidine

(4) 1-propyl-4-(4-pyridylcarbonyl)piperidine

(5) [3-(2-(2-thienylmethyl)phenoxy)-2-hydroxypropyl]-4-(4-pyridylcarbonyl)piperidine

(6) 4-(4-pyridylcarbonyl)piperidine

(7) 1-benzyl-4-(4-pyridylcarbonyl)-1,2,5,6-tetrahydropyridine

(8) 3-(4-pyridylcarbonyl)piperidine

(9) 1-benzyl-3-(4-pyridylcarbonyl)piperidine

(10) 1-(2-(4-benzyloxyphenyl)ethyl)-4-(N-(2-pyridyl)-N-benzylcarbamoyl)piperidine

(11) 1-formyl-4-(4-peredelka bemail)piperidine

(12) 4-(3-pyridylcarbonyl)piperidine

(13) 1-isopropyl-4-(4-pyridylcarbonyl)piperidine

(14) 1-methyl-4-(4-pyridylcarbonyl)piperidine

(15) 1-hexyl-4-(4-pyridylcarbonyl)piperidine

(16) 1-benzyl-4-(4-pyridylcarbonyl)piperidine

(17) 1-(2-phenylethyl)-4-(4-pyridylcarbonyl)piperidine

(18) 1-(2-(4-methoxyphenyl)ethyl)-4-(4-pyridylcarbonyl)piperidine

(19) 1-(2-(4-methoxyphenyl)ethyl)-4-(2-pyridylcarbonyl)piperidine

(20) 1-(2-(4-chlorophenyl)ethyl)-4-(4-pyridylcarbonyl)piperidine

(21) 1-diphenylmethyl-4-(2-pyridylcarbonyl)piperidine

(22) 1-[2-(4-(5-methyl-3-oxo-2,3,4,5-tetrahydropyridine-6-yl)phenyl)ethyl]-4-(2-pyridylcarbonyl)piperidine

(23) 1-(4-(4,5-dihydro-2-furyl)phenyl)-4-(4-pyridylcarbonyl)piperidine

(24) 1-(2-nitrophenyl)-4-(4-pyridylcarbonyl)piperidine

(25) 1-(2-AMINOPHENYL)-4-(4-pyridylcarbonyl)piperidine

(26) 1-nicotinoyl-4-(4-pyridylcarbonyl)piperidine

(27) 1-isonicotinoyl-4-(4-pyridylcarbonyl)piperidine

(28) 1-(3,4,5-trimethoxybenzoyl)-4-(4-pyridylcarbonyl)piperidine

(29) 1-acetyl-4-(4-pyridylcarbonyl)piperidine

(30) 1-(3-(4-perbenzoic)propyl)-4-(4-pyridylcarbonyl)piperidine

(31) 1-(3-(4-perbenzoic)propyl)-4-(2-pyridylcarbonyl)piperidine

(32) 1-(1-(4-hydroxybenzoyl)ethyl)-4-(2-pyridylcarbonyl)piperidine

(33) 1-(1-(4-benzyloxybenzyl)ethyl)-4-(2-pyridylcarbonyl)piperidine

(34) 1-(2-(4-hydroxyphenoxy)ethyl)-4-(2-pyridylcarbonyl)Pipa is one

(35) 1-(4-(4-forfinal)-4-hydroxybutyl)-4-(4-pyridylcarbonyl)piperidine

(36) 1-(1-methyl-2-(4-hydroxyphenyl)-2-hydroxyethyl)-4-(2-pyridylcarbonyl)piperidine

(37) 1-cinnamyl-4-(2-pyridylcarbonyl)piperidine

(38) 1-(2-hydroxy-3-phenoxypropan)-4-(4-pyridylcarbonyl)piperidine

(39) 1-(2-hydroxy-3-phenoxypropan)-4-(3-pyridylcarbonyl)piperidine

(40) 1-(2-hydroxy-3-phenoxypropan)-4-(2-pyridylcarbonyl)piperidine

(41) 1-(2-phenylethyl)-4-[N-(2-pyridyl)-N-(2-(N,N-dimethylamino)ethyl)carbamoyl]piperidine

(42) 1-benzyloxycarbonyl-4-(2-pyridylcarbonyl)piperidine

(43) 1-(3-chlorophenyl)carbamoyl-4-(4-pyridylcarbonyl)piperidine

(44) 1-[N-(2-pyridyl)-N-(2-(N,N-dimethylamino)ethyl)carbamoyl]piperidine

(45) 1-methyl-4-(4-pyridylcarbonyl)-1,2,5,6-tetrahydropyridine

(46) 1-nicotinoyl-3-(4-pyridylcarbonyl)piperidine

(47) 1-[2-(4-perbenzoic)ethyl]-4-(4-pyridylcarbonyl)piperidine

(48) 1-(6-chloro-2-methylimidazo[1,2-a]pyridine-3-carbonyl)-4-(4-pyridylcarbonyl)piperidine

(49) 1-(4-nitrobenzyl)-4-(4-pyridylcarbonyl)piperidine

(50) 1-hexyl-4-(4-pyridylcarbonyl)piperidine

(51) 1-benzyloxycarbonyl-4-(2-chloro-4-pyridylcarbonyl)piperidine

(52) 4-(2-chloro-4-pyridylcarbonyl)piperidine

(53) 1-(2-chloronicotinoyl)-4-(4-pyridylcarbonyl)piperidine

(54) 3-(2-chloro-4-pyridylcarbonyl)piperidine

(55) 1-(4-phthalimidobutyl)-4-(4-pyridylcarbonyl)piperidine

(56)1-(3,5-di-tert-butyl-4-g is toxicodynamic)-4-(4-pyridylcarbonyl)piperidine

(57) 1-carbamoylmethyl-4-(4-pyridylcarbonyl)piperidine

(58) 1-benzyloxycarbonyl-4-(5-nitro-2-pyridylcarbonyl)piperidine

(59) 4-(5-nitro-2-pyridylcarbonyl)piperidine

(60) TRANS-4-benzyloxycarbonylamino-1-(4-pyridylcarbonyl)cyclohexane

(61) TRANS-4-aminomethyl-1-(4-pyridylcarbonyl)cyclohexane

(62) TRANS-4-formimidoyl-1-(4-pyridylcarbonyl)cyclohexane

(63) TRANS-4-dimethylaminomethyl-1-(4-pyridylcarbonyl)cyclohexane

(64) N-benzyliden-TRANS-(4-pyridylcarbonyl)cyclohexylethylamine

(65) TRANS-4-benzylamino-1-(4-pyridylcarbonyl)cyclohexane

(66) TRANS-4-isopropylaminomethyl-1-(4-pyridylcarbonyl)cyclohexane

(67) TRANS-4-nicotinamine-1-(4-pyridylcarbonyl)cyclohexane

(68) of TRANS-4-cyclohexylamino-1-(4-pyridylcarbonyl)cyclohexane

(69) TRANS-4-benzyloxycarbonyl-1-(4-pyridylcarbonyl)cyclohexane

(70) TRANS-4-amino-1-(4-pyridylcarbonyl)cyclohexane

(71) TRANS-4-(1-amino-ethyl)-1-(4-pyridylcarbonyl)cyclohexane

(72) TRANS-4-aminomethyl-CIS-2-methyl-1-(4-pyridylcarbonyl)cyclohexane

(73) (+)-TRANS-4-(1-benzyloxycarbonylamino)-1-cyclohexanecarbonyl acid

(74) (+)-TRANS-4-(1-benzyloxycarbonylamino)-1-(4-pyridylcarbonyl)cyclohexane

(75) (-)-TRANS-4-(1-benzyloxycarbonylamino)-1-(4-pyridylcarbonyl)cyclohexane

(76) (+)-TRANS-4-(1-aminopropyl)-1-(-pyridylcarbonyl)cyclohexane

(77) (-)-TRANS-4-(1-aminopropyl)-1-(4-pyridylcarbonyl)cyclohexane

(78) (-)-TRANS-4-(1-benzyloxycarbonylamino)-1-(4-pyridylcarbonyl)cyclohexane

(79) (+)-TRANS-4-(1-benzyloxycarbonylamino)-1-(4-pyridylcarbonyl)cyclohexane

(80) (+)-TRANS-4-(1-amino-ethyl)-1-(4-pyridylcarbonyl)cyclohexane

(81) (-)-TRANS-4-(1-amino-ethyl)-1-(4-pyridylcarbonyl)cyclohexane

(82) TRANS-4-(4-chlorbenzoyl)aminomethyl-1-(4-pyridylcarbonyl)cyclohexane

(83) TRANS-4-aminomethyl-1-(2-pyridylcarbonyl)cyclohexane

(84) TRANS-4-benzyloxycarbonylamino-1-(2-pyridylcarbonyl)cyclohexane

(85) TRANS-4-methylaminomethyl-1-(4-pyridylcarbonyl)cyclohexane

(86) TRANS-4-(N-benzyl-N-methylamino)methyl-1-(4-pyridylcarbonyl)cyclohexane

(87) TRANS-4-aminomethyl-1-(3-pyridylcarbonyl)cyclohexane

(88) TRANS-4-aminomethyl-1-[(3-hydroxy-2-pyridyl)carbamoyl]cyclohexane

(89) TRANS-4-benzyloxycarbonylamino-1-(3-pyridylcarbonyl)cyclohexane

(90) TRANS-4-benzyloxycarbonylamino-1-[(3-benzyloxy-2-pyridyl)carbamoyl]cyclohexane

(91) TRANS-4-phthalimidomethyl-1-(4-pyridylcarbonyl)cyclohexane

(92) TRANS-4-benzyloxycarbonylamino-1-(3-methyl-4-pyridylcarbonyl)cyclohexane

(93) TRANS-4-aminomethyl-1-(3-methyl-4-pyridylcarbonyl)cyclohexane

(94) 4-(TRANS-4-benzyloxycarbonyloxy-carbonyl)-amino-2,6-dimethylpyridine-N-oxide

(95) 4-(TRANS-4-aminomethylpropanol)amino-2,6-dimethylpyridine-N-oxide

(96) TRANS-4-aminomethyl-1-(2-methyl-4-pyridylcarbonyl)cyclohexane

(97) TRANS-4-(1-benzyloxycarbonylamino)-1-(4-pyridylcarbonyl)cyclohexane

(98) TRANS-4-(1-amino-1-methylethyl)-1-(4-pyridylcarbonyl)cyclohexane

(99) TRANS-4-(2-amino-ethyl)-1-(4-pyridylcarbonyl)cyclohexane

(100) TRANS-4-(2-amino-1-methylethyl)-1-(4-pyridylcarbonyl)cyclohexane

(101) of TRANS-4-(1-aminopropyl)-1-(4-pyridylcarbonyl)cyclohexane

(102) TRANS-4-aminomethyl-TRANS-1-methyl-1-(4-pyridylcarbonyl)cyclohexane

(103) of TRANS-4-benzylamino-CIS-2-methyl-1-(4-pyridylcarbonyl)cyclohexane

(104) TRANS-4-(1-benzyloxycarbonyl-1-methylethyl)-1-(4-pyridylcarbonyl)cyclohexane

(105) TRANS-4-benzyloxycarbonylamino-1-(N-methyl-4-pyridylcarbonyl)cyclohexane

(106) TRANS-4-(1-ndimethylacetamide-1-methylethyl)-1-(4-pyridylcarbonyl)cyclohexane

(107) TRANS-N-(6-amino-4-pyrimidyl)-4-aminomethylenemalonate

(108) TRANS-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-aminomethylenemalonate

(109) (+)-TRANS-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)cyclohexanecarboxylic

(110) TRANS-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-1-methylethyl)cyclohexanecarboxylic

(111) TRANS-N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-aminomethylenemalonate

(112) (+)-TRANS-N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-(1-and inatel)cyclohexanecarboxylic

(113) TRANS-N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-(1-amino-1-methylethyl)cyclohexanecarboxylic

(114) (+)-TRANS-N-(2-amino-4-pyridyl)-4-(1-amino-ethyl)cyclohexanecarboxylic

(115) TRANS-N-(1H-pyrazolo[3,4-d]pyrimidine-4-yl)-4-aminomethylenemalonate

(116) (+)-TRANS-N-(1H-pyrazolo[3,4-d]pyrimidine-4-yl)-4-(1-amino-ethyl)cyclohexanecarboxylic

(117) TRANS-N-(1H-pyrazolo[3,4-d]pyrimidine-4-yl)-4-(1-amino-1-methylethyl)cyclohexanecarboxylic

(118) of TRANS-N-(4-pyrimidinyl)-4-aminomethylenemalonate

(119) TRANS-N-(3-amino-4-pyridyl)-4-aminomethylenemalonate

(120) TRANS-N-(7H-imidazo[4,5-d]pyrimidine-6-yl)-4-aminomethylenemalonate

(121) of TRANS-N-(3H-1,2,3-triazolo[4,5-d]pyrimidine-7-yl)-4-aminomethylenemalonate

(122) of TRANS-N-(1-benzyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-4-aminomethylenemalonate

(123) TRANS-N-(1H-5-pyrazolyl)-4-aminomethylenemalonate

(124) TRANS-N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-aminomethylenemalonate

(125) TRANS-N-(4-pyridazinyl)-4-aminomethyl-cyclohexanecarboxylic

(126) TRANS-N-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-4-aminomethylenemalonate

(127) TRANS-N-(2-amino-4-pyridyl)-4-aminomethylenemalonate

(128) TRANS-N-(thieno[2,3-d]pyrimidine-4-yl)-4-aminomethylenemalonate

(129) TRANS-N-(5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-7-yl)-4-aminomethylbenzoic Roxane

(130) TRANS-N-(3-cyano-5-methylpyrazolo[1,5-a]pyrimidine-7-yl)-4-aminomethylenemalonate

(131) TRANS-N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-(1-amino-1-methylethyl)cyclohexanecarboxylic

(132) TRANS-N-(2-(1-pyrrolidinyl)-4-pyridyl)-4-aminomethylenemalonate

(133) TRANS-N-(2,6-diamino-4-pyrimidyl)-4-aminomethylenemalonate

(134) (+)-TRANS-N-(7-methyl-1,8-naphthiridine-4-yl)-4-(1-amino-ethyl)cyclohexanecarboxylic

(135) TRANS-N-(1-benzyloxyethyl[2,3-b]pyridine-4-yl)-4-aminomethylenemalonate

(136) (+)-TRANS-N-(1-methylpyrrole[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)cyclohexanecarboxylic

(137) TRANS-N-benzyl-N-(2-benzylamino-4-pyridyl)-4-(1-amino-1-methylethyl)cyclohexanecarboxylic

(138) TRANS-N-(2-azide-4-pyridyl)-4-aminomethylenemalonate

(139) TRANS-N-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-yl)-4-aminomethylenemalonate

(140) TRANS-N-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-1-methylethyl)cyclohexanecarboxylic

(141-1) TRANS-N-(2-carboxy-4-pyridyl)-4-aminomethylenemalonate

(141-2) (R)-(+)-TRANS-N-(3-bromo-1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)cyclohexanecarboxylic

(142) TRANS-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-guanidinonaltrindole

(143) TRANS-N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-guanidinonaltrindole

(144) of TRANS-N-(4-pyridyl)-4-guanidinoacetic cancervaccine

(145) TRANS-N-(1-methylpyrrole[2,3-b]pyridine-4-yl)-4-(guanidinate)cyclohexanecarboxylic

(146) of TRANS-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(2-imidazolin-2-yl)aminomethylenemalonate

(147) TRANS-N-(1-benzyloxyethyl[2,3-b]pyridine-4-yl)-4-guanidinonaltrindole

(148) TRANS-N-(2-amino-4-pyridyl)-4-guanidinonaltrindole

(149) TRANS-N-(1-benzyloxyethyl-1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(2-imidazolin-2-yl)aminomethylenemalonate

(150) TRANS-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(3-benzylguanine)cyclohexanecarboxylic

(151) of TRANS-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(3-fenilselendiimidy)cyclohexanecarboxylic

(152) of TRANS-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(3-propylaniline)cyclohexanecarboxylic

(153) TRANS-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(3-octylaniline)cyclohexanecarboxylic

(154) TRANS-N-(1-benzyloxyethyl[2,3-b]pyridine-4-yl)-4-(2-benzyl-3-ethylguanidine)cyclohexanecarboxylic

(155) TRANS-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(imidazol-2-yl)aminomethylenemalonate

(156) TRANS-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(thiazol-2-yl)aminomethylenemalonate

(157) (R)-(+)-N-(4-pyridyl)-4-(1-amino-ethyl)benzamide

(158) N-(4-pyridyl)-4-(1-amino-1-methylethyl)benzamide

(159) N-(4-pyridyl)-4-aminomethyl-2-benzyloxybenzoate

(160) N-(4-pyridyl)-4-aminomethyl-2-ethoxybenzyl is d

(161) (R)-(-)-N-(4-pyridyl)-4-(1-amino-ethyl)-3-nitrobenzamide

(162) (R)-(-)-N-(4-pyridyl)-3-amino-4-(1-amino-ethyl)benzamide

(163) (R)-(+)-N-(4-pyridyl)-4-(1-amino-ethyl)-3-chlorobenzamide

(164) N-(4-pyridyl)-3-aminomethylbenzoic

(165) (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)benzamide

(166) (R)-(+)-N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-(1-amino-ethyl)benzamide

(167) N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-guanidinonaltrindole

(168) N-(4-pyridyl)-4-guanidinonaltrindole

(169) (R)-(+)-N-(4-pyridyl)-4-(1-amino-ethyl)-3-perbenzoic

(170) N-(4-pyridyl)-4-aminomethylbenzoic

(171) N-(4-pyridyl)-4-aminomethyl-2-hydroxybenzamide

(172) N-(4-pyridyl)-4-(2-amino-ethyl)benzamide

(173) N-(4-pyridyl)-4-aminomethyl-3-nitrobenzamide

(174) N-(4-pyridyl)-3-amino-4-aminomethylbenzoic

(175) (S)-(-)-N-(4-pyridyl)-4-(1-amino-ethyl)benzamide

(176) (S)-(-)-N-(4-pyridyl)-2-(1-amino-ethyl)benzamide

(177) (R)-(+)-N-(4-pyridyl)-4-(1-amino-ethyl)-2-chlorobenzamide

(178) (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-(3-propylaniline)ethyl)benzamide

(179) (R)-(-)-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)-3-azidobenzoyl

(180) (R)-(+)-N-(4-pyridyl)-4-(1-amino-ethyl)-2-nitrobenzamide

(181) (R)-(-)-N-(4-pyridyl)-4-(1-amino-ethyl)-3-ethoxybenzene

(182) (R)-(+)-N-(3-iodine-1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)benzamide

(183) (R)-(+)-N-(3-iodine-1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)-3-azidobenzoyl

(184) (R)-(-)-N-(4-pyridyl)-4-(1-amino-ethyl)-3-hydroxybenzamide

(185) N-(1H-feast of the ash[3,4-b]pyridine-4-yl)-4-guanidinate-3-nitrobenzamide

(186) (R)-N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-(1-guanidinate)-3-nitrobenzamide

(187) (R)-N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-(1-amino-ethyl)-2-nitrobenzamide

(188) N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-guanidinopentanoic

(189) (R)-N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-(1-amino-ethyl)-3-nitrobenzamide

(190) (R)-N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-(1-guanidinate)benzamid

(191) N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-(1-amino-2-hydroxyethyl)benzamide

(192) N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-aminomethyl-3-nitrobenzamide

(193) N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-piperidinecarboxylic

(194) N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-4-piperidinecarboxylic

(195) N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-1-aminoacetyl-4-piperidinecarboxylic

(196) N-(1-methoxymethyl-1H-pyrazolo[3,4-b]pyridine-4-yl)-4-piperidinecarboxylic

(197) N-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-yl)-4-piperidinecarboxylic

(198) N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-(2-phenylethyl)-4-piperidinecarboxylic

(199) N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-amidino-4-piperidinecarboxylic

(200) N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-(3-phenylpropyl)-4-piperidinecarboxylic

(201) N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-1-benzyl-4-piperidinecarboxylic

(202) N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-1-(2-phenylethyl)-4-piperidinecarboxylic

(203) N-(1H-pyrazolo[3,4-b]pyridine-4-yl)-1-(3-phenylpropyl)-4-piperidinecarboxylic

Preferred are compounds(80), (109), (110), (112), (115), (142), (143), (144), (145), (153), (157), (13), (165), (166) and (179).

The compound may be a pharmaceutically acceptable acid additive salt, where as an example, acids can be specified inorganic acid such as hydrochloric acid, Hydrobromic acid, sulfuric acid and the like, and organic acid, such as methanesulfonate acid, fumaric acid, maleic acid, mandelic acid, citric acid, tartaric acid, salicylic acid and the like. The compound containing a carboxyl group may be converted into a salt formed from a metal, such as sodium, potassium, calcium, magnesium, aluminum and the like, salts formed with amino acid such as lysine and the like. Moreover, the scope of the present invention included monohydrate, dihydrate, 1/2 hydrate, 1/3 hydrate, 1/4 hydrate, 2/3 hydrate, 3/2 hydrate, 6/5 hydrate and the like. Preferably, the compound is an (R)-(+)-N(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)benzamide· monohydrochloride.

The connection can be synthesized using the method described, for example, in JP-A-62-89679, JP-A-3-218356, JP-A-5-194401, JP-A-6-41080, WO95/28387, WO98/06433, etc.

When the amide compound represented by the formula (I)contains an optical isomer, its racemate or CIS-TRANS isomers, all of them can be used in the present invention. These isomers can be separated using STD is bound method or can be obtained using the source materials for the production of such isomers.

The compound of the present invention possesses an action aimed at reducing intraocular pressure, the effect of improving blood flow to the optic nerve, and action, contributing to outflow of intraocular fluid in mammals, including humans, cows, horses, dogs, mice, rats and the like. Therefore, they can be used as a tool for the prevention and treatment of various types of glaucoma, such as primary open-angle glaucoma, glaucoma with normal pressure, with hypersecretion glaucoma, ocular hypertension, acute angle-closure glaucoma, chronic angle-closure glaucoma, symptoms of plateau iris, glaucoma combined mechanism of steroid glaucoma, capsular glaucoma, pigmentary glaucoma, secondary glaucoma associated with amyloidosis, neovascular glaucoma, malignant glaucoma and the like.

Because the connection of the present invention inhibits the contraction of the ciliary muscle in mammals, such as man, bull, horse, dog, mouse, rat and the like, the liquid composition is water-based according to the present invention is used as a means for the prevention or treatment of asthenopia or pseudomyopia caused by prolonged excessive tension of the ciliary muscle, etc.

Because the connection on this image is the shadow has effect, aimed at straightening axons of retinal ganglion, and action aimed at the regeneration of cells of the optic nerve in mammals, including man, ox, horse, dog, mouse, rat and the like, the connection is considered as designed to improve functional disorders of vision caused by injury, degeneration and other retinal nerve or optic nerve. Therefore, the liquid composition is water-based according to the present invention is considered effective for improving visual function with visual impairment, which is caused by damage as a result of inflammation of the retina, etc. (retinal neuropathy, retinal vascular occlusion, periferic retinal disease Needle, ischemic ophthalmopathy, microaneurysms arterioles of the retina, retinopathy, caused by hypertension, kidney disease and blood disease, diabetic retinopathy, retinal dystrophy, dystrophy yellow spots, chorioretinopathy, macular degeneration, macular edema, the detachment of the pigment epithelium retinal degenerative retinosis, retinoblastoma, retinal pigment epithelium etc) and the like; improve visual function in the visual disturbances caused by degeneration, damage to the optic nerve (retro-bulbar neuritis, capillary angioma of the optic is not the VA, ischemic ocular neuropathy, defects in the nerve fiber layer of the retina, atrophy of the retina, full anatomic interruption of the optic nerve, traumatic optic neuropathy, swelling of the optic nerve, coloboma of the optic nerve, optic nerve hypoplasia, toxic optic nerve atrophy etc); improvement of visual function in disorders of vision due to atrophy, degeneration, etc. of the optic nerve, caused by elevated intraocular pressure (glaucoma etc) and the like; and, in addition, proliferation and functional maintenance of photoreceptor cells, including cells in the retinal ganglion, the transplantation of retinal and regeneration of the optic nerve at transplantation of the optic nerve.

Because the connection of the present invention promotes the formation of protrusion of the corneal nerve in mammals, such as man, bull, horse, dog, mouse, rat and the like, the liquid composition is water-based according to the present invention is useful for treatment of disorders of the sensitivity of the cornea, caused by damage to the corneal nerve, or dry eyes, caused by dysfunction of the sensitivity of the cornea. More specifically, it is used as a means for prevention or treatment of disorders of the sensitivity of the cornea after chirurgeons the second operation in connection with cataracts, laser futurefactories keratotomy (PRK), laser assisted in situ Keratomileusis (LASIK, LASEK or cornea transplantation, dysfunction of the sensitivity of the cornea, caused by neurodegeneration of the cornea, such as neuroparalytic keratopathy, corneal ulcer, diabetic keratopathy etc., dry eye syndrome and similar disorders.

The liquid composition is water-based according to the present invention typically includes forming an ion pair reagent, contributing intraocular penetration of the active ingredient.

In the present invention of forming an ion pair reagent refers to a reagent that forms an ion pair with the compound of the present invention in the liquid phase. Forming an ion pair reagent preferably selected in accordance with the pH of the liquid composition on a water basis of the present invention, so that could be formed ion pair compound according to the present invention (active ingredient) in the liquid phase. For example, when the pH is about 7, you can use sorbic acid, octanoic acid, N-lauroyl-L-glutamic acid, along with dehydroacetic acid or saccharin or its pharmacologically acceptable salt, preference is given sorbic acid, octanoic acid or N-lauroyl-L-glutamic acid or pharmacologically praml is my salt of such acid. If the pH is about 5, you can use acetyltryptophan, saccharin, sorbic acid, octanoic acid or along with dehydroacetic acid, or a pharmacologically acceptable salt of such acids, with a preference for the saccharin or its pharmacologically acceptable salt. Examples of the above salts include alkali metal salts such as sodium salt, potassium salt and the like.

When the liquid composition is water-based according to the present invention is used in the form of eye drops, the pH of the liquid composition is preferably adjusted to about 7. Thus, forming an ion pair reagent, preferably selected from sorbic acid, octanoic acid, N-lauroyl-L-glutamic acid and pharmacologically acceptable salts of such acid.

Mixing ratio of the compounds of the present invention and the above forming ion pair reagent in a molar ratio, as a rule, is a combination of: forming an ion pair reagent = 1:0.01 to 1:100, preferably 1:0.1 to 1:10. Ion pair effectively formed in the liquid composition of water based on the present invention, depending on the choice of forming an ion pair reagent and the above mixing ratio and can be activated intraocular penetration of compounds of the present invention.

In other the Ohm variant embodiment of the liquid composition is water-based according to the present invention usually contains a water-soluble polymer to provide intraocular penetration of the active ingredient.

Examples of water-soluble polymer include xanthan gum, hyaluronic acid, polyethylene glycol, polyvinylpyrrolidone, hypromellose, methylcellulose, hydroxyethyl cellulose, alginic acid, polyglutamic acid, chitosan, carboxymethylcellulose, its salt, carboxyvinyl polymer, polyvinyl alcohol and the like. Preferred is xanthan gum, able to provide a suitable viscosity of liquid composition is water-based.

For example, the average molecular weight of xanthan gum is usually 100000-50000000, preferably 200000-20000000, particularly preferably 1000000-10000000. As xanthan gum use Comedy series ECHO GUM, such as ECHO GUM T, ECHO GUM F and the like, commercially available from Dainippon Sumitomo Pharma Co., Ltd., Comedy series SAN-ACE, such as SAN-ACE NXG-S and the like, commercially available from San-Ei Gen F.F.I., Inc., Comedy series KETROL, such as KETROL CG, KETROL CG-T and the like, commercially available from SANSHO Co., Ltd., and similar gums, are preferred ECHO GUM T and KETROL CG-T.

The concentration of water-soluble polymer (e.g., xanthan gum) in the liquid composition on a water basis of the present invention, generally, is 0.02 to 1.0% wt./about., preferably of 0.1-0.5% wt./about.

The viscosity of the liquid composition on a water basis of the present invention, containing vodarac warily polymer, measured using a rotational viscometer of the type E (10 rpm), as a rule, is not less than 30 MPa·s. The liquid composition is water-based with this viscosity range is preferred because, for example, it is easy to look at her intraocular injection of local way, and it has the best performance storage intraocular liquid composition.

For example, when using xanthan gum, are preferred eye drops concentration of xanthan gum in the range of 1.0% wt./about., because it supports a suitable static viscosity of the composition has a low viscosity in terms of the (dynamic), such as the instillation and the like, and easy to use. It is also preferable to obtain a liquid composition is water-based, because it has a suitable viscosity, and sterilization by filtration can be performed under normal conditions.

The liquid composition is water-based according to the present invention is administered orally or parenterally. Examples of forms for administration include forms for oral administration, such as syrup and the like, and a form for parenteral administration, such as external means (e.g., solution, suspension or emulsion for injection, eye drops and the like). Preferably, it is used the form for local ocular administration, and particularly preferably it is used in the form of eye drops.

The composition in the above dosage form can be obtained by mixing the compounds of the present invention with the addition required for the formulation of the composition, such as a typical carrier, excipient, binder, stabilizer and similar substances, and using the standard method. For example, the compound of the present invention is mixed with pharmaceutically acceptable carrier (e.g., excipient, binder, baking powder, substance to adjust the taste, Corrigendum, emulsifier, diluent, solubilizers substance and similar substances) obtaining a pharmaceutical composition or pharmaceutical preparation in the form of syrup, liquid compositions, emulsions, suspensions, injections (e.g., liquid composition, suspension and the like), eye drops and the like in a form suitable for oral or parenteral compositions.

To obtain a liquid composition used additives such as sodium chloride, glucose, sorbitol, glycerol, propylene glycol, ethanol and the like.

To obtain a composition for injection using a sterile aqueous solution, such as saline, isotonic solution, oil and the like. If necessary, at the same time can be used on lesofat suitable suspendisse agent, such as sodium carboxymethyl cellulose, non-ionic surfactant, a solubilizer (e.g., benzyl benzoate and benzyl alcohol), and similar substances.

Moreover, to get eye drops to use an aqueous solution or suspension, which, in particular, is a sterile aqueous solution for injection. Is appropriate when the eye drops contain various additives such as a buffer, stabilizer, humectant, emulsifier, suspendisse substance, a surfactant, a means to give isotonicity of the solution, preservative and thickener.

The buffer can represent, for example, phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer, amino acid and the like.

The stabilizer may represent, for example, edetate sodium, citric acid and the like.

The humidifier may represent, for example, glycerin and the like.

Suspendisse substance may represent, for example, hypromellose, methylcellulose and the like.

Surfactant may constitute, for example, Polysorbate 80, polyoxyethylenesorbitan castor oil and the like.

Means for imparting isotonicity of the solution can represent, for example, saccharides such as sorbitol, glucose, m is net and the like, polyhydric alcohols such as glycerin, propylene glycol and the like, salts such as sodium chloride and the like.

The preservative may represent, for example, Quaternary ammonium salt, such as benzylaniline, benzathine and such, para-hydroxybenzoate, such as methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate and the like, benzyl alcohol, finitely alcohol, sorbic acid and their salts, thimerosal, chlorobutanol and the like.

The thickener may represent, for example, hydroxyethyl cellulose, hydroxypropylcellulose, methylcellulose, hypromellose, carboxymethylcellulose, their salts and the like.

When used in the form of eye drops pH is usually adjusted to about 4 to 9, preferably up to about 6-8,5.

The liquid composition is water-based according to the present invention contains an active ingredient generally in amounts of 0.0001-10% wt./about., preferably, 0.001 to 1% wt./about., more preferably, 0.01 to 0.1% wt./about. of the composition. Despite the fact that the dose and frequency of injection vary depending on symptom, age, body mass and form of administration, if it is applied in the form of eye drops for adults, the composition comprising a compound of the present invention in a proportion of 0.0001-10% wt./about., preferably, 0.001 to 1% wt./about., enter several times a day, preferably 1-2 times per day, more preferably once a day, several drops, preferably 1-3 drops each time.

Examples

The present invention is explained in detail using the following Examples and Experimental Examples, which are not restrictive.

Examples 1-3 and Comparative Example 1

Getting eye drops

In accordance with the formulations shown in Table 1, was given eye drops containing the compounds having inhibitorbased action against Rho kinase, (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)benzamide·monohydrochloride (compound A). Mix ratio (molar ratio) of the compounds A and forming an ion pair reagent in Examples 1-3 was 1:2.

Table 1
IngredientExample 1Example 2Example 3Comparative Example 1
Connection A0,0565 g0,0565 g0,0565 g0,0565 g
Octanoate sodium0,052 g---
Sodium sorbate-0,047 g--
N-lauroyl-L-glutamate sodium--0.11 g-
Sodium dihydrophosphate0.1 g0.1 g0.1 g0.1 g
Sodium chloride0,85 g0,85 g0,85 g0,85 g
Benzylaniline0.005 g0.005 g0.005 g0.005 g
Hydroxide /sodium hydrochloridee.q.e.q.e.q.e.q.
Sterile purified watere.q.e.q.e.q.e.q.
The total number of100 ml 100 ml100 ml100 ml
pH7,07,07,07,0

Experimental Example 1

Penetration test compound A in intraocular fluid by adding forming ion pair reagent

Eye drops of Examples 1-3 and Comparative Example 1 was administered by instillation (50 ál, once, n=4) in the eyes of the male white rabbits (body weight of 2.1-2.7 kg). The rabbits used euthanasia within 1 hour after start digging through the introduction of excessive quantities of pentobarbital sodium. The external segment of the eye was rinsed with saline solution and a syringe with needle for injection 27G were selected for the research sample of intraocular fluid. Retrieved intraocular fluid was filtered using 0.45 µm of chromatolysis and the filtrate was used as sample solution. HPLC was carried out under the following conditions and measured the concentration of compound A.

<Conditions for HPLC>

detector: ultraviolet absorptiometer (measurement wavelength: 248 nm)

column: YMC-Pack ODS A-302 (4.6 mm×15 cm, 5 μm)

the column temperature: a constant temperature of about 40°C

mobile phase: mixed solution of methanol:0,02 mo the e/l of sodium perchlorate (pH 2,5) = 18:82

flow rate: 1.0 ml/min

the volume of injected sample: 50 ál

<Results>

The results are presented in Table 2.

Table 2
GroupConcentration (ng/ml) compound A in intraocular fluid*
Comparative Example 123,7±14,7
Example 144,0±5,7
Example 246,6±23,3
Example 349,1±47,0
* each value represents the mean ± standard deviation.

As shown in Table 2, the concentration of compound A in aqueous humor in the group introduction Example 1, under the administration of Example 2 and under the administration of Example 3 was increased compared with those in group introduction Comparative Example 1. Based on this it is obvious that adding octanoate sodium sorbate or sodium N-lauroyl-L-glutamate sodium, which are the reagents for the formation of ion pairs in the liquid composition is water-based, containing the compound A causes the joint is A in intraocular fluid.

Example 4 and Comparative Example 2

Getting eye drops

In accordance with the formulations shown in Table 3, was given eye drops containing compound A.

Table 3
IngredientExample 4Comparative Example 2
connection A0,0565 g0,0565 g
xanthan gum (ECHO GUM T: registered trademark, Dainippon Sumitomo Pharma Co., Ltd.)0.2 g-
sodium dihydrophosphate0.1 g0.1 g
sodium chloride0,85 g0,85 g
hydroxide/sodium hydrochloridee.q.e.q.
sterile purified watere.q.e.q.
the total number of100 ml100 ml
pH7,07,0

Experimental Example 2

Penetration test compound A in ocular tissue by adding a water-soluble polymer

Eye drop of Example 4 and Comparative Example 2 was administered by instillation (50 ál, once, n=5) in the eyes of the male white rabbits (body weight of 2.2-2.6 kg). The rabbits used to be euthanized after 1 hour or 2 hours after you start digging through the introduction of excessive quantities of pentobarbital sodium. The external segment of the eye was rinsed with saline and were selected for testing samples of intraocular fluid and conjunctiva. Intraocular fluid was collected for studies syringe with needle for injection 27G, intraocular fluid (100 μl) was added methanol (10 ml) and the following internal standard solution (10 μl), the mixture was dried under a stream of nitrogen, dissolved in methanol (20 ml) and the following solution A, mobile phase (180 μl) and used as a sample solution of intraocular fluid. Took the conjunctiva, was added acetonitrile (5 ml) and the conjunctiva were crushed and separated supernatant (4,5 ml). The composition was dried under a stream of nitrogen and diluted in the following solution for dilution (500 μl). To the resulting solution (100 ml) was added methanol (10 ml) and rastvorennogo standard (10 μl) and the mixture was dried under a stream of nitrogen. The residue was dissolved in methanol (20 ml) and A solution of the mobile phase (180 μl) and used as a sample solution of the conjunctiva. HPLC was carried out under the following conditions and measured the concentration of compound A in each sample solution.

<Conditions for HPLC>

detector: MS/MS

column: Capcell Pak UG-120 S-3 (2.0 mm×5 cm, 5 μm)

restrictive column: Rheodyne Column Inlet Filter (3 mm ID Frit)

the column temperature: 30°C

the mobile phase solution A: 0.1% aqueous formic acid and 10 mm ammonium formate

the mobile phase solution B: acetonitrile

the volume of injected sample: 20 ál

the solution for dilution: mixed solution of methanol:saline = 1:9

the internal standard solution: substance constituting the internal standard, ((+)-TRANS-4-(1-amino-ethyl)-1-(4-pyridylcarbonyl)cyclohexane·dihydrochloride·monohydrate), about 1.4 mg/ml methanolic solution

Table 4
Conditions MS/MS: ionization method: Turbiny spray, cationic mode
SubstanceQ1 (m/z)Q3 (m/z)
connection281264
the internal standard substance 24895

Table 5
The terms of the gradient
Time (min)Flow rate (ml/min)The ratio of solution And mobile phase (%V/V)The ratio of solution In mobile phase a (%V/V)
0,00,251000
7,00,258020
7,00,251000
15,00,251000

<Results>

The results are presented in Table 6.

Table 6
GroupConcentration (ng/ml) compounds And in the intraocular fluid*Concentration (ng/g) connection And in the conjunctiva of the eye*
within 1 hour after instillation2 hours after instillationwithin 1 hour after instillation2 hours after instillation
Comparative example 256,2±34,164,3±33,0159,8±64,465,1±33,1
Example 4153,7±146,4to 96.9±38,9291,2±to 136.4142,3±161,8
* each value represents the mean value ± standard deviation

As shown in table 6, the concentration of compound A in aqueous humor in the group introduction Example 4 increased compared with the value in the group the introduction of Comparative Example 2 as in 1 hour and 2 hours after instillation. The concentration of compound A in the conjunctiva of the eyes in group introduction Example 4 increased compared with the value in the group the introduction of Comparative Example 2 as in 1 hour and 2 hours after instillation. Based on this it is evident that the addition of xanthan gum, which is a water-soluble polymer, liquid to whom is osili water-based, containing the compound A, promotes the penetration of compound A in the intraocular tissue.

Experimental Example 3

Penetration test compound A in ocular tissue by adding a water-soluble polymer

Eye drop of Example 4 and Comparative Example 2 were tested by the method similar to that described in Experimental Example 2, and measured the concentration of compound A in intraocular fluid and conjunctiva of the eye after 6 hours and 12 hours after instillation (n=3).

<Results>

The results are presented in Table 7.

Table 7
GroupConcentration (ng/ml) compounds And in the intraocular fluid*Concentration (ng/g) connection And in the conjunctiva of the eye*
group introduction Comparative Example 2group introduction Example 4group introduction Comparative Example 2group introduction Example 4
after 6 hours18,6±3,841,5±22,034,2±35,2 61,6±55,2
after 12 hours2,7±1,58,3±7,513,4±20,215,9±15,9
* each value represents the mean value ± standard deviation.

As shown in table 7, the concentration of compound A in aqueous humor in the group introduction Example 4 increased two times or more compared to group the introduction of Comparative Example 2 as 6 hours, and 12 hours after instillation. The concentration of compound A in the conjunctiva of the eyes in group introduction Example 4 increased by approximately half compared with a group introduction Comparative Example 2 through 6 hours after instillation. Based on this it is evident that the addition of xanthan gum, which is a water-soluble polymer, water-soluble liquid composition containing the compound A, promotes the penetration of compound A in ocular tissue, and it lasts for a long time.

Obtained after instillation of the concentration of compound A in intraocular fluid and the concentration of compound A in the conjunctiva of the eye in Experimental Example 2 and Experimental Example 3, described above, are presented in figure 1 and Figure 2 with therefore, its.

Industrial applicability

In accordance with the liquid composition of water based on the present invention is activated intraocular penetration of compounds of the present invention, which is an active ingredient that is effective for the treatment concentration of the active ingredient may for a long time supported the intraocular tissue, and the frequency of injection can be reduced. In accordance with the present invention provides a composition having higher characteristics in regard to the ability to achieve the active ingredient to the site of its action, the effective use of the ingredient and reducing the frequency of injection compared with the known compositions containing the same concentration of active ingredient. Moreover, in accordance with the present invention even composition containing a low concentration of the active ingredient, can demonstrate the effectiveness equivalent to the efficiency of the known compositions, and to increase the interval between doses. Thus, it may be given less burdensome composition, especially for patients who need long-term introduction of such a composition.

This application is based on patent application No. 2006-209102 (filing date: July 31, 2006), poda is Noah in Japan, the contents of which are fully incorporated into the present application by reference.

1. Liquid composition for water-based activation intraocular penetration of compounds of formula (I), comprising the amide compound represented by the following formula (I)

where Ra represents a group of the formula


in formulas (a) and (b),
R represents hydrogen, alkyl or cycloalkyl, cycloalkenyl, phenyl or aralkyl, which optionally contains substituents on the ring, or a group of the formula

where R6represents hydrogen, alkyl or of the formula-NR8R9,
where R8and R9are the same or different from each other and each represents hydrogen, alkyl, aralkyl or phenyl, R7represents hydrogen, alkyl, aralkyl, phenyl, nitro or cyano, or
R6and R7in combination represent a group forming a heterocycle, optionally additionally containing in the ring oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R1represents hydrogen, alkyl or cycloalkyl, cycloalkenyl, phenyl or aralkyl, which optionally contains substituents on the ring, or
R and R1in op is Tania's story form together with the adjacent nitrogen atom group, forming a heterocycle, optionally additionally containing in the ring oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R2represents hydrogen or alkyl,
R3and R4are the same or different from each other and each represents hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkylated, cyano, acyl, mercapto, alkylthio, Uralkali, carboxy, alkoxycarbonyl, carbamoyl, alkylaromatic or azide, and
A represents a group of the formula

where R10and R11are the same or different from each other and each represents hydrogen, alkyl, halogenated, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, or R10and R11represent a group which, when combined forms cycloalkyl, and l, m and n each represent 0 or an integer having a value of from 1 to 3,
in the formula (C),
L represents hydrogen, alkyl, aminoalkyl, mono - or dialkylaminoalkyl, tetrahydrofurfuryl, carbamoylethyl, phthalimidomethyl, amidino or a group of the formula


where In represents hydrogen, alkyl, alkoxy, aralkyl, aralkylated, aminoalkyl, Hydra is cialkis, alkanoyloxy, alkoxycarbonyl, α-aminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridine,
Q1represents hydrogen, halogen, hydroxy, aralkylated or thienylmethyl,
W represents alkylene,
Q2represents hydrogen, halogen, hydroxy or aralkylated,
X represents alkylene,
Q3represents hydrogen, halogen, hydroxy, alkoxy, nitro, amino,
2,3-dihydrofuran or 5-methyl-3-oxo-2,3,4,5-tetrahydropyridine-6-yl;
and Y represents a simple bond, alkylene or albaniles, and
in the formula (C),
the dotted line represents a simple bond or double bond, and
R5represents hydrogen, hydroxy, alkoxy, alkoxycarbonyl, alkanoyloxy or uralelectromontrage;
Rb represents hydrogen, alkyl, aralkyl, aminoalkyl or mono - or dialkylaminoalkyl; and
Rc represents an optionally substituted heterocycle containing nitrogen,
its isomer and/or its pharmaceutically acceptable additive and salt forming ion pair reagent,
where forming the ion pair reagent selected from the group consisting of octanoic acid, N-lauroyl-L-glutamic acid, DHA, saccharin, acetyltryptophan or their pharmacologically acceptable salts.

2. The liquid composition is water-based according to claim 1, where the forming ion pair reagent is an octane acid or N-lauroyl-L-glutamic acid or its pharmacologically acceptable salt.

3. The liquid composition is water-based according to claim 1, where the compound represented by formula (I)represents the (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)benzamide monohydrochloride.

4. The liquid composition is water-based according to any one of claims 1 to 3, which represents the eye drops.

5. The activation method of the intraocular penetration of compounds represented by formula (I)according to claim 1, its isomer and/or its pharmaceutically acceptable salt additive, which includes the addition of forming an ion pair reagent selected from the group consisting of octanoic acid, N-lauroyl-L-glutamic acid, DHA, saccharin, acetyltryptophan or their pharmacologically acceptable salts to aqueous solution comprising the compound represented by formula (I)or its isomer and/or its pharmaceutically acceptable additive salt.

6. The method of prevention or treatment of a disease selected from the group including glaucoma, asthenopia and pseudomyopia caused by prolonged excessive tension of the ciliary muscle, functional vision disorders caused by damage to or degeneration of the retinal nerve or optic nerve dysfunction of the sensitivity of the cornea, caused by damage to the corneal nerve, and dryness of the eyes, caused by dysfunction of the sensitivity of the cornea, which which includes the introduction of an effective amount of a compound according to claim 1, represented by formula (I), its isomer and/or its pharmaceutically acceptable salt additive to the subject, together with forming an ion pair reagent selected from the group consisting of oktanovoe acid, N-lauroyl-L-glutamic acid, DHA, saccharin, acetyltryptophan or their pharmacologically acceptable salts.

7. The method according to claim 6, where forming the ion pair reagent is an octane acid or N-lauroyl-L-glutamic acid or its pharmacologically acceptable salt.

8. The method according to claim 6 where the compound represented by formula (I)represents the (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)benzamide monohydrochloride.

9. The method according to any of p-8, which relates to eye drops.

10. The use of compounds according to claim 1, represented by formula (I), its isomer and/or its pharmaceutically acceptable salt additive and forming an ion pair reagent selected from the group consisting of oktanovoe acid, N-lauroyl-L-glutamic acid, DHA, saccharin, acetyltryptophan or their pharmacologically acceptable salts for obtaining aqueous liquid medicines for the prevention or treatment of a disease selected from the group including glaucoma, asthenopia and pseudomyopia caused by prolonged excessive tension of the ciliary muscle function is optional visual disturbances, caused by damage to or degeneration of the retinal nerve or optic nerve dysfunction of the sensitivity of the cornea, caused by damage to the corneal nerve, and dryness of the eyes, caused by dysfunction of the sensitivity of the cornea.

11. The use of claim 10, where forming the ion pair reagent is an octane acid or N-lauroyl-L-glutamic acid or its pharmacologically acceptable salt.

12. The use of claim 10 where the compound represented by formula (I)represents the (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridine-4-yl)-4-(1-amino-ethyl)benzamide monohydrochloride.

13. The use according to any one of p-12, which refers to the eye drops.

14. A commercial package comprising a liquid composition on a water basis according to any one of claims 1 to 4, and a written statement, clearly indicating that the liquid composition is water-based can or should be used for prevention or treatment of a disease selected from the group including glaucoma, asthenopia and pseudomyopia caused by prolonged excessive tension of the ciliary muscle, functional vision disorders caused by damage to or degeneration of the retinal nerve or optic nerve dysfunction of the sensitivity of the cornea, caused by damage to the corneal nerve, and dryness of the eyes, caused by dysfunction of the CHUV is titelliste of the cornea.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to use of substituted sulphonamides of general formula (I) where R1 is CO or SO2, R2 is NH or O, R includes a tertiary diC1-4alkylamine group in which alkyl fragments are identical or different, or an amino group whose alkyl groups together form a 5, 6 or 7-member ring with saturated bonds or the ends of the alkyl fragments are bonded to an O heteroatom, or R is 4-(N,N-diethylaminoethoxy)benzyl, where R1 is SO; and R2 is NH; or R is 4-[N-(morpholinopropyl)sulphamoyl]phenyl, where R1 is CO and R2 is NH, n is the number of carbons in the connecting aliphatic chain, where n is equal to 0, 2 or 3; and/or physiologically acceptable salts thereof in production of a medicinal agent for treating glaucoma. The invention also relates to substituted sulphonamides of formula (Ia) (where values of radicals are given in the claim) and physiologically acceptable salts thereof, a method for production thereof and a medicinal agent based thereon, for treating eye diseases.

EFFECT: compounds can be used as carbonic anhydrase inhibitors.

11 cl, 3 dwg, 4 tbl, 19 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to ophthalmology, and can be used for treatment of glaucomatous optic neuropathy. Method includes carrying out sinus trabeculectomy and introduction of medication citicoline (ceraxon). Citicoline is introduced in dependence on structural and functional eye disorders after sinus trabeculectomy in differentiated manner, combining intravenous introduction of citicoline with its intake. To patients with I-II stage of glaucoma citiciline is introduced intravenously fy drop infusion in dose 500 mg daily during 5 days with further transition to intake in dose 200 mg 3 times per day during 10 days. Patients with III stage of glaucoma citicoline is introduced intravenously by drop infusion in dose 1000 mg daily during 5 days with further transition to intake in dose 200 mg 3 times per day during 15 days.

EFFECT: method ensures efficient treatment of disease, making it possible to avoid "excessive" drug load and reduce probability of development of side effects, especially in elderly patients.

2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular, to ophthalmology and pharmacy, and is intended for reduction of intraocular pressure. Method includes introduction of specially elaborated medications from the group of angiotensin-converting enzyme into conjunctival cavity. Medication is characterised by the following: inhibitor is introduced in composition of calcium-phosphate biodegradable nanoparticles with radius 30-350 nm and in concentration 0.1% - 3%.

EFFECT: selection of nanoparticle size and corresponding concentration of said preparations, when they are introduced into conjunctival cavity, makes it possible to ensure enhance of prolongation of effect of intraocular pressure reduction with reduction of risk of local and general side effects, including application of prodrug forms of said inhibitors.

6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

EFFECT: compounds have inhibiting activity on IKKβ, which enables their use as a preventive or therapeutic agent for treating IKKβ mediated diseases.

26 cl, 1 tbl, 29 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to ophthalmology. A preventive and therapeutic agent is applied in posterior eye diseases. Pramipexole being a non-ergotamine selective D2 receptor antagonist, or its salt show inhibitory action on neovascularisation, suppressive action on photoreceptor cell damage and suppressive action on vascular hyperpermeability in posterior eye tissues, such as choroid or retina.

EFFECT: group of invention enables applying the agent as a preventive or therapeutic agent in posterior eye diseases, such as age-related macular degeneration, diabetic retinopathy or diabetic macular oedema.

14 cl, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula II which have the values of radicals and symbols specified in the patent claim. The present invention also refers to a pharmaceutical composition containing said compounds, as well as application of said compounds for preparing drug preparations for treating and preventing amyloid and/or amyloid-like protein associated diseases or conditions.

EFFECT: compounds may be used in treating a group of amyloid protein associated disorders and abnormalities, such as Alzheimer's disease, and amyloid protein associated diseases or conditions; the compounds of the present invention may be used for treating ocular diseases related to pathological disturbances and changes in visual system tissues.

19 cl, 5 tbl, 32 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to ophthalmology and can be used for treatment of glaucoma or higher intraocular pressure (IOP) in patient. For this purpose efficient amount of composition, containing preparation inhibiting PAI-1 binding with vitronectin, is introduced to patient. Also claimed is method of treating PAI-1-associated eye disease.

EFFECT: group of inventions ensures treatment of glaucoma and IOP due to reduction of separation of trabecular meshwork tissue and reduction of increased resistance to intraocular fluid outflow, and also due to increase of TM tissue cellularity and preservation of phagocytosis.

14 cl, 8 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: invention relates to ophthalmology and can be used for prevention and treatment of excessive scarring after penetrating anti-glaucoma operations of filter type. 14-30 days after operation in zone of filter pad needling with application of collalysin solution, which contains 50 KU/ml, in dose 0.2 ml, is performed a single time. During the following 10-20 days the same solution is dripped into conjunctival cavity 6 times within 1 hour.

EFFECT: method makes it possible to destroy already formed scar tissue in zone of newly formed way of outflow and prevent further scarring, thus increasing anti-glaucoma operation efficiency and reducing necessity of repeated surgery.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular to ophthalmology. A composition for treating patients with primary open-angle glaucoma on the basis of phospholipids, sulphated glycosaminoglycans in physiologic saline represents a liposomal emulsion formed by phospholipids in the form of liposomes of average particle size 0.05-0.22 mcm and sulphated glycosaminoglycans, and additionally contains a hypotensive preparation with phospholipids presented by phosphatidyl choline and/or cardiolipin, and sulphated glycosaminoglycans presented by keratan sulphate sodium salt and chondroitin sulphate sodium salt with the ingredients taken in the following proportions, wt %: Phospholipid 0.001-2.0; Sulphated glycosaminoglycans 0.0001-0.1; The hypotensive preparation 0.0025-0.02; Physiologic saline - the rest with sulphated glycosaminoglycans and the hypotensive preparation found both inside the liposomes, and outside the liposomes, in physiologic saline.

EFFECT: invention provides a prolonged hypotensive effect, prevents lachrymal production, reduces tear evaporation, as well as enables avoiding pathological changes in conjunctival and corneal epithelial cells.

7 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmacology and represents a pharmaceutical composition for integrated treatment of ocular surface diseases in the patients suffering primary open-angle glaucoma, on the basis of phospholipids and sulphated glycosaminoglycans, differing by the fact that composition represents a liposomal emulsion formed by phospholipids in the form of liposomes, of average particle size 0.05-0.22 mcm, and sulphated glycosaminoglycans with sulphated glycosaminoglycans presented by keratan sulphate sodium salt and chondroitin sulphate sodium salt with the ingredients of the composition taken in certain proportions, wt %.

EFFECT: invention provides preventing lachrymal production from decreasing, reducing tear evaporation, as well as avoiding pathological changes in conjunctival and corneal epithelial cells.

5 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely ophthalmology, and may be used for treating postoperative corneal oedemas in age-related cataract surgery. For this purpose, 0.25% derinate is instilled for 3 times for 1 minute from the first postoperative day. Immediately after the last instillation, the cornea is exposed to a travelling pulse magnetic field generated by the AMO-ATOS apparatus with its radiation head placed at 3 mm from the external cornea. It is combined with the laser light exposure. A laser beam generated by the LAST-01 apparatus is directed through an axial hole in the field radiation head. Radiator frequency is 5-10 Hz; diaphragm position is 4; exposure time is 5 min; the therapeutic course is 2-3 sessions.

EFFECT: method improved the surgical outcomes and reduces the length of treating the gerontological patients suffering the declared pathology ensured by reducing the length of recovering the normal anatomic-physiological and optical corneal state, reducing the rate of chronic bullous keratopathy, recovering developed mechanisms causing energy and metabolic cell reserves.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular to ophthalmology. An agent is applicable for a cross-linking procedure accompanying corneal ectasias. The agent contains riboflavin mononucleotide, chitosan succinate, sodium chloride, tris-(hydroxymethyl)-methylamine, Nipagin, disodium dihydrogen ethylenediaminetetraacetate and purified distilled water in certain proportions.

EFFECT: invention provides prolonged action of the agent, improves bacteriological availability for active ingredients, reduces the length and number of instillations for the procedure, provides agent saving.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely ophthalmology, and may be used in separation and organotypic preservation of an allogenic limb transplant. A method involves early surgical separation of the limb transplant from a whole corpse donor eyeball with eliminated perforation after donor's death. The transplant is preserved within 28 days in a medium containing insulin, dexamethasone, blood serum, penicillin, streptomycin, dextran 40000, HEPES M-solution, 7.5% bocarbonate, 40% glucose, L-glutamine, penicillin, streptomycin, amphotericin B and Hanks salt medium 199 under certain proportion of the components. The preservation is performed at temperature 37°C with the medium changed every 3 days. The same medium, but serum-free is used for washing. The method provides preserving transplant viability with proliferating progenitor cells that leads to achieving stable, long-term epithelisation, stroma defect recovery, prevention of corneal conjunstivisation.

EFFECT: prepared transplant may be used for surgical management of the patients with limb cell insufficiency syndrome of various aetiologies.

2 cl, 1 ex, 9 dwg

FIELD: medicine.

SUBSTANCE: there are described versions of humanized monoclonal anti-factor D antibodies and their functional fragments. There are offered: a coding nucleic acid, an expression vector, as well as a cell for preparing c the antibody containing the vector. What is described is a method for preparing the anti-factor D antibody by cell culture and expressed antibody purification. Also, there are offered: an antibody composition and use of the antibody for treating disorders mediated by a complement system.

EFFECT: higher clinical effectiveness in the diseases related to excessive or uncontrolled activation of the complement system.

32 cl, 9 dwg, 4 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, particularly to ophthalmology. An agent for promotion of corneal endotheliocyte adhesion containing an Rho kinase inhibitor, a culture medium for corneal endotheliocytes containing the Rho kinase inhibitor, a solution of cornea preservation containing the Rho kinase inhibitor, and a method for making a preparation of corneal endothelium involving the stage of corneal endotheliocyte culture with the use of the above culture medium.

EFFECT: group of inventions provides an ability for effective growing of corneal endotheliocytes and stable delivery of the preparation of corneal endothelium.

43 cl, 17 dwg, 19 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to ophthalmology, and may be used for treating chalazion. That is ensured by surgical excision of chalazion. The surgery is terminated by the introduction of Kenalog 0.2-0.3 ml into an incisional wound of eyelid tissue after the removal of chalazion.

EFFECT: method reduces a possibility of recurrences within a site of chalazion thereby enabling removing greater chalazion without recurrent surgical interventions.

1 ex

FIELD: medicine.

SUBSTANCE: cell population is recovered from peripheral blood or umbilical blood by a method involving positive cell secretion from peripheral blood or umbilical blood able for immune reaction with an antibody specified in a group consisting of aHTH-CD44, anti-CD11b and their combination. The recovered myeloid-like cell population contains the cells expressing CD44 antigen, CD11b antigen and hypoxia-induced factor lα (HIF-lα). The prepared population is used for recovery and stabilisation of the functional vasculature, stimulation of microgliacyte formation, and for stimulation of physiologic intra-retinal vascularisation of hypoxic retinal tissue in simultaneous suppression of abnormal preretinal vessel formation.

EFFECT: invention enables preparing the cells with vasculotrophic and neurotrophic activity which possess a considerable therapeutic potential in the intraocular introduction into a mammal suffering a degenerative ocular disease.

7 cl, 63 dwg, 2 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly ophthalmology. Eye drops containing recombinant interferon stabilising the biological and physicochemical properties, stabilising resistance to microbial contamination, an antioxidant and a buffer mixture, contain antihistamine preparations specified in a group: antazoline, azelastin, tetryzoline, diphenhydramine hydrochloride as stabilising the biological and physicochemical properties, contains specified in the group: low-molecular polyvinylpyrrolidone, macrogol 400-12000, propylene glycol as stabilising resistance to microbial contamination contains specified in a group: Nipasol, sorbic acid, boric acid, besides it contains sodium chloride and/or sodium acetate in the following proportions in 1 ml of the solution. As an antioxidant, the eye drops contain disodium dihydrogen ethylenediaminetetraacetate and/or buthylhydroxytoluene in the amount of 0.0001-0.1 g in 1 ml of the solution. The eye drops contain recombinant interferon specified in a group: alpha-, beta-, gamma-interferon. As a buffer mixture, the eye drops contain borate-acetate or phosphate, or borate buffer.

EFFECT: invention provides higher antiviral activity of the eye drops.

4 cl, 5 ex

FIELD: medicine.

SUBSTANCE: invention relates to ophthalmology and is intended for conservative treatment of dacryostenosis. Furacilinum-based ophthalmic gel is introduced into lacrimal canaliculus. Furacilinum-based ophthalmic gel is introduced by means of syringe in dose 3 ml, every second day, 8-10 times in total.

EFFECT: method ensures recovery of lacrimal passages and prevention of stenosis recurrences in postoperative period after dacryorhinocystostomy, as well as possibility of application in patients with allergic predisposition to antibiotics.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutical compositions for preparing infusion solutions of antibacterial and antimycotic preparations, and to methods for preparing them. The declared pharmaceutical compositions are presented in the form of powder, contain sodium chloride and dextrose and particles of colloidal silicone dioxide among which a portion of particles of 5 mcm and less makes less than 35%, in certain weight proportions. A method for preparing said pharmaceutical compositions consists in the fact that sodium chloride in the form of powder and dextrose in the form of powder are mixed with powdered colloidal silicone dioxide in certain proportions; the prepared mixture is mechanically treated by impact abrasion to increase a weight portion of fine particles of silicone dioxide of 5 mcm or less to min. 35%.

EFFECT: group of inventions provides the intensified therapeutic effectiveness of parenteral forms of the antibacterial and antimycotic preparations.

4 cl, 4 tbl, 3 ex

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