Pharmaceutical composition and methods of treating dry-eye syndrome

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely ophthalmology, and may be used for treating dry eye syndrome and recovered function of lachrymal fluid secretion in a mammal. For this purpose, a composition containing a pharmaceutically effective amount of a Janus kinase 3 inhibitor of the following structure is introduced in a mammal: 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl}-3-oxopropionitryl.

EFFECT: introduction of the Janus kinase 3 inhibitor enables considerable increase of the secreted lachrymal fluid volume.

11 cl, 2 tbl, 6 ex, 8 dwg

 

This application claims priority under provisional application U.S. No. 60/949216, filed on July 11, 2007, and provisional application U.S. No. 61/060032, filed June 9, 2008, the content of which is introduced in the present invention fully by reference.

The level of technology

Dry eye, also known as keratoconjunctivitis sicca, is a common eye disorder, which affects millions of Americans each year. Dry eye is a multifactorial disease associated with the secretion of the lacrimal fluid and the surface of the eye, which causes symptoms of discomfort, visual disturbances and instability of the tear film with possible damage to the eye surface. It is accompanied by increased osmolarity of the tear film and inflammation of the eye surface.

Dry eyes can affect individuals with varying degrees of severity. Dryness of the eyes, in particular, is widely prevalent in women after menopause due to hormonal changes after the loss of the ability to bear children. In milder forms of the disease the patient may experience a burning sensation, dryness and constant irritation similar to that caused by small particles that fall between eye eyelid and eye surface. In severe cases, vision may be damaged considerable is. Other diseases, such as sjögren's disease and cicatrizing pemphigoid, are complications with dry eyes.

Etiopathogeny classification of dry eye was first developed in 1995, National Eye Institute/Industry Dry Eye Workshop, and then expanded in January 2007 definitions. The Ocular Surface, vol.5, no. 2, 75-92 (2007). The main classes of dry eye include dry eyes when lack of water components of tear fluid and dry eyes as a result of evaporation. Dry eyes with lack of water components of tear fluid includes two main subclasses, dry eye in sjögren's syndrome and dry eye not associated with Sjogren syndrome (primary and secondary defects of the lacrimal gland, obstruction of the channels of the lacrimal glands, reflex hipocresia, lock motor reflexes). Dry eyes as a result of evaporation, which is the result of excessive water loss from exposed to external influences the surface of the eye with normal secretion of the lacrimal fluid, includes subclasses for internal reasons (dysfunction of the meibomian gland, diseases of the holes century and diseases of the century/the eyeball, low frequency blinking) and external reasons (illness or disease of the eye surface, the wearing of contact lenses, allergic conjunctivitis, such as vernal keratoconjunctivitis).

Even though it appears that dry eye may sniket the result of a number of unrelated pathogenic causes, all manifestations of complications have a General effect, namely a violation of the ocular tear film, resulting in dehydration of the exposed external influences external surface and many of the symptoms outlined above (Lemp, Report of the national Eye Institute/Industry workshop on Clinical Trials in Dry Eyes, the CLAO Journal, vol.21, no. 4, p.221-231 (1995)).

Practitioners use several approaches for the treatment of dry eye. One General approach is that you need to fill and stabilize the ocular tear film, applying the so-called artificial tears, burying during the day. Other approaches include the use of eye inserts that mimic ocular fluid or stimulate the endogenous secretion of tear fluid.

Examples of the approach with the use of tear fluid substitute include the application buffer, isotonic saline solutions, aqueous solutions containing water-soluble polymers, which give the solution more viscous and, therefore, less easily drain from the eye. The tear film also trying to restore the addition of one or more components of the tear film, such as phospholipids and oils. It is shown that the phospholipid compositions are suitable for the treatment of dry eye; see, for example, McCulley and Shine, Tear film structure and dry eye, Contactologio, vol.20(4), p.145-9 (1998). Also known delivery system of phospholi innych medicines, contains phospholipids, a propellant and an active substance, see U.S. patent No. 5174988.

Another approach includes the use of lubricants instead of artificial tears. For example, in U.S. patent No. 4818537 (Guo) describe the application of lubricating compositions based on liposomes and in U.S. patent No. 5800807 (Hu et al.) describe compositions containing glycerol and propylene glycol, for the treatment of dry eye.

Although the application of these approaches have achieved some success, problems in the treatment of dry eye, however, remain. The use of substitutes lacrimal fluid, although temporarily and effectively, usually require repeated applications during the hours of wakefulness of the patient. Often the patient is forced to use a solution of artificial tear fluid 10-20 times during the day. This process is not only tedious and time consuming, but it is also potentially very expensive. Reported that the temporary symptoms of dry eye associated with refractive surgery, occur in some cases during the period of time from six weeks to six months or more after surgery.

In addition to research aimed directly at alleviating symptoms associated with dry eye, also are searching for methods and compositions designed for the treatment of a condition in which there is dryness of the eyes is. For example, in U.S. patent No. 5041434 (Lubkin) describe the use of sex steroids, such as conjugated estrogens to treat conditions with dry eyes in women after menopause; in U.S. patent No. 5290572 (MacKeen) describe the application of finely divided compositions containing calcium ions, in order to stimulate the generation of a tear film on the front surface of the eye; and in U.S. patent No. 4966773 (Gressel et al.) describe the use of microparticles of one or more retinoids for the normalization of eye tissues.

In some printed reports suggest that patients suffering from the syndrome of dry eye, disproportionate show distinctive signs of excessive inflammation in the relevant ocular tissues, such as the lacrimal and meibomiae iron. Describe the application of various compounds for the treatment of patients with dry eye, such as steroids, for example, in U.S. patent No. 5968912; Marsh, et al., Topical nonpreserved methylprednisolone therapty for keratoconjunctivities sicca in Sjogren's syndrome, Ophthalmology, 106(5): 881-816 (1999); Plugfelder et al, in U.S. patent No. 6153607; inhibitors of the release of tsitokinov (Yanni, J. M.; et al WO0003705 A1), cyclosporine A [Tauber, J. Adv. Exp. Med. Biol. 1998, 438, (Lacrimal Gland, Tear Fiom and Dry Eye Syndromes 2), 969] and 15-HETE (Yanni et al., U.S. Pat. No. 5696166).

In addition to dryness of the eye, Jak3 inhibitors may be useful for treatment of other eye diseases associated with inflammation, including, but not limited to, Glauco is, uveitis, diabetic retinopathy and age-related macular degeneration. If funded CNIB studies have found that patients who have a biomarker of inflammation, anticardiolipin were four times more likely to develop glaucoma. Previously Jak3 inhibitors are recommended for the treatment of diabetes, although, apparently, they are not considered as medicines, in particular, for the treatment of diabetic retinopathy. Cetkovic-Cvrle, M. and Uckun, F. M., Arch Immunol Ther Exp (Warsz), 52(2), 69-82 (2004). Rodrigues found that the secretion of immunoglobulins, proteins of the complement system, cytokines and activated microglia in the cells of the retinal pigment epithelial (RPE) and druzak demonstrates the role of inflammation in age-related macular degeneration with dry eyes. Rodrigues E.B., Ophthalmologica, 221(3):143-52 (2007).

The invention

The present invention relates to a method for treatment of dry eye, which comprises the administration to a mammal of a composition containing a pharmaceutically acceptable carrier and a pharmaceutically effective amount of an inhibitor of Janus kinase-3 ("Jak3"). In one aspect of Jak3 inhibitors are compound of formula I:

,

where

R1represents a group of the formula

,

in which y is 0, 1 or 2;

R4selected from the group consisting of hydrogen, (C1 6)alkyl, (C1-C6)alkylsulfonyl, (C2-C6)alkenyl, (C2-C6)quinil, in which alkyl, Alchemilla and Alchemilla group optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C1-C4)alkoxy, (C1-C6)acyloxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, cyano, nitro, (C2-C6)alkenyl, (C2-C6)quinil or (C1-C6)acylamino; or R4is a (C3-C10)cycloalkyl in which cycloalkyl group optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C1-C6)acyloxy, (C1-C6)acylamino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, cyano, cyano(C1-C6)alkyl, trifluoromethyl(C1-C6)alkyl, nitro, nitro(C1-C6)alkyl or (C1-C6)acylamino;

R5is a (C2-C9)heteroseksualci in which heterocytolysine group must be substituted by 1-5 carboxy, cyano, amino, daarimi, hydroxy, (C1-C6)alkilani, (C1-C6)alkoxy, halogen, (C1-C6)atilov, (C1-C6)alkylamino, amino(C1-C6)alkilani, (C1-C6)alkoxy-CO-NH, (C1-C6)alkylamino-CO-, (C2-C6)alkene is Lamy, (C2-C6)akinyemi, (C1-C6)alkylamino, amino(C1-C6)alkilani, hydroxy(C1-C6)alkilani, (C1-C6)alkoxy(C1-C6)alkilani, (C1-C6)acyloxy(C1-C6)alkilani, nitro, cyano(C1-C6)alkilani, halogen(C1-C6)alkilani, nitro(C1-C6)alkilani, triptoreline, trifluoromethyl(C1-C6)alkilani, (C1-C6)acylamino, (C1-C6)acylamino(C1-C6)alkilani, (C1-C6)alkoxy(C1-C6)acylamino, amino(C1-C6)atilov, amino(C1-C6)acyl(C1-C6)alkilani, (C1-C6)alkylamino(C1-C6)atilov, ((C1-C6)alkyl)2amino(C1-C6)atilov, R15R16N-CO-O-, R15R16N-CO-(C1-C6)alkilani, (C1-C6)alkyl-S(O)m, R15R16NS(O)m, R15R16NS(O)m, (C1-C6)alkilani, R15S(O)mR16N, R15S(O)mR16N(C1-C6)alkilani, where m is 0, 1 or 2 and each R15and R16independently selected from hydrogen or (C1-C6)alkyl; or a group of the formula

,

where a is 0, 1, 2, 3, or 4; each of b, c, e, f and g are independently 0 or 1; d is 0, 1, 2 or 3;

X represents S(O)n

Y represents S(O)nwhere n is 0, 1 or 2; or a carbonyl; and Z is a carbonyl, C(O)O-, C(O)NR -, or S(O)nwhere n is 0, 1 or 2;

each R6, R7, R8, R9, R10and R11independently selected from the group consisting of hydrogen or (C1-C6)alkyl, optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, (C1-C6)acyloxy, (C1-C6)acylamino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, cyano, cyano(C1-C6)alkyl, trifluoromethyl(C1-C6)alkyl, nitro, nitro(C1-C6)alkyl or (C1-C6)acylamino;

R12represents carboxy, cyano, amino, oxo, deuterium, hydroxy, trifluoromethyl, (C1-C6)alkyl, trifluoromethyl(C1-C6)alkyl, (C1-C6)alkoxy, halogen, (C1-C6)acyl, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, amino(C1-C6)alkyl, (C1-C6)alkoxy-CO-NH, (C1-C6)alkylamino-CO-, (C2-C6)alkenyl, (C2-C6)quinil, (C1-C6)alkylamino, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)acyloxy(C1-C6)alkyl, nitro, cyano(C1-C 6)alkyl, halogen(C1-C6)alkyl, nitro(C1-C6)alkyl, trifluoromethyl, trifluoromethyl(C1-C6)alkyl, (C1-C6)acylamino, (C1-C6)acylamino(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)acylamino, amino(C1-C6)acyl, amino(C1-C6)acyl(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)acyl, ((C1-C6)alkyl)2amino(C1-C6)acyl, R15R16N-CO-O-, R15R16N-CO-(C1-C6)alkyl, R15C(O)NH, R15OC(O)NH, R15NHC(O)NH, (C1-C6)alkyl-S(O)m, (C1-C6)alkyl-S(O)m-(C1-C6)alkyl, R15R16NS(O)m, R15R16NS(O)m(C1-C6)alkyl, R15S(O)mR16N, R15S(O)mR16N(C1-C6)alkyl, where m is 0, 1 or 2 and each R15and R16independently selected from hydrogen or (C1-C6)alkyl;

each R2and R3independently selected from the group consisting of hydrogen, deuterium, amino, halogen, hydroxy, nitro, carboxy, (C2-C6)alkenyl, (C2-C6)quinil, trifloromethyl, triptoreline, (CrC6)alkyl, (C1-C6)alkoxy, (C1-C10)cycloalkyl, in which alkyl, alkoxy or cycloalkyl group optionally replace the 1-3 groups selected from halogen, hydroxy, carboxy, amino(C1-C6)alkylthio, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C5-C9)heteroaryl, (C2-C9)geterotsiklicheskie, (C3-C9)cycloalkyl or (C1-C10)aryl; or each R2and R3independently represents a C1-C10)cycloalkyl, (C1-C10)cycloalkane, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C10)arylamino, (C1-C6)alkylthio, (C1-C10)aaltio, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl, (C1-C6)acyl, (C1-C6)alkoxy-CO-NH-, (C1-C6)alkylamino-CO-, (C5-C9)heteroaryl, (C2-C9)heteroseksualci or (C6-C10)aryl, in which heteroaryl, geterotsyklicescoe and aryl groups are optionally substituted by 1-3 Halogens, (C1-C6)alkilani, (C1-C6)alkyl-CO-NH-, (C1-C6)alkoxy-CO-NH-, (C1-C6)alkyl-CO-NH-(C1-C6)alkilani, (C1-C6)alkoxy-CO-NH-(C1-C6)alkilani, (C1-C6)alkoxy-CO-NH-(C1-C6)alkoxy, carboxy, carboxy(C1-C6)alkilani, carboxy(C1-C6)alkoxy, gasoline is oxycarbonyl(C 1-C6)alkoxy, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C1-C10)Allami, amino, amino(C1-C6)alkilani, (C1-C6)alkoxycarbonyl, (C1-C10)aryl(C1-C6)alkoxycarbonyl, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylamino(C1-C6)alkilani, ((C1-C6)alkyl)2amino(C1-C6)alkilani, hydroxy, (C1-C6)alkoxy, carboxy, carboxy(C1-C6)alkilani, (C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl(C1-C6)alkilani, (C1-C6)alkoxy-CO-NH-, (C1-C6)alkyl-CO-NH-, cyano, (C5-C9)heteroseksualnymi, amino-CO-NH-, (C1-C6)alkylamino-CO-NH, ((C1-C6)alkyl)2amino-CO-NH-, (C6-C10)arylamino-CO-NH-, (C1-C6)heteroelement-CO-NH-, (C1-C6)alkylamino-CO-NH-(C1-C6)alkilani, ((C1-C6)alkyl)2amino-CO-NH-(C1-C6)alkilani, (C6-C10)arylamino-CO-NH-(C1-C6)alkilani, (C5-C9)heteroelement-CO-NH-(C1-C6)alkilani, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl(C1-C6)alkilani, (C6-C10 )arylsulfonyl, (C6-C10)arylsulfonyl, (C6-C10)arylsulfonamides(C1-C6)alkilani, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfonyl(C1-C6)alkilani, (C5-C9)heteroaryl or (C2-C9)heteroseksualnymi, or their pharmaceutically acceptable salts.

The present invention also relates to a method for treatment of glaucoma, uveitis, diabetic retinopathy and age-related macular degeneration, comprising the administration to a mammal of a composition containing a pharmaceutically effective amount Jak3 inhibitor, which is a compound of formula I.

Specific compounds of formula I include compounds where the specified connection selected from the group consisting of:

methyl[4-methyl-1-(propane-1-sulfonyl)piperidine-3-yl]-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amine;

methyl ester of 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-carboxylic acid;

3,3,3-Cryptor-1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}propane-1-it;

dimethylamide 4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-carboxylic acid;

ethyl ether ({4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-carbonyl}amino)acetic acid;

3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)the Mino]piperidine-1-yl}-3-oxopropanenitrile;

3,3,3-Cryptor-1-{4-methyl-3-[methyl-(5-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}propane-1-it;

1-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}-but-3-in-1-it;

1-{3-[(5-chloro-7H-pyrrolo[2,3-d]pyrimidine-4-yl)methylamino]-4-methylpiperidin-1-yl}propane-1-it;

1-{3-[(5-fluoro-7H-pyrrolo[2,3-d]pyrimidine-4-yl)methylamino]-4-methylpiperidin-1-yl}-propane-1-it;

N-cyano-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amino]-N'-propylpiperidine-1 carboxamidine and

N-cyano-4,N',N'-trimethyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-carboxamidine.

In a specific embodiment, the Jak3 inhibitor is 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}-3-oxopropionate (CP0690550), which has the structure:

In one aspect of the present invention the introduction of the Jak3 inhibitor significantly increases the amount of Sekretareva tear fluid in comparison with the volume Sekretareva tear fluid without treatment within two days. The following aspect of the present invention the introduction of the Jak3 inhibitor increases the amount Sekretareva lacrimal fluid, at least 30% compared with the initial volume of the tear fluid during the first two days of introduction. The following aspect of the introduction of the Jak3 inhibitor increases the amount Sekretareva CL is the heat of the fluid, at least 50% compared with the initial volume of the tear fluid during the first two days of introduction. The following aspect of the present invention the introduction of the Jak3 inhibitor increases the amount Sekretareva tear fluid of at least 100% as compared to the initial volume of the tear fluid during the first two days of introduction. In another embodiment, the Jak3 inhibitor increases the amount Sekretareva tear fluid to a level comparable with the level in the normal secretion of the lacrimal fluid. The following aspect of this variant implementation of the Jak3 inhibitor increases the amount Sekretareva tear fluid to a level comparable with the level in the normal secretion of the lacrimal fluid within 8 days of initial processing.

In an alternative embodiment, the present invention includes the restoration of normal secretion of the lacrimal fluid of a mammal, comprising administration to the mammal of a composition containing a pharmaceutically acceptable carrier and a pharmaceutically effective amount of an inhibitor of Janus kinase-3 ("Jak3"). In one aspect of this variant implementation of the JAK3 inhibitor is 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}-3-oxopropionate (SR).

In another aspect of the present invention, Jak3 inhibitor is administered no more than twice a day (BID). The following aspect of the Jak3 inhibitor is administered once daily (QD).

The following aspect of the present invention the composition is administered topically to the eye surface.

In another aspect of the present invention pharmaceutically effective amount Jak3 inhibitor is from 0.0001% to less than 1.0 wt.%. In the following aspect number Jak3 inhibitor is from 0.0003% to less than 0.1 wt.%. In another aspect of the present invention, the number of Jak3 inhibitor is from 0.0003 to 0.03 wt.%. In still another aspect, the number of Jak3 inhibitor is from 0.003 to 0.005 wt.%. In still another aspect, the number of Jak3 inhibitor is from 0.01 to 0.03 wt.%. Even following the embodiment, the number of Jak3 inhibitor is approximately of 0.003 wt.%, 0.005 wt.%, 0.01 wt.% or 0.03 wt.%.

In another aspect of the present invention, the ophthalmic composition for topical application, in addition, contains the agent regulating toychest, and buffer. Even the next aspect of the present invention, the agent regulating toychest, represents, or simple sugar, or sugar alcohol. In still another aspect of the present invention the buffer is selected from a phosphate or citrate.

In still another aspect of the present invention the composition also contains a surfactant. In the preferred embodiment, this is subramania surfactant selected from TritonX114 and tyloxapol. The following aspect of this variant implementation, the composition further contains a stabilizing polymer. Even the next aspect of the present invention the stabilizing polymer is a carbomer 974 p.

Brief description of drawings

The figure 1 shows the secretion of tear fluid from MRL/lpr mouse ("mouse dry eye") relative to the control C57 mice, as discussed in example 1 below.

The figure 2 shows the secretion of tear fluid from mice with dry eyes relative to C57 mice with the introduction of Jak3 inhibitor, 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}-3-oxopropanenitrile (CP0690550).

The figure 3 shows the secretion of tear fluid with the introduction of Jak3 inhibitor CP0690550 compared to Restasis®, which is the market-leading drug for the treatment of dry eye.

The figure 4 shows the dose-dependent effects SR at concentrations of 0.003 wt.%, 0.01 wt.% and 0.03 wt.% in the medium composition 1, compared with control groups with normal secretion of the lacrimal fluid and dry eyes.

The figure 5 shows the dose-dependent effects SR at concentrations of 0.001 wt.% and 0.003 wt.% in the environment of the composition 3, compared to control groups with normal secretion of the lacrimal fluid and dry eyes.

The figure 6 shows the dose-dependent effects SR at concentrations of 0.001 wt.%, 0003 wt.% and 0.01 wt.% in the environment of composition 4, compared with the control groups with normal secretion of the lacrimal fluid and dry eyes.

The figure 7 shows the dose-dependent effects SR at concentrations of 0.003 wt.% and 0.01 wt.% in the medium composition 3 in mice with artificially induced dry eye, compared with the control group with normal secretion of the lacrimal fluid and application group environment.

The figure 8 shows the dose-dependent effects SR at concentrations of 0.003 wt.% and 0.005 wt.% in the medium composition 5 in mice with artificially induced dry eye, compared with the control group with normal secretion of the lacrimal fluid and application group environment.

Detailed description of the present invention

According to the present invention, the inhibitors of Janus kinase-3 (Jak3) is administered to a mammal suffering from dry eye, and in particular, to a person suffering from dry eyes. In one aspect selective Jak3 inhibitors of the present invention have a selectivity in the inhibition of Jak3 in comparison with other proteinkinase, in particular, with the closely related family member, Jak2. The reason is that controls Jak2 signaling through receptor erythropoietin (EPO), colony stimulating factor, macrophage (M-CSF), colony stimulating factor granulocyte-macrophage (GM)-CSF and thrombopoietin (TPO). Over the CSOs, the lack of Jak2 is lethal for the embryo due to impaired erythropoiesis. One would expect that a significant pharmacological inhibition of Jak2 in vivo would result in anemia, thrombocytopenia, and leukemia. Pesu et al., Immunological Reviews 203, 127-142 (2005). At enzyme concentrations of Jak3 inhibitors of the present invention are at least 10 times more effective against Jak3 compared with Jak2 and are 3000 times more specific in comparison with other kinases.

The present invention relates to a method of treating dry eye, comprising the administration to a mammal of a composition containing a pharmaceutically acceptable carrier and a pharmaceutically effective amount of an inhibitor of Janus kinase-3 ("Jak3"), having the formula I and/or specific embodiments, as described above. Jak3 inhibitors described in U.S. patent No. 6627754 and 7091208, the content of which is introduced in the present invention by reference. Concrete option implementation of the present invention includes the introduction of the patient pharmaceutically effective amount of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}-3-oxopropanenitrile.

The term "alkyl", as used in the present invention, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals containing straight and the branched fragments or combinations thereof.

The term "alkoxy", as used in the present invention, includes O-alkyl groups in which "alkyl" is defined above.

The term "halogen", as used in the present invention, unless otherwise indicated, includes fluorine, chlorine, bromine or iodine.

Compounds of the present invention may contain a double bond. In the presence of double bonds in the compounds of the present invention exist in CIS and TRANS configurations and mixtures thereof.

Unless otherwise indicated, alkyl and Alchemilla group related to the present invention, as well as alkyl fragments of other groups related to the present invention (e.g., alkoxy), may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic fragments. If not specified, the halogen includes fluoride, chloride, bromide and iodide.

(C2-C9)Heteroseksualci, when applying the present invention relates to pyrrolidinyl, tetrahydrofuranyl, dihydrofurane, tetrahydropyranyl, pirania, thiopyrano, aziridinyl, oxiranyl, methylendioxy, chromenew, socialinio, 1,3-oxazolidin-3-DRS, isothiazolinones, 1,3-thiazolidin-3-DRS, 1,2-pyrazolin-2-DRS, 1,3-pyrazolidine-1-DRS, piperidinyl, tomorro is inilu, 1,2-tetrahydrothiophene-2-DRS, 1,3-tetrahydrothiophene-3-DRS, tetrahydrocannabinol, morpholinyl, 1,2-tetrahydropyrazin-2-DRS, 1,3-tetrahydropyrazin-1-DRS, tetrahydroazepine, piperazinil, chromanol etc. skilled in the art it is clear that the link between these (C2-C9)geterotsiklicheskikh rings via a carbon atom or heteroatom of nitrogen with sp3hybridisation.

(C2-C9)Heteroaryl, when applying the present invention relates to furillo, tieniu, thiazolyl, pyrazolyl, isothiazoline, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, indolinyl, pteridinyl, puresolo, 6,7-dihydro-5H-[1]the pyridinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydroquinolin-3-DRS, benzoxazolyl, benzothiazolyl, benzisothiazole, benzisoxazole, benzimidazolyl, tianeptine, isocyanates, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazoles, ishinryu, hinely, phthalazinium, khinoksalinona, girasolereale, benzoxazines etc. skilled in the art it is clear that the link between these (C2-C9)heteros who cycloalkyl rings via a carbon atom or heteroatom of nitrogen with sp 3hybridisation.

(C6-C10)Aryl, when used in the present invention, refers to phenyl or naphthyl.

Preferred compounds of formula I include compounds where a is 0; b is 1; X is carbonyl; c is 0; d is 0; e is 0; f is 0; and g is 0.

Additional preferred compounds of formula I include compounds where a is 0; b is 1; X is carbonyl; c is 0; d is 1; e is 0; f is 0; and g is 0.

Additional preferred compounds of formula I include compounds where a is 0; b is 1 ; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and g is 0.

Additional preferred compounds of formula I include compounds where a is 0; b is 1; X is-C(=N=cyano)-; c is 1; d is 0; e is 0; f is 0; and g is 0.

Additional preferred compounds of formula I include compounds where a is 0; b is 0; c is 0; d is 0; e is 0; f is 0; g is 1; and Z represents-C(O)-O-.

Additional preferred compounds of formula I include compounds where a is 0; b is 1; X represents S(O)n; n is 2; c is 0; d is 0; e is 0; f is 0; and g is 0.

Additional preferred compounds of formula I include compounds where a is 0; b is 1; X represents S(O)n; n ravno; c is 0; d is 2; e is 0; f is 1; g is 1; and Z represents a carbonyl.

Additional preferred compounds of formula I include compounds where a is 0; b is 1; X represents S(O)n; n is 2; c is 0; d is 2; e is 0; f is 1; and g is 0.

Additional preferred compounds of formula I include compounds where a is 0; b is 1; X is carbonyl; c is 1; d is 0; e is 1; Y is S(O)n; n is 2; f is 0; and g is 0.

Additional preferred compounds of formula I include compounds where a is 0; b is 1; X represents S(O)n; n is 2; c is 1; d is 0; e is 0; f is 0; and g is 0.

Additional preferred compounds of formula I include compounds where a is 1; b is 1; X is carbonyl; c is 1; d is 0; e is 0; f is 0; and g is 0.

Additional preferred compounds of formula I include compounds where a is 0; b is 1; X represents S(O)n; c is 0; d is 1; e is 1; Y is S(O)n; n is 2; f is 0; and g is 0.

Additional preferred compounds of formula I include compounds where a is 0; b is 1; X represents S(O)n; c is 0; d is 1; e is 1; Y is S(O)n; n is 2; f is 1; and g is 0.

Additional preferred with the unity of formula I include compounds where a is 0; b is 1; X is oxygen; c is 0; d is 1; e is 1; Y is S(O)n; n is 2; f is 1; and g is 0.

Additional preferred compounds of formula I include compounds where a is 0; b is 1; X is oxygen; c is 0; d is 1; e is 1; Y is S(O)n; n is 2; f is 0; and g is 0.

Additional preferred compounds of formula I include compounds where a is 0; b is 1; X is carbonyl; c is 1; d is 1; e is 1; Y is S(O)n; f is 0; and g is 0.

Additional preferred compounds of formula I include compounds where a is 0; b is 1; X is carbonyl; c is 1; d is 1; e is 1; Y is S(O)n; n is 2; f is 1; and g is 0.

Additional preferred compounds of formula I include compounds where R12represents cyano, trifluoromethyl, (C1-C6)alkyl, trifluoromethyl(C1-C6)alkyl, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C2-C6)quinil, cyano(C1-C6)alkyl, (C1-C6)alkyl-S(O)mwhere m is 0, 1 or 2.

Composition introduced according to the present invention contain a pharmaceutically effective amount of one or more of these Jak3 of inhibi the Directors. As used in the present invention, "pharmaceutically effective amount" is an amount that is sufficient to weaken or eliminate the signs of symptoms of dry eye or other disorders requiring the wetting of the eye. Effective dose can be administered one or more doses.

As is clear from the clinical context, the introduction of an effective amount of drug, compound or pharmaceutical composition can be done separately or in conjunction with another drug, compound or pharmaceutical composition. Thus, the "effective amount" or "effective dose" can be seen in the context of the introduction of one or more therapeutic agents, and the individual agent can be considered as input in an effective amount if, in conjunction with one or more other agents can be achieved or achieved the desired result.

As used in the present invention, "treatment" is an approach for therapeutic or desired results, including clinical results. For the purposes of the present invention a therapeutic or desired clinical results include, but are not limited to, mitigation and/or elimination of signs of symptoms of dry eye or other disorders requiring the wetting of the eye.

the OST practitioners diagnose and treat the syndrome of dry eye based on some symptoms (JAMA 2001; 286:2114-9). The responses to the questionnaire for the diagnosis of dry eye McMonnies & HO can be used as a means to identify symptoms of dry eye (value more than 14,5 corresponds to the determination of the dryness of the eyes). However, laboratory dryness of the eyes of the national Institute of eye diseases defines 'the symptoms of discomfort of the eyes' as only one aspect of 'dry eye'. Analysis of the observed lack of tear fluid, or the possibility of excessive evaporation of the tear fluid and damage to exposed externally exposed surface of the eye can provide confirmation of the diagnosis of 'dry eye'.

As used in the present invention, "substantially increases the secretion of tear fluid" refers to a statistically significant (i.e. p<0.05) increase in the secretion of the lacrimal fluid, as measured by standard ophthalmic ways, such as the Schirmer test or phenolic test using red thread test at the time of rupture of the tear film with fluorescein, or any of the tests described below.

The most common tests for dry eyes are tests at the time of rupture of the tear film, the Schirmer test and staining with fluorescein, although these tests are not exhaustive. The following well-known tests to determine the dryness of the eyes and thresholds, reflecting the possibility of the ity of the application of these tests for the diagnosis of dry eye:

Table 1
TestAnomalous thresholds for diagnosing dry eye
The Schirmer test ILess than or equal to 5 mm wetting in 5 minutes
Phenol test using red threadLess than 9 mm
The test at the time of rupture of the tear filmLess than or equal to 10 seconds
Test for staining with fluoresceinMore than 3 but less than 15
Test for staining with rose BengalMore than 3 but less than 18
Test the osmolarity of the tear filmLess than or equal to 312 mOsm/l
Method impressional CytologyMore than 1
Method of Cytology with special brushesMore than 1
Test lactoferrin in tearsLess than 1 or equal to 0, ug/ml

The Schirmer test I

In Schirmer test I measure the amount of tears, which is secreted by the eye: tears gather in for about 5 minutes or so, which allows the ophthalmologist to determine whether the secreted amount sufficient to maintain the eyes in a healthy state or not. If secreted a small amount of tear fluid, it is possible to diagnose dry eye as a result of lack of tear fluid. If secreted sufficient amount of tear fluid, but the patient still symptoms of eye discomfort, then you can diagnose dry eye through evaporation.

In Schirmer test I, a strip of filter paper with dimensions of 35 mm × 5 mm is used to measure the amount of tears that secreted within 5 minutes. The strip is placed at the junction of the middle and lateral thirds of the lower eye of the century in natural lighting. The patient is given instructions that he was looking forward and blinked with normal frequency during testing. The test gives a negative result (more than 10 mm wetting of the filter paper for 5 minutes), indicates that the patient secretes a normal amount of tear fluid. Patients with dry eye have values wetting smaller than 5 mm in 5 minutes.

An important constraint t is a hundred Schirmer is there is considerable variability in the results of the tests carried out at different times and by different doctors. In fact, this test is usually used to diagnose patients with severe dry eye.

Around Schirmer test I conducted the debate. When not used anesthetic eye drops, it is considered that this test allows you to measure basal and reflex secretion of tear fluid. When using anesthetic eye drops believe that this test allows you to measure only the basal secretion of tear fluid. There is a compelling reason to assume that the amount of tear fluid, the measured data in two different ways may differ slightly between basal and reflex secretion of tear fluid. Most doctors conduct this test after application of anesthetic eye drops to freezing eyes. However, laboratory dryness of the eyes of the National Institute of eye diseases recommends not to use anesthetic eye drops before conducting this test. The limit value is the same, using either the anesthesia or not. To measure the reflex secretion of ocular fluids can be Schirmer test II. The Schirmer test II conducted by irritation of the nasal mucosa with a cotton stick measured before the eat secretion of tear fluid.

Alternatively, tests Schirmer I or II, which some practitioners considered too invasive and has little value in the diagnosis of mild and moderate dry eye, you can apply phenol test using red thread (Quick Zone®). Use cotton thread impregnated with phenol red. Phenol red is sensitive to pH and changes its color from yellow to red when the wetting of the lacrimal fluid. Bent the end of the thread length of 70 mm was placed in the lower fornix of the conjunctiva. After 15 seconds the length of the section with the changed color of the thread - reflecting the length of the thread soaked in lacrimal fluid, measured in millimeters. The length of the wetted portion of the threads should generally be from 9 mm to 20 mm, Patients with dry eyes are the lengths of segments wetting smaller than 9 mm

The time of rupture of the tear film (BUT)

In patients with dry eye tear film is unstable and breaks faster. Therefore, the time of rupture of the tear film in patients who suffer from dry eye is shorter. The test time of rupture with the use of fluorescein (FBUT) is often used. Striped with fluorescein is used on the arch of the lower eyelid and then removed. The patient was asked to blink three times and then look straight ahead, not blinking. Plait the ku tear fluid were observed under the light, passed through cobalt filter slit lamp, and the time that has elapsed between the last blink and the appearance of the first break in the tear film, recorded using a stopwatch (the gap is visible as black spots on a blue surface). BUT with the use of fluorescein, less than 10 seconds or less, indicates the presence of dry eye.

To overcome the limitations caused by the potential invasiveness FBUT test, developed non-invasive methods of determining the time of rupture of the tear film (NIBUT). They are called non-invasive, because the eye does not touch. Devices, such as a keratometer, manual keratoscope or teashop need to measure NIBUT. Phase before rupture, which precedes actual rupture of the tear film, you can watch some ways. This phase before rupture is called the time of reducing the thickness of the tear film (TTT). The measurement is performed by monitoring the distortion (TTT) and/or rupture (NIBUT) label keratometer (reflected image of the lattice of the keratometer). The practitioner focuses and examines a clear label and then records the time spent on the distortion (TTT) and/or gap (NIBUT) image labels. NIBUT measurements are longer than the measurement time of rupture of the tear film with the use of fluorescein. NIBUT of magnitude smaller than 15 seconds, indicate the presence of dryness is LAZ. TTT/NIBUT test is considered more beneficial for the patient, reproducible and accurate.

As used in the present invention, the introduction of "together" involves the simultaneous introduction and/or introduction to different points in time. Introduction collaboration also includes the introduction in the form of a single composition or introduction as separate compositions. In the present invention means that the introduction of jointly includes any circumstance in which Jak3 inhibitor and the other agent is administered to the individual that can be performed simultaneously and/or separately. As will be discussed further in the present invention, it is clear that Jak3 inhibitor and another agent, you can enter with different dosing frequency or intervals. For example, Jak3 inhibitor can be administered daily, while another agent, you can enter less often. It is clear that Jak3 inhibitor and another agent can be entered using the same route of administration or different routes of administration.

"Individual" (alternatively called "subject"is a mammal, more preferably a human. "Mammal" includes, but is not limited to, farm animals (such as cows), sport animals, Pets (such as cats, dogs, horses), primates, mice and rats.

The term "restoration of normal secretion of tear fluid" refers to the elimination of the symptom is dryness in the eyes, as described in the standard ophthalmic techniques, such as the magnitude of the response is less than 14.5 V questionnaire to diagnose symptoms of dry eye McMonnies & Ho and/or the results of the tests (i.e. tests Schirmer test using phenol red test using fluorescein, etc. as shown in table 1)that are within the scope of the variable values corresponding to the normal state.

According to the methods of the present invention a composition comprising one or more of the specific Jak3 inhibitors and a pharmaceutically acceptable carrier for local ophthalmic injection or implantation into the conjunctival SAC or anterior chamber of the eye, enter the required treatment to the mammal. The composition is formed according to a method known in the art, for specific ways required the introduction.

Typically, for compositions intended for local injection into the eye in the form of eye drops or eye ointments, the total number of Jak3 inhibitor will be approximately from 0.0001 to less than 1.0 wt.%. The preferred range for the number of Jak3 inhibitor is from 0.0003 to less than 0.1 wt.%, while even more preferred range for the number of Jak3 inhibitor is from 0.003 to 0.03 wt.%. Another preferred range of the number of Jak3 inhibit the RA is 0.005 to 0.05 wt.%, and even more preferred range is from 0.01 to 0.03 wt.%.

Preferably the composition introduced according to the present invention, will be in the form of solutions, suspensions, emulsions, and other dosage forms for topical administration. Aqueous solutions are generally preferred because of the ease of preparation, as well as the patient's ability to easily enter data composition by putting one or two drops in the affected eye. However, the composition may also be suspensions, viscous or poluvyazkie gels or other types of solid or semi-solid compositions. Suspensions may be preferred for Jak3 inhibitors, which are moderately soluble in water.

Composition introduced according to the present invention may also contain various other ingredients, including, but not limited to, agents that regulate toychest, buffers, surfactants, stabilizing polymer, preservatives, co-solvents and agents that increase the viscosity. Preferred pharmaceutical compositions of the present invention contain the inhibitor agent, governing toychest, and buffer. The pharmaceutical compositions of the present invention may also optionally contain a surfactant and/or palliative agent or a stabilizing polymer.

Various agents, regulatory toychest, can be used to control toychest composition, preferably to toychest natural tear fluid for ophthalmic compositions. For example, can be added to the composition to approximately physiological toychest sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars, such as dextrose, fructose, galactose, and/or simple polyols such as sugar alcohols, mannitol, sorbitol, xylitol, lactic, isomalt, maltitol, and hydrogenated starch hydrolysis. This amount of an agent that regulates toychest, will vary depending on the particular agent that you want to add. However, typically, the compositions will contain the agent regulating toychest, in sufficient quantity to give a final composition ophthalmologist acceptable osmolarity (usually, approximately inlet 150 up to 450 mOsm, preferably 250-350 mOsm and more preferably approximately 290 mOsm). Typically, agents, regulatory toychest, the present invention will be present in amounts in the range from 2 to 4 wt.%. Preferred agents regulating toychest, of the present invention include simple sugars or sugar alcohols. A specific embodiment of the present invention is D-mannitol.

P is chodawu buffer system (for example, sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid) can be added to the composition in order to prevent the slow change of pH during storage conditions. The specific concentration will vary depending on the agent. However, preferably, the buffer will be chosen so as to maintain the final pH in the range pH 5-8, and more preferred final pH in the range pH 5-7.

Surfactants can optionally be used to deliver higher concentrations of inhibitor. Surfactants act, solubilizer inhibitor and stabilizing colloidal dispersion, such as a solution of micelles, microemulsion, emulsion and suspension. Examples of surfactants which can optionally be applied, include Polysorbate, poloxamer, poliosis 40 stearate, polyoxyl castor oil, tyloxapol, Triton and monolaurin sorbitan. Preferred surface-active substances, which are used in the present invention have a hydrophilic-lipophilic balance HLB in the range of 12.4-13.2 and are acceptable for ophthalmic applications, such as Triton and tyloxapol.

Compositions formulated for the treatment of diseases and disorders with dry eyes may include aqueous media, are intended to provide immediately the military, short-term relief of the States with dry eyes. The data carriers can be mixed as a phospholipid carrier or carrier for artificial lacrimal fluid, or mixtures thereof. As used in the present invention, "phospholipid carrier" and "carrier for artificial tear fluid" refers to aqueous compositions that: (i) contain one or more phospholipids (in the case of phospholipid carriers) or other compounds that grease, "moisturize", identical with the consistency of endogenous tears, contribute to the accumulation of the natural tear fluid or otherwise provide temporary relief of symptoms of dry eye and States with eye introduction; (ii) are safe; and (iii) provide a suitable environment for the delivery of local injection of an effective amount of one or more specific Jak3 inhibitors. Examples of compositions of the artificial lacrimal fluid, suitable as carriers of artificial tear fluid include, but are not limited to, commercially available products such as Visine Pure Tears ®, Visine Tears Natural Tears Formula ® (Johnson & Johnson) Tears Naturale ®, Tears Naturale II ®, Tears Naturale Free ®, Bion Tears ® (Alcon Laboratories, Inc. Forth Worth, TX.), Refresh Tears ®, Refresh Endura ®, Refresh Plus ® (Allergan Inc.). Examples of compositions with phospholipid carriers include compositions described in U.S. patent No. 4804539 (Guo et al.), 483658 (Holly), 4914088 (glonek), 5075104 (Gressel et al.), 5278151 (Korb et al.), 5294607 (Glonek et al.), 5371108 (Korb et al.), 5578586 (Glonek et al.); in the present invention by reference enter those parts of the above patents, which describe the phospholipid composition, suitable as phospholipid carriers of the present invention.

In the art known palliative compounds intended for lubrication, "moisture", identical with the consistency of endogenous tears, contributing to the accumulation of the natural tear fluid or otherwise provide temporary relief of symptoms of dry eye and States with eye introduction. Data palliative agents may in some cases perform a dual function as an agent for regulating toychest, such as Monomeric polyols (glycerol, propylene glycol, ethylene glycol). Palliative connections can increase the viscosity of the composition, and they include, but are not limited to: Monomeric polyols, polymeric polyols such as polyethylene glycol, hypromellose ("HPMC"), sodium carboxymethylcellulose, hydroxypropylcellulose ("HPC"), dextrans such as dextran 70; water soluble proteins such as gelatin; and vinyl polymers such as polyvinyl alcohol, polyvinylpyrrolidone, povidone, and carbomer, such as carbomer 941, carbomer 940, carbomer 971P, carbomer 974.

Additional agents that can be added to the ophthalmic compositions of the present invention, are tools that reduce the irritation, which act as a stabilizing polymer. Stabilizing the polymer must be ion-charged polymer, preferably used for local ocular administration, more specifically a polymer that carries a negative charge on their surface, which may have a Zeta-potential is equal to (-)10-50 mV, physical stability, and can form a dispersion in water (i.e. water-soluble). Preferred stabilizing polymer of the present invention could be polyelectrolyte or polyelectrolyte, if more than one, of the family of polyacrylates with crosslinking, such as carbomer and Pemulen®, especially carbomer R (polyacrylic acid), at a concentration of 0.1-0.5 wt.%. As already noted, carbomer can also act as a palliative connection.

Other compounds can also be added to ophthalmic compositions of the present invention to increase the viscosity of the medium. Examples of agents that increase the viscosity include, but are not limited to: polysaccharides, such as hyaluronic acid and their salts, chondroitin sulfate and its salts, dextrans, various polymers collection all the vines; vinyl polymers; and polymers derived from acrylic acid. Typically, the compositions with phospholipid carrier or a carrier for artificial lacrimal fluid will have a viscosity of from 1 to 400 centipoises ("cps").

Ophthalmic products for local use is usually Packed in mnogorazovye form. Thus, the need preservatives to prevent microbial contamination during use. Suitable preservatives include: benzylaniline, chlorbutanol, benzododecinium, methylparaben, propylparaben, phenethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1, or other agents known to specialists in this field of technology. These preservatives are usually used at a concentration of from 0.001 to 1.0%/about. Composition unit doses of the present invention will be sterile, but usually do not contain preservatives. Such compositions are therefore generally do not contain preservatives.

Preferred compositions of the present invention are intended for administration to a person suffering from dry eyes or symptoms of dry eye. Preferably song data will be entered locally. Usually the doses used for the above described purposes will vary, but will be an effective amount to remove, or to alleviate conditions with dry g is AZ. Usually 1-2 drops of the compositions will enter one or more times a day. Preferably song data will be entered one (QD) or twice (BID) twice a day.

Examples of compositions for the eye drops are given in example 2 below.

Example 1: 1-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}Etalon and 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}-3-oxopropionate.

Method A: (1-Benzyl-4-methylpiperidin-3-yl)methylamine

To a stirred solution of 1-benzyl-4-methylpiperidin-3-one (2.3 g, 11.5 mmol), obtained by means Lorio, M.A. and Damia, G., Tetrahedron, 26, 5519 (1970) and Grieco et al., Journal of the American Chemical Society, 107, 1768 (1985), (modified, with 5% of methanol as co-solvent), (both articles are entered entirely by reference), dissolved in 23 ml of 2 M methylamine in tetrahydrofuran was added to 1.4 ml (23 mmol) of acetic acid, and the resulting mixture was stirred in a sealed tube for 16 hours at room temperature. Added triacetoxyborohydride sodium (4.9 g, 23 mmol) and the resulting mixture was stirred at room temperature in a sealed tube for 24 hours, after which the reaction was stopped by adding 1 n sodium hydroxide (50 ml). Then the reaction mixture was extracted with 3×80 ml of ether, the combined ether layers were dried over sulfate n is sodium (Na 2SO4) and concentrated to dryness in a vacuum, receiving 1.7 grams (69%) indicated in the title compounds as white solids. LRMS: 219,1 (M+1).

Method B: (1-Benzyl-4-methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)Amin

A solution of 4-harperone[2,3-d]pyrimidine (2.4 g, 15.9 mmol)obtained by the method Davoll, J. Am. Chem. Soc, 82, 131 (1960) (entered entirely by reference), and the product of method A (1.7 grams of 7.95 mmol)dissolved in 2 equivalents of triethylamine was heated in a sealed tube at 100°C for 3 days. After cooling to room temperature and concentration under reduced pressure the residue was purified flash chromatography (silica gel; 3% methanol in dichloromethane)to give 1.3 g (50%) specified in the title compounds as colorless oils. LRMS: 336,1 (M+1).

Method C: Methyl(4-methylpiperidin-3-yl)-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)Amin

To the product from method B (0.7 gram, 2,19 mmol)dissolved in 15 ml of ethanol was added 1.5 ml 2 N. chloroethanol acid and the reaction mixture was degirolami by blowing with nitrogen. Then to the reaction mixture was added 0.5 grams of 20% palladium hydroxide on coal (50% water) (Aldrich) and the resulting mixture was shaken (Parr-Shaker) in an atmosphere of 50 psi of hydrogen at room temperature for 2 days. Filtered through celite, the reaction mixture conc the Wali to dryness in vacuo and the residue was purified flash chromatography (silica gel; 5% methanol in dichloromethane)to give 0.48 g (90%) specified in the connection header. LRMS: 246,1 (M+1).

Method D: 1-(4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl]alanon

To a stirred solution of the product of method C (0.03 grams, 0,114 mmol)dissolved in 5 ml of a mixture of 10:1 dichloromethane/pyridine was added (0,018 grams, 0,228 mmol) acetylchloride and the resulting mixture was stirred at room temperature for 18 hours. Then the reaction mixture was distributed between dichloromethane and a saturated solution of sodium bicarbonate (NaHCO3). The organic layer was washed again with saturated solution of NaHCO3, dried over sodium sulfate and concentrated to dryness in vacuo. The residue was purified preparative thin-layer chromatography (PTLC) (silica gel; 4% methanol in dichloromethane)to give 0.005 mg (15%) indicated in the title compounds as colorless oils. LRMS: GRASS 288,1 (M+1).

Method E: Synthesis of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}-3-oxopropanenitrile (CP0690550)

Specified in the title compound 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}-3-oxopropionate (CP0690550) were obtained using standard modification methods A-D, described above.

Method F: obtain the citrate salt of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}-3-o is coprophilia

Citrate salt was obtained by applying the methods described in WO 2007/012953. In a clean, dry, purged with nitrogen, 500-ml reactor was loaded methyl-4(-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amine (25,0 g is 0.102 mol) and methylene chloride (250 ml). The mixture was stirred at room temperature for at least 2.5 hours. In a clean, dry, purged with nitrogen 1-l reactor was loaded zanoxolo acid (18.2 g, 0,214 mol), methylene chloride (375 ml) and triethylamine (30.1 ml, 0,214 mol). The mixture was cooled to-15-5,0°C for one hour and added trimethylacetylchloride (25.6 ml, 0,204 mmol) with such a rate as to maintain the temperature below 0°C. the Reaction was sustained for at least 2.5 hours, then was added a solution of amine with such a rate as to maintain the temperature below 0°C. After stirring for 1 hour the mixture was heated to room temperature and was added 1 M sodium hydroxide (125 ml). The organic layer was washed with water (125 ml). The methylene chloride was replaced with acetone to a volume of 500 ml and reached a temperature equal to 55-65°C. was Added to a mixture of water (75 ml), keeping the temperature equal to 55-65°C. was Added to a mixture solution of citric acid (20,76 g, 0,107 mol) in water (25,0), and cooled to room temperature. The reaction mixture was stirred for at least 5 hours and then the resulting solid was isolated by filtration and washed what Cetona (2×75 ml), which was passed through the filter. Salt was loaded in a clean, dry, purged with nitrogen 1-l reactor with 2B ethanol (190 ml) and water (190 ml). The suspension was heated at 75-85°C for at least 4 hours. The mixture was cooled to 20-30°C and was stirred for additional 4 hours. The solid residue was isolated by filtration and washed with 2B ethanol (190 ml). After drying in a vacuum oven at 50°C with a weak blowing nitrogen was allocated 34,6 g (67.3 per cent) specified in the connection header.

1H NMR (500 MHz, DMSO-d6): δ to 8.14 (s, 1H), 7,11 (d, J=3.6 Hz, 1H), to 6.57 (d, J=3.6 Hz, 1H), 4,96 (kV, J=6.0 Hz, 1H), 4,00-3,90 (m, 2H), 3,80 (m, 2H), 3,51 (m, 1H), 3,32 (s, 3H), 2,80 (Abq, J=15.6 Hz, 2H), 2,71 (Abq, J=15.6 Hz, 2H), 2,52-of 2.50 (m, qH), 2,45-to 2.41 (m, 1H), is 1.81 (m, 1H), 1,69-of 1.65 (m, 1H), was 1.04 (d, J=6.9 Hz, 3H).

Method G: to obtain the free base of 3-((3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl)-3-oxopropanenitrile

Citrate salt of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}-3-oxopropionate obtained in method F above, were treated with 1 M sodium hydroxide in dichloromethane, receiving the corresponding free base. Then the free base was led from methanol and water, obtaining the crystalline form of the free base.

Example 2: a Pharmaceutical composition

Example 2a: Composition

In table 2, below, presents the various pharmaceutical compositions containing inhibitors.

Table 2
Code compositionDescription composition
Composition 150 mm pH 7.4 in phosphate buffer, 0.05% of Tween 80, and 0.5% NaCl
Composition 250 mm pH 7.4 in phosphate buffer, 0,36% HPMC, 0.2% glycerol, 1% PEG400, 0,35% NaCl
Composition 35 mm pH 7.4 in phosphate buffer, 0,36% HPMC, 0.2% glycerol, 1% PEG400, 5% cremophor ELP, 4.3% mannitol
Composition 410 mm citrate pH 5.8 buffer, 4.5% mannitol
Composition 510 mm citrate pH 5.8 buffer, 4.2% of mannitol, 0,36% HPMC, 0.2% glycerol
Composition 60.3% tyloxapol (nonionic surfactant), 0,5% carbopol (anionic polymeric stabilizer)2,25% D-mannitol, pH 6.5 phosphate buffer at 50 mm concentration, 230 mOsm/kg
Composition 70.3% tyloxapol (nonionic surfactant), 0,1% carbopol (anionic polymeric stabilizer)2,25% D-mannitol, pH 6.5 phosphate buffer at 50 mm concentration, 230 mOsm/kg

Example 2b: Obtain

Received each of the above compositions 1-5, containing Jak3 inhibitor SR in three dose quantities: of 0.001 wt.%, of 0.003 wt.% and 0.01 wt.%. Composition 5 was also obtained with the Jak3 inhibitor SR in the amount of 0.005 wt.% (see figure 8). Received compositions 6 and 7, containing Jak3 inhibitor in the amount of 0.03 wt.%.

The above composition was obtained by adding the required quantity of agent regulating toychest (hypromellose or mannitol)in the flask, heated to approximately 50°C in half the final volume of buffer (phosphate or citrate buffer, as shown). After heating portion inhibitor SR, weighed and dissolved additional excipients (glycerol, polyethylene glycol 400). Measured and added a portion of the free base of the Jak3 inhibitor as initial solution. Added purified water to 100%. The mixture was stirred for 5 minutes for homogenization and then filtered through a sterilizing membrane filter into a sterile receiver. If necessary, pH was adjusted by adding 1.0 M NaOH.

Compositions 6 and 7 are ophthalmic compositions, which contain the greatest amount of inhibitor SR (0.03 wt.%). In addition to the agent regulating toychest, and the data buffer compositions with a high concentration will also be with erati surfactant, and optionally a stabilizing polymer. Preferred surfactants of the present invention include TritonX114 and tyloxapol. Preferred stabilizing polymers include carbomer 974p.

Obtaining compositions 6 and 7 was carried out by first dispersing carbomer in buffer containing surfactant, at 10X final concentration (for example, 3% tyloxapol in 50 mm phosphate buffer at pH 6.5 with 2.5% of D-mannitol and 5% Carbonera 974p). Jak3 inhibitor CP690550 was dispersively in the primary concentrate also at 10X final concentration. The mixture is then homogenized, and the final composition was obtained 10x dilution of the filtered primary concentrate in a suitable buffer.

Example 3: Effect of selective Jak3 inhibitors on the secretion of tear fluid in MRL/lpr (Dry eyes) mice

To study the degree of secretion of tear fluid over time 10 MRL/lpr mice and 5 selected age C57 Black/6 control mice aged 8 weeks were purchased at the Jackson laboratory (Bar Harbor, ME, USA). Type mice MRL/lpr has a mutation that makes them prone to dryness of the eye, similar to Sjogren syndrome.

The initial volume of the tear fluid was determined by measuring the amount of tear fluid 4 times in one week to prove that dry eye is present in MRL/lpr mice compared to C57 mice. Secretion after the Noah fluid was measured cotton thread (Quick Zone®), held by the tweezers, and applied to the ocular surface in the corner of the eye slits within 15-30 seconds. Wetting of the filaments was measured in millimeters. The results of measurements of secretion of tear fluid MRL/lpr mice compared with C control mice are shown in figure 1.

Animals (5-10 mice per group) were treated with 2 μl of one of the media (phosphate buffer saline, PBS containing 0.05 wt.% Tween 80) or 0.1 wt.% CP-690550 twice a day for two weeks. S mouse also received Wednesday. The volume of the tear fluid was measured at 2, 3 and 6 days. Action CP-690550 on the secretion of tear fluid in MRL/lpr mice is shown in figure 2.

As shown in figure 2, SR able to significantly increase the amount of Sekretareva tear fluid in the first 2 days of application. In particular, SR increases the amount Sekretareva tear fluid by more than 100% of the original volume Sekretareva tear fluid in mice with dry eyes in the first 2 days of application.

Example 4: Comparative data for comparison CP-690550 with Restasis®

Volume measurement Sekretareva tear fluid was performed using the thread soaked in phenol red (Quick Zone®), and measurement of initial volume was performed before use of each drug. Medicines or environment was used at a concentration of 2 μl twice a day.

Processed by the environment the normal what's mice C57black/6 and MRL/lpr mice with dry eyes were used as normal control and control for dry eyes respectively. Environment for SR was phosphate buffer saline, PBS containing 0.05% Tween 80.

Experiment to compare the effectiveness SR and Restasis® was performed using Restasis® (cyclosporine 0.05%) of CP-690550 at a concentration of 0.01%, applied twice daily for W days. Control animals, including normal C57Black/6 mice and MRL/lpr mice were treated with PBS environment, and MRL/lpr mice were treated Refresh Endura® (environment for Restasis) (5-10 mice per group). Comparison of the secretions of the lacrimal fluid CP-690550 and Restasis® is presented in figure 3.

As shown in figure 3, SR has a much faster reaction rate compared to Restasis® and shows a significant increase Sekretareva tear fluid compared to Restasis®.

In addition, from figures 3 and 4 shows that the introduction SR, in the end, increases the amount Sekretareva tear fluid to a level comparable with the level in the normal secretion of the lacrimal fluid (within 5-10% of the secretion of tear fluid "normal" With 57 mice).

Example 5: the speed of response to the introduction of SR in MRL/lpr mice

As in example 4 above, processed by the environment the normal mice C57black/6 and MRL/lpr mice with dry eyes (5-10 mice per group) were used as normal control and control for dry eyes, respectively. Environments for SR were compounds 1, 3 and 4, as shown in example 2 to enter the. Jak3 inhibitor SSR was used at concentrations of 0.003 wt.%, 0.01 wt.% and 0.03 wt.%, as calculated for the concentration of free base. Processing for composition 1 was carried out for two weeks at a volume of 2 μl twice a day. Treatment for compositions 3 and 4 were conducted during two weeks at a volume of 1 µl once a day.

The figure 4 shows that within 8 days introduction CP69055U in the medium composition 1 at a concentration of 0.01 wt.% twice a day increases the secretion of tear fluid to a level comparable to the level of normal secretion of tear fluid (within 5-10% of the secretion of tear fluid Is normal mice). Similarly, figures 5 and 6 shows the speed response to the introduction of SR in the environment of compositions 3 and 4. All comparisons significant increase in the secretion of tear fluid was observed on day 2 after processing.

Example 6: Model mice with artificially induced dry eyes

Received injectable solution containing 2.5 mg/ml scopolamine (sigma) in saline solution for injection (1-1,5 ml per animal). Normal C mice (200-250) μl of scopolamine was administered four times every 2.5 hours in a striped back. Mice were placed in a special cell (with holes front and back) and placed in the case. The fan was placed in front of each cell, and included 16 night hours for five days.

Dimension Pro is the Odile daily. After 5 days believed that all animals caused by dry eyes.

As in examples 4 and 5 above, animals were treated with drug or environment with the volume of 1 µl once a day for 2 weeks. Processed by the environment S black/6 mice and mice with artificially induced dry eye (5-10 mice per group) were treated with compositions 3 and 5 obtained in example 2 above. In figures 7 and 8 shows that a significant increase in the secretion of tear fluid is observed after 2 days of treatment. After 4 days of treatment composition containing 0.01 wt.% SR inhibitor in the compositions 3 and 0.003 wt.% SR inhibitor in the composition 5, drove the value of the secretion of the lacrimal fluid to normal values.

The present invention is described with reference to certain preferred embodiments of; however, it is clear that it may be embodied in other specific forms or variations without going beyond its specific or key characteristics. Therefore, embodiments of described above, are considered as illustrative in all respects and non-limiting, and the scope of the present invention is reflected in the attached claims and not the foregoing description.

1. A method of treating dry eye, which comprises the administration to a mammal of a composition containing a pharmaceutically effective the effective amount of inhibitor of Janus kinase-3 ("Jak3"), where Jak3 inhibitor has the following structure:
.

2. The method according to claim 1, where the Jak3 inhibitor is administered no more than twice a day (BID).

3. The method according to claim 1, where the Jak3 inhibitor is administered once daily (QD).

4. The method of restoring the normal secretion of the lacrimal fluid of a mammal, comprising administration to the mammal of a composition containing a pharmaceutically acceptable carrier and a pharmaceutically effective amount of an inhibitor of Janus kinase-3 ("Jak3"), having the following structure: 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino]piperidine-1-yl}-3-oxopropionate.

5. Ophthalmic composition for topical application containing a pharmaceutically effective amount Jak3 inhibitor, where Jak3 inhibitor has the following structure:

and pharmaceutically acceptable carrier.

6. The ophthalmologic composition according to claim 5, where the pharmaceutically effective amount Jak3 inhibitor from 0.0001 to less than 0.1 wt.%.

7. The ophthalmologic composition according to claim 5, where the pharmaceutically effective amount Jak3 inhibitor is from 0.003 to 0.03 wt.%.

8. The ophthalmologic composition according to claim 5, where the pharmaceutically effective amount Jak3 inhibitor is from 0.01 to 0.03 wt.%.

9. The ophthalmologic composition according to claim 5, additionally containing Agay is t, regulatory toychest, and a buffer selected from a phosphate or citrate buffer.

10. The ophthalmologic composition according to claim 9, further containing a surfactant.

11. Ophthalmic composition of claim 10, where the surface-active substance is tyloxapol.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely ophthalmology, and can be used for ensuring regression of ocular neovascularisation. That is ensured by introducing a composition containing a therapeutically effective amount of a receptor tyrosine kinase inhibitor which blocks tyrosine autophosphorylation of VEGF receptor-2 with IC50≤ 10 nM and VEGF receptor-1 with 1C50≤ 10 nM and PDGFR with 1C50≤ 100 nM.

EFFECT: invention provides strong antiangiogenic effectiveness, ensured avoiding visual acuity loss related to ocular neovascularisation.

7 cl, 5 tbl, 8 ex, 9 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular to ophthalmology. The invention discloses an ophthalmic composition containing ketotifen and a hydrogen peroxide source supplying hydrogen peroxide in the amount approximately from 0.001 to approximately 0.1% (wt %) with pH making 4 to 5.3. What is also disclosed is a method of treating and preventing allergic conjunctivitis with using said composition.

EFFECT: invention provides minimum adverse side effects in treating and preventing conjunctivitis.

16 cl, 4 tbl, 1 ex

Eye drops // 2443416

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular ophthalmology. Eye drops have a formulation as follows (g/l): timolol maleate (timolol basis) 1.0-6.0; disodium hydrogen phosphate 5.5-16.5; sodium dihydrogen phosphate 0.8-1.5; sodium chloride 2.0-6.0; ethylenediaminetetraacetatic acid disodium salt 0.1-0.5; benzalkonium chloride 0.03-0.1; polyvinylpyrrolidone 1-100, hydroxypropyl methylcellulose 1.0-5.0, water for injections - to 1 l. The viscosity values range within 5 to 20 mPa·s.

EFFECT: invention provides higher viscosity of the eye drops thereby enabling drug prolongation, as well as promotes cornea moistening and causes no irritant action on eye tissues, has long manufacturing and storage stability of the properties.

1 tbl, 4 ex

FIELD: ophthalmology.

SUBSTANCE: main composition contains: (a) ketotifen fumarate to the concentration in calculation to free ketotifen from approx. 0.01 mas. % to approx. 0.1 mas.%;(b) source of hydrogen peroxide ensuring presence of hydrogen peroxide with trace quantities amounting from approximately 0.001 to approximately 0.1% (mas./vol.); (c) one or several stabilizers of hydrogen peroxide compatible with eyes; (d) hypromellose to the concentration from approximately 0.005 mas% to approximately 0.5 mas.%; and (e) sodium carboxymethyl cellulose to the concentration from approx. 0.005 mas.% to approx 0.5 mas.%. At this the value of composition pH amounts to approximately from 4.0 to 5.3.

EFFECT: invention is a method of treatment and prevention of allergic conjunctivitis which is ensured with application locally in the effective quantity of the mentioned eye composition to person with allergic conjunctivitis or sensitive to it.

13 cl, 15 tbl, 4 ex

FIELD: ophthalmology.

SUBSTANCE: invention is a medicine representing the exciter of neurite genesis of eye tissue, use of the stimulator and method of neurite genesis stimulation. The medicine for eye tissue neurite genesis contains N-(1-acetylpiperidine-4-yl)-4-fluorbenzamide or its pharmaceutically applicable salt and medicine for neurite genesis stimulation of cornea and retina containing N-(1-acetylpiperidine-4-yl)-4-fluorbenzamide or its pharmaceutically applicable salt. The method of neurite genesis stimulation of eye tissue, retina neurite genesis includes insertion of effective quantity of N-(1-acetylpiperidine-4-yl)-4-fluorbenzamide or its pharmaceutically applicable salt into subject who in need of eye tissue neurite genesis.

EFFECT: invention allows improving sensibility of retina, improves treatment of Ocular surface disease, disease of retina epithelium, eye disfunction.

15 cl, 1 tbl, 4 dwg

FIELD: pharmaceutical and cosmetic industry.

SUBSTANCE: invention refers in particular to the means of antioxidant, anti-inflammatory and antineoplastic properties. Water-soluble fraction clamat microseaweeds of Aphanizomenon Flos Aquae Ralfs ex Born. & Flah. Var. flos aquae (seaweed of the AFA), possessing antioxidant, anti-inflammatory and antineoplastic properties, including phycobilisome, containing fikotsianin/fikoeritrotsianin (C-PC/PEC), ficoviolobilin (PVB), phytochrome of the AFA, mikosporin-like amino acids, a chlorophyll and carotenes. The extracted biologically-active component of water-soluble fraction of clamat microseaweeds of the AFA. The composition containing water-soluble fraction either the extracted component, or their mix. The application of water-soluble fraction of clamat seaweed or their extracted component (variants).

EFFECT: above described fraction or biologically-active component possess effective antioxidant, anti-inflammatory and antineoplastic properties.

16cl, 37dwg, 2tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly intraocular drug delivery systems. The system contains a number of microsphres of average diameter within 8 micron to 14 micron, an aqueous carrier for microspheres where the microspheres consist of: brimonidine, where brimonidine makes approximately 0.5 wt % to approximately 15 wt % of the microspheres, and one or more biodegradable polymers representing polymer poly(D,L)lactides with inherent viscosity 0.4 dl/g to 0.8 dl/g where PMC polymer makes 85 wt % to 99.5 wt % of the microspheres, and where the drug delivery system can be injected in an intraocular region through a needle of a syringe calibre 20-26, and the microspheres can release approximately 0.5 mcg/day to approximately 20 mcg/day of brimonidine within a period of time approximately 10 days to approximately 100 days to provide treating eye conditions. The intraocular region represents a subtenon space, a subconjunctival or retrobulbar region.

EFFECT: invention provides release of the therapeutic agent in a therapeutically effective amount for a period of 10 days to one year.

4 cl, 13 tbl, 6 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely ophthalmology, and can be used for drug-induced treatment of an ischemic type of primary open-angle glaucoma (POAG) in individuals with near sight. For this purpose, a patient suffering the ischemic type of POAG in near sight is prescribed with suncutaneous injections of a drug mixture containing 1.0% nicotinic acid 1.0 ml and 2.0% lidocaine 1.0 ml, and also with intramuscular injections of the preparation Cortexin 10 mg in 0.5% novocaine 2.0 ml for the first 10 days of the treatment daily once a day in the area of a submaxillary lymph node 1.0 cm lower and 1.0 cm medially for an apex of a mastoid bone on the side of the injured eye. For the following 20 days, the preparation Ceraxon 300 mg is prescribed 3 times a day orally. Xalatan is instilled 1 drop once a day for the night from the first day of treatment constantly.

EFFECT: invention promotes the effective treatment of the disease ensured by normalised intraocular pressure, stabilised visual functions, improved cerebral and orbital blood flow in the given category of patients.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, in particular to ophthalmology. Self-preserved compositions are preserved effectively by means of a balanced buffer system containing zinc ions in the concentration 0.04-0.9 mm, preferentially 0.04-0.4 mm. One aspect of the balanced buffer system is the limited amount of buffering anions to the concentration 15 mM or less, preferentially 5 mM or less. In one version, the compositions contain borate or one or more borate/polyol complexes. Application of propylene glycol as polyol in such complexes is especially preferential. The limited amount of the bivalent metals different from zinc, and the amount of the present ionised salts, is important to maximise antimicrobial activity of the balanced buffer systems.

EFFECT: group of inventions provides prevention of the microbial infection, without the standard antimicrobial preservatives.

24 cl, 3 tbl, 13 ex

Antimicrobial lens // 2434646

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine. Contact lens, which contains, at least, one compound of ionised antimicrobial metal and polymer, obtained from reaction mixture, containing, at least, one hydrophobic component and hydrophilic components in concentration, ensuring hydrophilicity index of, at least, 44.

EFFECT: invention ensures permissible movement on eye in, at least, 90% of patients after, at least, approximately a hour of wearing.

28 cl, 4 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to two-layer tablet containing a compartment comprising a pharmaceutically acceptable compound of simvastatin; and a simultaneously separate compartment containing a compound of lisinopril and a pharmaceutically acceptable compound of folic acid as active ingredients. Preferentially, the tablet is prepared by using either direct compression technique, or wet granulation technique. The two-layer tablet under the invention is applied for purposes of preventing cardiovascular disturbances, including apoplexy and paralysis accompanying diseases and complications including those related with the age of 55 and older, stenocardia, fits, atherosclerosis, Charcot syndrome, diabetes, coronary disease, peripheral vessel disease, abnormal thrombocyte function, hemodialysis, hypercholesterolemia, hypertension, myocardial infarction, congestive cardiac failure, ischemia, nephropathy, high blood plasma homocysteine level, cardiac arrest or restenosis, diseases and complications associated with smoking, obesity and sedentary life-style causing a high risk of cardiovascular diseases in individuals, including apoplexy and paralysis.

EFFECT: preparing an effective drug for treating cardiovascular diseases.

28 cl, 3 dwg, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrido[2,3-d]pyrimidines of formula (V) and use of compounds of formula (I), containing a compound of formula (V), to prepare a medicinal agent used for inhibiting HCV replication in mammals infected with HCV, as well as a pharmaceutical composition based on said compounds. In formula (I)

R1 denotes hydrogen, amino, mono- or disubstituted amino, where amino group substitute(s) can be selected from C1-6alkyl, C1-4alkyloxyC1-4alkyl, diC1-4alkylaminoC1-4alkyl/piperidin-1-ylC1-4alkyl, phenylC1-4alkyl, where the phenyl group can further be substituted with C1-4alkoxy; L denotes -NR8-; R2 denotes Het2, where said Het2 denotes an aromatic monocyclic 6-member heterocycle which contains one nitrogen atom and is optionally substituted with one or more substitutes selected from C1-4alkyl; polyhalogenC1-4alkyl, halogen, -COOR7, -CONR4aR4b, -OR7, -SR5, and where C1-4alkyl can further be substituted with -COOR7; R3 denotes phenyl which is optionally substituted with one or two halogen atoms; each of R4a and R4b independently denotes hydrogen, C1-4alkyl, hydroxyC1-4alkyl; each R5 independently denotes C1-4alkyl; each R7 independently denotes hydrogen or C1-4alkyl; and each R8 independently denotes hydrogen or C1-10alkoxycarbonyl. The values of radicals in formula (V) are given in the claim.

EFFECT: improved method.

18 cl, 4 dwg, 1 tbl, 2 ex

Antiviral compouds // 2441869

FIELD: pharmacology.

SUBSTANCE: invention refers to the new compounds or its pharmaceutically acceptable salts where the compound has formula I possessing the activity towards hepatitis C virus (HCV). In the compound of formula I, Each W1 and W2 means nitrogen, W3 is chosen out of group consisting of nitrogen and -CH-, and W4 is -CH-; A is phenyl and is not mandatory substituted, X is chosen out of group consisting out of bond, -O- and -S-, Z is chosen out of group consisting of -CH2- and -NH-; R22 is chosen out of group consisting of hydrogen, benzimidazole, indole and thiophene, where R22 is not mandatory substituted, Y is chosen out of group consisting of C(O)N(R15)- and -N(R15)C(O)-, where R15 in each case is chosen out of group consisting of hydrogen and C1-C6alkyl; R50 is -L1-A1 where L1 is chosen out of group consisting of bond and C1-C6alkylene, and A1 is chosen out of group consisting of phenyl, pyridyl, benzothiazolyl, thiadiazole, isothiazole and thiophene, where A1 is not mandatory replaced, each R10 and R35 means hydrogen; R17 is C1-C6alkyl; and each C3-C18carbocyclil and M3-M18heterocyclil in -LE-Q-LE-(C3-C18carbocyclil) and -LE-Q-LE-( M3-M18heterocyclil) is not mandatory independently substituted in each case.

EFFECT: enhanced cure of hepatitis C.

13 cl, 12 dwg, 459 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

,

where R1 represents CH3; R2 represents halogeno or CN; R3 represents H or CH3; R4 represents H or CH3; n represents 0, 1 or 2; and to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition and to application of the compounds of formula (I) in preparing a drug exhibiting antagonist activity in relation to CX3CR1 receptor.

EFFECT: provided the compounds of formula (I) as CX3CR1 receptor antagonists.

20 cl, 1 tbl, 3 dwg, 10 ex

Antiviral compound // 2441010

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I) B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R18, A represents phenyl which is optionally substituted by one or more R18; each W1 and W2 are independently selected from N or C(R33); Z represents -NH-; each R10 and R33 containing of hydrogen; X is selected from a group consisting of -Ls-O-, -Ls-S-; R22 means hydrogen or phenyl optionally substituted by one or more R26 ; Y is selected from a group consisting of -Ls-O-, -Ls-S-; -Ls-C(O)- and -Ls-NH(SO)2-; R50 represents -L1-A1, where L1 represents a bond, and A1 is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C3-C6carbocyclyl, banzimidazolyl and C1-C6alkyl optionally substituted by phenyl where A1 is optionally substituted by one or more R30 ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) exhibiting the properties of proteinkinase Plk1 inhibitors. In formula (I): the ring A is a 5-member heteroaryl ring which contains atoms N as heteroatoms where the ring is optionally substituted by C1-6alkyl; X1 is NR8-; R1 is H, C1-10 aliphatic, C3-10 cycloaliphatic, phenyl, 5-6- member heteroaryl group containing atom S, N as a heteroatom where said R1 is optionally substituted by 0-5 J1; each R2 and R3, is independently H, C1-10 aliphatic group; R4 is C3-10 cycloaliphatic group; R8 is H, -C(O)OR; each J1 is independently C1-6 halogenalkyl, halogen, Q or -Z-Q; each Z is independently C1-6 aliphatic group where 0-3 -CH2- links in the specified C1-6 aliphatic group are optionally replaced by -NR-, -O-, -C(O)-, where any of the unsubstituted -CH2- links in the specified C1-6 aliphatic group is optionally substituted by 0-2 Jz ; each Q is independently H, C1-6 aliphatic group, 3-8- member aromatic or non-aromatic monocyclic ring having 0-3 heteroatoms independently selected from O and N where each Q is independently and optionally substituted by 0-2 JQ; Jz is halogen; JQ is -M; each M is independently H, C1-6 aliphatic group, halogen; each R is independently H or unsubstituted C1-6 aliphatic group.

EFFECT: preparing the pharmaceutical composition and method for inhibiting proteinkinase Plk1 activity.

31 cl, 43 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds selected from a group consisting of compounds of formula: and or to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition, as well as to using at least one compound under cl.1 and/or its pharmaceutically acceptable salts.

EFFECT: preparing new biologically active compounds which exhibit the properties of cycline-dependent kinase inhibitors.

11 cl, 86 tbl

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: method is realised by treating a compound of formula

with boronic acid or ether thereof of formula

,

in which two OR15 groups together with the boron atom with which they are bonded form a pinacolato boronate ester group in the presence of a Pd catalyst. The invention relates to a method of producing a pharmaceutically acceptable salt of thieno[3,2-d]pyrimidine of formula

.

The invention also relates to a pharmaceutical composition, having phosphatidyl inositol-3-kinase inhibitor activity, containing thieno[3,2-d]pyrimidine of formula (I) as an active ingredient, a method of preparing said composition and use of thieno[3,2-d]pyrimidine of formula (I) or pharmaceutically acceptable salt thereof in producing a medicinal agent for inhibiting phosphatidyl inositol-3-kinase.

EFFECT: use of the derivative as a phosphatidyl inositol-3-kinase inhibitor.

11 cl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is application of allopurinol or its pharmaceutically acceptable salt for treating or preventing palmoplantar erythrodysesthesia (PPE) induced by fluoropyrimidine chemotherapy, a related method of treating and a pharmaceutical composition for skin application of the same purpose, and the composition does not contain methyl sulphonyl methane or cetomacrogol.

EFFECT: relief, and in 66% of patients - delitescence of PPE symptoms in the absence of toxic effects on allopurinol and compliance of the patients is shown.

12 cl, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new substance eliciting an antiviral and antibacterial activity that is based on derivatives of 2,8-dithioxo-1H-pyrano[2,3-d;6,5-d']dipyrimidine and their 10-aza-analogues. This substance comprises derivative of indicated group of the general formula: A1*M: wherein X is taken among the group: oxygen atom (O), NH, N-alkyl; R1 is taken among the group: hydrogen atom (H), OH, chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, NH-Ar, N-(alkyl)2, SH, S-alkyl; R2 is taken among the group: unsubstituted or substituted phenyl, naphthyl, thienyl; R3 is taken among the group: hydrogen atom (H), chlorine atom (Cl), O-alkyl, NH2, NH-alkyl, S-dihydroxypyrimidinyl; M is absent or taken among the group: cation Na, K, Li, ammonium or any other pharmacologically acceptable cation; or complex of pharmacologically acceptable cation (see above) with anion of one of derivatives of A1 (variants R1-R3 are given above). Invention provides preparing new compounds eliciting an antiviral and antibacterial activity.

EFFECT: valuable medicinal properties of substance.

17 cl, 7 tbl, 16 ex

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