Treatment of dermatological allergic states

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, particularly to method of treatment of dermatological allergic state. Proposed method comprises injection of efficient amount of [4-(5-aminomethyl-2-fluorophenyl)piperidine-1-silt][7-fluorine-1-(2-metoxyethyl)-4-trifluorometoxy-1H-indol-3-il]methanon or its appropriate N-oxide, pharmaceutically acceptable salt or solvate.

EFFECT: higher efficiency.

5 cl, 1 ex, 1 tbl

 

The SCOPE of the INVENTION

This invention is directed to a method of treatment for patients-people and non-people, patients suffering from or prone to dermatological allergic conditions.

BACKGROUND of the INVENTION

Mediated mast cell inflammatory condition are a growing public health concern. Tryptase accumulated in secretory granules of mast cells and is the main protease of fat cells. Tryptase involved in diverse biological processes, including degradation of the vasodilator and bronchodilatory cortex (Caughey, et al., J. Pharmacol. Exp. Ther., 1988, 244, pages 133-137; Franconi et al., J. Pharmacol. Exp. Ther., 1988, 248, pages 947-951; and Tam, et al., Am. J. Respir. Cell Mol. Biol., 1990, 3, pages 27-32).

Consequently, tryptase inhibitors may be useful as anti-inflammatory agents (K. Rice, P.A. Sprengler, Current Opinion in Drug Discovery and Development, 1999, 2(5), pages 463-474) and may be suitable for the treatment or prevention of dermatological allergic conditions such as atopic dermatitis (A. Jarvikallio et al., Br. J. Dermatol., 1997, 136, pages 871-877).

This connection is certainly useful in the treatment of a patient suffering from conditions that can be alleviated by introducing an inhibitor of tryptase, for example, mediated mast cell inflammatory condition, inflammation and zabolevaniya disorders, associated with the degradation of the vasodilator neuropeptides, and has a reduced tendency to metabolizirovannom the formation-sensitive amine oxidase (SSAO).

The compound of the formula I (Compound A) is a selective and reversible effective inhibitor of human beta-tryptase and mouse MCPT-6 (the mouse ortholog of the human beta-tryptase) with Ki recombinant enzymes 38 and 920 nm, respectively.

The formula I

A BRIEF DESCRIPTION of the PRESENT INVENTION

Currently, the authors identified that the compound of Formula I or its pharmaceutically acceptable salts are suitable for the treatment of inflammatory diseases of the digestive tract.

Namely, this invention relates to a preventive or therapeutic drug when used for dermatological allergic conditions, in particular atopic dermatitis, comprising as active component a compound or its salt represented by the Formula I.

Also disclosed is a method of treatment of dermatological allergic conditions, in particular atopic dermatitis in a mammal, comprising the stage of introduction of a pharmaceutically effective amount of the compounds represented by Formula I below, or in the form of its pharmaceutically acceptable salts.

Faure is ula I

This compound is also known as [4-(5-aminomethyl-2-forfinal)piperidine-1-yl][7-fluoro-1-(2-methoxyethyl)-4-triptoreline-1H-indol-3-yl]metano.

This invention is directed to a compound of Formula I, which, as discovered in the present, is active in animal models of dermatological allergic conditions, in particular atopic dermatitis.

Another aspect of the present invention is a pharmaceutical composition for treating dermatological allergic conditions.

Another aspect of the present invention is the treatment of atopic dermatitis.

Another aspect of the present invention is the treatment of atopic dermatitis by treating the patient in most cases, the inhibitor of beta-tryptase.

DETAILED description of the INVENTION

Thus, in one aspect of the present invention is directed to pharmaceutical compositions containing the connection to the basic Formula I, which may also be known as [4-(5-aminomethyl-2-forfinal)piperidine-1-yl][7-fluoro-1-(2-methoxyethyl)-4-triptoreline-1H-indol-3-yl]metano or Connection A.

In the present description, the expression "compound of the present invention", and equivalent expressions, as is implied, cover the connection to the basic formula (I), as described earlier in this document, the expression of which includes text by the author esters prodrugs, pharmaceutically acceptable salt and solvate, e.g. hydrates, where the context so permits. Similarly, the reference to intermediate products, regardless of whether they are declared or not, as implied, covers their salts and solvate where the context so permits. For clarity, the special cases where the context so permits, sometimes point in the text, but these cases are illustrative only and does not assume that other cases are excluded where the context so permits.

Detailed description of cooking

The compound of the formula I can be obtained by application or adaptation of known methods, by which is meant methods used here or described in the literature, for example those described R.C. Larock in Comprehensive Organic Transformations, VCH publishers, 1989, or as described in this document.

In the reactions described below in this document, it may be necessary to protect reactive functional groups, e.g. amino groups, to avoid their unwanted participation in the reactions. You can apply the conventional protective groups in accordance with standard practice, for example, see T.W. Greene and P.G.M. Wuts in “Protective Groups in Organic Chemistry” John Wiley and Sons, 1991.

In particular, the compound of the formula I can be obtained as shown in Schemes 1-2.

For example, the connection this is subramania is achiral compound, preparation which includes a convergent synthesis. The compound of the present invention in the form of its benzoate get salt, as shown in the charts below.

Scheme 1

(i) Ethylchloride, pyridine, THF, 0°C, 100%; (ii) a: second-BuLi, THF, -78°C, b: I2, THF, -78°C, 52-68%; (iii) TMS-acetylene, TEA, CuI, Pd(PPh3)2Cl2, degassed THF, 60°C, 93%; (iv) KOH, tert-BuOH, 70°C, 91%; (v) powdered KOH, 2-methoxyethylamine, DMSO, room temp., 95%; (vi) TFAA, DMF, 40°C, 89%; (vii) 5M NaOH, MeOH, 85°C, 96%; (viii) 2,2,2-Cryptor-N-(fluoro-3-piperidine-4-ylbenzyl)ndimethylacetamide hydrochloride, EDCI, TEA, CH2Cl2(DCM), room temp., 99%; (ix) a: K2CO3, MeOH/H2O, b: 1M HCl in Et2O 90%.

Compound 1 is converted into compound 2 by protecting the amino group aminosidine means, such as ethylchloride in the presence of a suitable base, such as pyridine, to yield a protected connection 2.

Compound 2 is converted into compound 5 by way of three stages. Connection 2 coderoute position following carbamino complex ether by the reaction of 2 with a strong base, such as secondary utility with the formation of the anion, which reacts with a source of iodide, such as molecular iodine to obtain compound 3. Compound 3 is then converted into acetylene compound 4 with the catalyst at the conditions, such as copper iodide (I) dichloride and bis(triphenylphosphine)palladium (II) in the presence of trimethylsilylacetamide and bases, such as triethylamine. Connection 4 cyclist using strong bases such as potassium hydroxide, and heated to obtain indole compounds 5.

Compound 5 is converted into compound 6 by alkylation of its indole nitrogen alkylhalogenide in the presence of a strong base, such as potassium hydroxide, in a dipolar aprotic solvent such as dimethylsulfoxide at room temperature with the outlet connection 6.

Compound 6 is converted into compound 8 two-stage method. First, the compound 6 is converted into compound 7 by treatment of compound 6 triperoxonane anhydride in the presence of a solvent such as N,N-dimethylformamide and heated. Compound 7 is treated with a strong base, such as sodium hydroxide to obtain compound 8, which has an acid function in its position 3.

Compound 8 is converted into an amide 9 by reaction of the acid 8 hydrochloride 2,2,2-Cryptor-N-(fluoro-3-piperidine-4-ylbenzyl)ndimethylacetamide (compound 14) in the presence of acid binding reagent, such as EDCI, and organic bases such as triethylamine, in an inert solvent such as dichloromethane.

Compound 9 is converted into compound 10 by SN the development of protective groups with N-benzylacrylamide when processing soft base, such as potassium carbonate, in a solvent mixture such as methanol/water. Cleaners containing hydrochloride salt may be formed in the presence of a polar organic solvent, such as ether, to yield compound 10, which is cleaners containing hydrochloride salt ([4-(5-aminomethyl-2-forfinal)piperidine-1-yl]-[7-fluoro-1-(2-methoxyethyl)-4-methyl-1H-indol-3-yl]methanone) in the formula I.

Reaction of this scheme are the following.

Stage a: Preparation of complex ethyl ether (2-fluoro-5-trifloromethyl)carbamino acid (2)

To a solution of 1 (50,72 g, 0.26 mol) and pyridine (27,3 ml, 0.34 mol) in THF (500 ml) at 0°C add ethylchloride (32,2 ml to 0.39 mol) dropwise over a 30 minute period. After 1 h as LC/MS and TLC indicated that reaction was completed. The reaction mixture was partitioned between H2O and EtOAc. Two layers are separated and the organic layer washed with 1 M HCl, H2O and brine, dried over MgSO4filter and concentrate in vacuo. The crude material is purified on silica gel with heptane/EtOAc (95/5-70/30) as eluent to obtain 69,23 g (99%) of product 2 as a clear, colourless liquid.1H NMR (CDCl3) δ 8,11 (Shir. s, 1H), 7,07 (DD, J=to 9.1, and 9.3 Hz, 1H), 7,00-to 6.80 (m, 2H), 4,27 (sq, J=7,1 Hz, 2H), 1,33 (t, J=7,1 Hz, 3H);19F NMR (CDCl3) δ -57,84 (s, 3F), -134,01 (Shir. s, 1F); MS 309 (M+CH3CN+1, 100%), 268 (M+1).

Stage B: Preparation of complex of these is new ether (6-fluoro-2-iodine-3-trifloromethyl)carbamino acid (3)

To a solution of 2 (31,34 g, 117,2 mmol) in THF (180 ml) at -78°C add sec-BuLi (1.4 M in cyclohexane, 200 ml, 280 mmol) dropwise over a 1 hour period. After 20 min a solution of I2(44,6 g, 175,8 mmol) in THF (150 ml) is added dropwise over a 30 minute period. This mixture is then shaken at -78°C for 30 minutes Add saturated NH4Cl and remove the cooling bath. The reaction mixture was partitioned between H2O and EtOAc. Two layers are separated and the organic layer washed with 10% Na2SO3H2O, and brine, dried over MgSO4filter and concentrate in vacuo. The residue is suspended in DCM (50 ml) and added (300 ml) of heptane. White powder 3 (18,1 g, 39%) from the resulting suspension is collected by filtration with suction and dried in air. The filtrate is concentrated in vacuo, and the residue is suspended in heptane (200 ml). The other party 3 (3.8 g, 8%) collected by filtration with suction and dried in air. Additional product can be obtained by purification of the filtrate by chromatography on silica gel.1H NMR (CDCl3) δ 7,30-17,10 (m, 2H), 6,16 (Shir. s, 1H), 4.26 deaths (sq, J=7,1 Hz, 2H), 1,32 (t, J=7,1 Hz, 3H);19F NMR (CDCl3) δ -56,90 (s, 3F), -114,35 (d, J=8,5 Hz, 1F); MS 394 (M+1, 100%), 374, 364, 321, 267.

Stage C: Preparation of complex ethyl ester (6-fluoro-3-triptoreline-2-trimethylsilylethynyl is phenyl)is carbamino acid (4)

A mixture of 3 (18,1 g, at 45.9 mmol), Et3N (of 12.8 ml, 91,9 mmol), Pd(PPh)2Cl2(1.6 g, 5% mol), CuI (0.7 g, 8% mol) and TMS-acetylene (19.6 ml, 137,8 mmol) in degassed THF (180 ml) is heated at 60°C over night. The mixture is cooled to room temperature and then partitioned between H2O and EtOAc. This mixture is filtered through Celite to remove insoluble material. Two layers of the filtrate is separated and the organic layer was washed with H2O and brine, dried over MgSO4filter and concentrate in vacuo. The crude material is purified on silica gel with heptane/EtOAc as eluent to obtain 15.6 g (93%) of product 4 as a beige solid.1H NMR (CDCl3) δ 7,15-7,00 (m, 2H), 6,41 (Shir. s, 1H), 4.26 deaths (sq, J=7,1 Hz, 2H), 1,31 (t, J=7,1 Hz, 3H), of 0.27 (s, 9H);19F NMR (CDCl3) δ -57,59 (s, 3F), -118,15 (s, 1F); MS 364 (M+1, 100%).

Stage D: Preparation of 7-fluoro-4-triptoreline-1H-indole (5)

A mixture of 4 (28,9 g of 79.6 mmol) and KOH (35,7 g, 636,7 mmol) in degassed tert-BuOH (300 ml) is heated at 70°C during the night. LC/MS indicates that the reaction is complete. The mixture is cooled to room temperature and then partitioned between H2O and Et2O. the Two layers separated, and the aqueous layer was extracted with Et2O (2×). The combined organic layers washed with H2O and brine, dried over MgSO4filter the concentrate in vacuo. The crude material is purified on silica gel with heptane/EtOAc (100/0 60/40 on) as eluent to obtain 16 g (91%) of product 5 as a yellow liquid.1H NMR (CDCl3) of 8.47 δ (Shir. s, 1H), 7,35-7,20 (m, 1H), 6,95-to 6.80 (m, 2H), of 6.68 (d, J=2.5 Hz, 1H);19F NMR (CDCl3) δ -57,63 (s, 3F), -136,10 (d, J=8,5 Hz, 1F); MS 220 (M+1, 100%), 200.

Stage E: Preparation of 7-fluoro-1-(2-methoxyethyl)-4-triptoreline-1H-indole (6)

A mixture of 5 (16 g, for 72.8 mmol) and KOH powder (20.4 g, 364,2 mmol) in DMSO (150 ml) is shaken at room temperature for 10 minutes Add 2-methoxyethylamine (10.3 ml, 109,2 mmol). This mixture is shaken at room temperature overnight. LC/MS indicates that the reaction is complete. The mixture is partitioned between H2O and Et2O. the Two layers are separated and the aqueous layer was extracted with Et2O (2×). The combined organic layers washed with H2O and brine, dried over MgSO4filter and concentrate in vacuo. The crude material is purified on silica gel with heptane/EtOAc (100/0 to 50/50) as eluent to obtain 19.3 g (95%) of the product 6 as a yellow liquid.1H NMR (CDCl3) δ to 7.15 (d, J=2.1 Hz, 1H), 6.90 to to 6.75 (m, 2H), 6,56 (t, J=2.5 Hz, 1H), and 3.72 (t, J=5,2 Hz, 2H), and 3.72 (t, J=5,2 Hz, 2H), and 3.31 (s, 3H);19F NMR (CDCl3) δ -57,54 (s, 3F), -137,00 (d, J=11.3 Hz, 1F); MS 278 (M+1, 100%).

Stage F: Preparation of 2,2,2-Cryptor-1-[7-fluoro-1-(2-methoxyethyl)-4-triptoreline-1H-indol-3-yl]ethanone (7)

To a mixture of 6 (19.3 g, to 69.7 mmol) in DMF (135 ml) was added TFAA (26,2 ml, 188,2 mmol). This mixture is heated at 40°C during the night. TLC indicates that the reaction is complete. The mixture is cooled to room temperature and then partitioned between H2O and Et2O. the Two layers are separated and the organic layer was washed with saturated NaHCO3(2×), H2O and brine, dried over MgSO4filter and concentrate in vacuo. The crude material is purified on silica gel with heptane/EtOAc (100/0 to 50/50) as eluent to obtain and 23.4 g (89%) of product 7 in the form of a very pale green solid.1H NMR (CDCl3) δ 8,03 (d, J=1.4 Hz, 1H), 7,20-to 6.95 (m, 2H), 4,54 (t, J=4.9 Hz, 2H), 3,76 (t, J=4,8 Hz, 2H), 3.33 and (s, 3H);19F NMR (CDCl3) δ -57,74 (s, 3F), -71,10 (s, 3F), -134,95 (d, J=11.5 Hz, 1F); MS 374 (M+1, 100%).

Stage G: Preparation of 7-fluoro-1-(2-methoxyethyl)-4-triptoreline-1H-indole-3-carboxylic acid (8)

A mixture of 7 (23,4 g, and 62.6 mmol) in MeOH (100 ml) and 5 M NaOH (100 ml) is heated at 80°C during the night. LC/MS indicates that the reaction is complete. The reaction mixture is cooled to room temperature, and then concentrated in vacuo to remove most of MeOH. The residue is dissolved in H2O and then once washed with Et2O. the Aqueous layer was slowly acidified to pH ~2 using conc. HCl. The acidified suspension is extracted with Et2O, and the organic extract washed with H2 O and brine, dried over MgSO4filter and concentrate in vacuo. The residue is suspended in DCM/heptane (10/90). White powder 8 (19,4 g, 96%) in suspension are collected by filtration with suction and dried air.1H NMR (CDCl3) δ 8,02 (s, 1H), 7,15-7,05 (m, 1H), 7,00-of 6.90 (m, 1H), 4,49 (t, J=5.0 Hz, 2H, in), 3.75 (t, J=4.9 Hz, 2H), 3.33 and (s, 3H);19F NMR (CDCl3) δ -57,74 (s, 3F), -135,65 (d, J=11.3 Hz, 1F); MS 363 (M+CH3CN+1), 322 (M+1, 100%).

Stage H: Preparation of 2,2,2-Cryptor-N-(4-fluoro-3-{1-[7-fluoro-1-(2-methoxyethyl)-4-triptoreline-1H-indole-3-carbonyl]piperidine-4-yl}benzyl)ndimethylacetamide (9)

A mixture of the product 8 (19.1 g, to 59.6 mmol), Et3N (24,8 ml, 177, 9mm mmol), 2,2,2-Cryptor-N-(4-fluoro-3-piperidine-4-ylbenzyl)ndimethylacetamide hydrochloride (11 of 26.4 g, 77.5 mmol) of (14), and EDCI (17.1 g, 89,3 mmol) in CH2Cl2shaken at room temperature overnight. As TLC and LC/MS indicated that the reaction is complete. The mixture is partitioned between H2O and CH2Cl2. Two layers are separated and the organic layer washed with brine, dried over MgSO4filter and concentrate in vacuo. The crude material is purified on silica gel with heptane/EtOAc (40/60 by 0/100) as eluent to obtain the product 9 (36 g, 99%) as a white foam.1H NMR (CDCl3) δ 7,37 (s, 1H), 7,20-7,10 (m, 2H), 7,10-6,85 (m, 4H), 4.95 points (Shir. s, 1H), 4,60 is 4.35 (m, 4H), 3,90 (Shir. s, 1H), of 3.73 (t, J=5.0 Hz, 2H), 3,32 (s, 3H), 3.25 to 2,70 (m, 3H), 2.05 is of 1.50 (m, 4H) 19F NMR (CDCl3) δ -57,54 (s, 3F), -75,39 (s, 3F), -119,31 (s, 1F), -134,96 (d, J=11.3 Hz, 1F); MS 608 (M+1, 100%).

Stage I: Preparation of [4-(5-aminomethyl-2-forfinal)piperidine-1-yl]-[7-fluoro-1-(2-methoxyethyl)-4-triptoreline-1H-indol-3-yl]methanone hydrochloric salt (10)

To a mixture of 9 product (36 g of 59.3 mmol) in MeOH (400 ml) is added aqueous K2CO3(65,5 g, 474 mmol, dissolved in 120 ml of H2O). This mixture is shaken at room temperature overnight. LC/MS indicates that the reaction is complete. The reaction mixture was concentrated in vacuo to remove most of the methanol. The residue is partitioned between H2O and EtOAc. Two layers are separated and the organic layer was washed with H2O and brine, dried over MgSO4filter and concentrate in vacuo to yield 27.5 g (90%) of the product 10 in the form of a clear, colourless viscous resin.

1H NMR (CDCl3) δ 7,42 (s, 1H), 7,25-7,10 (m, 2H), 7,05-6,85 (m, 3H), 4.92 in (lat. s, 1H), 4,46 (t, J=5,2 Hz, 2H), 3,86 (Shir. s, 3H), 3,74 (t, J=5,1 Hz, 2H), 3,32 (s, 3H), 3,30-of 2.75 (m, 3H), 2,24 (Shir. s, 2H), 2.05 is-of 1.55 (m, 4H);19F NMR (CDCl3) δ -57,52 (s, 3F), -121,64 (s, 1F), -136,03 (d, J=11.3 Hz, 1F); MS 512 (M+1, 100%).

To a solution of the above material (2,856 g, 5,59 mmol) in Et2O (30 ml) is added 2 N HCl/Et2O (3 ml, 6 mmol) dropwise. Solid sedimentary forms and the ethereal solution is decanted. The solid is washed with additional Et2O, and then decanted. OST vreese pale yellow solid is dissolved in warm MeOH (10 ml), then add Et2O (50 ml) until then, until the solution becomes slightly turbid. After about 2 hours occurs a solid residue. Add additional Et2O (5-10 ml), and then the suspension is placed in the refrigerator overnight. The white crystalline product (2,475 g, to 4.52 mmol) is collected and dried under high vacuum for 4 hours.

1H NMR (DMSO (DMSO)-d6) δ 8,32 (Shir. s, 2H), 7,71 (s, 1H), 7,43 (d, 1H, J=7,2 Hz), was 7.36 (m, 1H), 7,26-7,20 (m, 1H), 7,12-was 7.08 (m, 2H), 4,49 (t, J=5,1 Hz, 2H), 4.00 points (s, 2H), 3,71 (t, J=5,1 Hz, 2H), 3,32 (s, 3H), 3,21-of 3.07 (m, 3H), 2,99 (Shir. s, 2H), 1,80-of 1.62 (m, 4H);19F NMR (DMSO-d6) δ -56,79 (s, 3F), -119,34 (s, 1F), -134,53 (d, J=9.6 Hz, 1F); MS 512 (M+1, 100%). CHN: Theoretical: C 53,06%, H 5,16%, N 7,42% (calculated as 1.0 H2O). Installed: C 53,03%, H 4,82%, N 7,22, Cl 6,64%.

[4-(5-aminomethyl-2-forfinal)piperidine-1-yl][7-fluoro-1-(2-methoxyethyl)-4-triptoreline-1H-indol-3-yl]methanone benzoate (10 benzoate salt)

20-liter reactor with a glass shell that already contains a solution of toluene, which is assumed to contain [4-(5-aminomethyl-2-forfinal)piperidine-1-yl][7-fluoro-1-(2-methoxyethyl)-4-triptoreline-1H-indol-3-yl]metano (1320 g, 2.58 mol), shaken and heated to 61°C. Add benzoic acid (316 g, 2.58 mol) and, after the benzoic acid has dissolved, add the cyclohexane (6,04 l). The reaction is heated to 77°C where it make a seed crystal in the form of [4-(5-aminomethyl-2-forfinal)piperidine-1-yl][7-fluoro--(2-methoxyethyl)-4-triptoreline-1H-indol-3-yl]methanone benzoate (0,100 g) from the previous batch. Crystallization proceeds at 77°C and after 15 min the reaction is cooled at a speed reduction of 10°C/h When the reaction reaches 61°C, as agitation and cooling is stopped and the reaction allow to cool to room temperature. After maturation during the night shaking resume and the product collected by filtration. The precipitate on the filter is washed with a mixture solvent prepared from toluene (3 l) and cyclohexane (1.5 l). After partial drying by suction, the product is transferred into a drying oven where it is dried at 40°C, providing [4-(5-aminomethyl-2-forfinal)piperidine-1-yl][7-fluoro-1-(2-methoxyethyl)-4-triptoreline-1H-indol-3-yl]methanone benzoate as a colourless solid. 1408,8 g (86%), TPL=156-159°C. Elemental analysis: calculated for C25H26F5N3O3C7H6O2: C, 60,66; H, 5,09; N, 6,63. Found: C, 60,44; H, Free 5.01; N, 6.87 In. Infrared spectral features (cm-1): 1612, 1526, 1511, 1501, 1394, 1362, 1256, 1232, 1211, 1158, 1117, 999, 826.

Scheme 2

3-bromo-4-forbindelsen hydrochloride (Wychem) is reacted with pyridine-4-Bronevoy acid (Clariant or Boron Molecular) in an alcohol solvent with a boiling point at least equal isopropyl alcohol, such as n-propyl alcohol, n-butyl alcohol and the like; polar aprotic solvent such as dimethylformamide,1-methyl-2-pyrrolidone, the sulfoxide and the like; ether solvent such as 2-methyltetrahydrofuran, dimethoxyethane, etc. From compound 12 and compound 13 in a mixture with any of the above solvents and water in the presence of a suitable catalyst, such as a complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride and dichloromethane (PdCl2dppf-CH2Cl2), Pd(PPh3)4, PdCl2(PPh3)2Pd(dtbpf)Cl2, etc. with sufficient heated from about 70°C to a temperature of the boiling point of the mixture of reaction compounds Suzuki receive pyridine.

The pyridine is converted into the compound of trifurcated 2,2,2-Cryptor-N-(4-fluoro-3-pyridine-4-ylbenzyl)ndimethylacetamide hydrochloride in triftoratsetata conditions using a suitable triptoreline tools, such as triperoxonane anhydride, triftoratsetata, pentaftorosilikata etc. in cryptorchidism a solvent such as complex ether solvent such as ethyl acetate, isopropylacetate, and the like; an aromatic hydrocarbon solvent such as toluene, and the like; chlorinated hydrocarbon solvent, such as methylene chloride, 1,2-dichloroethane, and the like, at the reaction temperature of triptoreline from about -20 to 30°C, followed by treatment with hydrochloric acid.

2,2,2-Cryptor-N-(4-fluoro-3-pyridine-4-ylbenzyl)AC is tumida hydrochloride restore the conditions of hydrogenation to compound 14 by treatment with hydrogen in the presence of means of hydrogenation catalyst PtO 2Pd/C, Pd(OH)2, Rh/C and the like, with or without added inorganic acid, such as HCl and the like, or organic acids such as acetic acid and the like, in a solvent of the hydrogenation reaction, such as an alcohol solvent, such as ethanol, isopropyl alcohol and the like; or acetic acid; or a mixture of an alcoholic solvent or acetic acid and water at the reaction temperature of the hydrogenation of from approximately 10 to approximately 60°C and a pressure of hydrogenation of from about 20 to about 1000 pounds per square inch.

The compound of the present invention is basic, and this connection is applicable in free base form or in the form of its pharmaceutically acceptable acid additive salt.

Acid additive salts can be more convenient form for use; and in practice the application form salts essentially boils down to the application forms of the free base. Acids which can be used to obtain the acid additive salts include preferably those which give, when combined with the free base, pharmaceutically acceptable salts, namely, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts so that the beneficial inhibitory effects inherent in the free base are not attenuated side effects due to the anions. Although PAA is asepticheski acceptable salts of the compounds are preferred, all acid additive salts are used as sources of the free base form even if the particular salt, by itself, is only required as an intermediate product as, for example, when the salt is formed only for purposes of purification and determination, or when it is used as an intermediate compound in the preparation of pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the present invention include the following, derived from mineral acids and organic acids, and include hydrogenogenic, such as hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetates, citrates, lactates, tartratami, malonate, oxalates, salicylates, propionate, succinate, fumarate, maleate, methylene-bis-b-hydroxynaphthoate, benzoate, tozilaty, gentisate, isethionate, di-p-toluoyltartaric, methansulfonate, econsultancy, bansilalpet, p-toluensulfonate, cyclohexylsulfamate and hinata. More specific salt is a salt of the compounds of formula I and is cleaners containing hydrochloride salt. Another specific salt of the present invention is the fumarate of the compound of formula I. the Preferred pharmaceutically acceptable salt of the present invention is a benzoate compound of formula I.

In addition to the application itself as the active connection, salts of the compounds of the present invention are applicable for the purposes of cleaning compound, for example by using differences in solubility between the salts and the parent compound, by-products and/or raw materials by techniques well known in the art of this technical field.

According to further features of the present invention, an acid additive salt of the compounds of this invention can be obtained by reaction of the free base with the appropriate acid, by application or adaptation of known methods. For example, the acid additive salts of the compounds of this invention can be obtained by dissolving the free base in water or aqueous alcohol solution or other suitable solvents containing the appropriate acid and the release of salt by evaporating the solution, or by reaction of the free base and acid in an organic solvent, where the salt separates directly or can be obtained by concentration of the solution.

Acid additive salts of the compounds of this invention can be recovered from the salts by the application or adaptation of known methods. For example, the source connection of the present invention can be recovered from their acid additive salts by treatment with alkali, for example aqueous solution of bi is carbonate sodium or aqueous solution of ammonia.

In particular, monobenzoate Compound A is preferred.

Raw materials and intermediate compounds can be prepared by application or adaptation of known methods, for example methods as described in the reference examples or their obvious chemical equivalents.

The present invention is also directed to some intermediate compounds in the above scheme 1, and, in fact, the methods described herein for their preparation, are further features of the present invention.

List of abbreviations

As used above and throughout the description of the present invention, the following abbreviations unless otherwise specified, as should be understood, have the following meanings:

ACN acetonitrile

AIBN 2,2'-azobisisobutyronitrile

bid twice a day

BOC or Boc tert-BUTYLCARBAMATE

BOP benzotriazol-1-yl-oxides(dimethylamino)phosphonium

n-Bu3SnH hydride tri-n-butyanova

t-Bu tert-butyl

Cbz benzylcarbamoyl

PTC catalyst phase transfer

DAST (diethylamino) sulfur TRIFLUORIDE (Et2NSF3)

DCC dicyclohexylcarbodiimide

DCM dichloromethane (CH2CI2)

DIC 1,3-diisopropylcarbodiimide

DIPEA diisopropylethylamine

DMAP 4-(N,N-dimethylamino)pyridine

DMP reagent reagent Periodinane dessa-Martin

DMF dimethylformamide

DMSO is metilsulfate

EA elemental analysis

EDCI 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide HCl

eq equivalent(s)

Et ethyl

Et2O diethyl ether

EtOH ethanol

EtOAc ethyl acetate

FMOC 9-fluorenylmethoxycarbonyl

HOAt 1-hydroxy-7-asobancaria

HOBT 1-hydroxybenzotriazole

HOSu (N-hydroxysuccinimide

HPLC high performance liquid chromatography

'lah aluminized lithium

Me methyl

MeI methyliodide

MeOH methanol

MeOC(O) methylchloroform

MOMCl methoxymethane

MOM methoxymethyl

MS mass spectroscopy

NaBH4sodium borohydride

Na2C4H4O6ttrat sodium

NMR nuclear magnetic resonance

P polymer communications

PO oral administration

PyBOP benzotriazol-1-yl-oxytrol-pyrrolidino-phosphonium hexaflurophosphate

TBD 1,5,7-diazabicyclo[4.4.0]-Dec-5-ene

RP-HPLC ortofena liquid chromatography under high pressure

TBSCl tert-butyldimethylsilyloxy

TCA trichloroacetic acid

TFA triperoxonane acid

Tf2O triflate anhydride

THF tetrahydrofuran

THP tetrahydropyran

TLC thin layer chromatography

Definition

As used above and throughout the description of the present invention, the following expressions, unless otherwise stated, it should be understood as having the following values:

"Bioisostere acid" means a group which, which has chemical and physical similarities, providing biological properties, approximately similar carboxylate (see Lipinski, Annual Reports in Medicinal Chemistry, “Bioisosterism In Drug Design”, 21, 283 (1986); Yun, Hwahak Sekye, “Application of Bioisosterism To New Drug Design” 33, 576-579, (1933); Zhao, Huaxue Tongbao, “Bioisosteric Replacement And Development Of Lead Compounds In Drug Design” 34-38, (1995); Graham, Theochem, “Theoretical Studies Applied To Drug Design ab initio Electronic Distributions In Bioisosteres” 343, 105-109, (1995)). Typical bioisostere acid include-C(O)-NHOH, -C(O)-CH2OH, -C(O)-CH2SH, -C(O)-NH-CN, sulpho, phosphono, alkylsulphonyl, tetrazolyl, arylcarbamoyl, N-methoxycarbonyl, heteroarylboronic, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidine or hydroxymercuri, such as 3-hydroxyethoxyethyl, 3-hydroxy-1-methylpyrazole etc.

"Effective amount" means an amount of a compound/composition according to the present invention, effective to obtain the desired therapeutic effect.

"Hydrate" means the MES, where the molecule(s) of the solvent is/are H2O.

"Patient" means humans and other mammals.

"Pharmaceutically acceptable ester" refers to esters which are hydrolyzed in vivo and include those that are easily dissolved in the body, leaving the parent compound or its salt, a Suitable complex ester group include, in the example, those derived from pharmaceutically acceptable carboxylic acids, in particular, alcamovia, alkenone, cycloalkanones and arcangioli acid, in which each half of alkyl or alkenyl is mostly not more than 6 carbon atoms. Typical esters include formate, acetate, propionate, butyrate, acrylates, ethylsuccinate etc.

"Pharmaceutically acceptable prodrugs"as used herein refers to those prodrugs of the compounds of the present invention which are, within the framework of a thorough medical judgment, suitable for use in contact with the tissues of patients with increased toxicity, irritation, allergic response and the like, respective reasonable ratio of benefit/risk, and effective for the deliberate use of compounds of the present invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. Functional groups that can quickly be transformed by metabolic cleavage in vivo form a class of groups that are reactive to a carboxyl group of the compounds of this invention. They include, but are not limited to, groups such as alkanoyl (such as acetyl, propane is, butanol, and the like), unsubstituted and substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as etoxycarbonyl), trialkylsilyl (such as trimethyl - and triethylsilyl), monologue esters formed with dicarboxylic acids (such as succinyl), etc. because of the ease with which metabolically degradable group of the compounds of this invention are oxidized in vivo, the compounds bearing such groups act as prodrugs. Compounds bearing metabolically degradable group, have the advantage that they may exhibit improved bioavailability as a result of increased solubility and/or rate of absorption attributed to the parent compound by the presence of metabolically degradable group. A detailed discussion is contained in Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985); Methods in Enzymology; K. Widder et al., Ed., Academic Press, 42, 309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bandaged, ed., Chapter 5; “Design and Applications of Prodrugs” 113-191 (1991); Advanced Drug Delivery Reviews, H. Bundgard, 8, 1-38, (1992); J. Pharm. Sci., 77.,285 (1988); Chem. Pharm. Bull., N. Nakeya et al., 32, 692 (1984); Pro-drugs as Novel Delivery Systems, T. Higuchi and V. Stella, 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, E.B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.

"Pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid-additionnaly and basically additive salts of the compounds of the present invention. These salts can be obtained in situ during the final isolation and purification of compounds. In particular, the acid additive salts can be obtained by a separate reaction purified compound in the form of its free base with a suitable organic or inorganic acid and highlight the thus formed salt. Typical acid additive salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naftilan, mesilate, glucoheptonate, lactobionate, sulfamate, malonate, salicylates, propionate, methylene-bis-β-hydroxynaphthoate, gentisate, isethionate, di-p-toluoyltartaric, methansulfonate, econsultancy, bansilalpet, p-toluensulfonate, cyclohexylsulfamate and laurylsulphate salt etc. See for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66, 1-19 (1977), which is incorporated herein by reference. Basically additive salts can also be obtained by a separate reaction purified compound in the form of its acid with a suitable organic or inorganic base and highlight the thus formed salt. Basically additive salts include pharmaceutically acceptable metal salts and amines. Suitable metal salts is clucalc salts of sodium, potassium, calcium, barium, zinc, magnesium and aluminum. Sodium and potassium salts are preferred. Suitable inorganic basic additive salts derived from bases metals, which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, etc. basically Suitable additive salts of amines derived from amines which have a basicity sufficient for the formation of a suitable salt, and preferably include those amines which are frequently used in medicinal chemistry because of their low toxicity and acceptability for medical use, such as, for example, ammonia, Ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N'-dibenziletilendiaminom, chloroprocaine, diethanolamine, procaine, N-benzylpenicillin, diethylamine, piperazine, Tris (hydroxymethyl)aminomethan, the hydroxide of Tetramethylammonium, triethylamine, dibenzylamine, fenamin, dehydroabietylamine, N-ethylpiperidine, benzylamine, Tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids such as lysine and arginine, and dicyclohexylamine etc.

"MES" means a physical Association of a compound of the invention with one or more solvent molecules. This physical Association which includes hydrogen binding. In certain cases, the MES is capable of separating, for example, when one or more solvent molecules are built into the crystal lattice of the crystalline solid. "MES" covers both the solution phase and measurable allocation of the solvate. Typical solvate includes hydrates, ethanolate, methanolate etc.

"Treatment" and "therapy" means the administration of the compounds to alleviate the state of the disease or disorder, or prevent a disease state or disorder. Or slow the progression of the disease state or disorder, and this also applies to the reduction of susceptibility to the condition, disease or disorder. These expressions also include, but without limitation, palliative therapy, which is non.

Embodiments of the

With reference to the inventions described in the present document, the following specific embodiments of, relating thereto.

Concrete option implementation of the present invention is a method for the treatment of dermatological and allergic conditions such as atopic dermatitis, comprising the administration to a patient in need, an effective amount of the compounds of formula I or its corresponding N-oxide, prodrug, pharmaceutically acceptable with the and or MES.

Another particular implementation of the present invention is a pharmaceutical composition for treating dermatological and allergic conditions such as atopic dermatitis, containing the compound of formula I or its corresponding N-oxide, prodrug, pharmaceutically acceptable salt, or salt, in combination with a pharmaceutically acceptable vehicle.

Another variant implementation of the present invention is a method for the treatment of dermatological and allergic conditions such as atopic dermatitis, comprising the administration to a patient in need, an effective amount of a compound which is an inhibitor of beta-tryptase.

The compounds of this invention do not necessarily come in the form of salts. Those salts that are pharmaceutically acceptable are of special interest as they are applicable in the introduction above compounds for medical purposes. Salts that are not pharmaceutically acceptable are used in the production process for separation and purification, and in some cases to use to separate stereoisomeric forms of the compounds of this invention. In particular relates to amine salts prepared from optically active amines.

Where the compound of the present invention sod is RIT carboxyl group or enough sour bioisostere, can be formed basically additive salt, which is simply a more convenient form for use; in practice, the application form salts essentially boils down to the application form of the free acid.

Also, when the compound of the present invention contains a basic group, or rather the main bioisostere, can form acid additive salts, which are simply a more convenient form for use; and in practice the application form salts essentially boils down to the application forms of the free base.

Another objective of the present invention is the provision of a pharmaceutical composition, comprising a pharmaceutically effective amount of the compounds of formula 1 and pharmaceutically acceptable carrier or diluent.

Another objective of the present invention is the provision of a pharmaceutical composition that is effective in itself, for use in a favorable combination therapy, because it includes many active ingredients that can be used in accordance with the present invention.

The present invention also provides kits or single packages combining two or more active ingredients that are applicable in the treatment or prevention of macular degeneration patient. The kit may provide the ü (single or in combination with a pharmaceutically acceptable carrier or diluent), the compound of formula 1 and an additional active ingredient, either alone or in combination with diluent or carrier).

The compounds of formula I can be prepared by application or adaptation of known methods, as known so far, and described in the literature or by methods disclosed in this document.

The amount of the compounds of formula 1 in any of the above applications can be pharmaceutically effective amount suboptimal effective amount or combinations thereof, provided that the resulting combination of ingredients is pharmaceutically effective amount of compounds that are effective in treating or preventing macular degeneration in a patient.

PHARMACOLOGY

Compounds according to the present invention, which, as described in this document are applicable because of the ability to inhibit beta-tryptase and also applicable for the treatment of inflammatory bowel disease.

A particular aspect of the present invention provides compounds related to the present invention, for introduction into the form of pharmaceutical compositions, although the connection can be used separately. "Pharmaceutical composition" means a composition including a compound of formula 1 and at least one compound selected from the group comprising pharmaceutically acceptable carriers, solvents, coatings, auxiliary means in the receiving means or fillers, such as preserving agents, fillers, disintegrating agents, moistening agents, emulsifying agents, stabilizing the emulsion agents, suspendresume agents, isotonic agents, sweetening agents, flavoring agents, perfumes, coloring agents, antibacterial agents, antifungal agents, other therapeutic agents, lubricating agents, retarding or accelerating the adsorption agents and dispensing agents, depending on the nature of the mode of administration and dosage forms. These compositions can be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups. Typical suspendresume agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, esters sorbitan, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant, or mixtures of these substances. Exemplary antibacterial and antifungal agents to prevent the action of microorganisms include para-aminobenzoic acid, chlorobutanol, phenol, sorbic acid and the like. Exemplary isotonic agents include sugar, sodium chloride and the like. Exemplary inhibiting adsorption agents, servants for prolonging the absorption include monostearate aluminum and Gelati is. Exemplary supports the adsorption agents that serve to enhance the adsorption include dimethyl sulfoxide and related analogues. Exemplary carriers, solvents, solvents, auxiliary funds, increase the solubility of tools, substances that promote emulsification and stabilizing the emulsion includes water, chloroform, sucrose, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, tetrahydrofurfuryl alcohol, benzyl benzoate, high molecular weight alcohols, propylene glycol, 1,3-butyleneglycol, glycerol, glycols, dimethylformamide, Tween® 60, Span® 60, cetostearyl alcohol, ministerului alcohol, glyceryl-mono-stearate and sodium lauryl sulfate, esters of fatty acids or sorbitan, vegetable oils (such as cottonseed oil, peanut oil, seed oil, cucumber, olive oil, castor oil and sesame oil) and injectable organic esters, such as etiloleat and the like, or suitable mixtures of these substances. Typical carriers include lactose, milk sugar, sodium citrate, calcium carbonate, dicalcium phosphate. Typical disintegrating agents include starch, alginic acid and certain complex silicates. Typical lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as glycols, having the e high molecular weight.

Other therapeutic agents can also be used in combination with the compounds of the present invention. Therapeutic agents used in combination with the compounds of the present invention can be applied separately, simultaneously or sequentially. The choice of material in pharmaceutical compositions, rather than the compound of formula 1, is generally determined in accordance with the chemical properties of the active compound, such as solubility, specific method of application and conditions to be observed in pharmaceutical practice. For example, carriers such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acid, certain complex silicates in combination with lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc, can be used for preparing tablets.

The pharmaceutical compositions can be presented in mixed forms, such as tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups.

The term "liquid dosage form" means that the dose of active compound must enter the patient in liquid form, for example, pharmaceutically applicable emulsions, solutions, suspensions, syrups and elixirs. In updat the Addendum to the active compounds, liquid dosage forms may contain inert solvents commonly used in the art, such as solvents, agents that increase the solubility, and emulsifying agents.

Solid compositions can also be used as fillers in soft and tverdotoplivnyh gelatin capsules using such media as lactose or milk sugar as well as glycols, high molecular weight, and the like.

When using aqueous suspension, they may contain emulsifying agents, or agents that facilitate the suspension.

The oil phase of the emulsion pharmaceutical composition may be constituted from known ingredients in a known manner. Although the phase may include only substance that promotes emulsification (also known as an emulgent), it is desirable to include a mixture of at least one emulsifier with a fat or oil or grease, and oil. In this embodiment, the hydrophilic emulsifier include together with a lipophilic emulsifier, which acts as a stabilizer. The emulsifier(s) with or without stabilizer(s) together form the emulsifying pasta and together with the oil and fat form the basis of emulsifying ointment base which forms the oily dispergirovannoyj phase compositions creams.

If desired, the aqueous phase of the cream of viewlocity, for example, not less than 30% mass parts (in/in) a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The compositions for external use can optionally include a compound which enhances absorption or penetration of the active ingredient through the skin or other treated area.

The choice of suitable oils or fats for medicinal compositions based on achieving the desired properties. So, the cream should preferably be a low-fat, no staining and washable product with suitable consistency to avoid leakage from tubes or other containers. You can use a straight or branched chain, mono - or complex dibasic esters Akilov, such as diisopropylamide, decillia, isopropyl, butilstearat, 2-ethylhexylamine or mixed or branched chain esters known as Crodamol CAP. They can be used independently or in combination depending on the desired properties. Alternatively, a high-melting fats, such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

In practice, connection/pharmaceutical compositions of the present invention can be applied in a suitable composition of the e people and animals for local or systemic injection, including oral, inhalation, rectal, nasal, buccal, sublingual, vaginal, colonic, parenteral (including subcutaneous, intramuscular, intravenous, subcutaneous, intrathecal and epidural), intracisternally and intraperitoneally. It should be borne in mind that the preferred path may vary depending on, for example, the state of the recipient.

"Pharmaceutically acceptable dosage forms" refers to dosage forms of the compounds of this invention and include, for example, tablets, pills, powders, elixirs, syrups, liquid preparations, including suspensions, sprays, inhalation tablets, diamond plate, emulsions, solutions, granules, capsules and suppositories as well as liquid preparations for injections, including liposomal drugs. Equipment and technology for the preparation of dosage forms can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition.

"Formulations suitable for oral administration may be presented as discrete units such as capsules, starch capsules or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or suspension in an aqueous liquid or non-aqueous liquid; or in the form of a liquid emulsion of the type oil-in-water or a liquid emulsion of the type water-is-oil. The active ingredient may also be presented as a ball, electuary or gruel.

The tablet can produce by compression or molding, optionally with one or more additional ingredients. Compressed tablets may be prepared by compressing in a corresponding machine the active ingredient in granular form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Shaped tablets can be manufactured by molding a particular vehicle, a mixture of powdered compounds moisturize inert liquid solvent. The tablets may optionally be coated or corrugated and may be formed so as to provide slow or controlled splitting of active ingredient in them.

Solid compositions for rectal applications include suppositories prepared in accordance with known methods and containing at least one compound of the present invention.

If it is desired, and for more effective distribution, the compounds can microencapsulate in, or attached to the systems slow release or targeted delivery systems such as biocompatible, biodegradable polymer mA is the matrix (for example, copolymer of d,l-lactide and glycoside), liposomes, and microspheres and subcutaneously or intramuscularly to enter using a technique called subcutaneous or intramuscular depot to provide continuous slow release of the compound(s) for a period of up to 2 weeks or longer. These compounds can be sterilized, for example, by filtration through a bacterial filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable media immediately prior to use.

"Formulations suitable for nasal or inhaled application" means a composition in a form suitable for nasal application or inhalation by the patient. These dosage forms may contain a carrier in the form of a powder having a particle size, for example, in the range from 1 to 500 microns (including particle sizes in the range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc). Suitable dosage forms, when the carrier is a liquid, for use, for example, nasal spray or nasal drops, include aqueous or oily solutions of the active ingredient. Dosage form suitable for aerosol applications, can be prepared according to conventional methods and which may be delivered with other therapeutic agents. Inhalation therapy is easily applied using the dosing inhaler.

"Formulations suitable for oral administration" means compounds that are in a form suitable for administration orally to the patient. The formulations may be presented as discrete units such as capsules, pills or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or suspension in an aqueous liquid or non-aqueous liquid; or in the form of a liquid emulsion of the type oil-in-water or a liquid emulsion of the type water-in-oil. The active ingredient may also be presented in the form of a ball, electuary or paste.

"Formulations suitable for parenteral administration" means compounds that are in a form suitable for administration to a patient parenterally. The compositions are sterile and include emulsions, suspensions, aqueous and non-aqueous injection solutions which may contain suspendresume tools and thickeners and antioxidants, buffers, bacteriostatic factors and solutions that transform the composition isotonic and have properly adjusted the pH with the blood of the intended recipient.

"Formulations suitable for rectal or vaginal administration" means compounds that are in the form, approach the soup for rectal or vaginal administration patient. Suppositories are a specific form of such compositions which can be prepared by mixing the compounds of this invention with suitable non-irritating fillers or carriers such as cocoa butter, polyethylene glycol or suppozitornyj wax, which are solid at ordinary temperatures but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

"Compositions suitable for systemic injections" means compounds that are in the form of 20 suitable for administration to the patient systemically. The composition is preferably administered by injection, including intramuscular, intravenous, intraperitoneally and subcutaneous. For injection, the compounds of the present invention is made in liquid solutions, in particular in physiologically compatible buffers such as a solution of Hank's or ringer's solution. In addition, the compounds can be in solid form and re-dissolved or suspended immediately prior to use. Lyophilized forms are also included. System introduction can also be obtained by transmucosal or transdermal means, or the compounds can be administered orally. For transmucosal or transdermal administration of penetrants appropriate to the barrier, which will be pre is to golematis, used in the composition. Such penetrants, generally known in the art, and include, for example, derivatives of bile salts and guideway acid for transmucosal introduction. In addition, to facilitate penetration can be used detergents. Transmucosally introduction can be accomplished through the use of nasal sprays or suppositories. For oral administration the compounds developed in the conventional oral administration forms such as capsules, tablets, and tonics.

"Formulations suitable for topical introduction" means compounds that are in a form suitable for local administration patient. The composition may be presented in the form of ointment for local application, balms, powders, aerosols and inhalers, gels (water or alcohol based), creams, known in this art, or is included in the matrix base for application in a patch, which would allow a controlled release of compound through the transdermal barrier. Composed in the form of an ointment, the active ingredients can be used with paraffin or water-soluble materials. In addition, the active ingredients can be prepared in the form of a cream on the oil-water cream base. Formulations suitable for local injection into the eye include eye drops, in which the asset is first ingredient is dissolved or suspended in a suitable carrier, especially in aqueous solvent of the active ingredient. Formulations suitable for local injection in the mouth include lozenges, containing the active ingredient in the flavor basis, usually sucrose and gum or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerol or sucrose and gum; and liquid mouth rinse containing the active ingredient in a suitable liquid carrier.

"Solid dosage form" means a dosage form of the compounds of the present invention in solid form, for example, capsules, tablets, pills, powders, tablets or granules. In such solid dosage forms of the compounds of the present invention admixed to at least one conventional inert excipient (or carrier)such as sodium citrate or dicalcium phosphate or (a) fillers or diluents, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binding agents, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum, (C) humectants, for example glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates and sodium carbonate, (e) drying retarders R is the target, as, for example, paraffin, (f) absorption accelerators, as for example, Quaternary ammonium compounds, (g) wetting, as, for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin, bentonite, and (i)lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, (j) fogging means (k) of the buffer means, and means which release the compound(I) of the present invention in a specific part of the stomach-intestinal tract with a delay.

The actual dose levels of active ingredient(s) in the compositions of the present invention can be modified to obtain the amount of the active ingredient(s)that is(are) effective to achieve the desired therapeutic response for a particular composition and method of use for the patient. The selected dosage level for each individual patient, therefore, depends on a number of factors, including the desired therapeutic effect, the route of administration, the desired duration of treatment, etiology and severity of the disease, the patient's condition, weight, sex, diet and age, type and effectiveness of each active ingredient, the rate of absorption, metabolism and/or excretion, and other factors.

The total daily dose of the compounds of the present invention that is administered to the patient in od is h or a few tricks, may be, for example, from about 0.001 to about 100 mg/kg of body weight per day and preferably from 0.01 to 10 mg/kg/day. For example, in adults, the dose is usually preferably from 0.01 to 100, from about 0.01 to 10 mg/kg of body weight per day by inhalation, from about 0.01 to 100, preferably from 0.1 to 70, especially from 0.5 to 10 mg/kg body weight / day when administered, and from 0.01 to 50, preferably from 0.01 to 10 mg/kg of body weight per day intravenously. The proportion of active ingredient in the composition can be changed, but it should be this part that was received appropriate dosage. The unit dosage of the composition may contain such number fraction of the unit, which can be used to compensate for a daily dose. Of course, several standard forms dosage can be entered at about the same time. Dose can be administered at the rate needed to obtain the desired therapeutic effect. Some patients may respond quickly to a higher or lower dose, and maintaining a much weaker dose may be sufficient. For other patients may need long-term treatment, from 1 to 4 doses per day, in accordance with the physiological needs of each individual patient. Needless to say that other patients will need to appoint not more than one Il is two doses per day.

The compositions can be prepared in a standard dosage form by any of the methods well known in the pharmaceutical field. These include the stage of connection of the active ingredient with the carrier which consists of one or more accessory ingredients. Basically, the compositions are prepared by homogeneous and close connection of the active ingredient with liquid carriers or finely powdered solid carriers or carriers of both types, and then, if necessary, shaping the product.

The formulations may be presented in the form of a container containing a single dose or multiple doses, for example sealed ampoules and vials with elastomeric stoppers, and can be stored in cryo-dried (lyophilized) condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use. Extemporally injection solutions and suspensions can be obtained from sterile powders, granules and tablets of the previously described types.

Compounds within the present invention exhibit significant pharmacological activity in the test described in the literature and below, the test results are believed to correlate on pharmacological activity in humans and other mammals.

The chemical reactions described the data quoted in the above sources, in common open from the point of view of their widespread use to obtain the compounds of the present invention. Sometimes reactions can not be applied as described to each compound included in the scope of the compounds described herein. Connection with which this occurs can determine the experts in this field. In all such cases, or the reaction can be successfully carried out using a conventional modifications known to specialists in this field, for example by ensuring appropriate protection of interfering groups, by changing to alternative conventional reagents, regular changes of the reaction conditions and the like, or other reactions described herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. All preparation methods, all starting materials are known or easily prigotovlyaemyh from known starting materials.

The mode for the treatment of patients suffering from allergic dermatological conditions such as atopic dermatitis, compound and/or composition of the present invention is selected in accordance with a number of factors, including age, weight, sex, diet and health status of the patient, the severity of the condition, the route of administration, pharmacological considerations such as the activity, efficacy, is farmakokineticheskie and toxicology profiles of the particular compounds used, and the use of the delivery system of the drug. Taking combinations of drugs described in this document, as a rule, should be continued during the period to achieve acceptable kupirovannom state. Patients treated with a combination of drugs described in this document may be the subject of continuous monitoring using traditional methods of measuring renal function to determine the effectiveness of therapy. Continuous analysis of data obtained using these methods allows you to change the treatment regimen during therapy, and thus impose the optimal amount of each component in the combination, and so that also determined the duration of treatment. Thus, the treatment regimen/dosing can rationally change during therapy, so that has introduced the most small amounts of each of the compounds used in combination, which together have a satisfactory efficiency, and so that the use of such compounds in combination lasts only as long as it is necessary for the successful treatment of dermatological allergic conditions such as atopic dermatitis.

EXPERIMENTAL EXAMPLE

Information about animals

For this study used male Primate species Macaca fascicularis aged 5 to 10 years. To which each animal is identified by a unique number tattoo, located on the chest. Group size was 12. The animals were supplied by Charles River and housed in the conditions set forth in the NIH guide for the care and use of laboratory animals in accordance with the USDA Laboratory Animal Welfare Act (the act laboratory animals USDA) is fully accredited by AAALAC facility. Food for primates Purina (product 5038) were fed twice a day, with the addition of fruits, vegetables and preparations. Water was available without restrictions.

The Protocol for the use of animals, which made this study was approved by the Committee on animal care and use (Institutional Animal Care and Use Committee).

Connection information

Connection As originally mentioned in the salt form (hydrochloride), was synthesized according to the scheme described above. Salt/active substance ratio (in/in)with 1.07.

Diphenhydramine hydrochloride (Bioniche Pharma, a number 1084899, lot number 070709) was used as positive control.

Structures

The compound a prepared solution containing 0.22 mg/ml, A sum (Ascaris sum) in phosphate buffer solution was dosed out 0,004, of 0.0004, 0,00004 and 0,000004 mg per injection in a volume of 40 μl.

Diphenhydramine hydrochloride was prepared in a solution containing 0.22 mg/ml of A suum in phosphate buffer solution. Diphenhydramine hydrochloride was administered at a dose of 0.4 mg per injection in a volume of 40 μl.

The process of constructing the s antigen

Extract of Ascaris suum (batch number XPB33X1A5, lot 30575) was set Greer Laboratories. The extract was dissolved in distilled water to a final concentration of stock solution 10 mg/ml

Procedure

Animals were narcoticyou using intramuscular (IM) injection of 5 to 10 mg/kg ketamine mixed with from 0.5 to 0.75 mg/kg of medetomidine. The chest and abdomen of the animal was shaved and cleaned with alcohol. Following injection (40 µl) was injected intradermally:

PBS (phosphate buffer solution)

Ascaris 8,8×10-3mg/ml

Ascaris 8,8×10-3mg/ml + 0.4 mg Diphenhydramine hydrochloride

Ascaris 8,8×10-3mg/ml + 0.004 mg SAR160719

Ascaris 8,8×10-3mg/ml + 0.0004 mg SAR160719

Ascaris 8,8×10-3mg/ml + 0,00004 mg SAR160719

Ascaris 8,8×10-3mg/ml + 0,000004 mg SAR160719

Reaction in the form of blisters was measured 15 minutes after injection using a Vernier caliper. The blister was measured in two diameters (D1 and D2) perpendicular to each other. The area of the blister was calculated by the formula:

Size (mm2)=((D1+D2)/4)2×3,142

After measuring hydrocortisone cream was applied to all the injection sites. Diphenhydramine hydrochloride 2 mg/kg was injected (IM), and atropine 0.1 mg/kg subcutaneously. Animals were returned with atipamezole hydrochloride (IM), were sent back to their home cages and observed for any further allergic reactions sludge is itching at the injection site.

Statistical analysis

Used a mixed model with repeated measures to analyze the data with the size of the blisters for different treatment groups, repeated measures, with treatment as fixed effects and animal as random effect. The correlation structure was chosen for compound symmetry. To obtain the results used robust estimation of covariance.

Results

Connection And entered intradermal together with A suum, reduced antigen-induced blisters when measured 15 minutes after injection. The average size of blisters (±SE) in the injection of A suum was 119,626±10,175 mm2. Connection And significantly reduced the average size of blisters at 0.0004 mg (97,680±8,012 mm2p=0,0475) and 0.004 mg (102,390±9,645 mm2p=0,0171) doses. Diphenhydramine hydrochloride, put together with A suum, significantly reduced the average size of blisters at 0.4 mg (84,196±7,364 mm2, p=0.0005).

The results are shown in Table I below.

The present invention can be implemented in other specific forms without departing from the essence or essential attributes.

1. A method of treating dermatological allergic condition, comprising administration to a patient in need, an effective amount of the compounds of formula I:

or its corresponding N-oxide, pharmaceutically acceptable salt or MES.

2. Pharmaceutical composition for treating dermatological allergic conditions, containing the compound of formula I or its corresponding N-oxide, pharmaceutically acceptable salt or MES in combination with a pharmaceutically acceptable filler.

3. The method of treatment of a human or non-human animal patient suffering from or susceptible to a condition, which can be facilitated, including the introduction of a pharmaceutically effective amount of the compounds of formula I:

4. The method according to claim 1, where the condition is atopic skin disease selected from atopic dermatitis, eczema, psoriasis, chronic urticaria and alopecia.

5. The method according to claim 4, where the compound is administered in the form of monobenzoate salt.



 

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