3-(1h-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione salts

IPC classes for russian patent 3-(1h-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione salts (RU 2487128):

C07D403/14 - containing three or more hetero rings

A61P37 - Drugs for immunological or allergic disorders

A61K31/517 -

Another patents in same IPC classes:

Chiral cis-imidazolines / 2487127

Described are novel chiral cis-imidazolines selected from a group which includes 2-{4-[(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-acetamide, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(1,1-dioxohexahydrothiopyran-4-yl)-piperazin-1-yl]-methanone, [(4S,5R)-2-(2-tert-butyl-4-ethoxypyrimidin-5-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazol-1-yl]-[4-(3-methanesulphonylpropyl)-piperazin-1-yl]-methanone, 2-{4-[(4S,5R)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxyethyl)-acetamide. 2-{1-[(48;5K)-2-(6-tert-butyl-4-ethoxypyridin-3-yl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl]-piperidin-4-yl}-acetamide and others described by the general structural formula (I), and pharmaceutical composition containing said compounds.

Pyrimidyl cyclopentanes as akt/protein kinase inhibitors / 2486181

Invention refers to new compounds of formula I, enantiomers and pharmaceutically acceptable salts thereof having the properties of AKT/protein kinase inhibitors. In formula 1 G represents phenyl, naphthalene, 5-member heteroaryl with 1 sulphur atom in a ring or 9-member bicyclic heteroaryl specified in indolyl wherein phenyl, naphthalene, 5-member heteroaryl is optionally substituted by one of three R^a groups; R¹ and R^1a are independently specified in H, Me, Et, -CH₂OH, CF₃, CHF₂ or CH₂F; R² represents H, -OH, -OMe or F; R^2a representsH, Me or F; R³ represents H, Me, Et; R⁴ represents H, 6-member heterocyclyl containing an oxygen atom as a heteroatom, cyclopropyl methyl or C₁-C₄ alkyl is optionally substituted F,-OH or -O(C₁-C₃ alkyl); R⁵ and R^5a are independently specified in H and C₁-C₄ alkyl, or R⁵ and R^5a together with an atom whereto attached form a carbonyl group or 5-6-member cycloalkyl; each R^a independently represents halogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl,-O-(C₁-C₆-alkyl), CF₃, CN, phenyl, pyrazole, CH₂F, CHF₂, -OCH₂F, -OCHF₂, -OH, -SO₂(C₁-C₆-alkyl), C(O)NH₂; and j represents 1 or 2; and provided j represents 2, j-ring carbon atom, opposite NR⁴, may be substituted by heteroatom O.

Pyrimidyl cyclopentanes as akt-protein kinase inhibitors / 2486178

Present invention refers to new compounds of formula I, enantiomers and pharmaceutically acceptable salts thereof which have selective inhibitory action on AKT protein kinase, in particular protein kinase B. In formula I: A represents R¹ and R^1a are independently specified in H, Me, Et. vinyl, CF₃, CHF₂ or CH₂F:R₂ represents H, OH, OMe or F; R^2a represents H, Me or F; R³ represents H. Me. Et or CF₃; G represents phenyl optionally substituted by one to four groups R^c, or 5-6-member heteroaryl containing one heteroatom specified in sulphur optionally substituted by halogen; R⁵ and R⁶ independently represent H, OCH₃, C₃-C₆-cycloalkyl independently substituted by F, OH, C₁-C₃alkyl or O(C₁-C₃alkyl), 4-6-member heterocyclyl containing one heteroatom specified in nitrogen optionally substituted by F, OH, C₁-C₃alkyl, cyclopropylmethyl or -C(=O)(C₁-C₃alkyl), or C₁-C₆-alkyl optionally substituted by one or more groups independently specified in OH, oxo O(C₁-C₆-alkyl), CN, F, NH₂. NH(C₁-C₆-alkyl), O(C₁-C₆-alkyl)₂. cyclopropyl. phenyl, imidazolyl, piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, oxetanil or tetrahydropyranyl. The other radical values are specified in the patent claim.

Method of producing substituted pyrimidin-5-yl carboxylic acids / 2485083

Invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

Method of producing benzimidazoles / 2482118

Invention relates to basic organic synthesis and specifically to a method of producing N,N'-bis and N,N,N,N-tetrakis-benzimidazolylmethyl N,N'-bis (piperazinoethyl) ethylenediamines, N,N'-bis and N,N,N,N-tetrakis-benzimidazolylethyl-N,N'-bis (piperazinoethyl) ethylenediamines, which are obtained by reacting carboxylic acids: N,N'-bis and N,N,N,N-tetrakis-carboxyethyl and N,N'-bis and N,N,N,N-tetrakis-carboxyethyl N,N'-bis (piperazinoethyl) ethylenediamine with ortho-phenylenediamine while heating first at temperature of 100-125°C for 0.6-1.5 hours and then at 130-150°C for 2.5-3.4 hours in the medium of an aromatic organic solvent with molar ratio hexamino diacid: phenylenediamine=1:2.1-2.15 and hexamino tetracid:phenylenediamine=1:4.1-4.15. The end product is separated by distilling the reaction mass. The aromatic organic solvent used is ortho-, meta- and para-xylenes or a mixture of ortho-, meta- and para-xylenes.

Crystalline modifications of 3-(1h-indol-3-yl)-4-(4-methylpiperazin-1-yl)quinazolin-4-yl)pyrrol-2,5-dione / 2481341

Present invention refers to novel crystalline forms of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrol-2,5-dione acetate salt, their use for the treating the diseases mediated by T-lymphocytes or PKC, to a pharmaceutical compositions thereof, and a method for preparing them. The presented crystalline forms have: a strong diffraction peak at the angle of 2θ making 21.5° for the A form, or a strong diffraction peak at the angle of 2θ making 9.7° for the B form. The mentioned crystalline forms can be prepared by dissolving 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrol-2,5-dione in 2-propanol at higher temperature, and then cooling after salt formation for preparing the A form, or dissolving 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrol-2,5-dione in ethyl acetate at higher temperature and then cooling after salt formation for preparing the B form.

Cyclopenta(d)pyrimidines as protein kinase akt inhibitors / 2481336

Invention refers to compounds of formula I , as well as to enantiomers and salts thereof, wherein R¹ and R^1a are independently specified in H, Me, Et, CH=CH₂, CH₂OH, CF₃, CHF₂ or CH₂F; R² and R^2a are independently specified in H or F; R⁵ represents H, Me, Et or CF₃; A is presented by formula: ; wherein G, R⁶, R⁷, R^a, R^b ,R^c, R^d, R⁸, m, n and p are presented in cl. 1 of the patent claim.

Phenylpyrazol derivatives / 2480456

Invention refers to a phenylpyrazol derivative presented by formula (1) or to its pharmaceutically acceptable salt: wherein R¹ and R², which may be identical or different, each represents C₁-C₆ alkyl, or R¹ and R² are coupled together with an adjacent nitrogen atom to form a 5-6-merous saturated heterocylic ring (wherein the mentioned saturated heterocylic ring may be substituted by halogen or C₁-C₆ alkyl), n represents an integer 0 to 2, T represents a hydrogen atom, halogen or C₁-C₆ alkyl, and R has one of formulas (I)-(V), (VII) or (VIII):

Method of producing n, n'-bis(β-piperazinoethyl)-2-aryl(alkyl)imidazolidines / 2479583

Invention relates to a method of producing N,N'-bis(β-piperazinoethyl)-2-aryl(alkyl)imidazolidines, which involves reaction of 60-80% aqueous solution of N,N'-bis(piperazinoethyl)ethylenediamine(hexamine) with an aromatic or aliphatic aldehyde at temperature of 100-120°C for 1-1.5 hours, and then at 175-185°C for 2-2.5 hours with distillation of water, wherein the molar ratio of hexamine to the aromatic or aliphatic aldehyde is 1:(1.1-1.3). The aldehyde used can be benzoic or salicylic or butyric or isobutyric aldehyde.

Heteroaryl pyrrolidinyl and piperidinyl ketone derivatives / 2479575

Invention relates to a compound of formula I or use thereof to prepare a medicine for treating depression, anxiety or both: or pharmaceutically acceptable salts thereof, where m is 0-3; n is 0-2; Ar is: optionally substituted indolyl; optionally substituted indazolyl; azaindolyl; 2,3-dihydro-indolyl; 1,3-dihydro-indol-2-one-yl; optionally substituted benzothiophenyl; benzothiazolyl; benzisothiazolyl; optionally substituted quinolinyl; 1,2,3,4-tetrahydroquinolinyl; quinolin-2-one-yl; optionally substituted naphthalenyl; optionally substituted pyridinyl; optionally substituted thiophenyl or optionally substituted phenyl; R¹ is: C_1-6alkyl; hetero-C_1-6alkyl; halo-C_1-6alkyl; halo-C_2-6alkenyl; C_3-7cycloalkyl; C_3-7cycloalkyl-C_1-6alkyl; C_1-6alkyl-C_3-6cycloalkyl-C_1-6alkyl; C_1-6alkoxy; C_1-6alkylsulphonyl; phenyl; tetrahydropyranyl-C_1-6alkyl; phenyl-C_1-3alkyl, where the phenyl part is optionally substituted; heteroaryl-C_1-3alkyl; R² is: hydrogen or C_1-6alkyl; and each R^a and R^b is independently: hydrogen; C_1-6alkyl; C_1-6alkoxy; halo; hydroxy or oxo; or R^a and R^b together form C_1-2alkylene; under the condition that, when m is 1, n is 2, and Ar is an optionally substituted phenyl, then R¹ is not methyl or ethyl, and where optionally substituted denotes 1-3 substitutes selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, amino, acylamino, monoalkylamino, dialkylamino, hydroxyalkyl, alkoxyalkyl, pyrazolyl, -(CH₂)_q-S(O)_rR^f; -(CH₂)_q-C(=O)-NR^gR^h; -(CH₂)_q-N(R^f)-C(=O)-Rⁱ or -(CH₂)_q-C(=O)-Rⁱ; where q is 0, r is 0 or 2, each R^f, R^g and R^h is independently hydrogen or alkyl, and each Rⁱ is independently alkyl, and where "heteroaryl" denotes a monocyclic radical having 5-6 ring atoms, including 1-2 ring heteroatoms selected from N or S, wherein the rest of the ring atoms are C atoms, "heteroalkyl" denotes an alkyl radical, including a branched C₄-C₇-alkyl, where one hydrogen atom is substituted by substitutes selected from a group consisting of -OR^a, -NR^bH, based on the assumption that the bonding of heteroalkyl radical occurs through a carbon atom, where R^a is hydrogen or C_1-6alkyl, R^b is C_1-6alkyl. Pharmaceutical compositions based on said compound are also disclosed.

Novel amide derivative and use thereof as medicinal agent / 2487124

Invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R¹ and R² are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R¹ and R² are not a hydrogen atom at the same time, R³ is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R^4a, R^4b and R^4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R^5a, R^5b and R^5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R^4a, R^4b and R^4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z¹ and Z² are each independently a carbon atom (substitute R³ is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

Use of oligosaccharides containing n-acetyllactosamine for eliciting immune responses in newborns / 2486904

Group of inventions refers to medicine, namely to paediatrics and may be used for preparing a drug or therapeutic nutritional composition for maturating an immune responses in a newborn infant. That is ensured by using an oligosaccharide specified in a group consisting of: lacto-N-tetrose, lacto-N-neotetrose, lacto-N-hexose, lacto-N-neohexose, para-lacto-N-hexose, para-lacto-N-neohexose, lacto-N-octose, lacto-N-neooctose, iso-lacto-N-octose, para-lacto-N-octose and lacto-N-decose. Also, the above oligosaccharide may be used for modulating the immune system of the newborn infant to ensure the developing beneficial intestinal microflora for the first weeks of life comparable to such found in breastfed infants.

Use of oligosaccharides containing n-acetyllactosamine for eliciting immune responses in newborns / 2486904

Method of obtaining immunotropic medication for prevention and treatment of inflammatory processes of agricultural animals / 2486897

Invention relates to field of biotechnology and veterinary medicine. Method of obtaining immunotropic medication for prevention and treatment of inflammatory processes of agricultural animals, includes mixing 90 wt.fr of 0.2-0.3% agar suspension, 2.5 wt.fr of concentrate of refined polysaccharide complex of yeast cells, 3.5 wt.fr. of (-)2,3,5,6-tetrahydro-6- phenylimidazo -[2,1-b]- thiazole hydrochloride and 0.2 wt.fr. of formalin, with additional introduction of 5.0 mln U of antibiotic kanamycin monosulfate and bringing volume of medication to 100 wt.fr.

Method of obtaining medication for activation of non-specific resistance, prevention and therapy of diseases in young agricultural animals / 2486896

Invention relates to field of biotechnology and veterinary medicine. Method of obtaining immunotropic medication for prevention and treatment of inflammatory processes in agricultural animals includes mixing 90 wt.fr. of 0.2-0.3% agar suspension, 2.5 wt.fr. of concentrate of refined polysaccharide complex of yeast cells, 3.5 wt.fr. (-)2,3,5,6-tetrahydro-6- phenylimidazo -[2,1-b]- thiazole of hydrochloride and 0.2 wt.fr. of formalin, with additional introduction of 5.0 mln U of antibiotic amoxicillin in mixing and bringing volume of medicine to 100 wt.fr.

Method of lymphotropic therapy in case of orthodontal abscesses in rabbits / 2486892

Invention relates to field of veterinary and is intended for therapy of orthodontal abscesses in rabbits. Method includes cutting abscess, sanitation of cavity with chlorhexidine solution and alternate lymphotropic introduction of 5 U of lydase, dissolved in 0.5 ml of 0.5% novocaine solution, 0.3 ml of furosemide. Then, alternately with 1 minute interval into hypodermic cellular tissue in area of lower-jaw lymph nodes projection introduced are 10 thousand U per 1 kg of live weight of roncoleukin, dissolved in 1 ml of 2% lidocaine solution, and after that, 2.5% enroflox solution in dose 5 mg per 1 kg of live weight one time per day during 5 days.

Crystalline antibodies against htnfα / 2486296

Method of batch crystallisation is provided for crystallising the antibody against hTNFα, comprising combining an aqueous solution of the antibody, salt of inorganic phosphate and acetate buffer, and incubating the resulting mixture. The crystalline antibody is considered, in particular the antibody D2E7 obtained by the method according to the invention, the pharmaceutical compositions including injectable liquid compositions comprising the antibody crystal, the crystal suspension, and also the methods of treatment the hTNFα-related disorder connected with, and application of the antibody crystals for obtaining the pharmaceutical composition for treatment such diseases.

Crystalline antibodies against htnfα / 2486296

Method of loading dendritic cells with antigen of infectious origin opistorchis felineus / 2486238

Monocytes are isolated from venous blood MNCs using the Percoll cushion bi-gradient of density: 47.5% SIP and 15% SIP, respectively, at cooling to +4°C. The monocytes are placed in a completely nutritional culture medium with adding 20 ng/ml IL-4 and 20 ng/ml GM-CSF. The completely nutritional culture medium is replaced on the day 3 of cultivation. On the day 4 of cultivation the antigen of infectious origin Opisthorchis felineus is added at a dose of 40 mcg/ml and maturation of dendritic cells is simultaneously induced with lipopolysaccharide E.coli of serotype 055: B5 in a dose of 1 mcg/ml. On the day 6 of cultivation the dendritic cells are washed and analysed.

Pyrimidyl cyclopentanes as akt/protein kinase inhibitors / 2486181

FIELD: chemistry.

SUBSTANCE: invention relates to 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione salts in crystalline form, where said salts are formed with an acid selected from hydrochloric acid, maleic acid, malonic acid and methanesulphonic acid. The invention also relates to a method of producing said salts, a pharmaceutical composition containing said salts and a method of treating diseases or disorders mediated by T lymphocytes and/or PKC, which involves addition of said salts.

EFFECT: high stability.

10 cl, 2 ex

The present invention relates to an acid additive salts of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione and their crystalline forms. The invention relates to methods for their preparation, to pharmaceutical compositions containing compounds of the present invention and to their use in therapeutic treatment of warm-blooded animals, especially humans.

3-(1H-Indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione, hereafter referred to as "compound of the invention can be represented by the following formula (I):

and is known from the patent EP 1337527, the full contents of which are included in the description of the present application by reference, and may be obtained as described in this information source.

The present invention relates to new and improved salts, polymorphs and the solvate, the known compounds of formula (I). The compounds of formula (I) include racemic or enantiomeric form.

The free base compounds of the invention shows a relatively low stability in aqueous medium. Therefore, it is difficult to directly and easily obtain pharmaceutical compositions, for example, for oral administration.

In the framework of the present invention it has been unexpectedly discovered that crudest is upon receipt of the compositions based on the free base can be overcome with the use of the compounds of the present invention. Unexpectedly, it was found that some of the salts of the compounds of formula I, for example, with certain acids have, in particular, useful farmcineticeskie properties and as additionally, it was found, have a special combination of favorable compositional properties, which makes them particularly suitable for obtaining pharmaceutical compositions containing the compound of the invention suitable for oral administration.

The present invention includes, for example, the following salts are known compounds of the formula (I): benzoate, chloride, citrate, fumaric, lactate, maleato, malatoy, malonate, mesilate (for example, methanesulfonate), phosphate, succinate and tartrate salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione, preferably methanesulfonate and malonate salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione (hereinafter called "the salt of the invention"). Preferred salts are malata salt and mutilata salt of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione.

Salt of the invention, for example Malaita and mutilata salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione, show a very good stability in the solid state, for example after one week at 80°C in a closed container the ore or at 80°C/75% Rel. VL. in an open container, or when exposed to light (1200 club, 300-800 nm).

Such crystalline forms exhibit improved stability and purity and, consequently, easy to handle in production.

In addition, in the framework of the present invention it has been unexpectedly discovered that under certain conditions, crystalline form or solvate forms can be obtained from the salts of the invention, for example, salts derived from benzoic acid, hydrochloric acid, citric acid, fumaric acid, maleic acid, malic acid, malonic acid, methanesulfonic acid, succinic acid or tartaric acid.

Preferably the crystalline forms of the salts of the invention, for example mesilate salt or maleate salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione, are essentially pure, for example, are essentially in pure form.

The term "essentially pure" in the context of the present invention means that the amount of impurities is less than 1%, preferably less than about 0.75%, more preferably less than 0.5% and the amount of residual solvent and water is less than 1%, preferably less than about 0.75%, more preferably less than 0.5% and even more preferably less than 0.25% by mass.

Selection criteria salts of the invention include: first dissolved in water, with the definition of the decay products and discoloration, ii) stability when heated in the solid state, (iii) light fastness (for example, to the light of a xenon lamp), (iv) corrosivity toward steel.

Figure 1 shows the SEM image mesilate salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione.

Figure 2 presents the SEM image maleate salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione.

Figure 3 presents the x-ray crystal forms mesilate salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione. On the radiograph, the angles of diffraction theta pending on the horizontal axis (x axis), and the peak intensity on the vertical axis (y-axis). Powder x-ray register on the diffractometer Bruker D8 Discover with CuKα radiation source (α1-radiation, wavelength λ=1,54056 Å).

4 shows the x-ray crystal forms maleate salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione. On the radiograph, the angles of diffraction theta pending on the horizontal axis (x axis), and the peak intensity on the vertical axis (y-axis). Powder x-ray register on the diffractometer Bruker D8 Discover with CuKα radiation source (α1-radiation, wavelength λ=1,54056 Å).

In the framework of the present invention C is acene the observed diffraction angle theta can deviate by ±0,1°, ±0,2°, ±0,3°, preferably ±10% or ±20% of the above-mentioned angles of refraction.

Salt of the invention can be obtained by suspendirovanie free base of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione in a suitable solvent, such as, for example, acetone, 2-propanol, ethanol, ethyl acetate, acetonitrile or a mixture thereof. Then salt-forming agent (SFA) is dissolved in an appropriate solvent (for tartaric, fumaric and citric acids can be added some water to improve the solubility of the SFA) and added to a suspension/solution of the free base. The mixture is stirred at a temperature in the range from 20°C to 60°C, for example between 30°C and 50°C between 40°C and 50°C. More preferably the mixture was stirred at ambient temperature.

Salt of the invention can be isolated by filtration and characterized, for example, powder x-ray diffraction, thermal methods and NMR spectroscopy.

The following salts were allocated in the form of crystalline solids, melting with decomposition at temperatures higher than 130°C:

Benzoate salt (1:1); form (A), to 154.2°C; MES with acetone (134,8°C).

Chloride: salt (1:1); at least four different polymorphic forms of (B; C; D; E); two isostructural the MES (S_Awith acetone, 270,6°C; S_Bwith 2-propanol).

Citrate: the ol (2:1); one polymorphic form (S).

The fumarate salt (2:1); one polymorphic form (A), 162,0°C; one methanol MES (S_A).

The maleate salt (1:1); one polymorphic form (A), 180,2°C.

Malate salt (2:1); polymorphic forms (And 157,7°C; In, 132,0°C; C; D; E), solvate (S_Awith methanol).

Malonate: salt (2:1); isomorphic solvate, 174,6°C.

Methylsulfonate: salt (1:1); two polymorpha (And 284,8°C; C), one MES with acetone (S_A).

The succinate salt (2:1); one polymorphic form (And 154,7°C), isomorphic to the fumaric salt, solvate.

The tartrate salt (2:1), one of the polymorphic form (S).

Values in °C as the melting point (the temperature at which the salt melt with decomposition). The melting temperature (in °C) measured at heating rate 10°C/min

In addition, the present invention relates to:

1.1 Salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione, obtained by acid selected from the group including benzoic, hydrochloric, citric, fumaric, lactic, maleic, malic, malonic, methansulfonate, succinic and tartaric acids, preferably maleic or methansulfonate acid.

1.2 Salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione in crystalline or solvate form, where is the salt formed with an acid selected from the group including benzoic, hydrochloric, citric, fuuma is new, lactic, maleic, malic, malonic, methansulfonate, succinic and tartaric acids, preferably maleic or methansulfonate acid.

1.3 Salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione or its crystalline form, as described above in paragraph 1.1 or 1.2, essentially, net, for example, are essentially in pure form.

The invention also relates to methods of producing salts of the invention, including the interaction of the compounds of formula I in free base form with a suitable acid and isolation of the salts from the reaction mixture. The method of the present invention can be efficiently carried out in the usual way, for example by reaction in a suitable inert solvent, such as acetone, acetonitrile, ethyl acetate, ethanol, 2-propanol or tert-butyl methyl ether. The mixture can be peremesheno, for example, at ambient temperature, at a temperature in the range between 40 and 50°C, or can be heated.

Optional can be added to the salt-forming agent, for example, sequential dissolution in a solvent and adding to the suspension/solution of the free base. To improve the dissolution of the salt-forming agent may be added some water.

In the framework of the present invention presents a method crystallizes and salts of the invention. Certain conditions under which crystals are formed, at the present time can be determined empirically, and in practice will carry out a number of ways, including conditions of crystallization, as described in the examples.

Salts of the invention are suitable for treatment and /or prevention of diseases or disorders mediated by T lymphocytes and/or the RCC, for example acute or chronic organ transplant rejection, tissue ALLO - or xenograft, or mediated T-cell inflammatory or autoimmune diseases, such as atherosclerosis, vascular occlusion caused by vascular injury such as angioplasty, restenosis, hypertension, heart failure, chronic obstructive pulmonary disease, CNS diseases such as Alzheimer's disease or amyotrophic lateral sclerosis, cancer, infectious diseases such as AIDS, septic shock or syndrome of respiratory disorders in adults, ischemic/reperfusion injury, e.g. myocardial infarction, stroke, ischemic bowel, renal failure or hemorrhage shock, or traumatic shock. The compounds of formula I are also suitable for the treatment and/or prevention of mediated T-cell acute or chronic inflammatory diseases or disorders or autoimmune diseases e.g. rheumatoid, Arti is a, osteoarthritis, systemic lupus erythematosus, Hashimoto thyroiditis, multiple sclerosis, myasthenia gravis, diabetes type I or II, and related diseases, respiratory diseases such as asthma or inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, cutaneous manifestations of diseases or diseases caused by disorder of the immune system, inflammatory and hyperproliferative skin diseases (such as psoriasis, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis, and other eczematous dermatitises, seborrhoeic dermatitis), inflammatory eye diseases, such as Sjogren syndrome, keratoconjunctivitis or uveitis, inflammatory bowel disease, Crohn's disease or ulcerative colitis.

In accordance with the foregoing the present invention additionally relates to

2.1 Method of preventing or treating disorders or diseases mediated by T lymphocytes and/or the RCC, for example, such as those listed above, the subject in need of such treatment, this method includes the introduction of a specified subject an effective amount of a salt of the invention or its crystalline form;

2.2 Method of preventing or treating acute or chronic transplant rejection or oposredovannyh T-cell inflammatory or autoimmune diseases, for example, such as those listed above, the subject in need of such treatment, this method includes the introduction of a specified subject an effective amount of a salt of the invention or its crystalline form;

3. Salt of the invention or its crystalline form for use as a pharmaceutical, e.g. in any of the ways specified above in paragraphs 2.1 and 2.2.

4. Pharmaceutical composition, e.g. for use in any of the above in subparagraphs 2.1 and 2.2 methods containing the salt of the invention or its crystalline form, together with a pharmaceutically acceptable diluent or carrier.

5. Salt of the invention or its crystalline form for use to obtain a pharmaceutical composition for use in any of the above in paragraphs 2.1 and 2.2 of ways.

6. Salt of the invention or its crystalline form in all cases, the above described methods.

Salt of the invention or its crystalline form, for example mutilata salt or malata salt of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione, can be introduced in the form of individual active ingredient or together with other drugs in immunomodulating regimens or other anti-inflammatory drugs, for example, for the treatment of the sludge is preventing acute or chronic rejection of ALLO - or xenotransplant, inflammatory or autoimmune disorders. For example, they can be used in combination with cyclosporine or ascomycin, or their immunosuppressive analogs, or derivatives, such as cyclosporin a, cyclosporin G, FK-506, ABT-281, ASM 981; an mTOR inhibitor, e.g. rapamycin, 40-O-(2-hydroxy)atrribution etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; agent, accelerating homing leukocytes, for example FTY 720; Leflunomide or its equivalent; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-desoxypeganine or its equivalent; immunosuppressive monoclonal antibodies, for example monoclonal antibodies to receptors of leukocytes, such as MHC, CD2, CD3, CD4, CD11a/CD18, CD7, CD25, CD27, B7, CD40, CD45, CD58, CD137, ICOS, CD150 (SLAM), OX40, 4-W or their ligands, e.g. CD154; or other immunomodulatory compounds, e.g. a recombinant binding molecule having at least part of the extracellular domain of CTLA4 or a mutant, for example, at least extracellular portion of CTLA4 or a mutant associated with a protein sequence that is not related to CTLA4, for example, CTLA41g (for example, designated as ATSS 68629) or a mutant, e.g. LEA29Y, or other inhibitors molecular adhesion, e.g. mAbs or low molecular weight inhibitors including antagonists of LFA-1 antagonists, selectin the antagonists of VLA-4. Salt of the invention or its crystalline form, for example mutilata salt or malata salt of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione, may also be introduced together with the anti-proliferative drug such as a chemotherapeutic drug, for example, in the treatment of cancer, or anti-diabetic drug in the treatment of diabetes.

In accordance with the foregoing the present invention also applies to the following objects.

7. The method as defined above comprising co-administration, e.g., simultaneously or sequentially, a therapeutically effective amount of a salt of the invention or its crystalline form, for example mesilate salt or maleate salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione, and the second drug, the second drug is immunodepressants, immunomodulatory, anti-inflammatory, antiproliferative or anti-diabetic drug, for example, as described above.

8. Therapeutic combinations, for example, the set containing a) a salt of the invention or its crystalline form, for example mesilate salt or maleato salt of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione, and (b) at least Odie the second agent, selected from immunodepressants, immunomodulating, anti-inflammatory, antiproliferative and anti-diabetic medicines. Component a) and component b) can be used simultaneously or sequentially. The kit may contain instructions for their implementation.

Salt of the present invention receive in accordance with the following examples which serve to illustrate the invention and do not limit its scope.

EXAMPLE 1

Getting mesilate salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione.

2,63 g (6 mmole) of free base of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione and 40 ml of anhydrous ethanol was placed in a 250 ml three-neck flask equipped with a mechanical stirrer, reflux condenser and addition funnel. The mixture is heated to 45°C and virtually transparent to the solution is added dropwise to 0.39 ml methanesulfonic acid (6 mol, 1 EQ.), dissolved in 5 ml of anhydrous ethanol. Of the transparent original solution of a solid material precipitates and the mixture is incubated at 45°C for two hours. Then it is cooled to room temperature and filtered yellowish-orange solid residue. Once washed with cold ethanol and dried overnight under vacuum.

EXAMPLE 2

Getting maleate salt 3-(1H-indol-3-yl)-4-[-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione.

2,63 g (6 mmole) of free base of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione and 40 ml of anhydrous ethanol was placed in a 250 ml three-neck flask equipped with a mechanical stirrer, reflux condenser and addition funnel. The mixture is heated to 45°C and almost transparent solution pin 0,70 g maleic acid (6 mol, 1 EQ), dissolved in 5 ml of anhydrous ethanol. Almost immediately is the loss of sediment, and the mixture is incubated at 45°C for two hours. Then it is cooled to room temperature and filtered to separate the orange solid residue. It twice washed with cold 2-propanol and dried under vacuum overnight.

1. Salt of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione in crystalline form, where this salt formed with an acid selected from hydrochloric, maleic, malonic and methanesulfonic acid.

2. Salt according to claim 1, where the acid is a maleic or methansulfonate acid.

3. Salt according to claim 1, where the acid is methansulfonate acid in crystalline form, and where this crystalline form is presented on the x-ray measured with CuKα radiation source, as, essentially, is reflected in figure 3.

4. Salt according to claim 1, where the acid is a maleic acid in crystalline f is RME, where is this crystal form is presented on the x-ray measured with CuKα radiation source, as, essentially, is reflected in figure 4.

5. The method of obtaining salt according to claim 1, including the interaction of the free base of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione acid and isolation of the salts from the reaction mixture, where the specified acid selected from hydrochloric, maleic, malonic and methanesulfonic acid.

6. The method of obtaining mesilate salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione according to claim 1, comprising heating a solution of the free base of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione in ethanol, adding methanesulfonic acid in a solution of free base of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione in ethanol and cooling the mixture.

7. The method of obtaining maleate salt 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione according to claim 1, comprising heating a mixture of the free base of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)hinzelin-4-yl]pyrrole-2,5-dione and ethanol, adding maleic acid in the mixture and cooling the mixture.

8. Pharmaceutical composition for use in treating diseases or disorders mediated by T lymphocytes is/or RKS, containing as the active ingredient salt according to any one of claims 1 to 4 in combination with a pharmaceutically acceptable diluent or carrier.

9. The pharmaceutical composition of claim 8 for use for the treatment or prevention of acute or chronic rejection of organ or tissue ALLO - or xenotransplantation, or mediated T-cell inflammatory or autoimmune diseases.

10. The method of treatment of diseases or disorders mediated by T lymphocytes and/or the RCC, such as acute or chronic rejection of organ or tissue ALLO - or xenotransplantation, or mediated T-cell inflammatory or autoimmune diseases, comprising an introduction to the needy in this patient salts according to one of claims 1 to 4 in therapeutically effective amounts.