Thieno[3,2-d]pyrimidine derivative as phosphatidyl inositol-3-kinase (pi3k) inhibitor

FIELD: chemistry.

SUBSTANCE: method is realised by treating a compound of formula

with boronic acid or ether thereof of formula

,

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

.

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

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

11 cl, 13 ex

 

Priority of invention

In this application claimed priority from provisional application U.S. No. 60/794966, which was filed on April 26, 2006. The full content of this provisional application is incorporated here by reference

The scope of the invention

The present invention relates to the derivatives of pyrimidine and to their use as inhibitors phosphatidylinositol-3-kinase (PIK).

Prior art

Phosphatidylinositol (hereafter abbreviated as "PHI") is one of a number of phospholipids found in cell membranes. In recent years it has become clear that the PHI plays an important role in intracellular signal transformation. In the late 1980-ies it was found that the kinase PI (FIC) is an enzyme that phosphorylates the 3-position of the Inositol ring of phosphatidylinositol (D. Whitman et al, 1988, Nature, 332, 664).

FIC initially considered a single enzyme, but at present it is found that in FIC there are many subtypes. Each subtype has its own mechanism of activity regulation. Three main classes FIC identified on the basis of substrate specificity in vitro (B. Vanhaesebroeck, 1997, the Trend in Biol. Sci, 22, 267). Substrates for class I FIC are PHOSPHATIDYLINOSITOL, PHOSPHATIDYLINOSITOL-4-phosphate (FIR) and PHOSPHATIDYLINOSITOL-4,5-bisphosphate (PI(4,5)P2). Class I FIC additionally divided into two groups, class Ia and class Ib, in terms of the mechanism of their activation. Class Ia is IC includes subtypes FIC 110α, 110β and 110δ that transmit signals from receptor-related receptor. Class Ib FIC includes subtype 110γ-activated receptor associated G-protein. PHI and PHI(4)P are known as substrates for class II FIC. Class II FIC includes subtypes FIC 2α, 2β and 2γ, which are characterized by a content of C2 domains at the C-end. Substrate class III FIC is only PHI.

In subtypes FIC subtype of class Ia at present, the most widely studied. Three subtypes of class Ia are heterodimeric catalytic subunit 110 kDa regulatory subunit of 85 kDa or 55 kDa. These regulatory subunits contain SH2 domains and are associated with the remnants of tyrosine phosphorylated receptors of growth factors with tyrosinekinase activity or products of oncogenes inducyruya through this activity FIC catalytic subunit R, which phosphorylates its lipid substrate. Thus, subtypes of class Ia consider associated with cell proliferation and carcinogenesis.

In WO 01/083456 described series of derivatives of condensed heteroaryl, which have activity as inhibitors FISK and which inhibit the growth of cancer cells.

Summary of the invention

At the present time made the discovery that specific thienopyrimidine is an effective inhibitor of the m FIC with physico-chemical and pharmacokinetic properties, such drugs. This compound exhibit a selectivity to the class Ia FIC compared to class Ib, in particular, to the subtype 110α.

Accordingly, the present invention proposed a connection, which is thienopyrimidine formula (I):

or its pharmaceutically acceptable salt.

Detailed description of the invention

Thienopyrimidine formula (I) represents 2-(1H-indazol-4-yl)-6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine

Suitable strategy synthesis for the preparation of compounds according to the invention uses the predecessor carboxaldehyde formula (II):

From this precursor, the synthesis includes in any order mediated by palladium (type Suzuki) reactions cross-coupling and reductive amination. Thus, the connection according to the invention can be obtained in such a way that:

(a) is treated with a compound of the formula (II):

Bronevoy acid or its ester of the formula (IV):

in which each R15represents N or C1-C6alkyl, or two groups OR15form together with the boron atom to which they are attached, ester pinacolateboryl group, presets the under catalyst Pd; and process the resulting compound of formula (III):

the amine of formula (V)

in the presence of a suitable reducing agent; or

(b) treated with a compound of the formula (II)

the amine of formula (V)

in the presence of a suitable reducing agent; and process the resulting compound of formula (VI):

Bronevoy acid or its ester of the formula (IV):

in which each R15represents N or C1-C6alkyl, or two groups OR15form together with the boron atom to which they are attached, ester pinacolateboryl group, in the presence of Pd catalyst.

Accordingly, the present invention is additionally a method for obtaining compounds according to the invention, as defined above, in which process a compound of formula (III):

the amine of formula (V)

in the presence of a suitable reducing agent

The method is defined as, can further include obtaining the compounds of formula (III) by treating the compounds of formula (II):

Bronevoy acid or its ester of the formula (IV):

in which each R15represents N or C1-C6alkyl, or two groups OR15form together with the boron atom to which they are attached, ester pinacolateboryl group, in the presence of Pd catalyst.

Further in the present invention, a method for obtaining compounds according to the invention, as defined above, in which process a compound of formula (VI):

Bronevoy acid or its ester of the formula (IV):

in which each R15represents N or C1-C6alkyl, or two groups OR15form together with the boron atom to which they are attached, ester pinacolateboryl group, in the presence of Pd catalyst.

The method is defined as, can further include obtaining the compounds of formula (VI) by treating the compounds of formula (II)

the amine of formula (V)

in the presence of a suitable reducing agent.

Pharmaceutically acceptable salt of thienopyrimidine formula (I) can be obtained using conventional methods. Typically in this method handle thienopyrimidine formula (I), ka is defined above, suitable acid in a suitable solvent

In the method according to the invention, as defined above, as stage amination and stage Pd-mediated cross-combination takes place in the conventional conditions. The palladium catalyst may be any catalyst typically used for reactions cross-combination of Suzuki type, such as dl2(h3)2. Reducing agent typically represents a borohydride, for example, N(SLA)3, NaBH4or NaCNBH4in particular, the N(SLA)3.

Pinacolateboryl ester may be, for example, obtained by the method described in any of the following reference examples 5 and 6.

The compound of formula (II), as defined above, can be obtained by a method in which process a compound of formula (VII):

literalism agent, and then N,N'-dimethylformamide (DMF). This reaction is typically carried out by adding a solution otherwisehe agent in a nonpolar organic solvent, for example in a hydrocarbon solvent such as hexane, to suspension of the compounds of formula (VI) in an organic solvent, such as tetrahydrofuran (THF). If using THF, adding occurs at a low temperature of about -78°C. Literaly agent typically represents alkality, for example n-butyl who ICI.

The compound of formula (VII)as defined above, can be obtained by a method in which process a compound of formula (VIII).

morpholine in an organic solvent. The solvent is typically an alcohol such as methanol. This reaction is typically performed at room temperature.

The compound of formula (VIII) can be obtained by the method described in reference example 1, or by analogy with this method.

Thienopyrimidine formula (I) can be converted into a pharmaceutically acceptable salt, and the salt can be converted into the free compound in a common manner. Examples of pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, Hydrobromic acid, iodine-hydrogen acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids such as methanesulfonate acid, benzolsulfonat acid, formic acid, acetic acid, triperoxonane acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, econsultancy acid, aspartic acid and glutamic acid. Typical salt is a mesilate, hydrochlori is, phosphate, bansilalpet or sulfate. The most typical salt is a mesilate or hydrochloride.

Salt, for example, salts with any of the inorganic or organic acids mentioned above can be monooly or bis-salt. Thus, for example, salt mesilate may represent monomethyl or bis-mesilate.

The compounds of formula (I) and their salts may exist in the form of hydrate or solvate.

In biological tests, it was found that the compound according to the invention is an inhibitor PI kinase. This compound is a selective class Ia PI kinases compared to class Ib and typically manifests at least 20-fold selectivity for class Ia compared with class Ib PI kinases. In particular, this compound is selective for the isoforms 110α.

The compound of the present invention can thus be used as inhibitor PI kinase, in particular, class Ia PI kinase. Accordingly, the compound of the present invention can be used for the treatment of a disease or disorder arising from abnormal growth, function or behavior of cells. Such abnormal growth, function or behavior of cells is typically associated with PI kinase. Examples of such diseases and disorders discussed Drees et al, Expert Opin. Ther. Patents (2004) 14 (5): 703-732. They include cancer, IMM is installed disorders, cardiovascular disease, viral infection, inflammation, disorders of metabolism/endocrine disorders and neurological disorders. Examples of disorders of metabolism/endocrine disorders include diabetes and obesity.

Examples of cancers for which treatment can be applied to these connections include leukemia, brain tumors, kidney cancer, stomach cancer and cancer of the skin, bladder, breast, uterus, lung, colon, prostate, ovary and pancreas. The patient, representing a human or animal suffering from an immune disorder, cancer, cardiovascular disease, viral infection, inflammation, disorder of metabolism/endocrine disorder or a neurological disorder, it is possible, therefore, to treat the way in which he administered the compound of the present invention, as defined above. The patient can thus be improved or relieved.

Diseases and conditions that are subject to treatment according to the methods of this invention include, but are not limited to, cancer, stroke, diabetes, gepatomegalia, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological races is trojstva, the disease associated with hormone state caused by the transplantation of organs, disorders caused by immunodeficiency, destructive bone disorders, proliferative disorders, infectious diseases, conditions caused cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), liver disease, pathologic immune system are involved in the activation of T cells, and CNS disorders in a patient. In one embodiment the patient is a person treated by a compound of formula I and pharmaceutically acceptable carrier, adjuvant or diluent, where the aforementioned compound of formula I is present in an amount such that the detectable to inhibit the activity PI kinase.

Cancers that can be treated according to the methods of this invention include, but are not limited to, cancer of the breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach cancer, skin, keratoakantoma, lung cancer, squamous cell and large cell carcinoma, non-small cell lung cancer (nmcrl), small cell lung cancer, adenocarcinoma of the lung, cancer of the bone, colon, adenoma, pancreas cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, apillary carcinoma, the seminoma, melanoma, sarcoma, carcinoma of the bladder, carcinoma of the liver and bile duct, carcinoma of the kidney, myeloid disorders, lymphoid disorders, leukemia reticuloendotheliosis, cancer of the oral cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, rectum and colon, large intestine, rectum, brain and Central nervous system, Hodgkin's and leukemia.

Cardiovascular diseases that can be treated according to the methods of this invention include, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction and congestive heart failure.

Neurodegenerative disease that can be treated according to the methods of this invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

Inflammatory diseases that can be treated according to the methods of this invention include, but are not limited to, rheumatoid arthritis, psoriasis, contact dermatitis and prolonged allergic reactions.

Besides possessing the biological efficacy of the compound in the image the structure shows the physico-chemical and pharmacokinetic properties, which make it particularly well adapted for use as a medicine. It showed, for example, the results of the biological assays described in the following Example 3. In particular, the compound has a high solubility in water at physiological pH; this solubility is higher than 100 μm. High solubility at physiological pH is desirable because it promotes bioavailability.

The compound also has a high metabolic stability, as shown, in particular, by analyzing the clearance of hepatocytes described in Example 3, which shows that the connection has a low ground clearance of hepatocytes. Low clearance hepatocytes correlates with a low rate of metabolism in the liver. Thus, it is seen that the compound of the present invention has improved physico-chemical and pharmacokinetic properties, at the same time keeping the biochemical efficacy as an inhibitor PI kinase.

The compound of the present invention can be introduced in several dosage forms, for example orally, such as in the form of pills, capsules, tablets, sugar or film coating, liquid solutions or suspensions, or parenterally, for example intramuscularly, intravenously or subcutaneously. The connection can, therefore, be administered by injection or infusion.

p> The dosage depends on a number of factors, including the age, weight and condition of the patient and route of administration. The daily dosage may vary within wide limits and should be adjusted according to individual requirements in each particular case. Typically, however, the dosage is adapted for each route of administration, when the compound is administered one to adults, from 0.0001 to 50 mg/kg, most often in the range of from 0.001 to 10 mg/kg of body weight, for example from 0.01 to 1 mg/kg, This dose can be given, for example, from 1 to 5 times per day. For intravenous injection of a suitable daily dosage of from 0.0001 to 1 mg/kg body weight, preferably from 0.0001 to 0.1 mg/kg of body weight. The daily dose can be administered as a single dose or in accordance with the regime of the fractional doses.

A typical dose for the treatment of patients-people can be in the range from about 10 mg to about 1000 mg of the compounds according to the invention. A typical dose may be from about 100 mg to about 300 mg of the compound. Dose can be administered once a day (QID), twice a day (BID) or more frequently depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism and the identification of specific compounds. In addition, the toxicity factors may influence the dosage and mode of administration. With the introduction of oral pill, cap the Ulu or the tablet can be taken orally daily or less frequently during a specified period of time. This mode can be repeated for several cycles of therapy.

The preparation of compounds is prepared for use as pharmaceutical or veterinary compositions containing pharmaceutically acceptable or acceptable in the veterinary carrier or diluent. The compositions are typically prepared following conventional methods and are administered in a pharmaceutically suitable or suitable in veterinary form. The connection can be entered in any conventional form, for example, as described below.

(A) Orally, for example in the form of tablets, coated tablets, pills, lozenges, dispersible tablets, aqueous or oily suspensions, liquid solutions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the field of machinery manufacture of pharmaceutical compositions and such compositions may contain one or more than one agent selected from the group consisting of sweeteners, corrigentov, dyes and preservatives, to provide pharmaceutically elegant and acceptable to the taste of drugs.

Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Atiextevent can represent for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, dextrose, saccharose, cellulose, corn starch, potato starch, calcium phosphate or sodium phosphate; granulating and loosening agents such as corn starch, alginic acid, alginates or sodium salt starch glycolate; binding agents, for example starch, gelatin or the Arabian gum; lubricating agents, for example silica, magnesium stearate or calcium, stearic acid or talc; effervescent mixture; dyes, sweeteners, moisturizing agents, such as lecithin, Polysorbate or valium. Tablets may be uncoated or coated by known techniques to delay opening and absorption in the gastrointestinal tract and, thus, they provide a prolonged action over a longer period. For example, you can use a substance that slows time, such as glycerylmonostearate or glycerylmonostearate. Such preparations can be prepared in a known manner, for example by mixing, granulation, tabletting, sugar coating or film coating.

Preparations for oral administration may be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid dilute the eat, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is present as such or in a mixture with water or an oil medium, for example peanut oil, liquid petroleum jelly or olive oil.

Aqueous suspensions contain the active substance in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspendresume agents, such as sodium carboxymethyl cellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum or Arabian gum; dispersing or moisturizing agents may be a natural phosphatides, for example lecithin, or condensation products of accelerated with fatty acids, for example polyoxyethylene, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters formed from fatty acids and exit, such as polyoxyethylenesorbitan monooleate, or condensation products of ethylene oxide with partial esters formed from fatty acids, and anhydrides of exit, such as polyoxyethylenesorbitan monooleate.

These aqueous suspensions may also contain one and more than one preservative, for example, ethyl or n-propyl-para-hydroxybenzoate, one or more than one coloring agent, such as sucrose or saccharin.

The drug is in the form of an oil suspension can be prepared by suspension of the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid petrolatum. Oily suspensions may contain a thickening agent, for example beeswax, hard vaseline or cetyl alcohol.

Sweeteners such as listed below, and corrigentov can be added to provide oral drug with acceptable taste. These compositions may be preserved by adding an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for the manufacture of aqueous slurry by adding water, contain the active ingredient mixed with dispersing or wetting agent, suspenders agent and one or more than one preservative. Examples of suitable dispersing or wetting agents and suspendida agents mentioned above. Additional excipients, for example sweetening, corrigentov and dyes, may also be present.

The pharmaceutical compositions according to the invention can also be in the form of emulsions of oil-in-water. The oil phase can pre is to provide a vegetable oil, for example olive oil or peanut oil, or mineral oil, such as liquid petrolatum, or a mixture thereof. Suitable emulsifying agents may be a natural resin, such as the Arabian gum or tragacanth gum, natural phosphatides, for example soy lecithin, and esters or partial esters formed from fatty acids, and anhydrides of exit, for example sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, for example of polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening and corrective agents. Preparations in the form of syrups and elixirs can be prepared with a sweetener, such as glycerol, sorbitol or sucrose. In particular, the syrup for patients-diabetics can contain as carriers only such products, for example sorbitol, which does not undergo metabolism to glucose or which undergo metabolism to glucose only in very small quantities.

These preparations may also contain gemulator, preservative and corrective and coloring agents.

B) Parenterally, either subcutaneously, or intravenously, or intramuscularly, or epigastric or by using infusion techniques, in the form of a sterile injectable aqueous or oil suspensions. The preparation of this suspension can be prepared in accordance the prior art, using those suitable emulsifying or moisturizing agents and suspendresume agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol.

Among the acceptable vehicles and solvents that can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are common used as a solvent or suspension medium. For this purpose you can use any mild non-volatile oils, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid find use in the manufacture of injectable drugs.

By inhalation, in the form of aerosols or solutions for nebulizers.

G) Rectally, in the form of suppositories, made by mixing the drug with a suitable non irritant excipient, which is solid at ordinary temperature but liquid at rectal temperature, and must therefore melt in the rectum to release the drug. Such substances are cocoa butter and polyethylene glycols.

D) Local path, in the form of creams, ointments, jellies, GLA is different drops, solutions or suspensions.

E) Vaginally in the form of preparations in the form of pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers which are known in the art as suitable.

You can prepare the preparations of the compounds according to the invention is extended release. Suitable examples of sustained release formulations release include a semi-permeable matrices of solid hydrophobic polymers containing a compound of formula I, where these matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of matrices prolonged release include polyesters, hydrogels (for example, poly(2-hydroxyethylmethacrylate) or polyvinyl alcohol)), polylactide (U.S. patent No. 3773919), copolymers of L-glutamic acid and gamma ethyl-L-glutamate, indestructible is a copolymer of ethylene and vinyl acetate, destructible copolymers of lactic acid and glycolic acid, such as the LUPRON DEPOT™ (injectable microspheres composed of a copolymer of lactic acid and glycolic acid and leuprolide acetate), and poly-D-(-)-3-hydroxybutiric acid.

The connection according to the invention can be applied separately or in combination with other therapeutic agents for the treatment of a disease or disorder described herein, such as hiperpool perative disorder (for example, cancer). In some embodiments of the compound according to the invention is combined in a pharmaceutical combination preparation or dosage regimen as combination therapy with a second compound which has antihypercholesterolemic properties or that is useful for the treatment of hyperproliferative disorders (e.g., cancer). The second compound of the pharmaceutical combination of the drug or dosage preferably have complementary activities in relation to the connection according to the invention, so that they do not have harmful influence on each other. Such compounds are suitable are present in combination in amounts that are effective for the intended purpose. In one embodiment of the composition according to this invention contains the compound according to the invention in combination with a chemotherapeutic agent such as described here.

Combination therapy can be entered as simultaneous or sequential mode. With the introduction of consistently combination can be entered for two or more than two. The combined introduction includes a joint introduction to the use of specific drugs or one pharmaceutical drug and consistent introduction in any order, preferably where there is a time period while both (or all) of the active ingredient is in simultaneously exert their biological activity.

Suitable dosages for any of the above simultaneously introduced agents are those that are currently used, and they may be reduced due to the combined action (synergy) of the newly identified agent and other chemotherapeutic agents or therapies.

Further, the invention described in the Examples below:

Reference example 1: 2,4-Dichlorethene[3,2-d]pyrimidine (VIII)

A mixture of methyl 3-amino-2-thiophenecarboxylate (13,48 g, 85,85 mmol) and urea (29,75 g, 5 EQ.) was heated at 190°C for 2 hours. Then the hot reaction mixture was poured into sodium hydroxide solution and any insoluble matter was removed by filtration. The mixture is then acidified (HCl, 2 h) to give 1H-thieno[3,2-d]pyrimidine-2,4-dione (IX) in the form of a white precipitate, which was collected by filtration and dried in air (9,49 g, 66%)

1H NMR (400 MHz, D6-DMSO) 6.90 (1H, d, J=5.2 Hz), 8.10 (1H, d, J=5.2 Hz), 11.60-11.10 (2H, br s).

A mixture of 1H-thieno[3,2-d]pyrimidine-2,4-dione (9,49 g, 56,49 mmol) and phosphorus oxychloride (150 ml) was heated under reflux for 6 hours. Then the reaction mixture was cooled and poured into ice/water with vigorous stirring to obtain a precipitate. Then the mixture was filtered to obtain 2,4-dichlorethene[3,2-a]pyrimidine (VIII) as a white solid (8,68 g, 75%).

1H I Is R (400 MHz, CDCl3) 7.56 (1H, d, J=5.5 Hz), 8.13 (1H, d, J=5.5 Hz).

Reference example 2: 2-Chloro-4-morpholine-4-illiano[3,2-d]pyrimidine (VII)

A mixture of 2,4-dichlorethene[3,2-a]pyrimidine (VIII) (8,68 g, 42,34 mmol), research (8,11 ml, 2.2 EQ) and Meon (150 ml) was stirred at room temperature for 1 h Then the reaction mixture was filtered, washed with water and Meon with getting the connection specified in the header, in the form of a white solid (11,04 g, 100%).

1H NMR (400 MHz, d6-DMSO) 3.74 (4H, t, J=4.9 Hz), 3.90 (4H, t, J=4.9 Hz), 7.40 (1H, d, J=5.6 Hz), 8.30 (1H, d, J=5.6 Hz).

Reference example 3: 2-Chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-carbaldehyde (II)

To a suspension of 2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine (VII) (1.75 g, 6,85 mmol) in dry THF (40 ml) at -78°C was added a 2.5 M solution of nBuLi in hexane (3.3 ml, 1.2 EQ.). After stirring for 1 h was added dry DMF (796 μl, 1.5 EQ.). The reaction mixture was stirred for 1 h at -78°C and then slowly warmed up to room temperature. After another 2 hours at room temperature the reaction mixture was poured on ice/water to obtain a yellow precipitate. This precipitate was collected by filtration and dried in air to obtain the connection specified in the header (1.50 g, 77%).

1H NMR (400 MHz, d6-DMSO) 3.76 (4H, t, J=4.9 Hz), 3.95 (4H, t, J=4.9 Hz), 8.28 (1H, s), 10.20 (1H, s).

Reference the use of the 4: 2-Chloro-6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine (VI)

N-BOC-piperazine and methanesulfonanilide together were subjected to interaction in dichloromethane and triethylamine to obtain 4-methanesulfonylaminoethyl-1-carboxylic acid tert-butyl ester. In the cleavage of the protective group BOC, using HCl (2 M in dichloromethane, received 1-methanesulfonamide, HCl salt.

A mixture of 2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-carbaldehyde (II) (1,00 g), 1-methysulfonylmethane (750 mg) and triethylorthoformate (3,80 ml) was stirred in 1,2-dichloroethane (30 ml) for 6 h at room temperature and To this mixture was added triacetoxyborohydride sodium (900 mg)and the reaction mixture was stirred for 24 hours at room temperature. The mixture is then extinguished the brine was extracted with dichloromethane, dried (MgSO4), and the solvent was removed in vacuum. The residue is triturated with hot ethyl acetate to obtain the connection specified in the header (VI), in the form of a white solid (1.01 g).

Reference example 5: 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazol (IVa) - path 1

To a solution of 3-bromo-2-methylaniline (5.0 g, 26.9 mmol) in chloroform (50 ml) was added potassium acetate (of 1.05 EQ., of 28.2 mmol, 2,77 g). Was added acetic anhydride (2.0 EQ, of 53.7 mmol, 5,07 ml) while cooling in a bath of ice-water. Then the mixture was stirred at anatoy temperature for 10 minutes, then formed a white gelatinous solid. Then was added 18-crown-6 (0.2 EQ., 5.37 mmol, 1.42 g) followed by the addition of isoamylamine (2.2 EQ., the 59.1 mmol, 7,94 ml) and the mixture was heated under reflux for 18 hours the Reaction mixture was allowed to cool and was distributed between chloroform (3×100 ml) and saturated aqueous sodium bicarbonate (100 ml). The combined organic extracts were washed with brine (100 ml), separated and dried (gSO4).

The crude product was evaporated onto silica gel and purified by chromatography, elwira 20%→40% tO-gasoline, obtaining 1-(4-brominator-1-yl)-ethanone (A) (3,14 g, 49%) as an orange solid and 4-bromo-1H-indazole (B) (2,13 g, 40%) as a pale orange solid.

And:1H NMR (400 MHz, CDCl3) 2.80 (3H, s), 7.41 (1H, t, J=7.8 Hz), 7.50 (1H, d, J=7.8 Hz), 8.15 (1H, s), 8.40 (1H, d, J=7.8 Hz).

In:1H NMR (400 MHz, CDCl3) 7.25 (1H, t, J=7.3 Hz), 7.33 (1H, d, J=7.3 Hz), 7.46 (1H, d, J=7.3 Hz), 8.11 (1H, s), 10.20 (1H, br s),

To a solution of 1-(4-brominator-1-yl)-ethanone (3,09 g, 12.9 mmol) in Meon (50 ml) was added 6 N. aqueous HCl (30 ml)and the mixture was stirred at room temperature for 7 hours Meon evaporated, and the mixture was distributed between EtOAc (2×50 ml) and water (50 ml). The combined organic layers were washed with brine (50 ml), separated and dried (MgSO4). The solvent was removed by evaporation under reduced pressure to obtain 4-the rum-1H-indazole (2,36 g, 93%).

To a solution of 4-bromo-1H-indazole (500 mg, 2.54 mmol) and bis(pinacolato)Debora (1.5 EQ, 3,81 mmol) in DMSO (20 ml) was added potassium acetate (3.0 EQ., to 7.61 mmol, 747 mg; dried in the spray drying) and PdCl2(dppf)2(3 mol%, 0,076 mmol, 62 mg). The mixture was degirolami with argon and heated at 80°C for 40 hours the Reaction mixture was allowed to cool and was distributed between water (50 ml) and ether (3×50 ml). The combined organic layers were washed with brine (50 ml), separated and dried (MgSO4). The crude substance was purified by chromatography, elwira 30%→40% tO-gasoline, obtaining an inseparable mixture of 3:1 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (369 mg, 60%) and indazole (60 mg, 20%); the connection specified in the header (IVa), provided in the form of a yellow resin, which solidify upon standing with the formation of a whitish solid.

1H NMR (400 MHz, d6-DMSO) 1.41 (N, s), 7.40 (1H, dd, J=8.4 Hz, 6 9 Hz), 7.59 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=6.9 Hz), 10.00 (1H, br s), 8.45 (1H, s), and indazol: 7.40 (1H, t), 7.18 (1H, t, J=7.9 Hz), 7.50 (1H, d, J=9.1 Hz), 7.77 (1H, d, J=7.9 Hz), 8 09 (1H, s).

Impurities at 1.25.

Reference example 6: 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazol (IVa) - path 2

To a solution of 2-methyl-3-nitroaniline (2,27 g, 14,91 mmol) in acetic acid (60 ml) was added a solution of sodium nitrite (1.13 g, 1.1 EQ) in water (5 ml). After 2 h, the dark red solution was poured on ice/water and p is obtained resulting precipitate was collected by filtration to obtain 4-nitro-1H-indazole (67) (1.98 g, 81%).

A mixture of 4-nitro-1H-indazole (760 mg, and 4.68 mmol), palladium on coal (10%, catalytic amount) and ethanol (30 ml) was stirred under a balloon of hydrogen for 4 h Then the reaction mixture was filtered through cellit and the solvent was removed in vacuum to obtain 1H-indazol-4-ylamine (631 mg, 100%).

An aqueous solution of sodium nitrite (337 mg, 4,89 mmol) in water (2 ml) was added dropwise to a suspension of 1H-indazol-4-ylamine (631 mg, 4,74 mmol) in 6 M hydrochloric acid (7.2 ml) at a temperature below 0°C. After stirring for 30 minutes to the reaction mixture was added tetrafluoroboric sodium (724 mg). This resulted in a very viscous solution, which was filtered and briefly washed with water to obtain 1 N-indazol-4-page, salt tetrafluoroborate (69) (218 mg, 20%) as a dark red solid.

Dry Meon (4 ml) was purged with argon for 5 minutes. To it was added 1H-indazol-4-diezani, salt tetrafluoroborate (218 mg, of 0.94 mmol), bis-pencollector (239 mg, 1.0 EQ) and [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride (20 mg). The reaction mixture was stirred for 5 h and then filtered through cellit. The residue was purified using flash chromatography to give the desired compound indicated in heading (IVa), (117 mg).

Reference example 7: 2-(1H-Indazol-4-yl)-4-morpholine-4-illiano[3,2-d]pyrimidine-6-carbaldehyde (III)

A mixture of 2-chloro-4-morpholine-4-illiano[3,2-d]pyrimidine-6-carbaldehyde (II) (100 mg, 0.35 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (70) (95 mg, 0,39 mmol) and sodium carbonate (112 mg) suspended in toluene (2.5 ml), ethanol (1.5 ml) and water (0.7 ml). To this mixture was added bis(triphenylphosphine)palladium (II) chloride (13.5 mg) and the reaction vessel was purged with argon flow. The reaction mixture was kept in a microwave oven at 120°C for 1 h, and then distributed between DHM and water, the organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuum. The resulting residue was purified using flash chromatography, to obtain the compound indicated in heading (III), (97 mg).

Example 1: 2-(1H-Indazol-4-yl)-6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine (I)

A mixture of 2-chloro-6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[3,2-a]pyrimidine (2.00 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (of 2.26 g), toluene (24 ml), ethanol (12 ml), water (6 ml), sodium carbonate (1,72 g) and dl2(h3)2(325 mg) was heated to 130°C. in microwave oven for 90 minutes.

The reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent was removed in vacuum. The residue was purified using flash chromatography (ethyl acetate, ZAT is 5% ethyl acetate/methanol), and then rubbing with ether, to give the desired compound indicated in heading (1.4 g).

Data MS: (ESI+): MH+ 514

These NMR: (CDCl3): 2.67-2.71 (4H, m), 2.81 (3H, s). 3 29-3 .33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 7.41 (1H, s), 7.51 (1H, t, J=7.2), 7.60 (1H, d, J=8.3), 8.28 (1H, d, J=7.5), 9.02 (1H, s), 10.10 (1H, br).

Example 2: 2-(1H-Indazol-4-yl)-6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine bismesylate

To 2-(1H-indazol-4-yl)-6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine (2.00 g, to 3.89 mmol) in dichloromethane (50 ml) and methanol (20 ml) was added methanesulfonyl acid (2 EQ, 505 μl). The reaction mixture was stirred for 3 hours at room temperature, during which time a white precipitate was gradually destroyed. Volatiles were removed in vacuo, the residue triturated with diethyl ether, the solvent decantation and the solid was dried in vacuum to obtain compound indicated in heading (2.70 g).

NMR (400 MHz, DMSO). Includes the following signals

2.32 (s, 6H), 3 00 (s, 3H), 3.84-3.86 (4H, m), 4 09-4 .11 (4H, m), 8.8 (1H, s).

Example 3 Biological testing

The connection according to the invention, obtained as described above were subjected to the following series of biological tests:

(i) Biochemical screening FIC

Inhibition FIC compound was determined in a radiometric analysis using purified recombinant the th enzyme and ATP at a concentration of 1 μm. The compound was serially diluted in 100% DMSO. Kinase reactions were incubated for 1 h at room temperature and the reaction stopped by the addition of the FSB. Then the values of the IC50was determined using a corresponding sigmoidal curve dose-response (variable slope). The connection had IC50against FIC less than 0.1 ám.

(ii) Inhibition of cell proliferation

Cells were sown at the optimum density in 96-well plate and incubated for 4 days in the presence of test compounds. Then in the analytical environment was added Alamar Blue™ cells were incubated for 6 h, and then were read at excitation 544 nm, emission 590 nm. The values of EC50was calculated using a corresponding sigmoidal curve dose-response. Connection mattered EC5050 μm or less in the number of used cell lines.

(iii) the Permeability of SASO-2

Cells SASO-2 were sown on tablets Millipore Multiscreen at a density of 1×105cells/cm2and were cultured for 20 days. Then conducted an assessment of the permeability of the compounds. The compound was applied to the apical surface (a) monolayers of cells and measured the penetration of compounds in basolateral (In) compartment. This measurement was performed in the reverse direction (B-A) for studies of active transport. To calculate the value of coefficientsaimust, Parrfor each connection, measure the speed of penetration of compounds through the membrane. The compounds were grouped into low (Rarr</=1,0×106cm/s) or high (Parr>/=1,0×106cm/s) capacity suction on the basis of comparison with a control connection established by absorption in humans.

To assess the ability of compounds to undergo active outflow was determined attitude basolateral (b) and apical (A) transport in comparison with A-Century Values And/a-b>/=1,0 pointed to the emergence of an active outflow from the cells. The connection was set to Parr>/=1,0×106cm/S.

(iv) Clearance of hepatocyte

Used suspension cryopreserved human hepatocytes. Incubation was carried out at concentrations of compounds 1 mm or 3 mm at a density of cells in 0.5×106viable cells/ml Final concentration of DMSO in the incubation amounted to 0.25%. A control incubation was also performed in the absence of cells to identify any not enzymatic destruction. The samples in the two repeats (50 ál) were taken from the incubation mixture after 0, 5,10, 20, 40 and 60 minutes (control sample only after 60 minutes) and added to the Meon-containing internal standard (100 μl) to stop the reaction. As control compounds used tolbutamide, 7-hydroxycoumarin and testost is Ron. The samples were centrifuged and the supernatant for each time point were combined for analysis with LC-MS/MS. Based on the chart of the relationship of the peak area In the peak area of starting compound/peak area of internal standard) against time, own clearance (CLint) was calculated as follows: CLint(ál/min/million cells) = V×k, where k represents the rate constant of elimination, based on the gradient In concentration, plotted on a graph against time; V is a designation of the amount derived on the basis of the volume of incubation and expressed as µl of 106cells-1.

Compounds classified into low (CL</=4,6 µl/min/106cells), medium (CL>/=4,6; </=25,2 µl/min/106cells) and high (>/=25,2 µl/min/106cells) clearance. The connection according to the invention was identified as having a low ground clearance of hepatocytes.

(v) Inhibition of cytochrome P450

Compounds according to the invention were subjected to screening against five targets CYP450 (1A2, 2S9, 2C19, 2D6, 3A4) at 10 concentrations in two repetitions at the highest used concentration of 100 μm. Standard inhibitors (furafylline, sulfaphenazole, tranilcipromin, quinidine, ketoconazole) were used as controls. Tablets read using BMG LabTechnologies PolarStar in fluorescence mode. Link is showed weak activity (IC 50>/=5 μm) against all isoforms of CYP450.

(vi) Induction of cytochrome P450

Freshly isolated human hepatocytes from a single donor were cultured for 48 h, after which was added a test compound at three concentrations and were incubated for 72 h Sample substrates for CYP3A4 and CYP1A2 was added for 30 minutes and for 1 hour before the end of incubation. After 72 h the cells and medium were removed and the extent of metabolism of each sample substrate was quantified using LC-MS/MS. The experiment was controlled by the use of inductors individual P450, inkubiruemykh at one concentration in three repetitions. The connection according to the invention showed negligible effects on the induction of cytochrome P450 enzymes.

(vii) the Binding of plasma proteins

Solutions of test compounds (5 μm, final concentration of DMSO of 0.5%) were prepared in buffer and 10% plasma (V/V in buffer). 96-well plates to dialysis NT was collected in such a way that each hole was divided into two semi-permeable cellulose membrane. Buffer solution was added to one side of the membrane, and the solution of the plasma on the other side; then incubation was performed at 37°C for 2 h in three repetitions. Then cells were devastated and solutions for each batch, the compounds were combined into two groups (available from plasma and contains the plasma), and then analyzed using LC-MSMS, is using two series of calibration standards for free from plasma (6 points) and containing plasma solutions (7 points). The value of the unbound fraction (Fu) for each compound was calculated: compounds with high binding protein (>/=90% binding) was Fu</=0,1. The connection according to the invention mattered Fu>/=0,1.

(viii) Blocking hERG channel

The connection according to the invention was evaluated on its ability to modulating the outflow of the rubidium cell SOME 294, stably expressing hERG potassium channels, using proven methodology outflow. Cells were prepared in a medium containing RbCl, and were sown in 96-well plates and grown overnight prior to the formation of monolayers of the Experiment for the outflow began by sucking the environment and wash each well 3×100 μl buffer pre-incubation (containing a low concentration of [+]) at room temperature. After the last extraction in each well was added 50 μl of the working of the concentrated solution (2) compounds, and incubated at room temperature for 10 minutes. Then to each well was added 50 μl of stimulating buffer (containing a high concentration of [K+]) to obtain the final concentrations of the tested compounds. Then hole the plates were incubated at room temperature for 10 minutes. Then 80 μl of supernatant from each well was transferred into equivalent wells of 96-hole tablet and analyzed using atomic emission the Oh spectroscopy. Screening compound was carried out in the form of curves IC50for 10 points in two repetitions, n=2, the highest concentration of 100 μm.

Example 4 a Composition in tablet form

Tablets, each of which has a mass of 0.15 g and contains 25 mg of the compounds according to the invention is prepared as follows:

The composition of 10,000 tablets

The active compound (250 g)

Lactose (800 g)

Corn starch (415 g)

Talc powder (30 g)

Magnesium stearate (5 g)

The active compound, lactose and half the corn starch are mixed. The mixture is then forced through a sieve with a pore size of 0.5 mm Corn starch (10 g) is suspended in warm water (90 ml). The resulting paste is used for granulation of powder. The granulate is dried and broken into small fragments on a sieve with a pore size of 1.4 mm, Add the remaining quantity of starch, talc and magnesium stearate, gently mixed and treated with reception of tablets.

Example 5: Injectable

Drug And

Active connection200 mg
A solution of hydrochloric acid 0.1 M or
The sodium hydroxide solution 0.1 M q.s. to pH4,0-7,0
Sterile is an ode q.s. to10 ml

The connection according to the invention is dissolved in most of the water (35°-40°C) and bring the pH to values between 4.0 and 7.0 with hydrochloric acid or sodium hydroxide, as appropriate. Then the batch volume is adjusted with water and filtered through a sterile micropore filter into a sterile vial 10 ml amber glass (type 1) and sealed with sterile closures and additional sealing means.

Drug B

Active connection125 mg
Sterile pyrogen-free phosphate
buffer pH 7 q.s. to25 ml
Active connection200 mg
Benzyl alcohol : 0.10 g
Glucotrol 751.45 g
Water for injection q.s to3,00 ml

The active compound is dissolved in glucotrole. Then add and dissolve benzyl alcohol and water is added to 3 ml. of the mixture is Then filtered through a sterile Millipore filter and sealed in sterile glass ampoules of 3 ml (type 1).

Example 6: Preparation of a syrup

Active connection250 mg
The solution of sorbitol1.50 g
Glycerin2,00 g
Sodium benzoate0.005 g
Corrigentof 0.0125 ml
Distilled water q.s. to5,00 ml

The connection according to the invention is dissolved in a mixture of glycerin and most of distilled water. Then to this solution was added an aqueous solution of sodium benzoate, and then add a solution of sorbitol and finally, corrigent. The volume was adjusted with distilled water and mix well.

1. The connection that represents thienopyrimidine formula

or its pharmaceutically acceptable salt.

2. The compound according to claim 1 where the pharmaceutically acceptable salt is a salt methanesulfonic acid.

3. The compound according to claim 1 where the pharmaceutically acceptable salt is a bis-Sol.

4. The compound according to claim 1 or 2, which is a bis-Sol with methanesulfonic acid.

5. The compound according to claim 1,which is 2-(1H-indazol-4-yl)-6-(4-methanesulfonylaminoethyl-1-ylmethyl)-4-morpholine-4-illiano[3,2-d]pyrimidine bismesylate.

6. A method of obtaining a compound as defined in claim 1, in which process a compound of formula (VI)

Bronevoy acid or its ester of the formula (IV)

in which two groups OR15form together with the boron atom to which they are attached, ester pinacolateboryl group, in the presence of Pd catalyst.

7. A method of obtaining a pharmaceutically acceptable salt as defined in claim 1, in which process thienopyrimidine formula (I)

suitable acid in a suitable solvent.

8. Pharmaceutical composition having activity of an inhibitor of phosphatidylinositol-3-kinase, which contains a pharmaceutically acceptable carrier or diluent and, as active ingredient the compound according to claim 1.

9. The composition according to item 8, which is prepared for oral administration.

10. The use of compounds according to claim 1 or its pharmaceutically acceptable salts in the manufacture of a medicine for inhibiting phosphatidylinositol 3-kinase.

11. A method of manufacturing the pharmaceutical composition of claim 8, in which the unite Union, as defined in claim 1 with a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae and including their stereoisomers, as well as pharmaceutically acceptable salt, where X denotes O or S; R1 is selected from H, F, CI, Br, I, CN, -CR14R15-NR16R17, -CR14R15-NHR10, -(CR14R15)NR10R11, -(CR14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)mOR10, -(CR14R15)nS(O)2R10, -C(OR10)R11R14, -C(R14)=CR18R19, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NHR12, -NR12C(=Y)R10, -S(O)2R10, -S(O)2NR10R11, C2-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C4 carbocyclyl, piperidinyl, thiopyranyl, phenyl or C5-C6 heteroaryl; R2 is selected from H, C2-C12 alkyl and thiazolyl; R3 denotes a condensed bicyclic heteroaryl selected from indazole, indole, benzoimidazole, pyrrolopyridine, imidazopyridine and quinoline; R10, R11 and R12 independently denote H, C2-C12 alkyl, C3 carbocyclyl, heterocyclyl selected from pyrrolidine, morpholine and piperazine, phenyl or heteroaryl selected from pyrazole, pyridine, benzothiophene; or R10 and R11 together with a nitrogen atom with which they are bonded possibly form a saturated C3-C6 heterocyclic ring, possibly containing one additional ring atom selected from N or O, where said heterocyclic ring is possibly substituted with one or more groups independently selected from oxo, (CH2)mOR10, NR10R11, SO2R10, C(=O)R10, NR12S(O)R11, C(=Y)NR10R11, C1-C12 alkyl and heterocyclyl selected from pyrrolidine; R14 and R15 are independently selected from H or C1-C12 alkyl; R16 and R17 independently denote H or phenyl; R18 and R19 together with a carbon atom with which they are bonded form a C3-C20 heterocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, phenyl, heteroaryl, piperidinyl and condensed bicyclic heteroaryl possibly substituted with one or more groups independently selected from F, CI, Br, I, CF3, -C(=Y)R10, -C(=Y)OR10, oxo, R10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)NR10R11, -NR12SO2R10, OR10, SR10, -S(O)2R10, -S(O)2NR10R11, possibly substituted with carbocyclyl, selected from cyclopropyl, possibly substituted heterocyclyl selected from piperazine, possibly substituted with alkyl and alkylsulphonyl, pyrrolidine, morpholine, piperdine, possibly substituted CH3, phenyl and possibly substituted heteroaryl selected from imidazole and triazole; Y denotes O; m equals 0, 1 or 2; n equals 1 and t equals 2. The invention also relates to a pharmaceutical composition which modulates lipid kinase activity, based on said compounds.

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used to treat lipid kinase-mediated diseases, for example, cancer.

48 cl, 2 tbl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for producing prasugrel hydrochloride which involves the following stages: (i) chlorination of a compound described by formula (III) by addition of an chlorinating agent, optionally drop-by-drop, in a solvent; (ii) reaction of the prepared compound of formula (IV) and a compound described by general formula (V) where R means a protective group for hydroxyl, or its salt in a solvent in the presence of a base; (iii) acetylation of the prepared compound described by general formula (II) by reaction with an acetylation agent in a solvent in the presence of a base and an acetylation catalyst; and (iv) addition of hydrochloric acid, optionally drop-by-drop, to the prepared compound described by formula (I) in a solvent to produce prasugrel hydrochloride described by formula (1a), and differs by the fact that at the stage (i) temperature during addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C, and reaction temperature after addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C. The invention also concerns a product containing prasugrel hydrochloride and CATP in an amount no more than 0.3 %, to the pharmaceutical composition suitable for prevention or treatment of thrombosis or embolism on the basis of the specified product.

EFFECT: production of low-CATP prasugrel hydrochloride.

31 cl, 3 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, more specifically to a method of olanzapine purification which involves mixing olanzapine with an organic acid in an organic solvent or a mixture of organic solvents to prepare acid-additive olanzapine salt, precipitation and isolation of acid-additive olanzapine salt and transforming acid-additive olanzapine salt in olanzapine; the organic acid is carboxylic acid which is selected from the group including oxalic, fumaric and benzoic acid.

EFFECT: invention refers to methods for producing pure olanzapine, intermediate products and acid-additive olanzapine salts which in turn can find application for producing pure olanzapine used for preparing a drug for treating mental disorders and conditions.

38 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where X denotes S; R1 and R2 taken together with atoms to which they are bonded form a 5-member carbocycle, substituted with up to two substitutes selected from alkyl and CF3; R3 is selected from a group consisting of a hydrogen atom and C1-8-alkyl; R3a denotes a hydrogen atom; R4 denotes a hydrogen atom; R4a denotes a hydrogen atom; R5 denotes a hydrogen atom; R5a denotes a hydrogen atom; R6 denotes a hydrogen atom; R6a denotes a hydrogen atom; R7 denotes a hydrogen atom; or pharmaceutically acceptable salts thereof. The invention also relates to compounds of the given formula, compounds selected from the group, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which modulate serotonin receptor activity.

6 cl, 19 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

Organic compounds // 2430921

FIELD: chemistry.

SUBSTANCE: invention relates to an azathiabenzo-azulene derivative of formula I

,

where R3 denotes C1-C6alkyl, R4 denotes OH, R5 denotes halogen and R6 denotes H or halogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having anti-inflammatory or analgesic action.

EFFECT: obtained compounds and pharmaceutical composition can be used to treat arthritis and arthritis-related conditions, and for relieving inflammation and pain associated with acute inflammation of body parts, primarily joints, as a result of injury or as a result of arthritic conditions or other diseased conditions.

17 cl, 8 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing prasugrel hydrochloride of the formula:

,

with low content of "ОХТР", involving preparation of free prasugrel containing "ОХТР" from 2-silyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, dissolving the obtained free prasugrel in an inert solvent and optionally adding hydrochloric acid in drops to the solution for reaction.

EFFECT: novel method of producing prasugrel with low content of impurities, specifically "ОХТР" by-product.

2 cl, 6 dwg, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of the formula I

, where: m equals 0, 1 or 2, where if m=0, disappears such that an open ring or single bond forms, n equals 0, 1 or 2, wherein when n=0, disappears such that an open ring or single bond forms; m' and n' are independently equal to 0, 1 or 2; X denotes a carbon atom; Y denotes a carbon or sulphur atom; provided that m and n are not equal to 0 at the same time; denotes a single or double bond, if needed; --- absence of a bond or a single bond, if needed; R1 is selected from a group comprising CN, Hal, OAIk, OH, NRCN, C(CN)=C(OH)(OAlk), SR, NRR', (Alk)p-C(O)NRR', piperidine, wherein Alk is optionally substituted with Hal or OAlk, where p=0 or 1; R3, R4, R5 and R6 are identical or different and are independently selected from a group comprising H, OAIk, Alk, Hal, OH; R2 is selected from a group comprising H and O, and p'=0 or 1; R7 is selected from a group comprising H, O, OH, N-OH, N-aryl, N-OAlk, N-O-aryl, N-O-Alk-aryl, N-NR-CONRR', N-O-CO-Alk, or 2 R7, bonded with the same Y, together form lioksalan; wherein said Alk is optionally substituted with OAlk, -CO-(NR-Alk-CO)p'-OAlk, and p'=0 or 1; R and R', which are identical or different, are independently selected from a group comprising H, and Alk; or pharmaceutically acceptable salt or optical isomer or diastereomer thereof, except those compounds for which: R3, R4, R5, R6=H, R1=CN, denotes a single bond, and denotes -C(=N-(2,4,6-trimethylphenyl))-, -C(=N-(2,6- dimethylphenyl))-, -C(=N-(2,6-diethylphenyl))-, -C(=N(2-methylphenyl))-, -C(=N(2-ethylphenyl))-, -C(=N-(2-trifluoromethylphenyl))-, -C(=N-(2-isopropylphenyl))-, -C(=N-phenyl)-, -C(=N-(naphthyl)- or -C(=O)-, -CH2-, or R3, R5, R6=H, R4=OMe, R1=CN, denotes a single bond, and denotes -C(=O)-, or R3, R4, R5, R6=H, R1=NH2, denotes a single bond, and denotes -CH2- or -CH2-CH2-; or R3, R4, R5, R6=H, R,=NH2, denotes -CH2- or -CH2-CH2-, and denotes a single bond. The invention also relates to a cysteine protease based pharmaceutical composition based on compounds of formula I, use of the compound of formula I to prepare a drug for inhibiting cysteine protease, for treating and preventing cancer, as well as inflammatory diseases and others.

EFFECT: novel compounds which can be used in medicine are obtained and described.

38 cl, 43 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting PI3 kinase inhibitor activity. In the formula (I), A represents a thiophen ring; n=1; R1 represents , where m=1; R30 represents H; R4 And R5 together with N atom whereto attached form a 5- or 6-members N-containing heterocyclic group which includes 0 or 1 additional heteroatom selected from N and O which is unsubstituted or substituted by one or more substitutes selected from C1-6alkyl, C1-6alkoxy, -N(R"')-alk-OR, -alk-OR, -O-alk-OR, -alk-C(O)NR2, -C(O)NR2, -alk-Het, -N(R)-Het, -O-Het, -N(R)-C(O)- alk-OR, -NR-S(O)2R, -N(R)-alk-S(O)2R, -N(R)-alk-OR, -alk-NR'R", -N(R"')-S(O)2R, S(O)2R"', -S(O)2-alk-ORf 5- or 6-members N-containing heterocyclic group, 5- or 6-members N-containing heteroaryl group which includes 0 or 1 additional heteroatom selected from N, O or S, oxo(=O), -SO2NR2, -SO2-alk-NR2 where alk means a C1-6alkylene chain; Het means a 5- or 6-members N-containing heteroaryl group or furan optionally substituted by C1-6alkyl; R means H or C1-6alkyl, or when 2 groups R are bound with N, they together with N atom form a saturated 5- or 6-members N-containing heterocyclic group; each R' and R" means independently H, C1-6alkyl or C1-6alkoxy; R'" represents C1-6alkyl, a 5- or 6-merous saturated N-containing heterocyclic group, or a 5- or 6-merous N-containing heteroaryl group; R2 means where R6 and R7 together with N atom whereto attached form a morpholine group; R3 represents an indazole group.

EFFECT: development of the effective method of preparing the compounds of formula (I), and their application for preparing a drug, a pharmaceutical composition, and a method of inhibition.

10 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the new fused pyrimidines of formula (I) and to their pharmaceutically acceptable salts exhibiting P13 kinase inhibitor properties; in formula (I), A represents a thiophen ring; n=1; R1 represents a group of formula , where m=1; R30 represents hydrogen; R4 and R5 together with N atom whereto attached form a 5- or 6-members saturated N-containing heterocyclic group which includes 1 additional heteroatom selected from N which is unsubstituted or substituted by C1-C3alkyl which can be substituted by OH; S(O)2C1-3alkyl; C(O)N(diC1-C3alkyl); N(CH3)2; CON(CH3)-CH2CH2OCH3; N(CH3)-CH2CH2OCH3; -C(O)morpholine or morpholine; R2 is selected from where R6 and R7 together with nitrogen atom whereto attached form a morpholine group which is unsubstituted; and R3 represents an indole group which is unsubstituted.

EFFECT: production of the compounds of formula (I), a pharmaceutical composition, their application for preparing a drug and a method of inhibition.

9 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of diazepane of formula , where A, X, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, n and m have values, given in description and formula of invention, as well as their physiologically acceptable salts. Said compounds are antagonists of chemokine receptors CCR-2, CCR-5 and/or CCR-3 receptor and can be used in medicine as medications.

EFFECT: obtaining novel diazepane derivatives.

20 cl, 505 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel salt of aliskiren, aliskiren hydrosulfate in crystalline or solvated form

,

as well as to its obtaining and application as medication or active ingredient in pharmaceutical composition.

EFFECT: obtaining novel aliskiren salt.

7 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and chemical-pharmaceutical industry, in particular, to medication, applied in case of myocardial infarction and operations on heart in conditions of artificial blood circulation. Water-soluble composition for intravenous introduction, contains ingredients with the following component ratio in wt %: D-glucose 23.40-28.60; potassium chloride 0.14-0.16; potassium salt of L-asparaginic acid 0.81-0.99; semi-magnesium salt of L-asparagenic acid (magnesium L-aspartate) 0.72-0.88; human insulin genetically engineered (in IU/l) 54.00-66.00; dinitrosyl complex of iron (II) with glutathione 0.19-0.23; water for injections - remaining part, with solution pH 7.4±0.1 at 22°C.

EFFECT: application of composition ensures limitation of myocardial infraction size, recovery of metabolic condition of heart at reperfusion, reduces injury of membranes of post-ischemic cardiomyocytes with smaller haemodinamics disorders as compared with traditionally applied medications.

2 dwg, 7 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutics in cardiology and can be applied for creation of hypotensive medication from vegetable raw material for treatment of teenagers with essential arterial hypertension. Hypotensive medication for treatment of teenagers with essential arterial hypertension includes dried milled natural raw material: grass of creeping thyme, grass of motherwort shaggy, grass of marsh cudweed, grass of stachys biacalensis fisch, fruits of black chokeberry with the following component ratio, g: creeping thyme, grass 20.0; motherwort shaggy, grass 20.0 marsh cudweed, grass 20.0; stachys biacalensis fisch, grass 20.0; black chokeberry, fruits 30.0. Water infusion is taken in dose 50 ml. 2 times per day in the morning and in the evening, 30 minutes after meal, course of treatment constitutes 3 weeks.

EFFECT: claimed hypotensive medication is simple in application, does not require complex technology of preparing, therefore can be applied in stationary and polyclinic conditions and does not have side effects.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to an agent for chronic venous insufficiency. The agent for treating chronic venous insufficiency contains dihydroquercetin and lipoic acid in the ratio 1:1 (weight parts).

EFFECT: agent is effective for chronic venous insufficiency.

1 dwg, 4 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a drug for glycogen synthesis stimulation in a cardiac muscle. The drug for glycogen synthesis stimulation in the cardiac muscle which represents an alcoholic extract of a porcine and foetal adrenal cortex. A method for glycogen synthesis stimulation in the cardiac muscle by parenteral introduction of the alcoholic extract of the porcine and foetal adrenal cortex in a certain dose.

EFFECT: agent effectively stimulates glycogen in the cardiac muscle with no side effects.

2 cl, 2 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, specifically cardiology and concerns treating ischemic heart disease (IHD). For this purpose, the standard integrated drug treatment involving statin is added with administration of the biologically active additive MARISTIM 4.5 mg/day.

EFFECT: method provides higher clinical effectiveness of statins in the given group of patients due to elimination of their inhibitory effect on enzymes of a mitochondrial respiratory chain.

2 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method of treating hypertension, congestive cardiac failure, stenocardia, myocardial infarction, atherosclerosis, stroke. A method of treating involves introduction to a patient requiring such treatment of the solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in which the active ingredient makes more than 46 wt % of total weight of the oral dosage form. The oral dosage form is presented in the form of a tablet or a film-coated tablet and produced by methods other than wet granulation with excipients by means of water and/or a water solution of a binding agent.

EFFECT: realisation of the specified purpose.

12 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method of treating hypertension, congestive cardiac failure, stenocardia, myocardial infarction, atherosclerosis, stroke. A method of treating involves introduction to a patient requiring such treatment of the solid oral dosage form containing a therapeutically effective amount of aliskiren or its pharmaceutically acceptable salt in which the active ingredient makes more than 46 wt % of total weight of the oral dosage form. The oral dosage form is presented in the form of a tablet or a film-coated tablet and produced by methods other than wet granulation with excipients by means of water and/or a water solution of a binding agent.

EFFECT: realisation of the specified purpose.

12 cl, 2 ex

FIELD: medicine.

SUBSTANCE: for the purpose of hypoestrogen-induced endothelial dysfunction correction in white female Wistar rats, hypoestrogen-induced endothelial dysfunction is simulated by bilateral ovariectomy. The dysfunction correction is ensured by introduction of mixed solutions of homoeopathic dilutions of polyclonal rabbit C12, C30, C200 antibodies to human endothelial nitrogen oxide synthase for 6 weeks following the ovariectomy. The specified mixture is added to drinking bowls once a day.

EFFECT: method provides effective correction with reducing an endothelial dysfunction coefficient in females to the level observed in intact animals ensured by the effect on various developmental mechanisms of this dysfunction in hypooestrogenic conditions.

2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of medicine and deals with medication for per oral treatment of diabetes mellitus and other diseases, accompanied by disturbance of tolerance to glucose, and method of obtaining such medication. Medication contains antibodies to beta-subunit of insulin receptor in activated form, obtained by multiple successive dilution and external impact in accordance with homeopathic technology. Method of obtaining hard drug form for per oral treatment of diabetes mellitus and other diseases, accompanied by disturbance of tolerance to glucose, includes mixing efficient amount of carrier, irrigated in pseudo-liquefied layer with water-alcohol dilution of antibodies in activated form to beta-subunit of insulin receptor, prepared by combination of multiple successive dilution - reduction of antibodies concentration and external impact according to homeopathic technology, and dried at temperature not higher than 35°C, with pharmaceutically acceptable additives and further tabletting of mixture by direct dry compressing.

EFFECT: medication can be used for efficient treatment and prevention of diabetes mellitus and other diseases, accompanied by disturbance of tolerance to glucose.

5 cl, 6 ex

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