Phthalimido-derivatives as monoamine oxidase b inhibitors

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to phthalimido-derivatives of the general formula (I): wherein X means -N= or -CH=; R1 means -CO-NR5R6, -CHR7-(CH2)n-CO-NR5R6, -(CH2)n-NR5R6, -(CH2)n-COOR8, -(CH2)n-CN, -CHR7-(CH2)n-CF3, -(CH2)n-NH-COR9, -(CH2)n-NH-COOR8, -(CH2)n-piperidinyl, -(CH2)n-morpholinyl, -(CH2)n-tetrahydrofuranyl, -(CH2)n-thiophenyl or -(CH2)n-isoxazolyl wherein a heterocyclic ring can be substituted with (C1-C6)-alkyl; -(CH2)n-phenyl wherein phenyl ring can be substituted with halogen atom or halogen-(C1-C6)-alkyl; -(CH2)p-OR8, -(CH2)p-SR8, -(CH2)p-SO-R9 or -(CH2)n-CS-NR5R6; R2 means hydrogen atom (H), (C1-C6)-alkyl, -(CH2)p-OR10, -(CH2)p-SR or benzyl; R3 means H, (C1-C6)-alkyl; R4 means halogen atom, halogen-(C1-C6)-alkyl, cyano-, (C1-C6)-alkoxy- or halogen-(C1-C6)-alkoxy-group; Each R5 and R6 means independently of one another H, (C1-C6)-alkyl; R7 means H, -OH, (C1-C6)-alkoxy-group; R8 means H, (C1-C6)-alkyl; R9 means (C1-C6)-alkyl; R10 means H, (C1-C6)-alkyl; m = 1, 2 or 3; n = 0, 1 or 2; p = 1 or 2, and their pharmaceutically acceptable salts. Compounds of the formula (I) inhibit activity of monoamine oxidase B (MAO B) that allows their using as a drug.

EFFECT: valuable medicinal and biochemical properties of compounds.

14 cl, 4 sch, 1 tbl, 53 ex

 

The present invention relates to phthalimidopropyl General formula

where X represents-N= or-CH=;

R1represents a-CO-NR5R6; -CHR7-(CH2)n-CO-NR5R6;

-(CH2)n-NR5R6;

-(CH2)n-COOR8;

-(CH2)n-CN;

-CHR7-(CH2)n-CF3;

-(CH2)n-NH-COR9;

-(CH2)n-NH-COOR8;

-(CH2)n-piperidinyl, -(CH2)n-morpholinyl, -(CH2)n-tetrahydrofuranyl; -(CH2)n-thiophenyl or -(CH2)n-isoxazolyl, where the heterocyclic ring may be substituted C1-C6-alkyl;

-(CH2)n-phenyl, where the phenyl ring may be substituted with halogen or halogen-(C1-C6)-alkyl;

-(CH2)p-OR8;

-(CH2)p-SR8;

-(CH2)pSO-R9or

-(CH2)n-CS-NR5R6;

R2represents hydrogen, C1-C6-alkyl;

-(CH2)p-OR10;

-(CH2)p-SR10or benzyl;

R3represents hydrogen or C1-C6-alkyl;

R4represents halogen, halogen-(C1-C6)-alkyl, cyano, C1-C6-alkoxy or Gal is gene-(C 1-C6)-alkoxy;

R5and R6independently from each other represent hydrogen or C1-C6-alkyl;

R7represents hydrogen, hydroxy or C1-C6-alkoxy;

R8represents hydrogen or C1-C6-alkyl;

R9represents a C1-C6-alkyl;

R10represents hydrogen or C1-C6-alkyl;

m denotes 1, 2 or 3;

n denotes 0, 1 or 2 and

p denotes 1 or 2,

and their pharmaceutically acceptable salts.

It was found that compounds of General formula I are selective inhibitors of monoamine oxidase Century

The monoamine oxidase (MAO, EC 1, 4, 3, 4) is a flavin-containing enzyme responsible for oxidative diaminopropane endogenous monumentalisation, such as dopamine, serotonin, epinephrine, or norepinephrine, and trace amines, such as phenethylamine, and many aminocarbonyl. The enzyme exists in two forms, MAO-a and MAO-b, encoded by different genes (A.W.Bach and others, Proc. Natl. Acad. Sci. USA, 1988, 85, 4934-4938), they differ in their distribution in the tissue, the structure and specificity to the substrate. MAO-a has a higher affinity for serotonin, octopamine, adrenaline and noradrenaline, whereas natural substrates for MAO-b are phenylethylamine firemen. Dopamine is believed to be oxidized by both isoforms. MAO-b is widely distributed in certain organs, including the brain (A.M.Cesura and A.Pletscher, Prog. Drug. Research, 1992, 38, 171-297). The activity of MAO-b in the brain, as it turned out, increases with age. This increase was attributed to gliosis associated with aging (C.J.Fowler and others, J.Neural. Transm. 1980, 49, 1-20). Furthermore, the activity of MAO-b is significantly higher in the brain of patients with Alzheimer's disease (.Dostert and others, Biochem. Pharmacol. 1989, 38, 555-561), and found that it is expressed in astrocytes around senile plaques (Saura and others, Neuroscience 1994, 70, 755-774). In this context, as the oxidizing diaminopropane primary monoamines MAO leads to the formation of NH3, aldehydes and N2About2agents with established or potential toxicity, it is assumed that you can use selective inhibitors of MAO-b for the treatment of dementia and Parkinson's disease. Inhibition of MAO-b reduces enzymatic decontamination of dopamine and thereby prolongs the availability of neurotransmitters in dopaminergic neurons. Degeneration, age-related and disease Alzheimer's and Parkinson's may also be due to oxidative attack due to the increased activity of MAO and consistent increase in the formation of H2About2using MAO-Century Therefore, inhibitors of MAO-b can act across the reduced formation of oxygen radicals and lifting levels of monoamines in the brain.

Given the importance of MAO-b in the above-mentioned neurological diseases, there is a significant need for a strong and selective inhibitors, which would have controlled this enzymatic activity. Pharmacology of some well-known MAO inhibitors described IN, for example, D.Bentue-Ferrer and others in CNS Drugs, 1996, 6, 217-236. While the main limitation irreversible and non-selective activity of the MAO inhibitor is the need to adhere to dietary precautions because of the risk of stimulating hypertensive crisis when taken diet tiramina, as well as possible interactions with other therapeutic agents (D..Gardner etc., J. Clin. Psychiatry 1996, 57, 99-104), these adverse effects are reduced when using a reversible and selective MAO inhibitors, particularly MAO-C. Thus, there is a need to MAO inhibitors with high selectivity and without adverse side effects typical of irreversible MAO inhibitors with low selectivity for the enzyme.

The purpose of the present invention therefore is to provide compounds which have the above-described advantageous properties. It was found that the compounds of formula I of this invention and their pharmaceutically acceptable salts are highly selective inhibitors of MAO-Century Objects of this image is the shadow forth are medicines based on compound of formula I in accordance with the invention, a method of obtaining compounds of formula I and their pharmaceutically acceptable salts, and also the use of compounds of formula I for the control or prevention of diseases mediated by monoamine oxidase inhibitors, and, accordingly, the application for the production of the drugs.

Definitions used in this description of the General terms, regardless of whether or not you consider the terms separately or in combination, are the following. It should be noted that, as used in the description and in the claims, the singular number include the plural, unless the context clearly indicates otherwise.

The term "C1-C6-alkyl" ("lower alkyl")as used in this description, denotes a linear or branched saturated hydrocarbon residues with 1 to 6 carbon atoms, preferably 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.

The term "halogen" denotes fluorine, chlorine, bromine and iodine.

"Halogen-(C1-C6)-alkyl or halogen-(C1-C6)-alkoxy" denotes a lower alkyl residue or lower alkoxylates, respectively, as defined here, substituted in any position by one or n is the number of atoms of halogen, as defined here. Examples halogenating residues include, but are not limited to, 1,2-direcror, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-triptorelin, 2,2,2-trichlorethyl and 1,1,1-cryptochromes etc. "Halogenoalkane" includes cryptometrics.

"C1-C6-Alkoxy" means a residue-O-R, where R is a lower alkyl residue, as defined here. Examples of alkoxyalkyl include, but are not limited to, methoxy, ethoxy, isopropoxy etc.

"Pharmaceutically acceptable salts" of the compounds indicate salts which are pharmaceutically acceptable, which are generally safe, non-toxic and biologically and otherwise acceptable, and they possess the desired pharmacological activity of the first connection. These salts derived from inorganic or organic acids or bases.

Such salts include:

(1) acid additive salts derived from inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or derived from organic acids such as acetic acid, benzolsulfonat acid, benzoic acid, camphorsulfonic acid, citric acid, econsultancy acid, fumaric acid, glucoheptonate acid, gluconic acid, glutamic acid, glycoles the I acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonate acid, Mukanova acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, Dibenzoyl-L-tartaric acid, tartaric acid, p-toluensulfonate acid, trimethylhexane acid, 2,2,2-triperoxonane acid and the like; or

(2) salts obtained when the first connection is acidic proton, the substitution of a metal ion such as alkali metal ion, ion alkaline-earth metal or an aluminum ion; or a compound with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

It should be understood that all references to pharmaceutically acceptable salts include soluble additive form (solvate) or crystal forms (polymorphs) of the same acid additive salt.

Among the compounds of the present invention, certain compounds of formula I or their pharmaceutically acceptable salts are preferred.

Preferred compounds is the second of formula I are compounds in which X represents-CH=.

Especially preferred are the compounds of formula I, in which R1represents a-CO-NR5R6or-CHR7-(CH2)n-CO-NR5R6and where R5and R6independently from each other represent hydrogen or C1-C6-alkyl, R7represents hydrogen, hydroxy or C1-C6-alkoxy and n represents 0, 1 or 2.

Examples of such compounds are the following:

2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]acetamide", she

(S)-2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]propionamide,

(S)-2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-3-hydroxypropionate,

(R)-2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]propionamide,

2-[5-(3-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]propionamide,

(2-[5-(3-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl] ndimethylacetamide and

2-[5-(3-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-3-hydroxypropionate.

Also preferred are the compounds of formula I in which R1represents -(CH2)n-NR5R6, -(CH2)n-NH-COR9or -(CH2)n-piperidinyl and where R5and R6independently from each other represent hydrogen or C1-C6-alkyl, R9is the fight C 1-C6-alkyl and n denotes 0, 1 or 2.

The following compounds are examples:

N-{2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]ethyl}acetamide", she

2-(2-amino-ethyl)-5-(4-forbindelse)isoindole-1,3-dione and

5-(4-forbindelse)-2-piperidine-4-isoindol-1,3-dione.

Further preferred compounds of formula I are compounds in which R1represents -(CH2)p-OR8or-CHR7-(CH2)n-CF3and where R7represents hydrogen, hydroxy or C1-C6-alkoxy, R8represents hydrogen or C1-C6-alkyl and p denotes 1 or 2.

Examples of such compounds are the following:

5-(4-forbindelse)-2-(2-hydroxyethyl)isoindole-1,3-dione,

5-(4-forbindelse)-2-(2-methoxyethyl)isoindole-1,3-dione,

5-(3-forbindelse)-2-(2-methoxyethyl)isoindole-1,3-dione,

(S)-5-(4-forbindelse)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione,

(S)-5-(3-forbindelse)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione,

(S)-5-(2-forbindelse)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione,

(S)-2-(2-methoxy-1-methylethyl)-5-(4-triftormetilfosfinov)

the isoindole-1,3-dione,

(S)-5-(4-bromobenzylamine)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione,

(S)-5-(3,4-deferasirox)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione,

5-(3-forbindelse)-2-(2-hydroxyethyl)isoindole-1,3-dione,

5(4 forbindelse)-2-(3,3,3-Cryptor-2-hydroxypropyl)

the isoindole-1,3-dione and

5-(3,5-bis-triftormetilfosfinov)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione.

Preferred compounds of formula I are further compounds, in which R1represents -(CH2)p-SR8; -(CH2)pSO-R9or -(CH2)n-CS-NR5R6and where R5and R6independently from each other represent hydrogen or C1-C6-alkyl, R8represents hydrogen or C1-C6-alkyl, R9represents a C1-C6-alkyl and n denotes 0, 1, or 2.

Examples of such compounds are the following:

2-(2-ethylsulfanyl)-5-(4-forbindelse)isoindole-1,3-dione,

(S)-2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]thiopropionate and

2-(2-ethylsulfanyl)-5-(3-forbindelse)isoindole-1,3-dione.

Also preferred are the compounds of formula I in which R1represents -(CH2)nCN and n denotes 0, 1 or 2.

The following compounds are examples:

5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]acetonitrile and

[5-(3-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]acetonitrile.

Preferred are also the compounds of formula I in which R4represents a halogen. Especially preferred are the compounds of formula I in which R 4represents fluorine and m is 1.

Compounds of General formula I and their pharmaceutically acceptable salts can be obtained by reaction of compounds of formula

with the compound of the formula

obtaining the compounds of formula

and, if required, converting the compounds of formula I in a pharmaceutically acceptable salt.

Alternative compounds of General formula I and their pharmaceutically acceptable salts can be obtained by reaction of compounds of formula

with the compound of the formula

obtaining the compounds of formula

and, if required, converting the compounds of formula I in a pharmaceutically acceptable salt.

In accordance with the present invention compounds of General formula I can be obtained according to scheme 1: compound of formula VI is heated in the presence of ammonium carbonate. The obtained compound VII is then treated with benzyl bromide in the presence of potassium carbonate, receiving compound IV, which is then dissolved in THF and treated with sodium hydride and an electrophile of formula V, obtaining the compounds of formula I.

The alternative, according to the present invention, compounds of General formula I can be obtained according to scheme 2: compound of formula VI is heated in the presence of benzyl bromide and potassium carbonate, getting VIII, which is then amyraut bases such as LiOH, receiving IX. Processing IX activating agent such as carbonyldiimidazole, in an appropriate solvent, such as DMF or DMA or NMP, followed by heating (conventional or microwave) in the presence of amines III leads to the production of the compounds of formula I.

Scheme 2

Alternatively, in accordance with the present invention, compounds of General formula I can be obtained according to scheme 3: compound of formula VI is heated in the presence of amine III with an activating agent such as carbonyldiimidazole, in an appropriate solvent, such as dimethylformamide (DMF) or dimethylacetamide (DMA) or N-organic (NMP), followed by heating (conventional or microwave), obtaining the compounds of formula X, which in turn react with benzylbromide in the presence of potassium carbonate, obtaining the compounds of formula I.

Alternatively, in accordance with the present invention, compounds of General formula XVI may be obtained according to scheme 4: the compound of formula XI are oxidized to XII and glorious, receiving XIII sequential processing of m-chloroperoxybenzoic Inoi acid (m-SRV) and then phosphorus oxychloride.

Subsequent reaction with sodium salts of benzyl alcohols results in XIV, which, after saponification to compounds XV is treated with an activating agent such as carbonyldiimidazole in an appropriate solvent, such as DMF or DMA or NMP, followed by heating (conventional or microwave) in the presence of amines III, obtaining the compounds of formula XVI.

Scheme 4

Pharmaceutically acceptable salts of compounds of formula I can be obtained according to known methods, given the nature converted to the salt of the compound. Inorganic or organic acids, such as, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, p-toluensulfonate acid, etc. are suitable for the formation of pharmaceutically acceptable salts of basic compounds of formula I. Compounds that contain alkali metals or alkaline-earth metals, for example sodium, potassium, calcium, magnesium or the like, primary amines or basic amino acids, are suitable for the formation of pharmaceutically acceptable salts of acidic compounds.

The compounds of formula I and their pharmaceutical is Ki acceptable salt, as already mentioned above, are monoamine oxidase inhibitors and can be used for treatment or prevention of diseases in which inhibitors of MAO-b can be profitable. They include acute and chronic neurological diseases, disorders of perception and memory. Treatable neurological diseases are, for example, traumatic and chronic degenerative processes of the nervous system such as Alzheimer's disease, other types of dementia, minimal deterioration of cognition or Parkinson's disease. Other indications include mental illness, such as depression, anxiety, panic attack, social phobia, schizophrenia, nutritional and metabolic disorders such as obesity, and the prevention and treatment of syndromes of dependence on alcohol, nicotine, and other drugs. Other treatable indications may be deficient syndrome (G.M.Sullivan, WO 01/34172 A2), peripheral neuropathy caused by cancer chemotherapy (G.Bobotas, WO 97/33572 A1) or the treatment of multiple sclerosis (R.Y.Harris, WO 96/40095 A1) and other neuropeptidergic diseases.

The compounds of formula I and their pharmaceutically acceptable salts are particularly useful for the treatment and prevention of Alzheimer's disease and senile dementia.

The pharmacological activity of the compounds was Prov is Rena using the following method.

Encoding MAO-a and MAO-b cDNA man was quickly transfusional into EBNA cells using the procedure described E. J.Schlaeger and .Christensen (Transient Gene Expression in Mammalian Cell Grown in Serum-free Suspension Culture; Cytotechnology, 15: 1-13, 1998). After transfection the cells are homogenized using a homogenizer transmitter station in 20 mm buffer Tris HCL, pH 8.0, containing 0.5 mm EGTA and 0.5 mm phenylmethanesulfonyl. Cell membranes were obtained by centrifugation at 45000 rpm and after two washing stages 20 mm buffer Tris HCL, pH 8.0, containing 0.5 mm EGTA, membranes were re-suspended in the above buffer, and aliquots were stored at -80°s to use.

MAO-a and MAO-b enzyme activity was analyzed using spectrophotometric analysis at 96-cell substrates using the method described .Zhou and N.Panchuk-Voloshina (A One-Step Fluorometric Method for the Continuous Measurement of Monoamine Oxidase Activity, Analytical Biochemistry, 253: 169-174, 1997). Briefly, membrane aliquots were incubated in 0.1 M potassium phosphate buffer, pH 7.4, for 30 min at 37°With various concentrations of compounds or without them. Then the enzymatic reaction was initiated by addition of terminologi substrate MAO together with 1 U/ml horseradish peroxidase (Roche Biochemicals) and 80 μm N-acetyl-3,7-dihydroxyquinoxaline (Amplex Red, Molecular Probes). The samples then were incubated for 30 minutes at 37°With the resulting volume of 200 μl and then determined ogladanie at a wavelength of 570 nm, using counter SpectraMax (Molecular Devices). Background (non-specific) absorption was determined in the presence of 10 μm clorgyline for MAO-a or 10 μm of L-deprenyl for MAO-Century

The values of the IC50determined by the obtained curves of inhibition using nine concentrations of inhibitor twice, adjusting the data to a four parameter logistic equation using a computer program.

Compounds of the present invention are specific inhibitors of MAO-Century Values IC50compounds of the formula I, measured in the above test, are in the range of 10 μm or less, typically of 1 μm or less, ideally of 0.03 μm or less and more preferably of 0.1 μm or less.

The table below lists the specific values of the IC50preferred compounds.

ConnectionIC50MAO-b (μm)IC50MAO-A (μm)
(S)-2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]propionamide (Example 2)0,0080,776
5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl] acetonitrile (Example 7)0,034>10
2-(2-amino-ethyl)-5-(4-forbindelse)isoindole-1,3-dione 1:1 hydrochloride (Example 9)to 0.032>10
5-(4-Fluoro what ensilage)-2-(2-hydroxyethyl)

the isoindole-1,3-dione (Example 12)
0,0040,369
(S)-2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-3-hydroxypropionate (Example 14)0,017>10
2-(2-Ethylsulfanyl)-5-(4-forbindelse)

the isoindole-1,3-dione (Example 19)
0,011>10
4-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-3-hydroxybutyrate (Example 22)0,097>10
(S)-5-(4-Bromobenzylamine)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione (Example 28)0,034>10
(S)-5-(3-Methoxybenzyloxy)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione (Example 29)0,069>10
(S)-4-[2-(2-Methoxy-1-methylethyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-intoximeter]benzonitrile (Example 30)0,1296,200
(S)-5-(3,4-Deferasirox)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione (Example 31)to 0.0323,496
(S)-2-(2-Methoxy-1-methylethyl)-5-(4-cryptomaterial)isoindole-1,3-dione (Example 32)0,047>10
5-(4-Forbindelse)-2-thiophene-2-illtreating-1,3-dione (Example 34)of 0.081>10
2-(2-Econsultancy)-5-(4-forbindelse)

the isoindole-1,3-dione (Example 38)
0,115>10
(5-(4-Forbindelse)-2-(3,3,3-Cryptor-2-methoxypropyl)isoindole-1,3-dione (Example 43)0,045>10
(S)-2-[5-(3-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]propionamide (Example 44)0,0075,762
2-(2-amino-ethyl)-5-(3-forbindelse)isoindole-1,3-dione 1:1 hydrochloride (Example 50)0,039>10
(S)-2-[5-(3-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-3-hydroxypropionate (Example 52)0,020>10

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical compositions. The pharmaceutical compositions can be used orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be carried out rectally, for example in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic carriers for pharmaceutical compositions. For example, as that is their carriers for tablets, coated tablets, dragées and hard gelatin capsules can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts and other Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; depending on the nature of the active substance, however, for soft gelatin capsules usually do not require any medium. Suitable carriers for the receiving of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc. For aqueous injection solutions of water-soluble salts of compounds of formula I can be used adjuvants such as alcohols, polyols, glycerine, vegetable oils and the like, but usually they are not necessary. Suitable carriers for suppositories are, for example, natural or synthetic oils, waxes, fats, semi-liquid or liquid polyols and the like

In addition, the pharmaceutical compositions can contain preservatives, soljubilizatory, stabilizers, moisturizing agents, emulsification, sweeteners, colorants, odorants, salts for modifying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

As mentioned earlier, Lekarstvo the e means, containing the compound of formula I or its pharmaceutically acceptable salt and a therapeutically inert excipient, are also the object of the present invention, as a method of obtaining such medicines, which includes the introduction of one or more compounds of the formula I or their pharmaceutically acceptable salts and, optionally, one or more other therapeutically valuable substances in herbal dosage form together with one or more therapeutically inert carriers.

The dosage may vary within wide limits and will, of course, depend on the specific requirements of each specific case. In General, an effective dosage for oral or parenteral administration is between 0.01-20 mg/kg/day, the dosage is 0.1-10 mg/kg/day is preferred for all the above indications. The daily dosage for an adult weighing 70 kg, respectively, 0.7-1400 mg per day, preferably between 7 and 700 mg per day.

The following examples are given to illustrate the invention. They should not be construed as limiting the invention, but merely for his view.

Example 1

2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]ndimethylacetamide

(a) Bis-(4-terbisil)ether 4-(4-forbindelse)phthalic acid

A mixture of 4-hydroxyphthalic the acid (3.5 g, 19 mmol), potassium carbonate (23.9 g, 173 mmol) and 4-ftorangidridy (32.7 g, 173 mmol) in acetone (100 ml) and water (50 ml) was heated at the boil under reflux for 72 hours After cooling to room temperature the mixture was evaporated and the product was extracted with ethyl acetate. The organic extracts were then washed with brine, dried over sodium sulfate. Filtration and evaporation resulted in the receipt of the residue, which was purified by chromatography (SiO2; hexane-EtOAc 4:1), obtaining mentioned in the title compound (7.8 g, 80%) as a colourless oil. MS: m/e = 507,4 (M+H+).

b) 4-(4-Forbindelse)phthalic acid (Method A)

The mixture of bis-(4-terbisil)ether 4-(4-forbindelse)phthalic acid (7.8 g, to 15.4 mmol), monohydrate of lithium hydroxide (1.8 g, 46.2 mmol) in tetrahydrofuran (60 ml) and water (60 ml) was stirred at room temperature for 72 h the Mixture was then evaporated, followed by acidification to pH 2 at 0°using concentrated HCl. The organic layer was then dissolved in ethyl acetate, separated, washed with water and dried over sodium sulfate. Filtration and evaporation was half led to a white suspension, which was filtered and washed with ether, getting mentioned in the title compound (2.5 g, 56%) as a white solid. MS: m/e = 289,0 (M+H+).

b) 4-(4-Forbindelse)phthalic Ki the lot (Method B)

A mixture of 4-hydroxyphthalic acid (5.0 g, 27 mmol), potassium hydroxide (5.4 g, 30 mmol) and 4-ftorangidridy (5.7 g, 30 mmol) in water (13 ml) was heated at the boil under reflux for 5 hours After cooling to room temperature the mixture was washed with ether. The aqueous phase is then acidified to pH 2 at 0°With concentrated HCl and then was extracted with ethyl acetate. The organic extracts are then washed with water and dried over sodium sulfate. Filtration and evaporation resulted in the receipt of the residue, which was purified by chromatography (SiO2; CHCl3: acetone: Asón: 90:9:1), obtaining mentioned in the title compound (2.3 g, 29%) as a colourless oil. MS: m/e = 289,0 (M+H+).

g) 2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]ndimethylacetamide

A mixture of 4-(4-forbindelse)phthalic acid (185 mg, 0.64 mmol) and carbonyldiimidazole (109 mg, 0.67 mmol) in 1-methyl-2-pyrrolidinone (4 ml) was stirred at room temperature for 10 minutes and then was heated at 50°C for 15 minutes To this mixture was added the hydrochloride glycinamide (78 mg, 0.71 mmol) and pyridine (50 mg, to 0.63 mmol) and the resulting mixture was heated at 175 or 200°With microwave irradiation (reactor Smith) within 10 minutes After cooling to room temperature the mixture was dissolved in water and the resulting precipitate was filtered and purified by chromatography (SiO2; CH2l 2: 2 N. of NH3/Meon 9:1), obtaining mentioned in the title compound (146 mg, 69%) as a white solid. MS: m/e=329,3 (M+H+).

Alternative 2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]ndimethylacetamide was obtained from 5-hidroxizina-1,3-dione.

d) 5-Hidroxizina-1,3-dione

A mixture of 4-hydroxyphthalic acid (5.0 g, of 27.0 mmol), acetic acid (25 ml) and ammonium carbonate (5.3 g, 55 mmol) was heated at 120°C for 45 minutes, then was heated at 160°C for 2 hours After cooling to room temperature the reaction mixture was evaporated to half and then the reaction mixture was podslushivaet to pH 10 with 1 N. NaOH, then acidified to pH 5 with 0°With concentrated HCl. The precipitate was filtered off, washed with water, dried at 60°under high vacuum over night, getting mentioned in the title compound (3.2 g, 71%) as an almost white transparent solid substance. MS: m/e=162,1 (M+H+).

e) 5-(4-Forbindelse)isoindole-1,3-dione

A mixture of 5-hidroxizina-1,3-dione (200 mg, 1.0 mmol), potassium carbonate (178 mg, 1.05 mmol), 4-ftorangidridy (204 mg, 1.05 mmol) in ethanol (5 ml) was heated at 80°With during the night. After cooling to room temperature the reaction mixture was filtered and evaporated. The residue was purified by chromatography (SiO2; heptane-CH2Cl22:3, then CH2Cl23/Meon from 99:1: 95:5), receiving specified in the title compound (127 mg, 38%) as an almost white solid. MS: m/e=271,1 (M+).

g) 2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]ndimethylacetamide

A mixture of 5-(4-forbindelse)isoindole-1,3-dione (100 mg, of 0.37 mmol), sodium hydride (55% in mineral oil, 18 mg, 0.42 mmol) and 2-bromoacetamide (61 mg, 0.44 mmol) in dry tetrahydrofuran (5 ml) at 0°With was stirred at room temperature for 3 h and then was heated at 50°C for 1 h After cooling to 0°With added water (2 ml) and the product were extracted with ethyl acetate. The organic extracts were then washed with brine and dried over sodium sulfate. Filtration and evaporation resulted in the receipt of the residue, which was purified by chromatography (SiO2; heptane-CH2Cl22:3, then CH2Cl2-2 N. of NH3-Meon from 99:1: 4:1), obtaining mentioned in the title compound (78 mg, 65%) as a white solid. MS: m/e=329,3 (M+H+).

Example 2

(S)-2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]propionamide

As described in example 1D, 4-(4-forbindelse)phthalic acid (185 mg, 0.64 mmol) were converted into listed in the title compound (106 mg, 49%) (using H-alanine-NH2HCl instead of hydrochloride of glycinamide), which was obtained as a white solid. MS: m/e=343,3 (M+H +).

Example 3

(S)-2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-3-methylbutyrate

As described in example 1D, 4-(4-forbindelse)phthalic acid (185 mg, 0.64 mmol) were converted into listed in the title compound (115 mg, 48%) (using N-valine-NH2HCl instead of hydrochloride of glycinamide), which was obtained as a white solid. MS: m/e=371,3 (M+H+).

Example 4

Amide (S)-2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-4-methylpentanoic acid

As described in example 1D, 4-(4-forbindelse)phthalic acid (185 mg, 0.64 mmol) were converted into listed in the title compound (126 mg, 51%) (using H-leucine-NH3HCl instead of hydrochloride of glycinamide), which was obtained as a white solid. MS: m/e=385,3 (M+H+).

Example 5

(R,S)-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-4-methylsulfinylbutyl

As described in example 1D, 4-(4-forbindelse)phthalic acid (165 mg, or 0.57 mmol) were converted into listed in the title compound (42 mg, 18%) (using DL-ethionamide-HCl instead of hydrochloride of glycinamide), which was obtained as an almost white foam. MS: m/e=403,4 (M+N+).

Example 6

Ethyl ester of [5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]acetic acid

As described in example 1D, 4-(4-forbindelse)phthalic acid (185 mg, 0.64 mmol) of p is obrisovyvali specified in the title compound (110 mg, 48%) (using ether glycine-HCl instead of hydrochloride of glycinamide), which was obtained as a white solid. MS: m/e=358,2 (M+N+).

Example 7

5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]acetonitrile

As described in example 1D, 4-(4-forbindelse)phthalic acid (300 mg, 1.0 mmol) were converted into listed in the title compound (215 mg, 67%) (using aminoacetonitrile instead of hydrochloride of glycinamide), which was obtained as a white solid. MS: m/e=328,2 (M+NH4+).

Example 8

N-{2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]ethyl}ndimethylacetamide

A mixture of 4-(4-forbindelse)phthalic acid (185 mg, 0.64 mmol) and carbonyldiimidazole (109 mg, 0.67 mmol) in N,N-dimethylacetamide (3 ml) was stirred at room temperature for 10 minutes and then was heated at 50°C for 15 minutes To this mixture was added N-acetylethylenediamine (78 mg, from 0.76 mmol) and the resulting mixture was heated at the boil under reflux for 20 minutes After cooling to room temperature the mixture was evaporated and the residue was purified by chromatography (SiO2; CH2Cl2: 2 N. of NH3/MeOH from 98:2 to 9:1), obtaining mentioned in the title compound (139 mg, 62%) as an almost white solid. MS: m/e=357,3 (M+H+).

Example 9

2-(2-amino-ethyl)-5-(4-forbindelse)isoindole-1,3-dione 1:1 hydrochloride

a) tert-Butyl ester 2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]ethyl}carboxylic acids

As described in example 8, 4-(4-forbindelse)phthalic acid (1,012 g, 3.5 mmol) were converted into listed in the title compound (130 mg, 9%) [using tert-butyl N-(2-amino-ethyl)carbamate instead of N-acetylethylenediamine], which was obtained as a white solid. MS: m/e=415,4 (M+H+).

b) 2-(2-amino-ethyl)-5-(4-forbindelse)isoindole-1,3-dione 1:1 hydrochloride

A mixture of tert-butyl methyl ether {2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]ethyl}carboxylic acid (200 mg, 0.5 mmol) and HCl in dioxane (4 N., 5 ml) was stirred at room temperature for 72 hours the Precipitate was filtered and washed with ether, getting mentioned in the title compound (102 mg, 60%) as a white solid. MS: m/e=351,8 (M+H+).

Example 10

5-(4-Forbindelse)-2-(2-piperidine-1-retil)isoindole-1,3-dione

As described in example 8, 4-(4-forbindelse)phthalic acid (200 mg, 0.7 mmol) were converted into listed in the title compound (215 mg, 67%) [using 1-(2-amino-ethyl)piperidine instead of N-acetylethylenediamine], which was obtained as a pale yellow solid. MS: m/e=383,3 (M+N+).

Example 11

5-(4-Forbindelse)-2-(2-morpholine-4-retil)isoindole-1,3-dione

As described in example 8, 4-(4-forbindelse)phthalic acid (200 is g, 0.7 mmol) were converted into listed in the title compound (179 mg, 68%) [using 1-(aminoethyl)morpholine instead of N-acetylethylenediamine], which was obtained as an almost white solid. MS: m/e=385,3 (M+N+).

Example 12

5-(4-Forbindelse)-2-(2-hydroxyethyl)isoindole-1,3-dione

As described in example 8, 4-(4-forbindelse)phthalic acid (200 mg, 0.7 mmol) were converted into listed in the title compound (116 mg, 53%) [using ethanolamine instead of N-acetylethylenediamine], which was obtained as a white solid. MS: m/e=316,2 (M+N+).

Example 13

5-(4-forbindelse)-2-(2-methoxyethyl)isoindole-1,3-dione

As described in example 8, 4-(4-forbindelse)phthalic acid (200 mg, 0.7 mmol) were converted into listed in the title compound (137 mg, 60%) [using 2-methoxyethylamine instead of N-acetylethylenediamine], which was obtained as a white solid. MS: m/e=330,4 (M+N+).

Alternative 5-(4-forbindelse)-2-(2-methoxyethyl)isoindole-1,3-dione was obtained starting from 5-hydroxy-2-(2-methoxyethyl)isoindole-1,3-dione.

a) 5-Hydroxy-2-(2-methoxyethyl)isoindole-1,3-dione

A mixture of 4-hydroxyphthalic acid (0,91 mg, 5.0 mmol) and carbonyldiimidazole of 0.85 g, 5 mmol) in N,N-dimethylacetamide (3 ml) was stirred at room temperature for 45 minutes To this mixture was added 2-methoxyethylamine (0,47 g, 6.0 mmol and the resulting mixture was heated at the boil under reflux for 15 minutes After cooling to room temperature the mixture was evaporated and the residue was purified by chromatography (SiO2; CH2Cl2: 2 N. of NH3/MeOH 19:1 to 9:1), obtaining mentioned in the title compound (1.1 g, 95%) as a pale yellow solid. MS: m/e=to 220.1 (M-N+).

b) 5-(4-Forbindelse)-2-(2-methoxyethyl)isoindole-1,3-dione

A mixture of 5-hydroxy-2-(2-methoxyethyl)isoindole-1,3-Dionis of example 13A (570 mg, 2.6 mmol), potassium carbonate (445 mg, 3.2 mmol) and 4-ftorangidridy (526 mg, 2.8 mmol) in acetone (40 ml) was heated at the boil under reflux for 17 hours After cooling to room temperature the mixture was filtered, evaporated and the residue was purified by crystallization from diethyl ether : heptane (1:2), getting mentioned in the title compound (560 mg, 66%) the form of a white solid. MS: m/e=330,4 (M+N+).

Example 14

(S)-2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-3-hydroxypropionate

As described in example 8, 4-(4-forbindelse)phthalic acid (200 mg, 0.7 mmol) were converted into listed in the title compound (126 mg, 51%) [using L-(-)-Suriname HCl and pyridine (65 mg, 0.8 mmol) instead of N-acetylethylenediamine], which was obtained as a white solid. MS: m/e=359,2 (M+H+).

Example 15

Methyl ester of (S)-2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]propionic acid

As the description is about in example 14, 4-(4-forbindelse)phthalic acid (200 mg, 0.7 mmol) were converted into listed in the title compound (148 mg, 53%) [using methyl ester of L-alanine-HCl instead of L-(-)-serinaid HCl], which was obtained as a white solid after crystallization from Meon. MS: m/e=358,2 (M+N+).

Example 16

(S)-2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-3-phenylpropionamide

As described in example 8, 4-(4-forbindelse)phthalic acid (200 mg, 0.7 mmol) were converted into listed in the title compound (221 mg, 77%) [using L-(-)-phenylalaninamide instead of N-acetylethylenediamine], which was obtained as a white solid. MS: m/e=359,2 (M+N+).

Example 17

(R)-2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]propionamide

As described in example 14, 4-(4-forbindelse)phthalic acid (200 mg, 0.7 mmol) were converted into listed in the title compound (148 mg, 53%) [using H-D-Ala-NH2-HCl instead of L-(-)-serinaid HCl], which was obtained as a white solid followed by rubbing with Meon. MS: m/e=343,2 (M+H+).

Example 18

2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-3-phenylpropionamide

As described in example 8, 4-(4-forbindelse)phthalic acid (1.2 g, 4.0 mmol) were converted into listed in the title compound (200 mg, 13%) [using methyl ether 2-methylalanine instead of N-is citrateindian], which was obtained as a white solid. MS: m/e=372,3 (M+H+).

Example 19

2-(2-Ethylsulfanyl)-5-(4-forbindelse)isoindole-1,3-dione

As described in example 8, 4-(4-forbindelse)phthalic acid (290 mg, 1.0 mmol) were converted into listed in the title compound (212 mg, 59%) [2-(ethylthio)ethylamine instead of N-acetylethylenediamine], which was obtained as a white solid after crystallization from Meon. MS: m/e=360,2 (M+H+).

Example 20

(R,S)-2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]butyramide

As described in example 1B, 4-(4-forbindelse)phthalic acid (290 mg, 1.0 mmol) were converted into listed in the title compound (210 mg, 59%) [using hydrochloride (rat)-2-mode instead of hydrochloride of glycinamide and N, N-dimethylacetamide instead of 1-methyl-2-pyrrolidinone], which was obtained as a white solid. MS: m/e=357,3 (M+N+).

Example 21

4-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl] butyramide

As described in example 20 4-(4-forbindelse)phthalic acid (290 mg, 1.0 mmol) were converted into listed in the title compound (103 mg, 29%) [using hydrochloride 4-mode instead hydrochloride (rac)-2-mode], which was obtained as a white solid after crystallization from Meon. MS: m/e=357,3 (M+N+).

Example 22

4-[5-(4-CFT is benzyloxy)-1,3-dioxo-1,3-dihydroindol-2-yl]-3-hydroxybutyrate

As described in example 21, 4-(4-forbindelse)phthalic acid (290 mg, 1.0 mmol) were converted into listed in the title compound (108 mg, 22%) [using hydrochloride 4-amino-3-hydroxybutyrate instead of hydrochloride of the 4-mode], which was obtained as an almost white solid. MS: m/e=373,3 (M+H+).

Example 23

5-(3-Forbindelse)-2-(2-methoxyethyl)isoindole-1,3-dione

As described in example 13B, a mixture of 5-hydroxy-2-(2-methoxyethyl)isoindole-1,3-dione (example 13A, 400 mg, 1.8 mmol) were converted into listed in the title compound (427 mg, 72%) (using 3-florantyrone instead of 4-ftorangidridy) (376 mg, 2.0 mmol) and heating at boiling under reflux for 67 h, which was obtained as a white solid after purification by chromatography (SiO2; CH2Cl2: 2 N. of NH3/Meon from 99:1 to 19:1).

MS: m/e=330,4 (M+N+).

Example 24

(S)-5-(4-Forbindelse)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione

As described in example 8, 4-(4-forbindelse)phthalic acid (300 mg, 1.0 mmol) were converted into listed in the title compound (286 mg, 81%) [using (S)-1-methoxy-2-Propylamine instead of N-acetylethylenediamine], which was obtained as a white solid after trituration with hexane. MS: m/e=to 344.4 (M+N+).

Example 25

(S)-5-(3-Forbindelse)-2-(2-methoxy-1-methylethyl)isoindole-1,3-di is n

a) (S)-5-Hydroxy-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione

As described in example 13A, 4-gidroksiflavona acid (8.0 g, 44 mmol) was converted into the specified title compound (8.7 g, 84%) [using (S)-1-methoxy-2-Propylamine instead of 2-methoxyethylamine], which was obtained as light yellow crystals after purification by chromatography (SiO2; EtOAc:hexane 1:1). MS: m/e=234,1 (M-N2).

b) (S)-5-(3-Forbindelse)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione

As described in example 23, a mixture of (S)-5-hydroxy-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione (example 25A, 200 mg, 0.9 mmol) were converted into listed in the title compound (200 mg, 69%) (using 3-florantyrone instead of 4-ftorangidridy), after heating at boiling under reflux for 1 hour, which was obtained as a white solid after crystallization from ethyl acetate : hexane (1:1). MS: m/e=343,2 (M+).

Example 26

(S)-5-(2-Forbindelse)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione

As described in example 23, a mixture of (S)-5-hydroxy-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione (example 25A, 200 mg, 0.9 mmol) were converted into listed in the title compound (235 mg, 81%) (using 2-florantyrone instead of 4-ftorangidridy), after heating at boiling under reflux for 1 h, which was obtained in the form of a white solid substance of postcrystallization from ethyl acetate : hexane (1:1). MS: m/e=343,2 (M+).

Example 27

(S)-2-(2-Methoxy-1-methylethyl)-5-(4-triftormetilfosfinov)

the isoindole-1,3-dione

As described in example 23, a mixture of (S)-5-hydroxy-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione (example 25A, 200 mg, 0.9 mmol) were converted into listed in the title compound (265 mg, 79%) [using 4-(trifluoromethyl)benzylbromide instead of 4-ftorangidridy], after heating by boiling under reflux for 1.5 h, which was obtained as a white solid after crystallization from ethyl acetate : hexane (1:1). MS: m/e=393,2 (M+).

Example 28

(S)-5-(4-Bromobenzylamine)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione

As described in example 23, a mixture of (S)-5-hydroxy-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione (example 25A, 200 mg, 0.9 mmol) were converted into listed in the title compound (296 mg, 86%) (using 4-bromobenzylamine instead of 4-ftorangidridy), after heating at boiling under reflux for 1.5 h, which was obtained as a white solid after crystallization from ethyl acetate : hexane (1:1). MS: m/e=403,2/405,2 (M+).

Example 29

(S)-5-(3-Methoxybenzyloxy)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione

As described in example 23, a mixture of (S)-5-hydroxy-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione (example 25A, 200 mg, 0.9 mmol) were converted into listed in the title compound (280 mg, 93%) (IP is by using 3-methoxybenzylamine instead of 4-ftorangidridy), after heating at boiling under reflux for 3 h, which was obtained as a white solid after crystallization from ethyl acetate : hexane (1:1). MS: m/e=355,4 (M+).

Example 30

(S)-4-[2-(2-Methoxy-1-methylethyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-intoximeter] benzonitrile

As described in example 23, a mixture of (S)-5-hydroxy-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione (example 25A, 200 mg, 0.9 mmol) were converted into listed in the title compound (280 mg, 94%) (using 3-bromomethylbiphenyl instead of 4-ftorangidridy), after heating at boiling under reflux for 1.5 h, which was obtained as a white solid after crystallization from ethyl acetate : hexane (1:1). MS: m/e=350,2 (M+).

Example 31

(S)-5-(3,4-Deferasirox)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione

As described in example 23, a mixture of (S)-5-hydroxy-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione (example 25A, 200 mg, 0.9 mmol) were converted into listed in the title compound (235 mg, 77%) (using alpha-bromo-3,4-dipertua instead of 4-ftorangidridy), after heating at boiling under reflux for 2 h, which was obtained as a white solid after crystallization from ethyl acetate : hexane (1:1). MS: m/e=361,2 (MN).

Example 32

(S)-2-(2-Methoxy-1-methylethyl)-5-(4-cryptomaterial)ISO the Dol-1,3-dione

As described in example 23, a mixture of (S)-5-hydroxy-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione (example 25A, 200 mg, 0.9 mmol) were converted into listed in the title compound (306 mg, 88%) [using (4 triptoreline)benzylbromide instead of 4-ftorangidridy], after heating by boiling under reflux for 3 h, which was obtained as a white solid after crystallization from ethyl acetate : hexane (1:1). MS: m/e=409,4 (M+N+).

Example 33

5-(4-Forbindelse)-2-(tetrahydrofuran-2-ylmethyl)isoindole-1,3-dione

As described in example 1D, 4-(4-forbindelse)phthalic acid (290 mg, 1.0 mmol) were converted into listed in the title compound (249 mg, 70%) [using tetrahydrofurfurylamine instead of hydrochloride of glycinamide and pyridine, and N,N-dimethylacetamide instead of 1-methyl-2-pyrrolidinone], which was obtained as a white solid. MS: m/e=356,3 (M+N+).

Example 34

5-(4-Forbindelse)-2-thiophene-2-illtreating-1,3-dione

As described in example 33, 4-(4-forbindelse)phthalic acid (290 mg, 1.0 mmol) were converted into listed in the title compound (269 mg, 73%) [using 2-thiophenemethylamine instead tetrahydrofurfurylamine], which was obtained as a white solid. MS: m/e=367,1 (M+H+).

Examples 35

(S)-2-[5-(4-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]thiopropionate

A mixture of (S)-2[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]propionamide (171 mg, 0.5 mmol) and reagent Lawesson (243 mg, 0.6 mmol) in tetrahydrofuran (20 ml) was stirred at room temperature for 72 hours Then the mixture was evaporated and the residue was purified by chromatography (SiO2; CH2Cl2: 2 N. of NH3/MeOH 99:1 to 19:1), obtaining mentioned in the title compound (65 mg, 36%) as an almost white solid after recrystallization from Meon. MS: m/e=359,2 (M+N+).

Example 36

5-(4-Forbindelse)-2-piperidine-4-isoindol-1,3-dione 1:1 hydrochloride

As described in example 33, 4-(4-forbindelse)phthalic acid (590 mg, 2.0 mmol) were converted into the specified header connection [using 4-amino-1-BOC-piperidine instead of tetrahydrofurfurylamine] followed by treatment with HCl in dioxane (4 ad, 2 ml) and stirring at room temperature for 12 hours the Precipitate was filtered and washed with acetone and ether, getting mentioned in the title compound (73 mg, 9%) as a white solid. MS: m/e=355,3 (M+N+).

Example 37

5-(4-Forbindelse)-2-(5-methylisoxazol-3-yl)isoindole-1,3-dione

As described in example 33, 4-(4-forbindelse)phthalic acid (290 mg, 1.0 mmol) were converted into listed in the title compound (166 mg, 47%) [using 3-amino-5-methylisoxazol instead of tetrahydrofurfurylamine] in the form of a white solid. MS: m/e=353,3 (M+N+).

Example 38

2-(2-Econsultancy)-5-(4-Forbes is lexi)isoindole-1,3-dione

A mixture of 2-(2-ethylsulfanyl)-5-(4-forbindelse)isoindole-1,3-dione (96 mg, 0.27 mmol) and 3-phenyl-2-(phenylsulfonyl)oxaziridine (84 mg, 0.32 mmol) in CH2Cl2(3 ml) was stirred at room temperature for 72 hours Then the mixture was evaporated and the residue was purified by chromatography (SiO2; CH2Cl2: 2 N. of NH3/Meon from 97:3 to 9:1), obtaining mentioned in the title compound (34 mg, 34%) as a white solid. MS: m/e=375,2 (M+N+).

Example 39

(S)-2-[2-(4-Forbindelse)-5,7-dioxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-yl]propionamide

a) Diethyl ether 1-oxypyridine-2,3-dicarboxylic acid

A mixture of diethyl-2,3-pyridinedicarboxylate (10 g, 45 mmol) and 3-chloroperoxybenzoic acid (13.8 g, 56 mmol) in CH2Cl2(150 ml) was stirred at 0°and was heated at room temperature for 30 minutes and left overnight. Then evaporation was half led to the residue, which was purified by chromatography (SiO2; EtOAc: EtOAc:MeOH, 19:1), obtaining mentioned in the title compound (8.2 g, 77%) as a white solid. MS: m/e=239,2 (M+).

b) Diethyl ether 6-chloropyridine-2,3-dicarboxylic acid

A mixture of diethyl ether 1-oxypyridine-2,3-dicarboxylic acid (8.0 g, 33 mmol) and phosphorylchloride (25.6 g, 167 mmol) was heated at 100°within 1.5 hours After cooling to room temperature the mixture was evaporated, the click was dissolved in CH 2Cl2. Then the organic phase is washed with water, with brine and then dried over sodium sulfate. Filtration and evaporation resulted in the receipt of the residue, which was purified by chromatography (SiO2; heptane-EtOAc from 9:1 to 1:1), obtaining mentioned in the title compound (5.5 g, 63%) as a colourless oil. MS: m/e=258,1 (M+N+).

C) Diethyl ether 6-(4-forbindelse)pyridine-2,3-dicarboxylic acid

A mixture of sodium hydride (55% in mineral oil), 254 mg, 0.6 mmol) and 4-tormentingly alcohol in tetrahydrofuran (30 ml) was heated at 60°C for 30 minutes and then after cooling to 0°solution was added diethyl ether 6-chloropyridine-2,3-dicarboxylic acid (1.3 g, 0.5 mmol) in tetrahydrofuran (20 ml) for 10 minutes the mixture was kept at 0°C for 1 h and then added water. The mixture was then extracted with ethyl acetate and the combined organic extracts were washed with water, with brine and then dried over sodium sulfate. Filtration and evaporation resulted in the receipt of the residue, which was purified by chromatography (SiO2; heptane-EtOAc from 9:1 to 3:1), obtaining mentioned in the title compound (1.3 g, 74%) as a colourless oil. MS: m/e=348,4 (M+N+).

g) Diethyl ether 6-(4-forbindelse)pyridine-2,3-dicarboxylic acid

A mixture of diethyl ether 6-(4-forbindelse)pyridine-2,3-dicarbonic the th acid (1.2 g, 3.5 mmol) and potassium hydroxide (0.6 g, 11.5 mmol) in water (25 ml) and tetrahydrofuran (10 ml) was heated at 80°C for 4 h After cooling to room temperature the mixture was washed with ether. The aqueous phase is then acidified to pH 2 at 0°With concentrated HCl and then was extracted with ethyl acetate. The organic extracts are then washed with water and with brine and dried over sodium sulfate. Filtration and evaporation resulted in the receipt of the residue, which was purified by crystallization from diethyl ether : heptane (2:1), obtaining mentioned in the title compound (0.9 g, 88%) as a white solid. MS: m/e = 290,0 (M-N-).

d) (S)-2-[2-(4-Forbindelse)-5,7-dioxo-5,7-dihydropyrrolo[3,4-b]pyridine-6-yl]propionamide

As described in example 14, 4-(4-forbindelse)phthalic acid (200 mg, 0.7 mmol) were converted into listed in the title compound (40 mg, 12%) [using H-Ala-NH2HCl instead of L-(-)-serinaid HCl], which was obtained as a white solid after purification HPLC (Waters Xterra RP18 (5 μm×50×19 mm), elwira AcCN/0.1% of TFA/water. MS: m/e=344,3 (M+N+).

Example 40

5-(4-Forbindelse)-2-(3-morpholine-4-ylpropyl)isoindole-1,3-dione

a) 5-Hydroxy-2-(3-morpholine-4-ylpropyl)isoindole-1,3-dione

As described in example 13A, 4-gidroksiflavona acid (1.0 g, 5.5 mmol) were converted into listed in the title compound (780 mg, 49%) [ispolzuya-(3-aminopropyl)morpholine instead of 2-methoxyethylamine], which was obtained as a pale yellow solid. MS: m/e=291,3 (M+N+).

b) 5-(4-Forbindelse)-2-(3-morpholine-4-ylpropyl)isoindole-1,3-dione

As described in example 13B, 5-hydroxy-2-(3-morpholine-4-ylpropyl)isoindole-1,3-dione (770 mg, to 2.65 mmol) were converted into listed in the title compound (210 mg, 28%)which was obtained as a white solid after purification by chromatography (SiO2; CH2Cl2: 2 N. of NH3/Meon from 99:1 to 19:1). MS: m/e=RUB 399.4 (M+N+).

Example 41

2-(4-Terbisil)-5-(4-forbindelse)isoindole-1,3-dione

A mixture of 5-hidroxizina-1,3-dione (200 mg, 1.0 mmol), potassium carbonate (178 mg, 1.05 mmol), 4-ftorangidridy (204 mg, 1.05 mmol) in ethanol (5 ml) was heated at 80°With during the night. After cooling to room temperature the reaction mixture was filtered and evaporated. The residue was purified by chromatography (SiO2; heptane-CH2Cl22:3, then CH2Cl2-2 N. of NH3-Meon from 99:1: 95:5), receiving specified in the title compound (13 mg, 3%) as a white solid. MS: m/e=379,4 (M+).

Example 42

5-(4-Forbindelse)-2-(3,3,3-Cryptor-2-hydroxypropyl)

the isoindole-1,3-dione

As described in example 8, 4-(4-forbindelse)phthalic acid (500 mg, 1.7 mmol) were converted into listed in the title compound (567 mg, 86%) [using 3-amino-1,1,1-Cryptor-2-propanol instead of N-acetylate is lenediamine], which was obtained as a white solid after purification by chromatography (SiO2; hexane-EtOAc 2:1). MS: m/e=384,3 (M+).

Example 43

(5-(4-Forbindelse)-2-(3,3,3-Cryptor-2-methoxypropyl)isoindole-1,3-dione

To a suspension of sodium hydride (45 mg, 1.0 mmol) in tetrahydrofuran (8 ml) was added 5-(4-forbindelse)-2-(3,3,3-Cryptor-2-hydroxypropyl)isoindole-1,3-dione (360 mg, 0.9 mmol) at room temperature, then added logmean (159 mg, 1.1 mmol) and after 14 h was added water. The mixture was then extracted with ethyl acetate and the combined organic extracts were washed with water, with brine and then dried over sodium sulfate. Filtration and evaporation resulted in the receipt of the residue, which was purified by chromatography (SiO2; hexane-EtOAc 3:1), obtaining mentioned in the title compound (120 mg, 32%) as a white solid. MS: m/e=398,4 (M+N+).

Example 44

(S)-2-[5-(3-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]propionamide

a) (S)-2-(5-Hydroxy-1,3-dioxo-1,3-dihydroindol-2-yl)propionamide

As described in example 13A, 4-gidroksiflavona acid (1,82 g, 1.0 mmol) was converted into the specified title compound (845 mg, 36%) [using N-Ala-NH2HCl and pyridine instead of 2-methoxyethylamine], which was obtained as a pale yellow solid. MS: m/e=233,0 (M-N-).

b) (S)-2-[5-(3-Forbindelse)-1,3-dioxo-1,3-Digue is drosendahl-2-yl]propionamide

As described in example 13B, (S)-2-(5-hydroxy-1,3-dioxo-1,3-dihydroindol-2-yl)propionamide (250 mg, 1.1 mmol) were converted into listed in the title compound (70 mg, 19%) (using 3-florantyrone instead of 4-ftorangidridy), which was obtained as a white solid after purification by chromatography (SiO2; CH2Cl2: 2 N. of NH3/Meon 9:1). MS: m/e=343,3 (M+N+).

Example 45

(2-[5-(3-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl] ndimethylacetamide

a) 4-(3-Forbindelse)phthalic acid

As described in example 1A and b, 4-gidroksiflavona acid (5.0 g, 27 mmol) were converted into listed in the title compound (6.9 g, 87%) [using 3-florantyrone instead of 4-ftorangidridy), which was obtained as a white solid after recrystallization from diethyl ether : hexane (1:3). MS: m/e=289,0 (M-N-).

b) (2-[5-(3-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]ndimethylacetamide

As described in example 1D, 4-(3-forbindelse)phthalic acid (200 mg, 0.69 mmol) were converted into listed in the title compound (151 mg, 66%)which was obtained as a white solid. MS: m/e=328,2 (M+).

Example 46

5-(3-Forbindelse)-2-(2-hydroxyethyl)isoindole-1,3-dione

As described in example 8, 4-(3-forbindelse)phthalic acid (200 mg, 0.69 mmol) were converted into the specified header joint is (179 mg, 82%) [using ethanolamine instead of N-acetylethylenediamine], which was obtained as a white solid after purification by chromatography (SiO2; EtOAc : hexane 1:1). MS: m/e=315,2 (M+).

Example 47

2-(2-Ethylsulfanyl)-5-(3-forbindelse)isoindole-1,3-dione

As described in example 8, 4-(3-forbindelse)phthalic acid (200 mg, 0.69 mmol) were converted into listed in the title compound (217 mg, 88%) [2-(ethylthio)ethylamine instead of N-acetylethylenediamine], which was obtained as an almost white solid after purification by chromatography (SiO2; EtOAc : hexane 1:3). MS: m/e=359,2 (M+).

Example 48

(5-(3-Forbindelse)-2-(3,3,3-Cryptor-2-hydroxypropyl)isoindole-1,3-dione

As described in example 8, 4-(3-forbindelse)phthalic acid (200 mg, 0.69 mmol) were converted into listed in the title compound (235 mg, 89%) [using 3-amino-1,1,1-Cryptor-2-propanol instead of N-acetylethylenediamine], which was obtained as a white solid after purification by chromatography (SiO2; hexane-EtOAc 2:1). MS: m/e=383,2 (M+).

Example 49

5-(3-Forbindelse)-2-(3,3,3-Cryptor-2-methoxypropyl)isoindole-1,3-dione

As described in example 43, (5-(3-forbindelse)-2-(3,3,3-Cryptor-2-hydroxypropyl)isoindole-1,3-dione (120 mg, 0.31 mmol) were converted into listed in the title compound (25 mg, 21%)which was obtained as a white solid washes the VA after purification by chromatography (SiO 2; hexane-EtOAc 3:1). MS: m/e=398,3 (M+N+).

Example 50

2-(2-amino-ethyl)-5-(3-forbindelse)isoindole-1,3-dione 1:1 hydrochloride

a) tert-Butyl ether {2-[5-(3-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]ethyl}carboxylic acids

As described in example 9a, 4-(3-forbindelse)phthalic acid (300 mg, 1.0 mmol) were converted into listed in the title compound (338 mg, 79%)which was obtained as a white solid after purification by chromatography (SiO2; hexane-EtOAc 3:1). MS: m/e=415,4 (M+H+).

b) 2-(2-amino-ethyl)-5-(3-forbindelse)isoindole-1,3-dione 1:1 hydrochloride

As described in example 9b, tert-butyl methyl ether {2-[5-(3-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]ethyl}carboxylic acid (311 mg, 0.75 mmol) were converted into listed in the title compound (249 mg, 94%)which was obtained as a white solid. MS: m/e=315,3 (M+N+).

Example 51

[5-(3-Forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]acetonitrile

As described in example 1D, 4-(3-forbindelse)phthalic acid (200 mg, 0.69 mmol) were converted into listed in the title compound (176 mg, 82%) (using aminoacetonitrile instead of hydrochloride of glycinamide), which was obtained as a white solid after purification by chromatography (SiO2; hexane-EtOAc 3:1). MS: m/e=310,2 (M+).

Example 52

(S)-2-[5-(3-Forbindelse)-1,3-dioxo-1,3-is hydroisotop-2-yl]-3-hydroxypropionate

As described in example 8, 4-(3-forbindelse)phthalic acid (200 mg, 0.69 mmol) were converted into listed in the title compound (76 mg, 31%) [using L-(-)-Suriname HCl and pyridine (65 mg, 0.8 mmol) instead of N-acetylethylenediamine], which was obtained as a pale orange solid. MS: m/e=359,2 (M+H+).

Example 53

(S)-5-(3,5-bis-Triftormetilfosfinov)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione

As described in example 23, a mixture of (S)-5-hydroxy-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione (200 mg, 0.9 mmol) were converted into listed in the title compound (314 mg, 81%) [using 3,5-bis(trifluoromethyl)benzylbromide instead of 4-ftorangidridy], after heating by boiling under reflux for 1 h, which was obtained as a white solid after crystallization from ethyl acetate : hexane (1:1). MS: m/e=461,2 (M+).

Example

Tablets of the following composition was obtained in the usual way:

mg tablet
The active ingredient100
Powder lactose95
White corn starch35
Polyvinylpyrrolidone8
Na carboximetilkrahmal10
Magnesium of steara the 2
Weight pills250

Example B

Tablets of the following composition was obtained in the usual way:

mg tablet
The active ingredient200
Powder lactose100
White corn starch64
Polyvinylpyrrolidone12
Na carboximetilkrahmal20
Magnesium stearate4
Weight pills400

The example In

Capsules of the following composition is obtained:

mg/capsule
The active ingredient50
Crystalline lactose60
Microcrystalline cellulose34
Talc5
Magnesium stearate1
The full weight capsules150

The active ingredient, having a suitable particle size, crystalline lactose and microcrystalline cellulose homogeneous mixed with each other, sieved and then mixed into t is lik and magnesium stearate. The resulting mixture was filled into hard gelatin capsules of suitable size.

Example D

The injection solution may have the following composition and can be obtained in the usual way:

The active ingredient1.0 mg
1 N. HCl20,0 ml
Acetic acid0.5 mg
NaCl8.0 mg
phenol10.0 mg
1 N. NaOHto pH 5
H2Aboutto 1 ml

1. Compounds of General formula

where X represents-N= or-CH=;

R1represents a-CO-NR5R6; -CHR7-(CH2)n-CO-NR5R6;

-(CH2)n-NR5R6,

-(CH2)n-COOR8;

-(CH2)n-CN;

-CHR7-(CH2)n-CF3;

-(CH2)n-NH-COR9;

-(CH2)n-NH-COOR8;

-(CH2)n-piperidinyl, -(CH2)n-morpholinyl, -(CH2)n-tetrahydrofuranyl;

-(CH2)n-thiophenyl or -(CH2)n-isoxazolyl, where the heterocyclic ring may be substituted C1-C6-alkyl;

-(CH2)n-phenyl, where the phenyl ring may be substituted with halogen or halogen-(C1-C6)-alkyl;

-(CH2)p-OR8;

-(CH2)p-SR8;

-(CH2)pSO-R9or

-(CH2)n-CS-NR5R6;

R2represents hydrogen, C1-C6-alkyl;

-(CH2)p-OR10;

-(CH2)p-SR10or benzyl;

R3represents hydrogen or C1-C6-alkyl;

R4represents halogen, halogen-(C1-C6)-alkyl, cyano, C1-C6-alkoxy or halogen-(C1-C6)-alkoxy;

R5and R6independently from each other represent hydrogen or C1-C6-alkyl;

R7represents hydrogen, hydroxy or C1-C6-alkoxy;

R8represents hydrogen or C1-C6-alkyl;

R9represents a C1-C6-alkyl;

R10represents hydrogen or C1-C6-alkyl;

m denotes 1, 2 or 3;

n denotes 0, 1 or 2 and

p denotes 1 or 2,

and their pharmaceutically acceptable salts.

2. The compounds of formula I according to claim 1, in which X represents-CH=.

3. the value of the formula I according to claim 1 or 2, in which R1represents a-CO-NR5R6or-CHR7-(CH2)n-CO-NR5R6and in which R5and R6independently from each other represent hydrogen or C1-C6-alkyl, R7represents hydrogen, hydroxy or C1-C6-alkoxy and n represents 0, 1 or 2.

4. The compounds of formula I according to claim 3 where the compound is selected from the group consisting of

2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]acetamide", she

(S)-2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl] propionamide,

(S)-2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-3-hydroxypropionate,

(R)-2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl] propionamide,

2-[5-(3-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl] propionamide,

(2-[5-(3-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]ndimethylacetamide and

2-[5-(3-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]-3-hydroxypropionate.

5. The compounds of formula I of claim 1 or no 2 in which R1represents -(CH2)n-NR5R6, -(CH2)n-NH-COR9or -(CH2)n-piperidinyl and in which R5and R6independently from each other represent hydrogen or C1-C6-alkyl, R9represents a C1-C6-alkyl and n train is achet 0, 1 or 2.

6. The compounds of formula I according to claim 5, where the compound is selected from the group consisting of

N-{2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl] ethyl} acetamide", she

2-(2-amino-ethyl)-5-(4-forbindelse)isoindole-1,3-dione and

5-(4-forbindelse)-2-piperidine-4-isoindol-1,3-dione.

7. The compounds of formula I according to claim 1 or 2, in which R1represents -(CH2)p-OR8or-CHR7-(CH2)n-CF3and in which R7represents hydrogen, hydroxy or C1-C6-alkoxy, R8represents hydrogen or C1-C6-alkyl and p denotes 1 or 2.

8. The compounds of formula I according to claim 7 where the compound is selected from the group consisting of

5-(4-forbindelse)-2-(2-hydroxyethyl)isoindole-1,3-dione,

5-(4-forbindelse)-2-(2-methoxyethyl)isoindole-1,3-dione,

5-(3-forbindelse)-2-(2-methoxyethyl)isoindole-1,3-dione,

(S)-5-(4-forbindelse)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione,

(S)-5-(3-forbindelse)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione,

(S)-5-(2-forbindelse)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione,

(S)-2-(2-methoxy-1-methylethyl)-5-(4-triftormetilfosfinov)isoindole-1,3-dione,

(S)-5-(4-bromobenzylamine)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione,

(S)-5-(3,4-deferasirox)-2-(2-methoxy-1-methylethyl)isoindole-,3-dione,

5-(3-forbindelse)-2-(2-hydroxyethyl)isoindole-1,3-dione,

5-(4-forbindelse)-2-(3,3,3-Cryptor-2-hydroxypropyl)isoindole-1,3-dione and

5-(3,5-bis-triftormetilfosfinov)-2-(2-methoxy-1-methylethyl)isoindole-1,3-dione.

9. The compounds of formula I according to claim 1 or 2, in which R1represents -(CH2)p-SR8; -(CH2)pSO-R9or -(CH2)n-CS-NR5R6and in which R5and R6independently from each other represent hydrogen or C1-C6-alkyl, R8represents hydrogen or C1-C6-alkyl, R9represents a C1-C6-alkyl and n denotes 0, 1 or 2.

10. The compounds of formula I according to claim 9, where the compound is selected from the group consisting of

2-(2-ethylsulfanyl)-5-(4-forbindelse)isoindole-1,3-dione, (S)-2-[5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl]thiopropionate and

2-(2-ethylsulfanyl)-5-(3-forbindelse)isoindole-1,3-dione.

11. The compounds of formula I according to claim 1 or 2, in which R1represents -(CH2)nCN and n denotes 0, 1 or 2.

12. The compounds of formula I according to claim 11 where the compound is selected from the group consisting of

5-(4-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl] acetonitrile [5-(3-forbindelse)-1,3-dioxo-1,3-dihydroindol-2-yl] acetonitrile.

13. The compounds of formula I is about to claim 1, in which R4represents a halogen.

14. Drug containing one or more compounds according to any one of claims 1 to 13 and pharmaceutically acceptable excipients for the treatment and prevention of diseases that are mediated by monoamine oxidase inhibitors Century

15. Drug containing one or more compounds according to any one of claims 1 to 13 and pharmaceutically acceptable excipients for the treatment and prevention of Alzheimer's disease and senile dementia.

16. The compound of formula I according to any one of claims 1 to 13, as well as its pharmaceutically acceptable salts as inhibitors of monoamine oxidase B (MAO-b).



 

Same patents:

FIELD: medicine.

SUBSTANCE: the present innovation deals with describing the efficient quantity of, at least, one heterocyclic compound of formula (I) or its salts, moreover, the compound of formula (I) should be chosen out of (i) the compounds of formula (III) or their salts, in which Z, Z' indicate O, X indicates S (thiazolidine dionic group), G indicates O or S; at least, one out of R2 and R3 indicates CF3, OR0 or COOR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C10-C10-alkyl, (ii) compounds (VI) or their salts: in which Z, Z' and G independently indicate O or S, at least, one out of R2 and R3 indicates hydrogen, CN, CF3, NO2, OR0, COOR0 or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, possibly substituted OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, (iii) compounds (VII) or their salts in which Z, Z' and G independently indicate O or S; R indicates saturated linear or branched C1-C10-alkyl; at least, one out of R2 and R3 indicates saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, NO2, OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl. The compounds in question reveal improved action upon stimulation of keratin fibers growth, particularly, human keratin fibers, that prevents their falling down and increases their density.

EFFECT: higher efficiency.

31 cl, 13 ex, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel indolyl-derivatives of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkyl substituted with from one to three halogen atoms; R2 means hydrogen atom, (C1-C8)-alkyl; R3 means (C1-C8)-alkoxy-group; R4 means hydrogen atom; A means oxygen atom or sulfur atom; n = 1,2 or 3. Synthesized compounds possess agonistic activity with respect to PPARα- and/or PPARγ-receptors. Also, invention relates to methods for their synthesis, a pharmaceutical composition based on thereof and their using for preparing medicinal agents, and to a method for treatment and/or prophylaxis of diseases.

EFFECT: improved method of synthesis and treatment, valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 7 sch, 17 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means hydrogen atom or lower alkyl; R2 means substituted or unsubstituted thiazolinyl or oxazolinyl residue; each R5 and R6 means independently hydrogen atom or protective group; X means oxygen (O), sulfur atom (S) or -NR7 wherein in each case R7 means hydrogen atom or lower alkyl; RB means in each case independently hydrogen atom, (C1-C6)-alkyl, -CY3, -CHY2 or -CH2Y wherein Y means F, Br, Cl or J. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I) and possessing cytotoxic activity, and using this compound in treatment of malignant tumor with multiple drug resistance.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

44 cl, 77 dwg, 13 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of aminotetraline of the formula (I) wherein R1 means (C1-C6)-alkyl; R2 means halogen atom or -OR'; R3 means hydrogen atom (H) or -OR' wherein R' means (C1-C6)-alkyl or -SO2R'' wherein R'' means phenyl, thienyl, isoxazolyl; R4 means (C1-C6)-alkyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepinyl, furanyl, isoxazolyl, imidazolyl and pyrazolyl that can be substituted optionally, and pharmaceutical compositions containing derivatives of aminotetraline. Proposed compounds are selective antagonists of M2/M3 muscarinic receptors and designated for treatment and prophylaxis of diseases associated with smooth muscle disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 1 tbl, 16 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to alkylated (1H-benzimidazol-5-yl)-(-4-substituted phenyl)-amine derivatives, in particular compound of formula and pharmaceutically acceptable salts or solvates thereof, wherein R1, R2, and R9, are independently hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluorimethoxy, azido, etc.; R7 is optionally substituted C1-C10-alkyl, C3-C10-cycloalkyl, etc.; A is-OR3 or NR4R3; R8 is hydrogen, -Cl, -Br, -F, cyano, nitro, etc.; and meanings of the rest substituents are as defined in specification. Also disclosed is composition for MEK inhibition and uses of benzinidazole compounds.

EFFECT: new compounds with value biological properties.

32 cl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R means -C(O)R1 wherein R1 is chosen from the series: (C1-C6)-alkyl, -C=CH-COOH, -NHCH2-CH2R2, -N(CH2-CH2OH)CH2-CH2OH, -N(CH3)CH2-CH2-NHCH3, -N(CH3)CH2-CH2N(CH3)CH3, saturated 4-, 5- and 6-membered cycles and saturated and unsaturated 5- and 5-membered cycles comprising at least one heteroatom from a series sulfur (S), nitrogen (N) and oxygen (O), and optionally substituted with a group chosen from the series: (C1-C6)-alkyl, -C=O-R5, -OH, (C1-C6)-alkyl substituted with hydroxy-group optionally, (C1-C6)-alkyl substituted optionally with a group of the series: -NH2, -N-(C1-C6)-alkyl, -SO2CH3, =O, and 5- and 6-membered saturated cycles comprising at least one heteroatom chosen from N and O, and wherein R5 is chosen from the series: hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-alkyl substituted with hydroxy-group optionally, and (C1-C6)-alkyl substituted with NH2-group optionally; R2 is chosen from the series: -N(CH3)CH3, -NH2, morpholinyl and piperazinyl; X1, X2 and X3 are chosen independently from the series: -OH, (C1-C2)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CH2OCH3 and -CH2OCH2CH3, or one among X1, X2 or X3 means hydrogen atom, and two others are chosen independently from the series: hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CF3, -CH2OCH3, -CH2OCH2CH3, -OCH2-CH2R3, -OCH2-CF3 and -OR4, morpholylmethyl, -N(CH3)CH3, -CH2OH, -COOH, or one among X1, X2 or X3 means hydrogen atom, and two others in common with two carbon atoms including bonds between them in benzene cycle to which they are bound optionally form 5- or 6-membered saturated cycle comprising at least one heteroatom chosen from S, N and O, and wherein R3 is chosen from the series: -F, -OCH3, -N(CH3)CH3, saturated 5-membered cycle comprising at least one heteroatom N; R4 means 3-5-membered saturated cycle, and each Y1 and Y2 is chosen independently from the series: -Cl, -Br, -NO2,-C≡N and C≡N, and compound of the formula (II) also given in the invention description. Also, invention relates to a pharmaceutical composition possessing anti-proliferative activity and based on these compounds. Invention provides preparing novel compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 39 ex

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N3-alkylated benzimidazole derivatives for preparing a drug used in inhibition of MEK activity. Invention describes benzimidazole compound of the formula (I): and its pharmaceutically acceptable salts and solvates wherein R1, R2, R9 and R10 are chosen independently from hydrogen atom, halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-, azido-group, -OR3, -C(O)R3, -C(O)OR3, -OC(O)R3, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group; R3 is chosen from hydrogen atom, trifluormethyl group, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl group is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R' wherein R' is chosen independently from hydrogen atom, lower alkyl; R4 represents independently hydrogen atom or (C1-C6)-alkyl; R6 is chosen from trifluoromethyl group or (C1-C10)-alkyl, (C3-C10)-cycloalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R', -OR'; R7 is chosen from (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; W is chosen from -C(O)OR3, -C(O)NR3R4, -C(O)NROR3, -C(O)R4OR3, -C(O)(C3-C10)-cycloalkyl, -C(O)(C1-C10)-alkyl. Also, invention describes compositions used for inhibition of MEK activity, using such compounds for preparing a drug used in inhibition of MEK activity and preparing a drug used in cancer treatment.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with describing the efficient quantity of, at least, one heterocyclic compound of formula (I) or its salts, moreover, the compound of formula (I) should be chosen out of (i) the compounds of formula (III) or their salts, in which Z, Z' indicate O, X indicates S (thiazolidine dionic group), G indicates O or S; at least, one out of R2 and R3 indicates CF3, OR0 or COOR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C10-C10-alkyl, (ii) compounds (VI) or their salts: in which Z, Z' and G independently indicate O or S, at least, one out of R2 and R3 indicates hydrogen, CN, CF3, NO2, OR0, COOR0 or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, possibly substituted OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, (iii) compounds (VII) or their salts in which Z, Z' and G independently indicate O or S; R indicates saturated linear or branched C1-C10-alkyl; at least, one out of R2 and R3 indicates saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, NO2, OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl. The compounds in question reveal improved action upon stimulation of keratin fibers growth, particularly, human keratin fibers, that prevents their falling down and increases their density.

EFFECT: higher efficiency.

31 cl, 13 ex, 6 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to new enantiomerically pure (-)3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-thienyl)methyl)phenol, pharmaceutical composition containing the same having antagonistic activity in relates to μ- and/or δ-opioid receptors; methods for treatment of pain, cough, functional diarrhea, functional pain, heart diseases, emesis; method for receptor-mediated analgesia; method for amelioration, treatment and prevention of drug-mediated respiratory depression; method for screening of compounds suppressing opioid respiratory depression; pharmaceutical composition containing biologically active agent for treatment of pain, cough, functional diarrhea, functional pain, heart diseases, emesis, respiratory depression and claimed compound; and method for performance of reaction mediated with opioid receptors.

EFFECT: therapy of increased effectiveness.

17 cl, 6 dwg, 4 tbl, 7 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: Described are derivatives of general formula I (all symbols are as described in specification), pharmaceutically acceptable salts thereof or cyclodextrin clathrates. Such compounds hardly bind of EP2 subtype of PGE receptor and are useful in prophylaxis of immune diseases, allergy, death of neuronal cells, liver or kidney insufficiency, etc.

EFFECT: new agent for prophylaxis of various diseases.

18 cl, 388 ex, 68 tbl, 3 dwg

FIELD: organic chemistry.

SUBSTANCE: invention relates to new pyrasole derivatives of formula I wherein R5 represents phenyl or heteroaryl ring of formulae IIIa-IIIh meanings of the rest substituents are as defined in specification. Also disclosed are pharmaceutical composition based on said derivatives of formula I and uses thereof.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same for HIV inhibition.

13 cl, 54 ex, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 1-[1-(hetero)aryl-1-perhydroxyalkylmethyl]piperazine compounds of the general formula (I): wherein A means naphthyl, phenyl optionally substituted with methoxy-group, heteroaryl chosen from group comprising thienyl, furyl, indolyl or (C3-C6)-alkenyl optionally substituted with phenyl; Z means subgroup of the general formula: wherein k, l, m and n mean 0 or 1; R6 and R7 mean halogen atom, and to their physiologically acceptable acid-additive salt. Compounds possess antagonistic activity with respect to tachykinin receptors and can be used in treatment of digestive tract functional and inflammatory disorders. Also, invention describes a method for synthesis of proposed compounds and intermediate substances used in realization of this method, and medicinal agents containing indicated compounds.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

9 cl, 3 tbl, 40 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to a new biologically active compound of 4-oxoquinoline that is useful as an anti-HIV agent and to its pharmaceutically acceptable salt. Invention describes an anti-HIV agent comprising compound of 4-oxoquinoline represented by the following formula [I] or its pharmaceutically acceptable salt as an active component wherein ring Cy represents phenyl group, naphthyl group or pyridyl group and each this group is substituted optionally with 1-5 substituted chosen from the following group A wherein A represents the group consisting of cyano-group, phenyl group, nitro-group, halogen atom, (C1-C4)-alkyl group, halogen-(C1-C4)-alkyl group, halogen-(C1-C4)-alkoxy-group, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3 and -COORa1 wherein Ra1 and Ra2 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or benzyl group, and Ra3 represents (C1-C4)-alkyl group; R1 represent a substitute chosen from the following group B, or (C1-C10)-alkyl group optionally substituted with 1-3 substitutes chosen from halogen atom and the following group B wherein the group B represents the group consisting of phenyl group optionally substituted with phenyl group or 1-5 halogen atoms; (C3-C6)-cycloalkyl group, imidazolyl group, benzothiophenyl group, thiazolyl group optionally substituted with 1-3 (C1-C6)-alkyl groups, morpholinyl group, pyridyl group, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4 and -NRa5COORa6 wherein Ra4 and Ra5 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or phenyl group; Ra6 represents (C1-C4)-alkyl group; R2 represents hydrogen atom or (C1-C4)-alkyl group; R31 represents hydrogen atom, cyano-group, hydroxy-group, halogen atom or (C1-C4)-alkoxy-group; X represents -C-R32, and Y represents -C-R33 or nitrogen atom wherein R32 and R33 are similar or different and each represents hydrogen atom, cyano-group, halogen atom, pyrrolidinyl group, (C1-C10)-alkyl group optionally substituted with 1-3 halogen atoms, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10 or -N=CH-NRa10Ra11 wherein Ra7 and Ra8 are similar or different and each represents hydrogen atom, phenyl group or (C1-C10)-alkyl group optionally substituted with (C3-C6)-cycloalkyl group or hydroxy-group; Ra9 represents (C1-C4)-alkyl group and Ra10 and Ra11 are similar or different and each represents hydrogen atom or (C1-C4)-alkyl group. Also, invention describes compound of the formula (III) given in the invention description, integrase inhibitor, antiviral agent, ant-HIV composition, anti-HIV agent, using compound of 4-oxoqionoline, method for inhibition of integrase activity, method for prophylaxis or treatment of viral infectious disease, pharmaceutical composition used for inhibition of integrase activity, antiviral composition and commercial package (variants). Invention provides the development of a pharmaceutical agent possessing inhibitory effect on activity of integrase.

EFFECT: valuable medicinal properties of compound, agent and composition.

40 cl, 7 tbl, 250 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

Muscarinic agonists // 2269523

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein Z1 represents -CR1 or nitrogen atom (N); Z2 represents -CR2; Z3 represents -CR3 or N; Z4 represents -CR4; W1 represents oxygen (O), sulfur (S) atom or -NR5; one of W2 and W3 represents N or -CR6 and another among W2 and W3 represents CG; W1 represents NG; W2 represents -CR5 or N; W3 represents -CR6 or N; or W1 and W3 represent N and W2 represents NG; G represents compound of the formula (II): wherein Y represents oxygen atom (O), -C(O)- or absent; p = 1, 2, 3, 4 or 5; Z is absent; each t = 2. Also, invention describes a method for enhancing activity of the muscarinic cholinergic receptor and a method for treatment of morbid states when modification of cholinergic and, especially, muscarinic receptors m1, m4 or both m1 and m4 offers the favorable effect.

EFFECT: valuable medicinal properties of agonists.

14 cl, 2 tbl, 101 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: method relates to piperazinedione compounds of formula I wherein and are independently direct bond or double bond; F represents H or CH(RaRb), when is single bong, or C(RaRb), when is double bond; Z represents R3O-(Ar)-B, wherein B represents CH(Rc), when is single bond or C(Rc), when is double bond; Ar represents piridyl; and R3 represents alkyl, aryl, C(O)Rd, C(O)NRdRe or SO2Rd ; R1 and R2 are independently H, C(O)Rd. Compounds of formula I have antitumor activity. Methods for treatment of tumors and angiogenesis inhibition also are disclosed.

EFFECT: new compounds useful in treatment of tumors and angiogenesis inhibition.

42 cl, 23 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with describing the efficient quantity of, at least, one heterocyclic compound of formula (I) or its salts, moreover, the compound of formula (I) should be chosen out of (i) the compounds of formula (III) or their salts, in which Z, Z' indicate O, X indicates S (thiazolidine dionic group), G indicates O or S; at least, one out of R2 and R3 indicates CF3, OR0 or COOR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C10-C10-alkyl, (ii) compounds (VI) or their salts: in which Z, Z' and G independently indicate O or S, at least, one out of R2 and R3 indicates hydrogen, CN, CF3, NO2, OR0, COOR0 or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, possibly substituted OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, (iii) compounds (VII) or their salts in which Z, Z' and G independently indicate O or S; R indicates saturated linear or branched C1-C10-alkyl; at least, one out of R2 and R3 indicates saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, NO2, OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl. The compounds in question reveal improved action upon stimulation of keratin fibers growth, particularly, human keratin fibers, that prevents their falling down and increases their density.

EFFECT: higher efficiency.

31 cl, 13 ex, 6 tbl

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