Lysin-specific demethylase-1 inhibitors and use thereof

FIELD: chemistry.

SUBSTANCE: present invention relates to novel compounds of formula (1) or pharmaceutically acceptable salts thereof having inhibitory effect on LSD1 (lysin-specific demethylase-1 inhibitors). Said activity enables their use for treating or preventing some diseases such as cancer. Above cancer is selected from the group including breast cancer, colorectal cancer, lung cancer, prostate cancer, testicular cancer, cerebral cancer, skin cancer and blood cancer. In compounds of formula 1

,

(A) denotes a pyridyl or phenyl; each (A′), if conained, is independently selected from a group consisting of phenyl, phenyl-C1-C4-alkoxy group, phenyl-C1-C4-alkyl, halogen, C1-C4-alkoxy group and halogen-C1-C4-alkyl, where each (A′) contains 0, 1, 2 or 3 substitutes independently selected from a group comprising halogen, halogen-C1-C4-alkyl, phenyl, C1-C4-alkyl and C1-C4-alkoxy group; X equals to 0, 1 or 2; (B) denotes cyclopropyl ring, where (A) and (Z) covalently connected with different carbon atoms in (B); (Z) denotes -NH-; (L) is selected from rhe group including a single link, -CH2-, -CH2CH2-, -CH2CH2CH2- and -CH2CH2CH2CH2-; and (D) denotes C3-C7-cycloalkyl or benzo-C5-C7-cycloalkyl, where said C3-C7-cycloalkyl or said petrol-C5-C7-cycloalkyl, contains 0, 1, 2 or 3 substitutes independently selected from the group, including -NH2, halogen, amido group, C1-C4-alkoxy group and halogen-C1-C4-alkyl; or its pharmaceutically acceptable salt. Compound, which is substituted with heteroarylcyclopropylamine or substituted arylcyclopropylamine and correponds to formula 2

,

where (R3) is present or is not, if (R3) is present, it is selected from the group consisting of phenyl-C1-C4-alkyl and phenyl-C1-C4-alkoxy group, where the said group (R3) contains 0, 1, 2 or 3 substitutes independently selected from the group including halogen, C1-C4-alkyl, C1-C4-alkoxy group, halogen-C1-C4-alkyl and phenyl; (W) denotes phenyl or pyridyl group, where the said (W) contains 0, 1 or 2 substitutes selected from the group including halogen, C1-C4-alkoxy group, halogen-C1-C4-alkyl and phenyl; (L′) denotes a bridge of formula -(CH2)n-, where n equals 0, 1, 2, 3 or 4; and R4 is C3-C7-cycloalkyl or benzo-C5-C7-cycloalkyl, wherein the above C3-C7-cycloalkyl or said benzo-C5-C7-cycloalkyl contains 0, 1, 2 or 3 substitutes, selected from the group including halogen, C1-C4-alkoxy group, halogen-C1-C4-alkyl, amine group and C-amido group; may be used as LSD1 selective inhibitor for identification method within the group of formula 2 compounds, which inhibits LSD1 in greater degree than MAO-A and/or MAO-B.

EFFECT: said compounds may be used for production of medicinal agent having LSD1 inhibiting activity for in treatment or preventing diseases or pathological condition.

51 cl, 1 tbl, 21 ex

циклопропил - cyclopropyl

 



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel cyclic compounds of general formula which possess properties of CaSR modulator. In general formula I group represents cycloalkyl, which contains 4-7 carbon atoms, optionally substituted with one or several similar or different substituents, selected from R2, R3, R4 or R5; A represents 1-naphthyl; R1 represents methyl, ethyl or n-propyl, each of which is optionally substituted with one or several, similar or different substituents, selected from halogen and hydroxy; R2 and R3 represent hydrogen; R4 represents hydrogen, halogen, hydroxy or C1-6alkyl; each R5 represents independently one or several similar or different substituents, represented by hydrogen or C1-6alkyl; G represents -C(O)NH2, C3-8cycloalkyl, C1-6heterocycloalkyl, C1-6heterocycloalkenyl, C3-8cycloalkenyl, C6-14aryl, C1-10heteroaryl, C6-10arylamino, hydroxyaminocarbonyl, C6-10arylaminocarbonyl, C1-4aminocarbonyl, C1-6heterocycloalkylcarbonyl, C1-10heteroarylaminocarbonyl, C6-10arylsulfonylaminocarbonyl, C6-14aryloxy, or C1-4alkoxycarbonyl, where said substituents are optionally additionally substituted with one or several, similar or different substituents. Other values of radicals are given in the formula of invention.

EFFECT: compounds can be applied in treatment, relief or prevention of physiological disorders or diseases, associated with impairment of activity of CaSR, such as hyperparathyreosis, and other diseases.

23 cl, 9 dwg, 3 tbl, 315 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for synthesis of a pharmaceutically acceptable salt of (1S,2R)-milnacipran of formula . The method involves the following sequential stages. At the stage (a), phenylacetonitrile and (R)-epichlorohydrin are reacted in the presence of a base containing an alkaline metal, then processed with the same base and an acid to prepare lactone of formula (II). At the stage (b), lactone of formula reacts with MNEt2, wherein M represents an alkaline metal, or with NHEt2 in the presence of a complex of Lewis acid and amine to prepare amide alcohol of formula (III). At the stage (c), amide alcohol of formula reacts with thionyl chloride to prepare chlorine amide of formula . At the stage (d) chlorine amide of formula (IV) reacts with phthalimide salt, such as potassium salt to prepare a phthalimide derivative of formula . The stage (e) involves hydrolysis of the phthalimide group of the phthalimide derivative of formula (V) to prepare (1S,2R)-milnacipran. The stage (f) provides preparing a (1S,2R)-milnacipran salt in the applicable solvent system in the presence of a pharmaceutically acceptable acid. The stages (a)-(e) are performed in a reaction medium containing the same solvent representing toluene. The invention also refers to a compound of formula (IV) in its (1S,1R) enantiomer form.

EFFECT: using the same solvent at all the stages, except for the last one, enables making the procedure free from the recovery of intermediate products, and simplifying the process.

9 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1-amino-3,5-dimethyladamantane, involving reaction of 1,3-dimethyladamantane with formamide in concentrated acids to obtain 1-formamido-3,5-dimethyladamantane, provided that neither SO3-containing sulphuric acid nor 100% nitric acid is used, wherein the concentrated acids are 30-70% nitric acid and 90-100% sulphuric acid and further conversion of 1-formamido-3,5-dimethyladamantane to 1-amino-3,5-dimethyladamantane through hydrolysis with aqueous hydrochloric acid.

EFFECT: high efficiency of the method.

3 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to amide of δ-amino-γ-hydroxy-ω-arylalcane acid of formula and its pharmaceutically acceptable salts. Also described are pharmaceutical compositions, which include said compounds, and application of said compounds for preparation of medication, intended for treatment of pathological states, associated with renin activity, in particular for treatment of hypertension.

EFFECT: obtaining pharmaceutically acceptable salts, which possess rennin-inhibiting ability.

21 cl, 161 ex

FIELD: chemistry.

SUBSTANCE: formula compound is described, where X is oxygen; R1 is a linear or branched C1-C8-alkyl chain, substituted with phenyl, optionally substituted with halogen atoms; R2, R3 independently represent hydrogen, C1-C3-alkyl chain, halogen, methoxy; R4, R5, R6, R7 independently represent hydrogen, as well as a method of obtaining formula (I) compound, and a pharmaceutical composition.

EFFECT: use of the compound to make a medicinal agent which is effective as a modulator of the sodium and/or calcium channel and, consequently, suitable for preventing, relieving and treating a wide range of pathologies which include neurological, psychiatric, cardiovascular, phlogistic, eye, urological, metabolic and intestinal diseases, where the above mentioned mechanisms are described as playing a pathological role.

6 cl, 11 ex

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining a formula compound. The method includes a stage of binding a formula compound with a formula compound in the presence of a base with the formation of the formula (I) compound. In formula (I) stereochemical configurations in the positions, marked with asterisks, are relative; Rb represents hydrogen; R00 represents a C1-10 aliphatic group or a C6-14 aryl group, including one-three rings; Rd, Re, Re', Rf, Rh, Rh', Rk represent hydrogen; Rg represents chlorine, fluorine, iodine or bromine; Rm represents a protective hydroxyl group; values of radicals Ra, R*, Rc are given in the invention formula. In formulas (II) and (III) Ra, Rb, Rc, Rd, Re, Re', Rf, Rg, Rh, Rh', Rj, Rk and Rm are such as determined in formula (I) and R1 represents -CH2CHO. The invention also relates to methods of obtaining compounds of formulae (V), (VI), (VId) and to a compound of the structural formula (IIa). Structural formulae of compounds (V), (VI), (VId), (IIa) are given in the invention formula.

EFFECT: method makes it possible to carry out synthesis in a regioselective way and use the obtained product without purification.

15 cl, 1 tbl, 26 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel cyclic compounds of general formula which possess properties of CaSR modulator. In general formula I group represents cycloalkyl, which contains 4-7 carbon atoms, optionally substituted with one or several similar or different substituents, selected from R2, R3, R4 or R5; A represents 1-naphthyl; R1 represents methyl, ethyl or n-propyl, each of which is optionally substituted with one or several, similar or different substituents, selected from halogen and hydroxy; R2 and R3 represent hydrogen; R4 represents hydrogen, halogen, hydroxy or C1-6alkyl; each R5 represents independently one or several similar or different substituents, represented by hydrogen or C1-6alkyl; G represents -C(O)NH2, C3-8cycloalkyl, C1-6heterocycloalkyl, C1-6heterocycloalkenyl, C3-8cycloalkenyl, C6-14aryl, C1-10heteroaryl, C6-10arylamino, hydroxyaminocarbonyl, C6-10arylaminocarbonyl, C1-4aminocarbonyl, C1-6heterocycloalkylcarbonyl, C1-10heteroarylaminocarbonyl, C6-10arylsulfonylaminocarbonyl, C6-14aryloxy, or C1-4alkoxycarbonyl, where said substituents are optionally additionally substituted with one or several, similar or different substituents. Other values of radicals are given in the formula of invention.

EFFECT: compounds can be applied in treatment, relief or prevention of physiological disorders or diseases, associated with impairment of activity of CaSR, such as hyperparathyreosis, and other diseases.

23 cl, 9 dwg, 3 tbl, 315 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing optically active compounds: (S)-(-)-2-(N-propylamino)-5-methoxytetraline and (S)-(-)-2-(N-propylamino)-5-hydroxytetraline. Said method involves optical separation of a mixture of enantimers of 2-(N-propylamino)-5-methoxytetraline and 2-(N-propylamino)-5-hydroxytetraline in the presence of an optically active form of N-(3,5-dinitrobenzoyl)-α-phenylglycine. The method enables to obtain a product with high optical purity.

EFFECT: invention also relates to use of salts of (S)-(-)-2-(N-propylamino)-5-methoxytetraline and (S)-(-)-2-(N-propylamino)-5-hydroxytetraline as intermediate compounds when producing rotigotine.

7 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of cycloalkylamines, possessing inhibiting activity with respect to, at least, one monoamine transporter, selected from group, consisting of serotonin transporter, dopamine transporter and norepinephrine transporter. In formula (IV): n equals 1; s equals 1; Y and Z each independently represents halogen; X represents OR5; where R5 stands for H or non-substituted C1-C10alkyl; A represents H, non-substituted C1-C10alkyl or halogen; R1 and R2 each independently represents H; R3 and R4 each independently represents H or on-substituted C1-C10alkyl.

EFFECT: invention relates to pharmaceutical composition, containing said compounds and to method of treatment or prevention of neurological disorder or eating disorder, mediated by activity of monoamine transporter, selected from group, consisting of serotonin transporter, dopamine transporter and norepinephrine transporter, such as depression, neurodegenerative disease, abuse with psychoactive substances, fibromyalgia, pain, sleep disorder, syndrome of attention-deficit disorder, syndrome of attention-deficit disorder with hyperactivity, restless legs syndrome, schizophrenia, anxiety, obsessive-compulsive disorder, panic disorder, post-traumatic stress, premenstrual dysphoria.

35 cl, 6 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel aminoindane derivatives of formula (Ia) or pharmaceutically acceptable salts thereof, which have NMDA receptor antagonist effect, and can be used to prepare a medicinal agent for treating dementia. In formula (Ia):

,

R1 is a lower alkyl, C5-C6 cycloalkyl, phenyl which can be substituted with OH, lower alkyl, halogen atom, O-alkyl, C5-C6 heteroaryl containing a S atom as a heteroatom, or lower alkyl substituted with one or more halogen atoms, R2 and R3 are identical or different, each denoting alkyl or phenyl, R4 and R5 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-lower alkyl, -lower alkylene-OH or -lower alkylene-O-lower alkyl, R6-R9 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-lower alkyl, halogen atom, lower alkyl substituted with one or more halogen atoms, OH, CN, lower alkenyl or nitrogen-containing C5-C6 heterocyclic group, R10 and R11 are identical or different and each denotes a hydrogen atom or lower alkyl. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: improved properties of the derivative.

6 cl, 15 tbl, 130 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

The invention relates to 1-phenyl-2 - dimethylaminomethylene-1-alowyn compounds, method of their production and to their use in medicinal products

FIELD: chemistry.

SUBSTANCE: invention relates to novel aminoindane derivatives of formula (Ia) or pharmaceutically acceptable salts thereof, which have NMDA receptor antagonist effect, and can be used to prepare a medicinal agent for treating dementia. In formula (Ia):

,

R1 is a lower alkyl, C5-C6 cycloalkyl, phenyl which can be substituted with OH, lower alkyl, halogen atom, O-alkyl, C5-C6 heteroaryl containing a S atom as a heteroatom, or lower alkyl substituted with one or more halogen atoms, R2 and R3 are identical or different, each denoting alkyl or phenyl, R4 and R5 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-lower alkyl, -lower alkylene-OH or -lower alkylene-O-lower alkyl, R6-R9 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-lower alkyl, halogen atom, lower alkyl substituted with one or more halogen atoms, OH, CN, lower alkenyl or nitrogen-containing C5-C6 heterocyclic group, R10 and R11 are identical or different and each denotes a hydrogen atom or lower alkyl. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: improved properties of the derivative.

6 cl, 15 tbl, 130 ex

FIELD: chemistry.

SUBSTANCE: described is a compound of formula

or its pharmaceutically acceptable salt, where m, p, q, Ar, R1 and R2 are as given in the description, as well as a pharmaceutical composition with selective affinity to 5-HT receptors which contains a formula (I) compound.

EFFECT: obtained compounds have selective affinity to 5-HT receptors and can be used, as expected, in treating certain central nervous system disorders.

21 cl, 1 tbl, 6 ex

FIELD: chemical technology, pharmacy.

SUBSTANCE: invention relates to an improved method for preparing sertraline hydrochloride form V that possesses the antidepressant effect. Method involves the following steps: (a) dissolving or suspending sertraline mandelate in a protonic solvent or a mixture of protonic solvents; (b) decreasing pH value of solution or suspension by addition of HCl aqueous solution of HCl solution in protonic solvent with addition of water to form a clear solution, and (c) isolation of the sertraline hydrochloride form V. At step (a) solvents from group comprising alcohol, water or their mixtures are chosen as solvents. For example, an alcoholic solvent used in step (a) can be chosen from group comprising methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, tert.-butyl alcohol and isobutyl alcohol or their mixtures but isopropyl alcohol is preferable. The dissolving or suspending step (a) is carried out at heating and/or stirring in solvent at temperature in the range 20-90oC usually. Decreasing the pH value in step (b) is carried out usually up to the range 1-3 preferably. Sertraline hydrochloride form V obtained at step (c) is isolated by cooling the mixture obtained at step (b). Cooling is carried out under natural conditions to room temperature or using mild cooling agents, such as cold water, water, alcohol or their mixtures wherein indicated alcohol is chosen from group comprising monohydric alcohol, dihydric alcohol or their mixtures. Also, invention relates to a method for preparing a pharmaceutical composition with immediate releasing the sertraline hydrochloride form V that involves mixing sertraline hydrochloride form V prepared by cl. 1 having particles size less 20 mcm and in the amount 90% of the total amount of particles, not less, with a pharmaceutically acceptable diluting agent, carrier or carrier. Proposed method provides simplifying the process for preparing the preparation based on decreasing the total amount of steps.

EFFECT: improved preparing method.

14 cl, 4 sch, 2 dwg, 1 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel derivatives of fullerenes comprising organic amines and hydrogen atoms bound to fullerene-C60 molecule by 6,6-double bonds of the general formula: C60Hn(R1R2N)n wherein R1 means -C6H5CH2; R2 means -C6H5CH2; n = 4 (tetra-(dibenzylaminohydro)[60]fullerene); R1 means -C5H9; R2 means hydrogen atom (H); n = 3 (tri-(cyclopentylaminohydro)[60]fullerene). Also, invention relates to using derivatives of fullerenes, in particular, (tetra-(benzylaminohydro)[60]fullerene, (tetra-(dibenzylaminohydro)[60]fullerene, tri-(cyclopentylaminohydro)[60]fullerene, 2-(azahomo[60]fullereno)-5-nitropyrimidine, 1,3-dipropyl-5-[5'-(azahomo[60]fullereno)pentyl]-1,3,5-triazin-2,4,6(1H,3H,5H)-trione, O,O-dibutyl-(azahomo[60]fullereno)phosphate as acceptors of electrons in composites polymer/fullerene designated for photovoltaic cells. Also, invention relates to photovoltaic device comprising mixture of poly-conjugated polymer and abovementioned fullerene derivative or their mixture as an active layer. Also, invention relates to a method for synthesis of derivatives of fullerenes comprising aromatic amines and hydrogen atoms bound to fullerene-C60 molecule by 6,6-double bonds. Method involves interaction of C60 with the corresponding organic amine in solution, and this reaction is carried out in aromatic solvent medium in amine excess at temperature 25-70°C for 2-5 days followed by evaporation of solution and precipitation of the end product by addition of alcohol.

EFFECT: improved method of synthesis.

6 cl, 1 tbl, 2 dwg, 6 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to new substituted 1,2,3,4-tetrahydro-2-naphthalenamine formula I, where R1and R2independently represent hydrogen, C1-4alkyl, C1-4alkoxy, halogen, trifluoromethyl; R3represents hydrogen, hydroxyl, C1-4alkoxyl, cyano, carbarnoyl; R4and R5independently represent hydrogen, C1-4alkyl, hydroxy2-4alkyl, or form together with the nitrogen atom to which they are attached, piperidine; in the form of free bases or salts obtained by attaching acid

The invention relates to analogs of 2-aminoindane General formula I, where R1and R2independently represent hydrogen, C1-C8alkyl; X is CH2R3or NHSO2R4; Y represents hydrogen, NHSO2R4, SO2(Ph); R3is NHSO2R4,

SO2R4, CONR1R2; R4represents C1-C8alkyl, phenyl or phenyl, substituted by-CN or-CF3; and their pharmaceutically acceptable salts, active receptor Dopamine D3
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