Compositions comprising enzyme-cleavable ketone-modified opioid prodrugs and optional inhibitors thereof

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula KC-(II), use thereof in treating or preventing pain, method for production thereof, pharmaceutical compositions based thereon, single dose containing same, method for production thereof, method of identifying a compound of formula KC-(II), method of reducing potential abuse of composition containing a compound of formula KC-(II). In general formula KC-(II), Ra is hydrogen or hydroxyl; R5 is selected from (1-6C)alkyl and (1-6C) alkyl, substituted with (1-6C)alkxoycarbonyl group; each R1 is independently selected from hydrogen and (1-6C)alkyl; each R2 is independently selected from hydrogen, (1-6C)alkyl, and-C(O) NR21R22, where R21 and R22 are independently selected from a group consisting of hydrogen, (1-6C)alkyl and (1-6C)alkyl, substituted -C(O)OR60, where R60 is hydrogen; n equals a whole number from 2 to 4; R3 is hydrogen; R4 is , where each R6 is independently selected from hydrogen and (1-6C)alkyl, substituted guanidyl group or an amino group; W is -NR8-; R8 is hydrogen; p equals 1 or 2; and R7 is selected from acyl and acyl substituted with -COOH or-NHCOCH3.

EFFECT: novel pharmaceutical compositions.

18 cl, 20 dwg, 25 tbl, 41 ex

 



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to therapeutic or preventive means in case of disease(s) of biliary tracts, which are caused or are aggravated by sphincter of Oddi contraction. As effective component, claimed means contains compound, presented by general formula

.

In formula (I) double line, which contains from dotted line and solid line, represents double bond or single bond, R1 represents C4-C7-cycloalkylalkyl, R2 represents linear or branched C1-C5-alkyl, and B represents - CH=CH-.

EFFECT: invention also relates to compound of formula (I) and to method of treatment or prevention in case of disease(s) of biliary tracts, which are caused or intensified by sphincter of Oddi contraction.

6 cl, 1 dwg, 1 ex

FIELD: biotechnologies.

SUBSTANCE: conjugate represents benzoate-hydrocodone that has the following structure: benzoate-hydrocodone (Bz-HC). Invention also pertains to the application of pharmaceutical compound for obtaining the drug for curing the patient with illness, disease or condition mediated by opioid binding to the opioid receptors of the patient.

EFFECT: improvement of medical treatment efficiency or prevention of drug abuse, drug withdrawal symptoms or pain relief.

10 cl, 11 ex, 4 tbl, 20 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention declares a compound of structural formula (I) or its pharmaceutically acceptable salt, solvate or hydrate wherein: X is phenol opiate wherein a hydrogen atom of a hydroxyl phenol group of substituted by a covalent bond with -C(O)-Y-(C(R1)(R2))n-N-C(R3)(R4);Y is -NR5-, R5 is (C1-6)alkyl; n is equal to 2 or 3, each of R1 and R2 is independently hydrogen, alkyl or substituted alkyl; R3 is hydrogen or methyl; R4 is a residue of L-amino acid or a residue of their N-acyl derivatives, as well as Hydromorphone 3-(N-methyl-N-(2-N'-acetylarginine amino)ethyl carbamate, or their pharmaceutically acceptable salt. What is also specified is a method for preparing the compound of formula (I) or its pharmaceutically acceptable salt.

EFFECT: what is declared is a pharmaceutical composition controlling phenol opiate release and a method of pain management in a patient in need thereof involving the introduction of an effective amount of the composition.

19 cl, 20 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, particularly a method for making the oxymorphone derivative naltrexone being an opiate antagonist by naltrexone processing by diazomethane in the presence of palladium acetate.

EFFECT: method eliminates using hardly accessible and expensive parent compounds, and it is characterised by ease of implementation.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula in which R1 represents C1-C10-alkyl with a straight or branched chain, optionally substituted by an aromatic ring, or -(CH2)nX(CH2)n- in which each n is equal to an integer from 0 to 2, X represents O, S, NH and where R2 represents H or C1-C6-alkyl with the straight or branched chain. Also, the invention refers to application of buprenophine derivative esters on a hydroxyl group of phenol for treating opiate dependences and/or moderate to strong pain, and to application as an agent releasing a therapeutic amount of buprenophine into a human body.

EFFECT: preparation of new buprenophine derivatives a hydroxyl group of phenol for treating opiate dependences and/or moderate to strong pain.

20 cl, 7 dwg, 1 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: disclosed method of determining opium alkaloids involves extraction sample preparation carried out using a water-acetonitrile mixture with ratio of water to acetonitrile ranging from 38:12 to 42:8, as well as analysis of the obtained extract through high-performance liquid chromatography, carried out at wavelength 210 and 220 nm. The rate of extraction of alkaloids can be increased by adding mineral acid, for example orthophosphoric acid, to the extracting water-acetonitrile mixture.

EFFECT: shorter analysis time and fewer operations while preserving the degree of extraction of alkaloids.

3 cl, 9 dwg, 1 ex

The invention relates to a method for producing derivatives of morphinan, which are intermediate compounds for obtaining derivatives of 14-hydroxymorphinone, which, in turn, are used to obtain opiate antagonists derived Oxymorphone

The invention relates to organic chemistry, specifically to a method for producing esters of N-substituted 14-hydroxymorphinone that are important narcotic analgesic and/or antagonistic means - opiate receptor blockers prolonged action

The invention relates to organic chemistry, particularly to esters of N-substituted 14-hydroxymorphinone that are important narcotic analgesic and/or antagonistic means - opiate receptor blockers prolonged action and to methods for their preparation

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel heterocyclic compounds of general formula (I) or enantiomers, diastereomers or pharmaceutically acceptable salts thereof, where Y is: phenyl or a heteroaryl selected from thiazolyl, pyridyl, pyrimidinyl, 1,3,5-triazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and 1,3,4-thiadiazolyl; wherein the phenyl or heteroaryl is optionally substituted with one substitute selected from fluorine, chlorine, bromine, iodine, C1-4alkyl, trifluoromethyl, C1-4alkoxy, C1-4alkylthio, nitro and cyano; r=1-2; R2 is absent or is an oxo-group; Z is: (a) phenyl substituted with NRaRb; where Ra is: H or C1-4alkyl; where Rb is: C1-4alkyl, cycloalkyl, phenyl, furanylmethyl, or phenyl(C1-2alkyl); and wherein the phenyl or the furanyl are optionally substituted with iodine; alternatively, Ra and Rb are taken together with the nitrogen atom to which they are bonded to form a 5-8 member heterocyclyl, which is optionally condensed to a benzene ring; (b) biphenyl-3-yl or biphenyl-4-yl; where the interior phenyl ring, attached to the carbonyl in formula (I) is optionally substituted with a fluorine atom; and where the terminal phenyl ring is optionally substituted with a substitute selected from trifluoromethyl, C1-4alkoxy, chlorine, dichloro, fluorine, and iodine; (c) phenyl substituted with a substitute selected from C5-8cycloalkyl, -NHC(=O)cyclohexyl, phenyloxy, phenylcarbonyl, phenyl(C1-3)alkyl, phenyl(C1-3)alkoxy, pyrrolyl, pyrazolyl, imidazolyl, isoindol-2-yl-l,3-dione, 2,3-dihydro-isoindol-2-yl; l-(tert- butoxycarbonyl)piperidin-4-yloxy, and 1-(tert-butoxycarbonyl)piperidin-4-yl; (d) phenyl substituted with 1-2 substitutes independently selected from: C1-6alkyl, C1-4alkoxy, iodine, chlorine and nitro; (e) phenyl(C1-2)alkyl; where the phenyl is optionally substituted with 1 or 2 substitutes independently selected from iodine, fluorine, C1-6alkyl, phenyl and NRcRd; where Rc: H or C1-4alkyl; where Rd is: C1-4alkyl or C1-6cycloalkyl(C1-4)alkyl; and where the C1-2alkyl of phenyl(C1-2)alkyl is optionally substituted with phenyl; (f) phenyl(C2-4)alkenyl; where the phenyl is optionally substituted with a substitute selected from C1-4alkyl, C1-4alkoxy, trifluoromethyl, trifluoromethylthio and phenyl; (g) naphthyl; where the naphthyl is optionally substituted with one C1-4alkoxy substitute; (h) fluorenyl or xanthenyl; where the fluorenyl or xanthenyl is optionally substituted with an oxo group; (i) C5-8cycloalkyl; where the C5-8cycloalkyl is optionally substituted with one C1-6alkyl substitute; (j) benzene ring-condensed C5-8cycloalkyl or benzene ring-condensed C5-8cycloalkyl(C1-4)alkyl; where said C5-8cycloalkyl fragment is optionally substituted with 1-4 methyl groups; (k) bicyclo[2.2.2]octyl-1-yl; where the bicyclo[2.2.2]octyl-l-yl is optionally substituted with C1-6alkyl; (1) a heteroaryl or benzene ring-condensed heteroaryl selected from benzooxazolyl, quinolinyl, benzimidazolyl, pyridinyl, indolyl, thienyl, furanyl, pyrazolyl, oxazolyl, benzothienyl and benzofuranyl; where the heteroaryl or benzene ring-condensed heteroaryl is optionally substituted with 1 or 2 substitutes independently selected from C1-4alkyl, trifluoromethyl, C5-8cycloalkyl, phenyl, phenyl(C1-2)alkoxy, phenyl(C2-4)alkynyl and dichlorophenoxy; and where the phenyl substitute in the heteroaryl is further optionally substituted with C1-4alkyl, C1-4alkoxy or trifluoromethyl; (m) l,5-diphenyl-lH-pyrazol-3-yl; where the pyrazol-3-yl is optionally substituted with a methyl group; and where each of the phenyl groups of the 1,5-diphenyl substitutes is also optionally substituted with substitutes selected from chlorine, dichloro or aminosulphonyl; (n) 1,2,3,4-tetrahydroquinolin-6-yl; where the 1,2,3,4-tetrahydroquinolin-6-yl is optionally substituted with phenyl or trifluoromethyl-substituted phenyl; and (o) benzene ring-condensed heterocyclyl(C2-4)alkenyl; where the benzene ring-condensed heterocyclyl is attached to the C2-4alkenyl via the benzene ring; and where benzene ring-condensed heterocyclyl is further optionally substituted with C5-6cycloalkyl; taking into account constraining conditions indicated in claim 1. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of producing said pharmaceutical composition, a method of treating said pathological conditions and use of the compound of formula (I).

EFFECT: obtaining novel heterocyclic compounds having MGL inhibiting activity.

21 cl, 5 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: biocompatible implant (BI) made of magnetic material in a biocompatible matrix (BM) is placed loosely along a posterior surface of an injured spinal cord of an experimental animal (EA) The EA is immersed periodically into a constant magnetic field. Its magnetic vector is aligned with a craniocaudal direction of spinal tracts. The BM of the BI is animal or herbal gelatine, wherein ferromagnetic magnetite or ferromagnetic ferrite nanoparticles 18-42 wt % with a particle size of 2.0-38 nm and at a magnetic field intensity (N) of 5-10 mT are immobilised as a magnetic material of the BI. The magnetic exposure covering the traumatic spinal injuries involves the combined effect of the magnetic field of the BI and the external rotating magnetic field at a magnetic induction of 0.15-0.35 T. The external magnetic exposure frequency is 1 or 2 times a day; the length is from 2 to 8 minutes per one session; the number of sessions is from 2 to 4. Animal gelatine in the BM of the BI can represent agar-agar, whereas herbal gelatine is pectin. The BM of the BI can additionally contain polyamines contributing to cell growth and proliferation, e.g. spermine or spemidine, in an amount of 1-5 wt %.

EFFECT: method enables recovering the spinal cord function sufficiently completely in the distal direction from the injury region, providing the favourable conditions for the adequate neuroglial growth with recipient's long neuron penetration from the intact proximal portion of the spinal cord into the distal one to ensure its conductive function, reducing the cicatrisation within the spinal injury, and eliminating the cerebral tissue oedema.

3 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition, containing compound of formula or for prevention or treatment of diseases, associated with oxidative stress, selected from group, consisting of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke episodes), MERRF syndrome (myoclonic epilepsy with ragged red fibres) or Kearns-Sayre syndrome, arrhythmia, cardioplegia or myocardium infarction. in formula (1) na stands for 1 or 2, Aa represents 5-membered heteroaryl or heterocycle, each of which has 2 heteroatoms, selected from N, O and S, Rla represents R5a-Xa-Ba-X′a-, Ba represents direct bond, Xa and X′a independently on each other represent direct bond or -OC(O)-, R5a represents hydrogen or 6-9-membered monocyclic or condensed cyclic heterocycle or heteroaryl, each of which has from 1 to 3 heteroatoms, selected from N, O and S, and is optionally substituted with oxo or C1-C6-alkyl, R2a represents -(CR8aR9a)pa-Ya-R7a, pa stands for number from 0 or 1, Ya represents direct bond or -O-, R7a represents hydrogen or phenyl, R3a, R8a, R9a, R10a represent hydrogen, R4a represents -(CH2)pa-Da-R10a-, Da represents C5-cycloalkyl or 6-membered heterocycle, which has 1 heteroatom, selected from N, S and O. Radical values for formula (2) are give in invention formula.

EFFECT: obtaining compositions for prevention or treatment of diseases, associated with oxidative stress.

19 dwg, 5 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in the general formula (I), R1 is specified in cyano, (2-4C)alkynyl, (1-4C)alkyl, (3-6C)cycloalkyl, (4-6C)cycloalkenyl, (6-8C)bicycloalkyl, (8-10C)bicyclic group, each of which can be substituted by (1-4C)alkyl, phenyl, biphenyl, naphthyl each of which can be substituted by three substitutes independently specified in halogen, (1-4C)alkyl substituted as may be necessary by one or more atoms of fluorine, (2-4C)alkynyl, (1-4C)alkoxy substituted as may be necessary by one or more atoms of fluorine, amino, di(1-4C)alkylamino and (3-6C)cycloalkyl, phenyl substituted by phenoxy, benzyl, benzyloxy, phenylethyl or a monocyclic heterocycle, each of which can be substituted by (1-4C)alkyl, 5-6-merous monocyclic heterocycle containing 1-3 heteroatoms specified in N, O and S substituted as may be necessary by a halogen, (1-4C)alkyl or phenyl substituted as may be necessary by (1-4C)alkyl, and 9-10-merous bicyclic heterocycle containing 1-2 heteroatoms specified in N and O substituted as may be necessary by (1-4C)alkyl; A is specified in -CO-O-, -NH-CO-, -CO-NH, -C=C-, -CCH3-O- and a binding group -Y-(CH2)n-X-, wherein Y is attached to R1 and specified in a bond, -O-, -SO2-, -CH2-O-, -CO-, -CO-O-, -CO-NH-, -NH-CO-, -C=C- and -C≡C-; n means an integer from 1 to 7; and X is attached to a phenylene group and specified in a bond, -O-, -S-, and -NH; the ring structure B represents phenylene; R2 means H, (1-4C)alkyl substituted as may be necessary by one or more atoms of fluorine, (1-4C)alkoxy or halogen; and R3 means (1-4C)alkylene-R5, wherein the alkylene group can be substituted by one or more atoms of a halogen, or R3 means (3-6C)cycloalkylene-R5 or -CO-CH2-R5, wherein R5 means -OH, -PO3H2, -OPO3H2, -COOH or tetrazol-5-yl; R4 means H or (1-4C)alkyl; R6 means one or more substitutes independently specified in H, (1-4C)alkyl or oxo; W means -O- or -S-.

EFFECT: invention refers to (thio)morpholine derivatives of formula (I) possessing the property of a sphingosine-1-phosphate (S1P) modulator, a based pharmaceutical composition and using them.

18 cl, 1 dwg, 237 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of structural formula

,

which can be applied for treatment, prevention or carrying out treatment of neurological disorder. In formula (Iva) m is equal 0; n is equal 1; R1 and R2 are, each independently, hydrogen, C1-C4alkyl or C3-C6cycloalkyl; R3 and R4 are, each independently, hydrogen or C1-C4alkyl; R5 is hydrogen and R6 and R7 are, each independently hydrogen, halogen, C1-C4alkyl, C6-C10aryl, 5-10-membered heteroaryl, which contains one O atom, one S atom and/or 1-4 N atom(s), 3-8-membered heterocyclyl, containing 1-2 heteroatoms, selected from O, S and N, C1-C4alcoxyl or aminoC1-C4alkyl.

EFFECT: invention relates to pharmaceutical industry, which contains claimed compound, and to method of treatment, prevention or carrying out of treatment of neurological disorder such as psychosis or schizophrenia.

54 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula A-I, where G1 stands for hydrogen atom or R'; G2 stands for halogen atom, CN, CF3, isopropyl or phenyl, where said isopropyl or phenyl is optionally substituted with up to three substituents, independently selected from WRW; G3 stands for isopropyl or (C3-C10)cycloaliphatic ring, where said G3 is optionally substituted with up to three substituents, independently selected from WRW; W stands for bond or (C1-C6)alkylidene chain, where up to two methylene groups of W residue are optionally and independently substituted for -CO2- or -O-; RW stands for R'; and R' is independently selected from hydrogen atom or (C1-C8)alkyl group. Invention also relates to method of obtaining compound of formula FF (stands for bromine atom, fluorine atom or tret-butyl; G3 stands for tret-butyl) by hydrogenation of respective nitrocompound in presence of palladium catalyst and to methods of obtaining C-9 and 433 compounds, which include stage of hydrogenation of respective nitrocompound in presence of palladium catalyst as intermediate stage.

EFFECT: formula A-I compounds, which are intermediate for synthesis of modulators of ATP-binding cassette ("ABC") transporters.

35 cl, 4 tbl, 80 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine and aims at treating attention deficit/hyperactivity syndrome (ADHD). The method of treating attention deficit/hyperactivity syndrome involves administering a therapeutically effective amount of a compound having formula , or its pharmaceutically acceptable salt into a mammal in need thereof, wherein R, R1 and R2 mean hydrogen and x=1. What is also provided is a pharmaceutical composition containing a compound having formula (1), or its pharmaceutically acceptable salt.

EFFECT: using the group of inventions provides the effective treatment of attention deficit/hyperactivity syndrome.

13 cl, 5 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to therapeutic agent for treatment of chronic somatoform pain disorder, which as active component contains aripiprazole or additive salt. Method of treating chronic somatoform pain disorder includes introduction of aripiprazole to patient in form of daily dose from 0.05 to 19 mg per a kg of body weight.

EFFECT: obtaining therapeutic agent for treatment of chronic somatoform pain disorder.

7 cl, 1 dwg, 1 ex

FIELD: medicine.

SUBSTANCE: claimed is the application of N-(2-adamantyl)-hexamethylenimine hydrochloride (himantane) as a medication for treating cerebral circulation disorders and brain traumas. An ability of himantane to reduce animal morbidity and increase cognitive and motor indices in case of its introduction after 3.5 hours after modelling a hematoma in rats and further introduction for 4 days was determined, which testifies to its possessing the neuroprotective potential on the model of the intracerebral post-traumatic hematoma. The technical result consists in the realisation of the claimed purpose: it has been shown that himantane in a dose of 5 mg/kg in case of intravenous introduction causes the increase of cerebral circulation in the rats' brain after ischemic brain affection without changing the level of arterial pressure.

EFFECT: medication did not produce a significant impact on the blood supply of the brain of the intact animals and did not cause a change in the heart rate and respiratory rate.

1 dwg, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of the general formula

,

wherein R1/R2 independently represent hydrogen, (CR2)o-C3-7 cycloalkyl optionally substituted by a lower alkyl or hydroxy, or represent a lower alkyl or tetrahydropyranyl, and o represents 0 or 1; and R can be identical or different, and represent hydrogen or a lower alkyl; or R1 and R2 can form together with a N atom to which they are attached, a heterocycloalkyl group specified in a group consisting of pyrrolidinyl, piperidinyl, 3-aza-bicyclo[3.1.0]hex-3-yl or 2-aza-bicyclo[3.1.0]hex-2-yl which are optionally substituted by hydroxy; R3 represents an S-lower alkyl, lower alkyl, lower alkoxy or C3-7 cycloalkyl; R3′ represents hydrogen, a lower alkyl substituted by a halogen, lower alkyl or lower alkoxy; R4 represents a lower alkyl substituted by a halogen; X represents -O- or -CH2-; X' represents -O- or -CH2-; provided one of X or X' always represent -O- and the other represents -CH2-; or a pharmaceutically acceptable acid-additive mixture, a racemic mixture, or a respective enantiomer and/or an optical isomer.

EFFECT: compounds of the general formula (I) are good inhibitors of glycine transporter 1 (GlyT-1) and hence can be used for treating schizophrenia and other neurological conditions, including pain.

13 cl, 1 tbl, 63 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to thermoformed pharmaceutical dosage form having a minimum tensile strength of 300 N; the above dosage form contains an opioid, a free physiologically acceptable carboxylic acid in an amount from 0.1 to 5.0 wt %, at total weight of the pharmaceutical dosage form and polyalkylene oxide having a minimum average molecular weight Mm of 500,000 g/mole. Carboxylic acid is specified in a group consisting of maleic acid, fumaric acid, glutaric acid, malonic acid and citric acid. The opioid is specified in a group consisting of oxymorphone, oxycodone, hydromorphone and their physiologically acceptable salts. The pharmaceutical dosage form can be packaged.

EFFECT: pharmaceutical dosage for according to the invention is characterised by the improved storage stability.

14 cl, 11 tbl, 9 ex

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