The method of preparation and intermediate compounds for obtaining inhibitors of 5-lipoxygenase
C07D405/12 - linked by a chain containing hetero atoms as chain links
C07D309/14 - Nitrogen atoms not forming part of a nitro radical
C07D309/08 - with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
The invention relates to a new method of producing compounds of the formula I
< / BR>
where a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, - inhibitors of 5-lipoxygenase, are useful for the treatment or relief of inflammatory diseases, Allergy and cardiovascular diseases. The invention also relates to new compounds of formula I, where a - C1-C6and intermediate compounds of the formula VIII
where X Is Br or Cl, necessary to obtain compounds of formula I. the Technical result consists in the development of a new, more simple and cheap method of obtaining inhibitors of 5-lipoxygenase. 3 C. and 23 C.p. f-crystals.
The background to the invention
This invention relates to a method and intermediate compounds for obtaining inhibitors of 5-lipoxygenase. Inhibitors of 5-lipoxygenase, obtained in accordance with the present invention, are disclosed in patent application U.S. serial number 09/0200140, which is a continuation 08/809901, filed June 13, 1997, now abandoned. This pending application s 5-lipoxygenase, obtained in accordance with the present invention are selective inhibitors of the enzyme lipoxygenase and are useful in the treatment or alleviation of inflammatory diseases, Allergy and cardiovascular diseases in mammals.
The present invention relates to a method for obtaining compounds of formula
in which a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, which includes the interaction of the compounds of formula II
in which a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, with the acid in the C1-C5Akilova alcohol; and the precipitation of the compounds of formula I by adding an organic solvent that is less polar than alcohol.
Acid is methansulfonate, and an organic solvent is diisopropyl ether or ethyl acetate.
The following aspect of the present invention the compound of formula II is produced by interaction of the compounds of formula III
in which AND -alkyl or benzyl, with the hydroxide in an alcohol solvent.
Hydroxide is a hydroxide of potassium, and alcohol is tert-butyl alcohol.
The following aspect of the present invention the compound of formula III is produced by interaction of the compounds of formula IV
in which a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, with an organic or mineral acid.
Acid is an acetic acid, sulfuric acid, formic acid or p-toluensulfonate. The preferred acid is formic acid.
The following aspect of the present invention the compound of formula IV obtained when the interaction of the compounds of formula V
in which a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, and in which X is Cl, Br, I or co3with the excess acetal of aminoacetaldehyde.
The following aspect of the present invention the compound of formula V in which X is Cl, Br or I, is produced by interaction of the compounds of formula VI
B>1-C3-alkyl or benzyl, with pentavalent phosphorus in an inert solvent. The compound of the formula V can also be obtained by the coupling of compounds of formula VI with (CH3)3O+BF4-with the formation of intermediate compounds in which X represents co3.
Pentavalent is patially phosphorus(III), patienty phosphorus (III) or pathiramanal phosphorus (III) and the solvent represents toluene. Preferred a is CH3.
In an additional aspect of the present invention the compound of formula VI is produced by interaction of the compounds of formula VIII
in which X is CL, Br or I, with an excess of 4-aminothiophenol with a base in an inert solvent with the formation of the compounds of formula VII
and subsequent treatment of the compounds of formula VII by acylation of galogenangidridy or acid anhydride.
Another preferred way of obtaining the compounds of formula VI is in the interaction of the compounds of formula VIII
in which X is CL, Br or I, with an excess of 4-aminothiophenol with a base in an inert solvent.
4-aminothiophenol is a 4-accessorie is a sodium carbonate/carbonate cesium.
The following aspect of the present invention the compound of formula VIII can be obtained by the coupling of compounds of formula
in which X is CL, Br or I, with bis 2-chloration ether, alkaline base and interfacial catalyst in an inert solvent.
Interphase catalyst is acidic sulfate, tetrabutylammonium. The base is a hydroxide of sodium.
The inert solvent is a mixture of tetrahydrofuran with water.
The invention relates also to a new compound of the formula
The invention also relates to a new compound of the formula
in which a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl.
in which a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, and in which X is Cl, Br, I or co3.
in which a represents a C1-C6is alkyl, aryl, which is6the alkyl.
The preferred connection is
These new compounds were used to obtain inhibitors of 5-lipoxygenase and their pharmaceutical compositions, useful in the treatment or alleviation of inflammatory diseases, Allergy and cardiovascular diseases in mammals.
A new method of synthesis is represented by the reaction scheme 1.
3-Bromophenylacetonitrile in tetrahydrofuran is treated with aqueous NaOH, acid sulfate and tetrabutylammonium bis 2-chloration ether, receiving arilbreds compound of formula VIII.
Arilbreds compound of formula VIII is treated with either 4-aminothiophenol getting aniline compound VII, followed by acylation or 4-aminothiophenol getting amide compound VI. Imidazole function enter when turning aminogroup formula VI by heating compound VI with pentachloride phosphorus (III) to give compound V to the imposition of the IV exists as a mixture of tautomers, which is not isolated and immediately subjected to acid-induced cyclization, getting imidazole compound III. Subsequent hydrolysis of the nitrile function imidazole compound III leads to the compound II - inhibitor of 5-lipoxygenase. Found the preferred salt form by treatment of compound II with methansulfonate that connects I.
In the new method of the present invention eliminated the previous two expensive of combination reaction on palladium (0) for introduction into the molecule of sulfide connection, as described in patent application U.S. 09/0200140, which is incorporated by reference. In addition, the aforementioned preferred sulfur atom previously introduced using TYPE C-Colnago reagent (TYPE C represents triisopropylsilyl), derived from toxic hydrogen sulfide and expensive TYPE C-chloride.
Compound I in which a represents a CH3is the preferred salt form of the inhibitor of 5-lipoxygenase, useful in the treatment or alleviation of inflammatory diseases, Allergy and cardiovascular diseases in mammals. In particular, compound I is useful in the treatment or alleviation of inflammatory diseases.
These useful of the various above-described conditions, these compounds and their pharmaceutically acceptable salts can enter the person or themselves, or preferably in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition in accordance with standard pharmaceutical practice. The compounds can be administered orally or parenterally in the usual way.
When the compound is administered to a person to prevent or treat inflammatory diseases, oral dosage will be from about 0.1 to 10 mg/kg body weight of the subject to be treated, per day, preferably from about 0.1 to 4 mg/kg / day in single or divided doses. If it is desirable parenteral administration, then the effective dose will be from about 0.05 to 5 mg/kg body weight of the subject to be treated, per day. In some cases it may be necessary to use dosages outside these limits, since the dosage will vary in accordance with age, weight and response of the individual patient and the severity of the symptoms of the disease and the effectiveness of a particular input connection.
For oral administration the compounds of this invention and their pharmaceutically acceptable salts can be entered, for example, in the form of tablets, powders, cakes, syrups or capsules illicitly include lactose and corn starch. In addition, it is usual to add lubricating agents such as magnesium stearate. In the case of capsules useful diluents include lactose and dried corn starch. When oral administration is required aqueous suspensions of the active ingredient is combined with emulsifying and suspendresume agents. Optionally, you can add certain sweetening and/or flavoring agents. For intramuscular, intraperitoneal, subcutaneous and intravenous administration is usually prepared sterile solutions of the active ingredient and pH of these solutions must be properly installed and buffered. With intravenous administration should control the total concentration of dissolved substances in order to get the preparation isotonic.
In addition, especially for the treatment of asthma, the compounds of formula I of this invention can enter the human body through inhalation. For this purpose they are administered in the form of a spray or aerosol in accordance with standard practice.
The present invention is illustrated by the following examples, but is not limited to their details.
Nitrile 4-(3-bromophenyl)-tetrahydropyran-4-carboxylic acid
3-Bromophenyl is whether dropwise bis 2-chlorotalonil ether (32 ml). The reaction mixture was heated at a temperature of education phlegmy 4 hours and then cooled. The mixture was diluted with EtOAc (400 ml), washed with 5% Hcl (200 ml), water (200 ml) and a saturated solution Panso3. After drying over Mg2SO4the solvent was removed, receiving raw CF-399,554 in the form of a waxy solid (75,4 g). This solid is suspended in a mixture of 1:1 isopropyl ether and hexane (100 ml) with nitrile 4-(3-bromophenyl)-tetrahydropyran-4-carboxylic acid (55,3 g, yield 80%).
Nitrile 4-[3-(4-aminophenylalanine)-phenyl]-tetrahydropyran-4-carboxylic acid
Nitrile 4-(3-bromophenyl)-tetrahydropyran-4-carboxylic acid (133,4 g), Na2CO3(363,6 g), Cs2CO3(223,1 g) and aminothiophenol (62.8 g) was heated in N-methylpyrrolidinone (2.3 l) at 130oWith in 24 hours. Added aminothiophenol (35,6 g) and continued heating for another 8 hours. The mixture was cooled to room temperature, poured into ice-cold water (6,8 l) and filtered. The product is suspended in water (2.5 l), again filtered and washed with water (1.5 l). After that, the product is suspended in EtOH (0.5 l), filtered, and dried at 40oC/20 mbar, resulting in nitrile 4-[3-(4-aminophenylalanine)-Phil)-phenylsulfanyl]-phenyl}ndimethylacetamide
Nitrile 4-(3-bromophenyl)-tetrahydropyran-4-carboxylic acid (1,33 g) was mixed with Na2CO3(1,59 g), Cs2CO3(0,651 g) and 4-acetamidophenol (1 g) in N-methylpyrrolidinone (15 ml). The reaction mixture was heated at 130oWith during the night. After cooling the mixture is poured into ice-cold water. The product precipitated in the form of a solid substance was collected by filtration with suction. The solid was recrystallize from a mixture of EtOAc and hexane, receiving N-{ 4-[3-(4-cyano-tetrahydropyran-4-yl)-phenylsulfanyl]-phenyl}ndimethylacetamide (1.4 g, yield 80%).
United examples 2 and 3
N-{4-[3-(4-cyano-tetrahydropyran-4-yl)-phenylsulfanyl]phenyl}ndimethylacetamide
Nitrile 4-[3-(4-aminophenylalanine)phenyl] -tetrahydropyranyloxy acid (93,57 g) and Et3N (53,1 ml) was dissolved in EtOAc (1,23 l) and heated to 50-60oC. To this solution for 30 minutes was added acetyl chloride (27.7 ml) in EtOAc (73 ml). The resulting suspension was filtered and washed filter cake EtOAc (3150 ml). The combined EtOAc solutions were washed with water (0.5 l), half-saturated aqueous Na2CO3(20.5 l), water (0.5 l) and saturated aqueous NaCl (0.25 l). The organic layers were dried over Na2SO4and boiled away in the 40oof the 40oC/20 mbar N-{4-[3-(4-cyano-tetrahydropyran-4-yl)-phenylsulfanyl]-phenyl} ndimethylacetamide (55,27 g, yield 52%).
Nitrile 4-{ 3-[4-(2-Mei-1-yl)-phenylsulfanyl] phenyl}-tetrahydropyran-4-carboxylic acid
Nitrile N-4-[3-(4-aminophenylalanine)phenyl] -tetrahydropyranyloxy acid (49,77 g) was dissolved in toluene (545 ml) and was heated to 60oIn terms of the azeotrope. From this solution azeotrope drove 20 ml of solvent to remove the remaining water. To this solution in several portions added PCl5(35,0 g). After stirring for 1 hour at 60oThe solvent was distilled. The residue was cooled to 10oWith and added a mixture of E3N (19,8 ml) and dimethylacetal of aminoacetaldehyde (15.2 ml) in EtOAc (500 ml). The resulting suspension was stirred for 30 minutes at 10oAnd then added EtOAc (150 ml). The mixture was washed with water (360 ml), then saturated aqueous NaCl (150 ml). The organic layers were dried over Na2SO4(52 g) and boiled away at the 50oC. the Residue was dissolved in formic acid (250 ml) and was heated to a temperature of education phlegmy for 1 hour. The reaction mixture was concentrated at 50oC/100 mbar and oil condition. This oil was dissolved in 10% soup half-saturated solution of K2CO3(175 ml) and was extracted with the solution in EtOAc (200 ml). The extract was dried over Na2SO4(48 g) and boiled away at the 50oC/100 mbar, having obtained after filtration through a layer of silica using as eluent CH2CL2/ 10% Meon, nitrile 4-{3-[4-(2-Mei-1-yl)-phenylsulfanyl] phenyl} -tetrahydropyran-4-carboxylic acid (27,6 g, total yield 55%).
Amide 4-{3-[4-(2-Mei-1-yl)-phenylsulfanyl]phenyl}-tetrahydropyran-4-carboxylic acid
Nitrile 4-{ 3-[4-(2-Mei-1-yl)-phenylsulfanyl] phenyl}-tetrahydropyran-4-carboxylic acid (27,35 g) was dissolved in tert-BuOH (280 ml) at 50oC. To this solution was added KOH (to 12.28 g) and the mixture was stirred over night. The suspension was cooled to room temperature and added water (180 ml). The resulting suspension was filtered and the filter cake was dried at 50oWith receiving amide 4-{3-[4-(2-Mei-1-yl)-phenylsulfanyl]phenyl}-tetrahydropyran-4-carboxylic acid (17,52 g, yield 55%).
Methylsulfonate amide 4-{3-[4-(2-Mei-1-yl)-phenylsulfanyl]phenyl}-tetrahydropyran-4-carboxylic acid
Amide 4-{ 3-[4-(2-Mei-1-yl)-phenylsulfanyl] phenyl}-tetrahydropyran-4-kalali methansulfonate until until all the substance is not dissolved. The resulting solution was filtered and washed filtrate Meon (20 ml). The combined solution Meon was treated with diisopropyl ether (280 ml) at room temperature. After stirring over night formed crystals, which were collected during the filtration and dried at 40oWith/19 mbar, receiving methylsulfonate amide 4-{ 3-[4-(2-Mei-1-yl)-phenylsulfanyl] phenyl} -tetrahydropyran-4-carboxylic acid (4,85 g, yield 77%).
1. The method of obtaining the compounds of formula I
in which a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl,
(a) includes the interaction of the compounds of formula
in which a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, with the acid in the C1-C5-Akilova alcohol;
C) deposition of the compounds of formula I by adding an organic solvent, the polarity of which is less than the above-mentioned alcohol.
2. The method according to p. 1, where the acid is methansulfonate.
3. The method according to p. 1, where the organic rastovac formula II is produced by interaction of the compounds of formula
in which a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3the alkyl or benzyl,
hydroxide in an alcohol solvent.
5. The method according to p. 4, where the hydroxide is a hydroxide of potassium.
6. The method according to p. 4, where the alcohol is a tributyl alcohol.
7. The method according to p. 4, where the said compound of formula III is produced by interaction of the compounds of formula
with organic or mineral acid.
8. The method according to p. 7, where the acid is an acetic acid, sulfuric acid, formic acid, or p-toluensulfonate.
9. The method according to p. 8, where the preferred acid is formic acid.
10. The method according to p. 7, where the said compound of formula IV is produced by interaction of the compounds of formula
in which a represents a C1-C6is alkyl, aryl, mono - or Disaese F, CL, Br, och3C1-C3the alkyl or benzyl;
X is CL, Br, I or co3, and the t dimethylacetal of aminoacetaldehyde or diethylacetal of aminoacetaldehyde.
12. The method according to p. 10, where the said compound of formula V in which X represents CL, Br, or I, is produced by interaction of the compounds of formula
in which a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3the alkyl or benzyl, with pentavalent phosphorus in an inert solvent; or in which X represents co3in formula V, C (CH3)3O+BF4-with the formation of intermediate compounds.
13. The method according to p. 12, where pentavalent is patially phosphorus, patienty phosphorus or pathiramanal phosphorus, and the solvent represents toluene.
14. The method according to p. 12, where the said compound of formula VI is produced by interaction of the compounds of formula
in which X represents Cl, Br, or I, with an excess of 4-aminothiophenol with a base in an inert solvent, with the formation of the compounds of formula
and subsequent treatment of the compounds of formula VII by acylation using gelegenheid or acid anhydride.
15. The method according to p. 14, where allerease agent represents acetyl chloride.
16. The method according to p. 12, where the said connection forms the Ohm 4-aminothiophenol with a base in an inert solvent.
17. The method according to p. 16, where 4-aminothiophenol is a 4-acetamidophenol.
18. The method according to p. 16, where the solvent is an N-organic or dimethylsulfoxide.
19. The method according to p. 16, where the base is a sodium carbonate/carbonate cesium.
21. The method according to p. 14, where the above-mentioned solvent is a sulfoxide or N-organic.
22. The method according to p. 16 where the above-mentioned compound of the formula VIII can be obtained by the coupling of compounds of formula
in which X represents CL, Br, or I, with bis 2-chloration ether, alkaline base and interfacial catalyst in an inert solvent.
23. The method according to p. 22, where an inert solvent is a mixture of tetrahydrofuran and water, the base is sodium hydroxide, and interfacial catalyst is an acidic sulfate, tetrabutylammonium.
24. The connection formulas
in which a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3the alkyl or benzyl.
25. Connection on p. Cl.
Derivatives of dibenzo[d, g][1,3]dioxazine and dibenzo-[d,g][1, 3,6]doxazocin, the method of production thereof, pharmaceutical composition and method of treating neurogenic inflammation, neuropathy and rheumatoid arthritis // 2178790
New derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease // 2177475
The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease
A method of producing an inhibitor of 5-lipoxygenase with different heterocyclic systems // 2177005
Substituted germanischer(thio)urea, the method of production thereof and pharmaceutical composition // 2170733
The invention relates to substituted chromalusion (thio)ureas of the formula (I):
where R (1) denotes hydrogen, alkyl with 1-4 C-atoms, alkoxy with 1-4 C-atoms, fluorine, chlorine, bromine, iodine, CF3, NH2, NH-alkyl with 1-4 C-atoms, N(alkyl)2with 1-4 C-atoms in the same or different alkyl residues, or S-alkyl with 1-4 C-atoms;
R (2a) denotes hydrogen or alkyl with 1 or 2 C-atoms;
R (2b) and R (2d), which are identical or different, denote hydrogen, alkyl with 1 or 2 C-atoms not substituted phenyl, substituted phenyl, unsubstituted benzyl or substituted phenyl residue, benzyl, and as the substituents in the phenyl residues are up to three identical or different substituents selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;
R (2c) and R (2e), which are identical or different, denote hydrogen or alkyl with 1 or 2 C-atoms;
R (3) denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, CH2-cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, or CF3;
Q represents (CH2)n;
where n = 1 or 2;
Z denotes serousily, selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;
A denotes the residue of a saturated or unsaturated lactam of the formula:
where B denotes albaniles or alkylene with 3, 4, 5 or 6 C-atoms, which is unsubstituted or substituted by up to three identical or different alkyl groups with 1, 2, 3 or 4 C-atoms;
A denotes the residue of a bicyclic system of the formula:
and their physiologically acceptable salts
Bicyclic compounds, the method of suppressing the adhesion of platelets and composition for its implementation // 2169146
The invention relates to bicyclic compounds useful as drugs, the neutralizing effect of glycoprotein IIb/IIIa, to prevent thrombosis
Derivatives of 5-naphthalene-1-yl-1,3-dioxane, methods for their preparation, drug and pharmaceutical composition based on them // 2163601
Taxanes, method for their production and pharmaceutical drugs based on them // 2163599
Carboxamide of benzofuran and pharmaceutical composition // 2162467
Sulfonamides and pharmaceutical drug // 2162084
Benzopyrane, the retrieval method, intermediate compounds and pharmaceutical compositions // 2160735
Derivatives of 1h-3-aryl-pyrrolidin-2,4-dione, the source and intermediate products for their production and the means to combat the damaging plants by insects and mites // 2144034
The invention relates to new derivatives of pyrrolidinone possessing biological activity, in particular derivatives of 1H-3-aryl-pyrrolidin-2,4-dione
Derivatives of 2,3-dihydropyrano[2,3-b]pyridine or its salt, the method of obtaining 2-aminomethyl-2,3-dihydropyrano(2,3-b) pyridine as starting substances for obtaining derivatives of 2,3-dihydropyrano[2,3-b]pyridine and method thereof // 2044737
The invention relates to chemical compounds with valuable properties, in particular derivatives of 2,3-dihydropyrano[2,3-b] pyridine of General formula
(I) where a lower alkylene;
R is a hydrogen atom or a group
A < / BR>
or their salts
Way optical separation pornoencaricaturas connection // 2026297
The invention relates to methods of optical separation pornoencaricaturas compounds, which are important intermediate product in the synthesis of optically active derivative of pianolasociety, useful in the treatment of hypertension (hypertension) and asthma
Derivatives of sulfonamides and pharmaceutical composition based on thereof // 2245876
FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.
SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.
EFFECT: valuable medicinal properties of compounds.
15 cl, 7 tbl, 56 ex
Inhibitors for producing/secretion of β-amyloid protein // 2304140
FIELD: organic chemistry, biochemistry, medicine.
SUBSTANCE: invention describes compound of the general formula (3): wherein R15 represents a heterocyclic group chosen from 3-7-membered saturated or 4,7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom, or 7-14-membered polycyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R16 represents a cycloalkyl group comprising 3-7 carbon atoms, monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms, or heterocyclic group chosen from 3-7-membered saturated or 4-7-membered unsaturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R17 represents a monocyclic aromatic hydrocarbon group comprising 6-14 carbon atoms or heterocyclic group chosen from 4-7-membered saturated monocyclic heterocyclic group comprising 1-4 atoms chosen from nitrogen atom, oxygen atom and sulfur atom that can comprises a substitute; R18 represents hydrogen atom or (C1-C)-alkyl group; X represents -S-, -SO- or -SO2; or N-oxide or S-oxide of this compound; their salt; or solvate of above described compound. Proposed compounds possess the inhibitory activity against producing/secretion of β-amyloid protein and can be used in treatment of such diseases as Alzheimer's disease, Down's disease and other diseases associated with amyloid deposition.
EFFECT: valuable medicinal properties of inhibitors.
7 cl, 1 tbl, 410 ex
Naphtylene derivative as cytochrome p450 inhibitors // 2363696
SUBSTANCE: present invention refers to the new naphtylene derivative having general formula (I-A) and to their pharmaceutically acceptable salts having the property of inhibition of the cytochrome ferment P450RAI (Cyp26) activity, to the pharmaceutic composition thereof and to the method of inhibition of cytochrome ferment P450RAI (Cyp26). , wherein X is selected from imidasolyl or triasolyl; R2 and R3, independently represent H, C1-10-alkyl; G1 is -NR72R82 or G1 and R3 taken together with attached carbon atom form 3-10-membered saturated ring or heterocyclic saturated ring containing N as heteroatom which is optionally substituted with substituting group R72, Z, R4b, R5b, Q1, R72, n2, n3 and n4 values are indicated in the formula of the invention.
EFFECT: present invention refers to the intermediates for compounds with general formula (I-A) and to their pharmaceutic salts thereof.
37 cl, 30 dwg, 7 tbl
Pyran derivatives, method for preparing and using them in perfumery and for aromatisation // 2459816
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to new pyran derivatives of general formula (I), wherein Y represents a 5-, 6- or 7-member ring, preferentially a 5- member ring, methyl- or ethyl- mono- or polysubstituted and optionally unsaturated; R1, R2, R3, R4 represent (each independently) a hydrogen atom or a linear or branched C1-5-alkyl group; X is present or absent when X is present, all R5, R6, R7, R8, R9 are present, while X is a hydrogen atom or the group OZ wherein Z is a hydrogen atom or the group R10 or the group C(O)R10; when X is absent, there is a double bond at a carbon atom in the 4th position, and R7, R8 and R9, and one of R5 or R6 are present (if R6 is present, then R5 is absent, and conversely), or one of R5, R6 and R7, and one of R8 or R9 are present (if R8 is present, then R9 is absent, and conversely), or R7 represent a group =C(R11)(R12), and R5, R6, R8, R9 are present; each of the groups R5-R12, when present, independently represent a hydrogen atom or a linear or branched C1-5-alkyl or C2-5-alkenyl group. The invention also relates to method for making these compounds, a pharmaceutical composition and using at least one pyran of formula (I) as a perfuming agent.
EFFECT: preparing new pyran derivatives.
14 dwg, 1 tbl, 4 ex
Substituted derivatives of 4-aminocyclohexane // 2525236
SUBSTANCE: invention relates to novel compounds of general formula (1), which possess affinity for µ-opioid receptor and ORL1-receptor, to medications, containing said compounds, and to application of said compounds for obtaining medications, suitable for treating pain, fear, stress and other diseases or conditions. In general formula (1) Y1, Y1', Y2, Y2', Y3, Y3', Y4 and Y4' stand for -H; R1 and R2 independently on each other stand for -H or -CH3; on condition that R1 and R2 both simultaneously do not stand for -H; Q stands for: -C6-16-aryl, non-substituted or mono- or poly-substituted with -F, -Cl, -Br or -I; or heteroaryl; R3 stands for: -C1-8-alkyl, non-substituted or mono- or poly-substituted -OR0, where R0 stands for non-substituted -C1-3-alkyl; non-substituted -C3-6-cycloalkyl-C1-4-alkyl; non-substituted -C1-4-alkyl-C3-6-cycloalkyl; -C6-16-aryl, non-substituted or mono- or poly-substituted with -F, -Cl, -Br, -I, -CN, -R0 or -OR0, where R0 stands for non-substituted -C1-8-alkyl; or heteroaryl; n stands for 0; X stands for -NRA-; RA stands for -H or -R0; where R0 stands for non-substituted -C1-4-alkyl; and RB stands for -C(=O)R0; where R0 stands for non-substituted -C2-8-alkenyl-C6-16-aryl or non-substituted -C1-8-alkyl-(C6-16-aryl)1-2.
EFFECT: obtaining compounds for obtaining medications, suitable for treatment of pain, fear, stress and other diseases or conditions.
10 cl, 14 tbl, 164 ex
Tetrasubstituted benzenes // 2527177
SUBSTANCE: invention relates to novel compounds of formula III or to its pharmaceutically acceptable salts, in which: R1 and R2 are independently selected from group, consisting of: (a) H, (b) (C2-C6)alkyl, (c) C1-C6 alkyl, interrupted by one or more groups -O-, (d) (C0-C3)alkyl-(C3-C7)cycloalkyl and (e) (CH2)nQ, where n=1-2 and where Q stands for aromatic ring system, which has from 5 to 6 ring atoms C, and Q can be independently substituted with groups up to 3 in number, selected from halogen, on condition that R1 and R2 simultaneously do not stand for H, and each alkyl of R1 and R2 can be independently substituted with one or more groups, selected from group, consisting of halogen, hydroxy, cyano, CF3 or C1-C4 alkyl, or R1 and R2 together with carbon, to which they are attached, form 3-7-member cycloalkyl or 6-member heterocycloalkyl ring, including one oxygen atom and which in case of necessity carries C1-C4 alkyl substituent, or R1 and R2 together with carbon, to which they are connected, form 3-7-member cycloalkyl ring, substituted with R20 and R21, and R20 and R21 together with carbon or carbons, to which they are connected, form 3-7-member cycloalkyl ring; R6 stands for C1-C6 alkyl; each R7 independently stands for C1-C6 alkyl; Y stands for -O-; R4 is selected from group, consisting of: (a) (C0-C3)alkyl-(C3-C7)cycloalkyl, (b) trifluoroethyl, and (c) trifluoropropyl; Z stands for phenyl or bicyclic ring system, which has 9 ring atoms, independently selected from C, N, O and S, on condition that not more than 3 ring atoms in any single ring differs from C, and said ring system can carry to 3 substituents, independently selected from group, consisting of R6, CF3 and SR6; and R5 is selected from group, consisting of NO2, NH2, F, Cl, Br, CN, SR6, S(O)2N(R7)2 and (C1-C4)alkyl, and each alkyl can be independently substituted with one or more halogens or CF3. Invention also relates to pharmaceutical composition for treatment of neurodegenerative disorder or improvement of cognitive function, containing therapeutically effective quantity of said compound; as well as to method of treatment of neurodegenerative disorder, for instance Alzheimer's disease, or improvement of cognitive function.
EFFECT: compounds act as modulators of gamma-secretase.
31 cl, 14 tbl, 3147 ex, 1 dwg
SUBSTANCE: invention relates to novel compounds of general formula (1), which possess an affinity to the µ-opiod receptor and the ORL1-receptor. The invention also relates to the application of the said compounds for obtaining medications, which can be used in treatment of fear, stress and associated with stress syndromes, depressions, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disorders (as nootropic), withdrawal syndromes, alcohol and/or drug abuse and/or abuse of medications and/or alcohol, narcotic and medication addiction, etc. In general formula (1) (1) Y1, Y1 ', Y2, Y2 ', Y3, Y3 ', Y4 and Y4 ' in each case stand for -H; Q stands for -R0, -C(=O)-R0, -C(=O)OR0, -C(=O)NHR0, -C(=O)N(R0)2 or-C(=NH)-R0; R0 in each case stands for -C1-8-aliphate, -C3-12-cycloaliphate, -aryl, -heteroaryl, -C1-8-aliphate-C3-12-cycloaliphate, -C1-8-aliphate-aryl, -C1-8-aliphate-heteroaryl, -C3-8-cycloaliphate-C1-8-aliphate, -C3-8-cycloaliphate-aryl or -C3-8-cycloaliphate-heteroaryl; R1 and R2 independently on each other stand for -C-1-8-aliphate; R3 stands for -C1-8-aliphate, -aryl, -heteroaryl or -C1-8-aliphate-C3-12-cycloaliphate; n stands for 0; X stands for -NRA-;RA stands for -C1-8-aliphate; RB stands for -C1-8-aliphate; on condition that R1, R2, RA and RB simultaneously do not stand for the non-substituted-C1-8-aliphate.
EFFECT: increased efficiency of the application of the compounds.
9 cl, 11 tbl, 164 ex
Ingenol-3-acylates iii and ingenol-3-carbamates // 2572549
SUBSTANCE: invention relates to compound of general structural formula which can be used for prevention, treatment, relieving course or prevention of physiological disorders or diseases, associated with hyperplasia or neoplasia. In formula (I) R stands for 5-10-membered mono- or bicyclic heteroaryl, containing 1-3 heteroatoms, selected from O, N and S, which can be optionally substituted with one or more substituents, independently selected from R7, or R stands for 5-10-membered heterocycloalkyl, containing 1-2 heteroatoms, selected from O, N and S, or 5-10-membered heterocycloalkenyl, containing 1-2 heteroatoms, selected from O, N and S, where said 5-10-membered heterocycloalkyl or 5-10-membered heterocycloalkenyl are optionally substituted with one or more substituents, independently selected from R8; or R stands for X; R7 represents halogen; or R7 represents (C1-C4) alkyl, (C2-C4) alkenyl, (C3) cycloalkyl, 6-membered heterocycloalkyl, containing 1 heteroatom, selected from N, C6-aryl, C6-aryl (C1-C4) alkyl, 6-membered heterocycloalkyl (C1-C4) alkyl, containing 1 heteroatom, selected from O, or (C3) cycloalkyl (C1-C4) alkyl, where said (C1-C4) alkyl or C6-aryl are optionally substituted with one or more substituents, independently selected from R9; or R7 represents -ORa; Ra represents (C1-C4) alkyl; Rc represents (C1-C4) alkyl; X represents -NR11R12, Rf represents (C1-C4) alkyl. Values of radicals R8-R13, Rd are given in the invention formula.
EFFECT: invention relates to pharmaceutical composition, containing said compound, and to method of prevention, treatment, relief of course or prophylaxis of physiological disorders or diseases, associated with hyperplasia or neoplasia, responding to stimulation of neutrophil oxidative burst, stimulation of IL-8 release from keratinocytes and to necrosis induction.
36 cl, 2 tbl, 753 ex