WO2006054912A1 - Derives d'aryl(hetaryl)-3-aminomethylchinolone-2 utilises en tant qu'inhibiteurs de no-synthetase et de cyclo-oxygenase-2, procedes de leur fabrication et compositions pharmaceutiques sur leur base - Google Patents

Derives d'aryl(hetaryl)-3-aminomethylchinolone-2 utilises en tant qu'inhibiteurs de no-synthetase et de cyclo-oxygenase-2, procedes de leur fabrication et compositions pharmaceutiques sur leur base Download PDF

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WO2006054912A1
WO2006054912A1 PCT/RU2004/000457 RU2004000457W WO2006054912A1 WO 2006054912 A1 WO2006054912 A1 WO 2006054912A1 RU 2004000457 W RU2004000457 W RU 2004000457W WO 2006054912 A1 WO2006054912 A1 WO 2006054912A1
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methyl
quinolin
phenylamino
aik
piperidin
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PCT/RU2004/000457
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English (en)
Russian (ru)
Inventor
Mihail Alekseevich Kirpichenok
Dmitriy Vladimirovich Genis
Oleg Gennad'evich Rodin
Roman Victorovich Kombarov
Valeriy Sergeevich Kochubey
Vladimir Nikolaevich Saekov
Il'ya Igorevich Afanas'yev
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Obchestvo S Ogranichennoy Otvetstvennost'u 'asineks Medhim'
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Priority to PCT/RU2004/000457 priority Critical patent/WO2006054912A1/fr
Publication of WO2006054912A1 publication Critical patent/WO2006054912A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to the field of organic chemistry and medicine, in particular to biologically active compounds that inhibit NO synthetase and cyclooxygenase-2, and pharmaceutical compositions based on them, which can be used in the treatment of cardiovascular, gastrointestinal diseases; various disorders of the functioning of organs; inflammatory processes in the body; strokes, Alzheimer's and Parkinson's disease; regulation of pain, duration of sleep, secretion of gastric juice, blood pressure, platelet aggregation, etc.
  • NO synthetase is an enzyme that catalyzes the conversion of L-arginine to nitric oxide (II) (NO). This process was first discovered in the late 80s, and since then until now have been discovered more and more NO functions in the body. Accordingly, the importance of NO synthetase for regulating various body functions is constantly increasing, and therefore, the importance of various inhibitors and modulators of this enzyme for the treatment of diseases associated with impaired functions is also increasing. In the general case, we can say that nitric oxide (II) is involved:
  • Cyclooxygenase is an enzyme that takes part in one of the main directions of arachidonic acid metabolism. It catalyzes the conversion of the latter to prostaglandins G 2 and H 2 , from which the remaining prostaglandins subsequently form.
  • COX-I and COX-2 Two main forms of cyclooxygenase (souslohepase, COX) are known: COX-I and COX-2.
  • the first of them is a constitutive enzyme, constantly contained in the gastric mucosa, platelets, endothelium of blood vessels and in the kidneys.
  • the second is inducible and is expressed in activated macrophages and monocytes, as well as in smooth muscle cells, epithelial and endothelial cells and neurons.
  • the literature describes structural analogues of the proposed compounds, which are biologically active compounds and are used in biology and medicine.
  • drugs used for these diseases including those based on the action of NO synthetase inhibitors.
  • Anti-inflammatory drugs are also known whose effect is caused by the inhibition of cyclooxygenase.
  • U.S. Pat. No. 5,874,472 discloses NO synthetase inhibitors in which the arginine side chain is modified to include five or six membered aromatic or heteroaromatic rings (thiophene, benzene, pyridine, etc.).
  • the data on activity against NO synthetase isolated from various sources show activity at the level of Ki of 0.5-50 and higher nM. No toxicity information is provided for the compounds presented in this patent.
  • JP N ° 10-120654 which describes 4-methyl-3,4-dehydro-2-imino-sherpidine derivatives.
  • Application EP N ° 439265 discloses heterocyclic compounds which are cyclooxygenase and lipoxygenase inhibitors, which are used as antiallergenic and antimicrobial agents.
  • JP 03-220160 discloses heterocyclic compounds, which are COX and lipoxygenase inhibitors, used to treat allergic and inflammatory diseases.
  • COX inhibitors have the structural formulas shown below:
  • USNa6509352 describes quinolone-2 derivatives used as immunosuppressants, anti-inflammatory and anti-allergic drugs.
  • Derivatives of quinolone-2 are known from the patent RU N ° 2167874 for the treatment of hypertension, ischemia, myocardial infarction, angina pectoris, etc.
  • Application JP N ° 58-225065 describes anti-allergic and anti-asthmatic substances based on quinolone-2 and its derivatives.
  • US Pat. No. 5,646,132 discloses quinolone-2 derivatives useful for treating various forms of epilepsy, Alzheimer's disease, schizophrenia and sclerosis.
  • quinolone-2 derivatives known from the application RU N ° 95-l 09098 are used as anticonvulsants.
  • US Pat. No. 6,605,616 describes quinoline derivatives which are amides of 4-oxo-quinol-2-one-3-carboxylic acids on aromatic amines, which necessarily contain a methyl substituent at the nitrogen atom. These compounds were tested as inhibitors of acute experimental autoimmune encephalomyelitis, however, there is no mention of their activity against NO synthetase or MOR.
  • the problem to which the present invention is directed is to obtain amino and hydroxy derivatives of phenyl-3-amino-methyl-quinolone-2, as well as derivatives of get-3-amino-methyl-quinolone-2, which have significantly higher activity (IC 50 1 -10 nM), as well as higher selectivity with respect to the corresponding enzyme isoforms (inducible and neuronal NO synthetase and inducible cyclooxygenase compared to endothelial NO synthetase and constitutive cyclooxygenase) with simultaneous pronounced synergism of action, little toxic to the human body with no identified side effects.
  • Another objective of the present invention is to develop methods for the synthesis of these compounds, as well as pharmaceutical compositions containing a therapeutically effective amount thereof in combination with a pharmaceutically acceptable carrier.
  • the present invention proposes new compounds, which are inhibitors of the arginine site of inducible and neuronal NO synthetases, do not affect its endothelial form in the physiologically acceptable concentration range, and while they are inhibitors of the inducible form of cyclooxygenase, which are highly active and do not affect the constitutive form in same range.
  • the description of the present application provides a method for inhibiting the conversion of arginine to nitric oxide by the inducible and neuronal forms of NO synthetase and a method for inhibiting cyclooxygenases of the first and second types, i.e., the concentrations of the inhibitors described below that are sufficient for effective inhibition of enzymes under physiological conditions, the conditions for their administration, as well as the method of their inhibition in conditions such as rheumatoid arthritis, pathologically low blood pressure, septic shock, colitis or autoimm nnye disorders, conditions and methods of administration and dosing of these inhibitors, sufficient to achieve a therapeutic effect.
  • the effectiveness of the proposed methods is due to the synergism of the actions of patented compounds as inhibitors of COX and inducible NO synthetase.
  • the proposed substances are new derivatives of quinolone-2, namely the amino and hydroxy derivatives of phenyl-3-aminomethyl-quinolone-2, as well as get -yl-3-aminomethyl-quinolone-2, and are positioned as inhibitors of the so-called inducible N and neuronal -synthetases responsible for the generation of NO, mainly in phagocytic cells and neurons, as well as cyclooxygenase, primarily of the second type, which ensures the generation of prostaglandins in them.
  • the compounds claimed in the present invention are mainly secondary amines, in contrast to the known analogues, which are tertiary amides. This important difference causes a difference in the methods of synthesis and physicochemical properties of the obtained compounds.
  • the substituent at position 4 of the quinoline ring is H or AIk, unlike the acloxy substituent (-OR) at the same position in the known compounds described in the above patents.
  • OAlk means an alkoxy group, i.e. an alkyl group attached to a fragment of the parent molecule through an oxygen atom.
  • alkoxy groups are methoxy, ethoxy, propoxy, butoxy, etc.
  • Alk means alkyl, i.e. straight or branched chain saturated hydrocarbon containing from 1 to 10 carbon atoms. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, etc.
  • SAlk means thioalkyl, i.e. an alkyl group attached to a fragment of the parent molecule through a sulfur atom.
  • thioalkyls include, for example, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl, etc.
  • SO 2 Alk means alkylsulfonyl, i.e. an alkyl group attached to a fragment of the parent molecule through a sulfonyl group — SO 2 .
  • alkylsulfonyls are. Without limiting the scope of this invention, methylsulfonyl, ethylsulfonyl, etc.
  • Ar means aryl, i.e. monocyclic aromatic system, for example, without limiting the scope of the invention, benzyl, phenyl, etc.
  • H means hydrogen.
  • NO 2 refers to a nitro group.
  • Hal means halogen: F, Cl or Br.
  • Het means a heterocycle and includes a mono- or bicyclic system.
  • the monocyclic system may contain a 3- or 4-membered ring containing a heteroatom independently selected from oxygen, nitrogen or sulfur; or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur.
  • 5-membered ring contains
  • Non-limiting examples of monocyclic heterocycles are furyl, imidazolyl, morpholinyl, scherazinyl, piperidinyl, pyranyl, etc.
  • Bicyclic systems are represented by any of the above monocyclic heterocycles attached to any aromatic group described above. Examples of such systems, not limiting the scope of this invention, are: indazolyl, quinolinyl, etc.
  • OH refers to a hydroxy group
  • CO means a carbonyl group
  • COOAlk means alkoxycarbonyl, i.e. alkoxygroup attached to the fragment of the original molecule through a carbonyl group.
  • alkoxycarbonyls are: methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.
  • CN means a cyano group.
  • COOH means a carboxy group.
  • amino derivatives of phenyl-3-aminomethyl-quinolone-2 are provided having the general formula (1): Where:
  • Rl, R2, R3, R4 are H;
  • Rl, R2, R3, R4 are independently the same or different, and at least one of Rl, R2, R3, R4 is selected from the group consisting of:
  • R 2 and R 3 are taken together and selected from - (CH 2 ) s -, - (CH 2 ) 4 -, -OCH 2 O-, - OCH 2 CH 2 O-, with Rl and R4 being the same or different and independently selected from H, AIk, OAIk, HaI;
  • R5 is independently selected from H or AIk
  • R6 is independently selected from H, AIk, CH 2 NO 2 ;
  • R7, R8, RlO, RIl are independently the same or different, and at least one of R7, R8, RlO, RIl is selected from AIk, OAIk, CH 2 OH, SAIk,
  • R9 is independently selected from H or from the following substituents:
  • X is independently selected from OH or AIk
  • Y is independently selected from AIk, OAIk, Ar, or He;
  • R22, R23 are independently selected from H, AIk, OAIk, SAIk, HaI, COOH, COOAIk, SO 2 AIk 5 NO 2 , CN;
  • R24, R25 are the same or different and are independently selected from H, AIk;
  • R26 is independently selected from H or AIk
  • R27, R28 are independently selected from H, AIk, OAIk, HaI, NO 2 , CN; or and
  • R8 and R9 are taken together and selected from - (CH 2 ) s-, - (CH 2 V? -OCH 2 O-, - OCH 2 CH 2 -, while R7, RIl are independently the same or different and are selected from H, HaI, NO 2 ; and RlO is H; Rl 2, Rl 3 are independently the same or different and are selected from the group consisting of H, AIk, Bz.
  • Specific compounds corresponding to the general formula (1) include, for example, the following, but not limited to: 3 - [(4-dimethylamino-phenylamino) methyl] -5,6,7-trimethoxy-S-quinolin-2 ⁇ one ;
  • hydroxy derivatives of phenyl-3-aminomethyl-quinolone-2 are provided having the general formula (2):
  • Rl, R2, R3, R4 are H;
  • Rl, R2, RZ, R4 are independently the same or different, and at least one of Rl, R2, RZ, R4 is selected from the group consisting of: AIk, OAIk, Ar, OAr, CH 2 C 6 H 5 , SAIk, F, Cl, Br, OCF 3 , NO 2 , NH 2 , NHAIk, N (AIk) 2 ; wherein the other or the other of Rl, R2, R3, R4 are H; or
  • R 2 and R 3 are taken together and selected from - (CH 2 ) s -, - (CH 2 ) 4 -, -OCH 2 O-, - OCH 2 CH 2 O-, with Rl and R4 being the same or different and independently selected from H, AIk, OAIk, HaI; R5 is independently selected from H or AIk;
  • R6 is independently selected from H, AIk, CH 2 NO 2 ; at least one of R7, R8, R9, RlO, RIl is OH, and the other or the other of R7, R8, R9, RlO, RIl are independently the same or different and are selected from H, AIk, OAIk, Ar, OAr, SAIk;
  • Rl 2, Rl 3 are independently the same or different and are selected from the group consisting of H, AIk, Bz.
  • Particular compounds corresponding to general formula (2) include, for example, the following, but not limited to: 3 - [(3,4-dihydroxy-phenylamino) methyl] -5,7-dimethyl-III-quinolin-2-one ;
  • Rl, R2, R3, R4 are H;
  • Rl, R2, RZ, R4 are independently the same or different, and at least one of Rl, R2, RZ, R4 is selected from the group consisting of: AIk, OAIk, Ar, OAr, CH 2 C 6 H 5 , SAIk, F, Cl, Br, OCF 3 , NO 2 , NH 2 , NHAIk,
  • R5 is independently selected from H or AIk
  • R6 is independently selected from H, AIk, CH 2 NO 2 ;
  • Rl 2, Rl 3 are independently the same or different and are selected from the group consisting of H, AIk, Bz.
  • R9 is independently selected from the following substituents:
  • RZO, R31 are the same or different and independently selected
  • R34 is independently selected from the following substituents:
  • R32, RZZ are independently selected from H, AIk, OAIk;
  • the problem is also solved by the methods of obtaining the proposed amino and hydroxy derivatives of phenyl-3-aminomethyl-quinolone-2, as well as getapyl-3-aminomethyl-quinolone-2, having the above general formulas (1-3), and biologically active compounds and a pharmaceutical composition based on them.
  • the synthesis of the proposed compounds having the general formula (1) is carried out by reacting the corresponding substituted 2-quinolone-3-carbaldehyde with the corresponding phenylenediamine derivatives. Further, the obtained azomethines or the so-called Piff compounds are reduced.
  • the synthesis of the proposed compounds having the general formula (2) is carried out by reacting the corresponding substituted 2-quinolone-3-carbaldehyde with various anisidines, then the resulting Schiff bases are reduced, after which the alkyl esters are cleaved with Lewis acids.
  • the synthesis of the proposed compounds having the General formula (3) is carried out by the interaction of the corresponding substituted 2-quinolone-3-carbaldehyde with various heterocyclic compounds containing an amino group, followed by reduction of the resulting Schiff bases.
  • substituted acetanilides are synthesized from anilines with substituents Rl, R2, R3, R4, such as described above.
  • the synthesized acetanilide is added to the Vilsmeier formative mixture obtained by dropping POCl 3 to dimethylformamide.
  • two options for its implementation are possible: with cooling the reaction mixture (example 1) or with its heating to 50 ° C (example 3). It should be noted that the choice of starting acetanilides for the reaction under consideration is determined by the nature of the substituents in the benzene fragment.
  • the presence of electron-donating substituents in the benzene ring leads to a significant decrease in the yield of the target reaction products.
  • the direction of the reaction is regioselective with the formation of almost one isomer, namely, 7-substituted quinolines.
  • the final stage in the synthesis of substituted 2-quinolone-3-carbaldehydes is the hydrolysis of the corresponding 2-chloropinquinoline-3-carbaldehydes by boiling them in aqueous acetic acid (the concentration of acetic acid is about 80-90%) (example 2).
  • the reaction time ranges from 4 to 12 hours.
  • the reaction product as a rule, is isolated in the form of a crystalline substance as the reaction proceeds, or after completion of the process by cooling the reaction mixture.
  • the resulting substituted 2-quinolone-3-carbaldehydes were usually used in further transformations without further purification. If necessary, the synthesized substances were brought to the required degree of purity by recrystallization from acetic acid or dimethylformamide.
  • 4-chloronitrobenzene can be used in which the substituents R7, R8, RlO, RI l are as described above.
  • the corresponding N, N-disubstituted p-nitrobenzene at 80-100 ° C is obtained as a result of nucleophilic substitution reaction (Example 43).
  • Substituent R9 is selected from the above groups. The reaction is usually carried out with an excess of the corresponding amine or the environment of the secondary amine itself.
  • the interaction is carried out in a medium of dimethylformamide (example 61) or another solvent (acetonitrile, dioxane, etc.) in the presence of an inorganic base (potash, soda, etc.).
  • an inorganic base potash, soda, etc.
  • Purification of the obtained nitro compounds is carried out by recrystallization from a suitable solvent or separation using silica gel column chromatography.
  • the obtained nitro derivatives are reduced to the corresponding amines using any reducing reagents available and suitable for this type of reaction (catalytic hydrogenolysis (example 44), reduction with hydrazine hydrate in the presence of Raney nickel (example 72), iron in hydrochloric acid, tin chloride and other).
  • the synthesized amines are purified by recrystallization or silica gel column chromatography is used. Often, the amines obtained are not stable substances and are rapidly oxidized by atmospheric oxygen, as a result of which there is a need to use these compounds in further syntheses immediately after their preparation.
  • Schiff bases and the corresponding hydroxyenamines are reduced to give the final desired products.
  • an intermediate allocation of Schiff bases is possible.
  • the reaction is most often carried out in dioxane or in dimethylformamide with temperature of about 100 0 C.
  • the resulting Schiff bases are reduced without further purification with sodium borohydride in alcohol (methanol, ethanol).
  • the reaction is carried out in an inert solvent (acetonitrile, dichloroethane, etc.). Initially, for some time (about 1 hour), the reaction between the corresponding aldehyde and the primary amine is carried out with gentle heating. Subsequently, sodium triacetoxyborohydride or sodium cyanoborohydride is added in portions with effective stirring in the reaction mass (example 73). If necessary, a small amount of acetic acid is added. At the end of the process, the reaction mixture is diluted with an aqueous solution of soda or potash. The organic layer was separated, dried. The resulting desired products are recrystallized from a suitable solvent or purified by silica gel column chromatography.
  • an inert solvent acetonitrile, dichloroethane, etc.
  • reaction is carried out at very low temperatures (up to -50 0 C) in inert solvents such as methylene chloride.
  • inert solvents such as methylene chloride.
  • the mixture is decomposed with absolute methanol. Purification of the resulting substances is carried out by recrystallization from a suitable solvent.
  • the starting compounds used are the corresponding substituted 2-quinolone-3-carbaldehyde synthesized according to Scheme I 5 and the corresponding heterocyclic compounds in which there are amino groups.
  • Schiff bases are obtained, which are then reduced.
  • the reaction is possible both with an intermediate isolation of Schiff bases, and without it. In the latter case, the synthesis is carried out under the conditions of a reductive amination reaction.
  • R6, Rl 2 and Rl 3 with other substituents other than H mentioned above can be carried out by reacting the compounds obtained in accordance with the above schemes 1-5 with reagents containing these groups by carrying out the corresponding reactions.
  • the compounds described in this invention may exist in the form of therapeutically acceptable salts. This means that the salts of these * compounds are soluble or dispersible in water or oils, toxic and acceptable for the treatment of diseases without side effects, do not cause allergies. Salts can be prepared by finishing the desired product or separately by reaction with a suitable acid.
  • Such salts may be alginates, aspartates, acetates, benzoates, benzosulfonates, bigluconates, bromides, butyrates, glycerophosphates, gluconates, camphorites, camphorsulfonates, lactates, maleates, nicotinates, oxalates, pectinates, persulfates, propionates, subcinates, tincinates, subcinate, citrates, sulfides, phosphates, etc.
  • Basic salts can be prepared in the process of final cleaning of the target product or separately by interaction with a base containing lithium, sodium, potassium, calcium, magnesium or aluminum ions.
  • the compounds described in this invention may exist as prodrugs.
  • prodrugs that are acceptable for contacting patients with diseases are non-toxic, do not cause side effects and allergies.
  • This term refers to compounds that are rapidly transformed ip vivo into compounds of formulas (1), (2) or (3), for example, by hydrolysis in blood.
  • compositions of the subject compounds include effective amounts thereof with one or more pharmaceutically acceptable excipients.
  • This term refers to non-toxic, solid, semi-solid and liquid fillers, solvents, encapsulating materials.
  • excipients are sugars, cellulose or its derivatives, oils, glycols, solutions; buffering, coloring, coating, softening, flavoring perfumes, etc.
  • the pharmaceutical compositions may be administered parenterally, intracisternally, orally, rectally or intraperitoneally.
  • Liquid forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups H elixirs. In this case, in addition to the claimed compounds, they contain solvents and / or emulsifiers.
  • oral compositions may include wetting, emulsifying, flavoring and perfuming agents. These drugs must be sterilized by filtration through filters that trap bacteria, or contain sterilizing agents.
  • Solid forms for oral administration are capsules, tablets, pills, powders or granules.
  • the claimed compound is mixed with at least one inert, therapeutically acceptable excipient, such as a carrier, diluent, adsorbent, wetting or lubricating material.
  • these compositions may also optionally include buffering agents.
  • Suppositories for rectal administration can be prepared by mixing the claimed compounds with excipients that are solid at ordinary temperature, but liquid when ingested.
  • the claimed compounds can be encapsulated or microencapsulated with one or more inert excipients described above. Tablets, dragees, capsules, pills or granules may be coated. To this end, the claimed compounds can be mixed with at least one inert solvent and a tabletting lubricant or additive.
  • the formulating mixture is prepared according to Example 1 and 37.3 g (0.25 mol) of N-ortho-tolyl acetanilide are added at a temperature of about 50 ° C. The resulting reaction mixture is maintained at the indicated temperature for 1 hour, then the temperature of the reaction mixture is raised to 90-100 0 C and withstand. Next, the reaction mixture is cooled and poured onto 1.5 kg of finely divided ice. After hydrolysis, the resulting suspension is filtered off, washed with water until slightly acidic or neutral (pH> 5). 28 g (54%) of product (III) are isolated. An analytically pure sample is obtained by recrystallization from acetone or chloroform. T. pl. 134-136 0 C.
  • Ni-NMR spectrum ( ⁇ , DMSO-d b ): 3.9 (ZN, s); 4.0 (ZN, s); 4.1 (ZN, s); 7.3 (IH, s); 8.75 (IH, s); 1 O. Z (1H, s).
  • Ni-NMR spectrum ( ⁇ , DMSO-d 6 ): 3.7 (S, s); 3.8 (ZN, s); 3.9 (ZN, s); 6.7 (IH, s); 8.4 (IH, s); 1O.2 (1H, s); 12.0 (IH 5 broad peak).
  • l-benzyl-4 (4-nitrophenyl) piperazine (17.3 g, 0.06 mol) is the product of LXXI, dissolved in 150 ml of methanol, the temperature of the reaction mixture is brought to 40-45 0 C and then hydrazine hydrate is added ( 80%, 10 ml, 0.15 mol) and then Raney nickel is added in portions. At the end of the reaction, the reaction mixture was filtered and concentrated. The resulting product is purified by passing through a layer of silica gel (KCK, 60/100 ⁇ m) in a chloroform-methanol system. The fractions containing the product are concentrated. 9.1 g (58%) of product LXXII are obtained. L ⁇ -Mass (M + H) + : 268.

Abstract

La présente invention se rapporte aux composés possédant la formule suivante (I), aux procédés de leur fabrication, aux composés bioactifs inhibant la NO-synthétase et la cyclo-oxygénase-2 et aux compositions pharmaceutiques sur leur base, qui peuvent s'utiliser pour traiter des maladies cardio-vasculaires ou gastro-intestinales ainsi que de divers troubles de fonctionnement des organes ou des processus inflammatoires dans l'organisme humain, des ictus, des maladies d'Alzheimer et de Parkinson, pour combattre la sensation de la douleur et réguler la durée du sommeil, la sécrétion du suc gastrique, la pression artérielle, l'agrégation des thrombocytes, etc.
PCT/RU2004/000457 2004-11-18 2004-11-18 Derives d'aryl(hetaryl)-3-aminomethylchinolone-2 utilises en tant qu'inhibiteurs de no-synthetase et de cyclo-oxygenase-2, procedes de leur fabrication et compositions pharmaceutiques sur leur base WO2006054912A1 (fr)

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Cited By (12)

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WO2008113006A1 (fr) * 2007-03-14 2008-09-18 Xenon Pharmaceuticals Inc. Procédés d'utilisation de composés à base de quinolinone dans le traitement des maladies ou des affections associées aux canaux sodiques
US20160083367A1 (en) * 2014-09-19 2016-03-24 Forma Therapeutics, Inc. Pyridinyl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US20160083349A1 (en) * 2014-09-19 2016-03-24 Forma Therapeutics, Inc. Pyridin-2(1h)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US9624175B2 (en) * 2015-04-21 2017-04-18 Forma Therapeutics, Inc. Fused-bicyclic aryl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US9815817B2 (en) 2014-09-19 2017-11-14 Forma Therapeutics, Inc. Quinolinone pyrimidines compositions as mutant-isocitrate dehydrogenase inhibitors
US9834539B2 (en) 2014-09-19 2017-12-05 Forma Therapeutics, Inc. Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
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US11013733B2 (en) 2018-05-16 2021-05-25 Forma Therapeutics, Inc. Inhibiting mutant isocitrate dehydrogenase 1 (mlDH-1)
US11013734B2 (en) 2018-05-16 2021-05-25 Forma Therapeutics, Inc. Treating patients harboring an isocitrate dehydrogenase-1 (IDH-1) mutation
US11311527B2 (en) 2018-05-16 2022-04-26 Forma Therapeutics, Inc. Inhibiting mutant isocitrate dehydrogenase 1 (mIDH-1)
US11376246B2 (en) 2018-05-16 2022-07-05 Forma Therapeutics, Inc. Inhibiting mutant IDH-1

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WO2008113006A1 (fr) * 2007-03-14 2008-09-18 Xenon Pharmaceuticals Inc. Procédés d'utilisation de composés à base de quinolinone dans le traitement des maladies ou des affections associées aux canaux sodiques
US10550099B2 (en) 2014-09-19 2020-02-04 Forma Therapeutics, Inc. Quinolinone pyrimidines compositions as mutant-isocitrate dehydrogenase inhibitors
US9771349B2 (en) * 2014-09-19 2017-09-26 Forma Therapeutics, Inc. Pyridinyl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
AU2021215141B2 (en) * 2014-09-19 2023-10-19 Forma Therapeutics, Inc. Pyridin-2(1h)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US20160083367A1 (en) * 2014-09-19 2016-03-24 Forma Therapeutics, Inc. Pyridinyl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
JP2017528491A (ja) * 2014-09-19 2017-09-28 フォーマ セラピューティクス，インコーポレイテッド 変異イソクエン酸デヒドロゲナーゼ阻害剤としてのピリジニルキノリノン誘導体
JP2017528489A (ja) * 2014-09-19 2017-09-28 フォーマ セラピューティクス，インコーポレイテッド 変異イソクエン酸デヒドロゲナーゼ阻害剤としてのフェニルキノリノン誘導体
US9815817B2 (en) 2014-09-19 2017-11-14 Forma Therapeutics, Inc. Quinolinone pyrimidines compositions as mutant-isocitrate dehydrogenase inhibitors
US9834539B2 (en) 2014-09-19 2017-12-05 Forma Therapeutics, Inc. Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10005734B2 (en) * 2014-09-19 2018-06-26 Forma Therapeutics, Inc. Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10253015B2 (en) 2014-09-19 2019-04-09 Forma Tm2, Inc. Pyridinyl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10266495B2 (en) 2014-09-19 2019-04-23 Forma Tm2, Inc. Phenyl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10280150B2 (en) 2014-09-19 2019-05-07 Forma Tm2, Inc. Quinolinone pyrimidines compositions as mutant-isocitrate dehydrogenase inhibitors
US11498913B2 (en) 2014-09-19 2022-11-15 Forma Therapeutics, Inc. Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
AU2019283765B2 (en) * 2014-09-19 2021-05-13 Forma Therapeutics, Inc. Pyridin-2(1h)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10414752B2 (en) 2014-09-19 2019-09-17 Forma Therapeutics, Inc. Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
AU2015317329B2 (en) * 2014-09-19 2019-10-31 Forma Therapeutics, Inc. Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10889567B2 (en) 2014-09-19 2021-01-12 Forma Therapeutics, Inc. Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10550098B2 (en) 2014-09-19 2020-02-04 Forma Therapeutics, Inc. Pyridin-2(1H)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US20160083349A1 (en) * 2014-09-19 2016-03-24 Forma Therapeutics, Inc. Pyridin-2(1h)-one quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
AU2015317322B2 (en) * 2014-09-19 2020-09-17 Forma Therapeutics, Inc. Phenyl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10294206B2 (en) 2015-04-21 2019-05-21 Forma Tm2, Inc. Fused-bicyclic aryl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10577329B2 (en) 2015-04-21 2020-03-03 Forma Therapeutics, Inc. Fused-bicyclic aryl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US9624175B2 (en) * 2015-04-21 2017-04-18 Forma Therapeutics, Inc. Fused-bicyclic aryl quinolinone derivatives as mutant-isocitrate dehydrogenase inhibitors
US10807976B2 (en) 2015-04-21 2020-10-20 Forma Therapeutics, Inc. Quinolinone five-membered heterocyclic compounds as mutant-isocitrate dehydrogenase inhibitors
US10407419B2 (en) 2015-04-21 2019-09-10 Forma Therapeutics, Inc. Quinolinone five-membered heterocyclic compounds as mutant-isocitrate dehydrogenase inhibitors
US10959994B2 (en) 2018-05-16 2021-03-30 Forma Therapeutics, Inc. Solid forms of ((S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile
US11013733B2 (en) 2018-05-16 2021-05-25 Forma Therapeutics, Inc. Inhibiting mutant isocitrate dehydrogenase 1 (mlDH-1)
US11376246B2 (en) 2018-05-16 2022-07-05 Forma Therapeutics, Inc. Inhibiting mutant IDH-1
US11311527B2 (en) 2018-05-16 2022-04-26 Forma Therapeutics, Inc. Inhibiting mutant isocitrate dehydrogenase 1 (mIDH-1)
US11013734B2 (en) 2018-05-16 2021-05-25 Forma Therapeutics, Inc. Treating patients harboring an isocitrate dehydrogenase-1 (IDH-1) mutation
US11497743B2 (en) 2018-05-16 2022-11-15 Forma Therapeutics, Inc. Treating patients harboring an isocitrate dehydrogenase 1 (IDH-1) mutation
US11576906B2 (en) 2018-05-16 2023-02-14 Forma Therapeutics, Inc. Inhibiting mutant IDH-1
US11723905B2 (en) 2018-05-16 2023-08-15 Forma Therapeutics, Inc. Solid forms of ((s)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile
US11738018B2 (en) 2018-05-16 2023-08-29 FORMA Therapeuetics, Inc. Inhibiting mutant isocitrate dehydrogenase 1 (mIDH-1)
US10532047B2 (en) 2018-05-16 2020-01-14 Forma Therapeutics, Inc. Solid forms of ((S)-5-((1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl)amino)-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile
US11963956B2 (en) 2018-05-16 2024-04-23 Forma Therapeutics, Inc. Inhibiting mutant isocitrate dehydrogenase 1 (mIDH-1)

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