WO2004103991A1 - Piperidines 2-substituees, bibliotheque focalisee et composition pharmaceutique - Google Patents

Piperidines 2-substituees, bibliotheque focalisee et composition pharmaceutique Download PDF

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WO2004103991A1
WO2004103991A1 PCT/RU2004/000187 RU2004000187W WO2004103991A1 WO 2004103991 A1 WO2004103991 A1 WO 2004103991A1 RU 2004000187 W RU2004000187 W RU 2004000187W WO 2004103991 A1 WO2004103991 A1 WO 2004103991A1
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substituted
optionally substituted
neοbyazaτelnο
compounds
gρuππu
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Russian (ru)
Inventor
Alexander Vasilievich Ivashchenko
Vladimir Yurievich Vvedensky
Anton Yurievich Agarkov
Yuriy Borisovich Sandulenko
Sergey Vladimirovich Shkavrov
Dmitri Vladimirovich Kravchenko
Sergey Yevgenievich Tkachenko
Alexander Viktorovich Khvat
Ilya Matusovich Okun
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'chemical Diversity Research Institute' Ltd
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'chemical Diversity Research Institute' Ltd
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Priority claimed from RU2003114719/04A external-priority patent/RU2228930C1/ru
Priority claimed from RU2003114720/04A external-priority patent/RU2228934C1/ru
Priority claimed from RU2004109819/04A external-priority patent/RU2259364C1/ru
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • ⁇ ⁇ ezul ⁇ a ⁇ e ⁇ vedenny ⁇ issled ⁇ vany, na ⁇ avlenny ⁇ on ⁇ is ⁇ n ⁇ vy ⁇ ⁇ izi ⁇ l ⁇ giches ⁇ i a ⁇ ivny ⁇ vesches ⁇ v, s ⁇ edineny-lide ⁇ v, iz ⁇ b ⁇ e ⁇ a ⁇ eli ⁇ luchili neizves ⁇ nye ⁇ anee substituted ⁇ i ⁇ e ⁇ idiny, ⁇ ym sv ⁇ ys ⁇ venna ⁇ izi ⁇ l ⁇ giches ⁇ aya a ⁇ ivn ⁇ s ⁇ , ⁇ az ⁇ ab ⁇ ali ⁇ usi ⁇ vannuyu bibli ⁇ e ⁇ u and ⁇ a ⁇ matsev ⁇ iches ⁇ uyu ⁇ m ⁇ zitsiyu, v ⁇ lyuchayuschuyu e ⁇ i s ⁇ edineniya.
  • the alkaline anabazine or 2- (3-pyridinyl) -pyrperidine is an alkaline agent [S. ⁇ réelle ⁇ réelle ⁇ , ⁇ . ⁇ . ⁇ réelle ⁇ réelle ⁇ réelle ⁇ , ⁇ . ⁇ , ⁇ . ⁇ technically ⁇ - ⁇ excellent ⁇ ITA ⁇ vie ⁇ . ⁇ réelle ⁇ ., 1995, 31 (8 and ⁇ 1.), ⁇ .51] and 2- (3-pyridyl) quinuclidine [ ⁇ . ⁇ réelle ⁇ êt ⁇ réelle ⁇ ' , ⁇ . ⁇ . ⁇ 1:00 ⁇ réelle ⁇ , ⁇ ⁇ .8. - ⁇ . ⁇ eg ⁇ . ⁇ 9607410, 1996; ⁇ réelle ⁇ ⁇ rion ⁇ réelle ⁇ réelle ⁇ . 1998, 20 (6), ⁇ .555], below:
  • anabazine As a matter of fact, the substance obtained by alkaline alkali cycling of anabazine (shown below) exhibits the property of a highly efficient ligand that is excluded from excitance. ⁇ . ⁇ réelle ⁇ ⁇ ⁇ publication. 2003, 11 (2): 225-234].
  • the non-existent anabazine is an antagonism of the aldoste [Anthony ⁇ agtasei ⁇ sa ⁇ Co., S. ⁇ 1997071586 ⁇ ags ⁇ 18, 1997].
  • the purpose of the present invention is the new substituted pyridine.
  • the stated goal is achieved by separate enantiomeric substituted pyr-pyridines or mixtures of their enantiomers of the general formula 1
  • ⁇ ⁇ represents an optionally substituted azahe-d-i-d-i-d-i-d-i-d-i-d-i-d-i-d-i-d-i-d-i-d-i-d-i d-i-d-i d-i-d-i d-i-d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i d-i
  • ⁇ ⁇ represents a non-necessarily substituted normal normal boolean radical, has the above meaning, and ⁇ and ⁇ instead of non-substituted amino acid.
  • ⁇ 7 is not necessarily substituted by an hydroxyl group, is optionally substituted by an amine group or is optionally substituted by an aminos, and is not substituted by an amine,
  • the preferred are also enantiomeric 1,2,3,4,5,6-1 'I-hexane bisulfide] or their pharmaceutically acceptable salts, oxides or hydrates, in the form of 1 and 6, have the above meaning, and ⁇ 9 does not involve any kind of food.
  • the preferred are also enantiomeric 1.5-iyl-i-amyl or i ⁇ ⁇ a ⁇ matsev ⁇ iches ⁇ i ⁇ iemlemye s ⁇ li, ⁇ sidy or gid ⁇ a ⁇ y in ⁇ y ⁇ ⁇ 1 and ⁇ 6 imeyu ⁇ vysheu ⁇ azann ⁇ e value and ⁇ 10 and ⁇ 11 nezavisim ⁇ d ⁇ ug ⁇ d ⁇ uga ⁇ eds ⁇ avlyayu ⁇ ne ⁇ byaza ⁇ eln ⁇ substituted gid ⁇ silnuyu g ⁇ u ⁇ u, ne ⁇ byaza ⁇ eln ⁇ substituted amin ⁇ g ⁇ u ⁇ u or ⁇ 10 and ⁇ 11 vmes ⁇ e with armored groups, which are connected to, and together with carbon atoms, are connected to non-arsenic groups,
  • the preferred are also enantiomer-1-i or their pharmaceutically acceptable salts, oxides or hydrates, in the case of ⁇ , ⁇ and ⁇ 10, have the above meaning.
  • ⁇ 1 has the above meaning
  • ⁇ 17 represents -C3, -C ⁇ 2 0 ⁇ , - C ⁇ 2 ⁇ 7 , -C ( ⁇ ) ⁇ 7 , where ⁇ 7 has the above meaning;
  • ⁇ 18 is self-contained; it is a non-hazardous substituent, ⁇ -protective substituent or electric substituent;
  • the purpose of the present invention is a new, comprehensive library of connections. ⁇ 2004 / 000187
  • the purpose of the present invention is a new pharmaceutical combination.
  • the goal is achieved by the pharmaceutical industry, which includes, at the very least, one 2-substituted general drug 1 or its pharmaceuticals, or
  • Lead Compound means a compound with outstanding activity that is related to a shared illness.
  • “Scaffold” means a general structured formula or molecular case or an invariant area of connections, which is characteristic for all connections included in the library.
  • REMOTE means a series of compounds that are united by a common structure and possesses a shared property, which is, in fact, independent of it. Last but not the least, a new concept a ⁇ iva ⁇ v ⁇ alievy ⁇ ⁇ anal ⁇ v "or” izves ⁇ ny ⁇ em ⁇ i ⁇ ⁇ inazny ⁇ ingibi ⁇ v "and ⁇ .d.
  • Preferred “inert substitutes” are C] - C alkyl, C 2 - C 7 alkenyl, C 2 - C alkynyl, C ⁇ - C 7 alkoxy, C 7 - C 12 aralkyl, C 7 - C 12 alkaryl, C 3 - C 10 cycloalkyl, C 3 - C 10 cycloalkenyl, phenyl, substituted phenyl, (C ⁇ 2 ) t - ⁇ - (C ⁇ - C 7 alkyl), - C 7 alkyl) ⁇ , aryl, substituted aryl, heterocyclyl and substituted heterocyclyl.
  • Alkoxylated for example, methylated, ethyloxylated, throttled butyl alcohol, 9-fluenyl methyl ester (UTOS) and others .
  • an optionally substituted Ci_C alkyl substituent for example, tert-butyl, benzyl, 2,4-dimethyl-sibenzyl, 9-phenylpluo-phenyl and the like
  • sulfonyl substituent for example, benzene sulfonyl, ⁇ -toluulosulfonyl and others.
  • Substituted g ⁇ u ⁇ a substituted ⁇ adi ⁇ al or s ⁇ e ⁇ ld ⁇ znachayu ⁇ , s ⁇ ve ⁇ s ⁇ venn ⁇ g ⁇ u ⁇ u, ⁇ adi ⁇ al or s ⁇ e ⁇ ld, y ⁇ y ⁇ imee ⁇ sya zames ⁇ i ⁇ el, v ⁇ lyuchaya, n ⁇ not ⁇ g ⁇ anichivaya: ine ⁇ ny zames ⁇ i ⁇ el, a ⁇ m gal ⁇ gena, ni ⁇ g ⁇ u ⁇ a, tsian ⁇ g ⁇ u ⁇ a, sul ⁇ g ⁇ u ⁇ a, gid ⁇ silnaya g ⁇ u ⁇ a, amin ⁇ g ⁇ u ⁇ a, carboxylic group, carboxylic group, carboxylic group.
  • substituted alkyl means alkyl, for one or several substitutes, for example, hydroxylalkyl or methyl-2-methyl, -methyl a substituted amine group means an amine group, which has one or two substituents, for example, an acylamine group, ⁇ , Frequently Too-dialkylamine group, an acyl group, an acyl group substituted phenyl means phenyl, which has One or several substitutes, for example 2-methoxyphenyl phenyl, 4-amine-3-methoxyphenyl phenyl, 3,4-diaminophenyl and others.
  • Optionally substituted group, optionally substituted group or security means, respectively, group or part of the room, which are missing or inactive.
  • Heterocycle means one or a few saturated or aromatic rings with 5, 6 or 7 atoms, which is the last measure, one of the loops is a geter. The preferred hetero- thems are sulfur, acid and nitrogen. “Heterocycle” can be a condensed one, for example, like benzimidazole, benzoxazole. benzothiazole, quinoline, or non-condensed, such as bipyridyl.
  • “Excluded” means a heterocycle, including, at the very least, one atom of nitrogen, for example, like benzimidazole, benzoxazole. benzothiazole, chinoline. “Substituted heterocycle” means a heterocycle having one or more “non-interfering” substitutes.
  • a new pharmaceutical component is obtained by including in its system, in the case of an external connection, a non-connected device Bi ⁇ l ⁇ giches ⁇ aya a ⁇ ivn ⁇ s ⁇ sin ⁇ ezi ⁇ vanny ⁇ s ⁇ edineny ⁇ edelyalas on ⁇ le ⁇ a ⁇ ⁇ abd ⁇ mi ⁇ sa ⁇ my in ⁇ y ⁇ ni ⁇ in ⁇ vy ⁇ etse ⁇ ⁇ n ⁇ li ⁇ ue ⁇ na ⁇ ievuyu ⁇ nitsaem ⁇ s ⁇ and ⁇ a ⁇ ⁇ ezul ⁇ a ⁇ , ⁇ le ⁇ chny ⁇ ansmemb ⁇ anny ele ⁇ iches ⁇ y ⁇ entsial, ⁇ y in sv ⁇ yu ⁇ che ⁇ ed, izme ⁇ yalsya with ⁇ m ⁇ schyu ⁇ a ⁇ y ani ⁇ nn ⁇ ⁇ lu ⁇ estsen ⁇ ny ⁇ z ⁇ nd ⁇ v ( ⁇ S 4
  • a total of 615 hours is obtained due to the activation of the cell membrane as a result of the inactivation of an inactive receptor, and the increase in the incidence of infection.
  • ⁇ 1 has the above meaning; ⁇ 20 It supplies hydrogen, or halogen, is optionally substituted with a hydroxy group, is optionally substituted with a medicine, or is optionally substituted with an amino; ⁇ Play Represents an optionally substituted phenyl, an optionally substituted aryl, or an optionally substituted heterocyclic, and ⁇ 22 and ⁇ 23 are independent from the other party.
  • ⁇ 24 and ⁇ 25 represent a water source or an inert substitute.
  • X represents refrigerant, imidazole-yl or the remainder of mixed anhydride.
  • the method of producing new enantiomeric pyrperidin-2-yl-pyridide [1,2- ⁇ ] pyrimidines or their mixtures of general formula 1.6 and 1.7 includes the interaction of amino-2,3-2,3 '] birpyridinyl 1.1.1a or 1.1.2a with maleic anhydrides 4.3 ⁇ scheme 6 scheme 6
  • ⁇ 1 and ⁇ 6 have the above meaning, and ⁇ 26 represents hydrogen, an inert substituent, an optionally substituted one, or an amorphous one.
  • ⁇ Appendix 14 is optionally substituted phenyl, optionally substituted aryl or optionally substituted hetero-cyclic, but 15 is not substituted.
  • Example 1.5 Brom-1-methyl-1,2,3,4,5,6-hexahydro- [2,3'] bi-pyridinyl-6'-ylamine 1.1.1 (1). It takes 5 mol of 1-methyl-1,2,3,4,5,6-hexahydro [2,3 '] birpyridinyl-b'-ylamine 2.1 in 10 ml of 10% ⁇ 2 8 ⁇ and 0.5 ml of concentrated ⁇ . With this slower stirring and stirring, add 5 moles of bromide. After that, as the bromine was added, precipitation began in the precipitate, which slowly recovered when heated to 50 ° ⁇ . The resulting solution mixes at 50 ° ⁇ 1 hour, refrigerate, and stand at 0 ° ⁇ for 24 hours.
  • EXAMPLE 2.5 5'-BROM-1-methyl-1,2,3,4,5,6-hexahydro- [2,3 '] bi-pyridinyl-2'-ylamine 1.1.2 (1). 5 ml of 1-methyl-1,2,3,4,5,6-hexahydrate [2,3 '] bi-pyridinyl-2'-ylamine 2.2 in 15 ml of acetic acid slows down the absorption of boron (5.2 mol). Then, the coolant is heated for up to 50 ° C and is stirred until the yellow liquid (approx. 1 hour). The reactive mass is poured into the water solution of the plant, which falls out of the sediment and filters out and removes from the aggregate. I get 1.1.2 (1) with an output of 70%.
  • [2,3 '] bipyridinyl-6'-ylamine 1.1.1 (1) in 10 ml of C ⁇ , cooled to 5 ° C, dissolving solution 2 (1.2 mol) in 0.5 ml of water. Za ⁇ em ⁇ e ⁇ emeshivayu ⁇ ⁇ i - 5 ° C (1.5 hours), vylivayu ⁇ ⁇ ea ⁇ tsi ⁇ nnuyu weight in v ⁇ dny ⁇ as ⁇ v ⁇ ⁇ a 2 S ⁇ 3 e ⁇ s ⁇ agi ⁇ uyu ⁇ e ⁇ ilatse ⁇ a ⁇ m, e ⁇ s ⁇ a ⁇ susha ⁇ over ⁇ a 2 8 ⁇ 4 and ⁇ ntsen ⁇ i ⁇ uyu ⁇ .
  • ⁇ ⁇ ( ⁇ - ⁇ ) 1.3 (m, 2 ⁇ ), 1.5-1.75 (m, 4 ⁇ ), 2.0 (s, ⁇ ), 2.1 ( ⁇ , ⁇ ), 3.0 (d, ⁇ ), 3.25 (d, ⁇ ), 8.1 (s, W), 8.45 (s, W).
  • EXAMPLE 4 5'-BROM-2- ⁇ -1-methyl-1,2,3,4,5,6-hexahydro- [2,3 '] birpyridinyl 1.1.5 (1). ⁇ locker Dissolving 10 mol 5'-bromo-1-methyl-1,2,3,4,5,6-hexahydro- [2,3 '] birpyridinyl-6'-ylamine 1.1.1 (1) in 20 ml 65% ⁇ in nirpidine ⁇ and -10 ° ⁇ slowly add more solid 2 (15 mol) for 1 hour.
  • ⁇ ⁇ ( ⁇ - ⁇ ) 1.3 (m, 2 ⁇ ), 1.4 (m, ⁇ ), 1.5- 1.75 (m, 4 ⁇ ), 2.0 (s, ⁇ ), 2.1 ( ⁇ , ⁇ ), 2.95 (d, ⁇ ), 3.07 (d, W), 8.1 (d, W), 8.27 (s, W). 19 ⁇ ⁇ ( ⁇ 1 3 ): -77.62 ( ⁇ ).
  • Example 5 1-Methyl-5 '- (2-thienyl) -1,2,3,4,5,6-hexahydro- [2,3'] bi-pyridinyl-2'-ylamine 1.1.7 (1).
  • EXAMPLE 6 1-Methyl-5'- ⁇ -myl-2- ⁇ -1,2,3,4,5,6-hexahydra- [2,3 '] birpyridinyl
  • EXAMPLE 7 1-Methyl-5 '- (3-phenylpropylamine) methyl-2- ⁇ -1,2,3,4,5,6-hexahydro- [2,3'] birpyridinyl 1.1.10 (1). Stir 12 hours for 1 mole of 1-methyl-5'- ⁇ ormyl-2- ⁇ -1,2,3,4,5,6-hexahydrate- [2,3 '] birpyridinyl 1.1.7 (2), 3 mol 3- phenylpropylamine and 3 moles of sodium borohydride in 20 ml of methanol. Then, add 20 ml of 10% C ⁇ , stir the mixture for 10 minutes, alkalize with 2 C ⁇ 3 and extract with ethyl acetate.
  • Example 11 - ⁇ - ⁇ (25) -1,2,3,4,5,6-Hexahydrotho- [2,3 '] bi-pyridyl-6'-methyl ⁇ phoramamide 1.1.20 (1).
  • the resulting residue is mixed with clean methylene (10.0 ml) and the insoluble salts are removed by filtration.
  • the resulting amine residue after removal of the solvent was mixed 1.1.16 (1) with formic acid (0.5 ml) and heated for 16 hours at 90 ° ⁇ .
  • the resulting mixture at 0 ° C is alkalized with aqueous ammonia and is efficiently cooled.
  • EXAMPLE 12 tri-Butyl (2_ -2- ⁇ 6 - [(acetylamine) methyl] -3-pyridinyl ⁇ tetrahydride-1 (2L) -pyridine hydroxyl 1.1.20 (2). 127 mg 43 mg (0.4) (0.4) butyl (25 -6'-cyano-1,2,3,4,5,6-hexahydrate- [2,3 '] bi-pyridyl-1-carboxylate
  • ⁇ ⁇ luchenn ⁇ y d ⁇ bavlyayu ⁇ mixture of 200 mg of 10% ⁇ / C and 4 hours ⁇ e ⁇ emeshivayu ⁇ a ⁇ m ⁇ s ⁇ e ⁇ e v ⁇ d ⁇ da.
  • ⁇ ea ⁇ tsi ⁇ nnuyu ⁇ as ⁇ edelyayu ⁇ mixture is between 10% and v ⁇ dnym ⁇ as ⁇ v ⁇ m ⁇ aS ⁇ e ⁇ ilatse ⁇ a ⁇ m (3 x 5 mL).
  • ⁇ bedinennye ⁇ ganiches ⁇ ie e ⁇ s ⁇ a ⁇ y susha ⁇ over ⁇ 8 ⁇ 4 , file They wash and concentrate in a vacuum.
  • EXAMPLE 14 5'-BROM-1-methyl-1,2,3,4,5,6-hexahydro-1'L- [2,3 '] bi-pyridinyl-2'-one 1.3 (1). 1 mol 5'-bromo-1-methyl-1,2,3,4,5,6-hexahydro- [2,3 '] birpyridinyl-6'-ylamine 1.1.2 (1) 10 ml 10% ⁇ 2 8 ⁇ 4 , cooled down to -5 ° ⁇ , prepares the solution 2 (1.2 mol) in 0.5 ml of water. Then stir at -5 ° C (1.5 hours), pour the reactive mass into an aqueous solution of 2 ⁇ , which is removed from the crystalline product and is filtered off.
  • Example 15 6- (1-Benzoylpyrperidin-2-yl) -pyrazole [1,5-a] pyridin-3- acid is ethyl ester 1.4.1 (1). It is found in 20 ml of water that contains 10 moles of 97% hydroxy-silamine-êtonne ⁇ -sulfates, 10 moles of 1-benzoyl-1,2,3,4,5,6-hexahydro-G # - [2,3 '] birpyridinyl and 10 mol ⁇ a ⁇ . The resulting mixture is stirred for 1 hour at 70-90 ° C, cooled to a large temperature, added 10 mols of CACOS and extracted with ethyl acetate 3x10 ml).
  • One phase is evaporated in a vacuum of 30 ° ⁇ .
  • Residue is added 6 ml of absolute ethanol, inorganic sediment is filtered off, the filter is cooled down to -20 ° ⁇ and added 47% 4 (0.72 ml). The resulting mixture is stirred at -20 ° C for 30 minutes, the precipitate is filtered and washed with 2 ml of cool, absolute ethanol.
  • the ejected mass is poured into 200 ml of water, it is extracted with ethyl acetate (3 x 50 ml), volatile substances are removed in vacuo, and the oily waste is cleaned by the patient. Obtained 1.4.1 (1) with an output of 25%.
  • EXAMPLE 18 2- (1-Methyl-pyrperidin-2-yl) -benzo [s] - [1.8] for ⁇ iridine 1.8 (1). With a solution of 3 moles of Na 2 S ⁇ 3 and 50mg ⁇ C1 2 ( ⁇ 1 3 ) 2 in 2 ml of water, add 1.5 moles of 2-phenyl phenyl acid 4.4 (1), and then add 1 mil-1-5 ml. , 3,4,5,6-hexahydro- [2,3 '] bi-pyridinyl-6'-ylamine 1.1.1 (1) in 2 ml of ⁇ . The inactive mass is heated for 10 minutes and mixed in a small furnace at 130 ° ⁇ .
  • the pourer is poured into the water part 2 ⁇ 3> ekstraguyut with ethyl acetate and podderuyut flash-storage.
  • ⁇ 6 ⁇ ) in 100 ml of absolute ethanol add 11 mol of bromic acid 4.5 (2) and the resulting mixture takes 3 hours. After cooling, the settled sediment is filtered and washed with ethanol. Receive 1.9.1 (2) with an output of 70%. ! ⁇ ⁇ ( ⁇ > 2 ⁇ ): 1.9 (m, ⁇ ), 2.15 ( ⁇ , ⁇ ), 2.25 (m, 2 ⁇ ), 2.4 (m, 2 ⁇ ), 2.85 (s, ⁇ ), 3.45 ( ⁇ , ⁇ ) , 3.9 (d, W), 4.6 (d, W), 8.15 ( ⁇ , 2 ⁇ ), 8.5 (s, W), 9.0 (s, W).
  • Example 21 The general procedure for the production of amides 6- (1-methyl-2-pyperidinyl) - imidase [1,2-a] pyridine-2-carboxylic acid 1.9.1 (3-5). It takes 1 mole of the hydride of 7- (1-methyl-2-pyperidinyl) imidase [1, 2-a] pyridine-4-acid, 1.9.1 (2), 1.1 ml of sugar and 3 ml pyridine and heat the resulting mixture for 15 minutes in a small furnace at 160 ° ⁇ .
  • ⁇ yperidinyl) imidazo [1,2-a] ⁇ pyridine 1.9.2 (9): ⁇ ⁇ ( ⁇ 8 ⁇ - ⁇ 6): 1.2-1.7 (m, 17 ⁇ ), 1.77 (d, W), 1.9 (s, ⁇ ) , 1.98 (s, W), 2.08 ( ⁇ , W), 2.82 (d, W), 2.95 (d, W), 4.3 (s, W), 6.7 (d, W), 7.1 (d, W), 7.35 (d, W), 7.45 (d, W), 7.6 (s, W), 8.25 (s, 1 ⁇ ), 8.7 (extended s, 2 ⁇ ).
  • H ⁇ (G> ⁇ 8 ⁇ - ⁇ 6): 0.9 ( ⁇ , ⁇ ), 1.3-1.7 (m, 7 ⁇ ), 1.78 (d, ⁇ ), 1.95 (s, ⁇ ), 2.05 (m, ⁇ ), 2.32 (s, ⁇ ), 2.9 (m, 2 ⁇ ), 3.4 (m, ⁇ ), 3.7 (m, ⁇ ), 7.0 ( ⁇ , 2 ⁇ ), 7.25 (d, 2 ⁇ ), 7.35 (m, ⁇ ), 7.6 (d, ⁇ ), 7.75 (m, 2 ⁇ ), 7.95 (d, W), 8.6 (s, W); ⁇ -benzoyl- ⁇ - ⁇ yl- ⁇ 2- (4-tolyl) -6- (1-methyl-2- ⁇ yperidinyl) imidazo [1,2-a] ⁇ -pyridin-3-yl ⁇ amine 1.9.2 (17): ⁇ ⁇ ( ⁇ - ⁇ ): 0.9 ( ⁇ , ⁇ ), 1.3-1.7 (m, 7 ⁇ ), 1.75 (d, ⁇ ), 1.85 and 1.95 (2 demander, ⁇
  • Example 24 8- (1-Methyl-2-pyrperidinyl) imidase [1,2-a] pyridine-3-carboxylic acid hydride 1.10.2 (1).
  • the garden is filtered and washed with ethyl acetate.
  • Example 25 The general method for the production of amides of 8- (1-methyl-2-pyperidinyl) imidase [1,2-a] pyridine-3-carboxylic acid 1.10.2 (2-3). Take 1 mole of compound 1.10.2 (1), 1.1 mole of SC1 3 and 1.5 mole of the corresponding amine 3.8 in 2 ml of dry pyridine and heat the mixture for 15 minutes in a small bake.
  • P ⁇ luchenny bestsve ⁇ ny ⁇ as ⁇ v ⁇ ⁇ il ⁇ vyvayu ⁇ ⁇ ⁇ sad ⁇ a ⁇ la ⁇ iny and ⁇ ntsen ⁇ i ⁇ uyu ⁇ on ⁇ n ⁇ m is ⁇ a ⁇ i ⁇ ele ⁇ i 80 ° C d ⁇ ⁇ s ⁇ yann ⁇ y weight .
  • Example 27 Combined library of 3-substituted ( ⁇ -U. ⁇ ⁇ -decahydro-YaA-1,5-methanopyridine [1,2-_ /] [1,5] diazocin-8-units 1.11.1 (2-6 ). Pa ⁇ allelny sin ⁇ ez ⁇ mbina ⁇ n ⁇ y bibli ⁇ e ⁇ i ⁇ v ⁇ dya ⁇ in sin ⁇ eza ⁇ e "S ⁇ Y8u ⁇ -012-3000".
  • ⁇ ea ⁇ tsi ⁇ nnye mixture ⁇ e ⁇ emeshivayu ⁇ ⁇ i ⁇ mna ⁇ n ⁇ y ⁇ em ⁇ e ⁇ a ⁇ u ⁇ e in ⁇ echenie 48 chas ⁇ v.
  • P ⁇ sle ⁇ il ⁇ vaniya and ⁇ ntsen ⁇ i ⁇ vaniya on ⁇ n ⁇ m is ⁇ a ⁇ i ⁇ ele d ⁇ ⁇ s ⁇ yann ⁇ y mass ⁇ luchayu ⁇ ⁇ mbina ⁇ nuyu b a connection, including 5 connections 1.1.1 ⁇ 2-5 ⁇ , which, according to HS / ⁇ 8, have a content of the main substances higher than 95%.
  • Example 29 Yazor-propyl 4 - [(55.75) -1,3-diazotricyclo- [3.3.1.1 3 ' 7 ] dec-4-yl] butane 1.11.5.1 (1)
  • the obtained oil provides a compound of 4 - [(15,55) -3,7-diazabicyclo [3.3.1] non-2-yl] butane 1.11.2.1 (6) [t / ⁇ 25 ( ⁇ + +1)], with the content of the main substance 95%; yield 2 g (97%).
  • Example 31 The methyl library of methyl 4 - [(15,55) -3-acetyl- (3,7-diazabicyclo- [3.3.1] non-2-yl)] butane 1.11.3.1 (1-5).
  • the parallel synthesis of the combined library is carried out in the synthesis of "Cells ⁇ êt ⁇ -012-3000". ⁇
  • Each of the 5 processes of the synthesis is loaded with only 1 g of the corresponding 7-substituted methyl butane 1.11.2.1 (1-5) and ⁇ 10 ml of acetic anhydride.
  • the active mass is mixed at room temperature for 12 hours and the active mixture is concentrated in a vacuum center.
  • EXAMPLE 32 The composite library was labeled 4 - [(15,55) - (3,7-diazabicyclic [3.3.1] -on-2-yl)] butane 1.11.3.1 (6-48): The parallel synthesis of the combiner 4 syntheses "CELLS ⁇ réelle ⁇ -012-3000". ⁇ Each of the 43 synthetic processes is loaded with 1 g of the corresponding 7-substituted methyl butane 1.11.2.1 (1-5) in a mixture of 10 ml of ethyl chloride and 660 eq. Corresponding acyl or sulfonylidea.
  • the stirred mixtures are stirred for 12 hours and at room temperature, added to each Reacted water ml of distilled water separates aqueous layers, organic layers concentrate in a vacuum. They receive a combination library that includes 43 connections 1.11.3.1 (6-48), which, according to the HS / ⁇ , have a basic content of more than 85%. Below, the names of the resulting compounds, outputs, physical and chemical are given.
  • EXAMPLE 35 [(15.55) -7-Benzyl-3- (t-tet-butyl hydroxylated) -3,7-diazabicyclo- [3.3.1] non-2-yl] butane acid 1.11.4.2 (1). Take up 0.454 g (1.09 mol) of the compound 1.11.3.1 (49) in 1 ml of dioxane, add 1 ml of the solution for storage and then remove the mixture, and then leave the mixture to dispense with it. The resulting mixture is stirred at room temperature for 24 hours, concentrated on the rotary evaporator, the solution is diluted, the solution is diluted, and the Combined by-products extracts wash water, dry over ⁇ 4 , and concentrate in a vacuum.
  • EXAMPLE 36 [(15,55 -3- (2] ”f / butylblocker) -3,7-diazabicyclo- [3.3.1] non-2-yl] butane acid 1.11.4.2 (2).
  • the solution is 0.378 g (0.94 mol) of the compound 1.11.4.2 (1) in 10 ml of methanol, add a 10% W / C catalyst and hydrate for 12 hours at a constant pressure of 1.0 1, 84% 2).
  • EXAMPLE 37 Di (/ i ⁇ __- butyl) 2- (4-morpholino-4-oxobutyl) -3,7-diazibicyclo- [3.3.1] nano-3,7-diacoboxylate 1.11.4.3 (1). With the active ethanolysis of the tetrahydrocytisine 1.11.1 (1) with the subsequent processed bicarbonate sodium (see the general method of the compounds 1.11.1 (1-5)), the .1] non-2-yl) butane 1.11.1 (7) GS- ⁇ t / ⁇ 267 ( ⁇ + +1).
  • P ⁇ luchenny ⁇ as ⁇ v ⁇ (4 mL, 1 m ⁇ l) ⁇ ntsen ⁇ i ⁇ uyu ⁇ on ⁇ n ⁇ m is ⁇ a ⁇ i ⁇ ele and ⁇ i ⁇ e ⁇ emeshivanii d ⁇ bavlyayu ⁇ ⁇ ⁇ s ⁇ a ⁇ u ⁇ G ⁇ 1 ml, 0.15 ml ⁇ ie ⁇ ilamina (1.1 m ⁇ l) ⁇ as ⁇ v ⁇ and 0.24 g (1.1 m ⁇ l) ⁇ S 2 ⁇ 1.5 ml ⁇ G ⁇ .
  • EXAMPLE 38 Di (i ⁇ __- butyl) 2- (4-morphobinutyl) -3,7-diazabicyclo [3.3.1] nano-3,7-dicarboxylate 1.11.4.4 (1). Dispenses 89 mg (0.185 mol) of di (tert-butyl) 2- (4-morpholino-4-oxobutyl) -3, 7-diazibicyclo [3.3.1] nonan-3, 7-diacibactylate
  • the concentration is up to 30 ⁇ and changes the fluorescence at zero time (° ⁇ ;).
  • the batteries last 10 minutes together with the substituted pyridines of the general formula 1, after which they perform a direct measurement of the fluorescence ( 10 ⁇ ;).
  • Example 40 ⁇ ezul ⁇ a ⁇ y s ⁇ ininga bi ⁇ l ⁇ giches ⁇ y a ⁇ ivn ⁇ s ⁇ i on ni ⁇ in ⁇ vy ⁇ etse ⁇ changed ⁇ units nes ⁇ l ⁇ i ⁇ % G ⁇ D d ⁇ nes ⁇ l ⁇ i ⁇ desya ⁇ v% G ⁇ D and svide ⁇ els ⁇ v ⁇ vali ⁇ ⁇ e ⁇ s ⁇ e ⁇ ivn ⁇ s ⁇ i n ⁇ vy ⁇ s ⁇ edineny general formula 1.
  • Example 40 The products containing 50 mg of the active ingredient are mixed, and then the mixture is 800 mg of dried food, 800 mg of ground food and 200 mg of white food ..
  • Example 42 Injectable formulations for internal, internal, or intraperitoneal injections are prepared by mixing 500 mg of an active compound of total 1 ml of 300 ml. The resulting product is filtered and placed at 1 ml in ampoules, which are sealed and sterilized in the autoclave. INDUSTRIAL APPLICABILITY The invention may be used in medicine, veterinary medicine, biochemistry, and general chemistry.

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Abstract

La présente invention concerne des pipéridines substituées énantiomères individuelles ou des mélanges de leurs énantiomères représentés par la formule (1) ou des sels, oxydes ou hydrates pharmaceutiquement acceptables de ces composés. Dans cette formule, W désigne un azahétérocycle éventuellement substitué, tel qu'un pyridin-3-yl, un pyrazolo[1,5-a]pyridin-6-yl, un 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-7-yl, un 3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-9-yl, un imidazo[1,2-a]pyrimidin-6-yl, un imidazo[1,2-a]pyrimidin-8-yl ou un [1,8]naphtyridin-3-yl; R1 désigne un atome d'hydrogène, un substituant inerte, un substituant de protection de NH ou un substituant électrophile; et R2 et R3 désignent un atome d'hydrogène, ou W désigne un radical butyle normal éventuellement substitué; R1 est tel que décrit plus haut et R2 et R3 forment ensemble un radical diméthylènamine éventuellement substitué au niveau de l'atome d'azote.
PCT/RU2004/000187 2003-05-20 2004-05-18 Piperidines 2-substituees, bibliotheque focalisee et composition pharmaceutique Ceased WO2004103991A1 (fr)

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RU2003114720 2003-05-20
RU2003114719/04A RU2228930C1 (ru) 2003-05-20 2003-05-20 Замещенные 3-пиридилметиламины и фокусированная библиотека
RU2003114719 2003-05-20
RU2003114720/04A RU2228934C1 (ru) 2003-05-20 2003-05-20 Замещенные 3,7-диазобицикло[3.3.1]нонаны, фокусированная библиотека и комбинаторная библиотека
RU2004109819/04A RU2259364C1 (ru) 2004-04-01 2004-04-01 Азагетероциклы, включающие фрагмент пиперидин-2-ила-, фокусированные библиотеки и фармацевтические композиции
RU2004109819 2004-04-01

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WO2008016131A1 (fr) 2006-08-04 2008-02-07 Takeda Pharmaceutical Company Limited Composé hétérocyclique à cycles fusionnés
FR2925903A1 (fr) * 2008-01-02 2009-07-03 Sanofi Aventis Sa DERIVES 6-HETEROCYCLIQUE-IMIDAZO[1,2-a]PYRIDINE-2- CARBOXAMIDES, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE
FR2925904A1 (fr) * 2008-01-02 2009-07-03 Sanofi Aventis Sa DERIVES DE N-HETEROCYCLIQUE-6-HETEROCYCLIQUE-IMIDAZO[1,2-a] PYRIDINE-2-CARBOXAMIDES, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE
WO2009097992A1 (fr) * 2008-02-07 2009-08-13 Bayer Cropscience Ag Arylpyrrolines insecticidés
JP2013529200A (ja) * 2010-05-12 2013-07-18 バーテックス ファーマシューティカルズ インコーポレイテッド Ａｔｒキナーゼ阻害剤として有用な化合物
US8716282B2 (en) 2009-10-30 2014-05-06 Janssen Pharmaceutica Nv Imidazo[1,2-b]pyridazine derivatives and their use as PDE10 inhibitors
US8859543B2 (en) 2010-03-09 2014-10-14 Janssen Pharmaceutica Nv Imidazo[1,2-a]pyrazine derivatives and their use for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases
US20140315794A1 (en) * 2009-12-17 2014-10-23 Merial Limited Antiparisitic dihydroazole compounds and compositions comprising same
US9334244B2 (en) 2010-05-12 2016-05-10 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9365557B2 (en) 2008-12-19 2016-06-14 Vertex Pharmaceuticals Incorporated Substituted pyrazin-2-amines as inhibitors of ATR kinase
US9550784B2 (en) 2012-07-09 2017-01-24 Beerse Pharmaceutica NV Inhibitors of phosphodiesterase 10 enzyme
US9630956B2 (en) 2010-05-12 2017-04-25 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9669035B2 (en) 2012-06-26 2017-06-06 Janssen Pharmaceutica Nv Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders
US9791456B2 (en) 2012-10-04 2017-10-17 Vertex Pharmaceuticals Incorporated Method for measuring ATR inhibition mediated increases in DNA damage
US9862709B2 (en) 2011-09-30 2018-01-09 Vertex Pharmaceuticals Incorporated Processes for making compounds useful as inhibitors of ATR kinase
US10478430B2 (en) 2012-04-05 2019-11-19 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase and combination therapies thereof
US10604523B2 (en) 2011-06-27 2020-03-31 Janssen Pharmaceutica Nv 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives
US10813929B2 (en) 2011-09-30 2020-10-27 Vertex Pharmaceuticals Incorporated Treating cancer with ATR inhibitors
US11464774B2 (en) 2015-09-30 2022-10-11 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of DNA damaging agents and ATR inhibitors

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EA019122B1 (ru) * 2008-01-02 2014-01-30 Санофи-Авентис Производные 6-гетероциклоимидазо[1,2-а]пиридин-2-карбоксамидов, их получение и их применение в терапии
FR2925903A1 (fr) * 2008-01-02 2009-07-03 Sanofi Aventis Sa DERIVES 6-HETEROCYCLIQUE-IMIDAZO[1,2-a]PYRIDINE-2- CARBOXAMIDES, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE
FR2925904A1 (fr) * 2008-01-02 2009-07-03 Sanofi Aventis Sa DERIVES DE N-HETEROCYCLIQUE-6-HETEROCYCLIQUE-IMIDAZO[1,2-a] PYRIDINE-2-CARBOXAMIDES, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE
KR101600635B1 (ko) 2008-01-02 2016-03-07 사노피 ６-헤테로시클릭-이미다조［１,２-ａ］피리딘-２-카르복스아미드의 유도체, 그의 제법 및 그의 치료학적 용도
WO2009106751A3 (fr) * 2008-01-02 2010-02-25 Sanofi-Aventis Dérivés de n-heterocyclique-6-heterocyclique-imidazo[1,2- a]pyridiνe-2-carb0xamides, leur préparation et leur application en thérapeutique
WO2009106750A3 (fr) * 2008-01-02 2010-02-25 Sanofi-Aventis Dérivés 6-heterocyclique-imidazo[1,2-a]pyrroine-2-carboxamides, leur préparation et leur application en thérapeutique
KR20100109940A (ko) * 2008-01-02 2010-10-11 사노피-아벤티스 ６-헤테로시클릭-이미다조［１,２-ａ］피리딘-２-카르복스아미드의 유도체, 그의 제법 및 그의 치료학적 용도
JP2011508760A (ja) * 2008-01-02 2011-03-17 サノフイ−アベンテイス ６−ヘテロ環式イミダゾ［１，２−α］ピリジン−２−カルボキサミド誘導体、この調製および治療用途
US8691990B2 (en) 2008-01-02 2014-04-08 Sanofi 6-heterocyclic imidazo[1,2-α]pyridine-2-carboxamide derivatives, preparation and therapeutic use thereof
US8314109B2 (en) 2008-01-02 2012-11-20 Sanofi 6-heterocyclic-imidazo[1,2-α]pyridine-2-carboxamide derivatives, preparation and therapeutic use thereof
US8304371B2 (en) 2008-02-07 2012-11-06 Bayer Cropscience Ag Insecticidal arylpyrrolines
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JP2011514315A (ja) * 2008-02-07 2011-05-06 バイエル・クロツプサイエンス・アクチエンゲゼルシヤフト 殺虫性アリールピロリン類
US9701674B2 (en) 2008-12-19 2017-07-11 Vertex Pharmaceuticals Incorporated Substituted pyrazines as ATR kinase inhibitors
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US8716282B2 (en) 2009-10-30 2014-05-06 Janssen Pharmaceutica Nv Imidazo[1,2-b]pyridazine derivatives and their use as PDE10 inhibitors
US20140315794A1 (en) * 2009-12-17 2014-10-23 Merial Limited Antiparisitic dihydroazole compounds and compositions comprising same
US8980893B2 (en) * 2009-12-17 2015-03-17 Merial, Inc. Antiparisitic dihydroazole compounds and compositions comprising same
US8859543B2 (en) 2010-03-09 2014-10-14 Janssen Pharmaceutica Nv Imidazo[1,2-a]pyrazine derivatives and their use for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases
US9334244B2 (en) 2010-05-12 2016-05-10 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
US9630956B2 (en) 2010-05-12 2017-04-25 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase
JP2013529200A (ja) * 2010-05-12 2013-07-18 バーテックス ファーマシューティカルズ インコーポレイテッド Ａｔｒキナーゼ阻害剤として有用な化合物
US10604523B2 (en) 2011-06-27 2020-03-31 Janssen Pharmaceutica Nv 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives
US10208027B2 (en) 2011-09-30 2019-02-19 Vertex Pharmaceuticals Incorporated Processes for preparing ATR inhibitors
US9862709B2 (en) 2011-09-30 2018-01-09 Vertex Pharmaceuticals Incorporated Processes for making compounds useful as inhibitors of ATR kinase
US10813929B2 (en) 2011-09-30 2020-10-27 Vertex Pharmaceuticals Incorporated Treating cancer with ATR inhibitors
US10822331B2 (en) 2011-09-30 2020-11-03 Vertex Pharmaceuticals Incorporated Processes for preparing ATR inhibitors
US10478430B2 (en) 2012-04-05 2019-11-19 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase and combination therapies thereof
US11110086B2 (en) 2012-04-05 2021-09-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of ATR kinase and combination therapies thereof
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US9791456B2 (en) 2012-10-04 2017-10-17 Vertex Pharmaceuticals Incorporated Method for measuring ATR inhibition mediated increases in DNA damage
US11464774B2 (en) 2015-09-30 2022-10-11 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of DNA damaging agents and ATR inhibitors

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