WO2001019801A1 - Substance bioactive a base de derives des 2-amino-6-aryloxypyrimidines et de produits de synthese intermediaires de ces derniers - Google Patents

Substance bioactive a base de derives des 2-amino-6-aryloxypyrimidines et de produits de synthese intermediaires de ces derniers Download PDF

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Publication number
WO2001019801A1
WO2001019801A1 PCT/RU1999/000358 RU9900358W WO0119801A1 WO 2001019801 A1 WO2001019801 A1 WO 2001019801A1 RU 9900358 W RU9900358 W RU 9900358W WO 0119801 A1 WO0119801 A1 WO 0119801A1
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different
thing
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οсη
fact
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PCT/RU1999/000358
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English (en)
Russian (ru)
Inventor
Rimma Iliinichna Ashkinazi
Mariya Borisovna Ganina
Evgeny Pavlovich Studentsov
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Rimma Iliinichna Ashkinazi
Mariya Borisovna Ganina
Evgeny Pavlovich Studentsov
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Application filed by Rimma Iliinichna Ashkinazi, Mariya Borisovna Ganina, Evgeny Pavlovich Studentsov filed Critical Rimma Iliinichna Ashkinazi
Priority to PCT/RU1999/000358 priority Critical patent/WO2001019801A1/fr
Priority to AU25826/00A priority patent/AU2582600A/en
Publication of WO2001019801A1 publication Critical patent/WO2001019801A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the claimed 2-amine-4,5,6-mixed pyrimidines are active ⁇ svi ⁇ usam, ⁇ a ⁇ d ⁇ vi ⁇ usam, ⁇ - and ⁇ a ⁇ ami ⁇ s ⁇ vi ⁇ usam. high activity, as an industry, high anti-chlamydial activity.
  • MEDICINES ARE ASSOCIATED WITH THE PARTICULARITIES OF THE VARIABLE EXCHANGE AND ITS SURFACE TIES WITH A DELIVERED INFECTED CELL. Therefore, the virus infectious. Herbal viruses caused by distributed viruses are difficult to treat due to the occurrence of resistance to even the most effective 5-drug treatment. such as acyclic. gancicles ⁇ [6.9]. Among bacterial infections, one of the most serious problems is tuberculosis. The use of combined chemotherapy and the treatment of tuberculosis and mycosis with the appointment of only a few symptoms, for example, of the aminoglycides,
  • 25It is used in the treatment of basal disease.
  • derivatives of barbic acids - narcotic, pharmaceutical and antimicrobial agents are used for diseases of the body.
  • Derivatives are used for diseases of the body.
  • aryl-aminopyrimidines (daraprim) are absent from effective antimalarial drugs;
  • 6-alkyl and 6-phenyl-pyrimidines were found [22-24]. Lately, they are patented as immunocompromised and immune-controlling agents, in particular for the treatment of anemia.
  • a ⁇ i ⁇ v and gi ⁇ e ⁇ nii [25] ⁇ a ⁇ ma ⁇ l ⁇ giches ⁇ ie sv ⁇ ys ⁇ va e ⁇ y se ⁇ ii s ⁇ edineny znachi ⁇ eln ⁇ zavisya ⁇ ⁇ ⁇ i ⁇ dy zames ⁇ i ⁇ elya in ⁇ i ⁇ imidin ⁇ v ⁇ m tsi ⁇ le and benz ⁇ ln ⁇ m ⁇ ltse, ⁇ me ⁇ g ⁇ for ⁇ yavleniya ⁇ i ⁇ l ⁇ giches ⁇ y a ⁇ ivn ⁇ s ⁇ i ⁇ ebue ⁇ sya administering a ⁇ ma gal ⁇ gena (b ⁇ m.
  • Vetkl gogezi ⁇ . ⁇ they have a positive activity on melanoma ⁇ 16, adenocarcinoma 755. leukemia 388 and suppresses the development of other animals. In addition, they exhibit a synergistic effect in combination with other therapeutic agents. Of course, due to the cyclospamid, the platinum. with a decrease in the effective dose of each of the drugs and their toxicity [24]
  • the closest claimed group of compounds for chemical compounds are derivative compounds.
  • 5 above 2-amino-5-galoid-6-phenylpyririmidin-4-ones ( ⁇ brp ⁇ irimin, ⁇ ) were found [24]. It is based on its coincidence with the declared biological activity of expressed activity: anti-chlamydia and drug-related drugs.
  • the invention and the technology belong to the class of pyrimidines.
  • the objective of the invention is the expansion of the arsenal of drugs for pharmaceutical and therapeutic activities. Consistent - New News
  • the present invention is a.
  • the posed problem is solved by the synthesis of a new group of pyrimidine bases - derivatives of 2-amine-6-aryloxyrpirimidines and intermittent interactions.
  • ⁇ selected from ⁇ réelle ⁇ . amine-. ⁇ - ⁇ 4- monoalkylamine-. dialkylamine-. ⁇ réelle ⁇ syalkylamine-. arylamine-. geterylamine group; 5 ⁇ ;> - the atoms of halogen. alkyl-, hydroxy. amine or alkoxy. ⁇ ? - atoms of water or halogen;
  • Compounds of the above formula and their pharmaceutically acceptable derivatives may be the active 5 ingredients of the medicinal product.
  • the basis for the implementation of the synthesis of the target compounds is based on the general methods of radiation for all members of the group, taking into account the chemical reactions of each of the above. In addition to that, with chemical
  • X - substituents in the environment, meta-, and para-location of the aromatic group halogen atoms, ⁇ - ⁇ -alkyl, cycloalkyl, alkoxy, nitrous oxide.
  • Version 1 of the synthesis of the claimed materials is the basic interconnected material used by us. and the name '2-amine-4.6-difluoropyrimidine (1) 5 ⁇ 250 g (4.3 mol) of different dry fluids increased the potency of 5.2 grams of diluted-18-whey alcohol 6 mg. The mixture was stirred vigorously for 15–20 minutes at 50 ° ⁇ and then 175 g (0.95 mol) of 2.4,6- ⁇ - ⁇ -roti-pyrimidine were added. At the end of the reaction, the mass was heated by stirring to 160 ° C for 2 hours, then
  • the temperature was raised to 175-1 0 ° ⁇ and they were removed from the reaction with a mixture of dimethylamide, which had a reaction with a temperature of 95-120 ° ⁇ .
  • 115 g (90%) of 2.4.6-potassium pyrimidine (t.k. 98-101 ° C) were obtained, mixed with 230 ml of water, and the mixture was heated.
  • Example 2 The embodiment of the first stage of the synthesis of the claimed substances is an intermediate substance. and specifically: 2-ethylamino-4.6-diflucto ⁇ imidine (II). 30 ⁇ of a mixture of 6.7 g (0.05 mol) of 2,4,6- ⁇ and ⁇ ⁇ ⁇ ⁇ ⁇ pyrimidine (see Example 1) in 10 ml of water was added to 5.4 g (0.12 mol) of ethylamine in 20 ml of water at a temperature and stirring at 0-5 °. The mixture was stirred for 1 hour at 10 ° ⁇ , and the plants were removed.
  • II 2-ethylamino-4.6-diflucto ⁇ imidine
  • EXAMPLE 8 Version 1 of the synthesis of the claimed substances - interim suspension. and 2-amine-4-hydroxy-5-iodo-6- ⁇ irimidine (XVII) 2 solution of 2 5 g (0 063 mol) sodium hydroxide in 250 ml of water was charged 7 5 g (0 058 mol-2 amine) -Hydroxy-6-fluoro-pyrimidine and then equip a solution of 14 8 g (0 058 mol) and 480 ml of water. Mix the mixture until it was taken ⁇ / ⁇ 99 / 00358
  • Example 9 a series of target 2-amine-4- ⁇ -6- ( ⁇ -aryloxy) pyrimidines, presented in Table 3, were synthesized.
  • Disruptive synthesis of this compound can be achieved by the condensation of 2-amine-4-oxi-6- ⁇ -stoopyrpyrimidine (XVIII) with a temperature of 10 ° C at a rate of 1 to 10 ° C.
  • This compound can be obtained by other means by condensation of 2-amino-5-bromo-4,6-difluoro-pyrimidine (XIII) (see example 4) with a phenom- enum that is used in conjunction with a 9-phase -measurement.
  • XIII 2-amino-5-bromo-4,6-difluoro-pyrimidine
  • a phenom- enum that is used in conjunction with a 9-phase -measurement.
  • -6- phenoxydimidine ( ⁇ criz) under conditions of Example 13, 57%, based on the initial compound, 2-amino-4-hydroxy-5-synchromes
  • Examples 16, 17 were synthesized for a range of target 2-amines (substituted amino) -4-hydroxy-5-bromo-6- ( perennial-aryloxy) pyrimidines, 6 days ago.
  • Example 18 synthesizes a series of target 2-amines (substituted amines) - 4-hydroxy-5-iod-6- ( perennial-aryloxy) pyrimidines, shown in Table 7
  • Kib i discharge ⁇ sectioni 7 Primary 2- ⁇ ( ⁇ excreted) 4-4- ⁇ Where-5- ⁇ --6- ( ⁇ torque. ⁇ ⁇ utiliz)) ⁇ debt) ⁇ debt ⁇ ) () other
  • P ⁇ eds ⁇ avlennye in ⁇ ablitsa ⁇ 6 and 7 ⁇ nechnye claimed vesches ⁇ va - 2- amin ⁇ -4-gid ⁇ si-5-gal ⁇ id-6- ( ⁇ -a ⁇ il ⁇ si) ⁇ i ⁇ imidiny - yavlyayu ⁇ sya vys ⁇ lav ⁇ imi s ⁇ edineniyami, ⁇ a ⁇ iches ⁇ i ne ⁇ as ⁇ v ⁇ imymi in ne ⁇ lya ⁇ ny ⁇ ⁇ ganiches ⁇ i ⁇ ⁇ as ⁇ v ⁇ i ⁇ elya ⁇ , n ⁇ ⁇ as ⁇ v ⁇ imymi in vys ⁇ lya ⁇ ny ⁇ ⁇ as ⁇ v ⁇ i ⁇ elya ⁇ , ⁇ i ⁇ a dime ⁇ ilsul ⁇ sid , dimethylphamide.
  • the USC and S929 cell cultures derived from the Cellular Banking Institute ⁇ were used in the process.
  • the scheme of the distribution of the experience - the vaults were tearing all flasks out of the neutral 5 glass in the environment of ⁇ -1640 with the addition of 10% of the flow rate of the discharge.
  • the experiment was placed in glass (lacking toxicity) of simple adjacent flasks with ordinary glass. ⁇ le ⁇ i vn ⁇ sili in s ⁇ edu in ⁇ nechn ⁇ y ⁇ ntsen ⁇ atsii 1x10 " ⁇ l / ml.
  • the control action of the standard antimicrobial preparation is a decrease in the number of CPUs by 5 compared to the previous control.
  • the toxicity of the claimed compounds is absent.
  • the control panel of the distributors - the effect on the cages is absent.
  • the other claimed compounds possess less pronounced activity in the presence of chlamydia cells in the selected conditions of the experiment.
  • the results were evaluated by the presence of the cytostatic effect of the virus on the cells after 36 hours of cultivation at 37 ° ⁇ in a ⁇ 0 2 incubator.
  • the anti-virus activity of the drug is an acyclic 0 4.
  • hematocyte (as described above) for the determination of the cytotoxic effects of the drugs.
  • the method used a solid immunodeficiency method with the use of the conversion of oxidase in the form of an indicator of the disease.
  • the activity of the bound transoxidases was measured using an automatic device for microplates with a microprocessor at a length of 450 nm.
  • the activity of the physical components of the standard components of the physical equipment, which are part of the known components, was shared.
  • calibrate, use and use The results of the analysis are expressed in ⁇ activity of ⁇ per ml in the given industrial system, containing 3x10 6 lymphocytes / ml. Each experimental and contact point was studied in 4 parallel parameters.
  • a standard strain was used that is suitable for all antimicrobial agents.
  • the evaluation of the antimicrobial activity was performed by the method of serial dilutions.
  • the compounds were disposed of in dimethyl sulfoxide ( ⁇ ), and were sold in the medium ⁇ -1, since this product was consumed at a 200 mg / hour.
  • the concentration of the drug in the environment of the neighboring facilities was two times different. ⁇ Brass On the other hand, we used ⁇ , which, on the other hand, used the same way and did the opposite. The result was taken into account after 72 hours of cultivating the activities at 37 ° ⁇ .
  • the value of the therapeutic index is greater than 3.
  • the DD_ of the 5th fluorescence of the indi vidual and 5-dose internal administration to mice was 54 mg / kg, and At the same time, a uniform with the connection of the agreed upon invention was observed, the active activity was 25 mg / kg. ⁇ .e And the 5-factor is equal to 2. The way the compounds are agreed to is 1.5 times that the 5-factor is increased.
  • connection as agreed to the invention does not have a negative effect on the impact of tangles. What is the evidence of a lack of neglected toxicity? Harmonious for all anti-cancer drugs. Lack of connection to a vehicle with a high speed of friction, an extra large brain. intestinal epidemiology, lymphoid organs are waiting for data. ⁇ reported in ⁇ fifteen. ⁇ ⁇ 01/19801

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne de nouveaux composés bioactifs de la famille des pyrimidines et des produits de synthèse intermédiaires de ces composés. Les nouveaux composés ont une activité prononcée au plan antimicrobien (notamment à l'égard d'une souche de mycobactéries résistant aux médicaments existants) comme au plan antiviral ainsi qu'une forte activité immunostimulante (interféronogène), et ce avec un faible niveau de toxicité. Les dérivés des 2-amino-6-aryloxypyrimidines et les produits de synthèse intermédiaires de ces derniers correspondent à la formule générale suivante: (formule I) dans laquelle R1 est de préférence sélectionné dans le groupe contenant des groupes amino, monoalkylamino C1-C4, dialkylamino, carboxyalkylamino, arylamino, hétérylamino; R2 représente des atomes d'halogènes ou un groupe alkyle, hydroxy, amino ou alcoxy; R3 représente des atomes d'hydrogène ou d'halogènes; R4 représente des atomes d'halogènes, des groupes aryloxy avec des substituants fonctionnels X dans les positions ortho-, méta- et para- du fragment aryle, les substituants X étant des atomes d'halogènes, des alkyles C1-C4, des groupes cycloalkyles, alcényle, alcoxy et nitro. L'invention concerne aussi leurs sels pharmaceutiquement acceptables.
PCT/RU1999/000358 1999-09-16 1999-09-16 Substance bioactive a base de derives des 2-amino-6-aryloxypyrimidines et de produits de synthese intermediaires de ces derniers WO2001019801A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/RU1999/000358 WO2001019801A1 (fr) 1999-09-16 1999-09-16 Substance bioactive a base de derives des 2-amino-6-aryloxypyrimidines et de produits de synthese intermediaires de ces derniers
AU25826/00A AU2582600A (en) 1999-09-16 1999-09-16 Bioactive substance containing derivatives of 2-amino-6-aryloxypyrimidines and intermediary products of synthesis thereof

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PCT/RU1999/000358 WO2001019801A1 (fr) 1999-09-16 1999-09-16 Substance bioactive a base de derives des 2-amino-6-aryloxypyrimidines et de produits de synthese intermediaires de ces derniers

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006041404A1 (fr) * 2004-10-15 2006-04-20 Astrazeneca Ab Composes amino substitues et utilisation de ces compose
EP2409980A1 (fr) 2005-04-14 2012-01-25 Applied Biosystems, LLC Oligonucléotides modifiés en 3' contenant des dérivés de la nucléobase pseudoisocytosine et leurs applications en tant qu'amorces ou sondes
WO2020142557A1 (fr) 2018-12-31 2020-07-09 Biomea Fusion, Llc Inhibiteurs irréversibles de l'interaction ménine-mll

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2433440A (en) * 1947-12-30 Jpyrimidine cosipounds
SU113789A1 (ru) * 1957-03-20 1957-11-30 А.В. Сергеев Устройство дл увеличени сцеплени ведущих колес трактора с почвой
GB854011A (en) * 1958-09-10 1960-11-16 Ici Ltd New pyrimidines
GB901749A (en) * 1957-12-06 1962-07-25 Ciba Ltd New 2-substituted pyrimidines
US3259623A (en) * 1963-06-14 1966-07-05 Olin Mathieson Process for preparing 2-(secondary amino)-halogenopyrimidines
SU547447A1 (ru) * 1975-08-08 1977-02-25 Ленинградский Ордена Трудового Красного Знамени Технологический Институт Им. Ленсовета Способ получени 6-фторизоцитозина
EP0310550A1 (fr) * 1987-09-28 1989-04-05 Ciba-Geigy Ag Produit antiparasite
DE3900471A1 (de) * 1989-01-10 1990-07-12 Basf Ag Verfahren zur herstellung von 2-amino-4-fluorpyrimidinderivaten
EP0742212A1 (fr) * 1995-05-11 1996-11-13 Bayer Ag Procédé de préparation de 2-fluoro-pyrimidine substitué

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2433440A (en) * 1947-12-30 Jpyrimidine cosipounds
SU113789A1 (ru) * 1957-03-20 1957-11-30 А.В. Сергеев Устройство дл увеличени сцеплени ведущих колес трактора с почвой
GB901749A (en) * 1957-12-06 1962-07-25 Ciba Ltd New 2-substituted pyrimidines
GB854011A (en) * 1958-09-10 1960-11-16 Ici Ltd New pyrimidines
US3259623A (en) * 1963-06-14 1966-07-05 Olin Mathieson Process for preparing 2-(secondary amino)-halogenopyrimidines
SU547447A1 (ru) * 1975-08-08 1977-02-25 Ленинградский Ордена Трудового Красного Знамени Технологический Институт Им. Ленсовета Способ получени 6-фторизоцитозина
EP0310550A1 (fr) * 1987-09-28 1989-04-05 Ciba-Geigy Ag Produit antiparasite
DE3900471A1 (de) * 1989-01-10 1990-07-12 Basf Ag Verfahren zur herstellung von 2-amino-4-fluorpyrimidinderivaten
EP0742212A1 (fr) * 1995-05-11 1996-11-13 Bayer Ag Procédé de préparation de 2-fluoro-pyrimidine substitué

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006041404A1 (fr) * 2004-10-15 2006-04-20 Astrazeneca Ab Composes amino substitues et utilisation de ces compose
JP2008516945A (ja) * 2004-10-15 2008-05-22 アストラゼネカ・アクチエボラーグ 置換されたアミノ化合物およびそれらの使用
EP2409980A1 (fr) 2005-04-14 2012-01-25 Applied Biosystems, LLC Oligonucléotides modifiés en 3' contenant des dérivés de la nucléobase pseudoisocytosine et leurs applications en tant qu'amorces ou sondes
WO2020142557A1 (fr) 2018-12-31 2020-07-09 Biomea Fusion, Llc Inhibiteurs irréversibles de l'interaction ménine-mll

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