WO2022146324A1 - Synthèse de dérivés de pyrimidine-4(1h)-one à partir d'hydrazineylidène nouveau - Google Patents

Synthèse de dérivés de pyrimidine-4(1h)-one à partir d'hydrazineylidène nouveau Download PDF

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Publication number
WO2022146324A1
WO2022146324A1 PCT/TR2021/051239 TR2021051239W WO2022146324A1 WO 2022146324 A1 WO2022146324 A1 WO 2022146324A1 TR 2021051239 W TR2021051239 W TR 2021051239W WO 2022146324 A1 WO2022146324 A1 WO 2022146324A1
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WIPO (PCT)
Prior art keywords
hydrazineylidene
tetrahydropyrimidin
formula
benzylidene
compound
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PCT/TR2021/051239
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English (en)
Inventor
Emin SARIPINAR
Hilal Janset BURCU
Hüseyin KEKEÇMUHAMMED
Michael TAPERA
Original Assignee
T.C. Erci̇yes Üni̇versi̇tesi̇
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Publication of WO2022146324A1 publication Critical patent/WO2022146324A1/fr

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    • 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
    • A61P33/00—Antiparasitic agents
    • 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
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms

Definitions

  • the present invention relates to the synthesis of pyrimidine-4 (IH)-one derivatives from Meldrum's acid, carbonyl compounds (aldehyde/ketone), and guanylhydrazone derivatives, and tautomers, enantiomers, and salts thereof.
  • Pyrimidines are one of the most commonly used heterocyclic scaffolds in nucleotide structure and also as a pharmacophore nucleus in drug chemistry.
  • the pyrimidine ring is also located in the structure of the DNA nucleic acid composition.
  • Guanine is a component of uracil and thymine ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) and cytosine. It is also found in the structure of many synthetic compounds such as barbiturates and HIV medicine, zidovudine.
  • RNA uracil and thymine ribonucleic acid
  • DNA deoxyribonucleic acid
  • cytosine It is also found in the structure of many synthetic compounds such as barbiturates and HIV medicine, zidovudine.
  • Various drugs containing the pyrimidine core are used as potent anticancer agents through different mechanisms of action.
  • 5-Fluorouracil I as a thymidylate synthase inhibitor
  • Merbarone II Ceritinib (LDK378) III as a DNA topoisomerase II (topoIl) catalytic inhibitor
  • Dasatinib IV as anaplastic lymphoma kinase (ALK) inhibitor
  • Imatinib V as a multiple targeting of the Bcr-Abl and Src family kinase inducer apoptosis inducer
  • Ibrutinib (IBR) VI Bruton tyrosine kinase (BTK) inhibitor21, Janus kinase (JAK) inhibitor and Nilotinib VIII23 as a tyrosine kinase inhibitor and apoptosis inducer
  • Trimethoprim drug are compounds used in Leuka
  • Trimethoprim and bacimethrin are antibiotics used in infections.
  • Azoxystrobin, cyprodinil, pyrimethanil, and diflumetorim compounds are important pyrimidine-derived pesticides used as fungicides in agriculture. It has been stated that the compound specified in patent document WO 2007/074238 A2 can be used in medicine.
  • N-Alk-(E)-Ylidene-N'-Pyrimidin-2-yl Hydrazine derivatives are synthesized in the invention in this patent document.
  • the primary object of the invention is to obtain new 2-hydrazinylidenetetrahydropyrimidine-4 (IH)-one and 2-hydrazinylidenedihydropyrimidine-4 (IH)-one derivatives based on hydrazine containing the pyrimidine ring unknown in the art. It is thought that cellular activity in these compounds can be used after animal experiments and after phase studies.
  • Another object of the invention is to use the compounds of the invention for biological activity in addition to enzyme inhibitors against various DNA and RNA viruses such as antimicrobial, antiviral, antituberculosis, anticancer, anti-inflammatory, antibacterial, antiparasitic, antifungal, antiobesity, antidiabetic, antihypertensive, analgesic, anticonvulsant, and AIDS.
  • enzyme inhibitors against various DNA and RNA viruses such as antimicrobial, antiviral, antituberculosis, anticancer, anti-inflammatory, antibacterial, antiparasitic, antifungal, antiobesity, antidiabetic, antihypertensive, analgesic, anticonvulsant, and AIDS.
  • 2-hydrazinylidenetetrahydropyrimidine-4 (IH)-one derivatives are suitable for use in the treatment of medicinal diseases were obtained and their synthesis was performed with the invention.
  • the 2-hydrazineylidenetetrahydropyrimidine-4 (IH)-one and 2- hydrazineylidenedihydropyrimidine-4 (IH)-one derivatives targeted within the scope of the invention are very important because they are expected to show biological activity for humans, animals, and plants and have potential pharmacological activity because they contain both the aminoguanidine group, which is a very important group in terms of pharmacological properties, and the hydrazine group and the tetrahydropyrimidine-4 (IH)-one and dihydropyrimidine-4 (IH)-one derivative in its structure.
  • Pyrimidine derivatives are generally molecules with biological activity and are known to be very expensive to synthesize and obtain. Syntheses of 2- hydrazinylidenetetrahydropyrimidine-4 (IH)-one and 2-hydrazinylidenedihydropyrimidine-4 (IH)-one derivatives, which are expected to be synthesized using inexpensive method and short duration of time with high probability to be bio-active, were synthesized in this invention.
  • Guanylhydrazones which are used as starting materials in the invention, are very important compounds as they promise interesting chemical and biological potential. Guanylhydrazones derivatives are also defined as an organic base because they contain an amidine (guanyl) group attached to the hydrazone part. It is very important to investigate and develop guanylhydrazone -based therapeutic agents due to the fact that guanylhydrazone synthesis is very easy and its production costs is low. In addition, these substances play an important role as intermediates in the synthesis of heterocyclic multi-functional nitrogen-containing compounds. Hundreds of guanylhydrazone derivatives have been synthesized and their structure-activity relationships have been examined in recent years.
  • Guanabenz (GWAHN-a- benz sold under the trade name Wytensin) is an alpha agonist of the alpha-2 adrenergic receptor used as an antihypertensive drug and is used to treat high blood pressure (hypertension).
  • Wytensin is an alpha agonist of the alpha-2 adrenergic receptor used as an antihypertensive drug and is used to treat high blood pressure (hypertension).
  • antihypertensive, antibacterial, and antimalarial properties were also examined.
  • Drugs containing the guanidine group are also subject to intensive clinical evaluations for antitumor therapy.
  • Compounds such as nifuroxazide, verazide, and salinazide contain hydrazone and are approved as antibacterial and antimicrobial drugs
  • the present invention relates to a 2-hydrazineyldinethrahydropyrimidine-4 (IH)-one (Formula I) and 2-hydrazineyldinedihydropyrimidine-4 (IH)-one (Formula II) or pharmaceutically acceptable salt, solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer or polymorphic crystal structure of compounds having the following Formulas characterized in that
  • the substituent Ri or R 2 may be one of amino groups, aryl groups, halogens, (-CH 2 _), carbonyl, -NH-, carboxyl, amide, sulfur, oxygen groups of functional groups linked to structures comprising a different number of carbons with straight, branched, aromatic or hetero rings or a combination.
  • the substituent Ari or Ar 2 maybe one of O, N, S, Si, P or B, or combinations thereof, instead of 10-membered monocyclic or bicyclic ring C containing hydrogen, alkyl, aromatic, heterocyclic, 3-7-membered aromatic groups, 3-7-membered alkyl groups, aromatic or nonaromatic at least one heteroatom.
  • Ari or Ar 2 groups may be groups such as furyl, pyril, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,5 thiadiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, quinazolinyl, pyridazinyl, sinolinyl, phthalazinyl, quinoxalinyl, xanthine, hypoxanthine, pteridinyl, 5-azacitidinyl, 5-azaurasilyl, triazolopyridiny
  • functional groups with biological activity such as fluorine may replace hydrogen, which is especially dependent on the carbons found in the pyrimidine ring.
  • C1CH 2 CH 2 - and C1CH 2 CH 2 O-, (C1CH 2 CH 2 ) 2 N- groups may also be used as alkylation means against cancer cells instead of H in the alkyl, aryl, heterohaline or non-arylated groups linked to Ari, Ar 2 , Ri and R 2 groups.
  • aryl as used herein includes a derived organic group. They may also be tautomeric structures, steroids or pharmacologically acceptable salts, esters, and amides of the compound of Formula I and II.
  • the "tautomer” used herein refers to the migration of protons between adjacent single and double bonds.
  • the compounds described herein may undergo any possible tautomerization physically and chemically.
  • the carbon atom to which it binds the Ari group in the pyrimidine ring can be chiral as well as achiral carbon atom.
  • the R and S isomers in the incoming groups may be present in the racemic state.
  • the compounds according to the present invention may be different polymorphs or modifications thereof. They contain pharmaceutically acceptable organic or inorganic base or acid salts of compounds given the general molecular formula. They may also be pharmacological salts of these compounds or metal complexes without toxic effects. They also comprise therapeutically active, non-toxic pharmaceutically acceptable forms of solutions of these compounds according to the invention. It may also be in aromatic and non-aromatic groups with hetero rings instead of rings to which the substituent Ri or R2 is attached.
  • the H's here can be replaced by different groups known in chemistry.
  • tautomeric structures steroids or pharmacologically acceptable salts, esters, and amides of the compound of Formula I and II.
  • the "tautomer” used herein refers to the migration of protons between adjacent single and double bonds. The compounds described herein may undergo any possible tautomerization physically and chemically.
  • the invention relates to a compound having Formulas (I and II) or pharmaceutical composition comprising pharmaceutically acceptable salt, solvate, hydrate or hydrated salt, optical isomer, racemic mixture, tautomer, enantiomer, stereoisomer or polymorphic crystal structure thereof; it may be used in the preparation of a medicament for the treatment of cancer or bacterial diseases. It can also be used in the treatment of epilepsy and measles, in the preparation of the drug to be used in the treatment of diseases such as germ and parasite killer, cancer chemotherapy, and hepatitis B virus inhibitor.
  • the compounds of the invention having Formula (I) and Formula (II) can be used against diseases such as antimicrobial, antiviral, antituberculosis, anticancer, anti-inflammatory, antibacterial, antiparasitic, antifungal, antiobesity, antidiabetic, antihypertensive, analgesic, anticonvulsant, and AIDS. These compounds can also be used against RNA and DNA viruses. It is contemplated that these new compounds may be useful in the treatment of mammals or in the prevention of diseases, as well as in herbal diseases.
  • a synthesis method of 2-hydrazinylidenetrahydropyrimidine-4 (IH)-one (Formula I) and 2- hydrazinylidenedihydropyrimidine-4(lH)-one (Formula II) compounds characterized in that it comprises the following steps; a) Dissolving Meldrum's acid and carbonyl compounds in methyl or ethyl alcohol at a ratio of 1 : 1 mol, b) Adding 0,01-0,1 ml basic catalyst and keeping them in room conditions or in ultrasonic water bath for 15-20 minutes, c) Then, by adding guanyl hydrazones in a ratio corresponding to one mole of Meldrum's acid, it is boiled in a condenser for 1-8 hours according to the selected derivatives, d) Then, cooling at -5 to -10°C and filtering the formed precipitate, e) Purification if it is crystallization or column chromatography, f) Obtaining the compound of Formula I, g)
  • Guanylhydrazone Derivatives have been synthesized as given in the literature and are substances known to be obtained and their structures.
  • General obtaining Equivalent mole of aldehyde/ketone is added on a solution of 50 g aminoguanidine salts in 200 ml of purified water. NaOH in the equivalent mole is added to neutralize the medium in the reaction balloon, which is mixed for one hour at room temperature in the magnetic stirrer. After the reaction time is completed, the obtained crude product is filtered, the product is first washed with distilled water (2x100 mL), then crystallized in organic solvents such as ethyl alcohol (EtOH).
  • EtOH ethyl alcohol
  • Table 1 The general structures of Ari and Ar2 groups and the names of compounds in some synthesized 2-hydrazineylidenetetrahydropyrimidine-4 (IH)-one derivatives are given as examples.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
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Abstract

La présente invention concerne la synthèse de dérivés de pyrimidine-4(1H)-one à partir d'acide de Meldrum, des composés carbonyles (aldéhyde/cétone), et des dérivés de guanylhydrazone et des tautomères, des énantiomères et des sels de ceux-ci.
PCT/TR2021/051239 2020-12-29 2021-11-19 Synthèse de dérivés de pyrimidine-4(1h)-one à partir d'hydrazineylidène nouveau WO2022146324A1 (fr)

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TR2020/22136 2020-12-29
TR2021/011437 2021-07-13
TR202111437 2021-07-13

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007074238A2 (fr) * 2005-12-28 2007-07-05 Trophos Nouveaux derives de n-alk-(e)-ylidene-n'-pyrimidin-2-yl-hydrazines et leurs utilisations comme medicaments cytoprotecteurs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007074238A2 (fr) * 2005-12-28 2007-07-05 Trophos Nouveaux derives de n-alk-(e)-ylidene-n'-pyrimidin-2-yl-hydrazines et leurs utilisations comme medicaments cytoprotecteurs

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
KHAZIR JABEENA, MIR BILAL AHMAD, CHASHOO GOUSIA, MAQBOOL TARIQ, RILEY DARREN, PILCHER LYNNE: "Design, synthesis, and anticancer evaluation of acetamide and hydrazine analogues of pyrimidine", JOURNAL OF HETEROCYCLIC CHEMISTRY, WILEY-BLACKWELL PUBLISHING, INC., US, vol. 57, no. 3, 1 March 2020 (2020-03-01), US , pages 1306 - 1318, XP055953705, ISSN: 0022-152X, DOI: 10.1002/jhet.3867 *
SAMIA CHEKIR ET AL.: "Design and synthesis of novel antimicrobial pyrimidinone hydrazones", CONFERENCE INJNC, 2016 *
VICTORIA V. LIPSON ; NIKOLAY YU. GOROBETS: "One hundred years of Meldrum’s acid: advances in the synthesis of pyridine and pyrimidine derivatives", MOLECULAR DIVERSITY, KLUWER ACADEMIC PUBLISHERS, DO, vol. 13, no. 4, 21 April 2009 (2009-04-21), Do , pages 399 - 419, XP019752117, ISSN: 1573-501X, DOI: 10.1007/s11030-009-9136-x *

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