Technical Field Related to the Invention

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.

State of the Art of the Invention (Prior Art)

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. Various drugs containing the pyrimidine core are used as potent anticancer agents through different mechanisms of action. For example, 5-Fluorouracil (5-FU) I as a thymidylate synthase inhibitor, Merbarone II, Ceritinib (LDK378) III as a DNA topoisomerase II (topoIl) catalytic inhibitor, 18, 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, Ruxolitinib (INC424) VII as receptor tyrosine kinase (TKI) inhibitor20, 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 Leukaemia.

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.

Brief Description and Objects of the Invention

2-hydrazineyldinetetrahydropyrimidine-4-one (Formula I) and 2- hydrazineyldinedihydropyrimidine-4 (IH)-one (Formula II) are synthesized, which are the derivatives of hydrazineylidene pyrimidine-4(lH)-on from the starting materials of Meldrum's acid (2, 2-dimethyl-l,3-dioxane-4, 6-dione) from the carbonyl compounds and 1,3 dicarbonyl compounds of guanylhydrazone derivatives obtained from carbonyl compounds (aldehyde/ketone) and aminoguanidine salts which are produced on the market and have a low cost and synthesis, the formulae are shown below. formula 1 formula 2

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. 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.

It is known that various derivatives have calcium antagonist, anti-inflammatory, analgesic, antitumor, antidepressant, antibacterial, and antifungal effects since these compounds synthesized by the invention are derivatives of pyrimidine, and it is thought that they will also be used as protective and therapeutic chemicals for living things.

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. Some studies have also found that it shows antiproliferative activity, antibacterial, anti-Trypanosoma and antifungal activities, as well as anti-glycation activity, to human cancer cells. 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). In addition, antihypertensive, antibacterial, and antimalarial properties were also examined. Drugs containing the guanidine group are also subject to intensive clinical evaluations for antitumor therapy. Structures containing the hydrazone pharmacophore group (>C=N-NH-) are known to have a wide range of biological activities. Compounds such as nifuroxazide, verazide, and salinazide contain hydrazone and are approved as antibacterial and antimicrobial drugs

Figures Describing the Invention

Figure 1: ^-NMR spectrum of Compound 1

13

Figure 2: C-NMR spectrum of Compound 1

Figure 3: Mass spectrum of Compound 1

Figure 4: IR spectrum of Compound 1

Figure 5: 1H-NMR spectrum of Compound 4

Figure 6: 13C-NMR spectrum of Compound 4

Figure 7: Mass spectrum of Compound 4

Figure 8: IR spectrum of Compound 4

Figure 9: 1H-NMR spectrum of Compound 19

Figure 10: 13C-NMR spectrum of Compound 19 Figure 11: Mass spectrum of Compound 19

Figure 12: IR spectrum of Compound 19

Figure 13: 1H-NMR spectrum of Compound 23

Figure 14: 13C-NMR spectrum of Compound 23

Figure 15: Mass spectrum of Compound 23

Figure 16: IR spectrum of Compound 23

Detailed Description of the Invention

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. In addition, 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, triazolopyridinyl, imidazolopyridinyl, pyrolopyrimidinyl, pyrazolopyrimidinyl, pyrrolidinyl, piperidinyl and piperazinyl. In addition, 2-hydrazinylidenetetrahydropyrimidine-4 (IH)-one derivatives of the biologically important hydrazine (NH ₂ NH-) group can be obtained by separating the carbonyl group in the (>C= N- NH-) group in these compounds. In addition, 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. The term “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. In addition, Sulphur (S) and imine (=N-) groups can also replace the ring-linked oxygen (O) atom. 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.

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 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) Keeping the filtrate for 2-5 days after crystallization and obtaining the compound of Formula II as a by-product.

Synthesis of Guanylhydrazone Derivatives: 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).

Synthesis of Hydrazineylidenetrahydropyrimidine-4 (IH)-One Derivatives:

The synthesis of the compounds of the invention took place in two stages. Different derivatives of guanylhydrazone were synthesized and purified in the first stage. Meldrum's acid (1 eq) and carbonyl (1 eq) compounds were dissolved in ethanol and 2-3 drops of triethylamine and some basic catalysts such as Steglich were added and mixed in room conditions or in ultrasonic water bath for 15-20 minutes in the second stage. Then, reactions were made by boiling in a condenser for 1-8 hours according to the selected derivatives by adding guanyl hydrazones. Then, the precipitate formed was left to the cold and filtered, crystallization or column chromatography was purified, and the yield rate of the compounds whose general formula is given in Formula I varies between 40-90%. Spectroscopic measurements of these compounds obtained were made and the structure was illuminated. The derivatives (2-hydrazineylidenedihydropyrimidine-4 (IH)-one) given in Formula II were synthesized with a yield of 5-10% when the filtrate was kept for a certain period of time after crystallization. It was understood considering this structure that Formula II was obtained by separating one mole of hydrogen by oxidizing the structure in Formula I. Spectroscopic measurements of the compounds numbered 1, 4, 19, 23 in terms of being an example are given in the Figures. The following reaction equation shows the reaction equation for obtaining the compounds given in Formula I and Formula II. These compounds can be in R,

S, and racemic mixture or in E/Z Structure.

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.