Synthesis of β-lactam penicillin antibiotics with peptide structure

Abstract

The invention relates to the synthesis of novel penicillin β-lactam antibiotics with synthetic peptide structures containing C-C and C-N multiple bonds, and the synthesis of their pharmaceutically acceptable salts, via four-component reactions using 6-aminopenicillanic acid (6-APA) as the aldehyde, amine, isonitrile, and carboxylic acid, or 6-aminopenicillanic acid (6-APA) as the aldehyde carboxylic acid and amine.

Description

[0001] SYNTHESIS OF p-LACTAM PENICILLIN ANTIBIOTICS WITH PEPTIDE STRUCTURE

[0002] Technical Field

[0003] The invention relates to the synthesis of novel penicillin P-lactam antibiotics with synthetic peptide structures containing C-C and C-N multiple bonds, and the synthesis of their pharmaceutically acceptable salts, via four-component reactions using 6-aminopenicillanic acid (6-APA) as the aldehyde, amine, isonitrile, and carboxylic acid, or 6- aminopenicillanic acid (6-APA) as the aldehyde carboxylic acid and amine.

[0004] State of the Art

[0005] P-lactam antibiotics are the most significant class of antibacterial compounds in clinical practice. The bactericidal properties of naturally occurring P-lactam antibiotics have triggered the synthesis of semi-synthetic antibiotics. Natural P-lactams typically consist of 6-aminopenicillanic acid containing a P-lactam ring and a bonded side chain.

[0006] The World Health Organization (WHO) reports that antibiotic resistance continues to rise and therefore warns that a time is approaching when infections may no longer be treatable with currently available antibiotics. The rise in antibiotic-resistant bacterial strains has created a need for the development of new antimicrobial agents that can be used in treatment. Recent epidemics and pandemics have revealed that public health is potentially under a global threat from infectious diseases, and the need for new and effective antimicrobial agents to combat emerging microbial diseases continues

[0007] Antimicrobial resistance is one of the greatest health threats that people face and will face in the future. Current antibiotics can prevent infection usually by killing or inhibiting microorganisms directly. However, by altering the targets of antibiotics, bacteria can rapidly develop resistance. Since bacteria evolves, the use of new antibacterial drugs is becoming essential to solve the problem of drug-resistant bacterial infections. Therefore, developing new antimicrobial agents is extremely urgent. Peptide drugs have significant advantages due to their high activity, low toxicity, absence of major side effects, and lack of potential for addiction. The superiority of dipeptides over poly- and oligopeptides in many cases is highly significant due to their ability to penetrate biological barriers and their oral bioavailability. Due to the structure of the beta-lactam ring and the substituted groups in the side chains, P-lactam antibiotics are known to play a role in biological activity. The 6-APA component found in penicillin consists of an adjacent five-membered thiazolidine ring and a four-membered beta-lactam ring. Its functionality and activity spectrum against Gram-negative or Gram-positive bacteria can be improved by bonding dipeptide groups to the amid and carboxylate groups bonded to the 6-APA side chain.

[0008] Antibiotic resistance refers to the development of new drugs, with pathogens becoming resistant to traditional antibiotics. Therefore, this has increased interest in antimicrobial peptides, both synthetic and naturally sourced. Antimicrobial peptides (AMPs) have been considered as potential alternatives for treating infections since antibiotic resistance emerged as a global problem. Antimicrobial peptides are small molecules of variable length, containing a series of amino acid sequences and structures. These molecules exhibit activity against a wide variety of microorganisms, including bacteria, fungi, viruses, and even tumor cells. Many peptide-structured molecules are used in preclinical and clinical studies. The disadvantage of these molecules is their high production costs] DOI: .197( 347].

[0009] The current system comprises patent / utility model applications and articles related to this subject. The patent number “EP 2 367 940 Bl” in the state of the art relates to novel and different acylation of the side chain of the beta-lactam core. In patents W02003055998A2 and US8541199B2, new beta-lactam antibiotics were synthesized using a modified penicillin acylase enzyme. In the invention CN101177688, novel P-lactam antibiotics were synthesized by activating the side chain from the P-lactam core via an enzymatic process. In patent W098 / 20120, the cefradin beta-lactam antibiotic was synthesized using the penicillin G acylase enzyme.

[0010] In patent TR 2019 22977 B, amino acid-based urea derivatives were obtained by reacting to amino acids with isocyanate or thioisocyanate, and then imidazole and pyrimidine derivatives were obtained by reacting to these with oxalyl chloride and malondichloride. These imidazole and pyrimidine derivatives were converted to acyl chlorides, and subsequently, imidazole and pyrimidine-containing penicillin derivatives were obtained from their reaction with 6-aminopenicillinic acid (6-APA). Current literature and patent studies have shown that no penicillin derivatives with a dipeptide structure exist, and that penicillin with a dipeptide structure are not detected by Ugi reactions. Furthermore, in present systems, side-chain modifications of beta-lactam antibiotics have generally been limited to enzymatic or chemical processes, and these methods often result in high production costs and limited chemical diversity. Furthermore, the high cost of producing antimicrobial peptides is a significant obstacle limiting their commercial use. This situation highlights the need to develop new synthesis methods, particularly because the advantage of dipeptide structures in penetrating biological barriers has not been sufficiently utilized, and because the forms of existing beta-lactam antibiotics with extended activity spectrum is limited.

[0011] Brief Description and Objectives of the Invention

[0012] The invention relates to the synthesis of novel penicillin P-lactam antibiotics with synthetic peptide structures containing C-C and C-N multiple bonds, via four-component reactions using 6-aminopenicillanic acid (6-APA) as an aldehyde, amine, isonitrile, carboxylic acid, or 6-aminopenicillanic acid (6-APA) as an aldehyde carboxylic acid and amine, and the synthesis of their pharmaceutically acceptable salts, which meets all the above-mentioned requirements and eliminates the shortcomings and disadvantages of the existing system.

[0013] The primary objective of this invention is to synthesize novel P-lactam antibiotics containing penicillin in peptide form, which can be obtained using short synthesis times and low-cost methods that are currently unknown in the field. Since the chemicals used for penicillin derivatives with this dipeptide structure are quite inexpensive, the compounds described in this invention have been synthesized economically. Synthesis at room temperature and at low cost without the use of catalysts offers a significant advantage. It is possible to synthesize numerous penicillin derivatives by using different derivatives or combinations of the substances used for its synthesis.

[0014] Another objective of the invention is to develop a formulation containing compounds with structures in Formulas I-II, or their pharmaceutically acceptable salts, solvates, hydrates, or hydrated salts, optical isomers, racemic mixtures, tautomers, enantiomers, esters, amide stereoisomers, or polymorphic crystal structures.

[0015]

[0016] Formulas I and III can be used for various biological activity purposes in addition to enzyme inhibitors such as antimicrobial, antiviral, antituberculosis, anticancer, antiinflammatory, antibacterial, antiparasitic, antifungal, anti-obesity, antidiabetic, antihypertensive, analgesic, anticonvulsant, and AIDS. Furthermore, these compounds, or formulations containing them, can be used against RNA and DNA viruses, and may be beneficial in the treatment or prevention of diseases in mammals, as well as in plant diseases.

[0017] Another objective of the invention is to develop formulations and production methods that can be obtained using short synthesis times and low-cost methods. The compounds given in Formulas I-II are derived from carbonyl compounds, amines, carboxylic acids, and isonitrile penicillin derivatives and beta-lactam derivatives, which are expected to exhibit biological activity and potentially possess antibiotic effects, have been synthesized using a peptide structure not known in the art.

[0018] Detailed Description of the Invention

[0019] The invention relates to Formula I-II compounds, whose general structure is shown below, and their pharmaceutically acceptable salts, solutes, hydrates or hydrated salts, optical isomers, racemic mixtures, tautomers, enantiomers, stereoisomers, polymorphic crystal structures, E and Z isomers, R and S or racemic mixtures. This invention performed the synthesis of P-lactam antibiotics containing novel penicillin derivatives in a synthetic peptide structure using aldehyde, amine, isonitrile, and P-lactam 6-aminopenicillanic acid (6-APA) core. According to the present invention, these new penicillin derivative compounds include non-toxic metal salts such as sodium and potassium salts, as well as non-toxic ammonium and substituted ammonium salts. In the first part of the invention, a dipeptide structure was formed via the carboxyl group of

[0020] 6-aminopenicillanic acid using 6-aminopenicillanic acid (6-APA) cores as aldehyde, amine, isonitrile, and P-lactam rings.

[0021] Formula I

[0022] Wherein L= O, S, C, N, S(O) or SO2

[0023] In the second part of the invention, a dipeptide structure was formed via the amino group of aldehydes, carboxylic acid, isonitrile, and aminopenicillanic acid (6-APA).

[0024] Formula III

[0025] R3-N+= C"

[0026] Wherein X= Br, Cl; Y= C, Si; Z= O, S.

[0027] In these compounds, the groups shown by L are atoms or groups such as O, S,CH2, NH, NR, S(O) or SO2. The R groups here can be one of the groups listed below. Hydrolysis of the compound indicated in Formula III replaces the -Y-R6 with a hydrogen (H) atom.

[0028] The R'-R7groups specified in Formulas I, II, and III are substituted or unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, cycloheteroalkyl, alkylaryl, alkylheteroaryl, alkinylaryl, alkenylheteroaryl, alkynylaryl, or alkynylheteroaryl; the hydrogens in these groups can be replaced by any of the groups listed above, or by hydroxyl, carbonyl, thiol, sulfide, amine, nitro, halogens, carboxyl groups, carboxylic acid derivatives, or combinations thereof, or they can be bonded to the groups mentioned above. Here, the R'-R7groups in the Formula I-III compounds given above can be the same or different and can also include aromatic or non-aromatic cyclic structures and combinations of these groups.

[0029] The term alkyl refers to carbon chains, or combinations thereof, which can be linear or branched. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and similar groups, and they can also have cyclic structures. "Alkenyl" refers to carbon chains containing at least one carboncarbon double bond, which can be linear, branched, or a combination thereof. Examples of alkenyls include vinyl, alkyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1 -propenyl, 2- butenyl, 2-methyl-2-butenyl, and such, or those with cyclic structures. "Alkynyl" refers to carbon chains containing at least one carbon-carbon triple bond, which can be linear, branched, or a combination thereof. Examples of alkynyls include ethinyl, propargyl, pentinyl, 2-heptinyl, and their derivatives. Cycloalkyl refers to monocyclic, disyclic, tricyclic, or bridged saturated carbocyclic rings, each containing 3 to 12 carbon atoms. It also contains monocyclic rings adjacent to an aryl group. Examples of cycloalkyl compounds include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and others. “Aryl” refers to mono- or bicyclic aromatic rings containing only carbon atoms. The groups mentioned above can be in structures containing straight chain branched and organic functional groups. Aryl refers to structures containing mono- or polycyclic aromatic rings with carbon atoms in their structure.

[0030] "Heteroaryl" refers to a mono- or polycyclic aromatic ring containing at least one heteroatom, or combinations thereof, selected from N, O, and S, where each ring contains 4 to 8 atoms. Examples of heteroaryls include pyrrolyl, isoxazolyl, isothiazolyl, pyrazoly, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazoly, benzimidazolyl, benzofuranil, benzothiophenyl, furo, pyridyl, quinolyl, indolyl, isoquinolyl, and similar groups.

[0031] Cycloheteroalkyl refers to mono- or polycyclic or bridged saturated rings containing at least one heteroatom chosen from N, S, and O; each of these rings may have 3 to 12 atoms, where the bonding point can be carbon or a heteroatom.

[0032] In some structures, the hydrogens in groups R'-R7can be replaced by a substituted group or groups with a biologically acceptable substituent. These groups may include halogens; hydroxyls; alkoxy, alkenoxy, alkinoxy, aryloxy, heterooxy, and heteroalkoxy groups; carbonyls; carboxylic acids and their derivatives; oximes; hydroxylamines; alkoxyamines; thiols; sulfites; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines and their derivatives; azides; ureas and their derivatives; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; and nitrile groups. Another preferred embodiment of the invention is that the structures of Formulas I-III can be combinations of the groups mentioned above. Additionally, alkyl bonded to R'-R7groups may be groups CICH2CH2-, CIC LC LO-and (C1CH2CH2)2N- used as alkylating agents against cancer cells, replacing the H in both aromatic (Aryl) and non-aromatic groups.

[0033] Compounds given in formulas I-III may contain one or more asymmetric centers and can therefore exist as racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. The present invention makes it possible for compounds of Forms I-III to contain all such isomeric forms. Here, some of the compounds may contain both E and Z geometric isomers because they have olefinic double bonds. The compounds described here can exist at different hydrogen bonding points, such as in keto-enol isomers, called tautomers, or in mixtures thereof at certain rates. There can be individual tautomers and their mixtures, as well as separate stereoisomers. Preferably, compounds may have different polymorphic forms or modifications.

[0034] This refers to pharmaceutically acceptable, non-toxic bases or acid salts, including inorganic or organic bases and acids. Salts derived from inorganic bases include ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc, and others. Salts of primary, secondary, and tertiary amines can also exist as salts of amino acids, such as -olamine. The invention may be a compound with formulas I-III, or its pharmaceutically acceptable solvate, hydrate, or hydrated salt, or a polymorphic crystal structure.

[0035] These compounds can also exist as metal complexes that are non-toxic. According to the invention, these compounds may also include therapeutically active, non-toxic, pharmacologically acceptable solution forms.

[0036] The Formula I, II, and III compounds described in this invention may be used in an antimicrobial, antiviral, antituberculosis, anticancer, anti-inflammatory, antibacterial, antiparasitic, antifungal, anti-obesity, antidiabetic, antihypertensive, analgesic, or anticonvulsant combination and may be used as medicinal products for plants, animals, and humans.

[0037] Synthesis Studies In the synthesis of formula I derivatives, the aldehyde (1 mmol) is dissolved in 10-30 ml methanol, then the primary amine derivatives (1 mmol) are added and boiled under reflux for (1-5) hours to obtain the Schiff base. After the reaction mixture has cooled to room temperature, 6-Aminopenicillinic acid (1 mmol) and 5-10 ml of DMF solvent are added and stirred at room temperature for 30-60 minutes. Next, isonitrile (isocyanide) derivatives (1 mmol) are added to the reaction medium. This solution is stirred at room temperature (for 2-10 days). After the reaction is complete, 50-100 ml of pure water is added to the reaction medium. This mixture is extracted 3-6 times with ethyl acetate. The product taken to the ethyl acetate phase is dried with anhydrous sodium sulfate, after which the ethyl acetate solution is separated. Ethyl acetate is removed under low pressure. The solid phase is first separated into its components by column chromatography (Methanol 1 : chloroform: 99). For further purification, it is purified by silica gel thin-layer chromatography (hexane 95:5 ethyl acetate).

[0038] Some examples of compounds synthesized using this general method are given below.

[0039] Formula LI: 6-Amino-N-(2-(cyclohexylamino)-l-(4-methoxyphenyl)-2-oxoethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0040] Formula (1.1)

[0041] Closed Formula: C29H36N4O4S, mass (calcd: 536.69-found: 536.69) g / mol, Light yellow, yield: 59%, E.N: 108-111.1HNMR (400 MHz, DMSO): 5 7.86-7.88 (d, 1H, N-H), 7.24- 7.39 (d, 2H, Ar-H), 7.21-7.22 (d, 2H, Ar-H), 7.05-7.07 (t, 3H, Ar-H), 7.02 (s, 1H, C-H), 6.87-6,91 (t, 2H, N-H), 6.68-6.70 (d, 2H, N-H), 6.60-6.62 (t, 1H,C-H), 6.14-6.16 (d, 1H, C-H), 5.45 (s, 1H, C-H), 3.84 (s, 3H, O-CH3), 3.72 (m, 1H, C-H), 1.99-2.01 (m, 1H, C-H), 1.55-1.63 (m, 6H, CH3), 1.15-1.29 (m, 9H, CH2). FT-IR (cm'1): 3319.4 (N-H), 3060 (Aril), 2847.2-2925.1 (Csp3-H), 1764.2 (C=O amide), 1649.8 (C=O -lactam), 1602.2, 1509.0, 1448.7, 1386.2, 1302.0, 1245.0, 1157.4, 1098.4, 1025.7, 830.25, 751.68.

[0042] Formula 1.2: 6-Amino-N-(l-(4-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0043] Formula (1.2)

[0044] Closed Formula: C28H33CIN4O3S, mass (calcd: 541.10- found: 540.19334) g / mol, Light yellow, yield: 52%, E.N: 86-88. 'H NMR (400 MHz, DMSO): 5 8.26-8.28 (d, 1H, N-H), 7.50-7.52 (d, 3H, Ar-H), 7.37-7.39 (d, 3H, Ar-H), 7.04 (t, 1H, Ar-H), 7.00-7.02 (t, 3H, Ar- H), 6.60-6.62 (d, 2H, N-H), 6.60 (s, 1H, C-H), 6.51-6.55 (t, 1H,C-H), 6.14-6.16 (d, 1H, C- H), 5.02-5.04 (d, 1H, C-H), 3.72 (s, 1H, C-H), 1.75 (m, 1H, C-H), 1.52-1.63 (m, 6H, CH3), 1.09-1.23 (m, 9H, CH2). FT-IR (cm'1): 3304.1 (N-H), 3047.0 (Ar-H), 2848.1-2921.6 (Csp3- H), 1765.6 (C=O amide), 1643.8 (C=O -lactam), 1590.6, 1488.8, 1440.6, 1390.6, 1296.9, 1243.8, 1086.6, 1009.4, 821.97, 746.88, 691.79.

[0045] Formula 1.3: 6-amino-N-(2-(cyclohexylamino)-l-(4-methoxyphenyl)-2-oxoethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0046]

[0047] Closed Formula: C28H32CIFN4O3S, mass (calcd: 559.10- found: 558.18626) g / mol, Light yellow, yield: 51%, E.N: 95-98. 'H NMR (400 MHz, DMSO): 5 7.33-7.35 (d, 1H, N-H), 7.23-7.29 (t, 1H, Ar-H), 7.14-7.18 (t, 2H, Ar-H), 7.11 (t, TH, Ar-H), 7.02-7.04 (d, 1H, Ar- H), 6.91-6.94 (d, 2H, N-H), 6.69-6.73 (d, 3H, Ar -H), 6.66-6.68 (s, 1H, C-H), 6.30-6.33 (t, 1H, C-H), 6.17-6.19 (d, 1H, C-H), 5.47-5.48 (s, 1H, C-H), 3.76-3.77 (s, 1H, C-H), 1.99- 2.02(m, 1H, C-H), 1.50-1.76 (m, 6H, CH3), 1.15-1.29 (m, 9H, CH2). FT-IR (cm_1): 3350.5 (N-H), 3065.3 (Ar-H), 2839.0-2913,6 (Csp3-H), 1761,0 (C=O amide), 1659.5 (C=O 0- lactam), 1593.8, 1446.6, 1236.9, 908.72, 777.44, 692.56.

[0048] Formula 1.4: N-(l-(4-acetamidophenyl)-2-(cyclohexylamino)-2-oxoethyl)-6-amino-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0049] Formula (1.4)

[0050] Closed Formula: C30H37N5O4S, mass (calcd: 563.71- found: 563.25735) g / mol, Light yellow, yield: 62%, E.N: 108-111. 'H NMR (400 MHz, DMSO): 5 10.59 (s, 1H, N-H), 9.86 (s, 1H, N-H), 7.88 (d, 2H, Ar -H), 7.53-7.55 (t, 2H, Ar -H), 7.38-7.40 (t, 1H, Ar-H), 7.15-7.17 (d, 1H, Ar -H), 7.09-7.12 (d, 2H, Ar-H), 6.82-6.86 (d, 1H, Ar-H), 6.57-6.62 (t, 2H, N-H), 6.48-6.50 (s, 1H, C-H), 6.21-6.23 (d, 1H, C-H), 5.95-5.97 (t, 1H, C-H), 4.90- 4.92 (s, 1H, C-H), 3.70 (s, 1H, C-H), 2.10 (s, 3H, CO-CH3), 2.01-2.04 (m, 1H, C-H), 1.52- 1.66 (m, 6H, CH3), 1.02-1.23 (m, 9H, CH2). FT-IR (cm'1): 3382.0 (N-H), 3035.0 (Ar-H), 2839.0-2913,6 (Csp3-H), 1771.0 (C=O amide), 1659.5 (C=O P-lactam), 1593.8, 1490.0, 1446.6, 1236.9, 908.7, 777.44, 692.56.

[0051] Formula 1.5: 6-Amino-N-(2-(cyclohexylamino)-l-(4-hydroxyphenyl)-2-oxoethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0052] Closed Formula: C28H34N4O4S, mass (calcd: 522.66- found: 522.23055) g / mol, Light yellow, yield: 54%, E.N: 155-158.3H NMR (400 MHz, DMSO): 5 7.49-7.51 (s, 1H, O-H), 7.70-7.84 (d, 1H, N-H), 7.21-7.25 (d, 1H, Ar-H), 7.08-7.12 (t, 2H, Ar-H), 7.03-7.05 (d, 2H, N-H), 6.82-6.85 (t, 1H, Ar-H), 6.69-6.71 (d, 2H, Ar-H), 6.62 (s, 1H, C-H), 6.57-6.59 (d, 1H, Ar-H), 6.47-6.49 (d, 2H, Ar -H), 6.14 (t, 1H, C-H), 5.83-5.85 (d, 1H, C-H), 4.83-4.85 (s, 1H, C-H), 3.71 (m, 1H, C-H), 1.98(m, 1H, C-H), 1.51-1.88 (m, 6H, CH3), 1.04-1.23 (m, 9H, CH2). FT-IR (cm'1): 3237.6-3100 (N-H and O-H), 3040.0 (Ar-H), 2851,2-2929.5 (Csp3-H), 1752.9 (C=O amide), 1643.7 (C=O P-lactam), 160.1, 1583.9, 1511.1, 1490.3, 1446.1, 1225.3, 1154.8, 834.9, 741.28, 691.86.

[0053] Formula 1.6: 6- Amino-N-(2-(benzylamino)-l-(4-chlorophenyl)-2-oxoethyl)-3, 3 -dimethyl- 7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0054]

[0055] Formula (1.6)

[0056] Closed Formula: C29H29CIN4O3S, mass (calcd: 549.08- found: 549.15111) g / mol, Light yellow, yield: 54%, E.N: 74-77. 'H NMR (400 MHz, DMSO): 5 8.03 (t, 1H, N-H), 7.87- 7.89 (d, 2H, Ar-H), 7.70-7.73 (d, 1H, Ar-H), 7.56-7.59 (d, 2H, Ar-H), 7.37-7.39 (t, 2H, Ar- H), 7.29-7.34 (t, 4H, Ar-H), 7.20-7.24 (t, 2H, Ar-H), 7.13-7.15 (d, 1H, Ar-H), 7.05-7.07 (d, 1H, Ar-H), 6.91-6.95 (t, 2H, Ar-H), 6.75-6.78 (t, 1H, Ar -H), 6.68-6.70 (d, 1H, C-H), 6.17- 6.19 (d, 1H, C-H), 4.45-4.50 (dd, 1H, C-H), 4.41-4.45 (dd, 1H, C-H), 1.23 (s, 6H, CH3). FT-IR (cm'1): 3305.5 (N-H), 3022.0-3045.0 (Ar-H), 2921.7 (Csp3-H), 1747,5 (C=O amid), 1655.5 (C=O P-lactam), 1622.9, 1588.3, 1488.6, 1399.2, 1357.6, 1305.6, 1227.6, 1160.0, 1086.1, 1012.4, 820.15, 742.57, 689.49.

[0057] Formula 1.7: 6-Amino-N-(2-(benzylamino)-l-(2-chloro-6-fluorophenyl)-2-oxoethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0058] Formula (1.7)

[0059] Closed Formula: C29H28CIFN4O3S, mass (calcd: 567.07- found: 566.15508) g / mol, Light yellow, yield: 55%, E.N: 92-95. 'H NMR (400 MHz, DMSO): 5 8.55-8.58 (t, 1H, N-H), 7.37-7.38 (d, 1H, Ar-H), 7.35-7.36 (d, 1H, Ar-H), 7.33 (t, 2H, Ar-H), 7.31 (d, 1H, Ar-H), 7.29 (d, 1H, Ar-H), 7.26 (t, 2H, Ar-H), 7.24 (s, 1H, C-H), 7.20-7.22 (d, 2H, N-H), 7.07- 7.11 (t, 2H, Ar-H), 6.73-6.75 (d, 2H, Ar -H), 6.60-6.63 (t, 1H, Ar-H), 6.08-6.10 (d, 1H, C- H), 5.46-5.48 (d, 1H, C-H), 4.33-4.34 (d, 2H, C-H), 4.32 (s, 1H, C-H), 1.23 (s, 6H, CH3). FT-IR (cm'1): 3279.4 (N-H), 3025.0-3041.0 (Ar-H), 2908.6 (Csp3-H), 1763.0 (C=O amid), 1655.6 (C=O P-lactam), 1596.9, 1568.3, 1490.3, 1444.7, 1238.0, 1173.0, 1069.0, 896.93, 775.08, 730.87, 690.87.

[0060] Formula 1.8: N-(l-(4-acetamidophenyl)-2-(benzylamino)-2-oxoethyl)-6-amino-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0061] Closed Formula: C31H33N5O4S, mass (calcd: 571.69- found: 571.22407) g / mol, Light yellow, yield: 59%, E.N: 82-85. 'H NMR (400 MHz, DMSO): 5 10.43 (s, 1H, N-H), 9.99 (s, 1H, N-H), 7.95-7.97 (d, 1H, Ar-H), 7.75-7.78 (t, 2H, Ar-H), 7.50-7.52 (d, 2H, Ar-H), 7.34-7.37 (d, 2H, Ar-H), 7.28-7.30 (d, 2H, N-H), 7.20 (d, 2H, Ar-H), 7.13-7.15 (t, 4H, Ar- H), 6.87-6.89 (s, 1H, C-H), 6.67 (s, 1H, C-H), 6.61-6.62 (d, 1H, Ar-H), 6.49-6.51 (d, 1H, C-H), 5.93-5.94 (d, 1H, C-H), 5.00-5.01 (s, 1H, C-H), 4.45 (d, 2H, C-H), 2.10 (s, 3H, COOL), 2.04 (s, 3H, CH3), 1.23 (s, 3H, CH3). FT-IR (cm'1): 3305.5 (N-H), 3057.5 (Ar-H), 2846,0-2913,8 (Csp3-H), 1768,5 (C=O amide), 1645.6 (C=O P-lactam), 1589.1, 1490.3, 1446.1, 1386.2, 1303.0, 1243.2, 751.68, 693.34.

[0062] Formula 1.9: 6-Amino-N-(2-(benzylamino)-l-(4-hydroxyphenyl)-2-oxoethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0063] Formula (1.9)

[0064] Closed Formula: C29H30N4O4S, mass (calcd: 530.64 -found: 530.19954) g / mol, Light yellow, yield: 49%, E.N: 112-115.XH NMR (400 MHz, DMSO): 5 9.68 (s, 1H, O-H), 7.91- 7.93 (t, 1H, N-H), 7.71-7.73 (d, 1H, Ar-H), 7.66-7.68 (d, 1H, Ar-H), 7.38-7.39 (t, 1H, Ar- H), 7.26-7.30 (t, 3H, Ar-H), 7.15-7.18 (d, 2H, N-H), 7.05-7.09 (t, 1H, Ar-H), 6.93(s, 1H, C-H), 6.91 (t, 1H, Ar-H), 6.83-6.85 (d, 2H, Ar-H) 6.78-6.80 (d, 2H, Ar-H), 6.73-6.76 (t, 1H, Ar-H), 6.60-6.62 (s, 1H, C-H) 6.56 (s, 1H, C-H), 6.21-6.23 (d, 1H, C-H), 4.89 (s, 1H, C-H), 4.550-4.53 (dd, 1H, C-H), 4.40-4.45 (dd, 1H, C-H), 1.23 (s, 6H, CH3). FT-IR (cm'1): 3237.6-3100 (N-H and O-H), 3030.0 (Ar-H), 2850,0-2940.0 (Csp3-H), 1750.0 (C=O amide), 1640.6 (C=O -lactam), 1588.8, 1515.6, 1484.4, 1440.6, 1223.8, 1156.3, 1021.9, 828.31, 737.50, 693.20.

[0065] Formula LIO: 6-Amino-N-(l-(2-chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide.

[0066] Formula (1.10) Closed Formula: C28H33CIN4O3S, mass (calcd.: 541.10- found: 540.19649) g / mol, Light yellow, yield: 59%, E.N: 85-88. 'H NMR (400 MHz, DMSO): 5 8.10 (d, 1H, N-H), 7.61- 7.63 (d, 1H, Ar-H), 7.51-7.52 (d, 1H, Ar-H), 7.43-7.44 (t, 1H, Ar-H), 7.31-7.33 (t, 2H, Ar- H), 7.11-7.15 (t, 1H, Ar-H), 7.03-7.06 (t, 1H, Ar-H), 6.79-6.80 (d, 1H, Ar-H), 6.62-6.63 (d, 2H, N-H), 6.55-6.57 (t, 1H, Ar -H), 6.32 (d, 1H, C-H), 6.24 (d, 1H, C-H), 5.97 (s, 1H, C- H), 5.25-5.27 (d, 1H, C-H), 4.22 (m, 1H, C-H), 2.01 (m, 1H, C-H), 1.53-1.74 (m, 6H, CH3), 1.08-1.23 (m, 9H, CH2). FT-IR (cm'1): 3279.0 (N-H), 3050.0 (Ar-H), 2846.4-2915.4 (Csp3-H), 1765,6 (C=O amide), 1646.9 (C=O -lactam), 1590.0, 1493.8, 1434.4, 1390.6, 1306.3, 1246.2, 1025.0, 935.13, 749.74, 690.49, 659.38.

[0067] Formula 1.11: 6-Amino-N-(2-(cyclohexylamino)-l-(4-fluorophenyl)-2-oxoethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0068] Formula (1.11)

[0069] Closed Formula: C28H33FN4O3S, mass (calcd.: 524.65- found: 524.2262) g / mol, Light yellow, yield: 52%, E.N: 107-111. 'H NMR (400 MHz, DMSO): 5 7.95-7.97 (d, 1H, N-H), 7.41-7.343 (d, 1H, Ar-H), 7.34-7.35 (t, 2H, Ar-H), 7.24-7.27 (t, 2H, Ar-H), 7.16-7.20 (t, 1H, Ar-H), 7.11-7.13 (d, 2H, N-H), 6.90-6.92 (d, 1H, Ar-H), 6.88 (s, 1H, C-H), 6.73-6.75 (d, 2H, Ar-H), 6.60 (s, 1H, C-H), 6.48 (d, 1H, C-H), 6.12-6.14 (d, 1H, C-H), 3.83 (m, 1H, C-H), 2.01 (m, 1H, C-H), 1.54-1.70 (m, 6H, CH3), 1.23 (m, 9H, CH2). FT-IR (cm'1): 3297.4 (N-H), 3064.7 (Ar-H), 2849.1-2927.2 (Csp3-H), 1772,5 (C=O amide), 1650.6 (C=O P-lactam), 1591.5, 1503.4, 1490.9, 1449.7, 1393.8, 1368.0, 1297.0, 1247.6, 1224.5, 1150.8, 1090.6, 1011.1, 974.55, 835.68, 750.97, 699.65. Formula 1.12: 6-amino-N-(2-(cyclohexylamino)-l-(2-fluorophenyl)-2-oxoethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0070] Formula (1.12)

[0071] Closed Formula: C28H33FN4O3S, mass (calcd.: 524.65- found: 524.22655) g / mol, Light yellow, yield: 50%, E.N: 92-96. 'H NMR (400 MHz, DMSO): 5 7.80-7.84 (d, 1H, N-H), 7.55-7.58 (d, 1H, Ar-H), 7.36-7.37 (d, 1H, Ar-H), 7.27-7.29 (d, 2H, Ar-H), 7.21-7.25 (t, 2H, Ar-H), 7.09-7.15 (t, 2H, N-H), 6.90-6.93 (t, 2H, Ar-H), 6.81(s, 1H, C-H), 6.71-6.75 (t, 1H, Ar-H), 6.66-6.68 (t, 1H, C-H), 6.46-6.56 (d, 1H, C-H), 6.20-6.22 (d, 1H, C-H), 3.73 (m, 1H, C-H), 2,00 (m, 1H, C-H), 1.54-1.77 (m, 6H, CH3), 1.08-1.23 (m, 9H, CH2). FT-IR (cm'1): 3293.4 (N-H), 3051.7 (Ar-H), 2849.1-2925.1 (Csp3-H), 1768,8 (C=O amide), 1646.4 (C=O P-lactam), 1591.5, 1507.4, 1489.1, 1451.8, 1389.5, 1372.3, 1305.6, 1243.3, 1228.6, 1148.7, 1088.6, 1047.6, 1013.2, 974.55, 871.36, 830.51, 751.05, 692.82.

[0072] Formula 1.13: 6-Amino-N-(2-(cyclohexylamino)-2-oxo-l-(thiophen-2-yl)ethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0073] Formula (1.13) Closed Formula: C26H32N4O3S2, mass (calcd.: 512.69-found: 512.19138) g / mol, Light yellow, yield: 63%, E.N: 67-70. 'H NMR (400 MHz, DMSO): 5 7.77-7.78 (d, 1H, N-H), 7.60 (d, 1H, Ar-H), 7.56 (d, 1H, Ar-H), 7.33 (d, 1H, N-H), 7.23-7.25 (d, 2H, Ar-H), 7.21 (s, 1H, C-H), 7. 08-7.11 (t, 2H, Ar-H), 6.89-6.93(t, 2H, Ar -H), 6.75-6.80 (t, 1H, Ar-H), 6.69-6.70 (t, 1H, C-H), 6.09-6.11 (d, 1H, C-H), 5.47 (s, 1H, C-H), 3.82 (m, 1H, C-H), 2.02 (m, 1H, C-H), 1.54-1.72 (m, 6H, CH3), 1.22 (m, 9H, CH2). FT-IR (cm'1): 3291.5 (N-H), 3047.0 (Ar-H), 2840.1-2921.6 (Csp3-H), 1750,0 (C=O amide), 1650.0 (C=O -lactam), 1581.3, 1490.7, 1368.8, 1309.4, 1228.6, 1028.1, 1028.1, 843.75, 746.88, 690.53.

[0074] Formula I. 14: 6-Amino-N-(2-(cyclohexylamino)-2-oxo-l-(lH-pyrrol-2-yl)ethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0075] Formula (1.14)

[0076] Closed Formula: C26H33N5O3S, mass (calcd.: 495.64 -found: 495.22879) g / mol, Light yellow, yield: 61%, E.N: 85-88.XH NMR (400 MHz, DMSO): 5 11.87-11.88 (d, 1H, N-H), 8.31 (t, 2H, Ar-H), 7.75-7.78 (t, 3H, Ar-H), 7.35 (t, 2H, Ar-H), 7.07 (t, 3H, Ar -H), 6.89- 6.90 (t, 1H, C-H), 6.65-6.67 (d, 2H, C-H), 6.34-6.36 (d, 1H, C-H), 5.42 (d, 1H, C-H), 3.79 (m, 1H, C-H), 1.98-2.00 (m, 1H, C-H), 1.54-1.66 (m, 6H, CH3), 1.04-1.23 (m, 9H, CH2). FT-IR (cm'1): 3241.4 (N-H), 3050.0 (Ar-H), 2840.1-2915.4 (Csp3-H), 1678.1 (C=O amide), 1634.0 (C=O -lactam), 1582.5, 1484.4, 1403.1, 1281.3, 1215.6, 1112.5, 1031.3, 730.09, 684.38.

[0077] Formula 1.15: 6-Amino-N-(2-(cyclohexylamino)-2-oxo-l-(pyridin-4-yl)ethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0078]

[0079] Formula (1.15)

[0080] Closed Formula: C27H33N5O3S, mass (calcd.: 507.65 -found: 507.23049) g / mol, Light yellow, yield: 51%, E.N: 71-73. 'H NMR (400 MHz, DMSO): 5 8.73-8.75 (d, 2H, Ar -H), 7.77-7.79 (d, 2H, Ar-H), 7.51-7.53 (t, 1H, Ar-H), 7.29-7.33 (t, 2H, Ar-H), 7.15-7.19 (t, 1H, Ar -H), 6.89-6.91 (d, 2H, Ar -H), 6.87 (s, 1H, C-H), 6.79-6.81 (d, 2H, Ar -H), 6.72-6.76 (t, 1H, C-H), 6.08-6.10 (d, 2H, C-H), 3.84 (m, 1H, C-H), 2.05 (m, 1H, C-H), 1.56-1.62 (m, 6H, CH3), 1.23 (m, 9H, CH2). FT-IR (cm'1): 3316.6 (N-H), 3028.0 (Ar-H), 2846.4-2921.6 (Csp3-H), 1720.0 (C=O amide), 1668.8 (C=O -lactam), 1587.5, 1587.5, 1518.8, 1484.4, 1437.5, 1337.5, 1209.4, 1053.1, 834.38, 756.25, 687.50.

[0081] Formula 1.16: 6-Amino-N-(2-(cyclohexylamino)-2-oxo-l-(pyridin-3-yl)ethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0082] Formula (1.16)

[0083] Closed Formula: C27H33N5O3S, mass (calcd.: 507.65 -found: 507.2311) g / mol, Light yellow, yield: 57%, E.N: 109-113. 'H NMR (400 MHz, DMSO): 5 9.00 (s, 1H, Ar-H), 8.68-8.70 (d, 1H, Ar-H), 8.21 (d, 1H, Ar-H), 7.54-7.55 (t, 1H, N-H), 7.50-7.52 (t, 1H, Ar- H), 7.27-7.31 (t, 2H, N-H), 7.17 (s, 1H, C-H), 7.15 (t, 1H, C-H), 6.88-6.92 (t, 2H, C-H), 6.79-6.81 (d, 2H, C-H), 6.74-6.76 (t, 1H, C-H), 6.11-6.13 (d, 2H, C-H), 3.85 (m, 1H, C-H), 2.04 (m, 1H, C-H), 1.56-1.71 (m, 6H, CH3), 1.24 (m, 9H, CH2). FT-IR (cm'1): 3237.6 (N- H), 3050.0 (Ar-H), 2846.0-2924.3 (Csp3-H), 1700.0 (C=O amide), 1652.9 (C=O P-lactam), 1589.1, 1482.5, 1378.4, 1310.8, 1243.2, 1022.1, 754.28, 692.40, 660.65.

[0084] Formula 1.17: 6-Amino-N-(2-(cyclohexylamino)-2-oxo-l-phenylethyl)-3,3-dimethyl-7- oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0085] Formula (1.17)

[0086] Closed Formula: C28H34N4O3S, mass (calcd.: 506.66 -found: 506.23491) g / mol, Light yellow, yield: 55%, E.N: 127-130. 'H NMR (400 MHz, DMSO): 5 7.52 (d, 1H, N-H), 7.32-7.34 (d, 2H, Ar-H), 7.28-7.30 (d, 2H, N-H), 7.10-7.13 (t, 2H, Ar-H), 7.03 (s, 1H, C- H), 6.83-6.86 (t, 2H, Ar -H), 6.64-6.65 (t, 2H, Ar -H), 6.59-6.60 (d, 1H, Ar -H), 6.48-6.50 (d, 1H, C-H), 6.22 (t, 1H, C-H), 6.00-5.98 (d, 1H, C-H), 5.00-4.99 (d, 1H, C-H), 3.73 (m, 1H, C-H), 1.98 (m, 1H, C-H), 1.52-1.68 (m, 6H, CH3), 1.23 (m, 9H, CH2)._FT-IR (cm'1): 3305.5 (N-H), 3057.5 (Ar-H), 2846,0-2913,8 (Csp3-H), 1768,5 (C=O amide), 1645.6 (C=O P-lactam), 1589.1, 1490.3, 1446.1, 1386.2, 1303.0, 1243.2, 751.68, 693.34.

[0087] Formula 1.18: 6-Amino-N-(2-(cyclohexylamino)-l-(4-nitrophenyl)-2-oxoethyl)-3,3- dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0088] Formula (1.18)

[0089] Closed Formula: C28H33N5O5S, mass (calcd.: 551.66 -found: 551.22047) g / mol, Light yellow, yield: 64%, E.N: 108-111. 'H NMR (400 MHz, DMSO): 5 8.35-8.37 (d, 2H, Ar- H), 8.12-8.14 (d, 2H, Ar-H), 7.55 (t, 1H, N-H), 7.31-7.45 (d, 2H, N-H), 7.31- (s, 1H, C-H), 7.18-7.20 (t, 1H, Ar-H), 6.89 (t, 2H, Ar-H), 6.82-6.83 (d, 2H, Ar-H), 6.74-6.75 (t, 1H, C- H), 6.10-6.12 (t, 2H, C-H), 3.86 (m, 1H, C-H), 2.04 (m, 1H, C-H), 1.57-1.72 (m, 6H, CH3), 1.14-1.23 (m, 9H, CH2). FT-IR (cm'1): 3279.4 (N-H), 3050.0 (Ar-H), 2851.2-2913.8 (Csp3- H), 1700.0 (C=O amide), 1651.5 (C=O -lactam), 1594.3, 1515.6, 1487.7, 1440.9, 1381.0, 1340.8, 1240.6, 1102.8, 1024.7, 949.33, 850.88, 751.68, 693.23.

[0090] In the first step of the synthesis of formula II derivatives, a solution was prepared by dissolving 6-aminopenicillinic acid (1 mmol) in 10 ml of dichloromethane. Wherein it is cooled down to -10-0°C. 1-2 mmol of tri ethylamine is added to the solution as a catalyst. To the prepared solution, 1 mole of acyl chloride or Phthaloyl Chloride derivative solution, prepared in 10 ml of dichloromethane, is added dropwise over a period of 30-90 minutes. It is stirred for 1-2 hours at room temperature. After the reaction is complete, dichloromethane is removed in a rotavaporizer under low pressure. The remaining solid 6- aminopenicillinic acid is mixed with 30 ml of pure water and then extracted four times using 10 ml of ethyl acetate each time. The ethyl acetate phase is dried with anhydrous sodium sulfate and then filtered. Ethyl acetate is evaporated from the rotavapor at low temperature and pressure. The remaining solid matter is purified by passing it through a silica gel-filled column (chloroform / methanol). Solvents are removed in a rotary vaporizer to obtain pure 6-amidopenicillinatic acid solid.

[0091] In the second step of the synthesis of Formula II derivatives, the aldehyde (1 mmol) is dissolved in 10-30 ml of methanol, then primary aromatic or heterocyclic amine derivatives (1 mmol) are added and boiled under reflux for (1-5) hours to obtain the Schiff base. After the reaction mixture has cooled to room temperature, 6-Aminopenicillinic acid (6-APA) (1 mmol) and 5-10 ml of DMF solvent, prepared in the first step, are added and stirred at room temperature for 30-60 minutes, and then isonitrile (isocyanide) derivatives (1 mmol) are added to the reaction medium. This solution is stirred at room temperature (for 2-10 days). After the reaction is complete, 50-100 ml of pure water is added to the reaction medium. The mixture is extracted 3-6 times with ethyl acetate. The product taken to the ethyl acetate phase is dried with anhydrous sodium sulfate, after which the ethyl acetate solution is separated. Ethyl acetate is removed in the rotavapor at low pressure. The solid phase is first separated into its components (methanol / chloroform) using column chromatography. For further purification, the obtained product is purified again by silica gel thin-layer chromatography (hexane / ethyl acetate). Some examples of compounds synthesized using this general method are given below.

[0092] In the first step of the first reaction, one mole of halide derivatives of acyl, alkyl, sulfonyl, vinyl benzyl, and similar compounds are used to bond these groups in place of a hydrogen atom in the NH2 group of 6-APA.

[0093] In the second step of the first reaction, when the Ugi reaction is performed using the carbonyl compound, amine and isonitrile, and 6-APA as carboxylic acid, peptide is obtained from the carboxyl group of 6-APA.

[0094] In the first step of the second reaction, after reacting with 6-APA using one mole of acyl chloride or alkyl halides, using a second mole of halide derivatives of acyl, alkyl, sulfonyl, vinyl benzyl, and similar compounds results in different groups being bonded in place of the hydrogens in the NH2 group of 6-APA. R4and R5can be the same or different. In the second step of the second reaction, when the Ugi reaction is performed using the carbonyl compound, amine and isonitrile, and 6-APA as carboxylic acid, peptide is obtained from the carboxyl group of 6-APA. In the first step of the third reaction, cyclic amide structures are synthesized using 6-APA with one mole of diacyl chloride (e.g., Phthaloyl Chloride) or an alkyl benzyl or allyl compound, or a compound with one acyl side and the other an alkyl halide.

[0095] Some of the groups that can replace Phthaloyl Chloride are shown below. These groups can be straight-chain, or they can be aromatic, cycloalkyl, or cycloalkenyl groups.

[0096] In the second step of the third reaction, when a Ugi reaction is performed using the carbonyl compound, amine, isonitrile, carboxylic acid, and cyclic amide or cyclic amine derivatives of 6-APA, peptide is obtained by the carboxyl group of 6-APA. Wherein L= O, S, C, N, S(O) or SO2.

[0097] Two examples of compounds synthesized using this general method are given below.

[0098] F ormula II.1 : 6-benzamido-N-(2-(cyclohexylamino)- 1 -(4-methoxyphenyl)-2-oxoethyl)-

[0099] 3,3-dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxamide:

[0100] Formula (II.1)

[0101] Closed Formula: C36H40N4O5S, mass (calcd.: 640.79 -found: 640.27249) g / mol, Light yellow, yield: 39%, E.N: 83-85. 'H NMR (400 MHz, DMSO): 5 8.07-8.09 (d, 1H, N-H), 7.86-7.88 (d, 1H, N-H), 7.43-7.55 (d, 1H, Ar -H), 7.38-7.40 (d, 3H, Ar-H), 7.00-7.04 (d, 4H, Ar-H), 6.86-6.88 (t, 2H, Ar-H), 6,66-6,71 (s, 1H, C-H), 6.60-6.62 (t, 3H, Ar-H), 6.50- 6.54 (t, 1H, Ar-H), 5.98-6.00 (d, 1H, C-H), 4.88-4.89 (d, 1H, C-H), 3.98-4.12 (dd, 1H, C- H), 3.71 (s, 3H, O-CH3), 3.49 (m, 1H, C-H), 1.52-1.59 (m, 7H, CH3), 1.23 (m, 9H, CH2). FT-IR (cm'1): 3274.2 (N-H), 3062 (Ar-H), 2840.7-2924.3 (Csp3-H), 1770 (C=O amide), 1644.7 (C=O P-lactam), 1591.4, 1535.5, 1511.2, 1384.4, 1294.2, 1247.0, 1174.8, 1028.9, 832. 5, 701.71, 537.98.

[0102] Formula II.2: N-(2-(cyclohexylamino)-l-(4-methoxyphenyl)-2-oxoethyl)-6-(l,3- dioxoisoindolin-2-yl)-3,3-dimethyl-7-oxo-N-phenyl-4-thia-l-azabicyclo[3.2.0]heptane-2- carb oxami de:

[0103]

[0104] Formula (II.2)

[0105] Closed Formula: C37H38N4O6S, mass (calcd.: 666.79 -found: 667.25871) g / mol, Light yellow, yield: 65%, E.N: 90-94.^ NMR (400 MHz, DMSO): 5 8.06-8.08 (d, 1H, N-H), 7.91-7.95 (d, 1H, Ar-H), 7.54-7.53 (d, 1H, Ar -H), 7.39-7.41 (d, 2H, Ar-H), 7.23 (d, 1H, Ar-H), 7.07-7.11 (d, 1H, Ar-H), 7.00-7.04 (t, 2H, Ar-H), 6.86-6.88 (d, 2H, Ar-H), 6.68 (s, 1H, C-H), 6.59-6.61 (t, 2H, Ar-H), 6.50-6.55 (t, 1H, Ar-H), 5.99-6.01 (d, 1H, C-H), 4.86.88 (d, 1H, C-H), 3.85 (d, 1H, C-H), 3.71 (s, 3H, O-CH3), 3.60 (m, 1H, C-H), 1.98 (m, 1H, C-H), 1.53-1.73 (m, 6H, CH3), 1.23 (m, 9H, CH2). FT-IR (cm'1): 3271.3 (N-H), 3070 (Ar-H), 2840.4-2914.9 (Csp3-H), 1717.4 (C=O amide), 1644.4 (C=O -lactam), 1588.7, 1503.8, 1381.8, 1302.2, 1246.6, 1174.8, 1020.9, 747.60, 699.16, 534.28.

[0106] Preparation of imine from 6-APA in the first step of the synthesis of Formula III derivatives: Solution of 1 mmol of 6-aminopenicillinic acid, 1 mmol of aldehyde, and 10- 20 ml of methanol is boiled for 8 hours in a reflux condenser. After the reaction is complete, it is cooled, the precipitate is filtered and then dried to obtain imine (Schiff base) from 6-APA. The second step in the synthesis of Formula III derivatives involves obtaining the ester from 6-APA: 1 mmol of the obtained 6-aminopenicillinic acid imine (Shiff base) derivative obtained in the first step is dissolved in 10-25 ml of DMF and cooled in an ice bath, then, 1-2 mmol of trialkylamine (tri ethylamine and similar) is added as a catalyst. Alkyl and benzoyl bromides, trimethyl silyl chloride, or their derivatives are added dropwise to the solution as a protecting group to preserve the carboxylic group of the 6-aminopenicillinic acid (6-APA) imine compounds in an inert atmosphere such as argon. The mixture is stirred at room temperature for 24-48 hours. After the reaction is complete, 20-25 ml of water is added to the solution. The mixture is extracted at least four times with 20-50ml of ethyl acetate. Anhydrous sodium sulfate is added to the ethyl acetate phase, and the mixture is dried and then filtered. Ethyl acetate is evaporated from the rotavapor at low temperature and pressure. The remaining solid matter is purified by passing a solvent mixture such as chloroform / methanol through a column filled with silica gel. When the solvents are subsequently removed in the rotavapor, the imine derivative of 6- aminopenicillinic acid is converted into the ester derivative of the carboxylic acid.

[0107] Peptide production of 6-APA in the first path of the second step of the synthesis of Formula III derivatives: 1 mmol of the obtained (6-APA) imine carboxylic ester obtained in the second step is dissolved in a 50% methanol / DMF mixture. 1 mmol of carboxylic acid (or thiocarboxylic acid) is added to the solution and stirred at room temperature for 1- 5 hours. 1 mmol of isonitrile derivatives (isocyanates) is added to the solution and stirred at room temperature for 100-150 hours. After the reaction is complete, pure water is added to the reaction medium. The mixture is extracted 4-6 times with 10-50ml of ethyl acetate. The product taken to the ethyl acetate phase is dried with anhydrous sodium sulfate, after which the ethyl acetate solution is separated. Ethyl acetate is removed in the rotavapor at low pressure. The solid phase is first separated into its components in silica gel-filled column chromatography (methanol / chloroform). For further purification, the obtained product is purified again by silica gel thin-layer chromatography (hexane / ethyl acetate) to obtain new penicillin derivatives with a pure peptide structure. The reaction equation for penicillin derivatives synthesized in these three steps is given below.

[0108] In the second path of the second step of the synthesis of Formula III derivatives, (6-APA) imine carboxylic acid synthesized in the first step, is combined with 1 mmol each of different carboxylic acid derivatives and isonitrile derivatives to synthesize new penicillin derivatives in a pure peptide structure without needing to preserve the carboxyl group.

[0109] Formula III.1: Benzyl-6-(N-(2-(cyclohexylamino)-l-(4-methoxyphenyl)-2-oxoethyl)-4- fluorobenz amido)-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylate:

[0110]

[0111] Formula (III.1)

[0112] Closed Formula: C37H40FN3O6S, mass (calcd.: 673.79-found: 673.26253) g / mol, Light yellow, yield: 54%, E.N: 169-173. 'H NMR (400 MHz, DMSO): 5 8.75-8.77 (d, 1H, N-H), 8.11 (d, 1H, Ar-H), 7.95 (d, 1H, Ar-H), 7.54-7.56 (d, 2H, Ar-H), 7.38-7.41 (d, 5H, Ar-H), 7.31 (s, 1H, C-H), 7.23-7.26 (t, 3H, Ar-H), 6.96-6.98 (d, 2H, Ar-H), 5.18 (d, 1H, C-H), 5.14 (d, 1H, C-H), 4.13 (d, 2H, C-H), 3.78 (s, 3H, O-CH3), 3.57 (d, 1H, C-H), 2.31-2.32 (d, 1H, C-H), 1.99-2.00 (d, 1H, C-H), 1.35-1.51 (m, 5H, CH2), 1.23 (m, 9H, CH2). FT-IR (cm'x): 3216.7 (N-H), 3040 (Ar-H), 2924.3 (Csp3-H), 2300.0, 1974.0, 1737.3 (C=O amide),

[0113] 1664.5 (C=O P-lactam), 1602.1, 1508.5, 1453.9, 1365.4, 1241.5, 1139.2, 1019.5, 821.90, 743.88, 691.86, 606.04, 507.21.

[0114] Formula III.2: benzyl 6-(N-(2-(cyclohexylamino)-2-oxo-l-(4-oxo-4H-chromen-3-yl) ethyl)-4-methylbenzamido)-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2- carboxylate:

[0115]

[0116] Formula (III.2)

[0117] Closed Formula: C40H41N3O7S, mass (calcd.: 707.83 -found: ) g / mol, Light yellow, yield: 46%, E.N: 225-229 H NMR (400 MHz, DMSO): 5 8.48 (d, 1H, N-H), 8.33 (d, 1H, Ar-

[0118] H), 8.09-8.11 (t, 2H, Ar-H), 7.84-7.89 (d, 3H, Ar-H), 7.69-7.72 (t, 1H, Ar-H), 7.53-7.56 (d, 2H, Ar-H), 7.32-7.34 (m, 4H, Ar-H), 7.17-7.20 (s, 1H, C-H), 6.91 (s, 1H, CSP2-H), 6.25 (d, 1H, C-H), 5.51 (d, 1H, C-H), 5.18 (d, 1H, C-H), 3.70-3.80 (s, 2H, C-H), 3.59 (m, 1H, C- H), 2.38 (s, 3H, Ar-CH3), 1.55-1.68 (m, 7H, CH2), 1.22 (m, 9H, CH2). FT-IR (cm-1): 3295.0 (N-H), 3030 (Ar-H), 2846.0-2924.3 (Csp3-H), 2300.0, 1730.0 (C=O keton), 1719.1

[0119] (C=O amide), 1633.3 (C=O -lactam), 1596.6, 1461.7, 1430.5, 1287.4, 1204.2, 1089.8, 886.91, 806.29, 751.68, 699.66.

[0120] Formula III.3: Benzyl 6-(N-(2-(cy cl ohexylamino)-l-(4-methoxyphenyl)-2-thi oxoethyl) acetamido)-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylate:

[0121]

[0122] Formula (III.3)

[0123] Closed Formula: C32H39N3O5S2, mass (calcd.: 609.80 -found: 609.23411) g / mol, Light yellow, yield: 43%, E.N:205-210. 'H NMR (400 MHz, DMSO): 5 9.84 (d, 1H, N-H), 8.03 (d, 1H, Ar-H), 7.87 (d, 1H, Ar-H), 7.74 (d, 1H, Ar-H), 7.52 (d, 1H, Ar-H), 7.42 (d, 2H, Ar- H), 7.25 (t, 1H, Ar-H), 7.10 (s, 1H, C-H), 6.95 (d, 2H, Ar-H), 6.76 (t, 1H, Ar-H), 5.33 (d, 1H, C-H), 5.17 (d, 1H, C-H), 4.39 (d, 1H, C-H), 3.80-3.85 (d, 2H, C-H), 3.75 (s, 3H, O- CH3), 3.57 (m, 1H, C-H), 2.33(m, 1H, C-H), 1.89-1.98 (s, 3H, CO-CH3), 1.39-1.66 (m, 6H, CH2), 1.23 (m, 9H, CH2). FT-IR (cm'1): 3229.3 (N-H), 3030 (Ar-H), 2928.7 (Csp3-H),

[0124] 2300.0, 1974.0, 1739.3 (C=O amid), 1669.3 (C=O -lactam), 1612.1, 1518.5, 1443.9, 1335.2, 1235.5, 1136.2, 1021.1, 831.90, 753.88, 681.86.

[0125] Formula III.4: 6-(N-(2-(cyclohexylamino)-l-(4-methoxyphenyl)-2-oxoethyl)-4-methyl benzamido)-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid:

[0126] Formula (III.4) Closed Formula: C31H37N3O6S, mass (calcd.: 579.71 -found: 579.125478) g / mol, Light yellow, yield: 56%, E.N: 185-189, 'H NMR (400 MHz, DMSO): 5 8.32 (d, 1H, N-H), 8.19-8.21 (d, 1H, Ar-H), 7.89-7.93(d, 1H, Ar-H), 7.73-7.75 (d, 1H, Ar-H), 7.48-7.50 (d, 1H, Ar-H), 7.34-7.35 (d, 1H, Ar-H), 7.09 (s, 1H, C-H), 7.01-7.03 (s, 2H, Ar-H), 6.95-6.97 (d, 1H, Ar-H), 5.96 (d, 1H, C-H), 3.86 (d, 1H, C-H), 3.82 (d, 1H, C-H), 3.76(s, 3H, O- CH3), 3.57 (m, 1H, C-H), 2.38 (s, 3H, Ar-CH3), 1.64-1.74 (m, 7H, CH2), 1.23 (m, 9H, CH2). FT-IR (cm'1): 3325.6 (N-H), 3070 (Ar-H), 2851.2-2922.8 (Csp3-H), 1761.2 (C=O amide), 1639.2 (C=O -lactam), 1612.9, 1501.5, 1454.7, 1381.8, 1325.0, 1255.0, 1150.4, 1078.4, 1029.7, 850.1.

[0127] Antimicrobial test:

[0128] Some of the P-lactampenicillin derivatives designated by Formulas 1.9, 1.14, 1.16, II.1, II.2, III.2 and III.3 in the newly synthesized peptide structure were tested for antimicrobial activity against Gram-positive (Bacillus subtilis MTCC-5981, Staphylococcus aureus MTCC-740) and Gram -negative (Escherichia coli MTCC-118 and Salmonella typhimurium MTCC 3231) microorganisms using the agar disk diffusion test. Ampicillin and Cephalothin were used as reference substances in these studies. The antimicrobial test results of the newly synthesized peptide structure are given in the table below. The derivatives studied were found to possess antimicrobial activity.

[0129] Table-1 : Biological test results of penicillin P-lactam penicillin with the newly synthesized peptide structure.

Claims

CLAIMS1. Compounds of formula I, II or III, or pharmaceutically acceptable derivatives thereofFORMULA I FORMULA II FORMULA III wherein;R'-R7: one of O, N, S, Si, P or B or combinations thereof, aromatic or non-aromatic ring groups and / or combinations thereof, hydrogen, alkyl, aromatic, heterocyclic, 3-7 membered aromatic groups or groups bonded to a basic frame of 1-15 carbons, straight or branched, replacing hydrogen, alkyl, aromatic, heterocyclic, 3-7 membered aromatic groups, 3-7 membered alkyl groups, C with a 10-membered monocyclic or bicyclic rings containing at least one aromatic or non-aromatic heteroatomL: O, S, C, N, S(O) or SO2Y= C or SZ= O or S optionally comprising Q.

2. The compound according to Claim 1, characterized in that Ar substituent is selected from the group comprising furyl, pyrril, 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, cinnolinyl, phthalazinyl, quinoxalinyl, xanthine, hypoxanthine, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, pyrrolidinyl, piperidinyl and piperazinyl.

3. The compound according to Claim 1, characterized in that Q is selected from one of amino groups, aryl groups, halogens, (-CH2-), carbonyl, -NH-, carboxyl, amide, sulfur, acid salts, other aromatic or non-aromatic aryl derivatives or heterocyclicstructures, atoms of oxygen, nitrogen, sulfur, phosphorus or combinations thereof.

4. The compound according to Claim 1, characterized in that Q is straight-chain, branched, or cycloalkyl or alkenyl or alkynyl or aryl or alkylaryl or heterocyclic rings consisting of nitrogen, oxygen, or sulfur, or in the case of a ring structure, being aromatic with more than one hetero atom or aromatic rings.

5. The compound according to Claim 1, characterized in that Q is a heterocyclic group containing one or more different or the same heteroatoms selected from linear alkyl, branched or cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, nitrogen, oxygen, sulfur, and phosphate atoms.

6. The compound according to Claim 1, characterized in that Q is sulfony alkyl or sulfonyalkylaryl or sulfonylaryl groups.

7. The compound according to Claim 1, characterized in that Q is one or more groups, or combinations selected from halogens, hydroxyl, amino, cyano, nitro, carbonyl, carboxyl, amide, phosphate, and other functional groups.

8. A synthesis method according to Claim 1-7, characterized in that Q is selected from one of amino groups, aryl groups, halogens, (-CH2-), carbonyl, -NH-, carboxyl, amide, sulfur, acid salts, other aromatic or non-aromatic aryl derivatives or heterocyclic structures, oxygen, nitrogen, sulfur, and phosphorus atoms or combinations thereof.

9. The compound according to Claim 1, characterized in that alkyl substituents of Q is O, N, S, Si, P, or B, or combinations thereof, replacing hydrogen, alkyl, aromatic, heterocyclic, 3-7 membered aromatic groups, 3-7 membered alkyl groups, C with 10- membered monocyclic or bicyclic rings containing at least one aromatic or non- aromatic heteroatom.

10. The compound according to Claim 1, characterized in that Q is the groups of CICH2CH2- and CICH2CH2O-, (C1CH2CH2)2N- or groups with peptide structure, used as alkylating agents against cancer cells, replacing the H in alkyl, aromatic (Aryl) and non-aromatic groups.

11. A pharmaceutical composition containing compounds having Formula I— III according to any one of the preceding claims.

12. The composition according to Claim 1-11 for use as medicine.

13. The compound according to Claim 1, characterized in that it is selected from the following group.Formula (1.6)Formula (1.7)Formula (1.11)Formula (1.10)Formula (1.18)14. The compound according to Claim 1, characterized in that R4 and R5 in Formula II is selected from the following group.

15. The compound according to Claim 1, characterized in that it is selected from the following group.Formula (III.3)

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