مستخلص )احمذ عبذ االمير حسين. تحضير مشتقاث كيومارين جذيذة.(شهادة دكتوراه 7002, ._الجامعت المستنصريت : كليت العلوم : كيمياء 1-1 Coumarin compounds Coumarin was first isolated in 1820 by Vogel(1) from the seeds of Tonka beans (coumarouna adorata). Coumarins belong to one of the most widespread classes of natural compounds(1).Structurally coumarin is a fused benzene ring with pyron ring (2) in two ways: O O O O 2H-Pyrone Benzo-alfa-Pyrone 2H-Pyran-2-one 2H-1-Benzo-Pyran-2-one Alfa-Pyrone Coumarin 2 1 1- Benzo-α-pyron (coumarin) (1) O O O O 4H-Pyrone Benzo-gama-Pyrone 4H-Pyran-4-one 4H-1-Benzo-Pyran-4-one Gama-Pyrone Chromone 4 3 2- Benzo-γ-pyron (chromone) (2) Coumarin compounds are widely spread through the plant kingdom, microorganism and animals both in the free state and as glycoside (3). H3CO H3CO HO O O HO O O O-Beta-D-Glucopyranoside OCH3 Fraxin Isoraxidin 5 6 Coumarins can be classified according to chemical structure into (4): R O O R=Alkyl, Hydroxyl, Chloro.... 7 1- Coumarin substituted in benzene ring (7) 2- Coumarin substituted in pyrone ring (8). O OR O 9 O O R=Alkyl, Hydroxyl, Chloro.... 8 3- Furo Coumarins (9) O O O 10 4- Pyrano Coumarins (10) O O 11 5- 5,6-BenzoCoumarin (11). Coumarin or benzo-α-pyrone is found in avariety of plants such as Tonka beans lavender, sweet clover grass and licorice, but also occurs in food plants such as straw, berries, apricots, cherries, and cinnamon(5). Chemically(6) coumarin can occur either free or combined with the sugar glucose to produce a coumarin glycoside. Medically "coumarin was banned by the FAD as a food additive in 1940, due to studies showing liver toxicity. There is also evidence that it may be carcinogenic. Some coumarins have been shown(7) to have blood–thinning, anti- fungicidal, and anti-tumor activities. Warfarin(14) is the most commonly OH OH OH O O O O O 12 13 OH O O O 14 Anti-coagulant compounds used in oral anticoagulant medication. Hasnaa(8) found that 4-nitrowarfarin (15) has a special characteristic as anti-coagulant, "without bleeding" due to nitro group. NO 2 OH O O O 17 The isolated coumarins from plant so far investigated can be classified into five groups according to chemical structure and their uses: Some of the first groups of coumarin had been found to show hypnotic Cl H2N O O O O 6-Chlorocoumarin 6-Aminocoumarin 16 17 effect such as (16) and (17). 7-Methoxycoumarin (9) " Herniarin " (18) that was isolated from Matricaria in the north of Iraq was used as Antipyretics. H3CO O O 18 (9) Daphentin (disubstituted coumarin) (19) that was isolated from Daphnia Stifolia was used as anti-bacterial agent. Esculetin (20) was also used as anti-bacterial substance. Scopoletin (21) isolated from Coronnilla HO HO O O HO O O OH 19 20 H3CO HO O O 21 Varial has wide applications in plant growth. Chinese workers found (10) that isofraxidin(6) used in Amnesia, Insomnia and in sexual deficiency, are prepared from phenols. Kassier (11) and coworker synthesized 5-nitro isofraxidin and found out it H3CO HO O O OCH3 12 had anti-bacterial properties. Some coumarins (12) of 2nd group have insecticidal activity like Mammein (22), Hymecromone (23), and Haloxon (24). CH3 Ar CH3 H3C HO O O HO O O O 22 23 H3C CH3 CH3 O O O P O (OCH2CH2Cl)2 24 (13,14) Coumarins of 3rd group like Bergapten (25), and Psoralene (26) . O OH O O O O O 25 26 Bergapten isolated from Citron Poaceae have been used in medicine. Compounds(15,16) of 4th group, Pyranocoumarin, Cunatilake isolate 12 of coumarin derivatives from Rutaceae and found that they have a biological activity as anti-carcinogen and showed also photo biological activity and O O O 27 anti-proliferative effect. (17) Coumarins of 5th group: Benzocoumarins, Fisher and Nier found that coumarin derivatives of poly aromatic hydrocarbon were carcinogenic. Perry (18) found out that 7-nitro-5,6-benzocoumarin (27) have anti O O O2N 28 tumor activity “applied on rats”. 1-2 Synthesis Of Coumarins. Coumarin has been synthesized in the laboratory since 1868 and used to make perfums and flavorings. The most common methods of preparation are outlined below: 1-2-1 From Salicylaldehyde (19) The Perkin reaction has been widely used, the required salicylaldehyde is not always obtained and the yield of coumarin derivatives are generally low although it is claimed that they are improved by the addition of iodine(20). Perkin condensation involves coumarin derivatives by heating salicylaldehyde with acetic anhydride and anhydrous sodium acetate at CHO CH=CH-COONa MeCOONa + (MeCO)2O 160-200C0 OH OH O O 1 160-200C˚ for 60 min. 5,7-dihydroxycoumarin (lemtlin)(28) and 6-hydroxyl-5,7-dimethoxy (21-23) coumarin(29) (frascinol) were obtained from 2,4,6-trihydroxy OH OH O CH (CH3CO2)2O CH3CO2Na HO OH HO O O 28 OCH3 OCH3 HO O HO CH (CH3CO2)2O CH3CO2Na H3CO OH H3CO O O 29 benzaldehyde & 2,5-dihydroxy-4,6-dimethoxybenzaldehyde respectively. 3-Phenoxycoumarin and 3-benzalcoumarin(24) was synthesized from the reaction of salicylaldehyde with 2-Phenoxy (or 2-benzal) acetic acid in OHC OH O R Ph-O-P-Cl 2 RCH2CO2H NEt3 / heat O O 30 presence of phenyldichlorophosphate Ahluwalia and coworkers(25) found that the reaction of salicylaldehyde with N-(benzothiazolo-2-Yl thio) acetic acid hydrazide in presence of acetic acid and PPA to gave 3-(benzothiazol-2-Yl thio) coumarin. H2C C NHNH 2 S O R3 CHO N S 1)CH3COOH + 2)PPA R3 S N R2 OH R1 S R1=H, R2=OMe, R3=H R1=Me, R2=OMe, R3=H O O R2 R1 31 1-2-2 From Phenols The most important invaluable and widely used synthesis of coumarin derivatives is through the Pechmann reaction.(26,27) This involves the condensation of phenols with β-ketoesters in the presence of concentrated R R CO2CH2CH3 O O H2SO4 + CH3CCH2COC2H5 Heat OH OH CH3 R R= H, CH3, OH O O sulfuric acid to give substituted 4-methylcoumarin (32) . (28,29) Sonn found that condensation of resorcinol with ethyl alfa- cyanoacetate in presence of hydrochloric acid gave 4-hydroxy OH CO2CH2CH3 HCl + H2C HO OH CN HO O O 33 umbelliferone (33). (30-31) Pechmann and Duisbery suggested that the reaction proceeds through the addition of hydrogen of the ring ortho to the hydroxyl group, to the carbonyl group of the β-ketonic ester to give an intermediate hydroxyester. Ring closure, takes place with the elimination of one molecule each of water and ethanol to give the product. The effectiveness of such condensation depends on the reactivity of o- position to the hydroxyl group, when substituents like nitro or carbonyl group are present in the aromatic ring the reaction may not take place at all. Morever phenol derivatives may undergo Pechmann condensation with ethylacetate or its corresponding compounds in presence of other reagents such as phosphorous pentoxide, trifluroacetic acid, or aluminum chloride to give 4- CH3 O POCl3 Ph + CH3CCHPh HO OH NC HO O O 34 substituted coumarin derivatives. Koo(32) used polyphosphoric acid (PPA) in the synthesis of 7-hydroxy -4- OH CH3 O O PPA + CH3CCH2COCH2CH3 OH HO O O 23 methylcoumarin (23) from resorcinol. (33) Ethylbenzoylacetate was also used instead of ethylactoacetate. The reaction of ethylbenzoylacetate with 2,4,6-trihydroxy acetophenone gives 6-acetyl-5,7-dihydroxy4-phenyl coumarin and 8-acetyl-5,7-dihydroxy-4- phenyl coumarin. (34) Soliman and Kapp proved that resorcinol derivatives orcinol condensed with ethyl β-aminocrotonate to give 5,7-hydroxy-4- OH OH CH3 H3C NH 2 + EtO Heat HO OH O Me O O 35 OH OH CH3 H3C NH 2 + EtO H3C OH O Me O O methylcoumarin (35) (35) Al-Bayati discovered that the reaction of ethyl β-methoxycrotonate with phenol derivatives in presence of polyphosphoric acid gave 4-methyl OH CH3 H3C OMe EtO PPA R + R O O O coumarin derivatives. (36) Heating of β-methoxymethylmalonate with phenol derivatives in presence of CH3SO3H and CF3COOH gave coumarins substituted in H3C OCH3 CH3SO3H HO + H3CO OCH3 CF3COOH R O O CH3 CH3 COOCH3 1)H3O+ R R 2)-CO2 O O O O R=3,4-(OCH3)2 R=2,3-(CH3)2 R=2,3,5-(CH3)3 benzene and pyron ring. Michael (37) used the addition of m-alkoxyphenyl Lithium derivatives to the diethylethoxyethylmalonate to give coumarin substituted in benzene ring. OR OR EtO2C CO2Et n-BuLi + + Ether H3O+ OEt Li EtO H R=H,CH3 OR OR COOH -CO2 Heat O O O O (39) Panta prepared some coumarin derivatives by rearrangement of allylarylether. The reaction of 2-methylphenol with triethylacrylate gave 8- OH OEt Reflux + CH2=CH C OEt Torluene OEt Heat CH3 EtO O OEt CH3 KOH CO2H O OEt OH O O EtO CH3 CH3 CH3 37 methylcoumarin (37). Kanfmann and Kelly(40) in 1965 found that heating mixture of 1,3,5- trihydroxybenzene with propynoic acid in presence of zinc chloride gave OH OH ZnCl2 + HC C COOH HO OH HO O O 32 5,7-dihydroxycoumarin (28). 1-2-3 From o-Hydroxy Carbonyl Compounds Claisen condensation of 2-acetoxybenzoylchloride yields substituted O O O O CCl CO2Na OEt COCH3 OCOCH3 NaOH ONa OH O O OH CO2CH3 Na, 1.5h. 240 C0 OCOCH2-Et O O 38 coumarin (40-41). (42) The condensation of ethylcyanoacetate with 2-acetoxybenzoy lchloride (Knoevengal reaction) yields 3-cyano-4-hydroxycoumarin (39). OH O COCl CN + OEt OCOCH3 CN O O 39 Reformatski (43) reaction of o-methoxyacetophenone with ethyl α-bromopropionate followed by dehydration and demethylation leads to 3,4-dimethylcoumarin (40). OH O COCH3 O C + H3C Zn OEt OEt CH3 OCH3 Me Br OCH3 CH3 O Me C CH3 OEt HI CH3 OCH3 O O 40 (44) The reaction of methoxyphenylketones with corresponding R2 O R2 R1 O R3 CR1 R3 R + POCl3 R3C NEt 2 OMe O O R, R1 = H, CH3, C2H5 R2, R3 = OH,CH3, OCH3 diethylactamide in presence of POCl3 gives the respective coumarin. 1-2-4 From active methylene compounds Azeotropic distillation of a mixture of ethyl α-alkyl (or aryl) malonate and (45) substituted phenols gives the corresponding 4-hydroxy-3-alkyl (or aryl) OH R1 R1 R Heat R + O O OH O O OEt OEt 41 coumarin (41). While coumarin, unsubstituted in the pyran ring was obtained by condensation of maleic acid and its derivatives, with resorcinol in presence OH H2SO4 + O O OH C6H5NO2 HO O O OH OH 42 of nitrobenzene and concentrated sulfuric acid (46). (47) Dicoumarin (43) was obtained by condensation of pyrogallol with malic acid in presence of concentrated sulphuric acid at 100-120 C0. OH CH2COOH O OH HO OH H SO 2 4 + OH OH Heat O O OH HO O O O 43 Similarly, cyclocondensation (48) of substituted phenol with citric acid in the presence of concentrated sulfuric acid gave 4- substituted coumarin CH2CO2H R H2SO4 + Citric acid R OH O O 44 (44). 1-2-5 From Coumarin The oxidation of coumarin(49) by potassium persulfate in basic medium gives hydroxy group in position –6- of coumarin–(6-hydroxy coumarin (45)). HO + K2S2O8 KOH O O O O 45 Chauhan and Mathyr(50) found that the reaction of umbelliferone (41) with equivalent weight of benzoylperoxide and chloroform gave daphintin ( Benzoylperoxide HO O O CHCl 3 HO O O OH 41 19 yield 43% ) (19). Daphintin (19) can be also obtained by refluxing the umbelliferone (41) (51) with hexamethylenetetraamine in presence of acetic acid (Duff MeCOOH HO O O (CH2)6(NH2)4 HO O O 22 CHO H2O2 HO O O OH 21 reaction) then hydrogen peroxide to give daphintin (19). Fraxetin (46) can be synthesized(52) from umbelliferone ( 19) and then the hydroxyl group is transfered to the benzyl by benzyl chloride and oxidation at position –6- by potassium persulfate gave –6-hydroxy that is converted to 6-methoxy by CH3-I and potassium carbonate to give fraxetin O + Cl-C-CH3 HO O O HO O O C-CH3 O 1)PhCH2Cl 2)KOH MeO 1)CH3I/ K2CO3 K2S2O8 HO 2)H2O2/ NaOH 3)HCl HO O O PhCH2O O O OH C-CH3 46 O (46). Fraxinol (29) can be synthesized (53-54) from furanocoumarin by oxidation OCH3 OCH3 O H Na2Cr2O7 H2SO4 O O O HO O O 47 48 H3CO HO 1)MeI/ K2CO3 2)H2O2/ H2SO4 H3CO O O 29 of 5-methoxyfuranocoumarin (47) by sodiumdicromate in presence of concentrated sulfuric acid and then methylation of the hydroxy group at (position–7-) by methyl iodide and sodium carbonate then the formyl group in position –6- is changed to hydroxy group by hydrogen peroxide. 1-4-6 From Indan –1- ones The oxidation(55) of Indan–1-ones (49) by Baeyer-Villiger in presence of 30% hydrogen peroxide and acetic acid for 7-day at 50C0 gives coumarin R1 R4 O R2 7 R3 1 R 6 H2O2 R 2 MeCO2H 5 3 O O R3 4 R2 R4 R1 49 derivatives. 1-2-7 From Quinones (56) Dimethylcyclohexylaminomaleate reacts with p-benzoquinone in the presence of Lewis acid, ZnCl2 to give 4-carbmethoxy–3-(cyclohexyl amino)– O CO2CH 3 H H N CO2CH3 HO N ZnCl 2 + CO2CH3 O O O 50 6-hydroxy coumarin (50). The reaction (57) between γ-quinone and 2-aminodiethyl maleate in the presence of borontrifluoride gives 3-amino-4-carbethoxy-6-hydroxy coumarin (53). When the reaction was carried out at –75 Cْ, it give 4- CO2CH2CH3 HO NH 2 BF3 Ether O O O H2N CO2Et 52 + CO2Et CO2CH2CH3 HO OH O 0 BF3/ -75C 51 Ether O O 53 carbethoxy-3,6-dihydroxycoumarin (53). 1-2-8 From Chromenes and Chromone (58-59) Chromenes and chromones were used in synthesis of coumarin derivatives. Reflux of chromenes in 3M HCl, gave 41-85 % coumarin and oxidation of chromones by m-CPBA gave hydroxychromones and small R1 R1 R2 R2 CH3 Reflux/ HCl R3 O N R3 O O R4 O R4 54 O OH O OH m-CPBA + O O O O 55 12 56 amounts of 4-hydroxycoumarin(12). 1-2-9 Other Methods (60) Another important synthesis of 3- substituted coumarin involves cyclization of acrylonitriles, using pyridine–HCl. Coumarin was synthesized by cyclizing 2-(o-methoxyphenyl)–1- furyl acrylonitrile with pyridine –HCl. OCH3 O Pyridine O HCl CH=C O O 57 CN 58 Thermal rearrangement of α–aryloxymethylacrylic acid gave 3-methyl R2 HO2C CH2 R2 CH3 Heat R1 O R1 O O R R 59 60 R, R1, R2= CH3, OCH3, OH coumarin(61). 1-3 Reactions of Coumarins 1-3-1 Sulphonation (62) The oxygen of the lactone ring, directs the sulphonation to 6-position (para-director) in the coumarin. If this position was blocked, the sulphonation will go to the 8- position (o-director) HO3S HO3S H2SO4 H2SO4 0 0 O O 100C O 140C O O O SO3H 1 61 The presence of nitro group (63) at position 6 in coumarin, will deactivate the aromatic ring, and the orientation of the sulphonation group will go to 3- position. CH3 CH3 O2N O2N SO3H ClSO3H 0 O O 130-140C O O 62 63 (64) The orientation and substitution in the sulphonation process depend on the reactivity of substituted coumarin. Recently(64), 4,7-dimethylcoumarin–6-sulfonylchloride (64) was obtained, CH3 CH3 ClO2S ClSO3H H3C O O Heat O H3C O 64 65 by treating 4,7-dimethyl coumarin (65) with ClSO3H. 1-3-2 Nitration (65) Nitration of coumarin using concentrated nitric acid and concentrated sulfuric acid (0C0) gave 6-nitrocoumarin (66) 93% and 8-nitrocoumarin (67). O2N H2SO4 CH3 O HNO3 CH3 O O O O2N NO 2 1 66 CH3COOH 4 SO HNO3 + H2 OO3 O HO O HO O HN 32 NO 2 70 O O NO 2 67 4 3 SO O H2 HN O2N NO 2 O2N O O O O 68 NO 2 69 (66) Nitration of hymecromone (23) using HNO3, in acetic acid gave 7- hydroxy–4-methyl–3,6,8-trinitro-coumarin (70) in 74% yield. Nitration of 7-methoxy–4-methylcoumarin (71) gave 7-methoxy -4- methyl-6–nitrocoumarin (67) (72) and 7-methoxy–4-methyl-3,6-dinitro coumarin (73). CH3 CH3 O2N CH3COOH HNO3 H3CO O O O H3CO O 71 72 CH3 + O2N NO 2 O H3CO O 73 1-3-3 Reaction with Alkali Coumarins as lactones are readily hydrolyzed by diluting hot solution of NaOH Acid hot CO2Na O O O O OH 1 74 1 sodium hydroxide to a yellow solution of sodium coumarinate (68) (74). 7-methoxycoumarin(18) (Herniarine) was very(69) stable against alkali : O O- H3CO O + O H3CO : 20 75 because of the resonance that give phenoxide ion (75). When coumarin (1) is refluxed with alcoholic sodium ethoxide, the lactone ring is readily opened to o-hydroxycinnamte (76) that gives with acid o-hydroxycinamic acid (70) (77). COOCH2CH3 Hot NaOEt Hot H2O/ H+ O O OH 1 76 COOH OH 77 Trans-o-hydroxy cinnamic acid (71) Hydrolysis of 4,6,7-trimethoxy-5-methyl-3-phenylcoumarin (7) yields the corresponding 2-(6-Hydroxy-3,4-dimethoxy-2-methyl-phenyl)-2- methoxy-1-phenyl-ethanone (79). OCH3 CH3 OCH3 CH3 Ph H3CO ph H3CO C C NaOH H O H3CO O O H3CO OH 78 79 1-3-4 Halogenation of Coumarin Bromination of coumarin (1) leads to the (72) formation of 3-bromo coumarin (80), which can also obtain by means of NBS. Br Br Pyridine Br Cs2/ Br2 O O O O O O NBS 1 83 (73) Similarly, 3-chlorocoumarin (81) can be obtained by chlorination of coumarin (1) in 1,1,2,2-tetrachloroethan. Cl Cl2/ Br2 C2H2Cl4 O O O O 1 81 (74-75) The bromination of 7-methoxy-4-methylcoumarin (71), using NBS in CHCl3, gave 3-bromo-4-(bromomethyl)-7- methoxy coumarin. 1-3-5 Oxidation of Coumarins 1-3-5-1 Potassium Permanganate (76) Oxidation of coumarins with permanganate usually causes extensive degradation to salicylic acid derivatives. H3CO H3CO COOH KMnO4 H3CO O O H3CO OH OCH3 OCH3 82 83 1-3-5-2 Nitric Acid (78) Oxidation of 5,7,8-trimethoxycoumrain (84) by 50% nitric acid in presence of acetic acid gave quinone (85) that is reduced by sulphur dioxide to 5,8-dihydroxy-7-methoxycoumrain (86). OCH3 O OH HNO3/ 50% SO2 AcOH H3CO O O H3CO O O H3CO O O OCH3 O OH 85 87 86 1-3-5-3 Ozone (79) Ozonolysis of umbelliferone gave the corresponding substituted salicyladehyde (87). CHO O3 HO O O HO OH 88 1-4 Toxicity Of Coumarins(80-85) Coumarin is found in many plants , including lavender, woodruff, and sweet clover; and also in strawberries, apricots, cherries, and cinnamon. Coumarin smells like vanilla but what little flavor it has is bitter. This may serve to repel some insects. It is found in high percentages in the tonka bean ( dipteryx odorata, fabaceae ( pea) family ). Tonka bean extracted is commonly used to adultereate vanilla in mexico. Additionally, it is a factor in some cases of livestock poisoning. Some common molds break coumarin down into dicoumarol. Dicoumarol interferes with the body’s ability to produce vitamin K. which is essential to blood clotting. Thus, dicoumarol acts as an anticoagulant. When cattle eat sweet clover that has spoiled, the dicoumarol works to thin their blood, leading ( in more severe cases ) to internal and/ or external bleeding. Dicoumarol derivatives have been used as rat poisoning (namely, warfarin ). Rodents that are in poisoned this way die from internal bleeding. Coumarin itself may or may not have anticoagulant properties.A further derivative, warfarin sodium, is an anti-coagulant prescription drug, the use of which must be carefully monitored by a physician, let the patient bleed to death, But Kassier (8) found that 4-nitrowarfarin (17) has special characteristic as anti-coagulant. 1-5 Schiff's Bases(86-88) Schiff's bases are compounds which contain an isomethine group (N=C ), they are named after Schiff who prepared a number of these bases via condensation of aliphatic and aromatic aldehyes and ketones with primary amines. The general formula of these Schiffs bases (R-N=CRR-) and their nomenclature depend on the nature of the groups R, R1, R.11. Schiff’s bases, which are derived from ketones are known as ketemines, while those derived from aldehydes known as aldimines. 1-5-1 Synthesis of Schiff’s bases(89-90) In general, Schiff’s bases are prepared by refluxing equimolar amounts of the primary amines (aromatic or aliphatic or related derivatives) with carbonyl compounds (aldehyde or ketones, aromatic or aliphatic derivatives) in appropriate solvent (cyclohexane, benzene and preferentially ethanol). Sometimes, the reaction is catalyzed by few drops of glacial acetic or piperidine and refluxing for 2 hours. Ph OHC Ph N N X NH 2 + X CH3CH2OH/ H S Ref. 2h. Pipredine N C S 88 It is concluded that (91-92) Schiff’s bases may be prepared from aromatic aldehydes or heterocyclic aldehydes or ketones with aromatic amine such as those bases derived from 2- carboxyl-5-nitrofuran, amino anti pyrine, 2- amino-5-alkylthio-1,3,4- thiadiazole, and 3,4,5- amino, 1,2,4- triazoles as illustrated respectively. SO2NHR SO2NHR + H C N O2N O CHO H2N O O2N 89 Sciff’s bases which are known as hydrazone (93) have been synthesized via the condensation of suitable acid hydrazides with aldehydes or ketones in appropriate solvent as described. O CH N N Cl R H N SCH2CONHNH 2 + R 1 S Cl N N R H H N SCH2CONHN C S 1 R=H, 4-Cl, 4-CH3. R1=2-OMe, 3-NO2, 4-NO2, 4-Cl. R 91 1-5-2 Biological Activity(94-96) Schiff’s bases have been widely reported to be biologically versatile compounds having antifungal, fungicidal, herbicidal and plant growth regulating properties . The presence of imino linkage ( -N=C- ) in these compounds has been regarded as being assential for the enhancement of antibacterial and antimicrobaial (97) activities. H C N SO2NHR O2N O 92 In the medical area, some Schiff’s bases were reputed to be useful as antidepressant, analgesic, and antimicrobial agents (98). 10 R N CHR R9 R2 R4 R5 N 8 1 3 6 R R R R 7 R R= aryl, heteroaryl, R1-4 alkyl or alkoxy, R4-6 = H, Me, R5= R6=H, R7-10 = halo, CF3. 93 The following compound which also contains an imino group has been shown to posses contraceptive action (99). H2 C S H H2C N 3 R N O 2 1 R R N R 1 R=4-F ,R =F, sub.ph, R2=CHO ,R3=2-Cl, 2-NO2, 2-F. 94 Some hydrazones (100) have been synthesized with antimicrobial properties and moderate activity against some candida species. N N 1 R R SCH2CONHN C N Me R=H, CH3, CH2CH3. R1=4-Cl, 4-OH, 4-NO2, 2-Cl, 2-OH, 2-NO2. 95 1-6 Thiadiazoles The first 1,3,4-thiadiazole has been described by Fisher (101) in 1882 but the true nature of the ring system has been demastrated first in 1890 by Freund and Kuh. The pharmacutical interest in this kind of compounds started after the discovery of sulfa drugs and new interesting drugs have been discovered, the 1,3,4-thiadiazole compounds have found applications in pharmaceutical, agricultural and other areas (102-120).