Title of Invention

4-ARYL-2,6 DIMETHYL-3-CARBOETHOXY-5-CARBOMETHOXY-1,4-DIHYDROPYRIDINES USEFUL AS THERAPEUTIC AGENTS"

Abstract

Novel 4-aryl-2,6 dimethyl-3-carboethoxy-5-carbomethyl-l,4-dihydropyridines useful as therapeutic agents Novel 4-aryl-2,6 dimethyl-3-carboethoxy-5-carbomethyl-l,4-dihydropyridines useful as therapeutic agents. These dihydropyridines are potential cardiovascular agents. The main objective of the present invention is to provide the safe, clean, devoid of solvent, time-saving, high yield, inexpensive, environment friendly, one pot synthetic process for the preparation of 4 - aryl - 2,6 - dimethyl - 3 - carboethoxy - 5 - carbomethoxy - 1,4-dihydropyridines.

Full Text

*The present invention relates to, 4-afyi-2,6^imethyl-3-carboethoxy-5-carbomethoxy-1.4- dihyctfopyndtnes useful as therapeutic agents. These dihydropyridines are potential cardiovascular agents. The pretent investigation relates to the preparation of 4-aryl-2,6- dimemyl-3-cart>oetrwxy-5-cai1X)rn«thoxy-1,4-dihydropyndines as racemates in general and to the preparation of 4-(2,3-dichlorophenyl)-2,6-d!methyl-3-carboethoxy-5-carbometrioxy- 1,4-dihydfO-pyridine i.e. FekxRptne (1) in particular which is being marketed as racemic mixture. 1 } In the recent times there has been a tremendous interest in the microwave mediated organic synthesis. He main advantages are, a shorter reaction time, cleaner reaction, better yields, eat* of workup after reaction, reduction in thermal degradation, better selectivity and environment friendly conditions (Abramovrtch, R.A., Tetrahedron Lett., 32. 1991,5271. Bose, A.K.; Manhas, M.S.; Ghosh, M.: Shah, M.; Raju, V.S.; Ban, S.S.: Newaz, S.N.; Barak, B.K., Chaudhary, A.G.: Barkat. K.J., J. Org. Chem., 56, 1991. 6968. Caddick, S., TsJnnadren, 51,1906 10408. Slames, C.R.; Trainer, R.W.. Atut. J. Cham., 49,1996, 1fl96. Bow. AJC; Jayarraman, M.; Okawa, A.; tori, S.S.; Robb, E.W.; Manhas, M.S., Tetrhedron Lett., 37, 19i6, 6989. Verma. R.S.; Dahiya, R.; Saini R.K., Tetrahedron Lett., 38, 1997, 7029.). The reactions can be carried out from a few milligrams to 500 grams quantities in a simple household micowaye oven (Banik, B.K.; Manhas, M.S.: Kaulza Z.; Barakat K.J.; Bose A.K., Tetrahedron Lett,, 33, 1992, 3603.). Microwave ovens can range from simple house hold muttimode ovens to large scale batch as well as continuous rTHitemode ovens, in batch closed reactor, veaaeh or turntables having a capacity to contain a number of reaction vessels have been applied. Specifically in fopd industry large-scale (continuous rtiode) ovens are used frequently Galema. S.A , Chem. Sac. Rev., 26, 1997. Staruss, C.R.; Tramor, R.W., Aust. J. Cram., 48. 1995, 1665). Thus it is possible to scale up the reactions to industrial scale. The first generation dthydropyridmes are one possessing identical ester functions at position 3 and 5 in the dihydropyridine ring. The second gener=tion of dihydropyrtdine (DHP) development candidates have greater potency and are all chiral owing to non-identical ester functions (Meyer, H; Bossert, F.; Wehiger, E.; Stoepel, K; Vater, W., Arzneim.-ForschJDrug Res., 30, 1981, 407.) and can exist in enantiomeric forms differing in absolute configration at C-4 (Towart, R.; Wehinger, E.; Meyer, H.; Schmiedbergs, N., Arch. Pharmacol., 317,1981, 183.). Felocipine (1) is one of these DHP candidates, which have non-identical ester function and is characterized by pronounced peripheral vasodilation, so it appears to be particularly intsresting for therapy of hypertension (Ek, B.; Ahnoft, M.; Norlander, H.H.; Jung, BiL., Arch. Pharmacol., 313, 1980, Supl. R37.). (Figure Removed) Another DHP which has non-identical ester functionalities is nivaldipine (2; .vnich is also substituted at the position-2 by cyano group in place of customary metryl group (Jully, S.R.; Hardmann, H.F.; Gross, G.H., J. Pharmacol. Exp. Ther., 217 1981, 20.). Nitrendipine (3) another 1.4-dihydropyridine derivative with mixe: ester functionalities is being marketed as antihypertensive drug which has longer curation of action than nifedipine (4). A marked therapeutic response is obta ned on administration of nitrendipine (3) in hypertensive patients with corona-/ artey diseases who respond inadequately to p-blockers (Scriabine, A.; Vanov, S. Deek, K. Eds., Nitrendipine, Urban & Schwartzenberg, Tokyo, 1983.). HjCOHCOO COOCH' W (5) Nimodipine (5) due to its dilative action on spasm of cerebral vessels, has also become a drug of choice in patients with subarchanoid hemorrhage (Betz. E. Deek, K.; Hoffmeister, F. Eds., Nimodipine, Pharmacological and Clinical Properjes, F.K. Sctwttener Verlag, Stutgart, New York, 1985.). Moreover, nimodipine cresses the blood brain barrier and elicits some direct psyhotropic activity. It also dnates the cerbral vessels to a greater extent (Baldwin, J.J.; Hirschmann, R.; Engekhsrdt, E.L.; Pintieello, G.S.; Sweet, C.S.; Scribine, A, J. Med. Chem., 24, 1981, 628.). HjCOO COOCHjCH CH, TO, Nisoldipine i.e. Bay k 5552 (6) is one of the most potent blockers r voltage dependent Ca2* channels and is characterized by its predominating effec:s on the coronary and peripheral blood vessels (Kazda, S.; Garthoff, B.; Rams:n, K.D.; Schluter, G.. New Drugs of annual, Cardiovascular Drugs 1, A. Scribane E: Raven Press; New York, 243, 1983. Itoh, T.; Kannu'-a, Y.; Kanyama, H.. Suzuk^. - . Br. J. Pharmacol., 83, 1984, 243.). -MO, (Figure Removed) Amtodipine (7) another DHP with non-identical ester functionalites and a basic side chain at position 2 is a long acting dihydropyridine with a half life of 30 hrs ;n dogs. The bulk of the activity resides in (-) isomer of (7) which has shown extensive potential as antihypertensive and antianginal drug (Arrowsmith, J.E., Campbell S.F.; Croat, PE Stubbs, J.K.; Surges, R.A.; Gardiner, D.G.; Blackburn. K.J., J. 1. Chem., 29, 1986, 1696, Alker, D.; Campbell, S.F.; Cross, P.E.. J. Med. 7,, 34,1991,19.). Structural modifications among dihydropyridines continue to be concentrated on the ester and aryl substituents with the aim of discovering examples having sicw onset and long duration of action. Results with FRC-8653 (8) are encouraging. In spontaneous hypertensive rats, this compound exhibits an antihypertensr-e effect with slow onset and a longer duration of action (lida, H.; Fujiyoshi, T.; Iksda, K.; Hosoro, M.; Yanura, M.; Kase, N.; Sekive, A.; Uematsu, T., Japan. J. Phs'macol., 43, 1987,296.). CfiH6 "5, Similar long lasting effects were also observed in dogs with B844-39 (9) (Fisner, G. Krumple, G.; Mayer, N.: Schneider, W.; Raberger, G.J.. Cardiovasc. Fha'macol. 10, 1987,268.). More extensive structural modifications of ester moiety are found in R018-3017 (10) (HoHk, M.; Osterrieder, W., Br. J. Pharmac., 91, 1987, 61.). H3C (12) Another compound PN 200-110 (12) is more potent than (11) due to mixed ester functionalities (Hof, R.P.; Schweinitzer, M.E.; Neumann, P., Br. J. Pharmacol., 73, 1981,196.) (Figure Removed) FRC-8411 (13) shows good hypotensive and antianginal activites (Yamaura, T.: Kase, N.; Kita. H.; Uematsu, T., Arzeneim.-Forsch./Drug Res., 36, 1SS5. 29.). Compound YM - 09730 (14) shows greatest coronary vasodilating activity (Tamnzawa, K.; Arima, H.; Kojima, T.; Tsotnura, Y.; Okeda, M.; Fujita, S.; Furuya, T.; Takeneda. T.; Inagaski, 0.; Terai, M., J. Med. Chem., 29, 1986, 2504.). (Figure Removed) Compounds (15) and (16) have been reported to have activity similar to felodipine (1) which has been shown to be 1000 folds more potent than nifedipine (4) (Ohno, Si; tdmatsu, 0.; Miznokoshi, K.; Jahihara, K.; Nakamura, Y.; Marighima, I.; Sumuta, fc, J. Pharm. Dyn., 7,1984, 5). (17) Nigulidipine (17) developed orginally as a long acting calcium channel blocker. also increases the opening probability of Ca2+ activated K* channels and may be example of a compound acting in opposite fashion on two distinct ion channels (Robertson. D.W.; Steinberg, M.I., J. Med. Chem., 33, 1990, 1). H3COOC (Figure Removed) Some new dihydropyridines. benidipine (18), manidipine (19), CV-159 (2(T and P- 0285 (21), have been found to be more potent and have specific vascular effects than prototypes in the class of compounds related to nifedipine (4). They have been reported to have slow onset and long duration of action in animals without cardiodepressant effect which is characteristic of other dihydropyridines. (Figure Removed) CHjCOOCONH, , Compounds like NB-818 (22), are more potent and have longer duration of action in vivo than agents like nifedipine (4). Compound (23) has been reported to increase cerebral QQrtH*Wood flow and improves memory in certain models (Naurse, T., Kiozymi, Y., Japan. J. Pharmacol., 4S(Suppl.), 1988, 75. Nichikibe, A.; Nakajuma, A,, Life Sciences, 43,1988,1715.). From the study of the literature we reach at the conclusion that a number of methods have been reported for the preparation of 1,4-dihydropyridines which involve the condensation of various substituted aldehydes with methylacetoacetate or ethylacetoacetate in the presence of ammonia by using methanol or ethanol as the solvent. So Up no attempt has been made to provide dean, safe, time-saving, enwrafMnnt tritMty and an inexpensive method for the preparation of 1,4- dihvdropyrioines. This method can only be provided if the reaction is carried out under the influence of microwave irradiations. There is only one method in the literature for the preparation of 1,4-dihydropyridines with the help of microwave irradiations where the ammonia, alkylacetoacetate and aldehyde with ethanol as solvent have been used for the preparation of 1,4-dihydropyridines (Alajarin, R.; Viquero, J.J.; Garcia, Navio, J.L; Alavarez-Builla, J., Synlett., 1992, 297.). In the literature no method is available where the preparation of 1,4-dihydropyridines have been carried out under dry conditions on a solid support. The methods v»tiere the solvents such as ethanol or methanol are used for the preparation of various compounds under the influence of microwave irradiations suffer from one or the other drawbacks such as inflammability due to switching on and off of the magnetron of microwave oven to control the power out put. There is no method in literature where 4-aryl-2,6-dimethyl-3-carboethoxy-5-carbomethoxy-1,4-dihydropyridine have been prepared in a single step. The main objective of the present invention is to provide the safe, clean, devoid of solvent, time-saving, high yield, inexpensive, environment friendly, one pot synthetic process for the preparation of 4-aryl-2,6-dimethyl-3-carboethoxy-5-carbomethoxy- 1,4-dihydropyridines. Another objective of the invention is to develop new analogues felodipine, which could act as potent cardiovascular agents and can become the drugs of future. Accordingly, the present invention provides 4-aryl-2,6 dimethyl-3-carboethoxy-5- carbomethoxy-1,4-dihydropyridines useful as therapeutic agents. H3coo wherein R, is H, NO2, Cl, OAc, OH, R2 is H, NO2, CL,-O-CH2-O-Ome, OAc, OEt, OH, R3 is H, NO2, Cl, N(Me)2,-O-CH2-O-, OMe, OAc, OH, R4 is H, OMe, OAc, OH, R5 is H, Cl, I. benzaldehyde. 2-nitro-5-acetoxybenzaldehyde. 3-methoxy-4-acetoxyberz2 cehyde, 3-acetoxy-4-methoxybenzaldehyde, 2-acetoxy-3-methoxybenzaldehyae. ---acetoxy- 5-iodo-3-methoxybenzaldehyde, 2-aicetoxy-5-ethoxybenzaldehyde, 4-acatoxy-3- eftoxytoenzaldehyde, 3-acetoxybenzaldehyde, 4-acetoxybenzaldehyde and 2,4- diacetoxybenzaldehyde. The aromatic aldehydes used for preparation of dihydropyridines are as follows : (Table Removed) In an another embodiment of the present invention the source of ammonia used may be such as ammonium acetate, ammonium acetate solution, ammonia anrydrous. ammonium hydroxide solution or any other source of ammonia. (Figure Removed) In yet another embodiment of the invention the adsorbent used may be such as * oasic alumina, neutral alumina, alkali metal carbonate, or any other casic acorbent. §tj|| another embodiment of the present invention the hydrolysing agent Lsed may be such as ammonia, alkali hydroxide. Known method of preparation of the mixture of the reactants may be such as trituration, dissolving in the solvent and the removing the solvent in vacua, stirring with the help of a stirrer. Compounds of formula I may be recovered from the reactiion mixture by extracting with water immiscible organic solvent such as chloroform, dichloromethar.e. ether. ethyl acetate. The compounds prepared by the process of present invention are as follows: (Table Removed) y. Accordingly in a preferrea embodiment of the present invention, the process comprises of the following : 1. Take one mole of aldehycs (1A to 22A) in a mortar and to it add a premixed , ; j-jrjmiKj - . mixture of 1.1 moles of metnylacetoacetate and 1.1 moles of ethyl acetoacetate. Mix the two thoroughly witr the help of a pestle in a mortar. 2. Add ammonium acetate (1.2 moles) to the above reaction mixture and then triturate the mixture with the help of a pestle. 3. To the above mixture add basic adsorbents like potassium carbonate, calcium carbonate, aluminium oxide or magnesium oxide in small increments with thorough mixing so as tc adsorb whole of the above mixture on it till the adrafeMnt becomM free flowing. 4. Tranatar the adsorbent intc a conical flask much larger in capacity as compared to the volume of the adsorcent. Place a funnel on the flask as condenser. 5. Place the flask in the microwave oven cavity. Also place another flask containing ice (as heat sir.x) with a funnel as condenser in the microwave cavity along with the reaction flas reactants is less, if sufficsnt quantity of reactants is there to adsoro all the microwaves then heat sink s not required). 6. Subject the reaction vesse. :o microwave irradiations (MWI) at 250W to 400W for 30sec to 10 minutes. Allow tie reaction vessel to cool to room temperature. 7. Extract the compound w?r adequate quantity of haioalkane after srakmg it thoroughly with adsorbent :r stirring it on a magnetic stirrer. 8. Filter the organic extract trough the Buchner funnel on a filter paper. 9. Wash the organic layer wir adequate quantity of water. 10. Dry organic layer over anrv, ~rous sodium sulphate. 11. Filter the extract and remc(. e the solvent by distillation in vacuo to give residue. 12. The residue obtained abc\a is then taken in aprotic polar solvent to c;ve light yellow crystals of product (IB to 22B). 13. The acetate group in compcunds 13B to 22B are subject to hydrolysis by stirring one mole of compounds *3B to 228 with 1.1 mole of ammonium hydoxide solution in methanol for ere hour at 30-35°C on a magnetic stirrer snd then 14 • removing the solvent under vacuum. The compounds were recrystailised in petroleum ether to give compounds 23B to 32B respectively. 14. All the steps for processing of the product should be done in a dark chamber or in iwf lyftl to avoid decompositon of the compound by daylight / U.V. rays to achieve high yields. 1 5. The reaction should be carried out in glassware, earthenware, ceramic or plastic containers marked as microwave safe with such a shape so as to prevent escape of tbMKta0fe or produda.ii. the. vapour form during the reaction by effectively controlling the power out put. The procae* of preparation of 4-aryl-2,6-dimethyl-3-carboethoxy-5-carbomethoxyis detcribed in detail as given below which are provided by Example I One mmole of 2-nitrobenzaidehyde was taken in a mortar and to it added a premixed mixture of methyl acetoacetate(1.i mmoies) and ethyl acetoacetate( i.1 mmoies). The two were mixed thoroughly with the help of pestle in a mortar. Ammonium acetate(1.2 mmoies) was added to above reaction mixture and then triturated the mixture with the help of pestle. To the above mixture potassium carbonate was added in small increments with thorough mixing till the mixture became free flowing. Transferred the mixture to a conical flask much larger in capacity as compared to the volume of the adsorbent. Placed a glass funnel on the fiask as condenser. The reaction mixture was subjected to microwave irradiation at 400VV for six minutes in a microwave oven placing a heat sink aiongwitn it. Aiioweo the reaction mixture to cool to the room temperature. Extracted the compound with 3x50mi portions of chloroform after stirring it thoroughly with adsorbent. Filtered the organic extract througn the buchner funnel on a filter paper. Washed the organic layer with 2x100mi portions of water. Dried the organic layer over anhydrous sodium sulphate. Filtered the extract and removed the solvent by distillation under vacuum to give the residue which was recrystajiised in methanoi to give yellow coloured crystals of 4-(2-nitrophenyi)-2.6-dimetnyi-3-carDoethoxy-5-carDomer-xy-i.4.- dihydropyridines (m.p. 178°C) in 90% yield. One mmoie of 2-acetoxy-3-methoxyp^naldehyde was taken in a mortar and to it added a premixea mixture of methyl acetoacetate(1.1 mmoies) and ethyl acetoacetate a 11lui'Uff 3%f#f«SfluM acetaleO .'2 mm6fes)twasaadcfea"toJaBove reaction mixture and then triturated the mixture with the help of pestie. To the above mixture a;uminum oxide waS added in small increments with thorough mixing till the mixture became free ; Transferred JM> mixture to a contcaj flask much larger in capacity as compared to the volume of the adsorbent. Placed a glass funnel on the flask as condenser. The reaction mixture was subjected to microwave irradiation at 300W for nine minutes in a microwave oven placing a heat sink aiongwitn it. Aiicwed the reaction mixture to cool to the room temperature. Extracted the compound with 3x50mi portions of aicniorometnane after stirring it thoroughly with acsorbent. Filtered the organic extract through the buchner funnel on a filter paper. Wasned the organic layer with 2xiOOmi portions of water. Dried the organic layer over a~nydrous sodium sulphate. Filtered the extract and removed the solvent by distillation under vacuum to give tne residue which was recrystaiiised in methanoi to give yellow coloured crystals of 4-{2-actoxy-3-methoxypnenyl)-2.6-dimetnyi-3-carDoe:noxy-5- carbomethoxy-1,4,-dihydropyridines (m.p.162°C ) in 85% yield. Example iii One mmoie of 2-acetoxy-3-methoxyDenaidenyde was taken in a mortar and to it added a premixed mixture of methyl acetoacetate(1.1 mmoies) ars ethyi acetoacetate(i.1 mmoies).. The two were mixed tnoroughiy with the neip of :estie in a mortar. Ammonium acetate(1.2 mmoies) was added to above reaction mixrjre and then triturated the mixture with the help of pestie. To the above mixture a;uminum oxide was added in small increments with thorough mixing tiii the mixture cecame free flowing. Transferred the mixture to a conical flask much larger in capacity as compared to the volume of the adsorbent. Placed a glass funnel on the -"asK as condenser. I he reaction mixture was subjected to microwave irradiation at 300VV for nine minutes in a microwave oven placing a heat sinK aiongwitn it. Aiiowed the reaction mixture to cooi to tne room temperature. Extracted the compound with 3x§Qmf portions of dJetiloromethane after stirring it thoroughly with adsorbent. Filtered the organic extract through the bunchner funnel on a filter paper. Washed the organic layer with 2x100mi portidns of water. Dried the organic layer over anhydrous sodium sulphate. Filtered the extract and removed the solvent by distillation under vacuum to give the residue which was recrystaiised in methanoi to give yellow coloured crystals of 4-(2-actoxy-3-methoxyphenyi)-2,6-dimethyi-3- carboethoxy-5-carbomethoxy-1,4,-dihydropyridines (m.p.162°C ) in 85% yield. The acetoxy compound was subjected to hydrolysis by stirring one mole of compound with 1.1 mole of ammonium hydoxide soiution in methanoi for one hour at 3Q-35°C on a magnetic sftrrer and then removing the solvent under vacuum. The resulting compound was recrystaiiised in petroleum ether to give 4-(2-hydroxy-3- methoxyphenyi)-2,6-dimethyi-3-carboethoxy-5-carbomethoxy-1,4,-dihydropyridines (m. p. 170*0) in 75% yield. Advantages The main advantages of the present invention are : 1. A process for the preparation of 4-aryi-2,6-dimethyi-3-carboetnoxy-5- carbomethoxy-1.4-dihydropyridines as racemates (DHP compounds) where the reaction times are reduced i.e. from 16 hours to 10 minutes. 2. A process for the preparation of DHP compounds where the reaction yields are improved (50-60%). 3. A process for tne preparation of DHP compounds wnere tne minimum use of solvents is required as solvents are required for extraction ana recrystaiiisation only. 4. A process for tne preparation of DHP compounds where there are no fire nazaro as no solvents are used in the reaction. 5. A process for the preparation of DHP compounds whjch may be useful in future as antiangmal and nypotensive agents. 3.* A process for the preparation of the DHP compounds which may be useful as new test models in the development of agents which could be used as drugs in the future for the management of various cardiovascular ailments. 7. The entire process of synthesis is environment friendly. We claim: 1. 4-aryl-2,6 dimethyl-3-carboethoxy-5-carbomethoxy-l,4-dihydropyridines useful as therapeutic agents wherein RI is H, N02, Cl, OAc, OH, R2 is H, NO2, CL,-O-CH2-O-Ome, OAc, OEt, OH, R3 is H, NO2, Cl, N(Me)2,-O-CH2-O-, OMe, OAc, OH, R4 is H, OMe, OAc, OH, R5 is H, Cl, I. 2. 4-aryl-2,6 dimethyl-3-carboethoxy-5-carbomethoxy-l,4-dihydropyridines useful as therapeutic agents substantially as herein described with reference to the examples.

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