Title of Invention

"4-ARYL-2,6-DIMETHYL-3, 5-DICARBOETHOXY-1, 4-DIHYDROPYRIDINES AND CORRESPONDING HYDROXY DERIVATIVES"

Abstract This invention relates to 4-aryl-2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridines and corresponding hydroxy derivatives. The products are potential cardiovascular agents. 4-aryl-2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridines of the formula I where in R1 is H, NO2, CI, OAc, OH, R2 is H, NO2, CI, -O-CH2-O-, OMe, OAc, OEt, OH, R3 is H, NO2, CI, N(Me)2, -O- CH2 -O-, OMe, OAc, OH, R4 is H, OMe, OAc, OH and R5 is H, CI, I and corresponding hydroxy compounds of formula 1 wherein R1, is H, N02, CI, OH, R2 is H, NO2, CI, -O-CH2-O-, OMe, OEt, OH, R3 is H, NO2, CI, N(Me)2, -O- CH2 -O-, OMe, OH, R4is H, OMe, OH and R5 is H, CI, I.
Full Text The calcium entry blocker1,4-dihydropyridines have rapidly emerged as one of the most important class of nitrogen heterocycles which are being used for the management of cardiovascular diseases. These compounds have occupied an important position as therapeutic agents among the various types of the calcium entry blockers. The interest in the dihydropyridines chemistry can be traced back to the Co-enzyme reduced nicotinamide adenine dinucleotide and the unique ability of this compound in the biological systems to reduce unsaturated functionalities (carbonyls, conjugated olefins etc.). Thus, a considerable portion of today's efforts in dihydropyridine chemistry is extended to synthesizing NADH (2) mimics, exploring the reactions and mechanisms of these compounds and utilizing these compounds in a variety of synthetic reactions.
(Formula Removed)
The clinical usefulness of nifedipine (3), a prototype of dihydropyridines, in the management of cardiovascular diseases, (Fleckenstein, Von, A.; Trithart, H.; Doring, H.J.; Byon, K.X., Arzneim.-Forsch./Drug Res., 22, 1972, 1) stimulated extensive research in this area leading to the discovery of a large number of 1,4-
dihydropyridines which have been found to be even more potent than the nifedipine (3).
A large number of 4-aryl-2,6-dimethyl-3.5-dicarboethoxy-1.4-dihydropyridines have been reported to possess vasodilating effects. One of the most important among these is 4-(3-nitrophenyl)-2,6-dimethyl-3,5-dicarbodiethoxy-1,4-dihydropyridine (4), which has been found to exhibit imporved cardiac performance and longer duration of action than nifedipine (3). Moreover, it decreases heart rate whereas nifedipine increases it. It also has better activity than nifedipine in improving left ventricular function and in decreasing myocardial oxygen requirement and the peripheral vascular resistance. Thus, (4) is more beneficial than nifedipine(3) in treating congestive heart failure (Rao, M.; Liang, M.,XaoxuXuebao, 19, 1984, 101.).
(Formula Removed)
Various analogues of 4-aryl-2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridine class having functionality capable of inducing p-adrnergic blockage have been prepared and studied for cardiovascular activity. These compounds, for example (5), have ethyl ester functionality instead of the methyl ester at positions 3 and 5 (Baldwin, J.J.; Hirschmam, R.; Engelhardt, E.L; Pinticello, G.S.; Sweet. C.S.; Scriabine, A.O., J. Med. Chem., 24, 1981, 628.).
(Formula Removed)
Compounds of the type (6) are the examples of long acting dihydropyridine calcium channel blockers (Alker, D.; Campbell, S.F.; Cross, P.E.; Burges, R.A.; Caster A.J.: Gardiner, D.G., J. Med. Chem., 33, 1990, 585. Alker, D.; Campbell, S.F.;Cross. P.E.; Burges, R.A.; Carter, A.J.; Gardiner, D.G., J. Med. Chem., 33, 1990, 1805.).
(Formula Removed)
Compound WY-27569 (7) is also an example of 2-heteroaryl substituted dihydropyridine which contains ethyl ester function instead of the methyl ester function and is an antihypertensive agent (Robertson, D.W.; Steinberg, M.I., J. Med. Chem., 33, 1990, 1.).
The synthesis of 4-heteroaryl 1,4-dihydropyridines like (8) has also been carried out and these compounds possess good antihypertensive activity (Goldmann, S.; Born, L; Kazda, S.; Pittel, B.; Schramm, M., J. Med. Chem., 33,1990, 1413.).
(Formula Removed)
The 2,6-aryl substituted compound (9), with hindered rotation of aryl ring, has been found to possess very high hypotensive activity. Dihydropyhdine (10) contains some of the structural features of certain diuretics and shows only modest cardiovascular activity (Wiebelpaus, V.; Weinstock, J.; Mass, A.R.; Weinstock, T; Bender, D., Arch. Int. Pharmacodyn. Ther, 169, 1967, 429.).
(Formula Removed)’
FR7534 (11) is a DHP modified compound which is substituted in the position 2 by hydroxymethyl group in place of the customary methyl groups (Jully, S.R.; Hardmann, H.F.; Gross, G.H., J. Pharmacol. Exp. Ther, 217, 1981,20.)
Floridipine (12), a DHP with a substituent on the nitrogen atom, exhibits antihypertensive activity in rats and dogs when administered by oral route. An interesting correlation between the puckering of the DHP ring found by X-ray structure analysis and calcium antagonistic activity has also been studied in case of this compound. It has been reported in the literature that in the series of 4-phenyl substituted DHP's, an ortho substituent brings about a very slight deviation from the planarity of the DHP ring. This is an important criteria for higher activity
(Fossheim, R.; Svanteng, K.; Mastad. A.; Romming, C; Shefter, E.: Triggle. D.H.. J. Med. Chem., 25, 1982. 126. Stout, D.M.; Meyers. A.I.. Chem. Rev.. 82. 1982. 223).
(Formula Removed)
Compounds like UK-52,831 (13) and UK-56593 (14) are a class of 1,4-dihydropyridines with heterocyclic functionalities at position 2. They possess good hypotensive activity (Alker, D.; Campbell, S.F.; Cross, P.E., J. Med. Chem., 34, 1991, 19).(Formula Removed)
Compounds have been prepared by substituting nitrophenyl substituent in 1,4-dihydropyridines with benzoxadiazole group as in case of PY 108-068 (15) (Hof, R.P.; Schweinitzer, M.E.; Neumann, P., Br. J. Pharmacol., 73, 1981, 196.).
The pharmacological properties of dihydropyridines also include antitumour activity (Humphreys, S.R.; Vendetti, T.M.; Gotti, C.J.; Kline, J.; Goldin, A.; Kaplan, N.O., Cane. Res., 22, 1962, 483. Ross, W.C.J., J. Chem. Soc, 1965, 1816). 1,4-dihydropyridines have also been reported to possess some analgesic and curare properties (Phillips,A.P., J. Amer. Chem. Soc, 71, 1949, 4003). This type of compounds also possess CNS depressant (anticonvulsant and analgesic) activity (Swamay, S.K.; Reddy, T.M.; Reddy, V.M., Indian J. Pharm. Sci., 60, 1998, 102.). There are reports of this class of compounds possessing antiasthmatic activity by reducing in vitro lipoperoxidation and in vivo experimental hyper-reactivity and cell
infiltration (Cole, H.W.; Brown, C.E.; Magee, C; Roudebush, R.E.; Bryant, H.U., Gen. Pharmacol., 26, 1995, 431.). Donkor et al. have recently reported the radioprotective effects of 1,4-dihydropyridines (Donkor, I.O.; Zhou, X.; Schmidt, J.; Agarwal K.C.; Kishore, V., Bioorg. Med. Chem., 6, 1998, 563.).
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 far no attempt has been made to provide clean, safe, time-saving, environment friendly and an inexpensive method for the preparation of 4-aryl-2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridines. 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.; Vaquero, J.J.; Garcia, Navio, J.L.; Alavarez-Builla, J., Synlett., 1992, 297.). In the literature no method is available where the preparation of 4-aryl-2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridines has been carried out under dry conditions on a solid support. The methods where 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.
The main objective of the present invention is to provide 4-aryl-2,6-dimethyl-3,5-dicarboethoxy-1, 4-dihydropyridines and a novel process for preparation of said 1,4-
dihydropyridines as therapeutic agents and corresponding hydroxyl derivatives.This patent application is divided out of patent application no. 158/del/2000.
Accordingly the present invention relates to 4-aryl-2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridines of the formula I where in R,, is H, NO2, CI, OAc, OH, R2 is H, NO2, CI, -O-CH2-O-, OMe, OAc, OEt, OH, R3 is H, NO2, CI, N(Me)2, -O- CH2 -O-, OMe, OAc, OH, R4 is H, OMe, OAc, OH and R5 is H, CI, I and corresponding hydroxy compounds of formula 1 wherein R, is H, NO2, CI, OH, R2 is H, NO2, CI, -O-CH2-O-, OMe, OEt, OH, R3 is H, NO2, CI, N(Me)2, -O- CH2 -O-, OMe, OH, R4is H, OMe, OH and R5 is H, CI, I.

(Formula Removed)
Formula I In an embodiment of the present invention the aromatic aldehyde used may be such as benzaldehyde, 2-nitrobenzaldehyde, 3-nitrobenzaldehyde, 4-nitrobenzaldehyde, 2,3-dichlorobenzaldehyde, 2,4-dichlorobenzaldehyde, 2,6-dichlorobenzaldehyde, 4-(N,N-dimethyl)benzaldehyde, 3(4)-methylenedioxy benzaWehyde, 3,4,5-trimethoxy benzaldehyde, 2-nitro-3(4)-methylenedioxy benzaldehyde, 2-nitro-3(4)-trimethoxy benzaldehyde, 2-nitro-5-acetoxybenzaldehyde, 3-metiioxy-4-acetoxybenzaldehyde, 3-acetoxy-4-methoxy benzaldehyde, 2-acetoxy-3-methoxybenzaldehyde, 4-acetoxy-5-iodo-3-methoxy benzaldehyde, 2-acetoxy-5-ethoxybenzaldehyde, 4-acetoxy-3-ethoxybenzaldehyde, 3-acetoxybenzaldehyde, 4-acetoxybenzaldehyde and 2,4-diacetoxy benzaldehyde. The aromatic aldehydes used for preparation of dihydropyridines are as follows :


(Table Removed)
In an another embodimen; of the present invention the source of ammonia used may be
such as ammonium acetate, ammonium acetate solution, ammonia anhydrous.
ammonium hydroxide solution or any other source of ammonia.
In yet another embodiment of the invention the adsorbent used may be such as basic
alumina, neutral alumina, alkali metal carbonate, or any other basic adorbent.
Still another embodiment of the present invention the hydrolysing agent used may be
such as ammonia, alkali hydroxide.
Known method of preparation of the mixture of the reactants may be such as trituration,
dissolving in a organic solvent and then removing the solvent in vacuo, stirring with the
help of a stirrer.
Compounds of formula I may be recovered from the reaction mixture by extracting with
water-immiscible organic solvent such as chloroform, dichloromethane, ether, ethyl
acetate.
The compounds prepared by the process of present invention are as follows:
(Table Removed)
4-ary!-2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridines and a process for preparation of said 1,4-dihydropyridines of the formula I where in R, is H. N02, CI. OAc, OH. R2 is H, NO2, CI. -O-CH2-O-, OMe. OAc, OEt, OH, R3 is H, NO2, CI. N(Me)2, -O- CH2 -O-, OMe. OAc. OH, R4 is H, OMe. OAc. OH and R5 is H, CI, I. as therapeutic agents under dry conditions on a solid support under the influence of the microwave irradiations. No solvent is used as a medium for reaction. Accordingly in a preferred embodiment of the present invention, the process comprises of the following :
1. Take one mole of aldehyde (1A to 22A) in a mortar and to it add 2.2 moles of ethylacetoacetate. Mix the two thoroughly with 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 to adsorb whole of the above mixture on it till the adsorbent becomes free flowing.
4. Transfer the adsorbent into a conical flask much larger in capacity as compared to the volume of the adsorbent. 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 sink) with a funnel as condenser in the microwave cavity along with the reaction flask (Heat sink is to be placed only if the quantity of the reactants is less. If sufficient quantity of reactants is there to adsorb all the microwaves then heat sink is not required).

6. Subject the reaction vessel to microwave irradiations (MWI) at 350 to 600W for 30 seconds to ten minutes. Allow the reaction vessel to cool to room temperature.
7. Extract the compound with adequate quantity of water-immiscible organic solvent after shaking it thoroughly with adsorbent or stirring it on a magnetic stirrer.
8. Filter the organic extract through the Buchner funnel on a filter paper.
9. Wash the organic layer with adequate quantity of water.
10. Dry organic layer over anhydrous sodium sulphate or anhydrous magnesium sulphate.
11. Filter the extract and remove the solvent by distillation under vacuum to give residue.
12. The residue obtained above is then taken in aprotic polar solvent to give light yellow crystals of product (1B to 22B).
13. The acetate group in compounds 13B to 22B are subject to hydrolysis by stirring one mole of compound with 1.1 mole of hydrolysing agent solution in aprotic polar solvent for 15-75 minutes at 30-35°C on a magnetic stirrer. The solvent was removed under vacuum to give a residue, which was recrystallised to give compounds 23B to 32B respectively.
14. All the steps for processing of the product are done in a dark chamber or in red light to avoid decompositon of the compound by daylight / U.V. rays to achieve high yields.
15. The reaction is carried out in glassware, earthenware, ceramic or plastic containers marked as microwave safe with such a shape so as to prevent escape of the reactants or products in the vapour form during the reaction by effectively controlling the power out put.
The process of preparation of 4-aryl-2,6-dimethyl-3,5-dicarboethoxy-1,4,-dihydropyridines is described in detail as given below which are provided by way of examples for illustration only and could not be construed to limit the scope of the present invention. Example I
One mmole of 2-nitrobenaldehyde was taken in a mortar and to it added 2.2 mmoles of ethyl acetoacetate. The two were mixed thoroughly with the help of pestle in a mortar. Ammonium acetate (1.2 mmoles) 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 flask as condenser. The reaction mixture was subjected to miaowave irradiation at 460W for six minutes in a microwave oven placing a heat sink alongwith it. Allowed the reaction mixture to cool to the room temperature. Extracted the compound with
3x50ml portions of chloroform after stirring it thoroughly with adsorbent. Filtered the organic extract through the buchner funnel on a filter paper. Washed the organic solvent layer with 2x100ml portions of water. Dried the organic solvent layer over anhydrous sodium sulphate. Filtered the extract and removed the solvent by distillation under vacuum to give the residue which was recrystalised in methanol to give yellow coloured crystals of 4-{2-nitrophenyl)-2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridine (m.p.140°C) in 85% yield.
Example II
One mmole of 2-acetoxy-3-methoxybenaldehyde was taken in a mortar and to it added 2.2 mmoles of ethyl acetoacetate. The two were mixed thoroughly with the help of pestle in a mortar. Ammonium acetate (1.2 mmoles) was added to above reaction mixture and then triturated the mixture with the help of pestle. To the above calcium 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 flask as condenser. The reaction mixture was subjected to microwave irradiation at 400W for seven minutes in a microwave oven placing a heat sink alongwith it. Allowed the reaction mixture to cool to the room temperature. Extracted the compound with 3x50ml portions of dichloromethane after stirring it thoroughly with adsorbent. Filtered the organic solvent extract through the buchner funnel on a filter paper. Washed the organic layer with 2x100ml portions of water. Dried the organic solvent layer over anhydrous sodium sulphate. Filtered the extract and removed the solvent by distillation under vacuum to give the residue which was recrystallised in ethanol to give yellow coloured crystals of 4-(2-acetoxy-3-methoxyphenyl)-2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridine (m.p.135°C) in 80% yield. Example III
One mmole of 2-acetoxy-3-methoxybenzaldehyde was taken in a mortar and to it added 2.2 mmoles of ethyl acetoacetate. The two were mixed thoroughly with the help of pestle in a mortar. Ammonium acetate (1.2 mmoles) was added to above reaction mixture and then triturated the mixture with the help of pestle. To the above
calcium 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 flask as condenser. The reaction mixture was subjected to microwave irradiation at 400W for seven minutes in a microwave oven placing a heat sink alongwith it. Allowed the reaction mixture to cool to the room temperature. Extracted the compound with 3x50ml portions of dichloromethane after stirring it thoroughly with adsorbent. Filtered the organic solvent extract through the buchner funnel on a filter paper. Washed the organic layer with 2x100ml portions of water. Dried the organic solvent layer over anhydrous sodium sulphate. Filtered the extract and removed the solvent by distillation under vacuum to give the residue which was recrystallised in ethanol to give yellow coloured crystals of 4-(2-acetoxy-3-methoxyphenyi)-2.6-dimethyl-3;5-dicarboethoxy-1,4-dihydropyridine (m.p.135°C) in 80% yield. The acetoxy compound prepared was subjected to hydrolysis by stirring one mole of compound with 1.1 mole of ammonium hydoxide solution on methanol for one hour at 30-35°C on a magnetic stirrer and then removing the solvent under vacuum. The resulting compound was recrystallised in petroleum ether to give 4-(2-hydroxy-3-methoxyphenyl)-2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridine(m.p. 140°C) in 75% yield.
Advantages
The main advantages of the present invention are :
1. A process for the preparation of 4-aryl-2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridines (DHP compounds) where the reaction times are reduced i.e. from 16 hours to 6 minutes.
2. A process for the preparation of DHP compounds where the reaction yields are improved (80-90%).
3. A process for the preparation of DHP compounds where the minimum use of solvents is required as these are required for extraction and crystallization only.
4. A process for the preparation of DHP compounds where there are no fire hazard as no solvents are used in the reaction.
5. A process for the preparation of DHP compounds which may be useful in future as therapeutic agents particularly antianginal and hypotensive agents.
6. 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-3,5-dicarboethoxy-1,4-dihydropyridines of the formula I where in R,, is
H, N02, CI, OAc, OH, R2 is H, NO2, CI, -O-CH2-O-, OMe, OAc, OEt, OH, R3 is H, NO2, CI, N(Me)2, -O- CH2 -O-, OMe, OAc, OH, R4 is H, OMe, OAc, OH and R5 is H, CI, I and corresponding hydroxy compounds of formula 1 wherein RT is H, NO2, CI, OH, R2 is H, N02, CI, -O-CH2-O-, OMe, OEt, OH, R3 is H, NO2, CI, N(Me)2, -O- CH2 -O-, OMe, OH, R4is H, OMe, OH and R5 is H, CI, (SEQ ID NO Removed)
(Formula Removed)

2. 4-aryl-2,6-dimethyl-3,5-dicarboethoxy-1,4-dihydropyridines and corresponding hydroxy derivatives useful as therapeutic agents as herein described with reference to examples.


Documents:

37-del-2004-abstract.pdf

37-del-2004-claims.pdf

37-del-2004-correspondence-others.pdf

37-del-2004-correspondence-po.pdf

37-del-2004-description (complete).pdf

37-del-2004-form-1.pdf

37-del-2004-form-19.pdf

37-del-2004-form-2.pdf

37-del-2004-form-3.pdf

37-del-2004-form-5.pdf

abstract.jpg


Patent Number 244306
Indian Patent Application Number 37/DEL/2004
PG Journal Number 49/2010
Publication Date 03-Dec-2010
Grant Date 30-Nov-2010
Date of Filing 08-Jan-2004
Name of Patentee COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110001, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 NEERAJ MAHINDROO SCIENTISTS, REGIONAL RESEARCH LABORATORY, JAMMU.
2 RAVI KANT KHAJURIA SCIENTISTS, REGIONAL RESEARCH LABORATORY, JAMMU.
3 KASTURI LAL BEDI SCIENTISTS, REGIONAL RESEARCH LABORATORY, JAMMU.
4 KANAYA LAL DHAR SCIENTISTS, REGIONAL RESEARCH LABORATORY, JAMMU.
PCT International Classification Number C07D 211/82
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA