Field of the invention:
The present invention deals with novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted-[l,2,4]-triazolo [3,4-c][l,4] benzoxazines, their preparation and use as diuretics.
Background of the invention:
A diuretic is any drug that elevates the rate of bodily urine excretion and this process is known as diuresis. Diuretics also decrease the extra cellular fluid volume, and are primarily used to produce a negative extra cellular fluid balance. Caffeine, cranberry juice and alcohol are all weak diuretics.
In medicine, diuretics are used to treat heart failure, liver cirrhosis, hypertension and certain kidney diseases. Diuretics alleviate the symptoms of these diseases by causing sodium and water loss through the urine. As urine is produced by the kidney, sodium and water -which cause edema related to the disease - move into the blood to replace the volume lost as urine, thereby reducing the pathological edema. Some diuretics, such as acetazolamide, help to make the urine more alkaline and are helpful in increasing excretion of substances such as aspirin in cases of overdose or poisoning.
The antihypertensive actions of some diuretics (thiazides and loop diuretics in particular) are independent of their diuretic effect. That is, the reduction in blood pressure is not due to decreased blood volume resulting from increased urine production, but occurs through other mechanisms and at lower doses than that required to produce diuresis. Indapamide was specifically designed with this is mind, and has a larger therapeutic window for hypertension (without pronounced diuresis) than most other diuretics.
Chemically, diuretics are a diverse group of compounds that either stimulate or inhibit various hormones that naturally occur in the body to regulate urine production by the kidneys. Alcohol produces diuresis through modulation of the vasopressin system.
Some of the drugs, which are in clinical use presently, are furosemide, hydrochlorothiazide and spiranolactone. The former two produce diuresis by inhibiting the carbonic anhydrase enzyme and the latter produces the effect by inhibiting aldosterone.
Reports in Drugs of the Future 1985, 10, 554 and Indian Journal of Chemistry, 1984, 23B, 1279 describe data on the diuretic activity of [l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives. This is first time diuretic activity was identified in a novel system, which does

not contain any of the pharmacophores required for such activity viz -SO2NH2 (e.g. hydrochlorothiazide and furosemide) -COOH (ethacrynic acid) and amidino
(amiloride) functions. The most active of these compounds viz l-oxo-2,4-dihydro-6,8-dinitro- [l,2,4]-triazolo [3,4-c][l,4] benzoxazine of formula-II,

showed more activity than the comparative standards i.e. hydrochlorothiazide in rats.
The sodium and chloride excretion patterns were favourable but the potassium excretion pattern was slightly unfavourable. When the compound was tested in dogs, as secondary models, it did not show consistent activity. The comparative positive indications in a secondary model like dogs in the case of diuretics is essential in order to take it up for further studies. Hence this became a disadvantage. Since diuretics are important class as life saving drugs, there is an urgent need to develop drugs having this therapeutic activity.
Objectives of the present invention:
The product of formula II has shown excellent diuretic activity with good profile. This appears to be a very important lead towards achieving good therapeutic value as a diuretic.
- The main objective of the present invention is to provide novel 2,4-dihydrol -oxo-6,8- dinitro-2-substituted-[l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of general formula I defined earlier.
- Another objective of the present invention is to provide 2,4-dihydro-6,8-dinitro-l- oxo-2-substituted-[l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of general formula I, defined earlier with good pharmacological action
- Yet another objective of the present is to provide 2,4-dihydro-6,8-dinitro-l-oxo-2- substituted-[l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of general formula I, defined earlier with good diuretic activity.
- Still further objective of the present invention is to provide 2,4-dihydro-6,8-dinitro-l- oxo-2-substituted-[l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of formula I, with diuretic activity in the primary and secondary model viz rats and dogs respectively as well as human beings.

Still yet another objective of the present invention is to provide 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted-[l,2,4]-triazolo [3,4~c][l,4] benzoxazine derivatives of general formula I with diuretic activity superior to standard drug like hydrochlorothiazide
Accordingly, the present invention provides novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted-[l,2,4]-triazolo [3,4-c][l>4] benzoxazine derivatives of formula I

Where R is Na, K,l-4-alkyl or CH2-X where X is morpholine, piperidinyl or CH2OCOY where Y is CH3, C2H5, C6H5,2-furanyl, 2-thienyl, (CH2)2COOCH3, (CH2)2COOCH2 C6H5, or -COZ, where Z is 2-furanyl, 2-thienyl, phenyl, methyl, 2-pyridinyl (CH2)2COOC2H5, (CH2)2CON(C2H5)2, (CH2)2COOCH2 C6H5, CH2C1, CH2-phthalimidyl, or COOC2H5, SO2C6H4CH3(4), P(O)(OC2H5)2 or (CH2)AB, where A=B=COCH3, A=B= COOC2H5, A=B= COC6H5, A= COCH3, B= COOC2H5, A= COCF3) B= COOC2H5, A= COC6H5, B= COOC2H5, possessing good to excellent diuretic activity as well as their preparation
These compounds, mentioned here, are new, as they have not been reported in the literature.
Summary of the present invention:
The present invention relates to 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted-[l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of formula I, their preparation and diuretic activity.
According to one embodiment of the present invention, there is provided a process for the preparation of product of formula-1


where R is Na/K
by reacting the product of formula-II

with NaH / KH in an aprotic solvent like N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethylsulfoxide, acetonitrile etc., and precipitating the salt with an anti solvents like ether, diisopropyl ether etc.
The compounds of formula I, where R is Na/K can also be prepared by treating the product of formula II with NaOH/KOH in an alkanol and precipitating with an antisolvent like diethyl ether, idisopropyl ether etc.
The compounds of formula I, where R = Na is designated as Ilia and where R = K is designated asIIIb.
In another embodiment of the present invention, there is provided a process for the preparation of the compounds of formula I, wherein R is methyl, ethyl, n-propyl, isopropyl, n-butyl etc by reating the product of formula Ilia or Mb with the appropriate alkylating agent.

Reaction of Ilia or Mb with dimethylsulphate or methylbromide or methyl iodide in an aprotic dipolar solvent like N,N-dimethyl formamide gives product of formula I where R = CH3 and this compound is designated as IVa


Similarly reaction of the product of formula Ilia /IIIb with diethylsulphate or ethylbromide or ethyl iodide yields the compound of formula I, where R = C2H5 and this is designated as IVb

The other products of formula I, where R = n-Pr, 'Pr, n-Bu etc are prepared by reacting the product of formulaIIIa/IIIb with the appropriate alkyl bromide or alkyl iodide
The product of formula I, where R is n-propyl is designated in IVc, the product of formula I, where R is i propyl is designated as IVd and the product of formula I, where R is n-butyl is designated as IVe.
The above mentioned novel compounds can also be prepared by reacting the product of formula II with the appropriate alkylating reagent in an aprotic dipolar solvents containing alkali metal carbonate.
In yet another embodiment of the present invention, there is provided a process for preparation of products of formula I, wherein R is CH2X and X is either morpholinyl or piperidinyl, by reacting the product of formula II


with formaldehyde and the corresponding amine viz morpholine and piperidine respectively
in an alkanol.
The formed Mannich base is represented as Va/Vb

When X is morpholinyl, the product designated as Va and when X is piperidinyl, the product is designated as Vb
In still another embodiment of the present invention, there is provided a process for the preparation of the products of formula I, where in R = CH2OC(O)Y and Y is CH3, C2H5, C6H5, 2-furanyl, 2-thienyl, (CH2)2COOCH3, (CH2)2COOCH2C6H5 by reacting the product of formula II
with formaldehyde in an alkanol give the product of formula VI,

which is further reacted with an appropriate acid chloride in the presence a organic base and a promoter in a non polar solvent to give the product of formula VII,


where Y is CH3 is designated as VIIa, Y is C2H5 is designated as VHb, Y is C6H5 is designated as VIIc, Y is 2-furanyl is designated as VIId, Y is 2-thienyl is designated as VIIe, Y is CH2CH2COOCH3 is designated as VIIf and Y is CH2CH2COOCH2C6H5 is designated asVIIg.
In still further embodiment of the present invention, there is provided a process for the preparation of the products of formula I, wherein R is COZ and Z is 2-furanyl, 2-thienyl, phenyl, 2-pyridinyl, methyl, (CH2)2COOC2H5, (CH2)2CON(C2H5)2, (CH2)2COO CH2C6H5 and CH2C1 by reacting the product of formula II with the appropriate acid chloride in the presence of an organic base and promoter in a non polar solvent to give product of formula VIII

Where Z is CH3 is designated as VIIla, Z is 2-furanyl is designated as VIIIb, Z is 2-thienyl is designated as VIIIc, Z is phenyl is designated as VMd, Z is 2-pyridinyl is designated as VIIIe, Z is (CH2)2COOCH3 is designated as VIIIf, Z is (CH2)2COOCH2C6H5 is designated as VIIIg and Z is CH2C1 is designated as VIIIh. The product of formula VIIIi is prepared by reacting the product of formula VIIIh with potassium phthalimide in aprotic dipolar solvent.


In still yet another embodiments of the present invention, there is provided a process for the preparation of the products of formula I, wherein R is (CH)AB, in which A=B=C0CH3, COOC2H5, COC6H5; A= COCH3, B= COOC2H5; A= COCF3, B= COOC2H5; A- COC6H5, B= COOC2H5, by reacting the product of formula II with the reagent of formula IX

where W is chloro or bromo and A and B are A=B=COCH3, COOC2H5, COC6H5; A= COCH3, B= COOC2H5; A= COCF3, B= COOC2H5; A= COC6H5, B= COOC2H5 in an aprotic dipolar solvent in the presence of an alkali metal carbonate, an alkali metal bicarbonate, an organic base etc. at 15-85°C to give a product of formula X,

in which A=B=COCH3 gives Xa, A=B=COC6H5 gives Xb, A-B-COOC2H5 gives Xc; A= COCH3, B= COOC2H5gives Xd; A= COCF3, B= COOC2H5 gives Xe; A= COC6H5, B= COOC2H5gives Xf.
The compounds of formula Xa to Xe can also be prepared by reacting the product of formula II with formula IX in an aprotic dipolar solvent using NaH as scavenging agent at 10-30°C. The compounds of formula Xa to Xe can also be prepared by yet another method in which the product of formulaIIIa/IIIb is reacted with the product of formula IX in an aprotic dipolar solvent at 10 to 30 °C.

In another embodiment of the present invention, there is provided a process for the preparation of products of formula I, wherein R is COOC2H5, SO2C6H4CH3(4), P(O)(OC2H5)2, by reacting the product of formulaIIIa/IIIb with ethyl chloroformate, p-toluene sulfonyl chloride and diethyl chlorophospidate respectively. These products of formula XIa to XIc,

can be prepared by reacting the product of formula II with the appropriate chlorinated reagents viz ethyl chloroformate, p-toluene sulfonyl chloride and diethyl chloro phosphidate in an aprotic dipolar solvent containing sodium hydride or alkali metal carbonate or alkali metal bicarbonate.
In yet another embodiment of the present invention, there is provided a process for the preparation of the product of formula I, where R =CH2CH2CN and CH2CH2COO C2H5 and designated as Xlla and XIIb?

by reacting the product of formula II with acrylonitrile and ethyl acrylate respectively in the presence of catalytic amount of alkali metal carbonate or alkali metal hydroxide in combination with tetra alkyl ammonium halide as PTC or using catalytic amound of tetra allyl ammonium hydroxide.
Accordingly, the present invention provides novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted-[l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of formula I, where R is described above and whose preparations are described above.

These compounds viz Ilia,IIIb, IVa to IVc, Vb, VIIa toVIIg, VIIla to Vlffl, Xa to Xf and XIa to Xlf and XIa to XIc are new and have not been reported earlier. These compounds, in general, have shown superior diuretic activity in comparison to a standard during viz hydrochlorothiazide and their activity is comparable to the product of formula I. Some of the these compounds have shown diuretic activity in rats as well as dogs proving its superiorityover the products of formula II
Description of the present invention :
The product of formula II viz 2,4-dihydro-6,8-dinitro-l-oxo- [l,2,4]-triazolo [3,4-c][l,4] benzoxazine was prepared as reported in IJC 1984, 23B, 1279. The preparation of 1-oxo-[l,2,4]-triazolo [3,4-c][l,4] benzoxazine, which is the precursor to the product of formula II, was prepared by a modified method. Earlier method used [l,4]-benzoxazin-3(4H)-thione, which was converted into the corresponding thiomethyl derivative and on further reaction with methyl carbazate yielded a carbazic acid derivative. This was cyclized thermally in N,N-dimethyl formamide or orthodichlorobenzene to give the required compound. The modified method is given in scheme-I

In this method [l,4]-benoxazin-3(4H)-one was reacted with POC13 and triethylamine in acetonitrile at a temperature of 0 to 25°C and then on reaction with methyl carbazate yielded the intermediate viz methyl-2-[[l,4]-benoxazin-3yl]carbazate. This product was preferably cyclized in an alkanol using an alkali metal carbonate, like K2CO3 or Na2CO3 or alkali metal hydroxide like KOH or NaOH. The product l-oxo-[l,2,4]-triazolo-[3,4-c][l,4] benzoxazine could be isolated on acidification to a pH of 2-3 . The nitration of this product could be carried out as reported in IJC 1984, 23B, 1279.

The product of formula IIIa/IHb could be prepared by first reaction of the product of formula II with NaH/KH in an aprotic dipolar solvent at 0-25°C and then precipitating the product by the addition of an anti solvent like diethyl ether or diisopropylether. The reaction was preferably carried out by the treatment of the product of formula II with a metal hydride in a N,N-diemethylformamide at 0 to 25°C and the diluting the reaction mixture with diethyl ether at 25°C. These products could also be prepared by the treatment the product of formula II with 1-1.5 equivalent of the alkali metal hydroxide in an alkanol at 60-80°C, concentrating the solution and finally precipitating the Na/K salt by the addition of an anti solvent like diethyl ether. The reaction is represented in scheme II

The products of formula IVa and IVb can be prepared by the reaction of the product of formulaIIIa/IIIb with dialkylsulphate or the corresponding alkyl halide preferably in an aprotic dipolar solvents like acetonitrile, diemethylformamide, N,N-dimethyl acetamide etc. at 25-75°C.
Another method of preparing the products of formula IVa and IV b was, reacting the product of formula II with NaH in an aprotic dipolar solvent at 0-10°C and then subsequently with the appropriate dialkylsulphate or alkyl halide
A third method of preparing these products was, to conduct the reaction of the product of formula II with dialkylsulphate or alkyl halide in an aprotic dipolar solvent using alkali metal carbonate as base at 25 to 75°C. The most preferable method was the third one. In a similar fashion products of formula IVc to IVe were also prepared.
The products of formula Va and Vb were prepared by the treatment of the product of formula II with aqueous formaldehyde solution in the presence of the appropriate alicyclic amine in an alkanol at 60-80°C. The preferred alkanols were methanol, ethanol, n-propanol, isopropanol etc. The products were obtained in very good yields.
Reaction of the product of formula II with aqueous formaldehyde in an alkanol at 60 to 80°C yielded 6,8-dinitro-[3,4-c][l,4] of formula VI, which on treatment with the

appropriate acid chloride in a solvent like dichloromethane, ethyl acetate, 1,2-dimethoxy ethane etc. in the presence of an organic base like triethylamine or diethyl isopropyl amine and 4-dimethyl pyridine as promoter preferably at 10 to 30°C gave the product of formula VIIa - VIIg in excellent yields.
In a similar way, reaction of the product of formula II with the appropriate acid chloride in solvent like dichloromethane, ethyl acetate, 1,2-dimethoxy ethane, acetone, acetonitrile, N,N-dimethyl formamide using triethylamine or diethyl isopropyl amine as base and 4-dimethylamino pyridine as a catalyst at 5 to 10°C yielded the products of formula VIIla to VIIIc.
Products of formula Xa to Xf were prepared by any of the three methods adopted for the preparation of the product of formula IVa to IVb. The results were almost similar. In terms of simplicity and economy, these products could be preferably prepared by the reaction of the product of formula II with the appropriate a halo 1,3-diketo compounds in an aprotic dipolar solvents consisting of acetonitrile, diemethylformamide, N,N-dimethyl acetamide etc. containing alkali metal carbonate at 25-75°C to give the targeted products viz Xa to Xf.
In an almost identical fashion reaction of the product of formula II, with ethylchloroformate gave the product formula XIa, with para toluene sulfonyl chloride gave the product of formula Xlb and with diethyl chloro phosphidate yielded the product of formula-XIc.
Reaction of the product of formula-II with acrylonitrile using catalytic amount of triton B, at 5 to 25°C yielded the product of formula Xlla and a similar reaction of the product of formula II with ethyl acrylate yielded the product of formula Xllb. These reactions could be carried out using catalytic amount of the alkali metal carbonate and alkali metal hydroxide in the presence of tetra alkyl ammonium halide or catalytic amount of 40% tetramethylammonium hydroxide in methanol.
BILOGICAL ACTIVITY
Majority of the compounds which Ilia,IIIb, IVa to IVc, Vb, VIIa toVIIg, VIIla to VIHi, Xa to Xf and XIa to Xlf and XIa to XIc, Xlla and Xllb are pharmacologically safe as their LD50 in rats and mice are >1.0gm. Most of these novel compounds have shown pronounced diuretic activity in rats in comparison to hydrochlorothiazide as standard. Many of the derivatives have shown superior activity in comparison to hydrochlorothiazide in the dose level of l-25mg/kg. The compounds which showed good activity in rats, were taken up for testing in dogs.

Only the compounds substituted at the 2nd position of the product of formula II with 1,3-diketo systems viz Xa to Xf showed excellent activity in dogs. These compounds showed superior diuretic activity in comparison to hydrochlorothiazide in dogs at dose level of 1-25mg/kg
CONCLUSION
A number of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted-[l,2,4]-triazolo [3,4-c][l,4]
benzoxazine derivatives have been synthesized.
These derivatives have shown excellent diuretic activity in rats and are superior to the
standard drug viz hydrochlorothiazide.
Some of these derivatives have shown excellent diuretic activity in dogs and are superior to
the standard drug viz hydrochlorothiazide.
The following examples are intended toIIIustrate the invention and not to be construed as being limitation thereof.
Example 1
A mixture of 2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine(II) (27.9gm, 0.1mole)and sodiumhydroxide (4.2gm5 95% purity) in methanol (150ml) was stirred under reflux for 3 to 4 hours. The reaction mixture was concentrated to a fifth of the original volume, diluted with diethyl ether (100ml) and stirred for 30minutes. The precipitated solid was filtered and washed with diethyl ether. The crude product was crystallized by dissolution in methanol and precipitation by the addition of diethyl ether. The product, Ilia, was obtained in 80% yield (24gms), mp >300°C
Example-2
A mixture of 2,4-dihydro-6?8-dinitro-l-oxo-[l,294]-triazolo[3,4-c][l,4] benzoxazine(II) (27.9gm, 0.1mole)and potassium hydroxide (6.6gm, 85% purity) in methanol (150ml) was stirred under reflux for 3 to 4 hours. The reaction mixture was concentrated to a fifth of the original volume, diluted with diethyl ether (100ml) and stirred for 30minutes. The precipitated solid was filtered and washed with diethyl ether. The crude product was crystallized by dissolution in methanol and precipitation by the addition of diethyl ether. The product,IIIb, was obtained in 80% yield (27gms), mp >300°C

Example-3
a) A mixture containing the product of formula II (2.79gm, 0.01 mole) and anhydrous potassium carbonate (1.5gm) in dimethyl formamide(10ml) was stirred at 25°C and dimethyl sulphate (2.0gm) was added dropwise. After the addition, the reaction mixture was stirred at 40-50°C for 2 hours. The rection mixture was cooled to 25°C, diluted with water (20ml), the precipitated solid was filtered and dried. The crude product was crystallized from isopropyl alcohol to give pure IVa, in 75% yield (2.2gm).
b) The preparation 2,4-dihydro-6,8-dinitro-2-methyl-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine IVa was also carried out using the product of formulaIIIb and dimethyl sulphate.
To a solution of the product of formulaIIIb (3.17gm) in dimethyl formamide (15ml)
was added dimethyl sulphate (2.0gm) at 25°C. After the addition, the reaction
mixture was stirred at 40-50°C for 2 hours. The reaction mixture was cooled to 25°C
and worked up as given in example 3a to give pure IVa in 70% yield (2.0gm)
The following derivatives were also prepared using the procedure given in example
3a.
2,4-Dihydro-6,8-dinitro-2-ethyl-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine, IVb,
yield = 72%,
2,4-Dihydro-6,8-dinitro- -l-oxo-2-n-propyl-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine,
IVc, yield = 68%,
2,4-Dihydro-6,8-dinitro-2-(l-methyl-ethyl)-l-oxo-[l,2,4]-triazolo[3,4-c][l,4]
benzoxazine, IVd, yield 70%
and
2-n-Butyl-2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine,
IVe, yield 65%. Example 4
To a mixture containing the product of formula II (2.79gm), formaldehyde (6ml, 37% aqueous solution) in methanol (60ml) was slowly added morpholine (1.79gm) at about 10°C under stirring. The reaction mixture was later stirred under reflux for 5-6 hours. Subsequently, the solution was cooled to about 0-5°C and stirred for 30minutes. The

crystallized product was filtered, washed with chilled methanol and dried. The product, Va viz 6,8-dinitro-2-(morpholinyl)-methyl-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine was obtained in 75% yield (2.9gm) Adopting a similar procedure, the compound of formula Vb was prepared in 78% yield.
Example 5
A mixture of 2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine (11.16gm, 0.04moles) and formaldehyde (40ml, 37% aqueous solution) in methanol (200ml) was stirred under reflux for 5-6 hours. The reaction was cooled to about 5°C and the crystallized product was filtered, washed and dried. The product, 6,8-dinitro-2-hydroxymethyl-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine, VI was obtained in 90% yield.
Example 6
A mixture of 2,4-dihydro-6,8-dinitro-2-hydroxymethyl-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine (3.09gm, O.Olmole) and triethylamine (1.2g) and 4-dimethylaminopyridine (0.18gm)in methylene dichloride was cooled to 0°C. To this mixture was added under stirring, a solution of acetyl chloride (0.9gm) in methylene dichloride at 0°C. After the addition, the reaction mixture was stirred at room temperature for l hour. The methylene dichloride solution was washed first with 5% aqueous NaHCO3 solution and then with water. Then the organic solution was concentrated and the residue was crystallized from methanol to give 2-acetyl oxy methyl-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine, VIIa, in 80% yield. (2.8gm)
Adopting the method given under example 6, the following compounds were also prepared. 2,4-Dihydro-6,8-dinitro-l-oxo-2-(propionyloxy)methyl-[l?2,4]-triazolo[3,4-c][l,4]
benzoxazine, VIIb. 2,4-Dihydro-2-benzyloxymethyl-6,8-dinitro-l-oxo-[l,2?4]-triazolo[3,4-c][l,4] benzoxazine
VIIc, 2,4-Dihydro-6,8-dinitro-l-oxo-2-(2-furanoyloxymethyl)-[l,2,4]-triazolo[3,4-c][l,4]
benzoxazine, VIId 2,4-Dihydro-6,8-dinitro-l-oxo-2-(2-thienoyloxymethyl)-[l,2,4]-triazolo[3,4-c][l,4]
benzoxazine, VIIe

6,8-Dinitro-l-oxo-2-[l-(3-methoxycarbonyl)propionyloxymethyl)]-[l,2,4]-triazolo[3,4-
c][l,4] benzoxazine,VIIf,
2-[l-[(benzyloxycarbonyl)propionyloxy]methyl]-2,4-dihydro-6,8-dinitro-l-oxo-[l?2,4]-
triazolo[3,4-c][l,4] benzoxazine VIIg
Example 7
A mixture of 2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine (II)
(2.79gm, O.Olmoles), triethylamine (1.6gm, 0.015 mole) and 4-dimethylaminopyridine
(O.lgm)in methylene dichloride (50ml) was cooled to about 0°C. To the stirred mixture,
acetyl chloride (1.1 gm) in methylene dichloride (10ml) was added maintaining the
temperature 0-5°C. After the addition, the reaction mixture was stirred at 0-5°C for
15minutes and at 25-30°C for 2 hours. The reaction mixture was first washed with 5%
aqueous NaHCO3 solution and then with water. The methylene dichloride solution was
concentrated and the crude product was crystallized from methanol to give pure 2-acetyl-6,8-
dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine Villa in 85% (2.7gm) yield.
The following derivatives were prepared as per the procedure described under example 7
2,4-Dihydro-6,8-dinitro-2-(2-furanoyl)-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine, VIIIb
2,4-Dihydro-6,8-dinitro-2-(2-thienoyl)-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine, VIIIc
2-Benzoyl-2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l?4] benzoxazine, VIIId
2,4-Dihydro-6,8-dinitro-2-(2-pyridinoyl)-l-oxo-[l,2,4]-triazolo[3,4-c][l?4] benzoxazine,
VIIIe
2,4-Dihydro-6,8-dinitro-2-(3-ethoxycarbonyl)-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine,
VIIIf
2-(3-Benzyloxycarbonyl)-propionyl-2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-
c][ 1,4] benzoxazine, VIIIg and
2-Chloroacetyl-2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine, VIIIh
Example 8
To a solution of 2-choroacetyl-2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine, (VIIIh, 3.55gm, O.Olmoles) in dimethyl formamide (15ml),was added potassium phthalide (2gm) at 10-15°C. The reaction mixture was stirred at this temperature for about an hour and later at 25-30°C for 3 to 4 horus. On completion of reaction, water( 100ml) was added and the reaction mixture was stirred for 30minutes. The precipitate was filtered, washed with water, dried and recrystallized from DMF containing 10% water to

give 2,4-dihydro-6,8-dinitro-2-(phthalimidyl)-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine, VIIIi in80%yield(3.7gm)
Example 9
A mixture of 2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine II (2.79gm, 0.01mole)and anhydrous potassium carbonate (2.76gm, 0.02mole) in dimethyl formamide (15ml) was kept stirred at about 25°C and a solution of ethyl-2-chloro acetoacetate (2.0gm, 0.012mole) in DMF (5ml) was added dropwise. Later the reaction mixture was stirred at 50-60°C for about 3-4 hours. On completion of reaction (TLC), dimethyl formamide was distilled off under reduced pressure; the residue treated with water and the pH of the solution was adjusted to about 7 using acetic acid. The aqueous layer was extracted with ethylacetate (3 x 25ml). The organic extract was washed with water and concentrated. The residue, thus obtained, was crystallized from isopropyl alcohol to give ethyl-2-[(2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine)-2-yl]-3-oxo-butanoate, Xd in 75% (3.0gm) yield
The following compounds have also been prepared adopting the procedure described in example 8
3-[(2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4]benzoxazine)-2-yl]-2,4-pentanedione, Xa
l,3-Diphenyl-2-[(2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4]benzoxazine)-2-yl]-l,3-propanedione Xb
Diethyl-2-[(2,4-dihydro-6,8-dinitro-l-oxo-[l52,4]-triazolo[3?4-c][l,4]benzoxazine)-2-yl]-propane- 1,3-dioate Xc
Ethyl-2- [(2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine)-2-yl]-3-oxo-3-phenyl propionate Xf
Example 10
a) To a solution of potassium salt of 2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine (IIIb, 3.17gm, 0.01 mole) was added ethyl chloroformate (l.lgm, 0,01 mole) under stirring at 0-5°C. After the addition, the reaction mixture was stirred at 25-30°C for about 2-3 hours. Subsequently dimethyl formamide was distilled off under reduced pressure, the residue diluted with water and the product extracted with ethyl acetate. Ethyl acetate extract was washed with water and concentrated. The

crude product was crystallized from methanol to give 6,8-dinitro-2-ethoxy carbonyl-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine, XIa, in 77% (2.7gm) yield.
b) A suspension of NaH (4.6gm, 0.01 mole 50% suspension in paraffin) in dimethyl formamide (10ml) was cooled to about 5°C under nitrogen atmosphere and the compound II (2.79gm, 0.01 mole) was added slowly. After the addition, the solution was allowed to come to room temperature to allow all the hydrogen to escape. Then the solution was cooled to 5°C and treated with ethyl chloroformate (l.lgm, 0.01 mole). Later the reaction mixture was stirred at 25-30°C for 2 hours and worked up as given under example 9a to give product XIa in 72% yield.
c) A suspension of the product of formula II (2.79gm, 0.01 mole) in methylene dichloride containing triethylamine (1.2gm) and catalytic amount of 4-dimethylamino pyridine (0.2gm) was cooled to 0-5°C. To this reaction mixture a solution of ethyl chloroformate (l.lgm, 0.0lmole) in methylene dichloride (5ml) was added at 0-5°C. After the addition, the reaction mixture was stirred at 25-30°C for 3-4 hours. On completion, methylene dichloride solution was washed first with 5% aqueous sodium bicarbonate solution and then with water. Then methylene dichloride was distilled off and the crude product was crystallized from methanol to give pure XIa in 73% yield. Adopting any of the procedure given under example 9, the following two compounds were also prepared.
2,4-Dihydro-6,8-dinitro-2-(4-methyl phenyl sulofonyl)-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine, Xlb
Diethyl-[2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine]-2-yl-phosphate XIc
Example 11
To a suspension of 2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine (II, 2.79gm, O.Olmole) in ethyl acrylamide (25ml) at 0-5°C, triton B (40% methanolic solution, 0.5ml) was added. The reaction mixture was stirred at 5°C for about 6 hours and then at 25°C for 10-12 hours. Then excess ethyl acrylate was distilled off under reduced pressure and the residue was crystallized from methanol to give 2,4-dihydro-6,8-dinitro-2(2-cyanoether)-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine XIIa in 70% (2.4gm) yield.
When the reaction was repeated using ethyl acrylate instead of acrylonitrile, as given above, 2-(2-cyanoethyl)- 2,4-dihydro-6,8-dinitro-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine,
XIIb was obtained.

We Claim:
1. Novel 2,4-dihydro-6,8-dinitro-2-substituted-l-oxo-[l,2,4]-triazolo[3,4-c][l,4] benzoxazine derivatives of general formula I

wherein R is Na, K,l-4-alkyl or CH2-X where X is morpholine, piperidinyl or CH2OCOY where Y is CH3 , C2H5, C6H5, 2-furanyl, 2-thienyl, (CH2)2COOCH3, (CH2)2COOCH2 C6H5, or -COZ, where Z is 2-furanyl, 2-thienyl, phenyl, methyl, 2-pyridinyl (CH2)2COOC2H5, (CH2)2CON(C2H5)2, (CH2)2COOCH2C6H5, CH2C1, CH2-phthalimidyl, or or

where A=B=COCH3, A-B= COOC2H5, A=B= COC6H5, A= COCH3, B= COOC2H5, A= COCF3? B- COOC2H5, A= COC6H5, B= COOC2H5 and W - halogen, or COOC2H5, SO2C6H4CH3(4), P(O)(OC2H5)2, CH2CN, (CH2)2COOC2H5, possessing excellent diuretic activity (superior to standard drug like hydrochlorothiazide)
2. Novel compound of formula I, as claimed in claim 1, wherein R is Na and is represented by formula IIIa
3. Novel compound of formula I, as claimed in claim 1, wherein R is K and is represented by formula IIIb
4. Novel compound of formula I, as claimed in claim 1, wherein R is CH3 and is represented by formula IVa
5. Novel compound of formula I5 as claimed in claim 1, wherein R is C2H5 and is represented by formula IVb
6. Novel compound of formula I, as claimed in claim 1, wherein R is n-C3H7 and is represented by formula IVc
7. Novel compound of formula I, as claimed in claim 1, wherein R is 'C3H7 and is represented by formula IVd

8. Novel compound of formula I, as claimed in claim 1, wherein R is n-C4H9 and is represented by formula IVe
9. Novel compound of formula I, as claimed in claim 1, wherein R is CH2-morpholinyl and is represented by formula Va

10. Novel compound of formula I, as claimed in claim 1, wherein R is CH2-piperidinyl and is represented by formula Vb

11. Novel compound of formula I, as claimed in claim 1, wherein R is CH2OCOCH3 and is represented by formula VIIa
12. Novel compound of formula I, as claimed in claim 1, wherein R is CH2OCOOC2H5 and is represented by formula VIIb
13. Novel compound of formula I, as claimed in claim 1, wherein R is CH2OCOC6H5 and is represented by formula VIIc
14. Novel compound of formula I, as claimed in claim 1, wherein R is CH2OCO2- furanyl and is represented by formula VIId
15. Novel compound of formula I, as claimed in claim 1, wherein R is CH2OCO-2-thienyl and is represented by formula VIIe
16. Novel compound of formula I, as claimed in claim 1, wherein R is CH2OCO(CH2)2COOCH3-thienyl and is represented by formula VIIf
17. Novel compound of formula I, as claimed in claim 1, wherein R is CH2OCO(CH2)2COOCH2C6H5 and is represented by formula VIIg
18. Novel compound of formula I, as claimed in claim 1, wherein R is COCH3 and is represented by formula VIIla
19. Novel compound of formula I, as claimed in claim 1, wherein R is CO-2-furanyl and is represented by formula VIIIb

20. Novel compound of formula I, as claimed in claim 1, wherein R is CO-2-thienyl and is represented by formula VIIIc
21. Novel compound of formula I, as claimed in claim 1, wherein R is COC6H5 and is represented by formula VIIId
22. Novel compound of formula I, as claimed in claim 1, wherein R is CO-2-pyridinyl and is represented by formula VIIIe
23. Novel compound of formula I, as claimed in claim 1, wherein R is CO(CH2)2COOC2H5 and is represented by formula VIIIf
24. Novel compound of formula I, as claimed in claim 1, where R is CO(CH2)2COOCH2C6H5
and is represented by formula VIIIg
25. Novel compound of formula I, as claimed in claim 1, wherein R is COCH2CI and is represented by formula VIIIh
26. Novel compound of formula I, as claimed in claim 1, wherein R is COCH2- phthalimidyl
and is represented by formula VIIIi

27. Novel compound of formula I, as claimed in claim 1, wherein R is CH(COCH3)2 and is represented by formula X a

28. Novel compound of formula I, as claimed in claim 1, wherein R is CH(COC6H5)2 and is represented by formula X b


29. Novel compound of formula I, as claimed in claim 1, wherein R is CH(COC2Hs)2 and is represented by formula X c

30. Novel compound of formula I, as claimed in claim 1, wherein R is CH(COCH3)COOC2H5 and is represented by formula X d

31. Novel compound of formula I, as claimed in claim 1, wherein R is CH(COCF3)COOC2H5 and is represented by formula X e

32. Novel compound of formula I, as claimed in claim 1, wherein R is CH(COC6H5)COOC2H5 and is represented by formula X f


33. Novel compound of formula I, as claimed in claim 1, wherein R is COOC2H5 and is represented by formula XI a

34. Novel compound of formula I, as claimed in claim 1, wherein R is SO2C6H4CH3(4) and is represented by formula Xlb

35. Novel compound of formula I? as claimed in claim 1, wherein R is P(O)(OC2H5)2 and is represented by formula XIc

36. Novel compound of formula I, as claimed in claim 1, wherein R is (CH2)2CN and is represented by formula XIIa


37. Novel compound of formula I, as claimed in claim 1, wherein R is (CH2)2COOC2H5 and is represented by formula Xllb

38. A process for the preparation of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazines of claim 1 to 3 by,
a) reacting the product of formula II with alkali metal hydroxide in an alkanol at a suitable temperature or by reacting the product of formula II with alkali metal hydride in a aprotic dipolar solvent

b) diluting with an anti-solvent
c) purifying

39. A process, as claimed in claim 38a, wherein the alkali metal hydroxides are NaOH and KOH, alkanol is methanol and temperature is at reflux or where the alkali metal hydride is NaH and KH in dimethyl formamide
40. A process, as claimed in claim 38b, wherein the anti solvent is selected from the group of diethyl ether, diisopropyl ether, tetrahydrofuran and 1,4-dioxane
41. A process, as claimed in claim 38c, wherein, the purification of compounds Illa/IIIb is carried out by

a) dissolving in methanol in 1:2 volume
b) precipitating by adding 5 to 10 volumes of diethyl ether

42. A process for the preparation of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazines derivatives of claim 1 and claims 4 to 8, by reacting the product of formula II with dialkyl sulphate / alkyl halide in an aprotic dipolar solvent at a suitable temperature in the presence of alkali metal carbonate
43. A process as claimed in claim 42, wherein dialkyl sulphates are dimethyl sulphate and diethyl sulphate, alkyl halides are methyl iodide, ethyl bromide, ethyl iodide, n-propyl bromide, n-propyl iodide, i-propyl bromide, i-propyl iodide, n-butyl bromide, n-butyl iodide,
44. A process for the preparation of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazines derivatives of claim 1 and claims 9 to 10, by reacting the product of formula II with formaldehyde and a secondary amine in an alkanol at a suitable temperature
45. A process as claimed in claim 44, wherein the formaldehyde is aqueous 33-37% w/v solution, secondary amines are morpholine, piperidine, alkanol is methanol and temperature is at reflux
46. A process for the preparation of novel 2,4-dihydro-6,8-dinitro~l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of claim 1 and claims 11 to 17, by
a) reacting the product of formula II with formaldehyde in an alkanol containing a catalyst at a suitable temperature to give a product of formula VI

b) treating the product of formula VI with a suitable acid chloride in a non-polar solvent in the presence of an organic base and a promoter at a suitable temperature
47. A process, as claimed in claim 46a, wherein the product of formula II is reacted with aqueous formaldehyde solution (33-37% w/v) in methanol containing an alkali metal carbonate or trialkyl amine as catalyst at 40 to 65°C to give the product of formula VI
48. A process, as claimed in claim 46b, wherein the product of formula VI is reacted with acylchloride like acetylchloride, 2-furanoyl chloride, 2-thienoyl chloride, benzoyl chloride, 2-pyridinoyl chloride, 3-(methoxycarbonyl)-propionyl chloride and 3- (benzyloxycarbonyl)-propionyl chloride in solvents like methylene dichloride and

ethyl acetate containing triethylamine as base and 4-dimethylaminopyridine as promoter at 10 to 30°C
49. A process for the preparation of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of claim 1 and claims 18 to 25, by reacting the product of formula II with an acid chlorides in non-polar solvents or aprotic dipolar solvents containing an organic base in the presence of a promoter at a suitable temperature
50. A process, as claimed in claim 49, where the acidchlorides are acetylchloride, 2- furanoyl chloride, 2-thienoyl chloride, benzoylchloride, 2-pyridinoyl chloride, 3- (ethoxy carbonyl)-propionyl chloride 3-(benzyloxycarbonyl)-propionyl chloride and monochloro acetyl chloride in solvents like methylene dichloride, ethyl acetate, acetone, acetonitrile and dimethyl formamide containing triethyl amine and a promoter like 4-dimethylamino pyridine at 5 to 35°C
51. A process for the preparation of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of claims 1 and 26, by reacting the product of formula VIII h

with potassium phthalimide in solvents like acetone, acetonitrile, dimethylforamamide etc at 25 to 50°C
52. A process for the preparation of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of claim 1 and claims 27 to 32, by reacting the product of formula II with α-halo diketo compounds of formula IX,

where W is chloro or bromo and A=B=COCH3, A=B= COOC2H5, A=B- COC6H5, A= COCH3, B= COOC2H5, A= COCF3, B= COOC2H5, A= COC6H5, B= COOC2H5 in an aprotic dipolar solvent in the presence of a base at suitable temperature
53. A process, as claimed in claim 52, wherein the a-halo diketo derivatives are 3-chloro- 2,4-pantane dione, 2-chloro-l,3-diphenyl-1,3-propane dione, diethyl-2-bromo-l,3- propane dioate, ethyl-2-chloro-3-oxo butanoate, ethyl-2-chloro-3-oxo-4,4,4-

trifluorobutanoate and ethyl-2-chloro-3-oxo-3-phenyl propionate in solvents like N,N-dimethyl formamide, N,N-dimethyl acetamide and N-methyl pyrrolidone containing anhydrous potassium carbonate as base at 25 to 50°C
54. A process for the preparation of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of claim 1 and claims 27 to 32, by reacting the product of formula III a/IIIb with a-halo diketo compounds of formula IX, in an aprotic dipolar solvents consisting of N,N-dimethyl formamide N,N- dimethyl acetamide and N-methyl pyrrolidone at 25-50°C
55. A process for the preparation of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of claim 1 and claim 33 by reacting the product of formula II with ethyl chloro acetate in solvents consisting of N,N-dimethyl formamide, N,N-dimethyl acetamide and N-methyl pyrrolidone containing anhydrous potassium carbonate as base at 25 to 50°C
56. A process for the preparation of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of claims 1 and claim 34 by reacting the product of formula II with 4-methyl phenyl sulfonyl chloride in solvents consisting of N,N-dimethyl formamide, N,N-dimethyl acetamide and N-methyl pyrrolidone containing anhydrous potassium carbonate as base at 25 to 50°C
57. A process for the preparation of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of claims 1 and 35 by reacting the product of formula II with chloro diethyl phosphidate in solvents consisting of N,N-dimethyl formamide, N,N-dimethyl acetamide and N-methyl pyrrolidone containing anhydrous potassium carbonate as base at 25 to 50°C
58. A process for the preparation of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of claims 1 and 36 by reacting the product of formula II with acrylonitrile in the presence of a catalyst consisting of potassium carbonate, tetramethylammonium hydroxide and KOH at 0°C to 30°C for 8 to 16 hours
59. A process for the preparation of novel 2,4-dihydro-6,8-dinitro-l-oxo-2-substituted- [l,2,4]-triazolo [3,4-c][l,4] benzoxazine derivatives of claims 1 and 37 by reacting the product of formula II with ethyl acrylate in the presence of a catalyst consisting of potassium carbonate, tetramethylammonium hydroxide and KOH.