Benzofuroxan derivatives, their therapeutic uses and pharmaceutical compositions

The invention discloses use of a compound of the benzofuroxan series for treatment of cardiovascular disorders represented by the general formula (I) ##STR1## and pharmaceutically acceptable salts thereof wherein: PA1 R is halogen, acetoxy, --X--R', --C(O)NR"R'", or --C(O)Cl; PA2 X is oxygen, sulfur, --C(O)--, or --C(O)O--; PA2 R' is hydrogen, straight chain or branched lower alkyl (C.sub.1 -C.sub.8); PA2 R" and R'" are independently hydrogen, straight chain or branched lower alkyl (C.sub.1 -C.sub.8) or R" and R'" are linked together with or without a heteroatom selected from the group consisting of oxygen and nitrogen wherein substitution on nitrogen is with hydrogen or lower alkyl. The invention further discloses pharmaceutical compositions containing compounds of general formula I as active ingredients. The invention also discloses a method of treatment of mammal, including man, of coronary heart disease by administration of an effective amount of a compound of formula I as defined above.

BACKGROUND OF THE INVENTION
 1. Field of the Invention
 This invention relates to the use of the compounds of benzofuroxan series
 in therapeutics. In particular the invention concerns pharmaceutical
 compositions containing benzofuroxan derivatives as active ingredients and
 their use as tolerance resistant nitric oxide donors in treatment of
 angina pectoris.
 2. Description of the Prior Art
 After the discovery of endothelium-derived relaxing factor (EDRF) by
 Furchgott et al (1980), and the elucidation of the biochemistry of EDRF by
 a number of laboratories (Ignarro, 1989; Vane et al, 1990, Bassenge et al,
 1988; and Vanhoutte, 1989) it is now widely accepted that EDRF is the
 endogenous nitrovasodilator, nitric oxide (NO) donor. The organic nitrates
 and related compounds owe their pharmacological action to the release of
 nitric oxide (NO) and these compounds are collectively called
 nitrovasodilators. NO stimulates the guanylate cyclase enzyme in vascular
 smooth muscle cells resulting in increased levels of cyclic GMP. This
 leads to dephosphorylation of myosin light chain which results in
 relaxation of smooth muscles (Murad 1986). NO is known to be involved in a
 number of bio-regulatory processes like, vasodilatation, platelet
 deaggregation, vascular smooth muscle proliferation, etc.
 Organic nitrates are used in prophylaxis, treatment and management of
 patients with angina pectoris. These are also useful in congestive heart
 failure associated with acute myocardial infarction, hypertension
 associated with surgical procedures and to produce controlled hypotension
 during surgical procedures. Among organic nitrates, nitroglycerine
 (sublingual) which is currently in use, is the drug of choice for
 immediate relief of anginal symptoms. Prophylactic treatment of stable
 angina pectoris involves the use of one or more drugs such as long acting
 nitrates like isosorbide dinitrate, a beta-blocker and/or a calcium
 channel antagonist, particularly in patients likely to experience coronary
 spasm. In some cases this triple therapy satisfactorily control angina.
 They are quite effective in the treatment of these conditions when used
 intermittently.
 Frequently repeated use of nitrates result in decrease in their
 pharmacological effects, a phenomenon well recognized as nitrate
 tolerance. The mechanism of tolerance is not well defined As early as
 1973, Needleman and Johnson (1973) have reported that tolerance to
 nitroglycerine could occur in isolated rabbit arteries. It was
 hypothesized by them that depletion of sulphydryl groups was associated
 with the development of tolerance to nitroglycerine. This is a major
 problem in the clinical use of organic nitrates (Frampton et al, 1992).
 Currently, the development of tolerance is reduced by the use of
 intermittent dosing schedule with a nitrate-free interval of 10-12 hrs.
 However, this intermittent use is associated with decreased exercise
 tolerance during the last part of nitrate-free interval. This suggests
 possibility of increased frequency of or severity of angina during
 nitrate-free interval. The importance of development of tolerance has
 increased as these drugs are used more commonly in various dosage forms
 like oral, transdermal, and intravenous preparations and even as
 sustained-release preparations. Several indirect indices like exercise
 duration, systemic blood pressure, pulmonary artery pressures and
 pulmonary artery wedge pressure has been used to assess tolerance to
 organic nitrates. However, it is not clear whether decreased response to
 nitrates is due to tolerance of the vascular smooth muscle cells or
 changes in regulatory factors like activation of neurohumoral factors or
 fluid retention etc. (Armstrong and Moffat, 1983). Irrespective of the
 mechanisms of tolerance development, clinically it is important to develop
 nitric oxide donors with least tendency to develop tolerance.
 This problem of "tolerance" is still confronting the physicians as is be
 evident from
 (a) The Merck Manual of diagnosis and therapy (16th Edition 1992), pages
 498-505,
 (b) MARTINDALE, The Extra Pharmacopoea (30th Edition) 1993, pages
 1019-1021,
 (c) The Essential Guide to Prescription Drugs 1994 edited by James W Long
 and James J Rybacki, pages 42-46, (d) Harrison's Principles of Internal
 Medicine (13th Edition 1944) page 1077-1084 and (e) Goodman and Gilman's,
 The Pharmacological Basis of Therapeutics (9th edition, 1996) pages
 759-767.
 P B Ghosh et al. (Journal of Medicinal Chemistry, 1968) disclosed the
 method of synthesis of various benzo-2,1,3-oxadiazoles (benzofurazans) and
 their N-oxides (benzofuroxans) and their potential as antileukemic and
 immuno-suppressive drugs in vitro.
 P B Ghosh et al. (Journal of Medicinal Chemistry, 1972) tested 4-nitro
 benzofurazans and 4-nitrobenzofuroxans bearing electron withdrawing
 substitutents in the 5 and 6 position (relative to NO.sub.2) as potential
 antileukemic and immuno suppressive drugs in vitro.
 P B Ghosh et al (Journal of Medicinal Chemistry, 1974) tested benzofuroxan
 and its derivatives for their vasodilation activities and found
 flurazanobenzofuroxan, furazobenzothiadiazole and their N-oxides as potent
 vasodilators.
 Nishikawa et al. (The Journal of Pharmacology and Experimental
 Therapeutics, 1982) disclosed effect of
 N-ethoxycarbonyl-3-morpholinosydnonimine and its metabolites
 3-morpholinosydnonimine, cyanomethyleneamino morpholine,
 N-nitroso-N-morpholinoamino acetonitrile as novel antianginal agent.
 F. Murad (J. Clin. Invest, 1986) disclosed cyclic guanosine monophosphate
 as a mediator of vasodilation.
 James Frampton et al. (Drug Evaluation, Adis International Limited, 1992)
 gives a review of pharmacology and therapeutic efficiency of nicorandil in
 angina pectoris. Nicorandil, which has both vasodilator and venodilating
 properties was found to offer an effective alternative to established
 vasodilator therapy with conventional nitrates and calcium antagonists in
 the long term treatment of stable angina pectoris.
 U.S. Pat. No. 5,272,164 disclosed novel carboximidamide derivatives
 particularly N-cyano-N.sup.1 -substituted pyridine carboximidamide
 derivatives having vasodilating effect and hypotensive effect besides
 other physiological effects which are helpful in treatment of ischemic
 heart diseases.
 U.S. Pat. No. 5,424,326 disclosed phenyl-1,2,5-oxadiazole
 carboxamide-2-oxide and its derivatives, which are useful for the
 treatment of disorders of the cardiovascular system.
 EP-A-0 574726 disclosed fused 1,2,5-ozadiazole-2-oxides i.e. furoxan
 derivatives their preparation and use as pharmaceutically active compounds
 including pharmaceutical compositions for treatment of angina pectoris.
 F Benedini et. al. (J. Med. Chem. 1995) disclosed a new nitro
 ester-3-[(nitroxy)alkyl]-2H-1,3-benzoxazin-4(3H)-ones showing marked
 inhibitory activity against ischemia-induced electrocardiographic changes,
 with only limited systemic hemodynamic effects. These new nitro ester
 derivatives, endowed with marked anti-anginal activity, which is not
 associated with concurrent and pronounced fall in systemic blood pressure,
 are indicative of a new class of selective nitrovasodilators having a
 preferential action on large coronary vessels, which could be clinically
 relevant in the treatment of coronary artery diseases.
 However, none of the above prior art disclosures on the drugs specifically
 used as vasodilator for treatment of cardiac ailments tackles the problem
 associated with the conventional NO-donors to develop tolerance in the
 patient after continuous use for a period of time. The present invention
 evaluates the benzofuroxan derivatives for their NO donor activities
 particularly with reference to their tendency to develop tolerance for
 continued application of the drug. Significantly, the invention identifies
 the molecules showing vasodilator activity without tendency to develop
 tolerance unlike the conventional nitric-oxide donors.
 SUMMARY OF THE INVENTION
 The present invention provides, in the first aspect, benzofuroxan
 derivatives and pharmaceutically acceptable salts thereof, for their use
 in cardiovascular disorders like coronary heart diseases.
 Such salts include, but are not limited to, oxalate, tartarate, maleate,
 methyl sulphonate, p-toluene sulphonate, etc.
 The invention farther provides pharmaceutical formulations comprising
 benzofuroxan derivatives to be used for treatment of cardiac disorders.
 The invention also provides for a method of treatment of mammals including
 human being of coronary heart diseases by administration of a compound of
 benzofuroxan series.

DETAILED DESCRIPTION OF THE INVENTION
 The compounds of the benzofuroxan series used for cardiovascular disorders
 are represented by the general formula (I).
 ##STR2##
 and pharmaceutically acceptable salts thereof wherein:
 R is halogen, acetoxy, --X--R', --C(O)NR"R'", or --C(O)Cl;
 X is oxygen, sulfur, --C(O)--, or --C(O)O--;
 R' is hydrogen, straight chain or branched lower alkyl (C.sub.1 -C.sub.8);
 R' and R'" are independently hydrogen, straight chain or branched lower
 alkyl (C.sub.1 -C.sub.8) or R" and R'" are linked together with or without
 a heteroatom selected from the group consisting of oxygen and nitrogen
 wherein substitution on nitrogen is with hydrogen or lower alkyl.
 the representative compounds of the invention showing tolerance resistant
 NO defined above are given in the Table-1.
 TABLE 1
 Compound
 No. R
 1 --Cl
 2 --S--CH.sub.2 CH.sub.2 CH.sub.3
 3 --COOH
 4 --SCH.sub.3
 5 --OC(O)--CH.sub.3
 6 --COCl
 7 --CHO
 8 --COOCH.sub.3
 9 --OH.HCl
 10 --CONH.sub.2
 11 --COOC.sub.2 H.sub.5
 12 --COOCH.sub.2 --CH.sub.2 --CH.sub.3
 13 --COOCH(CH.sub.3).sub.2
 14 --COO.sup.t Bu
 15 --CON(CH.sub.3).sub.2
 16 substitution (a)
 17 substitution (b)
 18 --CONHCH(CH.sub.3).sub.2
 19 --CONH.sup.t Bu

##STR3##
 The alkoxy carbonyl benzofuroxan derivatives of the general formula (I),
 and their pharmaceutically acceptable salts can be prepared by a process
 which comprises,
 (a) reacting chlorocarbonyl benzofuroxan and an alcohol in solvent such as
 tetrahydrofuran at room temperature;
 (b) adding a base such as triethylamine to the reaction mixture;
 (c) refluxing the reaction mixture till the completion of the reaction;
 (d) removal of the solvent followed by addition of water and extraction
 with organic solvent such as ethyl acetate;
 (e) concentration of ethyl acetate layer;
 (f) purification by column chromatography, and
 (g) optionally transforming into the corresponding pharmaceutically
 acceptable salts.
 Said products of steps (f) and (g) are characterized by m.p. and the
 conventional spectroscopic techniques.
 The alkoxy carbonyl benzofuroxan derivatives of the general formula (I),
 and their pharmaceutically acceptable salts can also be prepared by a
 process which comprises,
 (a) reacting carboxy benzofuroxan with saturated solution of alcoholic HCl;
 (b) removal of excess of alcohol under reduced pressure to get the residue;
 (c) washing the residue with 0.2 N aq. NaOH solution, extracting with
 solvent such as ether and concentration of the ether layer,
 (d) purification by column chromatography, and
 (e) optionally transforming into the corresponding pharmaceutically
 acceptable salts.
 Said products of steps (d) and (e) are characterized by m.p. and the
 conventional spectroscopic techniques.
 The 5(6)-alkyl mercapto benzofuroxan derivatives of the general formula I,
 and their pharmaceutically acceptable salts can be prepared by a process
 which comprises,
 (a) reacting 2-nitro-4-alkylmercapto aniline with concentrated hydrochloric
 acid and sodium nitrite,
 (b) reacting the reaction product of step (a) with sodium azide to obtain
 2-nitro-4-alkylmercapto phenyl azide,
 (c) thermal cyclization of 2-nitro-4-alkylmercapto phenyl azide in a
 solvent, such as toluene, benzene, or xylene to produce 5(6)-alkylmercapto
 benzofuroxan,
 (d) purification by column chromatography, and
 (e) optionally transforming into the corresponding pharmaceutically
 acceptable salts.
 Said products of steps (d) and (e) are characterized by m.p. and the
 conventional spectroscopic techniques.
 The alkoxy carbonyl benzofuroxan derivatives of general formula I can be
 further prepared by a process which comprises,
 (a) reacting carboxy benzofuroxan and an equimolar amount of an alcohol
 such as methanol, ethanol, isopropanol, tertiary butanol, etc. in
 methylene chloride,
 (b) adding 4-dimethylamino pyridine and N,N'-dicyclohexyl carbodiimide
 under stirring and continuing the stirring for a period of 2 to 16 hours
 at room temperature, to complete the reaction,
 (c) filtering the reaction mixture when the filtrate on evaporation under
 reduced pressure gives the crude product,
 (d) the product thus obtained is purified by column chromatography, and
 (e) optionally transforming into the corresponding pharmaceutically
 acceptable salts.
 Said products of steps (d) and (e) are characterised by m.p. and the
 conventional spectroscopic techniques.
 Pharmaceutical Compositions for NO-donor Molecules
 The compounds according to this invention as given by general formula (I)
 or their salts or complexes can be administered orally, intravenously or
 parenterally as a pharmaceutical preparation in liquid or solid form. It
 may also be administered via topical, transdermal, sublingual, buccal or
 rectal route for example as a suppository, ointment, cream, powder,
 transdermal patch, metered aerosol or spray.
 The pharmaceutically acceptable carriers present in the composition of this
 invention are materials recommended for the purpose of administering the
 medicament. These may be liquid or solid materials, which are otherwise
 inert or medically acceptable and are compatible with the active
 ingredients.
 Evaluation of the Biological Activity
 Methods
 a) In Vitro Screening of NO Donors
 The method adopted was a modified method of Nishikawa et al (1982). Albino
 rabbits of either sex were stunned and exsanguinated. Thoracic aorta was
 quickly removed and cut helically (at an angle of 45.degree.) into strips
 4-5 mm wide and 25 to 30 mm long, after removal of adventitial connective
 tissue. The endothelium was rubbed off gently using a cotton swab soaked
 in Kreb's solution. Two strips were fixed vertically in organ baths
 containing 20 ml. Kreb's solution maintained at 37.degree. C. and bubbled
 with oxygen. A resting tension of 4 g was applied and the preparation was
 allowed to equilibrate for 30 min. Each preparation was exposed to two
 primer doses of KCl (30 mM). After the contraction reached a maximum, the
 bath was drained off and replaced with fresh Kreb's solution. Half an hour
 later, cumulative dose response curve for the test compound was taken on
 one tissue (test) and for glyceryl trinitrate (GTN) in the other
 (standard). The dose range used was from 10.sup.-9 M to 10.sup.-3 M with a
 contact period of 4 min. for each dose. After the maximum relaxation was
 achieved with the last dose, papaverine (10.sup.-4 M) was added to obtain
 the maximum relaxation.
 Tolerance was induced in both the tissues by adding 440 .mu.M of GTN for 90
 minutes. During this period the bath solution was changed every 30 min.
 and 440 .mu.M of GTN was replaced. Later both the tissues were washed
 thoroughly and the dose response curve (DRC) for both the test compound
 and the standard were repeated. The percentage relaxation with individual
 doses was calculated by taking the maximum relaxations to 10.sup.-4 M
 papaverine as 100% relaxation. A graph was plotted by taking the
 percentage relaxation vs the log (M) concentration of the compounds. The
 relaxant activity of the test compound was assessed by calculating the
 mean relative potencies (MRP) and the mean activity ratio (MAR), both
 before and after tolerance, as defined below:
 ##EQU1##
 Selection criteria for in vivo study: Compounds having MRP greater than 3
 and MAR greater than 1.3 after tolerance were selected for in vivo study.
 Dose response curve for compound 8 is given in FIGS. 1 and 2 of the
 accompanying drawings as an example for the estimation of MRP and MAR.
 b) In Vivo Pharmacological Screening
 A modified method of Benedini et al (1995) was adopted for studying the
 anti-anginal effect of the chosen compounds. Guinea pigs of either sex,
 weighing approximately 400-600 g were used for this study. Animals were
 anesthetized with urethane (1.25 g/kg, i.p.) and jugular vein was
 cannulated for intravenous administration of drugs/vehicle. Mean arterial
 blood pressure (MABP) was monitored by a cannula inserted into the right
 carotid artery and connected to a pressure transducer. Standard limb lead
 II electrocardiogram was recorded continuously. All the recordings were
 carried out on a MacLab system (AD Instruments, UK).
 The ability of the test compounds to suppress the vasopressin induced
 T-wave elevation was used as the model for studying the anti-anginal
 effects of the compounds. Guinea pigs were divided into two groups for the
 purpose of this study, i) control group (pretreated with the vehicle for
 the compound) and ii) drug treated group.
 i) Control Group
 In this group of animals the solvent used for dissolving the test compound
 was administered intravenously in a volume of 1 ml/kg. The basal T-wave
 heights, heart rates and MABP and changes after vehicle administration
 were noted. Thirty seconds later 1 I.U./ml/kg of vasopressin was
 administered intravenously. The T-wave heights, heart rates and MABP and
 their changes after vasopressin administration were also noted. The T-wave
 elevation (after vasopressin administration), maximum rise in MABP, and
 changes in heart rate were calculated from the above data and expressed as
 mean.+-.standard deviation.
 ii) Drug Treated Group
 The effects of the test compound in suppressing the T-wave elevation caused
 by vasopressin were evaluated with atleast three dose levels. Groups of 6
 guinea pigs were used for each dose. The test compound was injected 30
 seconds prior to vasopressin administration. Changes in MABP, heart rate
 and T-waves were recorded as described for the control group. The
 percentage inhibition of vasopressin induced T-wave elevation was
 calculated for each dose taking the T-wave height estimated in control
 group as 100%. From the dose vs percent inhibition relationship, the dose
 required for 50% inhibition (ED.sub.50) for the T-wave elevation was
 estimated.
 Determination of the ED.sub.20 Values for Drop in MABP
 In a separate group of animals the drop in MABP after administration of the
 test compound (dose range of 0.1-1000 .mu.g/kg, i.v.) was studied. Atleast
 three animals were used for each dose. Care was taken so that the doses
 were given only after the MABP had stabilized from the effects of the
 previous dose. All doses were injected in a final volume of 1 ml/kg. The
 drop in MABP was noted for increasing concentrations of the test compound
 and a dose response curve was drawn. From this graph the dose required to
 produce a 20% fall in MABP (ED.sub.20) was calculated. The specificity of
 the test compound was defined by the selectivity index, which was
 calculated as shown below.
 ##EQU2##
 Compounds having selectivity ratio greater than 30 times that of GTN were
 selected for initial toxicology evaluation. The selectivity index for GTN
 was estimated to be 0.017.
 Results of in Vitro Screening of NO Donors
 The results of in vitro screening of the NO donors are given in the
 following Table 2.
 TABLE 2
 In vitro activity of NO donors
 Mean Relative Mean Relative Mean Activity Mean Activity
 Compound Potency Potency Ratio Ratio
 No. before tolerance after tolerance before tolerance after
 tolerance
 1. 0.03 1.2 0.7 1.3
 2. 1.7 2.9 1.0 1.3
 3. Low Potency Low Potency 0.5 0.2
 4. Low Potency Low Potency 1.3 1.2
 5. Low Potency Low Potency 0.7 0.4
 6. 0.8 3.4 1.3 1.5
 7. 0.17 0.54 1.05 1.5
 8. 0.18 7.99 1.44 1.36
 9. Low Potency Low Potency 0.32 0.52
 10. 0.08 1.6 1.2 1.25
 11. 0.79 16.36 1.17 1.72
 12. 0.44 9.0 1.06 1.6
 13. 0.4 10.6 1.1 1.6
 14. 0.71 11.5 1.1 1.25
 15. 0.028 2.73 0.92 0.88
 16. 0.06 0.46 1.07 0.92
 17. 0.017 0.85 0.75 0.85
 18. 0.046 3.79 0.82 1.43
 19. 0.06 9.28 1.03 2.07
 Results of in Vivo Evaluation
 The compounds, which were selected based on in-vitro studies, were
 subjected to in-vivo studies to assess their anti-anginal action.
 Compounds with sufficient selectivity (i.e. lower hypotension) and
 anti-anginal action are listed in Table-3.
 TABLE 3
 In vivo activity of selected Nitric Oxide donors
 Dose required for Dose required for 50% Selectivity
 20% fall in B.P. inhibition of T-wave Index
 Compound (ED.sub.20 .mu.g/kg,) (ED.sub.50 .mu.g/kg,) (A/B)
 No. (A) (B) (C)
 GTN 8.22 474.40 0.017
 6 383.19 170.70 2.25
 8 539.06 93.75 5.75
 12 248.86 681.68 0.37
 13 318.55 113.16 2.81
 It was observed that compounds 6, 8, 12 and 13 have a high selectivity
 index as compared to GTN. In the case of compounds 6, 8 and 13, the index
 is significantly higher. The index showed that these compounds could
 elicit anti-anginal activity at a dose, which had minimum systemic
 effects. Their selectivity in dilating the coronary arteries was quite
 high as compared to a conventional drug like GTN.
 The high selectivity index of these compounds as compared to nitroglycerine
 show that they selectively dilate the coronary arteries and have a lower
 tendency to cause hypotension during clinical usage. For example, the
 compound with lowest selectivity index, (compound 12), is 22 times more
 selective as compared to GTN. This shows that these compounds have very
 little tendency to cause hypotension. Conventional nitrates like GTN cause
 tachycardia, retrosternal discomfort, palpitations, collapse, syncope and
 postural hypotension, etc. as a manifestation of hypotensive effect. This
 could limit its use in selected patients. However, the compounds described
 in this invention due to a lower tendency to cause hypotension are
 superior to conventional nitrates.
 The benzofuroxans described in this invention can be used in cardiovascular
 disorders like acute effort angina, angina prophylaxis, mixed angina and
 silent ischemia, acute myocardial infarction, congestive heart failure,
 etc. They can be used alone or in combination with beta adrenergic
 blockers like propranolol, atenolol, carvedilol, etc. and calcium channel
 antagonists like verapamil, diltiazem, etc.
 The method of preparation of the representative compounds for use in
 treatment of cardiac disorders according to this invention are given in
 the following examples:
 EXAMPLE 1
 Preparation of 5(6)-n-propylmercapto benzofuroxan. (Compound 2)
 In a 250 ml round bottom flask, was added 10.0 g of
 2-nitro-4-thiopropylaniline. To it was added 50 ml of D.M. water and 40 ml
 concentrated HCl. It was stirred at 0-10.degree. C. for 1 hour. Then at
 0.degree. C., a solution of 4.7 g of sodium nitrite in 10 ml water was
 added. After 10 minutes 4.5 g of sodium azide in 10 ml water was added to
 obtain 6.2 g of 2-nitro-4-thiopropyl phenyl azide as a yellow solid.
 12 ml of dry toluene, was charged with 2.0 g of 2-nitro-4-thiopropyl phenyl
 azide. The dark brown solution which was formed was stirred at 80.degree.
 C. for 4 hours. The solvent was removed under vacuum to give a brown
 solid, which was further charcoalized in ethanol:water (7:3) and filtered
 to give 800 mg of 5(6)-n-propyl mercapto benzofuroxan.
 IR(KBr): 3092, 2967, 1605, 1517, 1456, 1293, 1125, 1090 cm.sup.-1
 PMR (CDCl.sub.3) .delta.: 6.8-7.5 (3H,m), 3.0 (2H,t), 1.8 (2H,m), 1.1
 (3H,t)
 Mass: 210 (M.sup.+), 150 (M.sup.+ -N.sub.2 O.sub.2)
 EXAMPLE 2
 Preparation of 5(6)-methylmercapto benzofuroxan. (Compound 4)
 To a stirred mixture of 2 g of 4-thiocyanato-2-nitroaniline in 20 ml
 methanol was added a solution of 1.2 g potassium hydroxide in 10 ml
 methanol. The solution became dark. The mixture was stirred at 20.degree.
 C. for 2 hours. Then 1 g of methyl iodide was added when a clear solution
 was obtained in 2 minutes and it was stirred at 20.degree. C. for 1 hour.
 Methanol was removed on a rotary evaporator at 40.degree. C. Then 50 ml of
 water was added to the residue and the product was extracted with ethyl
 acetate. The organic extracts were combined and dried over anhydrous
 Na.sub.2 SO.sub.4. Ethyl acetate was removed on a rotary evaporator when
 1.2 g of 4-methylmercapto-2-nitroaniline was obtained, which was used for
 the next step without further purification.
 To a stirred mixture of 0.75 g 4-methylmercapto-2-nitroaniline and 5 ml
 concentrated HCl was added 20 ml of water, and stirring was continued for
 another 5 minutes. The mixture was cooled to 0.degree. C. and then a
 solution of 1 g of sodium nitrite in 5 ml water was added and stirred at
 0.degree. C. for 2 hours. It was then filtered rapidly under suction and
 the filtrate was collected. To the filtrate was added a solution of 1.5 g
 of sodium azide in 5 ml water when a solid was precipitated with frothing.
 The solid was extracted with methylene chloride (50 ml.times.2). The
 combined organic extracts were dried over anhydrous Na.sub.2 SO.sub.4. The
 solvent was evaporated on a rotary evaporator when 0.5 g of
 4-methylmercapto-2-nitrophenyl azide was obtained. The solid was used for
 the next step without further purification.
 A mixture of 0.5 g 4-methylmercapto-2-nitrophenyl azide and 10 ml toluene
 was heated with stirring at 100.degree. C. for 2 hours. Toluene was
 removed under vacuum at 60.degree. C. and recrystallization was carried
 out with hexane:ethylacetate (5:7) when 0.41 g of 5(6)-methylmercapto
 benzofuroxan was obtained.
 m.p.: 114.degree. C.
 IR (KBr): 2920, 1600, 1515, 1460 cm.sup.-1
 EXAMPLE 3
 Preparation of 5(6)-n-propoxy carbonyl benzofuroxan (Compound 12)
 5(6)-Carboxy benzofuroxan (2.0 g, 0.11 mole) was refluxed in a saturated
 solution of n-propionolic HCl for 16 hours. n-Propanol was removed under
 vacuum and the residue was redissolved in diethyl ether (150 ml). The
 solution was then washed with aqueous NaOH (50 ml, 0.1 mole), followed by
 water (100 ml) and dried over Na.sub.2 SO.sub.4 Ether was removed under
 vacuum to give an oil which was purified by column chromatography.
 Yield: 1.0 g, (45%)
 m.p.: 30-32.degree. C.
 IR (KBr): 1725, 1613, 1585, 1540, 1490 cm.sup.-1
 P.M.R. (200 MHz, CDCl.sub.3) .delta.: 1.09-1.08 (2H,t,J=7.4 Hz),
 1.58-2.17(2H,m), 4.30-4.36 (3H,t,J=6.6 Hz), 7.36-7.86 (3H,m).
 Mass: 222(M.sup.+), 180, 163, 75.
 Alternatively, compound 12 can also be prepared by the following procedure:
 5(6)-Chlorocarbonyl benzofuroxan (100 mg) and n-propyl alcohol (150 mg)
 were dissolved in THF (10 ml) at room temperature. To the reaction mixture
 triethylamine (0.1 ml) was added and reaction mixture was refluxed for 24
 hrs. THF was removed under reduced pressure. To the residue 10 ml water
 was added and extracted with ethyl acetate (3.times.20 ml). Ethyl acetate
 was removed under reduced pressure to get sticky mass which was purified
 by column chromatography using ethylacetate: hexane (1:9) to give 65 mg of
 compound 12.
 Compound 12 can also be prepared by the method of preparation of compound
 13.
 EXAMPLE 4
 Preparation of 5(6)-isopropoxy carbonyl benzofuroxan. (Compound 13)
 To a solution of 5(6)-carboxy benzofuroxan (1.0 g, 0.0055 mole) and
 isopropyl alcohol (0.9 ml., 0.01 mole) in CH.sub.2 Cl.sub.2 (50 ml) were
 added 4-dimethylamino pyridine (70 mg) and N,N'-dicyclohexyl carbodiimide
 (2.28 g, 0.011 mole) under stirring. The reaction mixture was stirred for
 2 hours at room temperature. It was filtered and the filtrate on
 evaporation under reduced pressure gave crude product, which was purified
 by column chromatography (n-hexane) to give the title compound as yellow
 solid (0.7 g, 57%).
 m.p.: 65-67.degree. C.
 IR (KBr): 1716, 1622, 1585, 1537 cm.sup.-1
 PMR (200 MHz, CDCl.sub.3) .delta.: 1.3-1.41 (6H,d,J=6.2 Hz), 5.15-5.37
 (1H,m), 7.51-8.21 (3H,m),
 Mass: 222 (M.sup.+), 180, 163, 103, 75.
 Compound 13 can also be prepared by the method of preparation of compound
 12.
 Oral Formulations
 Orally they may be administered as solid dosage forms for example as
 pellets, granules, powder, sachet or as discreet units such as tablets or
 capsules, etc. Other orally administered pharmaceutical preparations
 include monophasic and biphasic liquid dosage forms either in ready to use
 form, or forms suitable for reconstitution such as mixtures, syrups,
 suspensions or emulsions. The preparations in addition may contain
 diluents, dispersing agents, buffers, stabilizers, solubilizers, surface
 active agents, preservatives, chelating agents and/or other pharmaceutical
 additives. Aqueous or non aqueous vehicles or their combination may be
 used and if desired may contain suitable sweeteners, flavouring agents or
 similar substances. In the case of a suspension or emulsion a suitable
 thickening agent, suspending agent or emulsifying agent may be present.
 Pharmaceutical preparations can have a slow, delayed or controlled release
 of active ingredients as is provided by a matrix or diffusion controlled
 system.
 Parenteral Formulations
 For parenteral administration, the compounds or their salts or suitable
 complexes may be presented in a sterile vehicle which may be an aqueous or
 non aqueous vehicle or a combination thereof The examples of vehicles are
 water, ethyl oleate, oils and derivatives of polyols, glycols and their
 derivatives. It may contain additives common in injectable preparations
 like stabilizers, solubilizers, pH modifiers, buffers, antioxidants,
 cosolvents, complexing agents, tonicity modifiers, etc. Some suitable
 additives are for example tartrate, citrate, or similar buffers, alcohols,
 sodium chloride, dextrose and high molecular weight liquid polymers.
 Another alternative is sterile powder for reconstitution. The compound may
 be administered in the form of injection, intravenous infusion/drip, or
 suitable depot preparation.
 When the present invention, its salts or a suitable complex is presented as
 a discrete unit dosage form like a tablet, it may contain in addition
 medically inert excipients as are used in art. Diluents such as starch,
 lactose dicalcium phosphate, lubricants or similar additives like talc,
 magnesium stearate, polymeric substances like methyl cellulose, hydroxy
 propyl cellulose, fatty acids and derivatives, sodium starch glycollate,
 etc. can also be used.
 EXAMPLE 5
 Preparation of Oral Dosage Form of the Benzofuroxan Derivatives Given in
 Table 1.
 The compounds described in Table 1 can be prepared in the form of tablets,
 containing the active ingredient in the range of 0.03 to 3 mg per tablet.
 A typical tablet has the following composition:

Active ingredient as given above
 Starch 27 mg
 Lactose 70 mg
 Polyvinyl pyrolidone (k-30) 1.0 mg
 Talc 1.5 mg
 Magnesium stearate 0.5 mg
 EXAMPLE 6
 Preparation of Parenteral Dosage Form of Benzofuroxan Derivatives Given in
 Table 1
 A preparation suitable for parenteral administration has the following
 composition:

Active ingredient 1 mg.
 Poly ethylene glycol - 400 0.5 ml
 Isotonic saline solution q.s. 1 ml
 or water for injection
 These examples are presented by way of illustration alone and in no way
 limit the scope of the invention.