Cyclooxygenase (COX)-inhibiting anti-inflammatory pro- ducts are known from previous patent applications in the name of the Applicant. See in particular the published pa- tent applications WO 94/04484, WO 94/12463, WO 95/09831, W095/30641. These patent applications referred to non-ste- roid anti-inflammatory products with a non-acid ending and to those with an acid ending mentioned as products known in the art.

Said products showed a much lower toxicity level compa- red to the reference products not containing group -ONO2.

The need for available products having an antithrombo- tic activity combined with lower toxicity in long term treatment was felt. In particular, the efficacy and safety of antithrombotic agents are closely related and research is aiming to find out new molecules with an increased therapeu- tic index, i.e. with improved efficacy and reduced toxicity (Goodman & Gilman: "The pharmacological basis of therapeu- tics", Ed. J. Hardman, h. Limbrid, page 1357, 1996).

It was unexpectedly and surprisingly found that the products of the invention as defined below are effective in inhibiting platelet aggregation induced by different kinds of stimuli, in particular collagen and thrombin, and at the same time exhibit high safety in general, in particular a high gastric safety, without causing lesions to the gastro- intestinal mucosa in the treated animals.

The results of the present invention are much more sur- prising considering that the new classes of products of the invention are not cyclooxigenase (COX) inhibiting products and, therefore, they cannot be drawn in any way from the products described in the known art, in particular in the above patents.

A subject of the present invention are the compounds, or their compositions, of the general formula: A - (X1-NO2)to or their salts, for use as medicaments, in particular as antithrombotic agents since they are effective in inhibiting platelet aggregation, where: to is an integer equal to 1 or 2; A = RNo where No = (COXu)t- or COON1 where t is an integer equal to zero or 1; u is an integer equal to 0 or 1; X = O, NH, NRic where Ric is a linear or branched alkyl ha- ving from 1 to 10 carbon atoms; N1 is a linear or branched alkyl having from 1 to 10 carbon atoms or hydrogen; R is chosen from the following groups: * Group A) Ia) where Ria and RIIa are equal or different one from the other and are H or a linear or whenever possible branched alkyl having from 1 to 3 C atoms, preferably Ria = RIIa = H; nia is an integer from 1 to 6, preferably from 2 to 4; RI can be: where N2 has the same meaning as No; at least one of the groups No or N2 having one free valence capable of binding to X1, (that is, t = 1), Ib) RIa, RIIa, nIa are as defined in Ia; N3 is H, (CH3)2CH-CH-OCOCH2CH3, or a free valence to which X1 binds (that is, N3 is absent); RIb is chosen from: N2 is as above defined, where at least one of the groups N3 or N2 has a free valence capable of binding to X1 (when it is N2, t = 1); N2, t = 1); Ic) where t = 1 where No is as above defined where t = 1, i.e. it has a free valence capable of binding to X1; RIc is chosen from H, -COCH3, or where N2 is as defined, and at least one of the groups N2 has a free valence (t = 1) capable of binding to X1; * Grout B where t = 1 and u = 0; where RIa, RIIa are as defined in Ia); RIIb has the meaning of RIa; RBA is chosen from: where, in group B), N2 is as above defined. and at least one of the N2 groups has a free valence capable of binding to X1, (that is, at least one N2 substituent has t = 1; Xl is a bivalent connecting bridge chosen from the following: - YO where Y is a linear or whenever possible branched C1-C2a alkylene, preferably having from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene ha- ving from 5 to 7 carbon atoms; - Y1 chosen from where n3 is an integer from 0 to 3; where nf' is an integer from 1 to 6, preferably from 2 to 4; where R1f = H, CH3 and nf is an integer from 1 to 6; preferably from 2 to 4.

The compounds which may be mentioned, and which are the preferred compounds, are those listed below where R can be obtained by the processes known in the art.

For example, the compounds and processes described in The Merck Index, Ed. 12 of 1996, herein fully incorporated by reference, can be mentioned as precursors and related processes. The precursors (according to the Merck nomencla- ture) as those shown below, where the various substituents shown in the formulas of group A) and group B) are as defi- ned in the compounds listed: Alacepril, Benazepril, Capto- pril, Ceronapril, Cilazapril, Delapril, Enalapril, Enalapri- lat, Fosinapril, Imidapril, Lisinopril, Quinapril, Ramipril, Spirapril, Temocapril, Trandolapril, Moveltilpril, Perindo- pril, Befunolol, Betaxolol, Bupranolol, Carteolol, Levobuno- lol, Metipranolol, Timolol, Oxprenolol, Mepindolol, Ateno- lol, Labetalol.

The connecting bridges X1 as above defined can be obtai- ned using the methods from the known art or modifying the known methods by introducing X1 bridges when these are diffe- rent from the connecting bridges described in the mentioned patents by processes known in the art. In general, the con- nection between A and X1 is, as seen, of an ester or amide type (NH or Uric, as defined in X). Any synthetic route well known for forming these bonds can be used.

In the case of esters, the most direct synthetic route includes reaction of acyl chlorides A-CO-Cl, or A-(CO-C1)2, in halogen alcohols of the type HO-Ya-Cl, HO-Ya-Br,- HO-Ya-I, where Ya is equal to Y or Y1 as above defined without the oxygen atom--O-, in experimental conditions which are part of the known art.

The reaction products of formula A-CO-O-Ya-Cl(Br,I) can also be obtained by reacting the sodium or potassium salts of said acids A-CO-OH with di-halogen derivatives of the ge- neral formula YaC12, YaBr2 or YaI2 The reaction products are converted into the final pro- ducts by reaction with AgNa3 in acetonitrile according to processes known in the prior art.

The general scheme is as follows: where X1 = Yaa.

The general scheme can also be as follows: where X1 = YaO.

In the case of amides, the synthetic sequence includes reaction of the same acyl chlorides A-CO-C1 with amino alco- hols of the general formula NH2-Ya-OH or NHRlc-Ya-OH to give amides of the general formula: A-CO-NH-Ya-OH or A-CO-NR1c-Ya-OH in accordance with known methods.

Reaction of these amides with halogenating agents such as, for example, PC15, PBr3, SOCl2, etc, leads to halogen de- rivatives of the general formula: A-CO-NH-Ya-Br(Cl) and A-CO-NRlc-Ya-Br(Cl).

By reaction with Ago 3 in acetonitrile according to known literature methods said latter products lead to the final products AX1NO2.

The sequence may be represented as follows: where YaO is X1.

An alternative route to ester formation is reaction of the sodium or potassium salts of acids with the nitric est- ers of halogen alcohols of the general formula: NO2-O-Ya-Cl(Br,I) to give directly the products of the invention.

The reaction scheme is as follows: where YaO is X1.

Other synthetic routes similar to those described above are the ones where dihalogen derivative Br2Ya is reacted with enolates. The reaction products are then converted by rea- ction with AgNa3 in acetonitrile according to the above re- action. The general scheme shown for an -OH belonging to group A is as follows: A general method for the -OH group is described in Example 1 only for illustrative purposes.

The processes to obtain these connecting groups X1 are described in patent application WO 95/30641 herein fully incorporated by reference.

The products of the invention as described above are novel as medicaments in general. In particular they are no- vel for their antithrombotic activity and are also no- vel as compounds as such.

Additional pharmaceutical uses which can be mentioned for the products of the invention are, for example, their antihypertensive activity (e.g. arterial hypertension, glau- coma) and their cardioprotective activity (e.g. angina pe- ctoris, cardiac failure, coronary ischaemia).

As to antihypertensive activity, it should be noted that the products of the invention showed an extremely sati- sfactory pharmaco-therapeutic profile with improved efficacy compared to the precursors which do not contain group -ONO2 and, at the same time, showed superior safety.

It should also be noted that the products of the in- vention exhibit an antihypertensive activity combined with an antithrombotic activity. This is an outstanding benefit in the treatment of cardiovascular disease in general since the purpose of any therapeutical approach is to ensure to the patient an altogether reduced risk of cardiovascular disease, such as myocardial or cerebral infarction and athe- rosclerosis (Goodman & Gilman "The pharmacological basis of therapeutics", Ed.J.Hardman, L. Limbrid, pages 747, 1354-7, 1996).

The following examples are being provided as an expla- nation not a limitation of the present invention.

EXAMPLES EXAMPLE 1: Chemical svnthesis and characterization of NO-ti- molol (NO-TIM) Synthesis of (R) - (4-nitroxy)butanoate of 1- [(1,1-dime- thyl)amino]-3-{[4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl] oxy}-2-propyl maleate.

The starting point is timolol maleate (a commercial product), the timolol having the general formula (S)-1-[(1,1-dimethylethyl)amino]-3-{[4-morpholinyl)-1,2,5- thiadiazol-3yl]oxy}-2-propanol.

Timolol maleate (2.0 g) was treated with a solution of 10% NaOH (30 ml). 30 ml of CH2Cl2 were added and then the phases were separated. The aqueous phase was extracted several times with CH2C12. The pooled organic phases were dried (Na2SO4) and the solvent evaporated at reduced pressu- re. 1.4 g of pure product were obtained (yield 96%).

1H NMR (300 MMz CDCl3:6 1.05 (9H,s,3CH3), 2.7 (2H, 2dd, CM2- NH), 3.5 (4H, m, morpnoline), 3,8 (4H, t, morpholine), 3.85 (1H, m, CH), 4.4 (2H, 2dd, O-CH2).

(S)-1-[(1,1-dimethylethyl)amino]-3-{[4-(4-morpholinyl)- 1,2,5-thiadiazol-3-yl]oxy}-2-propanol hydrochloride.

0.8 ml of a 7M HC1 solution in isopropanol was added dropwise to a magnetically stirred solution of timolol (1.4 g) in isopropanol (30 ml). The solution was stirred for 30 minutes. The reaction mixture was freed of the solvent at reduced pressure. 1.47 g of pure product was obtained (yield 91W) .

1H NMR (300 MMz CDC13): 6 1.45 (9H,s,3CH3) , 3.05 (2H, 2dd, CH2-NH), 3.5(4H,t,morpholine), 3.8 (4H,t,morpholine), 4.5 (2H,d,O-CH2), 4.55 (lH,m,CH).

(R)-(4-bromo)butanoate of 1-[(1,1-dimethylethyl)amino]-3- {[4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxylF-2-propyl 4-Bromobutyryl chloride (0.4 ml) was added dropwise in a nitrogen atmosphere to a magnetically stirred solution of timolol hydrochloride (0.82 g) in CMCl3 dried over P205 (20 ml). Stirring was continued for 4 days. The reaction mixture was then freed of the solvent at reduced pressure.

The residue was chromatographed on silica gel using diethyl ether with 3% Et3N as an eluant. 0.830 g of pure product was obtained from the intermediate fractions (yield 78k).

1H NMR (300 MMz CDCl3):# 1.05 (9H,s,3-CH3), 2.05 (2H, m, COCH2- CH2-CH2-ON02), 2.5 (2H,m,COCH2-CH2CH2-ONO2), 2.8(2H,d,CH2- NM), 3.5 (6H,m,morpholine, CH2-Br), 3.8 (4H,t,morpholine), 4.65 (2H, 2dd, O-CH2), 5.25 (lH,m,CH).

(R)-(nitroxy)butanoate of 1-[(1,1-dimethylethyl)amino]-3- {[4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy}-2-propyl.

A solution of AgNO3 (0.450 g) in CH3CN (5 ml)was added dropwise at ambient temperature to a magnetically stirred solution of timolol (4-bromo)butanoate (0.830 g) in CH3CN (10 ml). The temperature was progressively raised up to 600C and reaction was continued for 24 hours. The reaction mixture was freed of the solvent at reduced pressure. The residue was chromatographed on silica gel using diethyl ether with 3% Et3N as an eluant. 0.51 g of pure product was obtained from the first fractions (yield 64%) 1H NMR (300 MHz CDCL3): 6 1.05 (9M,s,3CM3) , 2.05 (2H, m, COCH2-CH2-CH2-ONO2), 2.5 (2H, 2t, COCH2-CH2-CH2-ONO2), 2.8 (2H,d,CH2-NH), 3.5 (4H,m,morpholine), 3.8 (4H,t,morpholine), 4.5 (2H,t,-CH2-ONO2), 4.58 (2H, 2dd, O-CH2), 5.25 (1H, m,CH).

MS:M+ 448 (R)-(4-nitroxy)butanoate of 1-[(1,1-dimethylethyl)amino]-3- {[4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy}-2-propyl ma- leate.

A solution of maleic acid (0.132 g) in acetone (5 ml) was added dropwise to a magnetically stirred solution of timolol (4-nitroxy)butanoate (0.50 g) in acetone (10 ml).

Stirring was continued for 2 hours. The reaction mixture was freed of the solvent at reduced pressure. The crude residue was grounded with diethyl ether to give 0.5 g of a white solid (m.p. 133-1360C, yield 70k) 1H NMR (300 MMz CDC13) : 6 1.48 (9H,s,3CH3), 2.05 (2H,m,- COCH2-CH2-CH2-ONO2}, 2.58 (2H, 2td, COCH2-CH2-CH2-ONO2), 3.3 (2H,2m, CH2-NH2), 3.5 (4H, m, morpholine), 3.8 (4H, t, morpholine), 4.5 (2H, t, CH2-ONO2) 4.7 (2H, 2dd, O-CH2), 5.55 (1H, m, CH), 6,47 (2H, s, maleic) EXAMPLE 2A: Chemical svnthesis and characterization of NO- enalapril (NO-ENA) The reaction scheme is as follows: 1) a 5 Hape DTBC (Di-t-butyl dicarbonyl M{t 3) HgC20 O Rooc ass . Acid hydrolysis c ,Wo thug t BCC ° 4) cit <e 11.

Step 1 3 g of diterbutyldicarbonyl (DTBC) was added at ambient tem- perature to a solution of 5 g of enalapril in 100 ml of di- methylformamide (DMF) and triethylamine (TEA) (2.76 g). The solution was stirred for 16 hours. Then the solution was washed twice with diluted HCl and water, extracted 3 times with 100 ml portions of ether. The dried and evaporated-off organic phases gave 3 g of a formula 2) product (an oil). In formula 2) tBOC = t-butyldicarbonyl.

Step 2 1.4 g of dicyclohexyl carbodiimide (DCC), and then 30 ml of a solution of 1.1 g of nitroxymethylphenol in CH2Cl2, were added to 3 g of N-protected enalapril (a compound of formula 2) dissolved in 50 ml of methylene dichloride. The mixture was stirred overnight, dicyclohexylurea was filtered off and the solvent was evaporated off the dryness. The residue was chromatographed on silica gel 60 Merck using an ethyl acetate/hexane mixture. A fraction of 2 g of intermediate of formula 3), where R was the residue of nitroxymethylphenol without OH, was collected.

Step 3 1 g of the product of formula 3) was dissolved at OOC in a 4N solution of 30 ml of dry HCl gas in ethyl acetate (ACO- Et) and stirred for 10 hours. The precipitate obtained was filtered and dried under vacuum 0.5 g of a product 4) was obtained.

EXAMPLE 2B: Chemical synthesis and characterisation of NO- enalaprilate (NO-E@@) The reaction scheme is as follows: 1 ) OH HOOC E C (Di-t-taui;yl dici-cr) MMX cit 3) acoc Acid hydrolysis COOR Bac Step I: 3 g of di terbutyldicarbanyl (DTBC) was added at ambient tem- perature to a solution of 5 g of enalaprilate in 100 ml of dimethylformamide (DMF) and triethylamine (TEA) (2.76 g).

The solution was stirred for 16 hours. Then the solution was washed twice with diluted HCl and water, extracted 3 times with 100 ml portions of ether. The dried and evapora- ted-off organic phases gave 3 g of a product 2) as an oil.

In formula 2) tBOC = t-butyldicarbonyl.

Step 2: 2.75 g of dicyclohexyl carbodiimide (DCC), and then 30 ml of a solution of 2.25 g of nitroxymethylphenol, were added to 3 g of N-protected enalaprilate dissolved in 50 ml of methy- lene dichloride. The mixture was stirred overnight, dicyclo- hexylurea was filtered off and the solvent was evaporated off to dryness. The residue was chromatographed on silica gel 60 Merck using an ethylacetate/hexane mixture. A fraction of 3 g of intermediate product 3) was collected.

R has the meaning as defined in Example 2A.

Step 3: 1 g of product 3) was dissolved at OOC in a 4N solution of 30 ml of dry HCl gas in ACOEt and stirred for 10 hours. The precipitate obtained was filtered and dried under vacuum.

0.7 g of a product 4) was obtained.

EXAMPLE 3: Pharmacoloical studies The products from Examples 1 and 2 had been administe- red in vivo always as 2%-by-weight suspensions in carboxy- methyl cellulose.

The experimental groups were made up of 6 to 8 samples to allow appropriate statistical evaluation, which was car- ried out when needed.

As far as acute toxicity for the compounds which are the object of the invention, it was evaluated after a single oral dose to groups of 10 mice each.

Death rate and presence of toxic symptoms were recorded during an observation period of 14 days. Even after a 50 mg/kg dose the animals showed no sign of apparent overt to- xicity.

EXAMPLE 3A STUDY OF ANTI PLATELET ACTIVITY The ability of NO-ENA and NO-TIM to inhibit platelet aggregation was evaluated using an in vivo model as descri- bed by Pinon (J. Pharmacol. Methods 12,79,1989). 5 groups of male Wistar rats (200 to 250 g) received an oral daily dose of 10 mg/kg of respectively, NO-ENA, enalapril, NOTIM, ti- molol or vehicle for 5 days. At an appropriate time on the forth day food (but not water) was withdrawn. 18 to 20 hours later the animals received the last treatment. One hour la- ter the animals were anaesthetized with 10% urethane (1 mg/kg intraperitoneally) and the left jugular vein and right carotid artery were incannulated. Collagen (type 6, Sigma) was then administered intravenously at a dose of 2 mg/kg.

Three minutes later two blood samples (A and B) were colle- cted from the carotid artery using 2.5-ml plastic syringes in the following manner: sample A, 0.4 ml of blood in 1.6 ml of EDTA/formalin buffer (ETDA tetrasodium salt 24 mM, KH2P04 1.3 mM, Na2PO4 13.4 mM), the samples were then transferred into 5-ml polystyrene test tubes and allowed to settle for 15 minutes at ambient temperature. After this time, the pla- telet aggregations in sample A were fixed in formalin, while those from sample B were treated with EDTA. Platelet count was then made in each sample using a conventional microsco- pe. The count for sample B was the total number of plate- lets, while for sample A were considered only non-aggregated platelets. The results were expressed as per-cent aggrega- tion, calculated as follows: [1- (platelet count in sample A)/(platelet count in sample B)] x 100k. The results were expressed as per-cent inhibition of the control group (vehi- cle) and shown in Table 1.

TABLE 1 STUDY OF ANTI PLATELET ACTIVITY OF NO-ENA OR NO-TIM VERSUS ENALAPRIL OR TIMOLOL IN RATS COMPOUND ANTIPLATELET ACTIVITY (%) NO-ENA 65 NO-TIM 58 ENALAPRIL 15 TIMOLOL 2 As shown in Table 1, differently from the reference pro- ducts, the nitroderivatives of the invention were able to inhibit aggregation induced by collagen.

EXAMPLE 3B: STUDY OF ANTITHROMBOTIC ACTIVITY 5 groups of male Charles River rats of the Swiss str- ain, 15 to 20 g, received a daily oral dose of 10 mg/kg of, respectively, NO-ENA, enalapril, NO-TIM, timolol or vehicle for 5 days. At an appropriate time on the fourth day food (but not water) was withdrawn. 18 to 20 hours later the ani- mals received the last treatment. One hour later the animals were injected into the caudal vein with 0.1 ml of a collagen (type 6, Sigma) mixture plus adrenaline hydrochloride (100 HM) diluted in a solution of 0.154 M sodium chloride. As previously explained (Cirino G. et al., Thrombosis Reasearch 79, 73, 1995), injection of this mixture caused death within 3 minutes in 90% of the control animals.

The results were expressed as inhibition percentage compared to the control group and are shown in Table 2.

TABLE 2 STUDY OF ANTITHROMBOTIC ACTIVITY OF NO-ENA OR NO-TIM VERSUS ENALAPRIL OR TIMOLOL IN RATS COMPOUND ANTITHROMBOTIC ACTIVITY li NO-ENA 53 NO-TIM 44 ENALAPRIL 11 TIMOLOL 6 As shown in Table 2, differently from the reference products, the nitroderivatives of the invention were able to inhibit thrombosis induced by collagen.

EXAMPLE 3C: STUDY OF ANTIHYPERTENSIVE ACTIVITY The ability of NO-ENA to inhibit hypertension was eva- luated using an in vivo model as described by Ribeiro et al.

(Hypertension 20, 298, 1992). 5 groups of male Wistar rats (235 to 284 g) received a daily intravenous dose of 10 mg/kg of, respectively, NO-ENA, enalapril, NO-TIM, timolol or ve- hicle for 5 days. Arterial hypertension was induced by admi- nistration of NW-nitro-L-argininemethyl ester (L-NAME) in the drinking water for 6 weeks. L-NAME was dissolved in the drinking water at a concentration of 60 to 70 mg 100 ml -i so as to administer a daily amount of about 60 mg kg-l One hour after treatment the systemic blood pressure-was measu- red by the tail-cap method (Zats, Lab. Anim. Sci.42, 198, 1 9 9 0 ) .

TABLE 3 STUDY OF ANTIHYPERTENSIVE ACTIVITY OF NO-ENA VERSUS ENALA- PRIL IN RATS COMPOUND MEAN BLOOD PRESSURE (mmHg) VEHICLE 170+7 NO-ENA 115+4 ENALAPRIL 163+5 *P< 0.05 versus the other two groups As shown by Table 3, differently from the reference product, the nitroderivative of the invention was able to inhibit blood hypertension induced by thrombosis induced by L-NAME.

EXAMPLE 3B: STUDY OF OCULAR HYPOTENSIVE ACTIVITY AND OCULAR SAFETY OF NO-ENA OR NO-TIM VERSUS ENALAPRIL OR TIMOLOL IN RABBITS In rabbits, the topical application of 100 yg of NO-ENA or NO-TIM gave a more pronounced and more lasting (more than 6 hours) reduction of intraocular pressure (6-7 mmHg respe- ctively) than the reference products timolol and enalapril.

Furthermore, for NO-TIM, the ratio between product concen- trations in plasma (P) and aqueous humor (AH) versus timolol was determined by an HPLC method. It was found that the P/AH ratio for NO-TIM was 5.5 times lower than that for timolol, suggesting that the systemic absorption of the nitroderiva- tive (and consequently any potential side effect from said derivative) was markedly reduced compared to the reference product.

EXAMPLE 3E: STUDY OF NO-ENA EFFECTS ON INDUCED BRONCHOCON- STRICTION IN GUINEA PIGS VERSUS ENALAPRIL Bronchoconstriction induced by capsaicin in Guinea pigs is an animal model related to the ability of ACE (angioten- sin-converting enzyme) inhibitors to cause cough in patients (Subissi et al., J. Cardiovasc. Pharmacol.20/1, 139-146, 1992).

Adopted test conditions were as previously described by Del Soldato et al.(J. Pharmacological Methods 5, 279, 1981).

Female Guinea pigs weighing 300 to 400 g were anaesthetised by intraperitoneal injection of sodium 5,5-diethylbarbitu- rate (200 mg/kg) and maintained under artificial respiration at constant positive pressure. The right jugular vein was incannulated for administering test compound. By a median incision of the abdomen, the duodenum was removed and through a small incision the tip of a suitable polyethylene cannula was inserted and fixed. The other end of the can- nula was connected to a syringe for intraduodenal admini- stration of NO-ENA (10 mg/kg), enalapril (10 mg/kg) or vehi- cle. 45 minutes later, 0.1 ml of capsaicin (1 yg/kg) was injected into the jugular vein of the animals. Before and after injection of capsaicin, changes in the tidal area were measured by a modified Konzett apparatus connected to a suitable polygraphic amplifier (Hewlett Packard).

The results were calculated as the ratio of the respon- ses obtained before and after administration of the test compound, expressed as a % of the response obtained with the vehicle alone, shown in Table 4.

TABLE 4 STUDY OF EFFECTS OF NO-ENA ON BRONCHOCONSTRICTION INDUCED IN GUINEA PIGS VERSUS ENALAPRIL TREATMENT BRONCHOCONSTRICTIVE RESPONSE (%) VEHICLE 100 NO-ENA 72 ENALAPR IL 327 As shown in Table 4, the nitroderivative of the inven- tion reduced bronchoconstriction induced by capsaicin diffe- rently from the reference product, which actually markedly enhanced the bronchoconstrictive response.

CONCLUSIONS As can be observed from the above examples, the nitro- derivatives which are an object of the present invention show marked antithrombotic and cardiovascular activity with excellent safety when compared to reference products.