Organic nitrates and the pharmaceutical composition having inhibitory platelet aggregation activity, based on them

 

(57) Abstract:

The invention relates to the field of organic chemistry. Describes the nitrates of the General formula or their salts, where t0= 1; A=RN0where N0=(COXu)tor COON1where t is an integer of 0 or 1; and a is an integer of 0 or 1; X=O, NR1cwhere R1crepresents an alkyl straight or branched chain, having from 1 to 10 carbon atoms; N1represents an alkyl straight or branched chain, having from 1 to 10 carbon atoms or hydrogen; R is selected from the following groups:

* Group a)

< / BR>
where RIaand RIIaare the same or different and represent H or a linear or when possible branched alkyl of 1-3 atoms, preferably RIa= RIIa= N; nIais an integer from 1 to 6, preferably from 2 to 4; RIcan be

< / BR>
where N2has the same meaning as N0and at least one group of N0or N2has a free valence capable of binding with1(i.e. t=1);

* Group C), where t=1 and u=0

< / BR>
where RIa, RIIahave the meanings specified for 1a); RIbhas a value of RIat values, above, and at least one of the N2groups has a free valence capable of contact1(i.e., at least one Deputy N2has t=1); X1represents a bivalent connecting bridge selected from: - Y0where Y represents a C1-C20alkylen with direct or, where possible, branched chain, preferably having from 2 to 5 carbon atoms; Y1selected from

< / BR>
where n3is an integer from 0 to 3.

Also describes a pharmaceutical composition having inhibitory platelet aggregation activity. The technical result obtained new compounds with useful biological properties with superior security compared to standard products. 2 C. and 7 C.p. f-crystals, 5 PL.

The invention relates to new products that have antithrombotic activity.

Inhibit cyclooxygenase (CSC) anti-inflammatory products are known from previous patent applications authored by the applicant. See, in particular, the published patent application WO 94/04484, WO 94/12463, WO 95/09831, WO 95/30641. These patent applications relate to non-steroidal anti-inflammatory is s.

These products are significantly lower toxicity compared with the reference products, not containing the group-ON2.

In WO 95/30641 described compounds with inhibitory CSC activity and possessing antithrombotic and antihypertensive activity.

EP 637583 concerns nitroethanol 1 aryloxy-3-alkylamino-2-propanol General formula

< / BR>
where R1represents - (CH2)m-Z-R2m is 1 or 2, Z represents a functional group-O - simple ether-amide CONH-or-COO - of ester and R2represents a C2-3alkyl straight or branched chain, having at least one nitroxyl. These compounds can be used as medicines in the field of cardiovascular diseases.

In WO 97/31896 described derivatives of the formula

< / BR>
where X represents-CH2-, -O-, -S-; R1represents alkanoyloxy group having one or more substituents, And is alkylen or group-B-D-E- (where b and E may be the same or different and each represents a single bond or alkylene, and D represents cycloalkyl, nknym action and can be used for prevention or treatment of angina.

There is a need for affordable products with antithrombotic activity in combination with low toxicity for long-term treatment. In particular, the efficacy and safety of antithrombotic funds are closely related, and research are aimed at the search of new compounds with high therapeutic index, i.e., with increased efficacy and reduced toxicity (Goodman & Gilman: The pharmacological basis of therapeutics, Ed. J. Hardman, L. Limbrid, p.1357, 1996).

Unexpectedly and surprisingly been found that compounds of this invention, which are defined below, are effective in the inhibition of platelet aggregation caused by various kinds of stimuli, in particular collagen and thrombin, and at the same time, in the main, are mainly a high degree of security, in particular, high security against gastro-intestinal tract without causing damage to the mucosa of the gastrointestinal tract in treated animals.

The results of the present invention is even more surprising if we take into account the fact that new classes of substances of this invention are not substances that inhibit CSC, and therefore in no way can be expected on the basis of soeding of the invention are compounds or a composition of General formula:

A-(X-NO2to< / BR>
or their salts for use as pharmaceuticals, in particular as antithrombotic funds, as they are effective in the inhibition of platelet aggregation, where:

tois an integer equal to 1 or 2;

A= RNowhere No=(COXu)tor COON1where t is an integer of zero or 1; and a is an integer of 0 or 1;

X= O, NH, NR1cwhere R1cis an alkyl straight or branched chain, having from 1 to 10 carbon atoms; N1is an alkyl straight or branched chain, having from 1 to 10 carbon atoms, or hydrogen;

R is selected from the following groups;

* Group a)

< / BR>
where RIaand RIIaare the same or different and represent H or alkyl with straight or, where possible, branched chain, having from 1 to 3 carbon atoms, preferably Ia=RIIa=N; nIais an integer from 1 to 6, preferably from 2 to 4; RIcan be:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where N2has the same meaning as No; and at least one group of NoIa, RIIanIahave the meanings as indicated for the Ia;

N3represents H, (CH3)2CH-CH-OSEN2CH3or a free valence is associated with X1(i.e., N3missing);

RIbselected from

< / BR>
< / BR>
N2has the meaning as defined above, where at least one of the groups of N3or N2has a free valence capable of binding with X1(when he represents the N2, t=1);

1C) where t=1

< / BR>
have the meanings as stated above, where t=1, i.e., it has a free valence capable of contact with XI;

RIcselected from H, -PINES3or

< / BR>
< / BR>
where N2matter, as stated above, and at least one group of N2has a free valence (t=1), capable of binding with X1;

when in group IC) RIcrepresents H or PINES3, X cannot be-NH.

* Group

where t=1 u=0;

< / BR>
RIa, RIIahave the meanings as defined for Ia);

RIIbhas a value of RIa;

RSAchosen from:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where in group b) N2matter, as indicated by the message at least one Deputy N2has t=1);

X1represents a bivalent connecting bridge, selected from the following:

- YO, where Y represents a C1-C20alkylen with direct or, where possible, branched chain, preferably having from 2 to 5 carbon atoms, or optionally substituted cycloalkyl having 5 to 7 carbon atoms;

- Y1selected from

< / BR>
where n3is an integer from 0 to 3;

< / BR>
< / BR>
where nf' is an integer from 1 to 6, preferably from 2 to 4;

< / BR>
where R1f=N, CH3and nf is an integer from 1 to 6, preferably from 2 to 4.

Compounds that may be mentioned and which are the preferred compounds are listed below, where R can be obtained using known in the field of methods.

For example, the compounds and methods described in The Merck Index, Ed. 12, 1996, can be specified as precursors and close methods. Predecessors (item Merck), as shown below, where different substituents specified in the formula of group a and group b) have the meanings as indicated for the following compounds: alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, telpri, perindopril, befunolol, betaxolol, bupranolol, carteolol, levobunolol, metipranolol, timolol, oxprenolol, mepindolol, atenolol, labetalol.

Connecting bridges X1as described above, can be obtained by methods known to experts in the field, or modification of known methods by introducing X1bridges that are different from the connecting bridges described in the aforementioned patents, using known in the art methods. Typically the relationship between a and X1as you can see, is an ester or amide (NH or NR1cas defined for X). For the formation of these relationships can be used by any well-known way of synthesis.

In the case of esters, the most direct way of synthesis involves the interaction of acylchlorides AND-CO-CL or a(CO-CL)2in halogenierter type HO-Ya-Cl, HO-Ya-Br, HO-Ya-I, where Yais identical with Y or Y1as described above, without an atom of oxygen in experimental conditions that are part of a well-known methodology.

The reaction products of the formula A-CO-O-Ya-Cl(Br, I) can be also obtained by reacting the sodium or potassium salts of these acids AND-WITH-IT with diproduksi is converted into the final products by interacting with AgNO3in acetonitrile, in accordance with methods known from the prior art.

The General scheme is the following:

And-CO-CL+HO-Ya-Br- -->A-CO-O-Ya-Br+AgNO3- -->A-X1NO2,

where X1=YaO

The General scheme can also be the following:

A-CO-ONa+Br2Ya- -->A-CO-O-Ya-Br+AgNO3- -->A-X1NO2,

where X1=YaO.

In the case of amides sequence of synthesis involves reacting the same acylchlorides AND-CO-CL with aminoalcohols of General formula NH2-Ya-OH or other1c-Ya-OH with getting AMILO General formula;

A-CO-NH-Ya-OH, or A-CO-NR1c-Ya-OH

in accordance with known methods.

The interaction of these amides with halogenation agents such as, for example, PCl5, PBr5, SOCl2and so on, gives one the General formula:

A-CO-NH-Ya-Br(Cl) and A-CO-NR1c-Ya-Br(Cl).

By interacting with AgNO3in acetonitrile according to known literature methods these latest products give the final products AX1NO2.

This sequence can be represented as follows:

< / BR>
where YaO prestatie sodium and potassium salts of acid esters of nitric acid and halogenation General formula:

NO2-O-Ya-Cl(Br, I)

obtaining products directly according to this invention.

The scheme of this reaction is the following:

A-CO-ONa+Br-Ya-ONO2- -->A-CO-O-Ya-ONO2< / BR>
where YaO is X1.

Other synthetic routes, such as those described above, are those in which dehalogenase derived Br2Yainteracts with enolate. The reaction products then transform by interacting with AgNO3in acetonitrile in the above reaction. The General scheme is shown to HE related to the group And is as follows:

< / BR>
A General method for a group-IT is described in example 1 only for purposes of illustration.

Methods of obtaining these linking groups X1described in patent application WO 95/30641.

Products according to this invention, which are described above, are new in the quality of medicines. In particular, they are new in relation to their antithrombotic activity, and are new in the quality of the connection.

Additional pharmaceutical application, which can be specified for the products according to the invention is represented, for example, their antigipertenzivnye, in angina, heart failure, coronary ischemia).

In relation to antihypertensive activity it should be noted that the products according to the invention showed an extremely satisfactory pharmacological profile, with increased efficiency compared to previous models, which do not contain the group-ONO2and at the same time showed excellent security.

It should also be noted that the products according to the invention exhibit antihypertensive activity in combination with antithrombotic activity. This gives an extremely valuable benefit in the treatment of cardiovascular diseases in General, as the goal of any therapeutic approach is to provide the patient, in the aggregate, reduce the risk of cardiovascular diseases such as heart attack or brain, and atherosclerosis (Goodman & Gilman's "The Pharmacological basis of therapeutics, Ed. J. Hardman, L. Limbrid, pages 747, 1354-7, 1996).

The following examples are provided to explain but not limit the present invention.

EXAMPLES

EXAMPLE 1: Synthesis and characterization of NO-timolol (NO TEAM)

Synthesis of (R)-(4-nitroxy)butanoate 1-[(1,1-dimethyl)amino)-3-{ [4-(4-morpholinyl)-1,2,5-thiadiazole-3-yl]oxy}-2-propylmalonate the>/BR>(S)-1-[(1,1-dimethylethyl)amino] -3-{ [4-morpholinyl)-1,2,5-thiadiazole-3-yl} oxy}-2-propanol.

Timelimit (2.0 g) is subjected to interaction with a 10% NaOH solution (30 ml). Add 30 ml of CH2CL2and then the phases are separated. The aqueous phase is repeatedly extracted with CH2Cl2. The combined organic phases are dried (Na2SO4) and the solvent is evaporated under reduced pressure. Obtain 1.4 g of pure product (yield 96%).

1H NMR (300 MHz, CDCl3): 1,05 (N,, SN3), 2,7 (2H, DD, CH2-NH), 3,5 (4H, m, morpholine), and 3.8 (4H, m, morpholine), 3,85 (1H, m, CH), 4,4 (2H, d, O-CH2).

< / BR>
Hydrochloride (S)-1-[(1,1-dimethylethyl)amino]-3-{[4-(4-morpholinyl)-1,2,5-thiadiazole-3-yl]oxy}-2-propanol.

to 0.8 ml of a 7M solution of Hcl in isopropanol are added dropwise to a stirred with a magnetic stirrer, the solution of timolol (1.4 g) in isopropanol (30 ml). The solution is stirred for 30 minutes. The reaction mixture is freed from solvent under reduced pressure. Obtain 1.47 g of pure product (yield 91%).

1H NMR (300 MHz, CDCl3): 1,45 (N,, SN3), was 3.05 (2H, DD, CH2-NH), 3,5 (4H, m, morpholine), and 3.8 (4H, m, morpholine), and 4.5 (2H, d, O-CH2), 4,55 (1H, m, CH).

< / BR>
(R)-(4-bromo)butanoate 1-[(1,1-dimethylethyl)and the nitrogen added to stir magnetic stirrer, a solution of the hydrochloride timolol (0,82 g) in l2, dried over R2ABOUT5(20 ml). Stirring is continued for 4 days. Then the reaction mixture is freed from solvent under reduced pressure. The residue is subjected to chromatography on silica gel using diethyl ether with 3% Et3N as eluent. Get 0,830 g of the pure product from the intermediate fractions (yield 78%).

1H NMR (300 MHz, CDCl3): 1,05 (N, s, 3-CH3), was 2.05 (2H, m, COCH2-CH2-CH2-ONO2), and 2.5 (2H, m, COCH2-CH2-CH2-ONO2), 2,8 (2H, d, CH2-NH),

3,5 (6N, m, morpholine, CH2-Br), and 3.8 (4H, m, morpholine} and 4.65 (2H, d, O-CH2in ), 5.25 (1H, m, CH).

< / BR>
(R)-(nitroxy)butanoate 1-[(1,1-dimethylethyl)amino] -3-{ [4-(4-morpholinyl)-1,2,5-thiadiazole-3-yl)oxy}-2-propyl.

A solution of AgNO3(0,450 g) in CH3SN (5 ml) dropwise at room temperature add to the mix a magnetic stirrer, a solution of timolol-(4-bromo)butanoate (0,830 g) in CH3SP (10 ml). The temperature is gradually increased until 60oC, and the reaction continued for 24 hours. The reaction mixture is freed from solvent under reduced pressure. The residue is subjected to chromatography on silica gel using diethyl ether with 3% Et3N as eluent. Get 0,51 is), is 2.05 (2H, m, COCH2-CH2-CH2-ONO2), and 2.5 (2H, 2T, COCH2-CH2-CH2-ONO2), 2,8 (2H, d, CH2-NH),

3,5 (4H, m, morpholine), and 3.8 (4H, m, morpholine), and 4.5 (2H, t, -CH2-ONO2), 4,58 (2H, d, O-CH2in ), 5.25 (1H, m, CH).

MS: M+448

< / BR>
(R)-(nitroxy)butanoate 1-[(1,1-dimethylethyl)amino] -3-{ [4-(4-morpholinyl)-1,2,5-thiadiazole-3-yl]oxy}-2-propylmalonate

A solution of maleic acid (0,132 g) in acetone (5 ml) was added dropwise to a stirred with a magnetic stirrer, the solution timolol-(4-nitroxy)butanoate (0.50 g) in acetone (10 ml). Stirring is continued for 2 hours. The reaction mixture is freed from solvent under reduced pressure. The crude residue is triturated in diethyl ether to obtain 0.5 g of a white solid substance (so pl. 133-136oC, yield 70%).

1H NMR (300 MHz, CDCl3): 1,48 (N, s, 3-CH3), was 2.05 (2H, m, COCH2-CH2-CH2-ONO2), 2,58 (2H, TD, COCH2-CH2-CH2-ONO2), 3,3 (2H, 2m, CH2-NH), 3,5 (4H, m, morpholine), and 3.8 (4H, m, morpholine), and 4.5 (2H, t, -CH2-ONO2), 4,7 (2H, d, O-CH2), to 5.55 (1H, m, CH), 6,47 (2H, s, maleic).

EXAMPLE 2A: Synthesis and characterization of NO-enalapril NO-AISNE)

Scheme 1 reaction are listed at the end of the text.

Stud is ml of dimethylformamide (DMF) and triethylamine (tea) (2.76 g). The solution is stirred for 16 hours. Then the solution is twice washed with diluted HCl and water, extracted 3 times with 100 ml portions of ether. Dried and evaporated organic phase to give 3 g of the product of formula 2) (oil). In the formula 2) tBOC = tert-butylcarbamoyl.

Stage 2

1.4 g of dichlorophenylisocyanate (DCC) and then 30 ml of a solution of 1.1 g of nitrosomethylurea in CH2Cl2add 3 g of protected N enalapril (compounds of formula 2), dissolved in 50 ml of methylenechloride. The mixture is stirred over night, dicyclohexylamine filtered off and the solvent is evaporated to dryness. The residue is subjected to chromatography on Merck silica gel 60, using a mixture of ethyl acetate/hexane. Collect the fraction 2 g of the intermediate compounds of formula 3, where R represents the balance of nitrosomethylurea without IT.

Stage 3

1 g of the product of formula 3) is dissolved at 0oWith in a 4N solution of 30 ml of dry gaseous HCl in ethyl acetate (ACO-Et) and stirred for 10 hours. The resulting residue is filtered and dried under reduced pressure to obtain 0.5 g of the product 4).

EXAMPLE 2B: Synthesis and characterization of NO-enalaprilat (NO-ANP)

Scheme 2 reaction are listed at the end of the text.

Stage 1:

3 is of formamide (DMF) and triethylamine (tea) (2.76 g). The solution is stirred for 16 hours. Then the solution is twice washed with diluted Hcl and water, extracted 3 times with 10 ml portions of ether. Dried and evaporated organic phase to give 3 g of the product 2) in the form of oil. In the formula 2) tBOC = t-butylcarbamoyl.

Stage 2

2,75 g dicyclohexylcarbodiimide (DCC) and then 30 ml of a solution of 2.25 g of nitrosomethylurea added to 3 g of the protected N enalaprilat dissolved in 50 ml of methylenechloride. The mixture is stirred over night, dicyclohexylamine filtered off and the solvent is evaporated to dryness. The residue is subjected to chromatography on Merck silica gel 60, using a mixture of ethyl acetate/hexane. Collect the fraction of 3 g of the intermediate product 3). R has a value, which is defined in example 2A.

Stage 3

1 g of the product 3) was dissolved at 0oWith in a 4N solution of 30 ml of dry gaseous Hcl in ACOEt and stirred for 10 hours. The precipitate is filtered off and dried under reduced pressure. Obtain 0.7 g of the product 4).

EXAMPLE 3: Pharmacological studies

The products of examples 1 and 2 were applied in vivo is always in the form of a 2% by weight suspension in carboxymethylcellulose.

The experimental group was composed of the necessary.

With regard to acute toxicity of the compounds that are the subject of this invention, it has been evaluated after a single dose of the compound orally to groups of 10 mice each.

The level of destruction and the presence of toxic symptoms were recorded during the observation period of 14 days. Even after the introduction of 50 mg/kg in animals revealed no visible signs of overt toxicity.

EXAMPLE 3A: Study antithrombotic activity

The ability of MO-AISNE and NO TIM to suppress platelet aggregation was evaluated using the model in vivo, which is described Pinon (J. Pharmacol. Methods 12, 79, 1989). In 5 groups of rats male Wistar (200-250 g) were administered daily oral dose of 10 mg/kg, respectively, NO-AISNE, enalapril, NO-TIM, timolol or media for 5 days. At the appropriate time, on the fourth day, consuming food (but not water). After 18-20 hours, the animals received the last dose. After one hour the animals were doing anesthesia with 10% urethane (1 mg/kg, intraperitoneally) and inserted a cannula into the left jugular vein and right carotid artery. Then intravenously injected collagen (type 6, Sigma) at a dose of 2 mg/kg Over 3 minutes was collected two blood samples (a and b) of the carotid artery, using a 2.5 ml plastic syringes, following on the>1.3 mm, Na2PO413,4 mm), then the sample was transferred into a 5-ml polystyrene tubes for the study and allowed to settle for 15 minutes at room temperature. After this period, the aggregation of platelets in the sample And were fixed with formalin, whereas the units of the sample was treated EDTU. Then made the platelets count in each sample, using an ordinary microscope. The calculation for the sample was the total number of platelets, whereas the calculation for sample And counted the number of non-aggregated platelets. The results were expressed as the percentage of aggregation, calculated as follows:

{ [1-(number of platelets in the sample)/(the number of platelets in the sample) 100} . The results are expressed as the percentage of suppression from the control group (carrier solvent) and shown in Table 1.

TABLE 1

THE STUDY PROTIVOTROMBOZNOE ACTIVITY NO-PARKING OR NO-TIM COMPARED WITH ENALAPRIL OR TIMOLOL IN RATS

CONNECTION - ANTITHROMBOTICS ACTIVITY (%)

NO-AISNE - 65

NO-TIM - 58

ENALAPRIL - 15

TIMOLOL - 2

As shown in table 1, unlike comparable products, nitro-derivatives according to this invention are able to suppress the aggregation caused by collagen.

Podili daily oral dose, equal to 10 mg/kg, respectively NO-AISNE, enalapril, NO-TIM, timolol or medium (solvent) for 5 days. At the appropriate time, on the fourth day, food (but not water) was taken. After 18-20 hours, the animals received the last dose. One hour into the tail vein of animals took an injection of 0.1 ml of a mixture of collagen (type 6, Sigma) plus hydrochloride epinephrine (100 μm) dissolved in 0,154 M solution of sodium chloride. As explained previously (G. Cirino et al., Thrombosis Research 79, 73, 1995), injection of this mixture causes death within 3 minutes 90% of the control animals.

The results are expressed as percent suppression compared to the control group are presented in table 2.

TABLE 2

THE STUDY ANTITHROMBOTIC ACTIVITY NO-PARKING AND NO-TIM IN COMPARISON WITH ENALAPRIL AND TIMOLOL IN RATS

CONNECTION - ANTITHROMBIN ACTIVITY (%)

NO-AISNE - 53

NO-TIM - 44

ENALAPRIL - 11

TIMOLOL - 6

As shown in table 2, unlike comparable products nitro-derivatives according to this invention are able to inhibit thrombosis caused by collagen.

EXAMPLE 3C: THE STUDY OF THE ANTIHYPERTENSIVE ACTIVITY

The ability of NO-AISNE to suppress hypertension was evaluated using the model in vivo, which is described Ribe is the only NO-AISNE enalapril, NO-TIM, timolol or media for 5 days. Arterial hypertension caused by introduction of NWnitro-L-argentinetango ester (L-NAME) in drinking water for 6 weeks. L-HAME was dissolved in drinking water to a concentration of 60-70 mg per 100 ml, so that a day was administered amount equal to about 60 mg/kg one hour after the end of treatment was measured systemic blood pressure using a method using a cuff on the tail-cap method) (Zats, Lab.Anim. Sci. 42, 198, 1990).

TABLE 3

THE STUDY OF THE ANTIHYPERTENSIVE ACTIVITY OF NO-AISNE COMPARED WITH ENALAPRIL IN RATS

CONNECTION - MEAN BLOOD PRESSURE (mm Od)

MEDIA - 1707

NO-AISNE - 1154*

ENALAPRIL - 1635

*P<0,05 in comparison with other groups

As shown in table 3, in contrast to comparable product nitro-derivatives according to this invention is able to reduce blood pressure caused by thrombosis induced by L-NAME.

EXAMPLE 3B: THE STUDY OF THE ANTIHYPERTENSIVE ACTIVITY AND SAFETY IN RELATION TO EYE NO-PARKING OR NO-TIM IN COMPARISON WITH ENALAPRIL OR TIMOLOL IN RABBITS

In rabbits, topical application of 100 µg NO-PARKING or NO-TIM gave a stronger and more prolonged (more than 6 hours) reduction wew the-TIM the relationship between the concentrations of the product in the plasma (P) and aqueous humor (AH) compared to timolol was determined by HPLC. It was found that the ratio P/an for NO-TIM was 5.5 times lower than the ratio for timolol, which suggests that systemic absorption of nitro-derivatives (and therefore, any potential side effects of this derivative) was significantly reduced compared to the reference product.

EXAMPLE 3E: STUDYING THE EFFECTS OF NO-AISNE ON INDUCED BRONCHOSPASM IN GUINEA PIGS IN COMPARISON WITH ENALAPRIL

Bronchospasm induced by capsaicin in Guinea pigs, an animal model that closely resembles the ability of ACE inhibitors (angiotensin converting enzyme (ACE) to cause coughing patients (Subissi et al., J. Cardiovasc. Pharmacol. 20/1, 139-146, 1992).

Taken the test conditions were as described previously Del Soldato et al. (J. Pharmacological Methods 5, 279, 1981). Female Guinea pigs weighing 300-400 g, were done under anesthesia by intraperitoneal injection of 5.5-diethylbarbituric sodium (200 mg/kg) and maintained artificial respiration at a constant positive pressure. In the right jugular vein was inserted cannula for injection of the test compounds. Using the mid-section of the peritoneum were isolated duodenum and through a small cross-section inserted the tip of a suitable polyethylene (10 mg/kg), enalapril (10 mg/kg) or media. After 45 minutes the animals in the jugular vein was done by injection of 0.1 ml of capsaicin (1 mg/kg). Before injection of capsaicin and after it was measured changes in wash area using the modified apparatus Konzett, United with the corresponding printing multiplier (Hewlett Packard).

The results are calculated as the ratio of the responses obtained before and after administration of the test compounds, expressed as % of the response obtained from one carrier, and are shown in table 4.

TABLE 4

THE STUDY OF NO-AISNE ON BRONCHOSPASM INDUCED IN GUINEA PIGS IN COMPARISON WITH ENALAPRIL

TREATMENT - REACTION BRONCHOSPASM

MEDIA - 100

NO-AISNE - 72

ENALAPRIL - 327

As shown in table 4, nitro-derivatives according to this invention reduces bronchospasm caused by capsaicin, unlike comparable product that actually markedly increased the reaction bronchospasm.

Conclusions

As you can see from the above examples, nitro-derivatives that are the subject of this invention provide significant antithrombotic action and the action on the cardiovascular system with excellent b is oxymethyl)benzoyloxy] -3-[(1-methylethyl)amino]propoxy]benzoylacetone (NO-atenolol).

< / BR>
1. Synthesis of 4-[2-[4-(chloromethyl)benzoyloxy] -3-((1-methylethyl)amino] propoxy]benzoylacetonate

to 0.8 ml of a 7M solution of Hcl in isopropanol (5 ml) is added dropwise to a stirred with a magnetic stirrer, the solution of atenolol (1.5 g, 5,63 mmol) in isopropanol (70 ml). The solution is stirred for 3 hours, then remove the solvent under reduced pressure, to obtain the hydrochloride of 4-[2-hydroxy-3-[(1-methylethyl)amino] propoxy] benzoylacetone (1.75 g) as a crude product, which is used in the synthesis without further purification.

4-(chloromethyl)benzoyl chloride (2.2 g, 11.6 mmol) are added to a solution of the hydrochloride of 4-[2-hydroxy-3-[(1-methylethyl)amino] propoxy] benzoylacetone (5,63 mmol) in chloroform (70 ml). The mixture is stirred at room temperature for 6 hours and treated with triethylamine until reaching a pH of 7. The organic layer was washed with water (450 ml), dehydrated with sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel, elwira a mixture of n-hexane/ethyl acetate 1/1. 4-[2-[4(chloromethyl)benzoyloxy] -3-[(1-methylethyl)amino] propoxy] benzoylacetone get (950 mg) as oil. Yield 40%.

2. Synthesis of 4-[2-[4-(nitroxymethyl)benzoyloxy] -3-[(1-methylethyl)amino] propoxy]b mg, 2.14 mmol) in acetonitrile (30 ml) is added silver nitrate (520 mg, a 3.06 mmol) and the mixture is heated under irrigation phlegm for 10 hours in the dark. The precipitate (silver chloride) is filtered off, the solvent is removed under reduced pressure and the residue purified by column chromatography on silica gel using as eluting solvent ethyl acetate to obtain 4-[2-[4-(nitroxymethyl)benzoyloxy]-3-[(1-methylethyl)amino] propoxy] benzoylacetone (600 mg, 1.3 mmol) in the form of oil. Yield 63%.

3. Synthesis maleate 4-[2-[4-(nitroxymethyl)benzoyloxy] -3-[(1-methylethyl)amino]propoxy]benzoylacetone (NO-atenolol)

A solution of maleic acid (180 mg, 1.55 mmol) in acetone (8 ml) is added dropwise to a solution of 4-[2-[4-(nitroxymethyl)benzoyloxy]-3-[(1-methylethyl)amino] propoxy] benzoylacetone (500 mg) in acetone (10 ml). The solution was stirred at room temperature for 1 hour, then the solvent is removed under reduced pressure. The residue is treated simple diethyl ether and the solid is filtered off. The resulting maleate 4-[2-[4-(nitroxymethyl)benzoyloxy]-3-[(1-methylethyl)amino]propoxy]benzoylacetonate get with the release of 85% in the form of a white amorphous substance.

Anal. races. for

Pharmacological study of the activity against platelet NO atenolol

(example 3A on page 23 bids)

The ability atenolol NO to inhibit platelet aggregation assessed using models in vivo, as described Pinon (J. Pharmacol. Methods 12, 79, 1989). 3 groups of male Wistar rats (200 to 250 g) receive a daily oral dose of 10 mg/kg NO atenolol, atenolol or the carrier within 5 days. On the fourth day at the appropriate time, they are denied food, while water yield on demand, as before. After 18-20 hours, animals anaesthetize 10% urethane (1 mg/kg administered intraperitoneally) into the jugular vein and right carotid artery kanyoro. Then intravenously injected collagen (type 6, Sigma) at a dose of 2 mg/kg Three minutes later, two blood samples, identified respectively as sample a and sample b are selected from the carotid artery using plastic syringes 2.5 ml in the following way: 0.4 ml blood in 1.6 ml of EDTA buffer/formalin (TETRANITRATE salt EDTA 24 mm KN2RHO41.3 mm, Na2PO4the 13.4 nm), then the sample is transferred into polystyrene tubes for testing capacity of 5 ml and left to precipitate for 15 minutes at ambient temperature. After this time, the aggregation of platelets in the sample And record what lsua an ordinary microscope. The number of samples is the total number of platelets, while in the sample And consider only non-aggregated platelets. The results are presented as interest aggregation, calculated as follows: {[1-(number of platelets in the sample)/(the number of platelets in the sample)]100}. The results are presented as the percentage inhibition of the control group (medium). The results are shown in table 1.1 below:

TABLE 1.1

Connection Activity against platelet count (%)

NO-atenolol - 40

Atenolol - 2

The table illustrates that the activity against platelet-NO-atenolol almost 20 times higher than the activity of the predecessor.

Pharmaceutical preparation in the form of eye drops containing as active ingredient a compound of the invention.

Components: - Percent (wt./about.)

NO-timolol - 0,445

The benzalkonium chloride - 0,010

Sodium chloride - 0,490

Monolatrist - 0,460

Centripetal - 0,880

The disodium salt of EDTA - 0,025

Water for injection to 100 ml

PREPARATION OF

NO-timolol get under approx. 1, page 14 of the application. Dosage form prepared in sterile conditions. Solubilizing 4,450 NO-timolol in 500 ml of water for injection (USP) by peremeci peremeshivayte until complete solubilization, g:

The benzalkonium chloride - 0,100

Sodium chloride - 4,900

Monolatrist - 4,600

Centripetal - of 8.800

The disodium salt of EDTA - 0,250

When all components solubilizers, the solution is transferred into a volumetric flask of 1 liter and adjusted to this volume by adding water for injection.

The solution is filtered using a sterilizing filter (0.22 μm PVDF).

Solution fill sterile vessels of RE capacity 10 ml

1. Organic nitrates General formula

< / BR>
or their salts,

where t0= 1;

A - RN0where N0= (COXu)tor COON1,

where t is an integer of 0 or 1;

u is an integer of 0 or 1;

X = O, NR1c,

where R1crepresents an alkyl straight or branched chain, having from 1 to 10 carbon atoms;

N1represents an alkyl straight or branched chain, having from 1 to 10 carbon atoms or hydrogen;

R is selected from the following groups:

* Group a)

< / BR>
where RIaand RIIaare the same or different and represent H or a linear or when possible branched alkyl of 1 to 3 atoms, preferably RIa= RIIa- the where N2has the same meaning as N0and at least one group of N0or N2has a free valence capable of binding with1(i.e. t = 1);

* Group C),

where t = 1 and u = 0

< / BR>
where RIa, RIIahave the meanings specified for 1a);

RIbhas a value of RIa;

nIamatter listed for 1A);

RBAchosen from:

< / BR>
< / BR>
where in group b) N2has the values listed above, and at least one of the N2groups has a free valence capable of contact1(i.e., at least one Deputy N2has t = 1);

X1represents a bivalent connecting bridge selected from: - Y0where Y represents a C1-C20alkylen with direct or, where possible, branched chain, preferably having from 2 to 5 carbon atoms; Y1selected from

< / BR>
where n3is an integer from 0 to 3.

2. Connection on p. 1, in which R, R1, R1c, RBAare remnants of enalapril, enalaprilat, timolol, atenolol.

3. Connection PP. 1 and 2, with antithrombotic activity.

4. Connection PP. 1 and 2, is of protector.

6. Pharmaceutical composition having inhibitory platelet aggregation activity containing a compound according to any one of paragraphs. 1 and 2, and a pharmaceutically acceptable carrier or diluent.

7. The composition according to p. 6, which is the antithrombotic composition.

8. The composition according to p. 6, which is the antihypertensive composition.

9. The composition according to p. 6, which is cardioprotective composition.

 

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< / BR>
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< / BR>
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< / BR>
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