Nitro compounds and pharmaceutical composition having anti-inflammatory and antithrombotic activities

 

(57) Abstract:

Describes new compounds or their compositions with the General formula A-X1-NO2or their salts, are used as medicines, where A = R (COX)t, t = 0 or 1, X = O, R means (a) where a denotes CH2-ONO2, - CH2CH2CH2CH2ONO2, -CH2CH2ONO2where Xo- X, R1means OCOR3group, where R3means methyl, R2means hydrogen, nitro, X1in the formula A1-X1-NO2denotes a bivalent connecting bridge, selected from the following: -YO-, where Y is selected from: linear or, when permissible, branched C1-C20alkylene, -(CH2-CH(R2a)-O)n-(YO)r- where n stands for integers 1 to 6, R2ameans H, CH3, r = 1, Y = CH2-CH2. The new compounds possess anti-inflammatory, analgesic and antithrombotic activities. 2 c. and 1 C.p. f-crystals, 1 PL.

The present invention relates to new products that have anti-inflammatory, analgesic and antithrombotic activities.

In particular, it relates to inhibitors of cyclooxygenase (SOH) of the class of aspirin, i.e., acetylinic the effectiveness of NSAIDs (non-steroidal anti-inflammatory drug), also known as FANS, but mainly their General tolerance, as it turns out, is significantly determined by their inhibitory activity of cyclooxygenase (SOH) in the inflamed area as well as in healthy tissue. See, e.g., FASEB Journal 1, 89, 1987; Bioch. Biochys. Acta 1083, 1, 1991. B generally assume that the most potent MOR-inhibitor is the most effective.

The disadvantage of these compounds is their toxicity.

In addition, it is also known that MOR-inhibiting properties are determined by several factors related to the physico - chemical and structural characteristics of molecules, such as, for example, an acid function. See, e.g., J. Pharmacol. Exp. Therap. 196, 226, 1976; Arch. Toxicol. 60, 261, 1987.

Known inhibitors of cyclooxygenase - mostly acid, which can be reduced to General structures, including:

- carboxylic acids, or their acetylated derivatives, for example, aspirin or triflusal, or deatsetilirovanie, such as, for example, salicylate, diflunisal, salsalate;

- acetic acid, for example, diclofenac, indomethacin, tolmetin, sulindac, etodolac, Ketorolac;

- propionic acid, such as, for example, ibuprofen, naproxen, pirprofen is, carprofen, suprofen.

See, for example, prior to the patent application in the name of the applicant PCT/EP 95/01233 given here as a reference, which describes prior knowledge about the above mentioned products.

As mentioned, the disadvantage of these products is that they are very effective, but extremely toxic.

The importance of the acid function is based on the fact that zamaskirovana this function in MOR-inhibitors leads to a really complete loss of their prostanoid-inhibiting properties. See, Drugs 35, 504, 1988.

Also known products that are highly effective in the inhibition of cyclooxygenase and have low toxicity, even if they do not contain an acid function in its molecule.

These products are known as esters of nitric acid with a non-acidic ends. See, for example, patent WO 94/04484, which describes a specific group of compounds consisting of a well-known commercial product diclofenac; WO 94/12463, which describes another specific group of compounds, including commercial products flurbiprofen and indoprofen, PCT/EP 94/03182, which describes another specific group of compounds including commerces other nitroethane, having non-acidic end, have been described, with various linking groups X1as indicated below.

These new described linking groups have the advantages of pharmacological and pharmaceutical point of view, in particular, pharmacokinetic and pharmacodynamic point of view, as they show a lower variability of the response. These products are described in the aforementioned patent application, also caused the inhibiting effect of inflammation caused by liposaccharide (LPS) and were also useful in septic shock. This result was unexpected because it is well known that anti-inflammatory products are mostly not significantly alter the activity of nitrogenates induced by lipopolysaccharide in the rat and in addition they are not useful in septic shock.

This technical problem is solved by the present invention, refers to inhibiting MOR products, the most effective in the inhibition petrinovic aggregation caused by arachidonic acid and thrombin, the latter plays a well-known primary pathogenetic role, even excelling in arachidonic acid and other stimulants aggregation above the mucous membrane of the treated animals.

The applicant has unexpectedly and surprisingly found a specific class of anti-inflammatory products that are described here below with improved inhibitory activity of SOKH in combination with low activity.

The object of the present invention are compounds or compositions of the General formula:

A - X1- NO2< / BR>
or their salts for use as pharmaceuticals, in particular anti-inflammatory and antiplatelet agents with improved efficacy in the inhibition petrinovic aggregation caused by arachidonic acid and/or thrombin, where:

A=R(COX)t,

where t stands for zero or 1;

X = O, NH, NR1C,

where R1Cmeans a linear or branched alkyl having from 1 to 10 carbon atoms, predominantly 1-4 C-atoms, or

< / BR>
< / BR>
where m and n denote integers from 1 to 6, preferably m is 1 to 3, and n is from 2 to 4; R2ameans H, CH3; linking with X1can be in any position of the ring, preferably in position 2; -OCOR3preferably, in the position ortho with respect to COXabout-; Xabout= X;

R is selected from:

< / BR>
where R1means OCOR3group, where R3means methyl, 5 or 6 atoms, which may be aromatic, partially or fully hydrogenomonas containing one or more heteroatoms independently selected from O, N and S;

R2means a hydrogen, hydroxy group, halogen, a linear or, when permissible, branched alkyl having from 1 to 4 carbon atoms, a linear or, when permissible, branched alkoxyl having from 1 to 4 carbon atoms, a linear or, when permissible, branched perfluoroalkyl having from 1 to 4 carbon atoms, for example trifluoromethyl; nitro, amino, mono - or dialkylamino in which alkylamine has from 1 to 4 carbon atoms; R1and R2together are dioxymethylene group, with the proviso that, when X = NH, then X1means ethylene and R2= H; R1cannot be OCOR3in position 2, when R3means methyl; and nl is 0 or 1;

X1in the formula A-X1-NO2means a bivalent connecting bridge, selected from the following:

-YO-

where Y is selected from:

- linear or, when permissible, branched C1-C20-alkylene, preferably having from 1 to 3 carbon atoms;

- cycloalkyl having 5 to 7 carbon atoms, optionally substituted;

< / BR>
where n denotes an integer Chi is UB>1-C10preferably C2-C6.

Preferred products according to the present invention, are those in which t = 0, Xaboutmean oxygen; a group that has NO2is in position 2 relative to COXabout; nl = 0; R3= CH3. In particular, the preferred products according to the present invention, are the following:

< / BR>
where means-CH2-ONO2, -CH2CH2CH2CH2ONO2, -CH2CH2ONO2, -CH2CH2OCN2CH2ONO2, -CH2CH2CN2ONO2.

Methods of making compounds of this invention are, for example, described in The Merck Index, XI ed., 1989, page 16, n. 95 or in the German patent 236.196, or the well-known chemical methods for the introduction of groups in different positions. Modifications of the compounds of General formula can be obtained using the methods described in the patent WO 92/01668.

The products of the present invention of General formula A-X1-NO2from the linking group X1as stated above get when using methods of the prior knowledge described above, or by modifications of the methods known for the introduction of binding with the introduction COXabout-group.

Generally, the relationship between a and X1is, as you can see, ester or amide type (NH or NR1Cas indicated in X). All well-known synthetic route for the formation of these relationships can be used to form this connection.

In the case of esters, the most direct synthetic path involves the reaction of acyl chlorides R-CO-Cl with halogenated alcohols, such as, BUT-Y-Cl, HO-Y-Br, HO-Y-I, in experimental conditions, well known in this field.

The reaction products into final products by reacting with AgNO3in acetonitrile, in accordance with what is well known from the literature.

A common way is the following:

R-CO-Cl + HO-Y - Br --->R-CO-O-Y-Br + AgNO3--->A-X1-NO2< / BR>
where X1= YO.

In the case of amides synthetic path includes the reaction of the above-mentioned acylchlorides RCOCl with aminoalcohols of General formula NH2-Y-OH, OTHER1C-Y-OH to obtain amides of General formula:

R-CO-NH-Y-OH and R-CO-NR1C-Y-OH

in accordance with known methods.

The reaction of the above-mentioned amides with halogenation agents such as, for example, PCl5, PBr5, SOCl2and so on, leads to halogen is AI with AgNO3in acetonitrile according to known literature methods, give the final products A-X1-NO2.

This path can be represented as follows:

< / BR>
R-CO-NR1C-Y-Cl + AgNO3---> R-CO-NR1C-Y-ONO2< / BR>
where YO means X1.

Alternative through the formation of ester is the reaction of the sodium or potassium salts of acids with nitropyrene halogenated alcohols of the General formula:

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

to get the products of this invention.

Reaction path following:

R-CO-ONa + Br-Y-ONO2---> R-CO-O-Y-ONO2< / BR>
where YO is the X1.

The following examples are given only as illustrative explanation and do not limit the present invention.

Examples.

Example 1: Comparison - receipt of products.

Used acetylsalicylic acid available on the market, aspirin Bayer.

Example 2: Comparison - receiving compound A-X1-NO2where R corresponds to the formula of aspirin, shown below, X1means -(CH2)4O-called here ANBE, and having the General formula:

2-acetoxy-benzoate(4-nitroxy)butyl

< / BR>
P is the target:

acetylsalicylic acid, 15.0 g and

the formamide - 50 ml

supported at 0oC in a stream of nitrogen was added in parts:

2.6 g Nal (suspension in vaseline oil 80% weight).

This mixture was stirred 1 hour and then was added dropwise for 5 hours at 25oC stir the solution:

2,2'-dibromobutan - 27.0 g and

the formamide - 50 ml

This mixture was stirred for 3 days, then dried under reduced pressure. This residue was treated with:

water - 50 ml

dichloromethane 50 ml

This mixture was stirred for 3 days, then dried under reduced pressure. This residue was treated with:

water - 50 ml

dichloromethane 50 ml

The phases were separated and the aqueous phase further extracted with 10 ml dichloromethane.

The combined organic phases were washed with water (3 x 25 ml), dried (MgSO4), was decolorized by animal charcoal (1 g) and dried under vacuum.

This residue (26.0 g) was used as raw material for the next reaction.

Getting ANBE.

In solution

ACK-(CH2)4Br - 26.0 g

acetonitrile and 65 ml,

supported at room temperature and protected from light, was added

silver nitrate - 21.0 grams

After 2 days the salt was filtered and from the filtrate solvent was removed under reduced pressure.

Received 18.0 g of sludge and spent chromatography on a column of silica gel (500 g of silica), elwira a mixture of toluene/ethyl acetate 95/5 about/about.

Faction was homogeneous in TLC (thin layer chromatography) analysis, and they were combined and dried, obtaining 15.0 g ANBE.

N1NMR (CDCl3) (80 MHz) analysis showed the following data:

2.28 (3H, s); 1.2 (4H, m); 4.30 (2H, t);

4.50 (2H, t); 7.3 (3H, m); 7.95 (1H, DD).

IR analysis (nujol) presented the following results:

CCA= 1780 cm-1;

SOO= 1725 cm-1;

N2= 1641 e 1287 cm-1.

Mass spectrometry showed a molecular weight of 297.

Example 3 to Obtain compound A-X1-NO2where R has the formula shown below, X1means -(CH2O, here called ANMPE having the formula:

2-acetoxy-benzoate (3-nitro methyl)phenyl

< / BR>
The intermediate compounds of the formula

< / BR>
In a 1 l flask was added:

3-OH-benzyl alcohol - 28.1 g (0.226 moles)

methylene chloride - 85 ml

HBr (48% weight in water) - 140 ml

and stirred at room temperature for an hour and a half.

After the phases were separated and the aqueous phase further extracted methylenchloride NaHCO35% (wt./about.) - 50 ml

Then they were obezvozhivani MgSO4and dried, obtaining 34.13 g of crystalline solid precipitate. This product was characterized by TLC analysis using a mixture of toluene/ethyl acetate 7/3.about. as eluent.

The thus obtained product is directly used for the next reaction.

In a 1 l flask equipped with a stirrer, thermometer, drip system, she added:

the residue from the previous reaction - 34 grams

acetonitrile - 100 ml

In the drip system was placed a solution:

silver nitrate - 38.5 g

acetonitrile 60 ml

was added dropwise in about 2 hours, protecting the bulb from the light and cooling it in a water bath.

The temperature was maintained between 20 and 30oC.

The reaction was left for 15 hours.

Then filtered and the filtrate was dried; to the precipitate was added ethyl acetate, about 500 ml, and then the silicon oxide (50 g) and charcoal (3 g).

The filtrate was dried again and held chromatography on 300 g of silica using toluene as eluent, using chromatographic system above.

Received 11.7 g of the product (dark oil) and was characterized by TLC.

Getting ANMPE

< / BR>
In - .95 g

potassium carbonate 7.0 g

the ethyl acetate 50 ml

Was cooled to 0oC and was added dropwise in a stream of nitrogen for 15 minutes the solution:

acetylsalicyloyl chloride - 5.01 g

the ethyl acetate 20 ml

Upon completion of the addition the mixture was left to react for about 4 hours at 20oC.

Carried out the reaction in TLC (toluene/ethyl acetate 9/1.vol.). At the end was added 70 ml of distilled water.

The phases were separated, the aqueous phase was again extracted with 30 ml ethyl acetate and the combined organic phases were washed with water (30 ml) containing sodium chloride (10 g).

The organic phase was obezvozhivani magnesium sulfate and dried; received 8.9 g of residue (yellow oil, which solidified when cooled at 0oC. crystallization from isopropyl ether there was obtained 6.5 g ANMPE in pure form. Analysis1H NMR (CDCl3) (80 MHz) showed the following data:

2.34 (3H, s); 5.45 (2H, s); 7.05-7.75 (7H, m); 8.24 (1H, DD).

Example 4: pharmacological examples.

The products, obtained above, was characterized from the point of view of pharmacology.

In vivo studies (e.g., toxicity) products obtained above were introduced in suspension in carboxymethylcellulose 1-2% of the weight.

2O in the ratio 1:10 by volume and then diluted to the concentrations shown in the table.

Samples obtained without the addition of substances for validation (ACK, ANBE, ANMPE), did not show any significant response.

The toxicity.

Acute toxicity was evaluated by oral administration of single doses 1, 3, 10, 30, 100, 200 mg/kg product group of 10 young rats.

Fatal cases and the emergence of symptoms of intoxication have been described for a period of 14 days. Even after a dose of 200 mg/kg animals did not show any obvious intoxication after ANMPA and ANBE.

The tolerance.

Gastrointestinal tolerance was determined by oral administration in the rat, in assessing the gravity induced gastropathy by the criteria specified Wallace et al. (Am. J. Physiol. 259, G642, 1990).

Piastrina tests.

Protivoalergicescoe piastrina activity (antithrombotic activity).

Protivoalergicescoe piastrina activity was determined in vitro on piastrina person caused by thrombin or arachidonic acid by the method described Bertle et al. (Science 220, 517, 1983).

defined in piastrina person method, described Patrono et al (Thrombosis Res. 17, 317, 1980). Enzyme activity was initiated to limit the Thromboxane B2 (TxB2) and was measured in ng/ml.

Piastrina adhesion.

Activity inhibition petrinovic adhesion was evaluated according to the method described Bellavite et al. (Anal. Biochem. 216, 444, 1994).

Intracellular patrimony calcium.

We measured the effect of the compounds of the invention or the comparative compounds on the concentration of calcium inside piastrina according to the method of Pollock et al. (Biochem. J. 235, 869, 1986).

RESULTS.

From the results table, you can see that ANMPE (compound of the invention) is much more efficient compared to ACK and ANBE when inhibition petrinovic aggregation caused by arachidonic acid. If ANMPE it is higher than in the case ANBE, and like ACK.

However, in the case petrinovic aggregation caused by thrombin, which is known to the higher pathogenic significance compared with arachidonic acid or other aggregation stimulus, ANMPE shows values remarkably higher compared to ANBE and ACK.

In the case of properties inhibition of MOR-product of the invention shows activity similar to ACK, but higher compared to ANBE.

Ÿ the gastric mucosa.

Indeed, tests on gastric tolerance has shown that at doses of 50-100 mg/kg ACK causes severe damage to the gastrointestinal mucous membrane of the treated animals.

As for the other petrinovich tests:

piastrina adhesion and intracellular patrimony calcium, only ANMPE very effectively leads to inhibition and dependent on dose by (10-5up to 10-4both pathological processes.

On the contrary, it is impossible to observe any inhibitory effect of the other compounds that were tested.

Example 5

Obtain 3-[2-(nitrocellulose)ethyl]fenilefrina 2-acetoxybenzoic acid

< / BR>
A) Obtaining 3-[(2-hydroxyethyl)]fenilefrina 2-acetoxybenzoic acid. To a solution of 3-hydroxyphenylacetamide alcohol (10 g, 0,072 mol) in toluene (50 ml) and triethylamine (9.8 g, 0.1 mol), cooled to 5-10oC, add a solution of O-atsetilsalitsilovaja (14.3 g, 0,072 mol) in toluene (50 ml). The mixture is stirred for 2 hours at 5-10oC. the Mixture was poured into water and extracted with CH2Cl2(2 x 100 ml). The organic layer was separated, washed successively with 25% solution of potassium carbonate, water, 3% solution of hydrochloric acid is IntelliTouch from isopropanol. Receive 3-[(2-hydroxyethyl)] venilator 2-acetoxybenzoic acid (10 g, 0,033 mol). Yield 46%.

1H-NMR (CDCl3) (M. D.): 2,30 to 2.35 (5H, m); 3,70 (2H, t); 7,07 to 8.2 (m, aromatics, 8H).

C) Obtaining 3-[2'-(2-bromoethoxy)ethyl] fenilefrina 2-acetoxybenzoic acid.

To a solution of 3-[2-hydroxyethyl]phenyl ester 2-acetoxybenzoic acid (10 g, 0,033 mole) in dimethylformamide (50 ml) add ethoxide sodium (2.25 g, 0,033 mol), the mixture is stirred for 1 hour and then added 1,2-dibromoethane (6 g, to 0.032 mol). The mixture is stirred for 6 hours, then poured into water (150 ml) and extracted with ethyl acetate (3 x 50 ml). The organic layer is washed with water, dehydrated with sodium sulfate and the solvent is evaporated under vacuum. The residue is purified chromatographically on a column of silica gel, elwira n-hexane/ethyl acetate (1:1 V/V) and receive 3-[2'-(2-bromoethoxy)ethyl] venilator 2-acetoxybenzoic acid (8,14 g of 0.02 mol). Yield 60%.

1H-NMR (CDCl3) (M. D.): by 8.22 (1H, dd); 7,66 (1H, td); 7,47 (1H, t); 7,40 (1H, td); to 7.32 (1H, d); 7.24 to 7,21 (2H, m); to 7.18 (1H, dd); 3,75-3,5 (6H, m); 2,30 is 2.33 (5H, m).

C) Obtaining 3-[2'-(2-nitroacetate)ethyl] fenilefrina 2 - acetoxybenzoic acid

To a solution of 3-[2'-(2 - bromoethoxy)ethyl]fenilefrina 2-acetoxybenzoic acid (8 g, 0,019 malempati 50oC for 12 hours. The precipitate is filtered and the solvent is evaporated under vacuum. The residue is purified chromatographically on a column of silica gel, elwira hexane/ethyl acetate (7/3 V/V), and obtain 3-[2'-(2 - nitroacetate)ethyl]venilator 2-acetoxybenzoic acid (5.8 g, and 0.15 mol). Yield 78%.

1H-NMR (CDCl3) (M. D.): by 8.22 (1H, dd); 7,66 (1H, td); 7,47 (1H, t); 7,40 (41H, td); to 7.32 (1H, d); 7.24 to 7,21 (2H, m); to 7.18 (1H, dd); 4,58 (2H, t); of 3.75 (4H, m); 2,30 is 2.33 (5H, m).

Example 6

Obtaining tablets containing 3-(nitroxymethyl)vinylether 2-(atomic charges)benzoic acid.

Composition:

3-(nitroxymethyl)vinylether 2-(atomic charges)benzoic acid - 300 grams

colloidal silicon dioxide is 0,300 g

microcrystalline cellulose - 143,7 g

talc 3 g

magnesium stearate 3 g

Each tablet contains 300 mg of active principle.

Description

The medicinal substance is first mixed by mortar and pestle with colloidal silicon dioxide. Then to the active mixture of microcrystalline cellulose according to the method of "successive dilutions". In conclusion, add talc. This physical mixture was poured into a mixer Tubula Tubula and stirred for 10 minutes before adding the magnesium stearate and then re is (Ronchi), contains standard concave surface for processing, and receive yellow round tablets with an average weight of 450 mg and the strength of 10 kg

1. Nitroarginine General formula

A-H1-NR2< / BR>
or their salts,

where A = R(SOH)t, t = 0 or 1,

X = 0;

R represents a

means-CH2-TNA2, -CH2CH2CH2CH2TNA2, -CH2CH2TNA2,

Xabout- X;

R1means R3group, where R3means methyl, R2means hydrogen, nitro,

X1in the formula A-X1-NR2means a bivalent connecting bridge, selected from the following: -PP-, where Y is selected from : linear or, when permissible, branched C1-C20alkylen,

< / BR>
where n denotes the integers 1 to 6, nl = 0, 1,

R2Ameans H, CH3,

r = 1, Y = CH2-CH2.

2. Connection on p. 1, where R is

where means-CH2-TNA2-CH2CH2CH2CH2TNA2, -CH2CH2TNA2.

3. Pharmaceutical composition having anti-inflammatory and antithrombotic activity, characterized in that it contains the connection

 

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