Nitroxoline and pharmaceutical composition based on them, have anti-inflammatory, analgesic and antiplatelet activity

 

(57) Abstract:

The invention relates to nitroglicerine General formula A-X1-NR2or their salts, where a and X1have the meanings indicated in the claims, as well as to pharmaceutical compositions based on them. Compounds and compositions can be used in medicine, such as the products have anti-inflammatory, analgesic and antithrombotic activities, as well as activity against septic shock. 2 c. and 2 C.p. f-crystals, 4 PL.

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

In particular, it relates to inhibitors of cyclooxygenase (COX).

It is known that anti-inflammatory and antithrombotics activity, but mainly tolerance NSAID (non-steroidal anti-inflammatory drugs, also known as FANS, apparently greatly determined by their cyclooxygenase (COX)-inhibiting activity in the inflamed area as well as in healthy tissue. See, for example, FACEB Journal 1, 89, 1987; Bioch. Biophys. Acta 1083, 1, 1991. Basically it is assumed that the most potent COX-inhibitor ablamovo, it is also known that COX-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, tiaprofenic acid, loxoprofen, indoprofen, oxaprozin, Ketoprofen, fenoprofen, fenbufen, flurbiprofen, carprofen, suprofen:

- enol acids, such as, for example, oxyphenbutazone, phenylbutazone, piroxicam, sudoxicam, tenoxicam, isoxicam, meloxicam.

See patents USP 3558690; USP 3755427; USP 3641127; FR 2112111; USP 4035376; USP 3997669; USP 3784701; USP 3896145; USP 3600437; USP 3843681; USP 3904682; USP 3228831; USP 4161538; USP 4233299; USP 3591584; DE 2537070; USP 3161654; USP 4061779; USP 4556672; USP 4089969.

The lack atlautla the fact, what disguise this function in COX-inhibitors leads to almost 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 even have a low toxicity, although they do not contain acid functionality in their molecules.

These products are known as esters of nitric acid with a non-acidic ends. See, for example, patent PCT WO 94/04484, which describes a specific group of compounds consisting of a well-known commercial product diclofenac; PCT/EP 93/03193, which describes another specific group of compounds, including commercial products flurbiprofen and indoprofen.

The applicant has unexpectedly found that other compounds having a terminal group-NO2when X1=-YO-as shown here below, have anti-inflammatory, analgesic and antithrombotic activity when used as a drug with high efficacy in the inhibition of cyclooxygenase and have low toxicity.

The next aim of the invention is that known products, as described in PCT WO 94/04484 and PCT/EP 93/03193, and new connections that are found will declare the x inhibitory activity of cyclooxygenase, the experiments conducted by the applicant showed high reactivity variability, on the order of 10-40%.

In most cases, these results are random and unpredictable actions, and thus to determine the exact dose is difficult.

In practice, to limit the above variability, should be applied to higher doses. The disadvantage of this is the increased risk of side effects.

Another disadvantage of these products is the difficulty of recipes from the point of view that oral or parenteral drugs are more difficult to prepare than traditional drugs, based on the acid FANS.

Molecular solubility is known to be one of the most important properties determining the molecular pharmokinetic and dynamics of processes.

For example, for parenteral administration, especially intravenous drugs should be presented in a soluble form.

Similarly, in oral introduction the dissolution process is crucial for the absorption and interaction with the effector.

In this regard, the special choice of solvents and/or excipients, including surfactants, is also crucial with the th components of blood.

Meanwhile, there are many facts that show that the surfactants and non-polar solvents can have irritating properties. See, for example, J. Pharm. Science 72, 1014, 1983.

Tests conducted by the applicant, using 0.1% tween 80 and 1%dimethyl sulfoxide with suspended nitrosomorpholine showed that this solvent irritate the stomach.

However, it was unexpectedly found that when using NO-flurbiprofen derived, as described below, which is part of the object of the present invention, the amount of tween 80 and dimethyl sulfoxide, necessary for the preparation of suspensions were smaller, so it does not have any irritating effect, although the solubility was found to be similar.

It was unexpected and unpredictable found after much research that it is possible to obtain anti-inflammatory products, as described below, having a high inhibitory cyclooxygenase activity in combination with low toxicity and satisfactory pharmacokinetics and having a very limited variability of the responses with an average rate of about half that of the known product which was unexpected and unpredictable in relation to factors which determine the anti-inflammatory and antithrombotic action of NSAIDS, dependent on different parameters. Therefore, it is impossible to predict the pharmacokinetics, for example, products of fractional absorption, pharmacological activity, toxicity and COX-inhibitory properties, and most of all, it is impossible to predict or limit the variability of the result.

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, where:

A=R(COXu)twhere t denotes zero or 1; u is zero or 1:

X=O, NH, NR1Cwhere R1Cmeans a linear or branched alkyl having from 1 to 10 carbon atoms; R is selected from the following groups:

- group I), where t = 1 and u = 1

< / BR>
where R1means OCOR3group, where R3means methyl, ethyl or a linear or branched C3-C5alkyl, or the residue of a heterocycle with one ring having 5 or 6 atoms, which may be aromatic, partially or fully gidrirovanny containing one or more heteroatoms, not the branched alkyl, having from 1 to 4 C atoms, a linear or when possible branched alkoxy having from 1 to 4 carbon atoms, a linear or when possible branched perfluoroalkyl having from 1 to 4 C atoms, for example, trifluoromethyl, nitro, amino, mono - or di-(C1-4)alkylamino:

R1and R2together mean dioxymethylene group, provided that when X=NH, then X1means ethylene and R2=H; R1cannot be OCOR3in position 2, when R3means methyl: nI is 0 or 1.

Preferably, Ia) X is O or NH, R1means acetoxy, preferably in the ortho-position relative to the-CO-, X1means (CH2-CH2-O)2, R2hydrogen, the most preferred following A-X1-NO2connection: 3-acetoxy-N-(2-nitroxyethyl)-benzamide, 4 - acetoxy-N-(2-nitroxyethyl)-benzamide, 3-acetoxy-N-(2 - nitroxyethyl)-benzamide; 2-acetoxy-n-(5-nitroxyethyl)- benzamide, N-2-(5-nitroxyethyl)-2-propionoxy-benzamide, 2-acetoxy - 2-nitroxy-ethylbenzoic, 2-acetoxy-N-(CIS-2-nitrobenzyloxy)- benzamid, 2-acetoxy-4-chloro-N-(2-nitroxyethyl)-benzamide, N-(2 - nitroxyethyl)-benzamide, N-(2-nitroxyethyl)-((4 - thiazolidine)carbonyloxy)-benzamide hydrochloride, 2 - nicotinergic-N-(2/BR> X 0, X1means ethylene: in this case Ib) means the remainder of acetylsalicylic acid;

Compounds Ic class Ic1) derivatives of 5-aminosalicylic acid (5-amino-2-hydroxybenzoic acid), known as mesalamine, when the valence is saturated with-COOH.

In the compounds Ic2at least one-COOH reacts to form compounds of the invention. When they react both-COOH; get bifunctional compounds. When the connection is saturated-COOH, it is known as olsalazine.

Compound Ic3it is known when the initial radical is-COOH, as alfalasi: 2-hydroxy-5-[(4-[(2- pyridinylamino)sulfonyl]phenyl)azo]benzoic acid.

Preferred compounds Ic) have X=O and u=1 and x1differs from-YO-,

- group II) where t = 1, u = 1

< / BR>
where RII5means hydrogen, linear or branched C1-C3alkyl, whenever possible, RII6has the same values as RII5or, when RII5means hydrogen, it can be a benzyl;

RII1, RII2and RII3independently from each other denote hydrogen, a linear or when possible branched C1-C6alkyl or C1-C6alkoxy, or Cl, F, Br;

RII 4Osnat and RII3means chlorine, and RII3located in the ortho-position relative to the NH;

RII5and RII6mean H, X is O and X1means (CH2-CH2-O)2;

IIb) means the residue of 2-[(2-methyl-3-(trifluoromethyl)phenyl)amino]- 3-pyridineboronic acid, and when the-COOH is present, it is known as flunixin.

Preferred compounds in which u=1 and X=O;

- group III), where t = 1, u = 1 and R means:

< / BR>
where: R2aand R3adenote H, linear or when possible branched, substituted or unsubstituted C1-C12alkyl, allyl, provided that when one of the two groups means allyl, other means hydrogen; preferably R2ameans H, alkyl having from 1 to 4 C, R3ameans H;

R1achoose from

< / BR>
< / BR>
< / BR>
III (D) has the following connections:

< / BR>
< / BR>
where values are the following:

in the compound of formula (IV) residue Ketoprofen;

RIII1means H, SRIII3where RIII3contains from 1 to 4 C atoms, a linear or when possible branched;

RIII2means H, hydroxy;

preferred compounds where RIII1and RIII2mean H, R3ameans H and R2ameans methyl, X=O;

in seedy alkyl, having from 1 to 6 C atoms, C1-C6alkoxycarbonyl associated with C1-C6the alkyl, C1-C6carboxylates, C1-C6alkanoyl, optionally substituted by halogen, benzyl or halogenic, benzoyl or Halogented;

Rxximeans H, halogen, hydroxy, CN, C1-C6alkyl, optionally containing OH groups, C1-C6alkoxy, acetyl, benzyloxy, SRxxi2where Rxxi2means alkyl, C1-C6; perfluoroalkyl having from 1 to 3 C atoms, C1-C6carboxyethyl, optionally containing OH groups, NO2, amino, sulfamoyl, dialkylamino with alkyl having from 1 to 6 C atoms, or diferuloylmethane with alkyl having 1 to 3 C atoms:

Rxxi1means halogen, CN, C1-C6alkyl containing one or more OH groups, C1-C6alkoxy, acetyl, ndimethylacetamide, benzyloxy, SRIII3as shown above, perfluoroalkyl having 1 to 3 C, hydroxy, carboxylic having from 1 to 3 C, hydroxy, carboxylic having from 1 to 6 C, NO2, amino, mono - or dialkylamino having from 1 to 6 C, sulfamoyl, dialkyl sulfamoyl having from 1 to 6 C, or diferuloylmethane, as shown above; or Rxxitogether with Rxxi1OZNA the second bridge is in position 2, Rxximeans H, Rxxi1means chlorine in paraprotein in relation to nitrogen;

R3ameans H, R2ameans methyl and X is O;

in the compounds of formula (XXXV), the remainder tiaprofenic acid:

Ar denotes phenyl, hydroxyphenyl, optionally mono - or politeley halogen, alkanoyl and alkoxy having from 1 to 6 C, trialkyl having from 1 to 6 C, preferably from 1 to 3 C, cyclopentyl, cyclohexyl, cycloheptyl, heteroaryl, preferably thienyl, furyl, optionally containing OH, pyridyl;

preferred (XXXV) compounds are, where Ar denotes phenyl, R3ameans H, R2ameans methyl and X is O;

in the compound of formula (II) balance of suprofen, one of which is shown the preferred, where R3ameans H, R2ameans methyl and X=O; its equivalents, as described and obtained in USP 4035376, which is incorporated fully herein as a reference, can also be used;

in the compound of formula (VI)

one of which is preferably indoprofen, when R2ameans CH3and indobufen, when R2aequal to H, R3a=-CH3and X=O, it was shown;

its equivalents, as described and obtained in accordance with USP 3997669, which is incorporated fully herein as the de R2a=R3a=H and X=O, it has been shown, and its equivalents, as described and obtained in accordance with USP 3843681, which is given here in full, as a reference, can also be used;

in the compounds of the formula (VII), of which one is preferable fenoprofen, where R3a=X, R2a=-CH3and X=O, it has been shown, and its equivalents, as described and obtained in accordance with USP 3600437, which is incorporated fully herein as a reference, you can also use

in the compounds of the formula (III), of which the preferred fenbufen, where R2a= R3a= H and X=O has been shown; its equivalents, as described and obtained in accordance with USP 3784701, which is incorporated fully herein as a reference, can also be used;

in the compounds of formula (IX), the rest of flurbiprofen, where R3ameans H, R2ameans-CH3and X=O;

in the compounds of formula (X), the remainder of tolmetin, where R2a=R3a=H and X=O; its equivalents, as described and obtained in accordance with the patent FR 1574570, which is incorporated fully herein as a reference, can also be used;

In class III (D) values are the following:

III a) when it contains-CH(CH3)-COOH, shown as pranoprofen: -methyl-5H-[1]benzopyran[2,3-b]pyridine-7-acetic acid.

the it-CH(CH3)-COOH, known as bioprotein: dibenzo[b,f]oxepin-2-acetic acid.

The preferred connection is u=1, X=O, R2a=H, R3a=CH3.

The residue (XXXI) is shown as CS-670: 2-[4-(2-oxo-1 - cyclohexylidene)phenyl]propionic acid, when radical means-CH(CH3)-COOH.

The preferred compound has an R2a=H, R3a=CH3, u=1, X=O.

The residue (XXXII) is derived from the well-known peredelka, which contains-CH2COOH group.

The preferred compound has an R2a=R3a=H, u=1 and X=O.

This residue (XXXIII) is known as pyrazoles when it is saturated-CH2COOH:

4-(4-chlorophenyl)-1-(4-forfinal)-3-pyrazolyl acid derivatives. Preferred compounds have R2a=R3a=H, u=1 and X=O.

Group, when R1ais the remainder (XXXVI), R2a=H, R3a=CH3, t=1, u=1 and X=O, known as zaltoprofen.

When the rest of saturated hydroxy or amino group or salts of acid compounds known as dibenzothiophene derivatives.

Preferred products have R2a=H, R3a=CH3, u=1, X=O.

The residue (XXXVII) is derived from the well-known maffesoli: 3,4-di(p-methoxyphenyl)isoxazol-5-the X=O.

group IV), in which t=1, u=1 and R means

< / BR>
where: RIVdand RIVd1means for at least one H, and the other a linear or when possible branched C1-C6alkyl, preferably C1and C2or diferuloyl with alkyl having from 1 to 6 C, C1preferred, or RIVdand RIVd1together form a methylene group;

RIVhas the following values:

< / BR>
where compounds of the group IV) have the following meanings:

in the compounds of formula (II):

Riv-iimeans 1-6 C alkyl, cycloalkyl having from 3 to 7 C, alkoxymethyl having 1 to 7 C, triptorelin having from 1 to 3 C, vinyl, ethinyl, halogen, alkoxy having from 1 to 6 C, diflorasone with alkyl having 1 to 7 C, alkoxymethyl having 1 to 7 C, alkylthiomethyl with alkyl having 1 to 7 C, altimetry with alkyl having 1 to 7 C, cyano, deformality, phenyl - or phenylalkyl, substituted by alkyl having 1 to 8 C;

preferably Riv-iimeans-CH3O, Rivdmeans H and Rivd1means-CH3, and is known as the radical naproxen;

X= NH and X1equal to -(CH2-CH2-O)2; also preferred is the compound where X is O;

in connecting the camping fully as standard, can be used as equivalents. Preferred compounds in which Rivdmeans H and Rivd1means-CH3X=NH and X1equal (CH2-CH2-O); also preferred is the compound where X is O;

in the compounds of the formula (III):

Riv-iiimeans C2-C5alkyl even branched when possible, C2and C3alkyloxy, allyloxy, phenoxy, phenylthio, cycloalkyl having 5 to 7 C atoms, optionally substituted in position 1 C1-C2by alkyl;

preferred is a compound where Riv-iiimeans

< / BR>
and Rivd= H, Rivd1means-CH3the connection is known as the residue of ibuprofen;

X=NH and X1equal (CH2-CH2-O)2; also preferably the same compound where X is O;

group V)

< / BR>
< / BR>
< / BR>
In group V) compounds have the following meanings:

in the compounds of formula (II)

Rviimeans H or a linear or when possible branched alkyl having 1 to 4 C;

Rvii-imeans Rviior a linear or when possible branched alkoxy having 1 to 4 C; Cl, Br, F; Rvii-iin the o-, m - or p-;

preferred is R

in which the residue is known tenidap shows, cash equivalents, as described and obtained in USP 4556672, which is incorporated fully herein as a reference, you can also use:

in these compounds of the formula (V) A=R and t=0,

in the compounds of the formula (VII),

in which the residue is known tenoxicam shows A means RCO and t=1 and u=0 or A means R and t=0: cash equivalents described and received in the patent DE 2537070, which is incorporated fully herein as a reference, can also be used;

in the compounds of formula (IX)

where A= R and t=0, or A=RCO with t=1 and u=0, in which the balance of the known piroxicam shown; their equivalents, as described and obtained in USP 3591584, which is incorporated fully herein, can be used;

in the compounds of the formula (III),

where A= RCOO, t= 1 and u=0 or 1; or t=0 and A=R, the rest are well-known nabumetone, cash equivalents described and received in USP 4061779, which is presented here in full as a reference, you can also use:

in the compounds of the formula (IV),

where A= RCOO, t=1 and u=1, the rest are well-known indomethacin, cash equivalents, as described and obtained in USP 3161654, which is presented here in full as a reference, can also be used.

in the compounds of formula (X):

the remainder (X) from the Yong as ampiroxicam, end group is-COOC2H5.

Preferred compounds have u=1 and X=O; or t=0.

- Radical (XII), saturated-CH2COO-, means, as is well known bromfenac.

Preferred compounds have u= 1, X=O and R2a=R3a=H; or t=0.

Group XIII) is obtained from the known Lornoksikama, when the valence is saturated H.

Preferred compounds have t=0.

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

-YO-

where Y means:

linear or when possible, substituted C1-C20alkylene, preferably having from 2 to 5 carbon atoms, excluding the connecting bridge, when R:

the radical group I), except for class Ib and Ic);

the radical group II), excluding IIb);

the radical group III), excluding the class of compounds of the IIID)

the radical group IV);

the radical group V), excluding X) and including -(CH2)4for compounds of formulas (III) and (IV);

or cycloalkyl having from 5 to 7 carbon atoms, optionally substituted;

< / BR>
where n3means 0 or an integer from 1 to 3

< / BR>
where nf denotes an integer from 1 to 6, preferably from 1 to 3;

Compounds Ic class Ic1), in which the radical means derivative of 5-aminosalicylic acid (5-amino-2-hydroxybenzoic acid), known as mesalamine when the initial radical contains-COOH, obtained by the reduction of m-nitrobenzoic acid Zn dust and HCl (see H. Weil et al., Ber. 55V, 2664 (1992)); or electrolytic recovery: Le Guyader, Peltier, Compt. Rend. 253, 2544 (1961). These publications are listed here as a reference.

The initial radical Ic2when it contains-COOH, known as olsalazine: 3,3'-azobis(6-hydroxybenzoic acid); it is obtained according to EP 36636 or USP 4528367, here both as a model.

Compounds Ic3) get according to USP 2396145, here shown as a reference. Equivalent to connect the Ic1), Ic2and Ic3contain the substituents specified in the above SS connecting bridges X1as described above in relation to compounds of group (I) can be obtained by using the above known methods or by modifying the known methods for the introduction of bridges X1described in the above patents.

Compounds where R is the group (II), described in patent WO94/04484 and USP 3558690, where production methods are also described. These patents incorporated fully herein for reference.

The initial connection from IIb), when the valence is saturated-COOH (flunixin), obtained according to USP 3337570 and USP 3689653 here as a reference. Compounds containing substituents mentioned in the above patents, equivalent flunixin.

In accordance with the compounds of group (II) linking bridges X1as defined above, can be obtained by using the above-mentioned known methods or by modifying the known methods for the introduction of bridges X1described in the above patents.

Compounds where R is from the group (III), as described and obtained by methods described in the following patents: patent application PCT/EP/93 03193; for compounds of formula (IV) see also USP 3641127; for compounds of formula (XXI) see also USP 3896145: for compounds of formula (IX), the rest of flurbiprofen, 97669; for compounds of formula (VIII) see also USP 3843681: for compounds of formula (VII) see also USP 3600437; for compounds of formula (III) see also USP 3784701. All of these patents incorporated fully herein for reference.

Methods for obtaining compounds of class IIID) the following:

IIIa) the remainder obtained by treatment of the acid compound according to USP 3931205, the valence is saturated-CH(CH3)-COOH. Compounds containing substituents mentioned in the above patent, is equivalent to pranoprofen.

The residue (XXX) received over a connection with a-CH(CH3)- COOH (bioprotein) according to USP 4238620, here shown as a reference.

Other equivalent products listed in the above patent.

The residue (XXXI) receive, starting with the appropriate acid-CH(CH3)-COOH, according to USP 4254274. Equivalent compounds are listed in the patent.

The residue (XXXII) are obtained according to EP 238226, here shown as a reference, when the valence is saturated-CH2COOH. Equivalent products listed in the above patent as substituted 1,3,4,9 tetrahydropyran[3,4-b]indole-1-acetic acid.

The residue (XXXIII) is obtained from pyrazole (valence is saturated - CH2COOH), as shown in EP 54812, here as this is about the UK patent 2035311, here as a reference, since zaltoprofen with end-CH(CH3)-COO-. Equivalent to the compounds listed in the above patent.

The method of obtaining radical XXXVII) start with Maffesoli and it is produced according to EP 26928. Equivalent products listed there.

With respect to compounds of group III) linking bridges X1as stated above, can be obtained using the above methods, or by modifying the known methods with the introduction of bridges X1when they differ from the connecting bridges described in the above patents.

Compounds where R is a group IV), described in British patent application 93205995, where production methods are also described. This patent is incorporated fully herein as a reference.

In group IV) compounds can be obtained: for compounds of formula (II), using patent USP 3904682; for compounds of formula (X) according to the patent USP 4161538; for compounds of formula (III), according to the patent 3228831. These patents are fully incorporated into the present application as reference.

With respect to compounds of group IV) linking bridges X1as described above, can be obtained using the above-mentioned known methods, or edit upomjanutyh patents.

Compounds where R is a group V), described in Italian patent MF 000916, where production methods are also described. This patent is incorporated fully herein as a reference. In group V) compounds can be obtained: for compounds of formula (II), using patent USP 4089969, which is incorporated fully herein as a reference: the compounds of formula (V) can be obtained according to the patent USP 4556672, which is incorporated fully herein as a reference.

The remainder (X) are obtained according to German patent 2756113. Equivalent products listed in the above patent.

The residue (XI) are obtained according to patent EP 147177, shown here as a reference, starting with ampiroxicam having an end group-COOC2H5.

Equivalent products listed in the above patent.

The residue (XII) are obtained according to J. Medicinal Chem., vol. 27, No. 11, Nov. 1984, Walsh et al, Antiinflammatory Agents. 3. Synthesis and Pharmacological Evaluation of 2-Amino-3-Benzoylphenilacetic Acid and Analogues, shown here as a reference. Equivalent products listed in the above publication.

Radical (XIII) receive, since Lornoksikama, where the valence is saturated with H. It is prepared according GBP 2003877. Equivalent products described in the aforementioned patent.

With regard to the known methods or by modifying the known methods of introducing bridges X1when they are different from the connecting bridges described in the above patents.

The relationship between A and X1is, as we have seen, mainly ester or amide type (NH or NR1cas defined in X), when R is selected from groups I), II), III), IV). All well-known path for the formation of these relations can be used for this connection.

In the case of esters of group (I), III) and IV) the main direction of the synthesis involves the reaction of acylchlorides R-CO-Cl with halogenated alcohols of the type HO-Y-Cl, HO-Y-Br, HO-Y-I in well-known experimental conditions.

The reaction products of the formula R-CO-O-Y-Cl(Br, I) can be also obtained for the class II reaction of salts of sodium or potassium aforementioned R-CO-OH acids with dihalogen derive the basic formula YCl2, YBr2or YI2.

The reaction products are converted into final products by reaction with AgNO3in acetonitrile, in accordance with the references.

The main ways for groups I), III), IV) the following:

R-CO-Cl+HO-Y-Br ---> R-CO-O-Y-Br+AgNO3---> A-X1-NO2where X1=YO.

The main path for group II the following:

R-CO-ONa + Br2Y ---> R-CO-O-Y-Br + AgNO3---> A-X1-NO2, Itami main formula NH2-Y-OH, OTHER1c-Y-OH to obtain amides of the main 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, PBr3, SOCl2and so on, leads to the halogen derivatives of the basic formula:

R-CO-NH-Y-Br(Cl) and R-CO-NR1c-Y-Br(Cl).

They respond with AgNO3in acetonitrile according to known literature methods, lead to final products A-X1-NO2.

This path may be in the following words:

PCl5< / BR>
R-CO-Cl + other1c-Y-OH ---> R-CO-NR1c-Y-OH ---> R-CO-NR1c-Y-Cl + AgNO3---> R-CO-NR1c-Y-ONO2< / BR>
where YO means Xx1.

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

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

getting the right product of the invention.

Reaction path following:

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

The way of synthesis is similar to that described above, can be used to produce Va and Vb group V), where dehalogenation Br2Y react with Yong AgNO3according to the above reaction.

The main path, shown below, relates to the piroxicam of the formula IX in group V).

< / BR>
The above products in various groups used for anti-inflammatory, analgesic and antiplatelet activities. For group I) there is no need to exclude values of X1.

For group II), III), IV) and V) values of X1limited, as stated above, for those methods, when X1=-YO for some compounds.

The next object of the invention is the unexpected discovery that the products of the invention containing-ONO2groups can have the effect of inhibiting inflammation induced by lipopolysaccharide (LPS), and, therefore, can be used in septic shock.

This was unexpected, as it is well known that usually anti-inflammatory activity does not change significantly the activity of nitrogenates caused by lipopolysaccharides in rats and, thus, cannot be used for septic shock.

Products that can be used for such pharmaceutical applications, are products of the General formula:

A-X1-NO2< / BR>
described videostic cannot be excluded, as those that were described in the previous patents for this purpose.

You have to understand that when the connection of the various groups contain at least one asymmetric carbon products can be used in racemic form or as the individual isomers. A well-known fact that when therapeutic use of the invention in General isomeric form is more active than others.

The following examples are given to explain, but they do not limit the present invention.

Examples

Example 1: Chemical examples of the resulting product.

Example 1a:

Obtain compound A-X1-NO2where R belongs to class I, X1means -(CH2-CH2-O)2-; here designated as ASA.NO-DEG, and has the General formula:

2-acetoxy-benzoate 2-[2-(nitroxy)ethoxy]ethyl

< / BR>
Obtaining an intermediate product of the formula:

2-acetoxy-benzoate 2-[2-(chloro)ethoxy]ethyl

< / BR>
1.0 g of sodium hydride (NaH) (80% suspension in light mineral oil) was added in portions to the solution:

acetylsalicylic acid - 5.6 g and

dimethylformamide - 20 ml

stood at 0oC in a stream of nitrogen.

The mixture was stirred one hour and then added dropwise to about oC. the Mixture was stirred for 3 days, then dried under reduced pressure. The residue was treated:

water - 50 ml and

dichloromethane - 50 ml.

The phases were separated and the aqueous phase was Proektirovanie dichloromethane 10 ml

The combined organic phases are washed with water (I ml), dried (MgSO4), decolorized with animal charcoal (1 g) and placed to dry in a vacuum.

The residue (11.2 g) was used crude for the next reaction.

Receiving ASA-NO-DEG:

8.6 g of silver nitrate was added to a solution of

ASA-(CH2)-O-(CH2)2Cl - 11.2 g and

acetonitrile - 25 ml

stood at ambient temperature and in the absence of light. After stirring for two days 2.2 g of silver nitrate added.

After two days in the same conditions, the insoluble salt was filtered and the filtrate was freed from solvent under reduced pressure.

The remainder of 7.0 g was obtained and chromatographical on a column of silica gel (500 g silica), elwira a mixture of toluene/ethyl acetate 95/5 about/about.

Fractions that were found homogeneous by TLC (thin layer chromatography) were combined and dried.

Yield 3.0 g ASA-NO-DEG.

1H-NMR analysis (CDClthe Alize (nujol) showed the following results.

OCO=1780 cm-1; COO=1725 cm-1; =1641 and 1287 cm-1.

Mass spectrometry showed a molecular weight of 313.

Example 1b:

Obtain compound A-X1-NO2where R belongs to class II), X1means -(CH2-CH2-O)2- here labelled as Diclofenac - NO-DEG and has the formula:

2-{N-[2-6-(dichloro)phenyl]amino}phenyl acetate 2-[2-(nitroxy)ethoxy] ethyl

< / BR>
Obtaining an intermediate product having the formula:

2-{N-[2,6-(dichloro)phenyl]amino}phenyl acetate 2-[2-(bromo)ethoxy]ethyl

< / BR>
Solution

Diclofenac sodium salt - 13.3 g and

dimethylformamide - 25 ml

added to the solution

2,2'-dibromomethyl - 12.3 g and

dimethylformamide and 15 ml

kept at ambient temperature in a stream of nitrogen.

The mixture is left to react for two days, and then the solvent was removed under reduced pressure. The residue was treated with ethyl acetate (50 ml), washed with 5% potassium carbonate solution (2x10 ml), then water (20 ml), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue weighed 16 g and was used for the next reaction without purification.

Receiving Diclofenac-NO-DEG:

Silver nitrate - 8 and

acetonitrile - 30 ml

stood at room temperature and the absence of light.

The mixture was stirred at ambient temperature for 3 days.

Silver nitrate 3 g after 1 day

Silver nitrate 3 g after 2 days

then added.

The mixture was stirred for further 2 days. Insoluble salts were then filtered and the solvent removed from the filtrate under reduced pressure. The residue was treated with ethyl acetate (50 ml), the insoluble salts were then filtered off and threw it away. The solvent was removed from the filtrate under reduced pressure. Was obtained residue 16.2 g and chromatographical on a column of silica gel (700 g of silica), blueraven first with toluene, then with a mixture of toluene/ethyl acetate 99/1 V/V, in the end - with a mixture of toluene/ethyl acetate 98/2 about/about.

Fractions that were found homogeneous by TLC analysis (thin layer chromatography) were combined and dried, yield 4.38 g of Diclofenac-NO-DEG.

1H-NMR analysis (CDCl3) (300 MHz) showed the following results:

3.69 (4H, t); 3.87 (2H, s); 4,3 (2H, m): 4.52 (2H, t); 6.55 (1H, d); 6.88 (1H, broad singlet for D2O, NH): 6.97 (2H, t); 7.11 (2H, d); 7.23 (2H, d); 7.35 (2H, d).

Mass spectrometry showed a molecular weight of 588.

Example 1c:

1
means-C6H5CH2- here designated as Ketoprofen-NO-DEG, and has the formula:

2-(3-benzoyl)phenylpropionate 3-(nitroxymethyl)phenyl

< / BR>
Obtaining an intermediate product having the formula:

< / BR>
Used the following reagents in these quantities reacted, as described below:

3-hydroxybenzoyl alcohol, 10 grams

48% HBr by weight - 50 ml

CH2Cl2- 30 ml

AgNO3- 13.7 g

CH3CN - 70 ml

3-Hydroxybenzoyl alcohol in CH2Cl2reacted with HBr 4 hours at ambient temperature.

CH2Cl2then boiled away under reduced pressure at 30oC after washing with an aqueous solution of 5% NaHCO3and dried over anhydrous Na2SO4.

Oily residue was dissolved in CH3CN (50 ml) and a solution of AgNO3the remaining amount of CH3CN was added dropwise. The flask was isolated from the world.

After 8 hours AgBr precipitate was filtered and the organic phase is boiled away under reduced pressure.

The oily residue thus obtained was dissolved in toluene (45 ml) and the solution was filtered on a column of silica gel (400 g). The eluate was dried under reduced pressure at 30oC and the-(3-benzoyl)phenyl propionic acid.

Ketoprofen - 20 g

Thionyl chloride in 50 ml

mixed and the solution boiled under reflux for 45 minutes. Thionyl chloride was boiled away under reduced pressure. Got a yellow oily residue weighing 21 grams and used without purification.

Receiving Ketoprofen-Ar-NO2.

Below used reagents in the following amounts:

Ketoprofen - COCl - 5.45 g

3-nitroxymethyl - 3.9 grams

< / BR>
K2CO3and AcOEt were added together;

Ketoprofen chloride was then added under nitrogen at t=0 within 30 minutes. All left to react for 5 hours at ambient temperature, then diluted with water (50 ml). The organic phase is washed with 5% NaOH (2x10 ml) and boiled away under reduced pressure. The obtained oily residue was chromatographically on silica, using a mixture of toluene/EtOAc 9.5/0.5 V/V as eluent. Evaporation of the eluate gave Ketoprofen-Ar-NO2with the release of 85%.

1H-NMR analysis (CDCl3) (300 MHz) showed the following results:

1.63 (3H, d): 4.00 (1H, q): 5.37 (2H, s); 7.01 - 7.89 (m, 13H).

Mass spectrometry showed a molecular weight of 405.

Example 1d:

Obtain compound A-X1-NO2here labeled Ibuprofen-NO-DEG, where R is kN3)2CHCH2C5H4-CH(CH3)-

Followed the procedure of example 1a, using the above R, the remainder of Ibuprofen instead of residue R in group I, as shown in example 1a.

Example 1e:

Obtain compound A-X1-NO2here designated as Flurbiprofen-NO-DEG, where R belongs to the group III, X1means -(CH2-CH2-O)2-, A=RCOO, R3a=H, R2a=CH3, R has the formula:

< / BR>
Followed the procedure of example 1a, using the above R, the rest of flurbiprofen, instead of residue R in group I, as shown in example 1a.

Example 1f:

Obtain compound A-X1-NO2, Ketorolac-NO-DEG, where R belongs to group V; X1means -(CH2-CH2-O)2-;

A=R, R of formula II having the formula:

< / BR>
Followed the procedure of example 1a, using the above R, the remainder of Ketorolac, instead of residue R in group I, as shown in example 1a.

Example 1g:

Obtain compound A-X1-NO2, Tiaprofenic acid NO-DEG, where R belongs to the group III, X1means -(CH2-CH2-O)2-, A=RCOO, R is a residue of formula XXXV, where R means:

< / BR>
Followed the procedure of example 1a, using the above R, the remainder theapr 2, Naproxen NO-DEG, where R belongs to the group IV, X1means -(CH2-CH2-O)2-, A=RCOO, R is a residue of formula II Naproxen, having the formula:

< / BR>
Followed the procedure of example 1a, using the above R, the remainder of Naproxen, instead of the remainder of the R groups I, as shown in example 1a.

Example 2: Pharmacological examples.

The examples used above, were characterized pharmacologically.

Example 2a: ASA-NO-DEG obtained in example 1a;

Example 2b: Diclofenac-NO-DEG obtained in example 1b;

Example 2c: Ketoprofen-NO-DEG obtained in example 1c;

Example 2d: Ibuprofen-NO-DEG obtained in example 1d;

Example 2e: Flurbiprofen-NO-DEG obtained in example 1e;

Example 2f: Ketorolac-NO-DEG obtained in example 1f;

Example 2g: Tiaprofenic acid NO-DEG obtained in example 1g;

Example 2h: Naproxen NO-DEG obtained in example 1h.

The toxicity.

Acute toxicity was evaluated by oral introduction of individual doses of 1, 3, 10, 100 mg/kg of product in groups of 10 mice.

Lethal dose and the beginning of symptoms of intoxication have been described for a period of 14 days. Even after applying a dose of 100 mg/kg animals did not show overt symptoms of toxicity.

Analgesic activity.

Analgesic activity was studied in mice breed Suisse, as described Hendershot and others (J. Pharm. Exp. Therap. 125, 237, 1959).

The tolerance.

Gastrointestinal tolerance was determined in oral introduction on rats, the gravity gastropathy in accordance with the criteria described by Wallace and others (Am. J. Physiol. 259, G642, 1990).

Antiplatelet activity.

Antiplatelet activity was studied in vitro on human platelets stimulated by thrombin in accordance with the method described Bertele and others (Science 220, 517, 1983).

Vasodilator activity.

Vasodilator activity was determined in isolated rat aorta by measuring the inhibition of the contraction induced by epinephrine in tissue prepared in accordance with the method described by Reynolds and others (J. Pharmacol. Exp. Therap. 252, 915, 1990).

COX inhibition.

Activity inhibition of cyclooxygenase was determined on isolated cells. Endothelial cells from bovine aorta were used as a source of COX, and macrophages lines J. 774.2 - as istochniki used.

Briefly, cells were kept in an incubator for 30 min with the test substance in certain concentrations and then in the next 15 minutes in a thermostat was added the substrate (arachidonic acid). The enzyme activity was determined by radioimmunoassay measurement of 6-keto-PGF 1 alpha. In the case of cell line J. 774.2, the cells were incubated for 12 hours with endotoxin to stimulate the formation of COX-2.

Inhibition of nitrogenates LPS.

Activity inhibition nitrogenates induced by lipopolysaccharide (LPS) was determined in rat neutrophils and stomach after the introduction of one of the tested substances and compared with that obtained after processing only the suspension media.

Briefly, rats of the Wistar breed for 24 hours before treatment was administered orally tested product (10 mg/kg) and intravenous (tail vein) was administered LPS (5 mg/kg).

After 4 hours the animals were killed and taken: blood for isolation of neutrophils, and stomach.

The enzyme activity was determined in accordance with the method described Assreuy, etc. (Br. J. Pharmacol., 108, 833, 1993).

The results:

The results obtained are described below.

As the form is here (table 1, column III) nitro-derivatives showed better balance compared to natural products.

Table 4 also shows that, like diclofenac nitrosotoluene ether, diclofenac nitro-derivatives, which is the object of this patent, is able to direct inhibition of cyclooxygenase COX-1 and COX-2, but with much lower variability.

Table 1 (Pharmacology Nr. I and II; Toxicology Nr. III).

The study of anti-inflammatory (I) and analgesic (II) properties (pharmacodynamics) and gastrointestinal tolerance (III) (toxicity) of the test compounds after oral administration of doses ranging from 3 to 30 mg/kg in karboksimetilcellyulozih suspensions and the construction of the curve depending on the dose. Shows the results indicate a ratio of activity compared with the standard.

Activity expressed as a ratio compared to the natural products used as a unit of the standard.

Nitro-derivatives, which are taken from the shown examples, and the corresponding natural connection as standard.

Table 2 (Pharmacodynamic activity).

Examples of anti-cyclooxygenase (I), antithrombotic (II) and vasodilator its environment water/alcohol with the addition of small amounts of DMSO (dimethyl sulfoxide).

Activity expressed as a ratio compared to the natural products used as a unit standard, as summarized in Table 1.

Table 3 (Biochemistry: effect on NOS for septic shock).

Study of the inhibitory activity properties nitroacetate (NOS) caused by liposaccharide (LPS) in rats using oral doses of 5 to 20 mg/kg in karboksimetilcelljuloza basis.

Table 4 (COX - inhibitory activity).

The study of anti-cyclooxygenase (COX-1/COX-2) properties in isolated cells.

Response expression as % of controls with relative response variability.

The method of obtaining oral dosage forms:

In a mortar mix 10 g of compound having laboratory name Diclofenac-NO-DEG (example Ib from page 35 description) with 3 g of starch, 1.5 g of glycol stearate, 2 g of talc and 1 g of magnesium stearate. Powder grind in a mortar to obtain a finely chopped consistency. To powder in a mortar portions add a solution of 4 g of sodium carboxymethyl cellulose in 50 ml of water under stirring, with intermediate drying at 60oC in vacuum, crushed and again dried. The obtained granules are forced through the grate from the Oia, has the following composition:

Diclofenac-NO-DEG - 25 mg

Stearate peg - 3.75 mg

Corn starch - 75 mg

Talc 5 mg

Magnesium stearate 2.5 mg

The sodium carboxymethyl cellulose 10 mg

Example 1i

Obtain compound A-X1-NO2where R belongs to group I, and represents the balance of the compounds of formula Ic1X1is YO, where Y is a linear C4alkylene. A=RCOO, R is the residue of mesalamine having the formula:

< / BR>
designated here as Mesalamine-NO-DEG and having the General formula: 5-amino-2-hydroxybenzoate 4(nitroxy)butyl

< / BR>
Obtaining the intermediate Boc-Mesalamine

5-tert-butoxycarbonylamino-2-hydroxy benzoic acid

Mesalamine - 15 g

Di-tert-butyl bicarbonate - 25.65 g

The triethylamine - 24.6 ml

Dioxane - 100 ml

Water - 150 ml

To a mixture of 5-amino-6-hydroxy benzoic acid in dioxane and water, add triethylamine and di-tert-butyl bicarbonate. After 4 days the solution was concentrated in vacuo, treated with HCl 5% to pH 2 and, after addition of NaCl, extracted with ethyl acetate. The organic layer is dehydrated with sodium sulfate and evaporated in vacuum. Get the crude residue weighing 23 g and use far without the Ino-2-hydroxy benzoic acid

5-Tert-butoxycarbonylamino-2-hydroxy benzoic acid, 23 g

Thionyl chloride - 7.15 ml

Pyridine - 0.25 ml

Methylene chloride (200 ml

To a mixture of 5-tert-butoxycarbonylamino-2-hydroxybenzoic acid in methylene chloride, cooled to a temperature of 0oC, add pyridine and thionyl chloride. The mixture is refluxed for 1 hour, the solvent is evaporated in vacuum. The crude residue (24.5 g) used in the next stage.

The intermediate compounds of the formula:

5-tert-butoxycarbonylamino-2-hydroxybenzoate-4-(chloro)butyl.

5-Tert-butoxycarbonylamino-2-hydroxybenzoyl chloride - 24.8 g

4-Chlorobutanol - 14 ml

The triethylamine - 25.4 ml

Methylene chloride and 150 ml

To a mixture of 5-tert-butoxycarbonylamino-2-hydroxy benzoyl chloride in methylene chloride, cooled to a temperature of 0oC, add triethylamine and 4-chlorobutanol. The mixture is stirred at room temperature for 4 hours, washed with water. The organic layer is dehydrated with sodium sulfate and the solvent is evaporated in vacuum. The residue is purified by chromatography on a column of silica gel, eluent n-hexane/ethyl acetate 8/2, to obtain 21.6 g of compound as amorphous solid Wei benzoate 4-(nitroxy)butyl

5-Tert-butoxycarbonylamino-2-hydroxy benzoate 4-(chloro)butyl - 21 grams

Silver nitrate - 16.4 g

Acetonitrile - 200 ml

To a solution of 5-tert-butoxycarbonylamino-2-hydroxy benzoate 4-(chloro)butyl in acetonitrile add the silver nitrate at room temperature and the resulting mixture was refluxed in the dark for 2 days. The precipitate is filtered off and the solvent is evaporated in vacuum. The residue is purified by chromatography on a column of silica gel, eluent n-hexane/ethyl acetate 7/3, to obtain 19 g of compound as a white solid. So pl.= 107-109oC.

Getting chloride Mesalamine-NO-DEG:

5-Tert-butoxycarbonylamino-2-hydroxy benzoate 4-(nitroxy) butyl - 19 g

The ethyl acetate/HCl 4.8 M - 41 ml

The ethyl acetate - 25 ml

To a solution of 5-tert-butoxycarbonylamino-2-hydroxy benzoate 4-(nitroxy)butyl in ethyl acetate at a temperature of 0oC added dropwise ethyl acetate/HCl 4.8 M the Mixture is stirred at room temperature for 4 hours. The precipitate is collected, washed with n-hexane to obtain 13.5 g of the chloride Mesalamine-NO-DEG in the form of a white solid. So pl.=136-140oC.

1H-NMR analysis (DMSO)(200 MHz) showed the following results:

1.80 (4H, m), 4.34 (2H,t); 4.-NO-DEG - 7 grams

Silver nitrate - 3.88 g

Acetonitrile and 500 ml

To a solution of chloride of Mesalamine-NO-DEG in acetonitrile add the silver nitrate. The mixture is stirred at room temperature. After 20 minutes, the silver chloride is filtered off, the solution was concentrated in vacuo (250 ml) and cooled at a temperature of 0oC. the Precipitate is filtered, washed with n-hexane to obtain 6.15 g of nitrate Mesalamine-NO-DEG in the form of a white solid. So pl. = 141 - 145oC.

Example 1j

Obtain compound A-X1-NO2where R belongs to the group of V, and is a remnant of the compounds of formula IV, X1is YO, where Y is a linear C4alkylene, A=RCOO, R is the residue indometacin having the formula:

< / BR>
designated here as Indomethacin-NO-DEG and having the General formula:

< / BR>
Receiving Indomethacin-COCl:

Chloride 1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid.

Indomethacin - 5 g

Oxalyl chloride 3.5 g

Toluene - 70 ml

N,N-dimethylformamide ml - 1

To a solution of indomethacin in toluene and N,N-dimethylformamide, cooled to 0oC add oxalyl chloride. The mixture is stirred at room temperature for 1 day. The solvent is evaporated in vacuum and the residue (5.2 g) is soil)-5-methoxy-2-methyl-1H-indole-3-acetate 4(chloro)butyl.

Indometacin COCl - 5.2 grams

4-Chlorobutanol - 2.2 ml

The triethylamine - 3.9 ml

Methylene chloride, 60 ml

To a solution of indomethacin COCl in methylene chloride add triethylamine and 4-chlorobutanol. The solution was stirred at room temperature for 6 hours, washed with water. The organic layer is dehydrated with sodium sulfate and evaporated in vacuum. The residue is purified by chromatography on a column of silica gel, eluent n-hexane/ethyl acetate 9/1 to obtain 3.74 g of compound as amorphous solid.

Getting Indometacin-NO-DEG:

1-(4-Chlorbenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate 4(chloro) butyl - 3.74 g

Silver nitrate - 1.77 g

Acetonitrile - 35 ml

To a solution of 1-(4-chlorbenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetate 4(chloro)butyl in acetonitrile add the silver nitrate at room temperature and the resulting mixture was refluxed in the dark for 2 days. The precipitate is filtered off and the solvent is evaporated in vacuum. The residue is purified by chromatography on a column of silica gel, eluent n-hexane/ethyl acetate 8/2, with 3 g of compound as a yellow solid. So pl. = 56-61oC.

1H-NMR analysis (CDCl3) (200 MHz) showed the following results:


Obtain compound A-X1-NO2where R belongs to the group IV and is a remnant of the compounds of formula X, X1is (CH2-CH2-OH)2, A=RCOO, R is the residue of loxoprofen having the formula:

< / BR>
designated here as Loxoprofen-NO-DEG and having the General formula:

- methyl-4-[(2-oxocyclopent)methyl]benzene acetate 2-[2- (nitroxy)ethoxy]ethyl.

< / BR>
Follow the procedure of example 1a, using the above R, the rest of loxoprofen, instead of the remainder of the R groups I, as described in example 1a.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

1.23 (3H,d); 1.43-2.42 (7H,m); 2.47 (1H,DD); 3.07 (1H,DD); 3.65 (1H,HF); 3.75 (4H,m), 4.29 (2H,t); 4.34 (2H,t); 7.19-7.06 (4H,m).

Example 1l

Obtain compound A-X1-NO2where R belongs to the group of V, and is a remnant of the compounds of formula IX, X1is C6H4-CH2Is O, R is the remainder of piroxicam having the formula:

< / BR>
designated here as Piroxicam-NO-DEG and having the General formula:

< / BR>
The intermediate compounds having the formula Piroxicam-WITH-C6H4-CH2Cl.

Piroxicam - 5 g

3-(Chloromethyl)benzoyl chloride 4.2 ml

The triethylamine - 4.2 ml

Tetrahydrate is. the via 3 hours the solvent is evaporated in vacuum and the residue is treated with water and extracted with ethyl acetate. The organic layer is dehydrated sodium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel, eluent n - hexane/ethyl acetate 6/4, obtaining 4.5 g of compound.

The intermediate compounds having the formula Piroxicam-NO-DEG:

Piroxicam-WITH-C6H4-CH2-Cl - 4.5 grams

Silver nitrate - 2.37 g

Acetonitrile - 100 ml

To a solution of Piroxicam-WITH-C6H4-CH2-Cl in acetonitrile add the silver nitrate at room temperature and the resulting mixture was refluxed in the dark for 2 hours. The precipitate is filtered off and the solvent is evaporated in vacuum. The residue is purified by chromatography on a column of silica gel, eluent n - hexane/ethyl acetate 6/4, obtaining 3.1 g of Piroxicam-NO-DEG.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

3.44 (3H,s); 5.40 (2H,s); 7.35-8.40 (12H,m).

Example 1m

Obtain compound A-X1-NO2where R belongs to the group of V, and is a remnant of the compounds of formula VII, X1is C6H4-CH2, A=RCO, K is the remainder of tenoxicam in the region have codice example 1l, using the above R, the remainder of tenoxicam, instead residue R group V, as described in example 1l.

1H-NMR analysis (DMSO) (200 MHz) showed the following results:

8.35 (1H, d); 8.17-8.11 (3H,m), 8.04 (1H,d); 7.87 (1H,d); 7.72( 2H,m); 7.46 (1H,d); 7.33 (1H,t); 5.76 (2H,s); 3.43 (3H,s).

Example 1n

Obtain compound A-X1-NO2where R belongs to the group of V, and is a remnant of the compounds of formula XIII, X1is C6H4-CH2-Oh, A=RCO, R is the remainder lornoksikama having the formula

< / BR>
designated here as Lornoxicam-NO-DEG and having the General formula:

< / BR>
Follow the procedure of example 1l, using the above R, the remainder lornoksikama, instead residue R group V, as shown in example 1l.

1H-NMR analysis (DMSO)(200 MHz) showed the following results:

8.35 (1H, d); 8.17-8.11 (3H,m); 7.87 (1H,d); 7.72 (2H,m); 7.50 (1H,s); 7.33 (1H,t); 5.76 (2H,s); 3.45 (3H,s).

Example 1o

Obtain compound A-X1-NO2where R belongs to group III and is a remnant of the compounds of formula XXXIII, X1is -(CH2-CH2-OH)2, A=RCOO, R is the remainder of pyrazole having the formula

< / BR>
designated here as Pyrazole-NO-DEG and having the General formula:

4-(4-chlorophenyl)-1-(4-forfinal)-1H-balance laroxetine, instead residue R group I, as shown in example 1a.

1H-NMR analysis (CDCl3)(80 MHz) showed the following results:

3.60 (4H, m); 3.98 (2H,s); 4.60 (2H,t): 4.17 (2H,t); 7.20-7.40 (5H,m); 7.50 (4H,m).

Example 1p

Obtain compound A-X1-NO2where R belongs to the group IIId and is a remnant of the compounds of formula IIIa, X1is -(CH2-CH2-OH)2, A=RCOO, R is the remainder of pranoprofen having the formula

< / BR>
designated here as Pranoprofen-NO-DEG and having the General formula:

- methyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetate 2-[2-(nitroxy)ethoxy] ethyl

< / BR>
Follow the procedure of example 1a, using the above R, the rest of pranoprofen, instead of the remainder of the R groups I, as shown in example 1a.

1H-NMR analysis (CDCl3)(80 MHz) showed the following results:

1.51 (3H, d); 3.60 (5H,m); 4.16 (4H,m), 4.61 (2H,t); 6.90 - 7.00 (3H,m); 7.35 (1H,DD); 7.40 (1H,s); 8.36 (1H,DD).

Example 1q

Obtain compound A-X1-NO2where R belongs to group III and is a remnant of the compounds of formula VIII, X1is -(CH2-CH2-O)2, A=RCOO, R is the remainder of etodolac having the formula

< / BR>
designated here as Etodolac-NO-DEG and having the General formula:

1,8-diethyl-1,3,4,UYa above R, the rest of etodolac, instead of the remainder of the R groups I, as shown in example 1a.

1H-NMR analysis (DMSO)(80 MHz) showed the following results:

0.75 (3H,t); 1.38 (3H,t); 1.65-1.95 (2H,m); 2.80 - 2.95 (4H,m); 3.55-3.78 (8H,m); 4.16 (2H,t); 4.58 (2H,t); 6.95 - 7.05 (2H,m); 7.15 (1H,d).

Example 1r

Obtain compound A-X1-NO2where R belongs to the group of V, and is a remnant of the compounds of formula X, X1is YO, where Y is a linear C3alkylene, A=RCO, R is the remainder of meloxicam having the formula

< / BR>
designated here as Meloxicam-NO-DEG and having the General formula:

< / BR>
Obtaining the intermediate Meloxicam-(CH2)3Br

Meloxicam - 5 g

4-Bromobutyryl chloride - 3.29 ml

The triethylamine - 3.97 ml

Tetrahydrofuran - 200 ml

To a solution of meloxicam in tetrahydrofuran add triethylamine and 4-bromobutyryl chloride. After 7 hours the solvent is evaporated in vacuum and the residue is treated with water and extracted with ethyl acetate. The organic layer is dehydrated sodium sulfate and evaporated. The residue is purified by chromatography on a column of silica gel, eluent n-hexane/ethyl acetate 1/1, to obtain 5.5 g of compound.

The intermediate compounds having the formula IU To a solution of Meloxicam-(CH2)3Br in acetonitrile add the silver nitrate at room temperature and the resulting mixture was refluxed in the dark for 8 hours. The precipitate is filtered off and the solvent is evaporated in vacuum. The residue is purified by chromatography on a column of silica gel, eluent n-hexane/ethyl acetate 1/1, to obtain 3.4 g of Meloxicam-NO-DEG.

1H-NMR analysis (DMSO)(80 MHz) showed the following results:

2.02 (2H, m); 2.30 (3H,s): 3.45 (3H.s): 4.17 (2H,t); 4.38 (2H,t); 7.16 (1H,s); 7.50 (1H,DD); 7.79 (1H,d); 7.90-8.05 (2H,m); 11.35 (1H,s).

Example 1s

Obtain compound A-X1-NO2where R belongs to group III and is a remnant of the compounds of formula VII, X1is-C6H4-CH3-O-, A=RCOO, R is the remainder of fenoprofen having the formula

< / BR>
designated here as Fenoprofen-NO-DEG and having the General formula:

- methyl-4-phenoxybenzoyl acetate 3 (nitroxymethyl)phenyl

< / BR>
Follow the procedure of example 1c, using the above R, the rest of fenoprofen, instead of the remainder of the R groups III, as shown in example 1c.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

1.61 (3H,d); 3.90 (1H,q); 5.41 (2H,c); 6.89-7.14 (4H,m); 7.35-7.80 (9H, m).

Example 1t

Obtaining compounds A-e Y is a linear C4alkylene, A=RCOO, R is the remainder of flunixin having the formula

< / BR>
designated here as Flunixin-NO-DEG, and having the General formula:

2[[2-methyl-3-(trifluoromethyl)phenyl] amino] -3-pyridinecarboxylic 4-(nitroxy)butyl.

< / BR>
Follow the procedure of example 1i, using the above R, the rest of flunixin, instead of the remainder of the R groups I, as shown in example 1i.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

1.65 (4H, m); 1.80 (3H,s); 4.59 (2H,7); 4.25 (2H,t); 6.45 (1H,d); 7.25 (1H,d); 7.48 (1H,d); 7.75 (1H,m); 7.93 (1H,d); 8.50 (1H.d); 8.90 (1H,s).

Example 1u

Obtain compound A-X1-NO2where R belongs to group III and is a remnant of the compounds of formula II, X1is -(CH2-CH2-O)2, A=RCOO, R is the remainder of suprofen having the formula

< / BR>
designated here as Suprofen-NO-DEG, and having the General formula:

- methyl-4-(2-thienylboronic)benzene acetate 2-[2-(nitroxy) ethoxy]ethyl

< / BR>
Follow the procedure of example 1a, using the above R, the remainder of suprofen, instead of the remainder of the R groups I, as shown in example 1a.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

1.51 (3H, d); 3.62 (5H,m); 4.20 (2H,t); 4.60 (2H,t); 6.96 (1H,d); 7.50 (2H,m); 7.65 (2H,m); who conducted the remainder of the compounds of formula XXI, X1is-C6H4-CH2-O, A=RCOO, R is the remainder of cuprofen having the formula

< / BR>
designated here as Cuprofen-NO-DEG, and having the General formula:

6-chloro - methyl-N-carbazole-2-acetate 3-(nitroxymethyl)phenyl.

< / BR>
Follow the procedure of example 1c, using the above R, the remainder of cuprofen, instead of the remainder of the R groups III, as shown in example 1c.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

1.60 (3H, m); 3.2 (1H,HF); 5.41 (2H.s); 6.89-7.14 (5H,m); 7.30 (1H,d); 7.39 (1H,d); 7.55 (1H,s); 7.60 (1H,s); 8.20 (1H.C).

Example 1w

Obtain compound A-X1-NO2where R belongs to group III and is a remnant of the compounds of formula VI, X1is-C6H4-CH2-Oh, A=RCOO, R is the remainder of indoprofen having the formula

< / BR>
designated here as Indoprofen-NO-DEG, and having the General formula:

4-(1,3-dihydro-1-oxo-2H-isoindole-2-yl) - methylbenzoate 3-(nitroxymethyl)phenyl.

< / BR>
Follow the procedure of example 1c, using the above R, the rest of indoprofen, instead of the remainder of the R groups III, as shown in example 1c.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

1.51 (3H,d); 4.60 (1H,HF); 4.70 (2H,DD); 5.43 (2H,s); tsya to group III and is a remnant of the compounds of formula X, X1is -(CH2-CH2-O)2, A=RCOO, R is the remainder of tolmetin having the formula

< / BR>
designated here as Tolmetin-NO-DEG, and having the General formula:

1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetate 2-[2- (nitroxy)ethoxy] ethyl

< / BR>
Follow the procedure of example 1a, using the above R, the remainder of tolmetin, instead of the remainder of the R groups I, as shown in example 1a.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

2.10 (3H, s); 3.18 (3H,s); 3.55-3.63 (4H,m); 3.84 (2H,s); 4.62 (2H,t); 4.15 (1H,t); 6.32 (1H,d); 6.60 (1H,d); to 7.18 (2H,d); 7.85 (2H,d).

Example 1z

Obtain compound A-X1-NO2where R belongs to group III and is a remnant of the compounds of formula III, X1is -(CH2-CH2-OH)2, A=RCOO, R is the remainder of fenbufen having the formula

< / BR>
designated here as Fenbufen-NO-DEG, and having the General formula:

- oxo-[1,1'-biphenyl]-4-butanoate 2-[2-(nitroxy)ethoxy]ethyl

< / BR>
Follow the procedure of example 1a, using the above R, the remainder of fenbufen, instead of the remainder of the R groups I, as shown in example 1a.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

2.71 (2H, t); 3.32 (2H,t); 3.57 (4H,m); 4.20 (2H,t); 4.61 (2H.t); 7.22 (3H,m); 7.40-7.55 (4H,m is aetsa the remainder of the compounds of formula XXX, X1is YO, where Y is a linear C4alkylene, A=RCOO, R is the remainder of bermudiana having the formula

< / BR>
designated here as Bioprotein-NO-DEG and having the General formula:

10,11-dihydro -,8 - dimethyl-11-Acadians[b, f] oxepin-2-acetate 4-(nitroxy)butyl.

< / BR>
Follow the procedure of example 1i, using the above R, the rest of bermudiana, instead of the remainder of the R groups I, as shown in example 1i.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

1.52 (3H,d); 1.59-1.67 (4H,m); 2.10 (3H,c); 3.61 (1H,HF); 4.04 (2H,DD); 4.10 (2H, t); 4.30 (2H,t); 6.71-6.95 (3H,m); 7.14 (1H,d); 7.51 (1H,d); 7.80 (1H,s).

Example 1ab

Obtain compound A-X1-NO2where R belongs to the group IIId and is a remnant of the compounds of formula XXXII, X1is YO, where Y is a linear C4alkylene, A=RCOO, R is the remainder of peredelka having the formula

< / BR>
designated here as Pemetaan-NO-DEG and having the General formula:

< / BR>
Follow the procedure of example 1i, using the above R, the remainder of peredelka, instead of the remainder of the R groups I, as shown in example 1i.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

0.76 (3H,t); 1.60-of 1.66 (4H,m); 1.75-1.95 (2H,m); 2.35-2.55 (2H,m); 3.40 (2H, DD)B>-NO2where R belongs to the group IIId and is a remnant of the compounds of formula XXXVI, X1is YO, where Y is a linear C4alkylene, A=RCOO, R is the remainder of zaltoprofen having the formula

< / BR>
designated here as Zaltoprofen-NO-DEG and having the General formula:

10,11-dihydro--methyl-10-Acadians[b,f]thiepin-2-acetate 4-(nitroxy)butyl.

< / BR>
Follow the procedure of example 1i, using the above R, the rest of zaltoprofen, instead of the remainder of the R groups I, as shown in example 1i.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

1.50 (3H,d); 1.60 (4H,m); 3.60 (1H,HF); 4.00 (2H,DD); 4.30 (2H,t); 4.60 (2H,t); 6.90-7.05 (2H,m); 7.30-7.45 (4H,m), 7.71 (1H,d).

Example 1ad

Obtain compound A-X1-NO2where R belongs to the group IIId and is a remnant of the compounds of formula XXXVII, X1is -(CH2-CH2-O)2, A=RCOO, R is the remainder of maffesoli having the formula

< / BR>
designated here as Movetalk-NO-DEG, and having the General formula:

3,4-bis(4-methoxyphenyl)-5-isoxazolyl 2-[2-(nitroxy)ethoxy] ethyl.

< / BR>
Follow the procedure of example 1a, using the above R, the remainder of maffesoli, instead of the remainder of the R groups I, as shown in example 1a.

Example 1ae

Obtain compound A-X1-NO2where R belongs to the group of Ve and is a remnant of the compounds of formula XI, X1is C6H4-CH2, A=RCO, R is the remainder of ampiroxicam having the formula

< / BR>
designated here as Ampiroxicam-NO-DEG, and having the General formula:

< / BR>
Follow the procedure of example 1 using the above R, the remainder of ampiroxicam, instead residue R group V, as shown in example 1m.

1H-NMR analysis (DMSO) (200 MHz) showed the following results:

1.45 (3H,d); 3.45 (3H,s); 5.41 (2H,s); 6.25 (1H,HF); 6.91 - 7.19 (4H,m); 7.30 (1H,t); 7.52 (1H,DD); 7.75 (2H,m); 8.00 (2H,m), 8.16 (1H,t); 8.35 (1H, d).

Example 1af

Obtain compound A-X1-NO2where R belongs to the group IIId and is a remnant of the compounds of formula XXXI, X1is YO, where Y is a linear C4alkylene, A=RCOO, R is the remainder of zaltoprofen having the formula

< / BR>
designated here as CS-670-NO-DEG, and having the General formula:

< / BR>
Follow the procedure of example 1i, using the above R, the rest of zaltoprofen, instead of the remainder of the R groups I, as shown in example 1i.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:1-NO2where R belongs to the group IV and is a remnant of the compounds of formula XII, X1is -(CH2-CH2-O)2, A=RCOO, R is the remainder of bromfenac having the formula

< / BR>
designated here as Bromfenac-NO-DEG and having the General formula:

2-amino-3-(4-bromobenzoyl)benzene acetate 2-[2-(nitroxy)ethoxy] ethyl.

< / BR>
Follow the procedure of example 1a, using the above R, the remainder of bromfenac, instead of the remainder of the R groups I, as shown in example 1a.

1H-NMR analysis (CDCl3) (80 MHz) showed the following results:

3.80 (2H, s), 3.57 (4H,m), 4.20 (2H,l), br4.61 (2H,t), 7,20 (1H,DD), 7,35 (1H,d), was 7.45 (3H,m), a 7.85 (2H,d).

Example 1ah

Obtain compound A-X1-NO2where R belongs to group I, and is a remnant of the compounds of formula I C3X1is -(CH2-CH2-O)2, A= RCOO, R is the remainder of bromfenac having the formula:

< / BR>
designated here as Sulfasalazin-NO-DEG, and having the General formula:

2-hydroxy-5-[[4-4 [(2-pyridinylamino)sulfonyl] phenyl] azo]benzoate 2-[2-(nitroxy)ethoxy]ethyl.

< / BR>
Should the method of example 1a, using the above R, the remainder of sulfasalazin, instead of the remainder of the R groups I, as shown in example 1a.

AND1H-NMR analysis (CDCl3) (80 MHz), obtaining the following data: 2,3 (3H,s), 4,25 (2H,t), 4,50 (2H,t) 7,30 (6H,m) to 7.67 (1H,m), to 8.20 (1H,d).

Example 1aj

Obtain compound A-X1-NO2where R belongs to the group IIID and represents the remainder of the compounds of formula IIIa, X is YO, where Y is a branched C2alkylene, A= RCOO, R is the remainder of pranoprofen having the formula:

< / BR>
and having the General formula:

< / BR>
The intermediate product I

L-methyl-5H-(1) benzopyrano(2,3-b)pyridine-7-acetic acid 1-chloro-2-methyl-2-propyl ether.

Pranoprofen is 5.1 grams

1-Chloro-2-methyl-2-propanol - 2.2 g

N,N'-dicyclohexylcarbodiimide to 4.2 grams

4-Dimethylaminopyridine - 0.25 grams

Chloroform - 100 ml

N,N-dimethylformamide 20 ml

To a solution of pranoprofen in chloroform and DMF was added to amasyali within 24 hours. The solid mass was filtered and the solution was washed with water. Allocated organic layer was concentrated under vacuum. The residue was purified in a chromatography column of silica gel, eluent n-hexane/ethyl acetate 7/3 to get 4,84 g of the intermediate product 1.

Receiving nitrate:

L-methyl-5H-(1) benzopyrano[2,3-b] pyridine-7-acetic acid 1 - nitroxy-2-methyl-2-propyl ether.

Intermediate - 4.5 g

Silver nitrate is 2.6 grams

Acetonitrile - 100 ml

The silver nitrate was added to a solution of intermediate 1 in acetonitrile and the mixture was irrigated in the dark for 2 days. Silver chloride was filtered and the solution concentrated under vacuum. The residue was purified in a chromatography column of silica gel, eluent - hexane/ethyl acetate 7/3 to obtain 3 g connection.

AND1H-NMR analysis (CDCl3) (80 MHz), obtaining the following data: of 1.29 (6H,s) and 1.51 (3H, d), 3,50 (1H,q) to 4.15 (4H, m), 6.90 to-to 7.00 (3H,m) to 7.35 (1H,dd), 7,40 (1H,s) at 8.36 (1H,dd).

1. Nitroglicerine General formula

A - H1- NO2< / BR>
or their salts,

where A = R(COXu)twhere t = 0 or 1, u = 0 or 1; X = O, NH; R is selected from the following groups:

group I), where t = 1, u = 1,

< / BR>
< / BR>
< / BR>
where R1means OCOR3UB>II1, RII2, RII3independently of one another denote hydrogen or CL, RII 4means RII1, RII5means hydrogen, RII6means hydrogen;

group III), where t = 1, u = 1 and R means

< / BR>
where R2Aand R3Adenote H, linear or when possible branched, substituted or unsubstituted WITH1-C12alkyl; preferably R2Ameans H, alkyl having from 1 to 4,

R3Ameans N;

R1Achosen from compounds of formulas

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
IIID) have the following connections:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
in the compound of formula (IV), the remainder of Ketoprofen:

RIII1means N, RIII2means H, the preferred compounds, where R3Ameans N, R2Ameans methyl, X = O; R3Ameans hydrogen;

in the compounds of formula (XXI), the rest of carprofen:

Rxxiomeans N, Rxximeans N, Rxxi1means halogen, the preferred compounds, where Rxxiomeans H, connecting the bridge in position 2, Rxxi1means chlorine in paraprotein to nitrogen; R2Ameans methyl and X = O;

in the compounds of formula (XXXV), the remainder tiaprofenic acids is achet hydrogen;

Rxxi1means halogen, CN, C1-C6alkyl containing one or more Oh groups, C1-C6alkoxy, acetyl, ndimethylacetamide, benzyloxy, SRIII3as shown above, perfluoroalkyl having from 1 to 3 hydroxy, carboxylic having from 1 to 6, NO2, amino, mono - or dialkylamino having from 1 to 6, sulfamoyl, dialkyl sulfamoyl having from 1 to 6, or diferuloylmethane, as shown above; or Rxxitogether with Rxxi1indicate alkylenedioxy having from 1 to 6;

preferred compounds where Rxxiomeans H, connecting the bridge in position 2, Rxximeans N, Rxxi1means chlorine in paraprotein in relation to nitrogen;

R3Ameans N, R2Ameans methyl and X is O;

in the compounds of formula (XXXV), the remainder tiaprofenic acid:

Ar denotes phenyl, hydroxyphenyl, optionally mono - or politeley halogen, alkanoyl and alkoxy having from 1 to 6, trialkyl having from 1 to 6, preferably from 1 to 3, cyclopentyl, cyclohexyl, cycloheptyl, heteroaryl, preferably thienyl, furyl, optionally containing IT, pyridyl;

preferred (XXXV) compounds are, where AG denotes phenyl, R3Ameans N, R2Ameans means methyl and X = O, or its equivalents;

in the compound of formula (VI) balance of indoprofen, where R2Ameans of CH3and the rest of indobufen, where R2Ameans N, R3A= -CH3and X = O and its equivalents;

in the compounds of the formula (VIII) balance etodolac, where R2A= R3A= H and X = O and its equivalents;

in the compounds of the formula (VII) balance of fenoprofen, where R3A= X, R2A= -CH3and X = O and its equivalents;

in the compounds of the formula (III) balance of fenbufen, where R2A= R3A= H and X = O and its equivalents;

in the compounds of formula (IX) balance of flurbiprofen, where R3Ameans N, R2Ameans-CH3and X = O;

in the compounds of formula (X) is the remainder of tolmetin, where R2A= R3A= H and X = O or its equivalents;

compound IIIa), when it contains-CH(CH3)-COOH, pranoprofen balance: alpha-methyl-5H-[1]benzopyran[2,3 b]-pyridine-7-acetic acid;

the preferred compound has an R2A= N, R3A= -CH3u = 1 and X = O;

compound (XXX), when it contains-CH(CH3)-COOH, bioprotein balance: dibenzo[b,f]oxepin-2-acetic acid;

the preferred connection is u = 1, X = O, R2A= N, R3A= CH3;

the compound (XXXI)-CS-670 OS is; the preferred compound has an R2A= N, R3A= CH3, u = 1, X = O;

the compound (XXXII) derived peredelka, which contains - CH2COOH group; a preferred compound has an R2A= R3A= H, u = 1, X = O;

the compound (XXXIII) means pyrazole residue when saturated - CH2COOH: 4-(4-chlorophenyl)-1-(4-forfinal)-3-pyrazolyl derived acid; the preferred compounds R2A= R3A= H, u = 1, X = O;

group, when R1Ais the remainder (XXXVI), R2A= N, R3A= CH3, t = 1, u = 1 and X = O, known as zaltoprofen when saturated hydroxy, or amino group, or salts of the acid or acid salt, it means one of the derivatives of dibenzothiophene, preferred products have R2A= N, R3A= CH3, u = 1, X = O;

compound (XXXVII) is derived from maffesoli: 3,4-di(p-methoxyphenyl)isoxazol-5-acetic acid, when the remainder of the means-CH2-COOH, preferred compounds R2A= R3A= H, t = 1, X = O;

group IV) in which t = 1, u = 1 and R means

< / BR>
where RIVdand RIVd1means for at least one H, and the other a linear or when possible branched C1-C6alkyl, preferably1and C2, which have a methylene group;

RIVhas the following values:

< / BR>
group 1V), where t = 1, u = 1, R means

< / BR>
where RIVdand RIVd1means, at least one N and the other a linear or when possible branched C1-C6-alkyl, preferably1and C2or RIVdand RIVd1together form a methylene group;

RIVhas the following values: (II), (X), (III)

< / BR>
< / BR>
< / BR>
where compounds of groups 1V) have the following meanings:

in the compounds of formula (II) RIV-iimeans-CH3Oh, preferably RIVdmean N and RIVd1means - CH3X = NH or O, X1= -(CH2-CH2-OH)2;

in the compounds of formula (X), the remainder of loxoprofen,

or its equivalent; preferably compounds in which RIVdmeans hydrogen and RIVd1means-CH3, X = NH or O and X1= (CH2-CH2-OH)2;

in the compounds of the formula (III) RIV-iiimeans

< / BR>
and RIVd= N, RIVd1means - CH3X = NH or O, X1= -(CH2-CH2-OH)2;

group V) values (VII), (IX), (IV), (II), (X), (XI), (XII), (XIII) -

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where in the compounds of formula (II) RVii in the compounds of formula (II) RIV-IImean 1 - 6 alkyl, cycloalkyl having from 3 to 7, alkoxymethyl having from 1 to 7, triptorelin having from 1 to 3, vinyl, ethinyl, halogen, alkoxy having from 1 to 6, diflorasone with alkyl having from 1 to 7, alkoxymethyl having from 1 to 7, alkylthiomethyl with alkyl having from 1 to 7, altimetry with alkyl having from 1 to 7, cyano, deformality, phenyl - or phenylalkyl, substituted by alkyl having from 1 to 8;

preferably Riv-iimeans-CH3OH, Rivdmean N and Rivdimeans of CH3that means the rest of naproxen;

X = NH or O and X1= -(CH2-CH2-OH)2;

in the compounds of formula (X) the rest of loxoprofen or its equivalent; preferred compounds in which RIVdmean N and RIVd1means-CH3, X = NH or O and X1= -(CH2-CH2-OH)2;

in the compounds of the formula (III): RIV-iiimeans2-C5-alkyl, branched when possible, WITH2and C3alkyloxy, allyloxy, phenoxy, phenylthio, cycloalkyl having from 5 to 7 atoms, optionally substituted in position 1 WITH1-C2-alkyl:

preferred compounds where RI and is selected from the following:

-YO-,

where Y means cycloalkyl having from 5 to 7 carbon atoms; branched C2aliphatic connecting bridge having two methyl groups and the carbon atom bound in the relation to the essential functions, except such bridge connection when R is a radical group I), excluding IC; radical group II), excluding IIB; radical group III), excluding the class of compounds of the IIID); radical group IV), the radical group V), excluding X) and including -(CH2)4for compounds of formula (IV); group

where n3= 0 or 1; group

< / BR>
where R1f= H, nfmeans an integer of 1 to 6, preferably 2 to 4.

2. Nitroglicerine under item 1, where group 1) in the compounds of the formula 1A):

X is Oh, R1means acetoxy, preferably in anthopology towards-CO-; X1means (CH2-CH2-OH)2, R2means hydrogen;

in group II: where RII1, RII2and RII 4mean hydrogen, RII3means chlorine and RII3in anthopology towards NH; RII5and RII6denote H; X = O and X1means (CH2-CH2-OH)2.

3. Nitroglicerine under item 1 or 2, which has anti-inflammatory, analgesic, antitraite, has anti-inflammatory, analgesic, antimicrobial activity and activity against septic shock, characterized in that it includes nitroxoline on PP.1 to 3, or their salts, and solvents and/or excipients.

Priority points:

10.05.94 - p. 1: compounds where R And represent a group V) of the formula (VII), (IX), (IV), (III), (II) with X1, which is linear or branched alkyl WITH1-C10;

09.08.94 - p. 1: the compounds of formula A-X1-NO2where R a is selected from groups: group 1): formula 1A), 1B); group II, group III): formula (II), (XXI), (IV), (XXXV), (VI), (VII), (VIII), (IX), (X), (III); group IV): formula (II), (X), (III); group V): formula (VII), (IX), (IV), (V), (III), (II) having a bivalent connecting bridge;

09.08.94 - PP.2 to 4.

 

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