RU96123280A - NITRO COMPOUNDS AND COMPOSITIONS ON THEIR BASIS, HAVING ANTI-INFLAMMATORY, ANALGETIC AND ANTI-THROMBOTIC ACTIVITY - Google Patents

Claims (7)

1. Compounds or their compositions of the general formula:
AX ₁ -NO ₂
or their salts,
where A = R (COX _u ) _t , where t is zero or 1; u means zero or 1; X = O, NH, NR _1c , where R _1c means a linear or branched alkyl having from 1 to 10 C atoms;
R is chosen from the following groups:
group I), where t = 1 and u = 1

where R ₁ means OCOR ₃ group, where R ₃ means methyl, ethyl or linear or branched C ₃ -C ₅ alkyl, or the residue of a heterocycle with one ring having 5 or 6 atoms, which can be aromatic, partially or fully hydrogenated, containing one or more heteroatoms independently selected from O, N, or S;
R ₂ means hydrogen, hydroxy, halogen, linear or, when possible, branched alkyl, having from 1 to 4 C atoms, linear or, when possible, branched alkoxy, having from 1 to 4 C atoms, linear or, when possible, branched perfluoroalkyl having from 1 to 4 C atoms, for example, trifluoromethyl, nitro, amino, mono- or di- (C _1-4 ) alkylamino;
R ₁ and R ₂ together mean a dioxymethylene group, provided that when X = NH, X ₁ means ethylene and R ₂ = H; R ₁ cannot be OCOR ₃ in position 2 when R ₃ is methyl; nI means 0 or 1;
group ii) where t = 1 and u = 1

where R _II5 means hydrogen, linear or, when possible, branched C ₁ -C ₃ alkyl, R _II6 has the same meaning as R _II5 , or, when R _II5 means hydrogen, it can be benzyl;
R _II1 , R _II2 and R _II3 independently of one another denote hydrogen, linear or, when possible, branched C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, or Cl, F, Br;
R _II4 means R _II1 or bromine;
group III), where t = 1, u = 1 and R means:

where R _2A and R _3A mean H, linear or, when possible, branched, substituted or unsubstituted C ₁ -C ₁₂ alkyl, allyl, provided that when one of the two groups means allyl, the other means hydrogen; preferably R _2a means H, alkyl having from 1 to 4 C, R _3a means H;
R _{1a is} chosen from

IIID) have the following compounds:

where the values are as follows:
in the compound of formula (IV), ketoprofen residue;
R _III1 means H, SR _III3 , where R _III3 contains from 1 to 4 C atoms, linear or, when possibly branched;
R _III2 means H, hydroxy;
preferred compounds wherein R _III1 and R _{III2 are} H, R _3a is H and R _2a is methyl, X = O;
in the compounds of formula (XXI), carprofen residue:
R _xxio means H, linear or, when possible, branched alkyl having from 1 to 6 C atoms, C ₁ -C ₆ alkoxycarbonyl, linked to C ₁ -C ₆ alkyl, C ₁ -C ₆ carboxylalkyl, C ₁ -C ₆ alkanoyl, optionally substituted with halogen, benzyl or halo benzyl, benzoyl or halo benzoyl;
R _xxi means H, halogen, hydroxy CN, C ₁ -C ₆ alkyl, optionally containing OH groups, C ₁ -C ₆ alkoxy, acetyl, benzyloxy, SR _xxi2 , where R _xxi2 means alkyl C ₁ -C ₆ ; perfluoroalkyl having from 1 to 3 C atoms, C ₁ -C ₆ carboxyalkyl, optionally containing OH groups, NO ₂ , amino, sulfamoyl, dialkylsulfamoyl with alkyl having from 1 to 6 C atoms, or difluoroalkylsulfonyl with alkyl having from 1 to 3 C atoms;
R _xxi1 means halogen, CN, C ₁ -C ₆ alkyl containing one or more OH groups, C ₁ -C ₆ alkoxy, acetyl, acetamide, benzyloxy, SR _III3 as shown above, perfluoroalkyl having from 1 to 3 C, hydroxy , carboxyalkyl, having from 1 to 6 C, NO ₂ , amino, mono- or dialkylamino, having from 1 to 6 C, sulfamoyl, dialkyl sulfamoyl, having from 1 to 6 C, or difluoroalkylsulfamoyl, as shown above; or R _xxi together with R _xxi1 means alkylenedioxy, having from 1 to 6 C; preferred compounds, where R _xxio means H, connecting the bridge at position 2, R _xxi means H, R _xxi1 means chlorine in the para position relative to nitrogen;
R _3a means H, R _2a means methyl and X means O; - in compounds of the formula (XXXV), the residue is tiaprofenic acid:
Ar means phenyl, hydroxyphenyl, optionally mono- or polysubstituted with 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 those wherein Ar is phenyl, R _3a is H, R _2a is methyl and X is O;
in the compound of formula (II), the residue of suprofen, where R _3a means H, R _2a means methyl and X = O, or its equivalents;
in the compound of formula (VI), the residue is indoprofen, where R _2a is CH ₃ , and the residue is indobufen, where R _2a is H, R _3a = -CH ₃ , and X = O and its equivalents;
in compounds of formula (VIII), the residue is etodolac, where R _2a = R _3a = H and X = O and its equivalents;
in compounds of formula (VII), the residue is fenoprofen, where R _3a = X, R _2a = -CH ₃ and X = O and its equivalents;
in compounds of formula (III), the residue is fenbufen, where R _2a = R _3a = H and X = O and its equivalents;
in the compounds of formula (IX), the residue is fluorobiprofen, where R _3a means H, R _2a means -CH ₃ and X = O;
in the compounds of formula (X), the residue is tolmetin, where R _2a = R _3a = H and X = O or its equivalents;
compound IIIa), when it contains -CH (CH ₃ ) -COOH, pranoprofen residue; α-methyl-5H- [1] benzopyran [2,3b] pyridine-7-acetic acid; the preferred compound has R _2a = H, R _3a = -CH ₃ , u = 1 and X = O; - compound (XXX), when it contains -CH (CH ₃ ) -COOH, bermoprofen residue: dibenzo [b, f] oxepin-2-acetic acid; the preferred compound is u = 1, X = O, R _2a = H, R _3a = -CH ₃ ; Compound (XXXI) - CS-670 residue: 2- [4- (2-oxo-1-cyclohexylidenemethyl) phenyl] propionic acid, when the radical means -CH (CH ₃ ) -COOH; the preferred compound has R _2a = H, R _3a = -CH ₃ , u = 1 and X = O; - compound (XXXII) pemedolak derivative, which contains the —CH ₂ COOH groups; the preferred compound has R _2a = R _3a = H, u = 1 and X = O; compound (XXXIII) means a pyrazole residue when saturated with -CH ₂ COOH: 4- (4-chlorophenyl) -1- (4-fluorophenyl) -3-pyrazolyl acid derivative; Preferred compounds R _2a = R _3a = H, u = 1 and X = O; - the group when R _1a is a residue (XXXVI), R _2a = H, R _3a = CH ₃ , t = 1, u = 1 and X = O, is known as saltoprofen when saturated with hydroxy, or amino, or salts of the acid, or an acid salt, it means one of the dibenzothiipine derivatives; preferred products have R _2a = H, R _3a = CH ₃ , u = 1 and X = O; - compound (XXXVII) derived from mashesolak; 3,4-di (p-methoxyphenyl) isoxazole-5-acetic acid, when the residue is —CH ₂ —COOH; Preferred compounds R _2a = R _3a = H, t = 1, X = O; group IV) in which t = 1, u = 1 and R means

where R _IVd and R _IVd1 mean at least one H and the other linear or, when possible, branched C ₁ -C ₆ alkyl, preferably C ₁ and C ₂ , or difluoroalkyl with alkyl having from 1 to 6 C, C ₁ preferred, or R _IVd and R _IVd1 together form a methylene group;
R _IV has the following meanings:

where the compounds of group IV) have the following meanings:
in compounds of formula (II):
R _IV-II means 1-6 C alkyl, cycloalkyl, having from 3 to 7 C, alkoxymethyl, having from 1 to 7 C, trifluoroalkyl, having from 1 to 3 C, vinyl, ethinyl, halogen, alkoxy, having from 1 to 6 C, difluoroalkoxy with alkyl having from 1 to 7 C, alkoxymethyloxy, having from 1 to 7 C, alkylthiomethyloxy with alkyl having from 1 to 7 C, alkyl methylthio with alkyl having from 1 to 7 C, cyano, difluoromethylthio, phenyl or phenylalkyl, substituted alkyl, having from 1 to 8; preferably R _iv-ii is -CH ₃ O, R _ivd is H and R _ivdi is -CH ₃ , which means naproxen residue;
X = NH or O and X ₁ is - (CH ₂ -CH ₂ -O) ₂ ;
in the compounds of formula (X), the residue of loxoprofen or its equivalents; preferred compounds in which R _IVd is H and R _IVd1 is -CH ₃ , X = NH or O, and X ₁ is (CH ₂ -CH ₂ -O) ₂ ;
in compounds of formula (III): R _IV-iii means C ₂ -C ₅ alkyl, branched, when possible, C ₂ and C ₃ alkyloxy, allyloxy, phenoxy, phenylthio, cycloalkyl, having from 5 to 7 C atoms, optionally substituted in position 1 C ₁ -C ₂ alkyl; preferred compounds, where R _IV-iii means

and R _ivd = H, R _ivd1 means -CH ₃ , the compound is known as an ibuprofen residue;
X = NH or O and X ₁ is (CH ₂ -CH ₂ -O) ₂ ;
group V)

in group V) the compounds have the following meanings:
in compounds of formula (II), R _vii is H or linear or, when possible, branched alkyl having from 1 to 4 C; R _vii-1 means R _vii or linear or, when possible, branched alkoxy, having from 1 to 4 C; Cl, F, Br; the position of R _vii-1 o-, m- or p-; preferably a Ketorolac residue, where R _vii and R _{vii-1 are} H and A = R and t = 0;
in compounds of formula (V), where A = R and t = 0, the residue of tenidap or its equivalents;
in compounds of formula (VII), where A means RCO and t = 1 and u = 0 or A means R and t = 0; a residue of tenoxicam or its equivalents;
in compounds of formula (IX), where A = R and t = 0 or A = RCO and t = 1 and u = 0, the residue of piroxicam or its equivalents;
in compounds of formula (III), where A = RCOO, t = 1 and u = 0 or 1; or t = 0 and A = R, the residue of nabumetone or its equivalents;
in compounds of formula (IV), where A = RCOO, t = 1 and u = 1 or the residue of indomethacin or its equivalents;
in compounds of formula (X), meloxicam residue, preferred compounds are those in which t = 0; the remainder (XI) ampiroxicam, when the end group means COOC ₂ H ₅ ; preferred compounds are t = 1 and X = O, or t = 0;
the group when R _1a is the residue (XII), R _2a = H, R _3a = H, t = 1, u = 1 and X = O, is known as saltoprofen;
preferred compounds are u = 1, X = O and R _2a = R _3a = H; or t = 0;
the remainder (XIII) is a Lornoxicam derivative, when the valence is saturated with H, the preferred t compounds have t = 0;
X ₁ in the formula AX ₁ -NO ₂ means a bivalent connecting bridge and is selected from the following:
-YO-
where Y means:
linear or, when possible, branched C ₁ -C ₂₀ alkylene, preferably having from 2 to 5 carbon atoms, excluding such a bridge bond, when R means:
a radical of group I), excluding Ib and Ic;
a radical of group II), excluding IIb);
radical of group III), excluding the class of compounds from IIID)
a radical of group IV);
a radical of group V), excluding X) and including - (CH ₂ ) _{4 -} for compounds of formulas (III) and (IV);
or cycloalkylene, having from 5 to 7 carbon atoms, optionally substituted; including this bridge when R is a radical of group Ia)

where n ₃ means 0 or an integer from 1 to 3

where nf means an integer from 1 to 6, preferably from 2 to 4

where R _1f = H, -CH ₃ and nf means an integer from 1 to 6, preferably from 2 to 4. 2. Compounds or their composition according to claim 1, where group I):
in compounds of formula Ia): X is O, R ₁ is acetoxy, preferably in the ortho position with respect to —CO—, X ₁ is (CH ₂ —CH ₂ —O) ₂ , R ₂ is hydrogen;
in Ib): R ₃ = CH ₃ , nl = O, X is O, X ₁ is ethylene; in this case Ib) means the residue of acetylsalicylsalicylic acid;
in group II: where R ₁₁₁ , R ₁₁₂ and R ₁₁₄ mean hydrogen, R ₁₁₃ means chlorine and R ₁₁₃ in position with respect to NH; R ₁₁₅ and R _{116 are} H; X is O and X ₁ is (CH ₂ -CH ₂ -O) ₂ .  3. Compounds or compositions according to claim 1 or 2, for use as a medicine. 4. The use of compounds or their compositions having the general formula
AX ₁ -NO ₂
for the production of drugs for therapeutic use for septic shock, where A has the meanings described in paragraph 1 or 2 and X ₁ means a bivalent connecting bridge and is selected from the following:
-YO-,
where Y means: linear or, when possible, branched C ₁ -C ₂₀ alkylene, preferably having from 2 to 5 carbon atoms, cycloalkylene, having from 5 to 7 carbon atoms, optionally substituted;

where n ₃ means 0 or an integer from 1 to 3

where nf means an integer from 1 to 6, preferably from 2 to 4

where R _1f = H, -CH ₃ and nf means an integer from 1 to 6, preferably from 2 to 4. 5. The use of compounds or their compositions having the general formula:
AX ₁ -NO ₂
for the manufacture of drugs for therapeutic use as an anti-inflammatory agent, where A has the meanings described in PP.1 or 2 and X ₁ means a bivalent connecting bridge and is selected from the following:
-YO-,
where Y means: linear or, when possible, branched C ₁ -C ₂₀ alkylene, preferably having from 2 to 5 carbon atoms, excluding such a connecting bridge, when R means:
a radical of group II), excluding IIb);
a radical of group III), excluding the class of compounds from IIID);
a radical of group IV);
a radical of group V), excluding X) and including - (CH ₂ ) _{4 -} for compounds of formulas (III) and (IV);
cycloalkylene having from 5 to 7 carbon atoms, optionally substituted;

where n ₃ means 0 or an integer from 1 to 3

where nf means an integer from 1 to 6, preferably from 2 to 4;

where R _1f = H, -CH ₃ and nf means an integer from 1 to 6, preferably from 2 to 4. 6. The use of compounds or their compositions having the general formula:
AX ₁ -NO ₂
as an anti-thrombotic, where A has the meanings described in claim 1 or 2 and X ₁ means a bivalent connecting bridge and is selected from the following:
-YO-,
where Y means: linear or, when possible, branched C ₁ -C ₂₀ alkylene, preferably having from 2 to 5 carbon atoms, excluding such a connecting bridge, when R means:
a radical of group II), excluding IIb);
a radical of group III), excluding the class of compounds from IIID);
a radical of group IV);
a radical of group V), excluding X) and including - (CH ₂ ) _{4 -} for compounds of formulas (III) and (IV);
cycloalkylene having from 5 to 7 carbon atoms, optionally substituted;

where n ₃ means 0 or an integer from 1 to 3

where nf means an integer from 1 to 6, preferably from 2 to 4;

where R _1f = H, -CH ₃ and nf means an integer from 1 to 6, preferably from 2 to 4. 7. The use of compounds or their compositions, of the general formula:
AX ₁ -NO ₂
for the manufacture of drugs for therapeutic use as an analgesic, where A has the meanings described in paragraph 1 or 2 and X ₁ means a bivalent connecting bridge and is selected from the following:
-YO-,
where Y means: linear or, when possible, branched C ₁ -C ₂₀ alkylene, preferably having from 2 to 5 carbon atoms, excluding such a connecting bridge, when R means:
a radical of group II), excluding IIb);
a radical of group III), excluding the class of compounds from IIID);
a radical of group IV);
a radical of group V), excluding X) and including - (CH ₂ ) _{4 -} for compounds of formulas (III) and (IV);
or cycloalkylene, having from 5 to 7 carbon atoms, optionally substituted;

where n ₃ means 0 or an integer from 1 to 3

where nf means an integer from 1 to 6, preferably from 2 to 4;

where R _1f = H, -CH ₃ and nf means an integer from 1 to 6, preferably from 2 to 4.