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Title:
NITRO COMPOUNDS AND THEIR COMPOSITIONS HAVING ANTI-INFLAMMATORY, ANALGESIC AND ANTI-THROMBOTIC ACITIVITIES
Document Type and Number:
WIPO Patent Application WO/1995/030641
Kind Code:
A1
Abstract:
New compounds and their compositions having anti-inflammatory, analgesic and anti-thrombotic activities, of the general formula: A-X1-NO2 or their salts, wherein: A is R(COXu)t, wherein t is zero or 1 and u is zero or 1; and X is O, NH or NR1C wherein R1C is C1-C10 alkyl; and R is Ia) wherein R1 is acetoxy, preferably in ortho-position with respect to -CO- and R2 is hydrogen; or derivatives of acetylsalylsalicyclic acid; and X1 is -YO- wherein Y is C1-C20 alkylene, C5-C7 cycloalkylene, oxy-alkyl derivatives and oxy-methyl benzyl derivatives.

Inventors:
Del, Soldato
Piero, Sannicolo'
Francesco
Application Number:
PCT/EP1995/001233
Publication Date:
November 16, 1995
Filing Date:
April 04, 1995
Export Citation:
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Assignee:
NICOX LIMITED DEL SOLDATO
Piero, Sannicolo'
Francesco
International Classes:
C07D333/22; A61K31/04; A61K31/21; A61K31/215; A61K31/24; A61K31/35; A61K31/38; A61K31/381; A61K31/40; A61K31/403; A61K31/4035; A61K31/405; A61K31/415; A61K31/42; A61K31/425; A61K31/44; A61K31/4433; A61K31/54; A61P7/02; A61P9/08; A61P25/04; A61P29/00; A61P31/04; A61P43/00; C07C203/04; C07C203/10; C07C205/41; C07C205/45; C07C211/54; C07C211/56; C07C225/22; C07C229/40; C07C233/16; C07C245/08; C07C323/62; C07D207/08; C07D209/28; C07D209/46; C07D213/74; C07D213/75; C07D213/76; C07D231/12; C07D261/08; C07D313/14; C07D333/24; C07D337/14; C07D409/06; C07D417/12; C07D487/04; C07D491/052; C07D513/04; (IPC1-7): C07C203/04; A61K31/21; A61K31/40; A61K31/405; C07D333/22; C07D487/04
Domestic Patent References:
WO1994004484A1
WO1992001668A1
WO1994012463A1
Foreign References:
EP0549797A1
Download PDF:
Claims:
O 95/3064159 CLAIMS
1. Compounds, or their compositions, of the general formula: A Xx NO, or their salts, wherein: A = R(COXu)t, wherein t is zero or 1; u is zero or 1, X = 0, NH, NRXC wherein R1C is a linear or branched alkyl having 1 to 10 C atoms, R is chosen from the following groups: group I) , wherein t = 1 and u = 1 la) nl 41 *& 60.
2. Ic) I=_) l 2) wherein: Rx is an OCOR3 group, wherein R3 is methyl, ethyl or a linear or branched C_ C3 alkyl, or the residue of a he terocycle with a single ring having 5 or 6 atoms which may be aromatic, partially or totally hydrogenated, containing one or more heteroatoms independently chosen from 0, N, and S; R2 is hydrogen, hydroxy, halogen, a linear or when per¬ missible branched alkyl having 1 to 4 C atoms, a linear or when permissible branched alkoxyl having 1 to 4 C atoms, a linear or when permissible branched perfluoro alkyl having 1 to 4 C atoms, for example trifluoro methyl, nitro, amino, mono or di (Cx,4) alkylamino; Rx and R, together are a dioxymethylene group, with the proviso that when X = NH, Xx is ethylene and R2 = H; Rx cannot be OCOR3 in position 2 when R3 is methyl; nl being 0 or 1, group II) wherein t = 1 and u = l Ila) lib) wherein: RIIS is H, a linear or when permissible branched C_C2 alkyl, RI16 has the same meaning as RI15, or, when RIIS is H, it may be benzyl; Rm. Rιi2 anc* ιn3/ independently from one anotner, are hydrogen, a linear or when permissible branched CxC6 alkyl or Cx C6 alkoxy , or Cl , F , Br ; RII4 is RIIX or bromine , group III), wherein t = 1, u = 1 and R is: 2a I Rla R3a wherein: R2a and R3a are H, a linear or when permissible branched, substituted or nonsubstituted CxCx2 alkyl, allyl, with the proviso that when one of the two groups is allyl, the other is H; preferably R2a is H, an alkyl having from 1 to 4 C, R3a is H; RXa is chosen from (ID (XXI ) (IV) (XXXV) (VI) (VII) (VIII) (IX) (X) (III) I ϋ) as t.lie foil owing compounds : IJJa) (XXX) (XXXI ) (xxxτi) (xxxui) (XXXVl) wherein the meanings are as follows : in the compound of formula (IV) , residue of Ketoprofen: RII1X is H or SRIII3 wherein RIII3 contains from 1 to 4 C atoms, linear or when permissible branched; RIII2 is H, hydroxy; preferred are the compounds wherein RIIIX and RIII2 are H, R3a is H and R2a is methyl, X = 0; in the compounds of formula (XXI) , residue of carpro fen: RXXlo is H, a linear or when permissible branched alkyl having from 1 to 6 C atoms, a CxC6 alkoxycarbonyl bound to a CxC6 alkyl, a CxC6carboxylalkyl, a CxC6 alkanoyl, optionally substituted with halogens, benzyl or halobenzyl, benzoyl or halobenzoyl; Rxxi is H, halogen, hydroxy, CN, a Cx C6 alkyl optionally containing OH groups , a CxC6 alkoxy, acetyl , benzyloxy, SRχ i2 wherein Rχχi2 is an alkyl CxC6 ; a perf luoroalkyl 41 67 having from 1 to 3 C atoms, a CxC6 carboxyalkyl optionally containing OH groups, N02, ammino, sulpha¬ moyl, a dialkyl sulphamoyl with the alkyl having from 1 to 6 C atoms, or a difluoroalkylsulphonyl with the alkyl having from 1 to 3 C atoms, Rxxn i*3 halogen, CN, a CxC6 alkyl containing one or more OH groups, a CxC6 alkoxy, acetyl, acetamide, benzyloxy, SRni3 as above defined, a perfluoroalkyl having from 1 to 3 C, hydroxy, a carboxyalkyl having from 1 to 6 C, N02, ammino, a mono or dialkylamino having from 1 to 6 C, sulphamoyl, a dialkyl sulphamoyl having from 1 to 6 C, or a difluoroalkylsulphamoyl as above defined; or R^ together with RχχlX is an alkylene dioxy having from 1 to 6 C; preferred are the compounds wherein R^.,. is H, the con¬ necting bridge is in position 2, RXXl is H, Rχχιx is chlo¬ rine and is in the para position relative to nitrogen; R3a is H, R2a is methyl and X is 0; in the compounds of formula (XXXV) , residue of tiapro fenic acid: Ar is phenyl, a hydroxyphenyl optionally mono or poly substituted with halogen, an alkanoyl and an alkoxy having from 1 to 6 C, a trialalkyl having from 1 to 6 C, preferably from 1 to 3 C, cyclopentyl, cylo hexyl, cycloheptyl, heteroaryl, preferably thienyl, a furyl optionally containing OH, pyridyl, the preferred (XXXV) compounds are those wherein Ar is phenyl, R3a is H, R2a is methyl and X is 0; in the compound of formula (II) , residue of suprofen, wherein R3a is H, R2a is methyl and X = 0, or its equi¬ valents, in the compound of formula (VI) , residue of indoprofen, wherein R2a is CH3, and residue of indobufen wherein R2a is H, R3a = CH3, and X = 0 and its equiva¬ lents; in the compounds of formula (VIII) , residue of etodo lac, wherein R2a = R3a = H and X = 0 and its equivalents; in the compounds of formula (VII) , residue of feno profen, wherein R3a = X, R2a = CH3 and X = 0 and its equivalents, in the compounds of formula (III) , residue of fenbufen, wherein R2a R3a = H and X = 0 and its equivalents; in the compounds of formula (IX) , residue of flurbipro fen, wherein R3a is H, R2a is CH3 and X = 0; in the compounds of formula (X) , residue of tolmetin, wherein R2a = R3a = H and X = 0 or its equivalents; compound Ilia) , when it contains the CH(CH3) COOH, is pranoprofen residue: αmethyl5H [1]benzopyrano [2,3b] pyridine7acetic acid; the preferred compound has R2a = H, R3a = CH3, u = 1 and X = 0; compound (XXX), when it contains CH(CH3) COOH is bermoprofen residue: dibenz [b, f] oxepin2acetic acid; the preferred compound has u = 1, X = 0, R2a = H, R3a = CH3; compound (XXXI) is CS670 residue: 2 [4 (2oxol cyclohexylidenemethyDphenyl]propionic acid, when the radical is CH(CH3) COOH, the preferred compound has R2a = H, R3a = CH3, u = 1, X = 0; compound (XXXII) derives from the pemedolac which con¬ tains the CH2C00H groups; the preferred compound has R2a = R3a = H, u = 1 and X = 0; compound (XXXIII) is pirazolac residue when is satu¬ rated with CH2C00H: 4 (4chlorphenyl) 1 (4fluor¬ phenyl) 3pyrazolyl acid derivatives, the preferred com¬ pounds have R2a = R3a = H, u = 1 and X = 0; compound (XXXVI) when saturated with CH(CH3) COO , is zaltoprofen residue, when saturated with an hydroxy or an amino group or the salts of the acid is one of the dibenzothiepin derivatives, the preferred products have a R2a = H, R3a = CH3, u = 1, X = 0; compound (XXXVII) is deriving from the mofezolac: 3,4 di (pmethoxyphenyl) isoxazol5acetic acid, when the residue is CH2C00H; the preferred compounds are R,a = R3a = H, t = 1, X = 0; group IV) in which t = 1 , u = 1 and R is Rτ RIV C IVdl wherein : Rιvd and Rιvdx are at least one H and the other a linear or when permissible branched Cx C6 alkyl , preferably Cx and C2 , or a difluoroalkyl with the alkyl having from 1 to 6 C , Cx is preferred, or Rιvd and Rιvdx together form a methylene group; RIV has the following meaning: (II) meanings: in the compounds of formula (II) : R1V.11 is a 16 C alkyl, a cycloalkyl having from 3 to 7 C, an alkoxymethyl having from 1 to 7 C, a trifluoro alkyl having from 1 to 3 C, vinyl, ethinyl, halogen, an alkoxy having from 1 to 6 C, a difluoroalkoxy with the alkyl having from 1 to 7 C, an alkoxymethyloxy having from 1 to 7 C, an alkylthiomethyloxy with the alkyl having from 1 to 7 C, an alkyl methylthio with the alkyl having from 1 to 7 C, cyano, difluoromethyl hio, phenylor phenylalkyl substituted with the alkyl ha¬ ving from 1 to 8 C; preferably Rlvll is CH30, Rιvd is H and RIvdx is CH3, which is a residue of naproxen, X = NH or 0 and Xx is equal to (CH2CH20)2, in the compounds of formula (X) , the residue of loxo¬ profen or its equivalents; preferred are the compounds in which Rιvd is H and Rιvdx is CH3, X = NH or 0 and Xx is equal to (CH2CH20)2; in the compounds of formula (III) : Rxv111 is a C2C5 alkyl, even branched whenever possible, a C2 and C3 alkyloxy, allyloxy, phenoxy, phenylthio, a cycloalkyl having from 5 to 7 C atoms, optionally substituted in position 1 by a CxC2 alkyl; preferred is the compound wherein Rxv111 is and Rιvd = H, Rιvdx is CH3 , which is a residue of ibupro fen ; X = NH or 0 and Xx is equal to (CH2CH20) 2 ; group V) ( IX) (rv) (V) (III) Vll (ID Class VE) (XIII) in group V) , the compounds have the following meanings: in the compounds of formula (II) , RV11 is H or a linear or when permissible branched alkyl having from 1 to 4 C; Rvni is R,lx or a linear or when permissible branched alkoxy having from 1 to 4 C; Cl, F, Br, the position of RV111 being o, m or p, preferred is the residue of Ketorolac, wherein RV11 and RV111 are H, and A = R and t = 0 in the compounds of formula (V) , wherein A = R and t = 0 the residue of tenidap or its equivalents; in the compounds of formula (VII) , wherein A is RCO and t = 1 and u = 0 or A is R and t = 0, the residue of tenoxicam or its equivalents; in the compounds of formula (IX) where A = R and t = 0, or A = RCO with t = 1 and u = 0, the residue of piroxicam or its equivalents, in the compounds of formula (III) where A = RCOO, t = 1 and u = 0 or 1; or t = 0 and A = R the residue of nabu metone or its equivalents, in the compounds of formula (IV) where A = RCOO, t = 1, u = 1 or the residue of indomethacin or its equiva¬ lents; In compounds of formula (X) the residue of meloxicam, the preferred compounds are those in which t = 0, the residue (XI) ampiroxicam when the termination is COOC,H5; the preferred compounds have u = 1 and X = 0; or t = 0; the residue (XII) when saturated with CH2C00 is brom fenac, the preferred compounds have u = 1, X = 0 and R2a = R3a = H; or t = 0; the residue XIII) derives from Lornoxicam when the va¬ lence is saturated with H, the preferred compounds have t = 0; Xx in the formula AXxN02 is a bivalent connecting bridge chosen from the following: YO where Y is : a linear or when permissible branched CxC20 alkylene, preferably having from 2 to 5 carbon atoms, excluding this connecting bridge when R is : a radical of group I) except classes lb and Ic, a radical of group II) excpet IIb) , a radical of group III) except class compounds Of HID) ; a radical of group IV) ; a radical of group V) , except X) and inclu SUBST1TUTESHEET(RULE26) ding (CH2)4 for the compounds of formulae (III) and (IV) ; or a cycloalkylene having from 5 to 7 carbon atoms optionally substituted; wherein n3 is 0 or an integer from 1 to 3 (CH2CHCH20)nf. ON02 wherein nf is an integer from 1 to 6, preferably from 2 to 4,* (CHCH20)nf R!f wherein Rlf = H, CH3 and nf is an integer from 1 to 6 preferably from 2 to 4. The compounds or their compositions according to claim 1, wherein, in group I) : O 95/30641 78 in the compounds of formula la) : X is 0, Rl is acetoxy, preferably in orthoposition with respect to CO, Xx is (CH CH20) ,, R2 is hydrogen; in lb) : R3 = CH3, nl = 0, X is equal to 0, Xx is ethyle ne; in this case lb) is the residue of acetylsalicyl salicylic acid; in group II: where RIIX, RII2 and RII4 are H, RII3 is chlo¬ rine and RII3 is in the ortho position relative to NH; RXIS and RXI6 are H; X is equal to 0, and Xx is (CH2CH20)2.
3. The compounds or their compositions according to claim 1 or 2, for use as a medicament.
4. Use of the compounds or their compositions having gene¬ ral formula. AXxN02 for the treatment of septic shock, wherein A has the meanings reported in claim 1 or 2 and Xx is a bivalent connecting bridge chosen from the following. Y0 where Y is : a linear or when permissible branched CXC20 alkyle¬ ne, preferably having from 2 to 5 carbon atoms, a cycloalkylene having from 5 to 7 carbon atoms optionally substituted; wherein n2 is 0 or an integer from 1 to 3 (CHaCHCH20). ONO, wherein nf is an integer from 1 to 6, preferably from 2 to 4, (CHCH,0)nf I !f wherein R = H, CH3 and nf is an integer from 1 to 6 preferably from 2 to 4. Use of the compounds or their compositions having gene¬ ral formula: AXxN02 as antiinflammatory, wherein A has the meanings repor¬ ted in claim 1 or 2 and Xx is a bivalent connecting bri¬ dge chosen from the following: Y0 where Y is : a linear or when permissible branched CxC20 alkyle¬ ne, preferably having from 2 to 5 carbon atoms, excluding this connecting bridge when R is: a radical of group II) except IIb) , a radical of group III) except class of com¬ pounds of HID) a radical of group IV) ; a radical of group V) , execpt X) and inclu¬ ding (CH)., for the compounds of formulae (III) and (IV) ; a cycloalkylene having from 5 to 7 carbon atoms optionally substituted; wherein n3 is 0 or an integer from 1 to 3 ( CH, CHCH, 0) nf ON02 wherein nf is an integer from 1 to 6, preferably from 2 to 4 (CHCH20) I Rlf wherein Rlf = H, CH3 and nf is an integer from 1 to 6, preferably from 2 to 4. 6. Use of the compounds or their compositions having gene¬ ral formula AXxN02 as antithrombotic wherein A has the meaning reported in claim 1 or 2 and Xx is a bivalent connecting bridge chosen from the following: YO where Y is: a linear or when permissible branched CxC20 alkyle¬ ne, preferably having from 2 to 5 carbon atoms, excluding this connecting bridge when R is. a radical of group II) except IIb) , a radical of group III) except class of com¬ pounds of HID) a radical of group IV) , a radical of group V) , except X) and inclu¬ ding (CH2)4 for the compounds of formulae (III) and (IV) ; a cycloalkylene having from.
5. to 7 carbon atoms optionally substituted; wherein n3 is 0 or an integer f rom 1 to 3 ( CH2 CHCH2 0) nf. 0N02 wherein nf is an integer from 1 to 6, preferably from 2 to 4 (CHCH20)nf lf wherein Rxf = H, CH3 and nf is an integer from 1 to.
6. preferably from 2 to 4. 7. Use of the compounds or their compositions of the gene¬ ral formula: AXxN02 as analgesic wherein A has the meanings reported in claim l or 2 and Xx is a bivalent connecting bridge cho¬ sen from the following: YO where Y is: a linear or when permissible branched CxC20 alkyle¬ ne, preferably having from 2 to 5 carbon atoms, excluding this connecting bridge when R is: a radical of group II) except IIb) , a radical of group III) except class of com¬ pounds of HID) a radical of group IV) , a radical of group V) , except X) and inclu¬ ding (CH2)4 for the compounds of formulae (III) and (IV) , a cycloalkylene having from 5 to 7 carbon atoms optionally substituted; wherein n3 is 0 or an integer from 1 to 3 (CH2CHCH20)nf. I 0N02 wherein nf is an integer from 1 to 6, preferably from 2 to 4 (CHCH20) I Rlf wherein Rxf = H, CH3 and nf is an integer from 1 to 6 , preferably from 2 to 4 .
Description:
NITRO COMPOUNDS AND THEIR COMPOSITIONS HAVING ANTI-INFLAMMATORY, ANALGESIC AND ANTI-THROMBOTIC ACTIVITIES

The present invention relates to new products having anti-inflammatory, analgesic and anti-thrombotic activities.

In particular it relates to inhibitors of cyclo-oxyge- nase (COX) .

It is known that the anti-inflammatory and anti-throm¬ botic efficacy, but most of all the tolerance, of NSAIDs (Non Steroid Anti-Inflammatory Drugs) , also known as FANS, seem to be considerably affected by their cyclo-oxygenase (COX) -inhibiting activity in the inflammatory site as well as in healthy tissue. See for example FASEB Journal 1, 89, 1987; Bioch. Biophys. Acta 1083, 1, 1991. It is generally believed that the more potent a COX inhibitor is the more effective it is.

The disadvantage of these products is that they are toxic.

Furthermore, it is also known that the COX-inhibiting properties seem to depend on some factors related to the physico-chemical and structural characteristics of the mole¬ cules themselves, such as for example the acidic function. See for example J. Pharmacol. Exp. Therap. 196, 226, 1976; Arch. Toxicol. 60, 261, 1987.

O 95/30641

2

The known cyclo-oxygenase inhibitors are generally acids which can be brought back to general structures, in¬ cluding: carboxyl acids, either acetylated such as, for example, aspirin and triflusal, or nonacetylated such as, for example, salycilate, diflunisal, salsalate; acetic acids, for example diclofenac, indomethacin, tolmetin, sulindac, etodolac, ketorolac,- propionic acids, such as, for instance, ibuprofen, na- proxen, pirprofen, tiaprofenic acid, loxoprofen, indo- profen, oxaprozin, ketoprofen fenoprofen, fenbufen, flurbiprofen, carprofen, suprofen; enolic acids, such as, for example, oxyphenbutazone, phenylbutazone, piroxicam, sudoxicam, tenoxicam, isoxi- cam, meloxicam.

See patents USP 3,558,690; USP 3,755,427; USP 3,641,127; FR 2,112,111; USP 4,035,376; USP 3,997,669; USP 3,784,701; USP 3,896,145; USP 3,600,437; USP 3,843,681; USP 3,904,682; USP 3,228,831; USP 4,161,538; USP 4,233,299; USP 3,591,584; DE 2,537,070; USP 3,161,654; USP 4,061,779; USP 4,556,672; USP 4,089,969.

The disadvantage of these products is that they are very effective but highly toxic.

The importance of the acidic function lies in the fact that a masking of this function in COX inhibitors results in a virtually complete loss of its prostanoid-inhibiting pro¬ perties. See Drugs 35, 504, 1988.

Also known are products which are highly effective in inhibiting cyclooxygenase and have a low toxicity even though they do not contain the acidic function in their mo¬ lecule.

These products are known as nitric esters with nonaci- dic ending. See for example patents PCT WO 94/04484, which describes a particular group of compounds including the well known commercial product diclofenac,- PCT/EP 93/03193, which describes another specific group of compounds including the commercial products flurbiprofen and indoprofen.

The Applicant has unexpectedly found that other com¬ pounds having the termination group -ON0 2 , when X : = -Y0-, as defined hereinafter, have anti-inflammatory, analgesic and anti-thrombotic activities when used as medicaments with high efficacy in cyclo-oxigenase inhibition and have low toxicity.

A further object of the invention is that the known products as reported in PCT WO 94/04484 and PCT/EP 93/03193 and the new compounds found by the Applicant having X = -YO-

have a pharmaco-dynamic disadvantage. In fact, in the bio¬ chemical test evaluating the cyclo-oxygenase-inhibiting activity, experiments conducted by the applicant showed a high response variability, in the order of 10-40%.

This generally results in an erratic and unpredictable efficacy, so that the determination of a correct dosage is difficul .

In practice, higher doses must be administered to limit the above variability. The disadvantage lies in the risks of a higher incidence of side effects.

Another disadvantage is that these products are diffi¬ cult from a formulation point of view because oral or paren- teral preparations are more difficult to prepare than tradi¬ tional preparations based on acidic FANS.

Molecule solubility is known be one of the most impor¬ tant properties affecting the molecule pharmacokinetic and dynamic processes.

For example, for parenteral administration, particu¬ larly by the intravenous route, drugs must be formulated in soluble form.

Similarly, by the oral route, the solubilisation pro¬ cess is decisive for absorption and interaction with the ef¬ fector.

,-,,. .-. O 95/30641

5 In this respect, the choice of particular solvents and/or excipients, including surfactants, etc., is also to- xicologically critical. For example, an intravenous formula¬ tion should not cause haemolysis or incompatibility with blood constituents.

However, there is much evidence which indicates that surfactants and apolar solvents may be irritant. See, for instance, J. Pharm. Science 72, 1014, 1983.

Trials conducted by the applicant using 0.1% Tween 80 and 1% dimethylsulphoxide to suspend nitroxybutylflurbipro- fen showed that this solvent was irritant to the gastric mucous membrane.

However, it was unpredictably found that, using a NO- flurbiprofen derivative as described below which is part of the object of the present invention, the amounts of Tween 80 and dimethylsulphoxide required for suspension were lower, such that no irritant effects were caused, even though re¬ sults were the same in terms of solubilisation.

It was unpredictably and surprisingly found after nume¬ rous investigations that it is possible to prepare anti-in¬ flammatory products, as described below, having a high cyclo-oxygenase-inhibiting activity combined with low toxi¬ city and pharmacokinetically satisfactory responses, and

95/30641

6 having a very limited response variability with an average variation coefficient of about one half that of known pro¬ ducts pharmacodynamically, and easier to formulate as oral or parenteral preparations .

This was totally surprising and unexpected as the fa¬ ctors which affect the anti-inflammatory and anti-thrombotic efficacy of NSAIDs depend on a number of parameters. There¬ fore, it is not possible to forecast pharmacokinetics, for example the product fraction absorbed, the pharmacodynamic activity, the toxicity and the COX-inhibiting properties and, most of all, no assumptions may be made to predict or limit response variability.

Object of the present invention are compounds, or their compositions, of general formula.-

A-X : -N0 2 or their salts, for use as medicaments, in particular as anti-inflammatory or antithrombotic agents, wherein.- A = R(C0X u ) t , wherin t is zero or 1; u is zero or 1, X = 0, NH, NR 1C wherein R 1C is a linear or branched alkyl ha¬ ving 1 to 10 C atoms,- R is chosen from the following groups: group I) , wherein t = 1 and u = 1

la)

A.

O

2 1

lb)

Ic)

!C 1 )

*. 2 >

IC

O 95/30641

wherein :

R x is an OCOR 3 group, wherein R 3 is methyl, ethyl or a linear or branched C 3 -C 5 alkyl, or the residue of a heterocycle with a single ring having 5 or 6 atoms which may be aromatic, partially or totally hydrogenated, containing one or more heteroatoms independently chosen from 0, N, and S; R, is hydrogen, hydroxy, halogen, a linear or when permissi¬ ble branched alkyl having 1 to 4 C atoms, a linear or when permissible branched alkoxyl having 1 to 4 C atoms, a linear or when permissible branched perfluoroalkyl having 1 to 4 C atoms, for example trifluoromethyl, nitro, amino, mono- or di- (Ci-,,) alkylamino;

Rj and R, together are a dioxymethylene group, with the pro¬ visos that when X = NH, then X is ethylene and R 2 = H,- R x cannot be 0C0R 3 in position 2 when R 3 is methyl; nl being 0 or 1.

Preferably, in la) X is equal to 0 or -NH, R x is acetoxy, preferably in ortho-position, with respect to -CO-, X x is (CH 2 -CH 2 -0) 2 , R 2 is hydrogen, most preferred are the following A-X 1 -N0 2 compounds: 3-acetoxy-N- (2-nitroxyethyl) -benzamide, 4-acetoxy-N- (2-nitroxyethyl) -benzamide, 3-acetoxy-N- (5-ni- troxypentyl) -benzamide,- 2-acetoxy-n- (5-nitroxypentyl)benza¬ mide, N-2- (nitroxyethyl) -2-propionoxy-benzamide, 2-acetoxy-

O 95/30641

9 2-nitroxy-eth l benzoate, 2-acetoxy-N- (cis-2-nitroxycyclo- hexyl) -benzamide, 2-acetoxy-4-chloro-N- (2-nitroxyethyl) -ben- z a m i d e , N - ( 2 - n i t r o x y e t h y l ) - 2 - ( ( 4 - thiazolyldinyl) carbonyloxy) -benzamide hydro chloride, 2-ni- cotinoyloxy-N- (2-nitroxyethyl) -benzamide, 2-acetoxy-5- nitroxypentylbenzoate,- preferably, in lb) R 3 = CH 3 , nl = 0;

X is equal to 0, X x is ethylene: in this case lb) is the re¬ sidue of acetylsalicylsalicylic acid;

Compounds Ic) of the class Ic 5-amino salicylic acid deri¬ vatives (5-amino-2-hydroxybenzoic acid) are known as mesala- mine when the valence is saturated with -COOH. In compounds Ic 2 ) at least one of the -COOH is reacted to form the compounds of the invention. When both -COOH are reacted one obtains bifunctional compounds. When the com¬ pound is saturated with -COOH, is known as olsalazine. Compounds Ic 3 ) are known, when the starting radical has a -COOH as sulfasalazine: 2-hydroxy-5- [ (4- [ (2-pyridinylami- no)sulphonylj henyl]azoj enzoic acid.

The preferred compounds of Ic) have X = 0 and u = 1 and X α is different from -Y0-. group II) wherein t = 1, u = 1

10

Ha )

lib) wherein :

R II5 is H, a linear or branched C 1 -C 3 alkyl when permissible R II6 has the same meaning as R IIS , or, when R II5 is H , it may be benzyl ,-

R m , R II2 and R III3 independently from one another are hydro¬ gen, a linear or when permissible branched C j -Cg alkyl , or C- -C 6 alkoxy, or Cl , F, Br,- R II4 is R or bromine ; preferred are the compounds wherein R m , R II2 and R II4 are H and R II3 is chlorine and R II3 is in the ortho position rela-

tive to NH;

R II5 and R IIβ are H, X is equal to 0, and X x is (CH 2 -CH 2 -0) 2 ; lib) is the residue of 2- [ (2-methyl-3- (trifluoromethyl) phenyl] amino] -3-pyridinecarboxylic acid] and when -COOH is present is known as flunixin.

Preferred compounds are those in which u = 1 and X = 0. group III), wherein t = 1, u = 1 and R is:

I

I

R 3 a wherein:

R 2a and R 3a are H, a linear or when permissible branched, sub¬ stituted or non-substituted alkyl, allyl, with the pro¬ viso that when one of the two groups is allyl, the other is H; preferably R 2a is H, an alkyl having from 1 to 4 C, R 3a is H; R la is chosen from

(ID

(IV)

(XXXV)

(VI)

(VII)

(VIII)

(IX)

(X)

(III)

I IJ) has t ; he foilowing compounds

IJJa) (XXX)

( XXUI) (XXXVI)

O 95/30641

15

) wherein the meanings are as follows : in the compound of formula (IV) , residue of Ketoprofen.-

R IIIl is H, SR III3 wherein R III3 contains from 1 to 4 C atoms, linear or when permissible branched;

R τ is H, hydroxy,- preferred are the compounds wherein R ι and R III2 are H,

R 3a is H and R 2a is methyl, X = 0,- in the compounds of formula (XXI) , residue of carpro- fen:

R i o is H a linear or when permissible branched alkyl having from 1 to 6 C atoms, a ^-C alkoxycarbonyl bound to a Ci-Cg alkyl, a C 1 -C 6 carboxylalkyl, a Ci-Cg alkanoyl, optionally substituted with halogens, benzyl or halobenzyl, benzoyl or halobenzoyl;

Rxxi is H, halogen, hydroxy, CN, a Cj- alkyl optionally containing OH groups, a alkoxy, acetyl, benzyloxy,

SRχχ i2 wherein Rχχ.j .2 is an alkyl C x -C β ; a perfluoroalkyl having from 1 to 3 C atoms, a carboxyalkyl

optionally containing OH groups, N0 2 , am ino, sulpha¬ moyl, a dialkyl sulphamoyl with the alkyl having from 1 to 6 C atoms, or a difluoroalkylsulphonyl with the alkyl having from 1 to 3 C atoms,-

R xn i* 3 halogen, CN, a alkyl containing one or more OH groups, a d-Cg alkoxy, acetyl, acetamide, benzyloxy, SR ni 3 as above defined, a perfluoroalkyl having from 1 to 3 C, hydroxy, a carboxyalkyl having from 1 to 6 C, N0 2 , ammino, a mono- or di-alkylamino having from 1 to 6 C, sulphamoyl, a di-alkyl sulphamoyl having from 1 to 6 C, or a difluoroalkylsulphamoyl as above defined; or R XXl together with R^^ is an alkylene dioxy having from 1 to 6 C; preferred are the compounds wherein R^^ is H, the con¬ necting bridge is in position 2, R^ is H, R χχix is chlo¬ rine and is in the para position relative to nitrogen; R 3a is H, R 2a is methyl and X is 0; in the compounds of formula (XXXV) , residue of tiapro- fenic acid:

Ar is phenyl, a hydroxyphenyl optionally mono- or poly- substituted with halogen, an alkanoyl and an alkoxy having from 1 to 6 C, a trialalkyl having from 1 to 6 C, preferably from 1 to 3 C, cyclo-pentyl, cylo-hexyl,

641

17 cyclo-heptyl, heteroaryl, preferably thienyl, a furyl optionally containing OH, pyridyl,- the 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) , residue of suprofen, of which the one preferred has been shown, wherein R 3a is H, R 2a is methyl and X = 0; its equivalents as de¬ scribed and obtained in USP 4,035,376, which is in¬ corporated herein in full as a reference, may also be used; in the compound of formula (VI) , of which the ones preferred indoprofen, when R 2a is CH 3 and indobufen when R 2a is equal to H, R 3a = -CH 3 and X = 0 have been shown,- its equivalents as described in and obtained in accor¬ dance with USP 3,997,669, which is incorporated herein in full as reference, may also be used; in the compounds of formula (VIII) , of which the one preferred, etodolac, wherein R 2a = R 3 a = H an d X = 0 has been shown,- its equivalents as described in and obtained in accordance with USP 3,843,681, which is incorporated herein in full as re¬ ference, may also be used;

in the compounds of formula (VII) , of which the one preferred, fenoprofen, wherein R 3a = X, R 2a = -CH 3 and X = 0 has been shown,- its equivalents as described in and obtained in accordance with USP 3,600,437, which is incorporated herein in full as re¬ ference, may also be used; in the compounds of formula (III) , of which the preferred, fenbufen, wherein R 2a = R 3a = H and X = 0 has been shown,- its equivalents as described in and obtained in accordance with patent USP 3,784,701, which is incorporated herein in full as a reference, may also be used; in the compounds of formula . (IX) , residue of flurbi- profen wherein R 3a is H, R 2a is -CH 3 and X = 0; in the compounds of formula (X) , residue of tolmetin, wherein R 2a = R 3a = H and X = 0; its equivalents as described in and obtained in accor¬ dance with patent FR 1,574,570, which is incorporated herein in full as a reference, may also be used;

In class III D) the meaning is the following:

Ilia) when it contains the -CH(CH 3 ) -COOH is known as pranoprofen: α-methyl-5H- [l]benzopyrano [2,3-b]pyridine-7- acetic acid.

In the preferred compound R 2a = H, R 3a = CH 3 , u = 1 and X =

0.

The residue (XXX) when contains -CH(CH 3 ) -COOH is known as bermoprofen: diben∑[b, f] oxepin-2-acetic acid. The preferred compound has u = 1, X = 0, R 2a = H, R 3a = CH 3 .

The residue of (XXXI) is known as CS-670: 2-[4-(2-oxo- l-cyclohexylidenemethyl)phenyl]propionic acid, when the ra¬ dical is -CH(CH 3 ) -COOH. The preferred compound has R 2a = H, R 3a = CH 3 , u = 1, X = 0.

The residue (XXXII) derives from the known pemedolac which contains the -CH 2 C00H groups. The preferred compound has R 2a = R 3a = H, u = 1 and X = 0.

This residue (XXXIII) is known as pirazolac when is saturated with -CH 2 C00H:

4- (4-chlorphenyl) -1- (4-fluorphenyl) 3-pyrazolyl acid deriva¬ tives . Preferred compounds have R 2a = R 3a = H, u = 1 and X = 0.

The residue (XXXVI) when saturated with -CH(CH 3 ) -COO- , is known as zaltoprofen.

When the residue is saturated with an hydroxy or an amino group or the salts of the acid, the compounds are known as dibenzothiepin derivatives. The preferred products have a R 2a = H, R 3a = CH 3 , u = 1,

95/30641

20

X = O .

The residue (XXXVII) is deriving from the known mofezolac:

3,4-di (p-methoxyphenyl) isoxazol-5-acetic acid when the residue is -CH 2 -COOH.

Preferred compounds R 2a = R 3a = H, t = 1, X = 0. group IV) in which t = 1, u = 1 and R is

R 2a

I

R la - -

I R 2a

wherein.-

R lvd and R Ivdl are at least one H and the other a linear or when permissible branched C x -C 6 alkyl, preferably C x and C 2 , or a difluoroalkyl with the alkyl having from 1 to 6 C, C x is preferred, or R ιvd and R 1VcU together form a methylene group,-

R IV has the following meaning:

(ID

(X)

wherein the compounds of group IV) have the following mea¬ nings: in the compounds of formula (II) :

R 1V _ 11 is a 1-6 C alkyl, a cycloalkyl having from 3 to 7 C, an alkoxymethyl having from 1 to 7 C, a trifluoro- alkyl having from 1 to 3 C, vinyl, ethinyl, halogen, an alkoxy having from 1 to 6 C, a difluoroalkoxy with the alkyl having from 1 to 7 C, an alkoxymethyloxy having from 1 to 7 C, an alkylthiomethyloxy with the alkyl having from 1 to 7 C, an alkyl methylthio with the alkyl having from 1 to 7 C, cyano, difluoromethylthio, phenyl-or phenylalkyl substituted with the alkyl ha-

41

22 ving from 1 to 8 C ; preferably R 1V . 13, is -CH 3 0, R ιvd is H and R ιvdl is -CH 3 , and is known as a residue of naproxen,-

X = NH and X x is equal to - (CH 2 -CH 2 -0) 2 ; also preferred is the same compound wherein X is equal to 0; in the compounds of formula (X) , of which the residue of loxoprofen has been shown, the residues described in USP 4,161,538, which is incorpo¬ rated herein in full as a reference, may be used as equivalents . Preferred are the compounds in which R ιvd is H and R ιvdx is -CH 3 , X = NH and X x is equal to (CH 2 -CH 2 -0) 2 ; also preferred is the same compound wherein X is equal to 0; in the compounds of formula (III) :

R ι v- ι _ is a C 2 -C 3 alkyl, even branched whenever possible, a C 2 and C 3 alkyloxy, allyloxy, phenoxy, phenylthio, a cycloalkyl having from 5 to 7 C atoms, optionally substituted in position 1 by a C x -C 2 alkyl,- preferred is the compound wherein R 1V . 1X1 is

and R lvd = H, R ιvdx is -CH 3 , a compound known as a residue

of ibuprofen;

X = NH and X is equal to (CH 2 -CH 2 -0) 2/ - also preferred is the same compound wherein X is equal to 0; group V)

(VII)

(IX)

(IV)

(III)

V2.1

(ID

Class VE)

(X)

(XI)

(XII)

(XIII)

641

26

In group V) , the compounds have the following meanings: in the compounds of formula (II)

R V11 is H or a linear or when permissible branched alkyl having from 1 to 4 C;

R i- ! is R V11 or a linear or when permissible branched alkoxy having from 1 to 4 C; Cl, F, Br; the position of R v n - ι being o-,m- or p-,- preferred is the residue of the known ketorolac, whe¬ rein R V11 and R ^ . 11-x are H, and A = R and t = 0 in the compounds of formula (V) , of which the residue of the known tenidap has been shown, its equivalents as described and obtained in USP 4,556,672, which is incorporated herein in full as a reference, may also be used; in these compounds of formula (V) A = R and t = 0, in the compounds of formula (VII) of which the residue of the known tenoxicam has been shown, A is RCO and t = 1 and u = 0 or A is R and t = 0; its equivalents as described and obtained in patent DE 2,537,070, which is incorporated herein in full as a reference, may also be used; in the compounds of formula (IX) where A = R and t = 0, or A = RCO with t = l and u = 0,

1

27

of which the residue of the known piroxicam has been shown, its equivalents as described and obtained in

USP 3,591,584, which is incorporated herein in full as a reference, may also be used; in the compounds of formula (III) where A = RCOO, t = 1 and u = 0 or 1; or t = 0 and A =

R, of which the residue of the known nabumetone has been shown, its equivalents as described and obtained in USP 4,061,779, which is incorporated herein in full as reference, may also be used; in the compounds of formula (IV) where A = RCOO, t = 1, u = 1 of which the residue of the known indomethacin has been shown, its equivalents as described and obtained in USP 3,161,654, which is incorporated herein in full as reference, may also be used. in compounds of formula (X) .- the residue (X) is known as meloxicam.

Preferred compounds are those in which t = 0.

The residue (XI) is known as ampiroxicam when the termination is -COOC 2 H 5 .

The preferred compounds have u = 1 and X = 0; or t = 0.

The residue (XII) when is saturated with -CH 2 C00- is

known as bromfenac.

The preferred compounds have u = 1, X = 0 and R 2a = R 3 a = H; or t = 0.

The residue XIII) derives from the known Lornoxicam when the valence is saturated with H. Preferred compounds have t = 0.

X x in the formula A-X--N0 2 is a bivalent connecting bri¬ dge chosen from the following: -YO- where Y is: a linear or when permissible branched C x -C 20 alkylene, preferably having from 2 to 5 carbon atoms, excluding this connecting bridge when R is: a radical of group I) except class lb) and Ic) ; a radical of group II) except II b ) ,- a radical of group III) except class of compounds of HID) a radical of group IV) ; a radical of group V) , except X) and inclu¬ ding -(CH 2 ) 4 - for the compounds of formulae (III) and (IV) ; or a cycloalkylene having from 5 to 7 carbon atoms op¬ tionally substituted;

wherein n 3 is 0 or an integer from 1 to 3

- ( CH 2 -CH-CH 2 -0) nf , -

I ON0 2 wherein nf is an integer from 1 to 6 , preferably from 1 to 3 ; - ( CH-CH 2 -0) -

R lf

wherein R = H, -CH 3 and nf is an integer from 1 to 6, preferably from 2 to 4.

The compounds containing R of group I of type la) are described in patent WO92/01668 wherein the preparation me¬ thods are also described. This patent is incorporated herein in full as a reference. The compounds of type lb) are prepa¬ red, for instance, using the method described in the Merck

Index, XI Ed., 1989, page 16, n.95, for the residue of acetylsalicylsalicylic acid. The changes in the compounds of formula lb) may be obtained applying the processes described in patent WO 92/01668.

Compounds Ic) of the class Ic x ) , in which the radical is a 5-amino salicylic acid derivative (5-amino-2-hydroxyben- zoic acid) known as mesalamine, when the starting radical contains -COOH, are prepared by reduction of m-nitrobenzoic acid with Zn dust and HC1 (see H. Weil et al . , Ber. 55B, 2664 (1922)) ,- or by electrolitic reduction: Le Guyader, Pel¬ tier, Compt. Rend. 253, 2544 (1961) . These publications are incorporated here by reference.

The starting radical Ic 2 ) when it contains -COOH is known as olsalazine: 3, 3 ' -azobis (6-hydroxybenzoic acid) ; and it is prepared according to EP 36,636 or USP 4,528,367, here both incorporated by reference.

Compounds Ic 3 ) are prepared according to USP 2,396,145 here incorporated by reference.

Equivalent compounds to Ic x ) , Ic 2 ) and Ic 3 ) contain the substituents indicated in the above references .

The products of the present invention having the gene¬ ral formula

A-X x -N0 2

with the connecting bridges X x as above defined, with respect to the compounds of group I) , may be obtained using the abo ¬ ve methods of the known art or changing the known methods by introducing bridges X x when these are different from the con¬ necting bridges described in the above patents .

The compounds wherein R is of group II) are described in patents WO94/04484 and USP 3,558,690 wherein the prepara¬ tion methods are also described. These patents are incorpo¬ rated herein in full as a reference.

The starting compound of lib) , when the valence is sa¬ turated with -COOH (flunixin) , is obtained according to USP 3,337,570 and USP 3,689,653 here incorporated by reference. Compounds containing the substituents indicated in the above patents are equivalent to flunixin.

With respect to the compounds of group II) , the conne¬ ctive bridges X x as above defined may be obtained using the above methods of the known art or changing the known methods by introducing bridges X x when these are different from the connecting bridges described in the above patents.

The compounds wherein R is of group III) are described and obtained by the processes explained in the following patents: patent application PCT/EP/93 03193; for the com¬ pounds of formula (IV) also see USP 3,641,127; for the com-

O 95/30641

22 pounds of formula (XXI) also see USP 3,896,145; for the com¬ pounds of formula (IX) , residue of flurbiprofen, also see USP 3,755,427; for the compounds of formula (II) also see USP 4,035,376; for the compounds of formula (VI) also see USP 3,997,669; for the compounds of formula (VIII) also see USP 3,843,681; for the compounds of formula (VII) also see USP 3,600,437; for the compounds of formula (III) also see USP 3,784,701. All these patents are incorporated herein in full as a reference.

The processes for the preparation of compounds of class III D) are the following:

Ilia) residue is obtained by preparing the acid com¬ pound, according to USP 3,931,205, the valence is saturated with -CH(CH 3 ) -COOH. Compounds containing the substituentε indicated in the above patent are equivalent to pranoprofen.

The residue (XXX) is prepared through the compound with -CH(CH 3 ) -COOH (bermoprofen) according to USP 4,238,620 here incorporated by reference. Other equivalent products are listed in the above patent.

The residue (XXXI) is prepared by starting from the corresponding acid -CH(CH 3 ) -COOH, according to USP 4,254,274. Equivalent compounds are listed in that patent.

The residue (XXXII) is prepared according to EP 238226

O 95/30641

33 here incorporated by reference when the valence is saturated with -CH 2 COOH. Equivalent products are reported in said pa¬ tent as substituted 1,3,4,9 tetrahydropyrane [3,4-b] indole- 1-acetic acids.

The residue (XXXIII) is prepared by pirazolac (the va¬ lence is saturated with -CH 2 COOH) , as indicated in EP 54,812 here incorporated by reference. Equivalent products are li¬ sted in the said patent.

The residue (XXXVI) is prepared according to the patent UK 2,035,311 here incorporated by reference, by starting from zaltoprofen having termination -CH(CH 3 ) -COO- . Equivalent products are listed in the said patent.

The process of preparation of the residue XXXVII) is obtained by starting from the Mofezolac and it is prepared according to EP 26928. Equivalent products are reported the¬ rein.

With respect to the compounds of group III) , the connecting bridges X x as above defined may be obtained using the above methods of the known art or changing the known methods by introducing bridges X x when these are different from the connecting bridges described in the above patents.

The compounds wherein R is of group IV) are described in the English patent application 9320599.5 wherein the pre-

paration methods are also described. This patent is incorpo¬ rated herein in full as a reference.

In group IV) the compounds may also be obtained: for the compounds of formula (II), using patent USP 3,904,682; for the compounds of formula (X) , in accordance with patent USP 4,161,538; for the compunds of formula (III) , in accor¬ dance with patent USP 3,228,831. These patents are fully included in the present application as a reference.

With respect to the compounds of group IV) , the connecting bridges X x as above defined may be obtained using the above methods of the known art or changing the known methods by introducing bridges X x when these are different from the connecting bridges described in the above patents.

The compounds wherein R is of group V) are described in the Italian patent MI94A 000916 wherein the methods of pre¬ paration are also described. This patent is incorporated herein in full as a reference. In group V) the compounds may also be obtained: for the compounds of formul? (II) , using patent USP 4,089,969 which is incorporated herein in full as a reference; for the compounds of formula (V) may be obtai¬ ned in accordance with patent USP 4,556,672 which is incor¬ porated herein in full as a reference.

The residue (X) is prepared according to German patent

2,756,113. Equivalent products are listed in the said patent.

The residue (XI) is prepared according to the patent EP 147,177 here incorporated by reference, by starting from ampiroxicam having the termination -COOC,H 5 . Equivalent pro¬ ducts are listed in the said patent.

The residue (XII) is prepared according to J. Medicinal Chem., vol. 27, No. 11, Nov. 1984, Walsh et al, Antiinflam- matory Agents. 3. Synthesis and Pharmacological Evaluation of 2-Amino-3-Benzoylphenylacetic Acid and Analogues, here incorporated by reference. Equivalent products are listed in said publication.

The residue (XIII) is prepared by starting by the Lor¬ noxicam, wherein the valence is saturated with H. It is pre¬ pared according to GBP 2,003,877. Equivalent products are described in said patent.

With respect to the compounds of group V) , the connecting bridges X x as above defined may be obtained using the above methods of the known art or changing the known methods by introducing bridges, X x when these are different from the connecting bridges described in the above patents.

Generally, the connection between A and X x is, as we saw, generally, of the ester or amide type (NH or NR 1C , as

O 95/30641

36 defined in X) when R is of groups I), .. ) , III), IV). All well known synthetic routes for forming these bonds may be used to form this connection.

In the case of esters of group I) , III) and IV) , the most direct synthetic route involves a reaction of acyl chlorides R-CO-C1 with halogen alcohols of the HO-Y-Cl, HO-Y-Br, HO-Y-I types, in the experimental conditions of the known art.

The reaction products of formula R-CO-O-Y-Cl (Br, I) may also be obtained for class II by reacting the sodium or po¬ tassium salts of said R-CO-OH acids with dihalogen derivati¬ ves of the general formula YC1 2 , YBr 2 or YI 2 .

The reaction products are converted into the final pro¬ ducts by reacting with AgN0 3 in acetonitrile, in accordance with literature reports.

The general route for groups I) , III) , IV) is as fol¬ lows:

R-CO-C1 + HO -Y- Br > R-CO-O-Y-Br + AgN0 3

A-X x -N0 2 wherein X x = YO.

The general route for group II is as follows.-

R-CO-ONa + Br 2 Y > R-CO-O-Y-Br + AgN0 3 > A-X x -N0 2 wherein X x = YO.

In the case of amides the synthetic route involves a

95/30641

37 reaction of the same acyl chlorides RCOC1 with amino alco¬ hols of the general formula NH 2 -Y-OH, NHR 1C -Y-0H to give ami¬ des of the general formula: R-CO-NH-Y-OH and R-CO-NR xc -Y-OH in accordance with known methods .

The reaction of said amides with halogenating agents such as, for example, PC1 S , PBr 3 , S0C1 2 , etc., leads to halo¬ gen derivatives of the general formula: R-CO-NH-Y-Br(Cl) and R-C0-NR 1C -Y-Br(CD .

These, by reacting with AgN0 3 in acetonitrile in accor¬ dance with known literature methods, lead to the final pro¬ ducts A-X x -N0 2 .

The route may be outlined as follows:

PC1 5

R-CO-Cl + NHR lc -Y-OH >R-CO-NR xc -Y-OH

R-C0-NR XC -Y-C1 + AgN0 3 >R-CO-NR xc -Y-ON0 2 wherein YO is X xx .

An alternative route to form the esters is a reaction of the sodium or potassium salts of the acids tfith the nitric esters of halogen alcohols of the general formula.-

N0 2 -0-Y-Cl(Br, I) to directly give the products of the invention.

The reaction route is as follows:

R- CO- ONa+Br- Y-ON0 2 -^R- CO- O- Y- ONO, wherein YO is X x .

Synthetic routes similar to those described above can be used for products Va and Vb • of group V) , wherein the dihalogen derivative Br,Y is reached with enolates, for example, of tenoxicam or piroxicam. The reaction products are then converted, in acetonitrile, by reacting with AgN0 3 in accordance with the above reaction.

The general route shown below relates to the piroxicam of formula IX in group V) .

The above indicated products in the various groups are used as anti-inflammatory, analgesic, and anti-thrombotic

O 95/30641

39 activities. For group I) no exclusion in the meanings of X x is necessary.

For groups II) , III) , IV) and V) , the meaning of X x is limited as above indicated for these uses, when X x = -YO- for some compounds.

A further object of the invention is that it was surprisingly found that the products of the invention con¬ taining -ONO- groups are capable of having an effect inhibi¬ ting the inflammation induced by liposaccharide (LPS) , and can, therefore, be used in septic shock.

This was surprising since it is well known that, gene¬ rally, anti-inflammatories do not significantly change the nitrosynthetase actitivity induced by lipopolysaccharides in rats and, therefore, cannot be used in septic shock.

The products which may be used for this pharmaceutical use are the products of the general formula

A-X x -N0 2 described above, wherein the bivalent connecting bridge X x has no limitation in this case, i.e. the known connecting bridges are not excluded as nothing was described in previ¬ ous patents for this use.

It must be understood that when the compounds of the various groups contain at least one asymmetric carbon, the

products can be used in racemic form or as single isomers.

It is in fact well known that in the therapeutic uses of the invention in general an isomeric form is more active than the others .

The following examples are being given as an explana¬ tion not a limitation of the present invention.

EXAMPLES Example 1: Chemical Examples - Product Preparation Example la:

Preparation of compound A-X x -N0 2 , wherein R belongs to class I, X x is - (CH 2 -CH 2 -0) 2 -, herein referred to as ASA.NO-DEG, and having the general formula: 2-acetoxy-benzoate of 2- [2- (nitroxy) ethoxy] ethyl

Preparation of the intermediate of the formula: 2-acetoxy-benzoate of 2- [2- (chloro) ethoxy] ethyl

95/30641

41

1.0 g of sodium hydride (NaH) (80% suspension in white mine¬ ral oil) was added portionwise to a solution of: acetylsalicylic acid 5.6 g and dimethylformamide 20 ml kept at 0°C in a stream of nitrogen.

The mixture was stirred for one hour and then added dropwise over 5 hours to a stirred solution of 2,2' -dibromo-diethylether 10.0 g and dimethylformamide 15 ml at 25°C. The mixture was stirred continuously for 3 days, then dried at reduced pressure. The residue was treated with: water 50 ml and dichloromethane 50 ml.

The phases were separated and the aqueous phase was extracted further with dichloromethane 10 ml. The pooled organic phases were washed with water (3 x 25 ml) , dried (MgS0 4 ) , decoloured with animal charcoal (l g) , and brought to dryness in vacuum. The residue (11.2 g) was used crude for the next reaction.

SUBSTITUTESHECT ( RULE26).

O 95/30641

42

Preparation of ASA-NO-DEG:

8.6 g of silver nitrate were added to a solution of ASA- (CH 2 ) 2 -0- (CH 2 ) 2 Cl 11.2 g and acetonitrile 25 ml kept at ambient temperature and sheltered from light. After stirring for two days, 2.2 g of silver nitrate were added.

After another two days in the same conditions, the insoluble salts were filtered and the filtrate was freed of the sol¬ vent at reduced pressure.

A residue of 7.0 g was obtained and chromatographed on a silica gel column (500 g of silica) eluting with a toluol/ethyl acetate 95/5 v/v mixture.

The fractions which were found to be uniform by TLC (Thin Layer Chromatography) were pooled and brought to dryness . They yielded 3.0 g of ASA-NO-DEG.

A X H NMR analysis (CDC1 3 ) (80MHz) provided the following data.-

2.28(3H,S); 3.7(4H,m); 4 .5 (2H, t) ; 4.52(2H,t); 7.3 (3H,m); 7.98 (lH,dd) .

The IR analysis (nujol) provided the following results. υ 0∞ = 1780 cm "1 ; υ c∞ = 1725 cm "1 ; u 0N02 = 1641 e 1287 cm "1 . Mass spectrometry gave a molecular weight value of 313.

Example lb :

Preparation of compound A-X x -N0 2 , wherein R belongs to class

II), X x is - (CH 2 -CH 2 -0) 2 -, herein referred to as DICLOFENAC-

NO-DEG, and having formula:

2-{N- [2, 6- (dichloro)phenyl] aminojphenylacetate of 2-[2-(ni- troxy)ethoxy] ethyl

Preparation of the intermediate having formula

2-{N- [2, 6- (dichloro)phenyl] aminojphenylacetate of 2-[2-(bro- o) ethoxy] ethyl

O 95/30641

44

A solution of

DICLOFENAC sodium salt 13.3 g and dimethylformamide 25 ml was added to a solution of

2.2' -dibromo-diethylether 12.3 g and dimethylformamide 15 ml kept at ambient temperature in a stream of nitrogen. The mixture was allowed to react for two days, and the solvent was then removed at reduced pressure. The residue was treated with ethyl acetate (50 ml) , washed with a 5% solution of potassium carbonate (2 x 10 ml) , then with wa¬ ter (20 ml) , dried over anhydrous sodium sulphate. The sol¬ vent was removed at reduced pressure.

The residue weight was 16 g and was used for the next rea¬ ction with no purification. Preparation of DICLOFENAC-NO-PEG: Silver nitrate 8 g in acetonitrile 16 ml were added to a solution of DICLOFENAC - (CH 2 ) 2 -0- (CH 2 ) 2 -Br 16 g and acetonitrile 30 ml kept at room temperature and sheltered from light. The mixture was stirred at ambient temperature for 3 days.

Silver nitrate 3 g after l day silver nitrate 3 g after 2 days were then added.

The mixture was stirred for another 2 days. The insoluble salts were then filtered and the solvent removed from the filtrate at reduced pressure. The residue was treated with ethyl acetate (50 ml) , the insoluble salts were then filte¬ red and discarded. The solvent was removed from the filtrate at reduced pressure. A residue of 16.2 g was obtained and chromatographed on a silica gel column (700 g of silica) eluting first with toluol, then with a toluol/ethyl acetate 99/1 v/v mixture, finally with a toluol/ethyl acetate 98/2 v/v mixture.

The fractions found to be uniform by TLC analysis (thin layer chromatography) were pooled and brought to dryness to yield 4.38 g of DICLOFENAC-NO-DEG.

A -NMR analysis (CDC1 3 ) (300 MHz) provided the following data: 3.69 (4H,t) ; 3.87 (2H,S) ; 4.3 (2H,m) ; 4.52 (2H,t) ; 6.55 (lH,d) ; 6.88 (1H, wide s exchanged for D 2 0, NH) ; 6.97 (2H,t) ; 7.11 (2H,d); 7.23 (2H,d); 7.35 (2H, d) . Mass spectrometry yielded a molecular weight value of 588. Example lc: Preparation of compound A-X x -N0 2 , wherein R belongs to class

III) and represents the residue of the compound of formula

IV, X x is -C β H 5 CH 2 -, herein referred to as KETOPROFEN-NO-DEG, and having formula:

2- (3-benzoyl)phenylpropionate of 3- (nitroxynethyl)phenyl

Preparation of intermediate 3-nitroxymethyl-nhenol havi.ng formula:

The reagents below are used in the amounts indicated and reacted as described below:

3-hydroxy-benzylalcohol 10 g 48% HBr by weight 50 ml CH 2 C1 2 30 ml AgN0 3 13.7 g

SUBSTITUTE SHEET (RULE..

47

CH 3 CN 70 ml

3-Hydroxy-benzylalcohol in CH 2 C1 2 was reacted with HBr at ambient temperature for 4 hours.

CH 2 C1, was then evaporated at reduced pressure at 30°C after washing with an aqueous 5% NaHC0 3 solution and drying over anhydrous Na 2 S0 4 .

The oily residue was dissolved in CH 3 CN (50 ml) and a solu¬ tion of AgN0 3 in the remaining amount of CH 3 CN was added dro¬ pwise. The flask was sheltered from light.

After 8 hours the AgBr precipitate was filtered and the organic phase was evaporated at reduced pressure. The oily residue so obtained was dissolved in toluene (45 ml) and the solution was filtered on a silica gel column (400 g) . The eluate was brought to dryness at reduced pres¬ sure at 30°C to give 20 g of 3-nitroxymethylphenol. Preparation of intermediate KETOPROFEN -COC1: a chloride of 2- (3-benzoyl)phenyl propionic acid KETOPROFEN 20 g thionyl chloride 50 ml were reacted and the solution was refluxed for 45 minutes. Thionyl chloride was evaporated off at reduced pressure. An oily yellow residue weighing 21 g was obtained and used with no further purification.

Preparation of KETOPROFEN-Ar-NO - i£-2W,

The reagents below were used in the following amounts

KETOPROFEN -COC1 5.45 g

3-nitroxymethylphenol 3.9 g

K 2 C0 3 5.5 g

AcOEt 50 ml

, K 2 C0 3 and AcOEt were added together;

ketoprofen chloride was then added under nitrogen at t = 0 in 30 minutes.

The whole was allowed to react for 5 hours at ambient temperature, then diluted with H 2 0 (50 ml) . The organic phase was washed with 5% NaOH (2 x 10 ml) and evaporated off at reduced pressure. The resulting oily residue was chro¬ matographed on silica using a toluol/EtOAc 9.5/0.5 v/v i-

xture as an eluant . The evaporation of the eluate gave KETOPROFEN-Ar-N0 2 with a yield of 85%.

A -NMR analysis (CDC1 3 ) (300 MHz) provided the following data: 1.63 (3H,d); 4.00 (1H Q) ; 5.37 (2H.S); 7.01-7.89 (m,13H) .

Mass spectrometry yielded a molecular weight value of 405. Example Id:

Preparation of compound A - X x - N0 2 , herein referred to as IBUPROFEN-NO-DEG, wherein R belongs to group IV; X, is

- (CH 2 -CH 2 -0) 2 -, A = RCOO, R residue of IBUPROFEN, having formula:

- (CH 3 ) 2 CHCH,C 5 H 4 -CH(CH 3 ) - The same procedure of example la was followed, using the above R, residue of IBUPROFEN, instead of residue R of group I as shown in example la. Example le:

Preparation of compound A-X x -N0 2 , herein referred to as FLURBIPROFEN-NO-DEG, wherein R belongs to group III; XI is

- (CH--CH--0) 2 -, A = RCOO, R 3a = H, R 2a = CH 3 , R having formula:

(IX)

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The same procedure of example la was followed, using the above R, residue of FLURBIPROFEN, instead of residue R of group I as shown in example la.

Example If:

Preparation of compound A-X x -N0,, KETOROLAC-NO-DEG, wherein R belongs to group V; X x is - (CH 2 -CH,-0) 2 - ,- A = R, R of formula

II, having formula

The same procedure of example la was followed, using the above R, residue of KETOROLAC, instead of residue R of group

I as shown in example la.

Example lcr:

Preparation of compound A-X x -N0 2 , TIAPROFENIC ACID NO DEG, wherein R belongs to group III; X x is - (CH 2 -CH,-0) 2 -,

A= RCOO, R is the residue of formula XXXV, wherein R is:

(XXXV)

51

The same procedure of example la was followed, using the above R, residue of TIAPROFENIC ACID, instead of residue R of group I as shown in example la. Example lh:

Preparation of compound A - X x - N0 2 , NAPROXEN NO-DEG, wherein R belongs to group IV; X x is - (CH,-CH,-0) 2 - , A = RCOO, R is the residue of formula II of NAPROXEN, having the gene¬ ral formula

(ID

The same procedure of example la was followed, using the above R, residue of NAPROXEN, instead of residue R of group I as shown in example la. EXAMPLE 2 : Pharmacological Examples

The products used above were pharmacologically cha¬ racterised. Example 2a: ASA-NO-DEG as prepared in example la;

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52

Example 2b: DICLOFENAC-NO-DEG as prepared in example lb;

Example 2c: KETOPROFEN-NO-DEG as prepared in example lc,-

Example 2d: IBUPROFEN-NO-DEG as prepared in example Id;

Example 2e: FLURBIPROFEN-NO-DEG as prepared in example le,-

Example 2f: KETOROLAC NO-DEG as prepared in example If;

Example 2g: TIAPROFENIC ACID NO-DEG as prepared in example

ig;

Example 2h: NAPROXEN NO-DEG as prepared in example lh. Toxicity

Acute toxicity was evaluated by orally administering a single dose of 1, 3, 10, 30, 100 mg/Kg of product groups of 10 mice.

The death rate and the occurence of toxic symptoms were reported over an observation period of 14 days. Even after administration of a 100 mg/Kg dose the animals showed no sign of apparent toxicity. Anti-inflammatory activity

Anti-inflammatory activity was determined by the carrageenin-oedema method as described by Winter et al. (Proc. Soc. Exp. Biol. Med. Ill, 544, 1962) in rats. Analgesic activity

Analgesic activity was determined in Swiss mice as described by Hendershot et al. (J. Pharmacol. Exp. Therap.

125, 237, 1959) . Tolerance

Gastric tolerance was measured by oral administration to rats assessing the severity of the gastropathy induced in accordance with the criteria described by Wallace et al . (Am. J. Physiol. 259, G642, 1990) . Platelet anti-aggregating activity

Platelet anti-aggregating activity was evaluated in vitro on human platelets stimulated by thrombin in accordan¬ ce with the method described by Bertele et al . (Science 220, 517. 1983) . Vasodilative activity

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

The activity inhibiting cyclo-oxygenase was determined in isolated cells. Endothelial cells of bovine aorta were used as a source of COX-1 and macrophage line J774.2 as a source of COX-2. The same conditions described byMitchell et al. (Proc. Nat. Acad. Sci. 90, 11693, 1993) for growth and

the viability test were used.

In brief, the cells were incubated for 30 minutes with scalar concentrations of the test product and the substrate (arachidonic acid) was then added and incubated for another 15 minutes. Enzyme activity was determined radioimmunologi- cally by measuring the formation of 6-keto-PGF 1 alpha. In the case of cell lines J.774.2, the cells were incubated for 12 hours with endotoxin to promote COX-2 formation. Nitrosynthetase inhibition by LSP

The nitrosynthetase inhibition activity induced by li- popolysaccharide (LPS) was determined in rat neutrophils and stomach after administration of one of the test compounds and compared with that obtained after treatment of the suspension vehicle only.

In brief, Wistar rats fasting for 24 hours before treatment were orally administered the test product (10 mg/Kg) and intravenously (caudal vein) administered LPS (5 mg/Kg) .

Four hours later the animals were sacrificed and the blood - for neutrophils isolation - and the stomach taken.

Enzyme activity was determined in accordance with the method described by Assreuy et al . (Br. J. Pharmacol. 108, 833, 1993) .

Results :

The results obtained are described below.

As it may be observed from the data shown in tables 1 to 4, the pharmacodynamic activities (I and II in Table 1; Table 2) and the tolerance (Table 1 column III) of the ni- troderivatives show a better balance as compared to natural products.

Table 4 also shows that, similarly to diclofenac nitroxybutylester, the diclofenac nitroderivative which is an object of this patent is capable of directly inhibiting cyclo-oxygenase COX-1 and COX-2, but with a significantly lower variability. TABLE 1 (Pharmacology col.I and II; Toxicology col.Ill)

Study of the anti-inflammatory (I) and analgesic (II) properties (pharmacodynamics) and gastrointestinal tolerance (III) (toxicity) of the test compounds after oral admini¬ stration of doses ranging from 3 to 30 mg/Kg in car- boxymethylcellulose suspensions and constructing dose- response curves. The results shown are the potency ratio as compared to the reference standard.

Activities are expressed as the potency ratio compared to the natural product used as a unit standard. The nitrode¬ rivative is that of the shown examples, the natural

reference compound is that shown as a reference.

TABLE 1

TABLE 2 (Pharmacodynamic activity)

Example of the anti-cyclooxygenase (I) , platelet anti-aggre- gating (II) and vasodilative (III) proper t ies of the test compounds tested in vitro at concentrations in the molar range from 10 "5 to 10 "7 of the product in water/alcohol with the addition of small amounts of DMSO (dimethylsulphoxide) . The activities are expressed as the potency ratio versus the natural product used as a unit standard, as stated in Table 1.

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57 TABLE 2

(°) % of inhibitory action of the vasospasm induced by epinephrine

TABLE 3 (Biochemistry: Action on NOS for Septic Shock)

Study of the inhibitory properties of the nitrosynthetase

(NOS) activity induced by liposaccharide (LPS) in rats using oral doses ranging from 5 to 20 mg/Kg suspended in a carboxymethylcellulose base.

TABLE 3 NOS (°°)

( 0o ) inhibition % relative to the group treated with LPS only.

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TABLE 4 (COX-Inhibition Activity)

Study of the anti-cyclooxygenase (COX-l/COX-2) properties in isolated cells.

Response expressed as a % of the controls with relative re¬ sponse variability.

TABLE 4