BARBITURIC ACID DERIVATIVES WITH ANTIMETASTATIC AND ANTITUMOR ACTIVITY

Abstract: The present invention relates to barbituric acid derivatives of general formula (I) wherein the meanings of R, n and A are disclosed in the claims. These compounds showed a marked activity as inhibitors of the metzincins and can be used as antitumor or antimetastatic agents.

Description: BARBITURIC ACID DERIVATI\ΕS WITH ANTIMETASTATIC AND ANTITUMOR ACTIVITY The present invention relates to new derivatives of the barbituric acid 5.5-bis-substιtuted 5 These compounds showed a marked antimetastatic and antitumor activity BACKGROUND OF THE INVENTION In the past the therapy of the tumors has been achieved by surgical intervention, radiation treatment and chemotherapy The drawbacks of this latter are mainly due to the toxicity of the cytotoxic drugs, which is usually not restπcted to the cancer cells, and to the acquired o resistance of the cancer cells to some of the most widely used drugs, which vanifies the final result of the therapy On the other hand, the elimination of the primary tumor bv surgerv is not always possible and in anv case does not prevent the most metastasizing tumors, such as for example breast cancer or melanoma, to invade other target organs, which develop further secondarv tumors 5 after months or years from the surgical treatment These secondary tumors are usually the main cause of death of the patient In the years it has become apparent that the therapy of the metastasizing tumors is unlikely to bring to the complete cure of the patient, therefore, the treatment with cytotoxic drugs is now seen as a palliative and life-prolonging method rather than a curative method A o cronical treatment with a drug having low toxicitv would be preferable while targeted to the control of the progression of the disease An example of sucn therapy is the treatment of invasive breast cancer with tamoxifen The efforts of many researchers have been focused recently to the development of drugs able to inhibit the invasive process of the tumor which brings to metastases ' formation 5 Among the targets that have been evaluated up to now to give πse to a possible antimetastatic activity, the inhibition of the matπx metalloproteinases seems to be one of the most promising The matπx metalloproteinases (or metalloproteases). which are upregulated in the cancer cells, degrade the extracellular matπx and bring to the propagation of the tumor cells into ϋ the blood stream to reach the target organs where the metastasis develop Moreover, they are associated with tumor growth and angiogenesis Nevertheless, since different types of such proteases exist in the organism and are implicated in the regulation of vital functions selected inhibition of certain combination of MMPs is desired, in order to avoid toxic side effects, especially in a chronical treatment. A number of compounds are known in the literature [see review article: Beckett et al.. DDT 1. 16 (1996)] or are described in the patent literature [WO-A-92/09563 by Glycomed. EP- A-497 192 by Hoffinann-LaRoche. WO-A-90/05719 by British Biotechnology, EP-A-489 577 by Celltech. EP-A-320 1 18 by Beecham. US-A-4,595.700 by Searle]. In particular, batimastat and marimastat have been developed by British Biotechnology and the latter is now under investigation in clinical trials. However, such compounds are broad inhibitors of matrix metalloproteinases. therefore therapy with these molecules might be associated to undesirable toxicity. It is therefore evident that there is still a high need of new compounds, which must have a low toxicity and a marked activity in inhibiting both the tumor growth and the metastasis process, as candidates for a chronical antitumor therapy. We have now found a new class of compounds that possesses a marked inhibitory activity against the matrix metalloproteinases and showed antimetastatic and antitumor activity DESCRIPTION OF THE INVENTION The present invention relates to compounds of the general formula (I): wherein: R is a W-V group, in which W is a bond or a linear or branched (Cι-C ϋ )alkyl or a (C -C 8 )alkenyl; V is a monocycle or bicycle, saturated or unsaturated. which can optionally contain from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur and which can be optionally substituted by a (Ci-Cøalkoxy. phenoxy or phenyl group; or W-V is a (Cι-C 2 o)alkyl group which can be optionally interrupted or terminated by one or more heteroatoms selected from oxygen or sulfur or by a - N(R 5 )- group, in which R 5 is selected from hydrogen. (C C )alkyl or (Cι-C )acyl, n is an integer from 1 to 3 ; A is selected from the following groups: R 1 , -N(R 2 )-(CH 2 ) m -N(R 9 )-T- R 10 , -N(R 2 )-CHR0CO-R 7 . -N(R 2 )-T-NR 3 R 4 . in which - T is a -CO- or -SO 2 - group, - m is an integer from 2 to 6; - R 1 is selected from -OH, (C C 4 )alkoxy,-NH , mono- or di-(Cι-C 4 )alkylamιno. benzylamino, phenoxy or benzyloxy groups, these two latter being optionally substituted with one or more groups selected from (Cι-C 4 )alkyl, (Cι-C )alkoxy, halogen. -OH, -NH 2 , mono- or di-(Cι-C 4 )alkylamino, nitro, (C C )alkylsulphonyl, (Cι-C4)alkylsulphonamido; or is a group of formula -N(R 9 )-CO-R 10 in which R 9 and R 10 . taken together with the N-CO group to which they are linked, form a 5- to 7- membered lactam. which can optionally be benzocondensed and/or substituted with a group selected from (Cι-C 4 )alkyl, (Cι-C 4 )alkoxy. halogen, -OH. -NH 2 . mono- or di-(Cι-C 4 )alkylamino, nitro, (C C 4 )alkylsulphonyl, (Cι-C 4 )alkylsulphonamido. - R 2 is selected from hydrogen. (C C 4 )alkyl, (C-t-C? (cycloalkyl, (C 3 -C7)cycloalkyl- (C,-C4)alkyl, phenyl or benzyl groups, these two latters being optionally substituted with one or more groups selected from (d-C )alkyl. (C C 4 )alkoxy, halogen. -OH, - NH 2 . mono- or di-(Cι-C 4 )alkylamino, nitro, (Cι-C4)alkylsulphonyl, (C C 4 )alkylsulphonamido; or R 2 is a Het-(Cι-C 2 )alkyl group, in which Het is a 5- or 6- membered heterocycle having from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, which can be optionally benzocondensed; - R is selected from hydrogen, (Cι-C )alkyl, (C -C7)cycloalkyl, phenyl. benzyl or phenetyl. which can be optionally substituted by a group selected from (C C 4 )alkoxy, -SO 2 NH 2 . - R 4 is a -(CH 2 ) P -B group, wherein p is 0. 1 or 2 and B is selected from (C ι-Cg)alkyl, benzydryl; monocycle or bicycle, saturated or unsaturated. which can optionally be benzocondensed and/or substituted with a group selected from (Cι-C 4 )alkyl. C 4 )alkoxy, halogen, -OH.-NH 2 , mono- or di-(Cι-C 4 )alkylamino, nitro. (Cι-C )alkylsulphonyl, (Cι-C4)alkylsulphonamido. 5- or 6-membered heterocycle having from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, which can be optionally benzocondensed and/or substituted with a group selected from (C C 4 )alkyl, (Cι-C 4 )alkoxy, halogen, -OH, -NH 2 , mono- or di-(Cι-C 4 )alkylamino. nitro, (Cι-C 4 )alkylsulphonyl, (Cι-C )alkylsulphonamido; or R J and R 4 , taken together with the nitrogen atom to which they are linked, form a 5- or 6-membered heterocycle having from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, which can be optionally benzocondensed and or substituted witn a group selected from (d- C 4 )alkyl, (C C )alkoxy, halogen, -OH, -NH 2 , mono- or dι-(Cι-C 4 )alkvlamιno. nitro, (Cι-C 4 )alkvlsulphonyl, (Ci-C alkvlsulphonamido. - R 6 is a -(CH 2 ) q -D group in which q is 0 1 or 2 and D is selected from hvdrogen, (C]-C 4 )alkyl, a monocycle or bicvcle. saturated or unsaturated. which can optionally be benzocondensed and/or substituted with a group selected from (C C 4 )alkvl, (C C )alkoxy. halogen, -OH, -NH 2 , mono- or dι-(Cι-C4)alkvlamιno. nitro. (C C 4 )alkvlsulphonvl, (Cι-C 4 )alkvlsulphonamιdo 5- or 6-membered heterocvcle having from 1 to 3 heteroatoms selected from nitrogen oxygen or sulfur, which can be optionally benzocondensed and or substituted with a group selected from (C C )alkvl (Cι-C 4 )alkoxv halogen -OH, -NH : mono- or dι-(C ι-C 4 )alkvlamιno nitro (Cι-C4)alkvlsulphonvl, (Cι-C4)alkvlsulphonamιdo - R 7 is selected from -OH, (C,-C8)alkoxγ -NHR ' -NH-CH(R 6 )-COR b , in which R 8 on its turn is selected from -OH or -NHR and R' is as above defined. - R 9 and R 10 have the same meanings as R ' and R 4 respectively, but when they are taken together with the N-CO group to which thev are linked, thev form a 5- to 7- membered lactam which can optionallv be benzocondensed and/or substituted with a group selected from (C ι-C 4 )alkvl, (Cι-C )alkoxv halogen -OH -NH 2 , mono- or dι-(C C4)alkvlamιno. nitro. (Cι-C )alkvlsulphonvl (C ι-C 4 )alkvlsulphonamιdo The present invention also encompasses enantiomers racemates diastereoisomers tautomers of the compounds of formula (I) or mixtures thereof as well as their salts with pharmaceutically acceptable acids or bases These compounds are endowed with a marked activity as inhibitors of the matrix metalloproteinases In the meanings of the present invention "halogen means an atom selected from chloπne. bromine, iodine or fluoπne With the terms monocycle" or "bicvcle are intended cvcloalkanes or aryl groups, such as for example cvlopropyl, cyclopentyl. cyclohexyl, decahnyl, phenyl or naphtalenyl groups Preferred examples of alkyl groups are methvl, ethyl, n-propyl. isopropyl, n-butyl, tert- butyl n-hexvl n-heptvl or n-octyl Preferred examples of 5- or 6-membered heterocycles, optionally benzocondensed. are pyrrolidine, piperidine. morpholine, tiomorpholine, piperazine. pyrane. oxadiazole. tiophene. furane, pyrazole. imidazole. thiazole, pyridine, pyrazine, pyrimidine. indole, indazole. quinoline, isoquinoline, benzopyrimidine. benzopyrazine. benzofurane, benzothiophene. benzothiazole. benzopyrane. Preferred examples of lactams, optionally benzocondensed. are pyrrolidinone. caprolactam. phtalimide, benzisothiazol-3(2H)one- 1, 1 -dioxide, 2-imidazolinone. benzopyrimidin-2.4- dione, benzopyrimidin-4-one, 8-azaspiro[4,5]decane-7.9-dione, piperidine-2,3-dione. Preferred compounds of formula (I) are those in which n is 1. A is a R 1 or a -N(R 2 )-(CH 2 ) m - N(R 9 )-COR 10 group and R is selected from a (C 6 -C 2 o)alkyl. biphenyl, phenoxyphenyl or (Cι-C 4 )alkoxyphenyl group. Particularly preferred are those in which m is 2 and R 2 is a (C C )alkyl, phenyl or benzyl group. Another object of the present invention is to provide a method for the preparation of the compounds of formula (I). A further object of the present invention is the use of the compounds of formula (I) in the treatment of those diseases which are susceptible of treatment with inhibitors of the matrix metalloproteinases, as well as pharmaceutical compositions containing effective dosages of one or more compounds of formula (I) in admixture with suitable excipients and/or diluents. PREPARATION OF THE CONffQUNDS OF THE INVENTION The compounds of formula (I) can be prepared according to the following multi -step process (a) reacting a compound of formula (II): in which R has the above meanings, with a reactant of formula (III): X-(CH 2 ) n -COR 1 (m) in which n and R 1 have the above meanings, but R 1 is preferably an ester group, and X is a leaving group such as for example a chlorine, bromine or iodine atom or a p- toluensulphonyloxy or a methanesulphonyloxy group. The reaction is usually perfomed in a solvent and in the presence of an inorganic or organic base, at temperatures ranging from 0°C to 100°C. preferably between room temperature and 50°C Preferred reaction conditions are the use of an aprotic dipolar solvent and of an alkaline or alkaline-earth metal carbonate (b) removing the R 1 ester group, for example bv alkaline hydrolysis in the case of an alkyl ester or by hydrogenolysis in the case of a benzyl ester (c) functionalizing the carboxy group in the compound obtained from step (b) with ammonia, mono- or di-(Cι-C 4 )alkylamιne or an intermediate of formula (IV) HN(R 2 )- (CH 2 ) m -N(R 9 )-T- R 10 , (V) HN(R 2 )-CHR0CO-R 7 . (VI) HN(R 2 )-T-NR 5 R 4 or (VII) HN(R 9 )-COR 10 , in which R 2 , R 3 . R 4 , R 6 . R 7 , R 9 , R 10 and m have the above meanings This reaction is performed bv activating the carboxy group in the usual ways, such as for example as acvl chloride (which can be obtained from the carboxy derivative bv means of thionvl chloπde), N-hvdroxysuccinimido ester (obtainable bv reaction of the carboxy group with N-hvdroxysuccinimide in the presence of morpholinoethyl isonitπle), lmidazo de deπvative (obtainable by reaction of the carboxy group with carbonyl diimidazole) and the like or by condensing the carboxy deπvative with the intermediates of formula (IV), (V) or (VI) in the presence of a condensing agent such as dicyclohexyl carbodiimide and the like Specific examples of such reactions with urea deπvatives of formula (VI) are reported in Z Chem . 25. 398-9 ( 1985), J Med Chem . 23. 857-861 ( 1980) and J Indian Chem Soc . 70(6) 597-9 ( 1993 ). which are herein incorporated bv reference (d) optionally separating the enantiomers or the diastereoisomers of the compounds of formula (I) bv means of the usual methods such as column chromatography or crystallization or optical resolution of enantiomers bv treatment with optically active acids or basis (e) optionally salifying the compounds of formula (I) obtained from steps (a), (b) or (c) with pharmaceutically acceptable acids or basis .ΛJI alternative method for obtaining the compounds of formula (I) in which A is a -N(R 2 )- CO-NR J R 4 and R J is hydrogen is to react a carboxy derivative of formula (I) (A = OH) or the acyl chloride or bromide thereof with a diirrude of formula (IX) R 2 N=C=NR 4 in a solvent and at temperatures ranging from 0°C to 50°C, more preferably at room temperature Example of such a reaction can be found in Synthesis, ϋ, 954 ( 1991 ). J Het Chem . 22(4). 1009- 10 ( 1985). Arch Pharm . 3 18(12). 1052-70 (1985). Helv Chim Acta 70( 1 ). 262-70 ( 1987), Eur. J. Med. Chem.. 24, 421 -6 ( 1989) and J. Org. Chem.. 54. 2428- 32 (1989), which are herein incorporated by reference. The compounds of formula (II) are known compounds or can be prepared according to methodologies well known to the expert in the art. For example, the synthesis of 5 -phenyl barbituric acid is reported in Acta Chim. Acad. Sci. Hung., 107. 139-45 ( 1981 ). In general, they are prepared by reacting a 2-substituted malonic derivative of formula (VIII): in which R has the above meanings and R' is a hydrogen or (C]-C 4 )alkyl group, with urea in the presence of a strong base such as for example an alkaline methoxide or ethoxide. in a solvent and at temperatures ranging from room temperature and the reflux temperature of the solvent. Preferred reaction conditions are the use of sodium methoxide in methanol at reflux. The compounds of formula (VIII) on their turn are known or commercial products or can be prepared, for example, from the corresponding dialkyl maionate by condensation with a suitable R-X group, wherein X has the above meanings, in the presence of a base. The intermediates of formula (III), (IV), (V), (VI), (VII) and (IX) are usually known compounds or can be prepared according to well known methodologies which are part of the general knowledge of the expert chemical technician. For example, compounds of formula (IV) can be obtained by functionalizing an I.α-diamine on the nitrogen atoms or by reacting an α-chioro- or bromo-amine with an other amine optionally in the presence of an excess of the same amine of another base. Compounds of formula (V) are aminoacids and can be natural or synthetic aminoacids These latter can be prepared for example according to the methods described in R.M. Williams. "Synthesis of Optically Active I-Aminoacids". Pergamon Press, 1989. Compounds of formula (VI) are urea or sulfamide derivatives and if necessary can be prepared by known methods which involve for example, for the urea derivatives, the reaction of an amine of formula R^R 4 NH with an isocyanate of formula R 2 -N=C=O or the sequential reactions of phosgene or carbonyldiimidazole with amines of formula R ~ R 4 NH and R 2 -NH 2 , respectively The acvlsulfamide deπvatives are obtained for example, bv reaction of a substituted sulfamide of formula R J R 4 N-SO -NH(R 2 ) with the acvl chloπde of the barbituric derivative as descπbed in J Het Chem . L5, 221 ( 1978) J Chem Soc Perk Trans 4 643-5 ( 1986) and Collect Czechosl Chem Com 49(4) 840-51 ( 1984) which are herein incorporated by reference Other synthesis of sulfamide deπvatives are described in Ber Dtsch Chem Ges , 100, 2719 ( 1967), J Med Chem 8, 766 ( 1965) J Org Chem , 54(24) 5824 ( 1989) and J Med Chem . 33 . , 585-91 ( 1990) which are also incorporated by reference BIOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION The compounds of the present invention have been tested in a pharmacological in vitro test of inhibition of MMP8 (human neutrophil collagenase) Said test provides for the determination via fluorescence of the inhibition of the degradation of a fluorescent substrate (DNP-Pro-Leu-Glv-Leu-Trp-Ala-D-Arg-NH? l 855 Bachem ) b\ means of the catalytic domain of MMP8 Reagents D DNP-substrate = DNP- Pro-Leu-Glv-Leu-Trp-Ala-D- rg-NH 2 (M1855 Bachem), M W 977, 1 g/mol concentration 25 μM in DMSO 2) measurement buffer = 0 mM TRIS/100 mM NaCl/10 mM CaCl 2 2H 2 O, adjusted at pH 7 6 with hydrochloric acid 3) Enzyme = catalytic domain of MMP8 (92 Kda), concentration 0 055 mg/ml in TRIS buffer Substrate and enzvme are maintained at 0°C with ice bath Inhibition asscn Total volume = 1 ml of solution kept under stirring in a cuvette Control 0 98 ml DMSO 0 01 ml of DNP-substrate 0 01 ml of enzvme Assay 0 98 ml DMSO 0 01 ml DNP-substrate 0 01 ml of enzvme 0 01 ml of inhibitor ( 10 μg/ml) It is measured the fluorescence at 346 nm both of the control solution (without inhibitor) and of the solution containing the inhibitor The inhibition of the catalytic activity of MMP8 results in the decrease of the DNP-substrate bond s lvsis w ith related decrease of the fluorescence of the solution The percentage of inhibition is expressed by the following formula: % Inhibition = 100 - (rel. unit/timew. ώ m hibito el. unιt/time conUO ι x 100) By repeating the experiment at different concentrations of inhibitor it is possible to determine the IC 50 value. The same test has been performed also on the MMP-9 (gelatinase 92 kD) and the selectivity between the two enzymes has been evaluated. Values of MMP-9/MMP-8 rate well below 1 are expected to give rise to less side toxic effects, since MMP-8 seems more involved in the regulation of vital functions that MMP-9 does. Table I shows the biological results for some representative compounds of the invention in comparison with the known matrix metalloproteinase inhibitor batimastat: Table I - Inhibition of MMP-8 and MMP-9 catalytic domain baumastat The data clearly show that the compounds of the invention exhibit an enhanced selectivity with respect to batimastat (MMP-9/MMP-8 rates from 0 18 to 0 2 vs a value of 0 93 for batimastat) This means that they should not be endowed with the typical toxicity that limits the use of matrix metalloproteinase inhibitors in the man The compounds of the present invention have also shown activity in a test of chemoinvasion. In the test of chemoinvasion the Costar Transwell chambers for cell culture (diameter 6 5 mm; pore size 8 urn) are coated with 100 ul of Type IV collagen (diluted solution 50 μg ml. then evaporation overnight) With the same procedure the chambers are coated with a second layer of Type IV collagen ( 100 μl of solution at concentration 50 μg/ml) Before use, the chambers are rinsed twice with sterile water and incubated for about 1 hour at 37°C in a serum-free medium (DMEM) The human fibrosarcoma HT1080 cells are harvested by trypsin-EDTA treatment, washed with DMEM - 10% FCS and incubated for at least 30 minutes at 37°C in the same medium The cells are then washed with serum-free DMEM and resuspended in serum-free DMEM added with 0 1% BSA (fraction V), counted and diluted to obtain a final density of 3x10 5 cell/ml Preincubated inserts are aspirated to remove the serum-free medium. The lower compartment of the chambers is filled with 600 μl of DMEM + 20% FCS + 1% BSA (fraction V) - compound to test. 200 μl of cell suspension ( 6xl 0 4 cells) containing the compound to test are added to the upper compartment and the chambers are incubated at 37°C under humid atmosphere with CO 2 After first 24 hour incubation the media from both lower and upper compartments are replaced by fresh suspensions and the chambers are incubated for additional 24 hours. Incubated filters are then washed with PBS, the cells are fixed 15 min. in 4% paraformaldehyde. permeabilized in methanol ( 10 minutes. -20°C) and stained with May- Grunwald-Giemsa. Cells which adhere to the top of the filters are removed with a cotton swab, filters are detached from the bottom of the chambers and analyzed with microscope to determine the number of cells on the lower side of the filters. In a control experiment in absence of metallo-proteinase inhibitor. HT1080 cells, which overexpress metalloproteinases, are able to degrade Type IV collagen and to migrate to the lower side of the filters. In the experiment with the inhibitor however the activity of the metalloproteinases is partially or totally inhibited and the number of cells which migrate to the lower side of the filters is decreased. The result of the experiment is expressed as percent of inhibition of chemoinvasion in the experiment with the metalloproteinase inhibitor (0% of inhibition in the control experiment). Compound (C) (R=octyl; A= -N(Bn)-(CH 2 ) 2 -NHCOMe) has shown 73% inhibition of chemoinvasion at a concentration 10" M. which can be compared with a 77% inhibition of the known metalloproteinase inhibitor GI 129471 (WO 90/05719 by British Bio- Technoloεv Ltd.): GI 129471 From what it is said above it appears that the compounds of the invention, in addition to their application in cancer therapy, may be used in the treatment of the conditions associated with the elevated or uncontrolled activity of the metzincins. as it is named the common family of zinc endopeptidases with high structural analogy which encompasses the MMPs, the astacins. the adamalysisns and the serralysisns. Examples of the diseases that can be treated with the compounds of the invention are inflammation, fibrosis, rheumatoid arthritis, osteoarthritis. atherosclerotic plaque rupture, aortic aneurism, heart failure, restenosis. septic arthritis, ulceration of the cornea, epidermic or gastric ulcerations, coronary thrombosis, proteinuria, pathological consequences of traumas, emphysema, multiple sclerosis, osteoporosis, periodontal disease or even as contraceptive agents. The compounds of the present invention can be administered in doses ranging from 0 01 mg to 0.4 g per kilogram of body weight daily. A preferred dosage regimen to obtain best results is that which provides for the use from about 1 mg to aoout 50 mg per kilogram of body weight daily, employing unitary doses so that to administer in 24 hours from about 70 mg to about 3 5 g of the active compound to a patient having approximately 70 kg of body weight Such a dosage regimen may be adjusted to achieve the best therapeutical effect For example, doses may be administered taking into account the therapeutical situation of the patient The active compound may be administered by oral, intravenous, intramuscular or subcutaneous route The pharmaceutical compositions of the present invention contain therapeutical effective amounts of at least one compound of the invention in admixture with pharmaceutically compatible excipients Oral compositions will generally include an inert diluent or an edible earner They can be included in gelatin capsules or compressed into tablets Other oral administration forms are capsules, pills, elixirs, suspensions or syrups The tablets, pills, capsules and similar compositions can contain the following ingredients ( in addition to the active compound) a binder such as microcrystalhne cellulose, tragacanth or gelatin, an excipient such as starch or lactose, a disintegrating agent such as alginic acid, pπmogel. maize starch and the like, a lubricant such as magnesium stearate. a fluidifier such as colloidal silicon dioxide, a sweetening agent such as sucrose or saccharine or a flavoring agent such as mint flavor, methyl salicylate or orange flavor When the composition selected is in form of capsules, it can contain in addition a liquid earner such as a fat oil Other compositions can contain various mateπal which change the pnvsical form thereof, for example coating agents (for tablets and pills) such as sugar or shellac The material used in the preparation of the compositions should be pharmaceutically pure and non toxic at the used dosages For the preparation of pharmaceutical compositions for the parenteral administration, the active ingredient can be included in solutions or suspensions w hich can comprise in addition the following components a sterile diluent such as water for injections, saline solution, oils, polyethylene glycols, glyceπn, propylene glycoi or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulfite, chelatmg agents such as ethylenediaminotetracetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting the tonicity of the solution, such as sodium chloride or dextrose. The parenteral preparation can be included in ampoules, mono-dose syringes, glass or plastic vials. The following examples further illustrate the invention. Preparation 1 - N-benzyl-N'-acetylethylenediamine To a solution of benzaldehyde (2 ml) in 40 ml of absolute ethanol. kept under nitrogen atmosphere and at room temperature is added N-acetylethylenediamine (2.2 ml) and stirring is continued for 18 hours. Successively is added portionwise sodium borohydride (969 mg) under vigorous stirring After 1 hour the reaction mixture is cooled to 0°C and quenched by dropwise addition of 6N hydrochloric acid (approx 6 ml) until gas evolution has ceased The solvent 'S evaporated and the resulting residue is dissolved in water (25 ml) and acidified with 6N hydrochloric acid until pHl 5-2 is reached The acidic aqueous phase is extracted twice with ethyl acetate (2 x 25 πύ) to remove some impurities, then is basified to pH 1 1 with 20% sodium hydroxide and further extracted twice with diethyl ether ( 2 x 50 ml) The pooled organic phases are dried over sodium sulfate and concentrated to dryness to give 1 367 g of the product as a clear oil which on standing solidifies. TLC [SiO 2 , eluant: chloroform/methanol/ammonium hydroxide 95 5 0 5)] detection u.v and I 2 Η-NMR in CDCh 1 40 ppm (bs. 1H). 1 98 ppm (s, 3H). 2 78 ppm (t. 2H), 3 35 ppm (q, 2H), 3 80 (s. 2H), 6 05 (bs. 1H), 7 30-7 40 (m, 5H) l3 C-NMR in CDCK. ppm 140 10. 128 46. 128.33. 128 04. 127 09. 126 84, 53 5 1. 48 79. 47 96. 39 16. 23.26 Preparation 2 - 5-(4-methoxyphenyl)barbituric acid a) preparation of ethyl 4-methoxyphenylacetate A solution of 4-methoxyphenylacetic acid (2 g) and para-toluensulfonic acid (230 mg) in 30 ml of ethanol is refluxed for 2 hours. The solvent is evaporated under reduced pressure and the residue is suspended in a saturated aqueous solution of sodium hydrogencarbonate and extracted twice with ethyl acetate. The organic extracts are collected, washed with water and dried over sodium sulfate to give, after evaporation of the solvent under reduced pressure, 2.14 g of the product. b) preparation of ethyl 4-methoxyphenyl maionate A mixture of ethyl 4-methoxyphenylacetate (27 8 g) and sodium (3 68 g) in 90 ml of diethylcarbonate is refluxed for 3 hours, then the solvent is evaporated under reduced pressure and the residue is diluted with water and neutralized with acetic acid The aqueous phase is extracted twice with diethvl ether The organic extracts are pooled and washed twice with 1 N sodium hydroxide and once with water, then the organic phase is dπed over sodium sulfate and concentrated to drvness 34 2 g of the product are obtained ς c) preparation of 5-(4-methoxyphenvl)barbιtunc acid To a solution of 660 mg of sodium in 50 ml of ethanol are added 3 86 g of ethvl 4- methoxyphenvl maionate and 1 28 g of urea The reaction mixture is refluxed for 3 hours A white solid separates, which is collected by filtration and redissolved in 15 ml of water The solution is acidified to pH = 1 -2 by adding 6 N hvdrochlonc acid A white solid separates 10 which is filtered and washed on the filter with water After drving under vacuum at 50°C for several hours. 2 28 g of the product are obtained Preparation 3 - ; '-[3-(4-methoxyphenyl)propyllbarbιtuπc acid a) preparation of 3-(4-methoxvphenvl)propιonvl chloπde To a suspension of 3-(4-methoxvphenyl)propιonιc acid ( 10 g) in 150 mi of toluene are 15 added 8 ml of thionyl chloride and the mixture is heated to 65°C for 4 hours The solvent is evaporated off under reduced pressure and the residue is redissolved in toluene and concentrated to drvness Such a step is repeated twice 1 1 g of the product are obtained as a yellow oil b) preparation of 5-[3-(4-methoxvphenyl)propιonvl]barbιtunc acid 0 To a suspension of barbituric acid (6 4 g) in 48 ml of pvπαine are added dropwise 1 1 g of 3- (4-methoxyphenvl)propιonvl chloride and the mixture is stirred at room temperature tor 18 hours The reaction mixture is then poured into ice and acidified to pH = 1 by adding 6 N hydrochloric acid A solid precipitates which is filtered ana resuspended in methanol The suspension is kept under stirπng for 15 minutes, then the solid is recovered by filtration to ^ give 12 2 g of the product, m p 248-250°C c) preparation of 5-[3-(4-methoxyphenyl)propyl]barbιtuπc acid To a suspension of 10 g of 5-[3-(4-methoxyphenyl)propιonvl]barbιtuπc acid in 100 ml of acetic acid are added portionwise 4 5 g of sodium cyanoborohvdπde, then the mixture is heated to 60°C After 1 hour the reaction mixture is cooled to room temperature and ιθ poured into ice After 30 minutes a solid is recovered bv filtration which is dried under vacuum at 50°C to give 8 74 g of the product, m p 195-197°C Preparation 4 - 5-benzylbarbιtuπc acid a) preparation of 5-benzylidenebarbituπc acid A suspension of 5 g of barbituric acid in 50 ml of water is heated until a compklete dissolution occurs, then it is added with 4 3 ml of benzaldheide The mixture is refluxed for 1 hour, then the solid which separated is filtered, washed several times with water and dried under vacuum at 100°C. to give 8 17 g of the product, m p >258°C b) preparation of 5-benzylbarbituπc acid To a suspension of 5-benzylidenebarbituπc acid (4 g) in 200 ml of methanol are added portionwise 1 4 g of sodium borohydride After 10 minutes from the end of the addition. 100 ml of water are added and the mixture is acidified with 1 N hydrochloric acid to pH = 2 The solvent is evaporated off and the aqueous phase is extracted with ethyl acetate The pooled extracts are dried over sodium sulfate and concentrated to dryness 3 6 g of the product crystallize, m p 207-209°C Preparation 5 - 5-(4-hvdroxyphenyl)barbιtuπc acid To a suspension of 5-(4-methoxyphenyl)barbιtuπc acid (222 mg) in 5 ml of methylene chloride, kept at -5/- 10°C and under nitrogen atmosphere, is dropped a solution of boron tribromide (473 ul) in 2 ml of methylene chloride The stirring is continued for additional 2 hours at -5°C. then the temperature is brought to room temperature and stirring is continued for further 20 hours The reaction mixture is again cooled to 0°C with an ice bath and it is basified to pH = 9- 10 by adding dropwise 5% sodium hydroxide The aqueous phase is separated, filtered through a cehte plug, cooled with ice bath and acidified to pH = 1 with 37% hydrochloric acid A white solid separates which after 1 hour is separated b\ filtration and dried under vacuum at 60°C to give 215 mg of the product Preparation 6 - 5-(4-methylphenyl)barbιτuric acid To a solution of sodium ( 184 mg) in 12 ml of ethanol are added 0 95 ml of diethyl 2-(4- methylphenyl)malonate and 360 mg of urea, then the mixture is refluxed for 3 hours A white solid separates, which is filtered and redissolved in 4 ml of water The solution is acidified to pH = 1 -2 by adding 6 N hydrochloric acid A white solid separates, which is collected by filtration, washed with 15 ml of water and dried under vacuum 619 mg of the product are obtained, m p. 271°C Preparation 7 - 5-octylbarbituric acid a) preparation of diethyl 2-octylmalonate To a solution of 2 63 of sodium in 100 ml of ethanol is added dropwise a solution of 19 1 ml of diethvlmalonate in 10 ml of ethanol The mixture is successively added with 20 4 ml of 1 -bromooctane dissolved in 10 ml of ethanol. then the mixture is refluxed for 6 hours The reaction mixture is concentrated to a little volume and the residue is partitioned between a saturated aqueous solution of sodium hvdrogenphosphate (200 ml) and ethvl acetate (200 ml) The organic phase is washed with 75 ml of water and 7 5 ml of saturated aqueous solution of sodium chloπde, dried over sodium sulfate and concentrated to drvness to give 3 1 8 g of the product as an oil Η-NMR in CDC 0 80-0 95 ppm ( m 3H), 1 15- 1 40 ppm ( m 18H), 1 88 ppm (q, 2H) 3 33 ppm (t. 1H), 4 19 ppm (q, 4H) b) preparation of 5-octvlbarbιtunc acid To a solution of sodium (5 32 g) in 400 ml of anhydrous etnanol is added a solution of diethyl 2-octvlmalonate (3 1 5 g) in 50 ml of ethanol and successivelv 10 27 g of urea, then the mixture is refluxed for 2 hours 30 minutes The mixture is rapidly cooled to room temperature and the solid which was formed is recovered bv filtration and washed with diethyl ether The solid is then dissolved in 200 ml of water and acidified with 6 N hydrochlonc acid until pH 1 5-2 is reached A solid separates The mixture is added with 200 ml of ethvl acetate and it is stirred for 2 hours, then it is added with additional 800 ml of warm ethvl acetate The organic phase is separated and the aqueous phase is washed with 200 ml of ethvl acetate The pooled organic phases are washed with 250 ml of saturated aqueous solution of sodium chloride dried over soαium sulfate and concentrated to drvness 21 03 g of the product are obtained 'H-NMR in d6-DMSO 0 77-0 80 ppm ι m, 3H) 1 23 ppm ι s 1 H), 1 80- 1 95 ppm (m 2H), 3 52 ppm (t, 1H), 1 1 15 ppm (s. 2H) Preparation 8 - 5-naphtylbarbιtuπc acid a) preparation of ethvl 2-naphtvlacetate To a solution of 2-naphtvlacetιc acid (5 g) in 50 ml of ethanol are added 0 5 g of para- toluensulfonic acid, then the reaction mixture is refluxed for about 4 hours The solvent is evaporated off and the residue is dissolved in diethvl ether washed twice with a saturated aqueous solution of sodium hvdrogencarbonate and once with bnne, then the pooled organic extracts are dried over sodium sulfate and concentrated to drvness 5 64 g of the product as a vellow oil are obtained b) preparation of diethyl 2-naphtylmalonate To a solution of ethyl 2-naphtylacetate (2 g) in 23.3 ml of diethylcarbonate. kept under stirring and at room temperature, are added portionwise 0 232 g of sodium. The reaction mixture is refluxed for 2 hours 30 minutes, then it is concentrated in order to eliminate the not reacted diethylcarbonate and it is added with 20 ml of cold water The resulting mixture is acidified with acetic acid until weak acidity is reached, then it is extracted three times with diethyl ether The pooled organic extracts are dried over sodium sulfate and the solvent is evaporated off. to give, after recrystallization from diethyl ether ( 19 ml), 1 015 g of the product as a white solid c) preparation of 5-naphtylbarbituπc acid A solution of sodium (0 32 g) in 30 ml of anhydrous ethanol is added with diethyl 2- naphtylmalonate (2 gj and successively with urea (0 63 g) The mixture is refluxed for 2 hours, then the solid which separated is recovered by filtration, then it is dissolved in 7 ml of water and acidified to pH = 1 with 6 N hydrochloric acid A white solid precipitates which, after 30 minutes under stirring, is filtered and washed with water The solid is dried overnight under vacuum at 40°C, to give 0 96 g of the product Preparation 9 - 5-(4'-biphenyl)barbituric acid a) preparation of ethyl (4 , -biphenyl)acetate A suspension of (4'-biphenyl)acetic acid (6 4 g) in 60 ml of ethanol is added with 1 1 g of para-toluensulfonic acid, then the reaction mixture is refluxed for 4 hours 30 minutes The solvent is evaporated off. the residue is dissolved in diethvl ether and the resulting organic phase is washed three times with a saturated aqueous solution of sodium hvdrogencarbonate and once with brine. The organic phase is then dried over sodium sulfate and the solvent is evaporated off to give 7 1 g of the product as a yellow oil b) preparation of diethyl (4'-biphenyl)malonate A solution of ethyl (4'-biphenyl)acetate (7 1 g) in 60 ml of diethylcarbonate, kept under nitrogen atmosphere, is added portionwise with sodium (0 734 g), then it is heated at 120°C for 3 hours. The solvent is evaporated off and the residue is dissolved in 65 ml of cold water and acidified with acetic acid until pH = 5-6 is reached. The aqueous phase is then extracted three times with diethyl ether and the pooled organic extracts are dried over sodium sulfate and concentrated to drvness The residue is purified by silica gel chromatography (eluent petroleum ether/ diethyl ether 9 4 0 6) to give 7 05 g of the product, m p 51-53°C c) preparation of 5-(4'-bιphenyl)barbιtuπc acid A solution of sodium (0 322 g) in 40 ml of anhydrous ethanol is added with diethyl (4 - bιphenyl)malonate (2 2 g) and successively with urea (0 63 g) The reaction mixture is refluxed for 3 hours 30 minutes, then it is cooled to room temperature and the solid is ^ recovered by filtration The obtained solid is redissolved in 40 ml of warm water and the resulting aqueous phase is acidified to pH = 1 with 6 N hydrochloric acid The solid which separates is kept 15 minutes under stirπng. then it is filtered and dried under vacuum at 60°C 1 1 g of the product are obtained, m p >240°C Preparation 10 - 5-(4'phenoxyphenyl)barbιtuπc acid lυ a) preparation of N-[(4'-phenoxvbenzyl)thiocarbonyl]morphohne A. mixture of (4'-phenoxyphenyl)methvlketone ( 19 1 g), morpholine (20 ml) and sulphur (4 32 g) is refluxed for 24 hours, then it is extracted with diethyl ether The organic pnase is concentrated to drvness to give, after crystallization form a petroleum ether/ethvl acetate mixture 8 2 (600 ml), 12 2 g of the product, m p 75-77°C 15 b) preparation of (4'-phenoxyphenyl)acetιc acid A suspension of N-[(4'-phenoxybenzyl)thιocarbonyl]morpholine ( 1 725 g) in 87 ml of 10% potassium hydroxide is refluxed for 8 hours 30 minutes, then the reaction mixture is brought to room temperature and acidified with IN hydrochloric acid A white solid separates, which is stirred for 30 minutes and filtered The solid is washed with water and dried under 20 vacuum, to give 1 095 g of the product, m p 70-72°C c) preparation of ethyl (4 -phenoxvpnenvl (acetate To a suspension of (4'-phenoxyphenvl)acetιc acid (0 456 gj in 4 ml of ethanol is added para-toluensulfonic acid (0 076 g) and the resulting mixture is refluxed for 2 hours The solvent is evaporated off. the residue is dissolved in diethyl ether and the organic phase is 25 washed with saturated aqueous solution of sodium hvdrogencarbonate and then with bπne The organic phase is dried over sodium sulfate and concentrated to drvness to give 0 458 g of the product as a brown oil d) preparation of 5-(4'-phenoxyphenyl)barbιtuπc acid A soultion of sodium ethoxide (0 27 g) in 3 ml of anhydrous ethanol is added with 0 657 g 30 of ethyl (4'-phenoxyphenyl)acetate dissolved in 5 ml of ethanol, then with urea (0 18 g) The reaction mixture is refluxed for 2 hours 30 minutes, then it is cooled to room temperature and the suspended solid is filtered The solid is redissolved in 8 ml of water and the solution is acidified with 1 N hydrochloric acid The sohd which separates is recovered by filtration to give 0. 165 g of the product, m.p >240°C Preparation 1 1 - 5-decylbarbituric acid a) preparation of diethyl decyimalonate A solution of sodium (0 46 g) in 10 of anhydrous ethanol is added with 3 35 ml of diethyl maionate in 3 ml of ethanol and successively with a solution of decylbromide (4 15 ml ) in 3 ml of ethanol The reaction mixture is refluxed for 4 hours, then the precipitate is filtered off and the filtrate is concentrated to dryness. The residue is redissolved in a saturated aqueous solution of sodium hydrogensulfate and it is extracted with ethyl acetate. The organic extract is dried over sodium sulfate and the solvent is evaporated off. The resulting residue is used as such in the successive reaction b) preparation of 5-decylbarbituric acid To a solution of diethyl decyimalonate of step a) in 40 ml of ethanol are added 2 72 g of sodium ethoxide and then 1 8 g of urea The reaction mixture is refluxed for 2 hours, then the precipitate is filtered and redissolved in 40 ml of water The resulting aqueous solution is acidified with 6 N hydrochloric acid. The solid which separates is recovered by filtration and dried under vacuum at 40°C overnight, to give 2 152 g of the product, m p 190°C Example 1 - 5-octyl-5-(ethoxycarbonylmethyl)barbituπc acid 4 05 g of 5-octylbarbituric acid (preparation 7) are dissolved in 25 ml of dimethylformamide. 1 16 g of sodium carbonate are added Ethyl bromoacetate (2.25 ml ) is added dropwise to the reaction mixture in 5 minutes, then tne mixture is kept at room temperature under stirring for about 3 hours. The reaction mixture is then partitioned between 400 ml of water, 17 ml of 1 N hydrochloric acid and 150 ml of ethyl acetate The organic phase is separated and washed with 150 ml of water and 100 ml of brine, then it is dried over sodium sulfate The aqueous phases are extracted with 100 ml of ethvl acetate and the organic extracts are pooled, dried over sodium sulfate and evaporated to dryness. to give 6 5 g an oily residue This residue is purified by silica gel chromatography (eluant methylene chloride/ ethyl acetate 9 1 ) to give 3 87 g of the product Elem Anal. (% found/calcd) C 58.79/58 88, H 8 04/8.03. N 8 47/8.58 Η-NMR in CDC1 3 0.80-0 95 ppm im. 3H), 1 15- 1 40 ppm < m. 15H), 1.80-1 95 ppm (m. 2H). 3 1 8 ppm (s. 2H); 4 12 ppm (q. 2H). 8.68 ppm (s. 1H) Example 2 - 5-octyl-5-(carboxymethyl)barbituπc acid 3 29 g of the ester of example 1 are dissolved in 35 ml of 1 N sodium hydroxide and the solution is kept under stirring at room temperature for abou 16 hours, then it is quenched by addition of 6 ml of 6 N hydrochloric acid. A white solid separates, which is kept under stirring for about 5 hours, then it is collected by filtration, washed with 0 05 M hydrochloric acid and water and finally dried under vacuum at 40°C 2 84 g of the product are obtained as a white solid Elem Anal (% found/calcd) C 55 63/56 36. H 7 39/7 43. N 9 18/9 39 Η-NMR in DMSO-dr, 0 80-0 95 ppm ( m, 3H), 1 00- 1 35 ppm (s. 12H). 1 60- 1 80 ppm (m. 2H). 2 90 ppm (s. 2H), 1 1 42 ppm ( s. 2H), 12 75 ppm ( br s. 1H) Example 3 - 5-octyl-5-(carboxymethyl)barbιtuπc acid hvdroxysuccinimide ester To a solution of 5-octyl- carboxvmethvl)barbιtuπc acid ( 103 mg. example 2) and N- hydroxysuccinimide (60 mg) in 2 5 ml of anhydrous tetrahvdrofuran. kept under nitrogen atmosphere and cooled at 0-5°C. is added morpholinoethvl isonitrile (71 ul) via syringe The mixture is allowed to warm to room temperature and is stirred for 70 hours The reaction mixture is concentrated to a little volume and the residue is partitioned between 0 1 N hydrochloric acid (20 ml) and ethyl acetate (25 ml) The organic phase is washed with 20 ml of saturated aqueous solution of sodium chloride and dried over sodium sulfate Removal of the solvent affords 130 mg of crude product, which is purified by column chromatography (SiO 2 , eluant dichloromethane/ethvl acetate 75 25) to give 60 mg of pure product as white amorphous solid ' Η-NMR in CDCh 0 80-0 95 ppm ( m. 3H). 1 15- 1 40 ppm i s. 12H). 1 80- 1 95 ppm ( m. 2H), 2 75 ppm ( s. 4H), 3 40 ppm (s. 2H). 9 28 ppm ( s. 2H) 13 C-NMR in CDCK ppm 171 06, 169 06. 166 84. 149 1 5. 52 87. 39 49, 36 50. 3 1 65. 29 21. 29 05. 29 00. 25 49. 23 96. 22 5 1. 14 1 1 Example 4 - 5-octyl-5-(carboxymethyl)barbituπc acid N ' -benzvi amide Method A To a solution of 5-octyl-5-(carboxymethyl)barbituπc acid hvdroxvsuccinimide ester (58 mg. example 3) in 1 5 ml of acetonitrile. kept under nitrogen atmosphere and at room temperature, is added benzylamine (40 μl). then the mixture is stirred at room temperature for 3 5 hours The reaction mixture is concentrated to a little volume and the residue is partitioned between 0 1 N hydrochloric acid ( 10 ml) and ethyl acetate ( 10 ml) The organic phase is washed with 10 ml of saturated aqueous solution of sodium bicarbonate, successively with 10 ml of saturated aqueous solution of sodium chloride and dried over sodium sulfate Removal of the solvent affords 47 mg of crude product as white solid Method B To a solution of 5-octyl-5-(carboxymethyl)barbituric acid (208 mg, example 1 ) in 2 5 ml of anhydrous tetrahydrofuran. kept under nitrogen atmosphere and cooled at 0-5°C. is added 1.0- carboriyldiimidazole ( 124 mg) The mixture is allowed to warm to room temperature and is stirre d for 4 hours Then benzylamine (76 ul) is added and stirring is continued for 20 hours The eactιon mixture is concentrated to dryness and the residue is partitioned between 0 1 N hydrochloric acid (10 ml ) and ethyl acetate ( 15 ml) The organic phase is washed with 10 ml of saturated aqueous solution of sodium chloride and dried o\ er sodium sulfate Removal of the solvent affords 265 mg of crude product, which is purified by column 5 chromatography (SiO 2 , eluant dichloromethane/ethyl acetate 8 2) to give 220 mg of pure product as white solid Η-NMR in DMSO-d 6 0 77-0 90 ppm (m, 3H). 1 23 ppm (s. 12H), 1 60- 1 75 ppm (m. 2H). 2 95 ppm (s. 2H). 4 1 5-4 25 ppm (d. 2H). 7 15-7 40 ppm (m. 5H). 8 55 ppm (t. 1H), 1 1 32 ppm ( s. 2H) 0 "C-NMR in DMSO-d ppm 173 36. 169 39, 150 36. 139 01. 128 24. 127 05. 126 77 5 1 57. 42 05 41 52. 38 10. 3 1 12. 28 67. 28 5 1. 28 42. 23 54. 22 00. 13 89 Elem Anal(% found/calcd) C 65 13/65 09. H 7 46/7 54. N 10 84/10 85 Example 5 - 5-octyl-5-(carboxymethyl)barbituπc acid N ' -acetyl N-ethylenediamide To a solution of 5-octyl-5-(carboxymethyl)barbitunc acid (246 mg, example 2) in 3 ml of 5 anhydrous tetrahydrofuran. kept under nitrogen atmosphere and cooled at 0-5°C, is added l . r-carbonyldiimidazole ( 147 mg) The mixture is allowed to warm to room temperature and is stirred for 4 hours Then N-acetylethylenediamine (88 ul) is added, after 30 minutes a white solid separates, then stirring is continued for 20 hours The reaction mixture is concentrated to dryness and the residue is partitioned between 0 1 N hydrochloric acid ( 10 d ml) and ethyl acetate (20 ml) The mixture is warmed until a complete solution is obtained then the organic phase is separated, washed with 10 ml of saturated aqueous solution of sodium chloπde and dried over sodium sulfate Removal of the solvent affords 295 mg of crude product, which is purified by crystallization from ethyl acetate/ethanol ( 10ml/2 5 ml) to give 199 mg of pure product as white solid Η-NMR in DMSO-d ή 0 77-0 90 ppm (m, 3H), 1 23 ppm ( s. 12H), 1 60- 1 75 ppm (m. 2H). 1 78 ppm (s. 3H); 2 83 ppm (s. 2H); 2.90-3 00 ppm (m. 4H); 7 75-7 85 ppm (m. 1H). 8 00-8 10 ppm (m. 1H), 1 1.25 (s, 2H) "C-NMR in DMSO-d 6 : ppm 173 32. 169 48; 169.30. 150.36, 5 1 47. 41 59. 38 34. 38 07. 31 1 1. 28.66. 28 50; 28 41 , 23 53, 22 57. 22.00 Elem Anal. (% found/calcd) C 55 75/56.53, H 7.90/7.91. N 14.36/14.65 Example 6 - 5-octyl-5-(carboxymethyl)barbituric acid N ' -acetyl-N-benzyl-N- ethylenediamide 5-octyl-5-(carboxymethyl)barbituπc acid (215 mg. example 2) is suspended in thionyl chloride (3 ml ) and the mixture is refluxed for 1 hour The resulting solution is concentrated to a small volume, diluted with anhydrous toluene and evaporated to dryness The obtained residue is taken up in dichloromethane (2 ml) and to the resulting solution. kept under nitrogen atmosphere and cooled to 0°C. is added N-benzyl-N'- acetylethylenediamine ( 180 mg; preparation 1 ) in one portion and successively pyridine (0 5 ml) The reaction mixture is stirred for 1 5 hours, then it is concentrated to a little volume and the residue is partitioned between IN hydrochloric acid (3 ml) and diethyl ether (3 ml) A white solid separates from the mixture which is recovered by filtration and successively washed on the filter with water and ethyl acetate. The isolated precipitate is dissolved on warming in ethyl acetate (20 ml) and the resulting solution is dried over sodium sulfate and concentrated to dryness The obtained residue is triturated with ethyl acetate at reflux to give 180 mg of the product as white solid TLC [SiO 2 , eluanf chloroform/methanol 85 • 15]. detection u v and I 2 .p = 184 5- 185 5 °C Η-NMR in DMSO-dft 0 80-0 95 ppm (m. 3H), 1 10- 1 35 ppm (s, 12 H), 1 60- 1 80 ppm (m. 2H). 1 70 and 1 85 ppm ( two s. 3H), 3 00-3 30 ppm ( m. 4H), 3 35 ppm (s. 2H). 4.45 and 4 60 ppm (two s, 2H), 7.05-7 45 ppm (m, 5H), 7 80 and 8 00 ppm (two t. 1H). 1 1.28 ppm (s, 2H) Elem Anal. % found calcd) C 64 10/63.54; H 7.89/7 68. N 1 1.62/1 1.86 Example 7 - According to the procedures described in the previous preparations and examples, starting from the suitable starting materials, the following barbituric acid derivatives are obtained: - 5-octyl-5-(carboxymethyl)barbituric acid N-benzopiperidinone; - 5-(4'-diphenyl)-5-(carboxymethyl)barbituric acid N ' -acetyl-N-benzyl-N-ethylenediamide; - 5-(4'-phenoxyphenyl)-5-(carboxymethyl)barbituric acid N ' -acetyl-N-benzyl-N- ethylenediamide: - 5-decyl-5-(carboxymethyl)barbituric acid N'-acetyl—N-ethylenediamide; - 5-octyl-5-(carboxymethyl)barbituric acid benzyl ester; - 5-octadecyl-5-(carboxymethyl)barbituric acid N'-acetyl-N-benzyl-N-ethylenediamide: - 5-octyl-5-(carboxymethyl)barbituric acid N'-methansulphonyl-N-benzyl-N- ethvlenediamide; - 5-octyl-5-( carboxymethyl)barbituric ac: d 2-(N ' -phtalamido)-N-ethylamide: - 5-octvl-5-(carboxymethyl)barbituric ac d 2-(N'-piperidine-2.3-dione)-N-ethylamide. - 5-octyl-5-(carboxymethyl)barbituric ac d 2-(N ' -caprolactam)-N-ethylamide: 15 - 5-octyl-5-(carboxymethyl)barbituric ac d 2-(N'-pyrrolidinone)-N-ethylamιde; - 5-octyl-5-(carboxymethyl)barbituric ac d N-amidoglycine ethyl ester; - 5-octyl-5-(carboxymethyl)barbituric ac: d N-amidophenylalanine ethyl ester; - 5-octyl-5-(carboxymethyl)barbituric ac d N-amidotriptophane methyl ester; - 5-octyl-5-(carboxymethyl)barbituric ac d N-amidophenylalaninamide; - 5-octyl-5-(carboxymethyl)barbituric ac d N-amidophenylalanin-(N'-benzyl)-amide: - 5-octyl-5-(carboxymethyl)barbituric ac d N-amιdoglycyl((L )-phenylalanιnamide ). - 5-octyl-5-(aminocarbonylaminocarbonylmethyl)barbituric acid; - 5-octyl-5-( aminosulphonylaminocarbonylmethyl)barbituric acid; - 5-octyl-5-[(N-pyrrolidinyl)carbonylaminocarbonylmethyl]barbituric acid; " > S - 5-octyl-5-[(N-piperazinyl)carbonylaminocarbonylmethyl]barbituric acid; - 5-octyl-5-[(N-thiomorpholinyl)carbonylaminocarbonylmethyl]barbituric acid

Claims: CLAIMS 1 Barbituric acid deπvatives of the general formula (I) wherein R is a W-V group, in which W is a bond or a linear or branched (C,-Cs)alkvl or a l V is a monocycle or bicvcle. saturated or unsaturated, which can optionalK contain from 1 to 3 heteroatoms selecteα from nitrogen oxygen or sulfur and hich can be optionalK substituted bv a ι C ι-C phenoxv or phem l group or W-\ is a (C!-C 2 o)alkyl group which can oe optionally interrupted or terminated bv one or more heteroatoms selected from oxygen or sulfur or by a - N(R0- group, in which R is selected from hydrogen. ( C C 4 )alkyl or (G-C 4 )acvl n is an integer from 1 to 3. A is selected from the following groups R 1 - (R ; )-( CH 2 ) m -N(R 9 )-T- R l " -N(R : )-CHR"-CO-R 7 -N(R 2 )-T-NR'R 4 . in which - T is a -CO- or -SO 2 - group. - m is an integer rrom 2 to 6 - R' is selected from -OH. mono- or dι-( C ι -C 4 )alkvlamιno benzylamino. phenoxv or benzvloxy groups, these two latter being optionally substituted with one or more groups selected from ( G-C )alkyl, (C . halogen. -OH. -NH 2 , mono- or di-(Ci-C )alkvlammo. nitro. (Cι-C 4 )alkvlsulphonvl (Cι-C 4 )alkylsulphonamιdo. or is a group of formula -VR0-CO-R 10 in which R " and R 10 . taken together with the N-CO group to which tne\ are linked, form a 5- to 7- membered lactam which can optionally be benzocondensed and/or substituted with a group selected from (Cι-C 4 )alkyl, nalogen. -OH. -NH 2 , mono- or di-(G-C )alkvlamιno. nitro. (Cι-C 4 )alkylsulphonvl (C -C 4 )alkylsulphonamido - R 2 is selected from hvdrogen. (G-C 4 )alkyl. (G-C- cloalkyl, (C -C 7 )cycloalkvl- (Cι-Cα)alkvl. phenvl or benzv l groups, these two latters being optionally substituted with one or more groups selected from ( i < C -C )alkoxy. halogen -OH - NH 2 , mono- or di-(G-G)alkylamino. nitro. (G-Gialkylsuiphonvl. (G- C 4 )alkylsulphonamido; or R 2 is a Het-(Cι-C 2 )alkyl group, in which Het is a 5- or 6- membered heterocycle having from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, which can be optionally benzocondensed; - R " is selected from hydrogen. (C ι-C 4 )alkyl, (C 6 -C-)cycloalkyl. phenyl. benzyl or phenetyl. which can be optionally substituted by a group selected from (G- C 4 )alkoxy. -SO 2 NH 2 ; - R 4 is a -(CH 2 ) P -B group, wherein p is 0. 1 or 2 and B is selected from (G-C 8 )alkyl; benzydryl; monocycle or bicycle, saturated or unsaturated. which can optionally be benzocondensed and/or substituted with a group selected from ( G-C 4 )alkyl. (G- C )alkoxy. halogen. -OH.-NH 2 . mono- or di-(G-C 4 )alkylamino. nitro. (G-G)alkylsulphonyl. (G-G .alkylsulphonamido; 5- or 6-membered heterocycle having from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, which can be optionally benzocondensed and/or substituted with a group selected from (G- 5 C )alkyl. (G-G)alkoxy. halogen. -OH. -NH 2 , mono- or di-(G-C )alkylamino. nitro. (Cι-C 4 )alkylsulphonyl. (G-C 4 )alkylsulphonamido: or R ' and R 4 . taken together with the nitrogen atom to which they are linked, form a 5- or 6-membered heterocycle having from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, which can be optionally benzocondensed and/or substituted with a group selected from (G- u Cøalkyl. (G-G)alkoxy. halogen. -OH. -NH 2 . mono- or di-(G-C 4 )alkylamino. nitro. (G-C 4 )alkylsulphonyl. (G-G)alkylsulphonamido; - R 6 is a -(CH 2 ) q -D group in which q is 0. 1 or 2 and D is selected from hydrogen; (G-G)alkyl; a monocycle or bicycle, saturated or unsaturated. which can optionally be benzocondensed and/or substituted with a group selected from (G-Cøalkyl. (G- 5 C )alkoxy. halogen, -OH. -NH 2 . mono- or di-(G-C 4 )alkylamino. nitro. (G- C 4 )alkylsulphonyl. (Cι-C )alkylsulphonamido; 5- or 6-membered heterocycle having from 1 to 3 heteroatoms selected from nitrogen, oxygen or sulfur, which can be optionally benzocondensed and/ or substituted with a group selected from ( G- C 4 )alkyl. (G-C 4 )alkoxy. halogen. -OH, -NH 2 , mono- or di-(G-C )alkylamιno. nitro. o (G-C 4 )alkylsulphonyl. (C|-C 4 )alkylsulphonamido: - R 7 is selected from -OH. (G-Cs)alkoxy. -NHR\ -\Η-CH(R ϋ )-COR β . in which R* on its turn is selected from -OH. (G-C8)alkoxy or -XHR 1 and R' is as above defined. - R 9 and R 10 have the same meanings as R ' and R 4 . respectively, but when they are taken together with the N-CO group to which they are linked, they form a 5- to 7- membered lactam. which can optionally be benzocondensed and/or substituted with a group selected from (G-G)alkyl, (G-C 4 )alkoxy. halogen. -OH. -NH 2 . mono- or di-(G-C 4 )alkylamιno. nitro. (G-C )alkvisulphonyl. (G-C 4 )alkylsulphonamιdo as enantiomers. racemates. diastereoisomers. tautomers or mixtures thereof, as well as their salts with pharmaceutically acceptable acids or bases The barbituric acid derivatives according to claim l in which n is 1 A is a -N(R0-(CH 2 ) m -N(R")-CO R 1 " group and R is selected from a (G-Gøalkvl biphenyl, phenoxyphenvl or ( G-G)alkoxyphenyl group The barbituric acid derivatives according to claim 1. in which n is 1. A is a (G- C )alkoxy group and R is selected from a (G-Go)alkyl. biphenyl. phenoxyphenyl or (G-C )alkoxyphenyl group The barbituric acid derivatives according to claim 3 in which m is 2 and R ~ is a (G- C )alkyl. phenvl or benzyl group The barbituric acid derivatives according to claim 1 which are selected from the following compounds - 5-octyl-5-(ethoxycarbonvimethyl)barbituπc acid. - 5-octyl-5-(carboxvmethyl)barbιturic acid, - 5-octyl-5-(carboxymethvl)barbιtuπc acid N-benz ι amide. - 5-octyl-5-(carboxvmethyl)barbιtuπc acid N'-acetvl N-ethylenediamide. - 5-octyl-5-(carboxymethyl)barbituπc acid N ' -acetyl N-ethylenediamide. - 5-octyl-5-(carboxymethyl)barbιtuπc acid N-benzopiperidinone. - 5-(4'-diphenyl)-5-(carboxymethyl)barbιtuπc acid N " -acetyl-N-benzyl- - ethvlenediamide. - 5-(4 ' -phenoxyphenyl)-5-(carboxymethyl)barbituπc acid N'-acetyl-N-benzyl-N- ethylenediamide, - 5-decyl-5-(carboxymethyl)barbιtuπc acid N ' -acetyl— N-ethylenediamide. - 5-octyl-5-(carboxymethyl)barbituric acid benzyl ester, - 5-octadecyl-5-(carboxymethyl)barbituπc acid N'-acetyl-N-benzyl-N- ethylenediarmde, - 5-octyl-5-(carboxymethyl)barbituric acid N'-methansulphonyl-N-benzyl-N- ethylenediamide, - 5-octyl-5-(carboxymethyl)barbιtuπc acid 2-(N'-phtalamιdo)-N-ethylamιde. - 5-octvl-5-(carboxymethyl)barbituπc acid 2-(N , -pιpeπdιne-2.3-dione)-N- ethvlamide, - 5-octvl-5-(carboxymethyl)barbιtuπc acid 2-(N ' -caprolactam)-N-ethvlamιde. - 5-octyl-5-(carboxymethyl)barbιtuπc acid 2-(N ' -pvrrolidinone)-N-ethylamιde - 5-octyl-5-(carboxymethyl)barbιtuπc acid N-amidoglycine ethyl ester. - 5-octyl-5-(carboxymethyl)barbituπc acid N-amidophenylalanine ethyl ester, - 5-octyl-5-(carboxymethyl)barbituric acid N-amidotπptophane methyl ester, - 5-octyl-5-(carboxymethyl)barbituric acid N-amidophenylalaninamide, - 5-octyl-5-(carboxymethyl)barbituπc acid N-amidophenylalanin-(N'-benzyl)-amιde. - 5-octvl-5-(carboxymethyl)barbιtuπc acid N-amιdoglycyK(L)-phenylalanιnamιde). - 5-octvl-5-(amιnocarbonylamιnocarbonvlmethvl)barbιtuπc acid. - 5-octyl-5-(amιnosulphonylamιnocarbonylmethyl)barbιtuπc acid. - 5-octyl-5-[(N-pyrrolidinyl)carbonylaminocarbonyimethyl]barbιtuπc acid. - 5-octyl-5-[(N-pιperazinyl)carbonylamιnocarbonylmethyI]barbιtuπc acid. - 5-octyl-5-[(N-thiomorpholinyl)carbonylamιnocarbonylmethyl]barbituπc acid 6 A process for preparing the barbituric acid derivatives of claim 1, which compπses the steps of (a) reacting a compound of formula (II) in which R has the same meanings as in claim 1. with a reactant of formula (III) X-(CH 2 ) n -COR' (III) in which n and R 1 have the same meanings as in claim 1. but R is preferably an ester group, and X is a leaving group, in a solvent and in the presence of an inorganic or organic base, at temperatures ranging from 0°C to 100°C. preferably between room temperature and 50°C, (b) removing the R 1 ester group. (c) functionaiizing the carboxy group in the compound obtained from step (b ) with ammonia, mono- or di-(G-C 4 )alkylamιne. or an intermediate of formula (IV) HN(R 2 )- (CH 2 ) m -N(R 9 )-T- R'°. (V) HN(R 2 )-CHR u -CO-R 7 (VI) HN(R0-T-NR 3 R 4 or (VII) HN(R )-COR'°. in which R 2 , R\ R 4 . R 6 . R 7 . R 9 . R 10 and m have the same meanings as in claim 1 , (d) optionally separating the enantiomers or the diastereoisomers of the compounds of formula (I), (e) optionally salifying the compounds of formula (I) obtained from steps (a), (b) or (c) with pharmaceutically acceptable acids or basis 7 Pharmaceutical compositions containing at least one compound according to claims 1 to 5 in admixture with pharmaceutically acceptable eccipients 8 Compounds according to claims 1 to 5 for the use as inhibitors of the metzincins 9 Compounds according to claim 8 as antitumor and antimetastatic agents 10 Compounds according to claim 8 for the use in the treatment of inflammation. fibrosis. rheumatoid arthritis, osteoarthritis, atherosclerotic plaque rupture, aortic aneurism, heart failure, restenosis. septic arthritis, ulcεration of the cornea, epidermic or gastric ulcerations. coronary thrombosis, proteinuria. pathological consequences of traumas, emphysema, multiple sclerosis, osteoporosis, periodontal disease or as contraceptive agents.

Inventors: DE CILLIS GIANPIERO, GRAMS FRANK, KRELL HANS-WILLI, LIVI VALERIA, MENTA ERNESTO, OLIVA AMBROGIO, ZIMMERMANN GERD, DE CILLIS, GIANPIERO, GRAMS, FRANK, KRELL, HANS-WILLI, LIVI, VALERIA, MENTA, ERNESTO, OLIVA, AMBROGIO, ZIMMERMANN, GERD
Applicants: BOEHRINGER MANNHEIM GMBH, CILLIS GIANPIERO DE, GRAMS FRANK, KRELL HANS WILLI, LIVI VALERIA, MENTA ERNESTO, OLIVA AMBROGIO, ZIMMERMANN GERD, DE CILLIS, GIANPIERO, GRAMS, FRANK, KRELL, HANS-WILLI, LIVI, VALERIA, MENTA, ERNESTO, OLIVA, AMBROGIO, ZIMMERMANN, GERD
Application year: 1998
Main classification: C07D401
IPC codes: A61K31, A61P1, A61P7, A61P9, A61P19, A61P27, A61P29, A61P35, A61P43, C07D239, C07D401, C07D403