10-DEACETYLBACCATINE III AND 10-DEACETYL 14 beta -HYDROXYBACCATINE III DERIVATIVES, A PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Abstract: The present invention relates to novel derivatives of 10-deacetylbaccatine III and of 10-deacetyl-14 beta -hydroxybaccatine III, having cytoxic and anti-tumoral activity. They are prepared starting from the so-called syntons or from other taxanes of natural origin, by selective oxidation of the hydroxyl in position 10 to keto function and subsequent esterification in position 13, if necessary, with isoserine chains variously substituted. The products of the invention can be administered by injection or orally, when suitably formulated.

Description: 1Q-DEACETYLBACCATINE III _ΔHD_ 10-DEACETYL 14B- HYDRQXYBACCATINE III DERTVATIVES . A PROCESS FOR IM PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM Paclitaxel (taxol), as it is already well-known, is a diterpenoid extracted from plants of the Taxus genus having anticancerogenic activity on different forms of human tumours. Its clinical use still involves some drawbacks due to the poor water solubility, which makes its administration complex, as well as to the onset of serious side-effects. Moreover, paclitaxel induces resistance quickly. Due to these reasons, researches have been in progress for some years aiming at synthesizing novel paclitaxel analogues which cause less adverse effects compared with the parent molecule. The present invention relates to novel derivatives with taxane skeleton endowed with a marked anti-tumoural activity. The novel derivatives have the general stru wherein R^ and R 2 are hydrogen atoms, or R^ is an hydrogen atom and R 2 is an hydroxyl or an acetyloxy group, or O 1 and R 2 together form a cyclic carbonate group of formula: R3 , which can be α- o β-oriented, is an hydrogen atom or an alkylsilyl group, preferably triethylsilyl (TES); R 4 is hydrogen, or the residue CH- CH- / C = C \ CH- C=0 I or an isoserine residue of formula Δ: wherein R 1 ' is a straight or branched alkyl or alkenyl group, containing one to five carbon atoms, or an aryl residue; R 2 ' is a straight or branched alkyl or alkenyl group, containing one to five carbon atoms, or an aryl residue, or a tert-butoxy group. The novel derivatives of general formula (1) are prepared by semisynthesis, starting from the natural syntons 10-deacetylbaccatine III (2) and 10-deacetyl- 1 4 β-hydroxybaccatine III (2). For this purpose, they are selectively oxidized in position 10 and then esterified in position 13 with a suitable acylating agent which allows to introduce the group R 4 . When taxanes of natural or synthetic origin already containing the desired isosenne chain in position 13, the molecules of structure 1 can be obtained from said taxanes by selective oxidation in position 10. As it will be described hereinafter, the selective oxidation in position 10 of 2 , 2 and of the taxanes already containing the isosenne chain n position 13, can be obtained by treatment with copper (II) salts. 10-Deacetylbaccatιne III (2) and its 14β-hydroxy (2) analogous can be recovered from suitably selected vegetable material (see. Indena Patent US-5 ,269 , 591 ) . However, and it is one of the objects of the present invention, it is possible to synthesize taxane syntons containing an oxygenated function in position 14, which are therefore useful for the preparation of compounds of structure 1, containing an oxygenated function in position 14, starting from 10- deacetylbaccatine III (2). In fact, it has surprisingly been found that, after protecting the hydroxyl in position 7 of compound 2 as a silyl ether, the oxidation to ketone of the carbon in 13 and the introduction of a β-oriented alcohol function on the carbon in 14 take place by treatment with manganese dioxide. After protection of the hydroxyls in 10 and 14, for example as acetates, by treatment with hydrides, the 13-keto function is reduced to 13α-hydroxy. The process, which is schematized below, leads to the formation of synton 4_, useful for the preparation of compounds with structure 1. From synton 4, after removing the protective groups with known methods described in literature, for example using hydrochloric acid to remove the silyl group and a base to remove the acetate groups, 10-deacetyl-14β- hydroxybaccatine III (2) is obtained. Therefore, as mentioned, in order to prepare compounds of formula I, 10-deacetylbaccatine III (2), 10-deacetyl-14β- hydroxybaccatme III (2), natural or semisynthetic , or other taxanes having an hydroxyl function at 10 ar.d already containing in position 13 the isosenne chair. represented by the group R. , must be available. It has surprisingly been found that ail these syntons, by treatment with copper (II) salts, preferably copper acetate, undergo a selective oxidation in position 10, without need for the protection of the other hydroxyl functions. For example, 10- deacetylbaccatme III (2), 10-deacetyl-14β- hydroxybaccatme III (2) and the natural taxane 10- deacetyl-cephalomannine give the respective 10-keto derivatives 2-1 in . :elds from 75 to 85%. The oxidation generally requires protracted times (100-140 hours) and an oxidizer excess, and it is carried out at room temperature and in alcoholic solvent. When, in the compound of formula 1 to prepare, the presence of a cyclic carbonate group between tne positions 1 and 14 is required, synton 2 is previously treated with phosgene in pyridine and the resulting carbonate is then oxidized in position 10 with copper (II) acetate, to give carbonate synton 2. By treatment with bases, diketones 5-8 undergo an inversion m position 7, i.e. the hydroxyl in position becomes α-oriented. Syntons 2, 2 and 2 or optionally their epimers in position 7, are therefore used for the preparation of taxanes of structure I, after protection of the alcoholic functions present. The alcohol function in 13, contrary to the other hydroxyalcohol functions, is poorly reactive to silylation and therefore does not undergo derivatization. For the esterification in position 13, the suitably activated isoserine chains are used, according to what reported in literature for the semisynthesis of paclitaxel and of its analogues (see. for example Eur. Pat. Appl. 400971, 1992; Fr. Dem. 86, 10400; E. Didier _ Αl . , Tetrahedron letters 2 , 2349, 1994; E. Didier e_t al.; j id 22, 3063, 1994). Preferably, isoserin chains are used in the activated forms of oxazolidmecarboxylic acids 2_a and 9b. In formulae ϋ_a and 2J2, R^ 'and R-, 1 have the meaning described above. The esteri ication of the oxazolid ecarboxylic acids with the taxane syntons and the subsequent elimination of the protective groups are carried out as described in literature for the synthesis of paclitaxel and the analogues thereof. Among the compounds of formula 1, compounds 1£_, ϋ and 12 turned out to be particularly active. Compound J_Q is 13-[(2R,3S )-3-ter-butoxycarbonylamino-2-hydroxy-3- isobutyl-propanoyl]-10-deacetyl-10-dehydro-baccatine III. Therefore, referring to general formula 1, compound 1£ has: R χ = R 2 = H, OR 3 = β-OH, R χ ' = iso-But , R~ ' = t- BuO. Compound H is 13-[ ( 2R, 3S )-3-ter- butoxycarbonylamino-2-hydroxy-3-isobutyl-propanoyl]-10- dehydro-10-deacetγl-14β-hydroxy-baccatme III 1,14- carbonate. Therefore H, referring to general formula 1, has )3. 1 , R 2 = -CO-O, OR 3 = β-OH, R 1 ' = iso-But, R- ' = t- BuO. Compound 12 is 13-[ ( 2R, 3S )-3-caproylammo-2- hydroxγ-3-isobutyl-propanoyl]-10-dehydro-10-deacetγl- 14β-hydroxy-baccatιne III 1 , 14-carbonate . Therefore 12, referring to general formula 1, has R-, , R = -CO-O, OR 3 = B-OH, R^ = iso-But, R 2 ' = 5 H χl . _L R 1 = R 2 = H , R 7 , = t -butoxγ 11 R lr R 2 = CO-O, R 2 . = t-butoxy 12 R χ , R 2 = CO-O, R 2 , = C 5 H 11 The cytotoxicity data of the compounds 10 and 11 compared with those of paclitaxel are reported in the following Table. Table ICC Q S of compounds 15 . , 11 and paclitaxel on 6 human tumour cell lines. Ce l l l ine Exposition Paclitaxel U_ 11 time (h) 1210 (murine leukemia) 48 7.0 ± 3.0 0.6 ± 0.1 2.0 ± 0.1 A121 (human ovarian) 72 3.7 ± 0.3 0.8 ± 0.3 1.6 ± 0.2 A549 (human NSCLC ) 72 5.4 ± 0.5 1.9 + 0.3 2.1 ± 0.3 HT-29 (human colon) 72 6.0 ± 0.6 0.4 ± 0.1 0.6 ± 0.4 MCF7 (human breast) 72 4.3 ± 0.1 1.2 ± 0.2 0.8 ± 0.2 MCF7-ADR (resistant) 72 395 ± 8.7 13 ± 2.2 28 ± 6.2 Standard conditions : basal medium = RPMI 1640 + 20 mM HEPES + 2 M L- Glutamine . Compounds of formula 1 show surprising advantages compared with paclitaxel on cell lines resistant to other anti-tu oural substances, such as adriamycin or cis-platinum. The differences between paclitaxel and these products are even more evident in In vivo models, such as athymic nude mouse with human tumour implant. Moreover, it has been found that the compounds of the invention in which R' 2 is an alkyl or alkenyl group are surprisingly devoid of cardiotoxic activity, contrary to taxol and the known derivatives thereof, and therefore they can advantageously be used in the treatment of tumours in cardiopathic patients who cannot be treated with taxol and its known derivatives. The products object of the invention can be incorporated in suitable pharmaceutical formulations for the administration of the products both parenterally and orally. For the intravenous administration, mixtures of Chremoform L and ethanol, polysorbateε or liposomial preparations prepared with natural or synthetic phosphatidylchol e or mixtures of natural phosphoiip ds in the presence of cholesterol are mainly used. The following examples further illustrate the invention. Example 1 - Preparation of 10-deacety1-10- dehydrobaccat e III (2)- 10 g of 10-deacetylbaccatme III (2) - (isolated as described by G. Chauviere et al . , C.R. Acad. Sc . Ser . II 293. 591. 1981) are suspended 350 ml of methanol and added with 65 g of Cu(OAc) 2 . The suspension is stirred at room temperature for 120 h. The salts are filtered off and the solution is chromatographed on 100 g of silica gel eluting with a hexane/ethyl acetate 6:4 mixture. Upon crystallization from ligroin, 9.5 g of (2) are obtained, M + a m/z 542. Example 2 - Preparation of 10-deacetyl-10-dehydro-14β- hydroxybaccatine III 1 ,14-carbonate (2). 10 g of. 10-deacetyl-14β-hydroxybaccatme III (2) . isolated as described by G. Appendino et al. , J. Chem. Soc. Perkin Trans I, 2925. 1992, are dissolved in 50 ml of anhydrous pyridine and treated for one hour with 1.5 eq. of 5% phosgene in toluene at -lO'C. The reaction mixture is poured onto ice and the aqueous suspension is extracted with ethyl acetate, washing thoroughly the organic phase with diluted HC1. After drying over Na 2 S0 4 the organic phase is concentrated to dryness. 9 g of 1 ,14-carbonate are obtained, which are suspended in 350 ml of methanol and treated with 50 g of Cu(OAc) 2 under stirring at room temperature for 120 h. The suspension is filtered and the solution is evaporated to dryness. The residue is chromatographed on 100 g c: silica gel eluting with a hexane/ethyl acetate 1.1 mixture. 8 g of (2) are obtained, M + a m/z 584. Example 3 - Preparation of 13- [ ( 2R , 3S )-3-ter- butoxycarbonylamιno-2-hydroxy-3-ιsobutyl-propanoyl ] 10- deacetyl-10-dehydrobaccatme III (12) A solution of 300 mg (1.84 mmol! of 7-_ > - trιethylsιlyl-10-deacetyl-10-dehydrobac atιne III . obtained from compound (2) (Example 1) by silylatio :r. position 7 with the method described by J. Denis et al . , J. am. Chem. Soc. 100. 5917. 1988. in 60 ml of toluene is added with 500 mg of (4S, 5R )-N-( ter-butoxy- carbonyl )-2.2-dιmethyl-4-ιsobutyl-5-oxazolιdmeecar- boxylic acid, 240 mg of dicyclohexylcarbodiimide (1.2 eq. ) and 24 mg of N,N-dirnethylaminopyridine (0.2 eq). The reaction mixture is kept at 80 * C for 2 hours, then is filtered and washed with water; the organic phase is concentrated to dryness. The residue is treated with ethanoi containing 0.1% of H 2 S0 4 at 10 β C. The methanol solution is diluted with water and the product is extracted with ethyl acetate; the organic phase is concentrated to dryness and the residue is chro atographed on silica gel eluting with acetone/hexane 4:6. 350 mg of (12) are obtained. M + a m/_ 785. Example 4 - Preparation of 13-[ { 2R , 3S )-3-tert- butoxycarbonyl-amino-2-hydroxy-3-ιsobutyl-propanoyl ]10- deacetyl-10-dehγdro-14β-hydroxybaccatine III 1,14- carbonate (11) . 0.5 g of 7-O-triethylεilyl-10-deacetyl-10-dehydro- 14β-hydroxybaccatine III 1 , 14-carbonate , obtained from compound (2) (Example 2) by silylation in position " according to what reported by J. Denis et al . , J. Am. Soc. 100. 5917. 1988. are dissolved m 60 ml of toluene The solution is added with 800 mg of ( 4S , 5R )-N-( er - butoxycarbonyl )-2.2-dιmethyl-4-ιsobutyl-5-oxazolιdιnee- arboxylic acid, 400 mg of cyclohexylcarbodii ide and 43 mg of N, N-dιmethyiamιnopy idme . The reaction mixture s kept at 80 o C for two hours, then s filtered and washed with water and the organic phase is concentrated to dryness. The residue is treated with methanol containing 0.1% of H-S0 4 at 10°C. The methanol solution is diluted with water and the product is extracted with ethyl acetate; the organic phase is concentrated to dryness and the residue is chromatographed on silica gel, eluting with acetone/hexane 4:6. 580 mg of (11) are obtained, M + a m/z 827. Example 5 - Preparation of 10-deacetyl-10-dehydro-14β- hydroxybaccatine III (2). 10 g of 10-deacetγl-14β-hydroxybaccatine III (2) are suspended in 350 ml of methanol and added with 65 g of Cu(0Ac) 2 - The suspension is kept under stirring at room temperature for 120 h. The salts are filtered off, the solution is evaporated to dryness and the residue is chromatographed on 100 g of silica gel eluting with a hexane/ethyl acetate 6:4 mixture. Upon crystallization from ligroin, 9.3 g of (2) are obtained, M + a m/z 558. Example 6 - Preparation of 10-deacetyl-lO-dehydro- cephalomannine (1). 0.4 g of 10-deacetylcephalomannine (J. L. Laughlin et al. , J. Nat. Prod. 44. 312. 1981) are dissolved in 5 ml of MeOH and added with 600 mg of Cu(OAc)-. The reaction mixture is left under stirring for 54 hours at room temperature. After eiiminazione of the salts for filtration, the solution The salts are filtered off, the solution is evaporated to dryness and chromatographed on silica gel (10 g) using a hexane-acetate d'ethyl 1:1 mixture as eiuent. 220 mg of { !_ ) are obtained, M + a m,'_ 829. Example 7 - Preparation of 7-tπethyIsiiyl-14β- hydroxybaccatine III (4.) 500 mg of 7-trιethylsιlyl-10-deacetylbaccatιne III, prepared according to the method by J. Denis et al . , J. Am. Chem. Soc. 100. 5917. 1988 are dissolved in 15 ml of a ethyl acetate-methylene chloride 9:1 mixture. The solution is added with 10 g of Mn0 2 leaving the suspension at room temperature under stirring for 24 hours. After filtration, the solution is evaporated to dryness and the residue is chromatographed on silica gel (20 g) eluting with a hexane-ethyl acetate 8:2 mixture. 310 mg of 7-tπethylsilyl-10-deacetyl-13-dehydro-14β- hydroxybaccatine III are obtained (M + a m/z 672). 300 mg of this product are dissolved in 2 ml of pyridine. The solution is added with 910 mg of Ac 2 0. After 16 hours the reaction mixture is poured onto ice and then extracted with ethyl acetate. The organic phase is washed with diluted HCl and then with water to neutrality. After evaporation of the solvent, the residue is crystallized from ether (220 mg , M*a m/z 756). The solid is dissolved in 10 ml of anhydrous TKF ; the solution is added with 160 μl of sodium bιs(2- methoxy-ethoxy)aluminium hydride (65% solution) . After about 10 minutes, 10 ml of a NH.C1 saturated solution are added, extracting then with ethyl acetate. The organic phase is evaporated to dryness. The residue is purified on silica gel (15 g) eluting with a hexane- ethyl acetate 7:3 mixture. 80 mg of (4) are obtained, M * a 716. Example 8 - Preparation of ' 4S , 5R )-N-caproyl-2- ( 2.4- dimethcxyphenyl ι-4-ιsobutyl-5-oxazolιdmee carboxylir acid methyl ester. 5 g of N-caproyl-β-isobutyi-isosenne methyl ester are dissolved in 200 mi of a mixture cf anhydrous TH? and benzene and the solution is treated with 2 equivalents of 2.4-dιmethoxy ben∑aldehyde dimethyl acetale the presence of 120 mg of pyπdinium p- toluenesulfonate . The solution is refluxed for 1 hour. The solvent is distilled and the residue is chromatographed on silica gel eluting the main compound with a ethyl acetate/hexane 8:2 mixture. After removing under vacuum the solvent from the fractions containing the degidered isomer, the residue is crystallized from hexane/isopropyl ether. 2.5 g of a compound having m.p. 98°C are obtained. Example 9 - Preparation of ( 43 , 5R )-N-caproyl-2- ( 2.4- dimethoxyphenyl )-4-ιsobutyl-5-oxazoIιdmee carboxylic acid 2 g of the compound of Example 8 are suspended in 50 ml of a mixture of methanol aqueous {8:2) containing 5 g of K 2 CO-. The reaction mixture is left under stirring until complete dissolution of the isosenne derivative. The reaction mixture is carefully acidified to pH 5. with stirring, in the presence of ethyl acetate. The aqueous phase is discarded, whereas the organic one is dried over sodiurr. sulfate and concentrated to dryness at low temperature under vacuum. The residue is dissolved in a toluene/ ethylene chloride mixture and it is ready for the reaction with t e selected taxanes. Example 10 - Preparation of 13- [ 2R , 3£ >-3-caproylamιr. - 2-hydroxy-3-ιsobutyl-propanoyl ] - C-dehydro-lO-deacetyl- 14β-hydroxy-baccatme III 1 , 14-carbonate ( ) 5 g of 1 , 14-carbonate-7-TES-10-dehydro-ba catme III are dissolved in 100 ml cf a mixture of toluene and methylene chloride a 8.2 ratio, together with 6 g of ( 4S , 5R)-N-caproyl-2-( 2.4-dιmethoxyphenγl )-4-ιsobutyl-5- oxazolidmee carboxylic acid. The reaction mixture is added with 500 mg of 4-dimethylamιnopyridine and 2.5 g of 1.3-dicyclohexylcarbodiιmide, then heated for 2 hours under mild reflux until the reagents disappear. The compounds insoluble in the medium are filtered off and the solution is concentrated to dryness. The residue is taken up with- 50 ml of methanol/HCl (0.01%) and the reaction mixture is left at room temperature for 1 hour. The solution is alkalinized to pH 5 and concentrated to dryness in the vacuum. The residue is chromatographed on a silica gel column eluting with a methylene chloride/methanol 98:2 mixture. Upon crystallization from ethyl acetate, 1.2 g of compound (12) are obtained. Example 11 - Solution of compound (12) for the parenteral administration Compound 10 2 mg Cre ophor EL 175 mg Absolute alcohol q.s. to 0.4 ml . Example 12 - Solution of compound (11) for the parenteral administration Compound 11 2 mg Cremophor EL 175 mς Absolute alcohol q.s. to 0.4 ml. Example 13 - Tablets containing compound ; ' 10 ) Compound 10 10 mg Cross-linked sodium carboxymethyl cellulose 15 mg Lactose (spray dried) 41.5 mg Microcrystall e cellulose 40 mg Colloidal silicon dioxide 0.5 mg Magnesium stearate 1 mg . Example 14 - Tablets containing compound (H) Compound 11 10 mg Cross-linked sodium carboxymethyl cellulose 15 mg Lactose (spray dried) 41.5 mg Microcrystalline cellulose 40 mg Colloidal silicon dioxide 0.5 mg Magnesium stearate 1 mg. Example 15 - Capsules containing compound ( 10 ) Compound 10 10 mg Lactose (spray dried) 30 mg Microcystalline cellulose 48.5 mg Pre-gelatinized starch 10 mg Magnesium stearate 1 mg Colloidal silicon dioxide 0.5 mg. Example 16 - Capsules containing compound (11) Compound 11 10 mg Lactose (spray dried) 30 mg Microcrystalline cellulose 48.5 mg Pre-gelatinized starch 10 mg Magnesium stearate 1 mg Colloidal silicon dioxide 0.5 mg .

Claims: _C_LΔ____S 1. 10-Deacetγlbaccatine III and 10-deacetyl-14β- hydroxybaccatine III derivatives of formula (1) wherein R. and ! are hydrogen atoms , '1 is a hydrogen atom and R 2 is an hydroxyl or an acetyloxy group, or OR. and R- > together form a cyclic carbonate group of formula: A 1 0 0 0 R- , which can be α- o β-oriented, is an hydrogen atom cr an aikylsilyl group, preferably triethylsilyi (TΞS); R 4 is hydrogen, or the residue CH- CH. / C = C \ CH- c=o I or an isoserine residue of formula Δ: wherein R^ ' is a straight or branched alkyl or alkenyl group, containing one to five carbon atoms, or an aryl 0 residue; R 2 ' is a straight or branched alkyl or alkenyl group, containing one to five carbon atoms, or an aryl residue, or a tert-butoxy group. 2. A compound according to claim 1, selected from the group consisting: 5 - 10-deacetyl-lO-dehydrobaccatine III; 10-deacetyl-10-dehydro-14β-hydroxybaccatine III; 10-deacetyl-lO-dehydrocephalomannine; 10-deacetyl-10-dehydro-14β-hydroxybaccatme III 1 , 14-carbonate; 20 - 13-[ ( 2R, 3S )-3-tert-butoxycarbonylamιno-2-hydroxy-3- lsobutyl-propanoyl]10-deacetyl-lO-dehydrobaccatme 13- [ ( 2R , 3S )-3-tert-butoxycarbonylamιno-2-hydroxy-3- ιsobutyl-propanoyl]10-deacetyi-10-dehyd o-14β- ? c hydroxybaccatine III 1 , 14-carbonate ; 13- [ ( 2R , 33 ) -3-caproyiammo-2-hydroxy-3-ιsobutyi- propanoyl ] -10-dehydro-10-deacetyl-14β-hydroxy- baccatme III , 14-carbonate . 3. A process for the preparation of 10- 30 deacetylbaccatme III and 10-deacetyl-14p- hydroxybaccatine III derivatives according to claim 1, characterized in that syntons of formula £ wherein R^ , R 2 , R 3 and R 4 have the meanings defined above , a) when R 2 = H or OH, or OR 1 and R 2 are together a carbonate group, and R 4 H, are oxidized position 10 by treatment with copper(II) salts; and optionally deprotected position 7; b) when R- = R l 4. = H, are oxidized in position 10 by treatment with copper(II) salts and optionally (previous silylation in 7 when R- = H) esterified IT. position 13 with acylating agents which allow tc introduce the group R 4 i- H A process for the preparation of syntons of formula £ according to claim 3, wherein R = OH and R^ H, characterized n that a 7-tπalkylsιlyl-10- deacetylbaccatme III (or the 7-epιmer) thereof is subjected to a selective oxidation in position 13 and a simoultaneous β-hydroxylation in position 14 by treatment with manganese dioxide, the resulting 7- trialkylsilyl-10-deacetyl-13-dehydro-14β-hydroxybac- catine III (or the 7-epimer thereof) is acetylated in 10 and in 14 and the 7-trialkylsilyl-13-dehydro-14β- hydroxy-14-acetylbaccatme III (or the 7-epιmer thereof) is subjected to a reduction with hydrides, to obtain the corresponding 13β-hydroxyderivative . 5. Syntons of formula £ according to claim 3. 6. Intermediates of formula 9b : wherein R_-.' has the meaning described above. 7. Pharmaceutical compositions containing as the active ingredient one or more compounds of formula 1 according to claim 1, with R 3 = H. 8. Pharmaceutical compositions according to claim 7, which can be administered parenterally or orally. 9. Compounds of claims 1-2 as anti-tumoural agents. 10. The use of taxanes of claim 1, wherein R'~ is an alkyl or alkenyl group, for the preparation of medicaments useful for the treatment of tumours m cardiopathic patients.

Inventors: BOMBARDELLI EZIO, DE BELLIS PAOLO, GABETTA BRUNO, BOMBARDELLI, EZIO, DE BELLIS, PAOLO, GABETTA, BRUNO
Applicants: BELLIS PAOLO DE, BOMBARDELLI EZIO, GABETTA BRUNO, INDENA SPA, BOMBARDELLI, EZIO, DE BELLIS, PAOLO, GABETTA, BRUNO, INDENA S.P.A.
Application year: 1996
Main classification: C07D305
IPC codes: A61K31, A61P35, C07D263, C07D305, C07D493, C07F7