ALDOSE REDUCTASE INHIBITORS AND PHARMACEUTICAL COMPOSITIONS

Abstract: Medicaments for treating diabetic complications contain a compound of formula (A), wherein at least one Y or one Y' is OH, and the remainder are selected from H, Hal, OH, OMe and NO2; X is O, S, keto or a direct link.

Description: ALDOSE REDUCTASE INHIBITORS AND PHARMACEUTICAL COMPOSITIONS The present invention provides the use, as Aidose Reductase Inhibitors (ARIs), for the manufacture of a medicament for the treatment and/or prevention of diabetic complications, of a compound represented by the following general formula (A) (A) wherein at least one of Y or Y' is OH and the others Y and Y' are independently selected from the group consisting of hydrogen, halogen, hydroxy, methoxy, and nitro; X is selected from the group consisting of O, S, and ketone, or both substituted benzyl groups are directly linked as a substituted biphenyl compound. In addition, these aidose reductase inhibitors can form salts with a pharmaceutically acceptable cation, all such salts are within the scope of this invention. In addition, some of the compounds of this invention can form hydrates or solvates and they are also within the scope of the invention. The present invention also provides six novel synthetic compounds having the following formula: Description FIELD OF THE INVENTION The present invention is directed to novel pharmaceutical compositions, which possess Aidose Reductase inhibitory activity, and are useful for the treatment and/or prevention of diabetic complications; the present invention is also directed to novel compounds which possess Aidose Reductase inhibitory activity. BACKGROUND OF THE INVENTION Diabetic neuropathy, diabetic cataract and retinopathy, diabetic corneal keratopathy, diabetic nephropathy, diabetic dermopathy and other diabetic microangiopathy have been known as chronic diseases as a result of diabetes which are difficult to treat. Accumulation of intracellular sorbitol, the reduced product of glucose, catalyzed by Aidose Reductase (AR) (EC 1.1.1.21), is thought to be the cause of the development of these diabetic complications 1 "3 . Accordingly, agents for inhibiting this Aidose Reductase have been thought to be effective for the therapy and the prevention of diabetic complications and have been studied 4"6 . However, despite numerous attempts over 16 years, the results of aidose reductase inhibitor (ARI) trials, with the known aidose reductase inhibitors, for the treatment of diabetic complications have not proven efficacy 7 ; also, despite the apparent structural diversity of aidose reductase inhibitors (ARIs), certain common electronic and steric features have become apparent through computer modeling, molecular orbital calculations, and known structure-activity relationships, and from competition studies using different aidose reductase inhibitors (ARIs) also suggest that ARIs interact at a single common site on the enzyme 8"10 . Under these circumstances, the inventors have conducted a study looking for new compounds structurally different of the known aidose reductase inhibitors (ARIs). As a result, the present invention provides a novel class of aidose reductase inhibitors (ARIs) having the general formula (A). These compounds exhibit an excellent inhibitory activity to Aidose Reductase. Compounds having the general formula (A) have long been known as antiseptic and antimicrobial agents 11 , as cardiac agents 12 , as antiinflammatory agents 13 , and as inhibitors of the enzymes: protein kinase C (PKC), protein tyrosine kinase (PTK), inosine monophosphate dehydrogenase (LMPDH), guanosine monophosphate synthetase (GMPS), and 15-lipoxygenase (15-LO) 14 Compounds having the general formula (A) have long been reported from marine sources 14-18 SUMMARY OF THE INVENTION The present invention provides the use, as inhibitors of Aidose Reductase, for the manufacture of a medicament for the treatment and prevention of diabetic complications, of a compound represented by the following general formula (A) (A) wherein at least one of Y or Y' is OH and the other Y and Y' are independently selected from the group consisting of hydrogen, halogen, hydroxy, methoxy, and nitro; X is selected from the group consisting of O, S, and ketone. or both subtituted benzyl groups are directly linked as a subtituted biphenyl compound. In addition, these aidose reductase inhibitors can form salts with a pharmaceutically acceptable cation, all such salts are within the scope of this invention. In addition, some of the compounds of this invention can form hydrates or solvates and they are also within the scope of the invention. The present invention further provides pharmaceutical compositions which contain as active ingredient a compound with the formula (A). Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable formulation of oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally. The correct dosage of a pharmaceutical composition comprising compounds with the formula (A), will vary according to the pharmaceutical formulation, the mode of application, and the particular situs, host and diabetic complication being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose. The present invention also provides six novel synthetic compounds having the following formula: A-I A-II as well as a process for their preparation. As hereunder, several examples of the methods of obtaining the compounds of the present invention are given. Example 1) 3,3',4,4',5,5'-hexabromo-2,2'-dihydroxy-oxydiphenyl (A-I) (general formula A, where X=O, Y 2 = Y 2 =OH, Y 6 =Y 6 =H, and Y 3 = Y 3 =Y 4 =Y 4 =Y 5 =Y 5 =Br). Was obtained as it is showed in Scheme 1. l) MeONa, benzene BBr, 2) σ-bromoanisol, C1CH 2 CH 2 C1 guaiacol CuCl, pyridine A.I Scheme 1 2,2 '-Oxydiphenol dimethyl ether (1) was synthesized from guaiacol and σ-bromoanisol as was previously described 19 . The dimethyl ether (1) was cleaved to 2,2 '-oxydiphenol (2) by treatment with boron tribromide in ethylene chloride as was previously described 20 . To a solution of 2.2'~oxydiphenol (2) (0.2 g) in acetic acid (6 ml) bromine (2 ml, 40 eq) was added dropwise and with stirring. After the addition, the reaction mixture was stirred at 90-95°C for 15h. The mixture was evaporated and the residue was chromatographed on silica gel (Hex-AcOEt 7/3) to afford 3,3',4,4',5,5'-hexabromo- 2,2'-dihydroxy-oxydiphenyl (A-I) (0.52 g, 78%), mp: 188-190°C. 13 C-NMR (CD 3 COCD 3 ), δ (ppm): 1 14.23 (s), 1 15.60 (s), 122.54 (d), 123.31 (s), 144.34 (s), 147.52 (s); 1H-NMR (CDC1 3 ), δ (ppm): 7.19 (s, 2H). Example 2) 3,3',4',5,5'-pentabromo-2,2\4-trihydroxy-oxydiphenyl (A-II) (general formula A, where X=O, Y 2 =Y 2' =Y =OH, Y*=Y° =H, and Y 3 =Y 3' =Y 4' =Y 5 =Y 5' =Br). Was obtained as it is showed in Scheme 2. 4-bromoresorcinol Scheme 2 To a solution of 4-bromoresorcinol (0.8 g) in acetone (5 ml), at room temperature and under argon, K 2 CO 3 (3.5 g, 6 eq) was added. After stirring for 30 min., methyl iodide (1.58 ml, 6 eq) was added. The reaction mixture was stirred overnight and then the solvent was evaporated off. The residue was poured into water, extracted with methylene chloride and dried over Na 2 SO 4 . The evaporation of the combined extracts gave a residue which was chromatographed on silica gel (Hex-AcOEt 9/1) to give (3) (0.836 g, 91%), 13 C-NMR (CDC1 3 ), δ (ppm): 55.45 (q), 56.01 (q), 99.82 (d), 102.27 (s), 105.77 (d), 133.02 (d), 156.40 (s), 160.12 (s); Η-NMR (CD 3 C1), δ (ppm): 3.78 (s, 3H), 3.85 (s, 3H), 6.38 (dd, IH, J= 8.4, 2.7 Hz), 6.47 (d, IH, J=2.7 Hz), 7.39 (d, IH, J= 8.4 Hz). A solution of guaiacol (0.4 g), benzene (3 ml) and sodium methoxide (0.26 g, 1.5 eq) was stirred at room temperature under argon, for 45 min. Then, the solvent was evaporated off. The residue in pyridine (4 ml) was treated with (3) (1.2 g, 1.7 eq) and copper (I) chloride (0.32 g, 1.0 eq). The reaction mixture was heated at 130°C for 7h. The cooled solution was poured into 5M hydrochloric acid, extracted with diethyl ether and dried over Na 2 SO 4 . The extract was concentrated and the residue was chromatographed on silica gel (CH 2 C1 2 -Hex 8/2) to give (4) (0.12 g, 14%). 13 C-NMR (CDCI3), δ (ppm): 55.42 (q), 55.73 (q), 55.81 (q), 100.37 (d), 103.69 (d), 112.09 (d), 116.29 (d), 120.53 (d), 120.86 (d), 122.53 (d), 138.59 (s), 147.32 (s), 149.53 (s), 151.80 (s), 156.74 (s); 1H-NMR (CDC1 3 ), δ (ppm): 3.78 (s, 6H), 3.89 (s, 3H), 6.40 (dd, IH, J= 8.7, 3 Hz), 6.56 (d, IH, J= 3 Hz), 6.68 (dd, IH, J= 7.8, 2.4 Hz), 6.80 (td, IH, J= 7.2, 2.4 Hz), 6.88 (d, IH, J= 8.7 Hz), 6.96 (m, 2H). Cleavage of (4) by the same procedure as for (1) gave (5) (97%). mp: 164-160°C. 13 C- NMR (CD 3 COCD 3 ), δ (ppm): 104.71 (d), 107.31 (d), 117.02 (d), 117.34 (d), 120.46 (d), 122.03 (d), 123.89 (d), 137.22 (s), 146.91 (s), 148.12 (s), 150.27 (s), 155.54 (s); 1H- NMR (CD 3 COCD 3 ), δ (ppm): 6.35 (dd, IH, J= 8.7, 2.7 Hz), 6.54 (d, IH, J= 2.7 Hz), 6.74 (m, 2H), 6.81 (d, IH, J= 8.7 Hz), 6.91 (m, 2H). To a solution of (5) (16 mg) in carbon tetrachloride (2 ml) was added bromine (1 ml). The mixture was stirred at room temperature for 24h and then evaporated in vacuo. The residue was chromatographed on silica gel (CH 2 Cl 2 -AcOEt 95/5) to give 3, 3', 4', 5,5'- pentabromo-2,2',4-trihydroxy-oxydiphenyl (A-EQ (36 mg, 80%). mp: 207-209°C; I3 C- NMR (CD 3 COCD 3 ), δ (ppm): 99.57 (s), 101.64 (s), 1 13.84 (s), 1 14.80 (s), 1 19.71 (d), 121.39 (s), 123.70 (d), 136.66 (s), 146.44 (s), 146.67 (s), 147.71 (s), 150 (s); Η-NMR (CD 3 COCD 3 ), δ (ppm): 7.13 (s, IH), 7.35 (s, IH). Example 3) 3,3',4,4',5,5'-Hexachloro-2,2'-dihydroxy-oxydiphenyl (A-m) (general formula A, where X=O, Y 2 =Y 2' =OH, Y 6 =Y 6 ' =H, and Y 3 =Y 3 =Y =Y 4 =Y 5 =Y 5 =C1). Was obtained as it is showed in Scheme 3. Scheme3 To a solution of (1) (60 mg), in SO 2 Cl 2 (1 ml) was added AJCI3 (19 mg, 0.5 eq). The reaction mixture was stirred at 95°C for 5h and then evaporated off. The crude is poured in water, extracted with AcOEt and the extract dried over Na 2 SO . Evaporation of the solvent gave a crude which was chromatographed on silica gel (Hex-AcOEt 95/5) to afford (6) (10 mg, 9%). 1H-NMR (CDC1 3 ), δ (ppm): 3.90 (s, 6H), 6.94 (s, 2H). The dimethyl ether (6) was cleaved by treatment with boron tribromide in ethylene chloride by the same procedure as for (1) to afford 3,3',4,4',5,5'-hexachloro-2,2'- dihydroxy-oxydiphenyl (A-ITJ) (70%). 13 C-NMR (CD3COCD3), δ (ppm): 1 19.26 (d), 122.12 (s), 123.08 (s), 127.52 (2), 144.43 (s), 146.79 (s); Η-NMR (CD 3 COCD 3 ), δ (ppm): 7.28 (s, 2H). Example 4) 3,3',5,5'-tetrabromo-2,2'-dihydroxybenzophenone (A-IV) (general formula A where X=CO, Y 2 =Y 2 =OH, Y 4 =Y 4 =Y 6 =Y 6 =H, and Y 3 =Y 3 =Y 5 =Y 5 =Br). Bromination of 2,2'-dihydroxybenzophenone by the same procedure as for (2), followed by chromatography of the crude on silica gel (Hex-Diethyl ether 8/2) gave 3,3',5,5'-tetrabromo-2,2'-dihydroxybenzophenone (A-IV) (96%). mp: 179.180°C. 13 C- NM (CD 3 COCD 3 ), δ (ppm): 1 1 1.76 (s), 113.24 (s), 125.40 (s), 133.60 (d), 140.34 (d), 155.12 (s), 198 93 (s), 1H-NMR (CDC1 3 ), δ (ppm) 7 54 (d, 2R J= 2 4 Hz), 7 92 (d, 2H, J= 2 4 Hz) Example 5) 2,2',3,3',5,5',6,6'-Octabromo-4,4 , -biphenol (A-V) (general formula A, where X-nothing, Y 4 =Y 4' =OH, and Y 2 =Y 2 =Y 3 =Y 3 =Y 5 =Y 5 =Y 6 =Y 6' =Br). 4,4'-Biphenol was treated with Mel by the same procedure as for o-bromoresorcinol to give 4,4'-dimethoxybiphenyl (98%) 13 C-NMR (CDC1 3 ), δ (ppm). 55.32 (q), 114 13 (d), 127.70 (d), 133 44 (s), 158 65 (s), Η-NMR (CDCI3), δ (ppm) 3 85 (s, 6H), 6.96 (d, 4H, J= 8 4 Hz), 7 49 (d, 4H, J= 8 4 Hz) To a solution of 4,4'-dimethoxybiphenyl (30 mg) in bromine (1 ml) was added iron powder (56 mg) The suspension was stirred at 80°C for 3h The cooled solution was poured into water, extracted with chloroform and dried with Na SO 4 . Evaporation of the organic layers gave a residue which was chromatographed on silica gel (Hex-AcOEt 7/3) to afford 2,2',3,3',5,5',6,6'-Octabromo-4,4'-biphenol (A-V) (90 mg, 78%). mp: 282°C, 13 C-NMR (CD 3 COCD 3 ), δ (ppm) 1 14 66 (s), 127 37 (s), 138 83 (s), 153 94 (s), EI m/z 817 (15%). Example 6) 2,2%3,3',5,5',6,6'-Octachloro-4,4'-biphenoI (A-VT) (general formula A, where X=nothing, Y 4 =Y 4' =OH, and y 2 =γ 2' =γ 3 =γ 3' =γ 5 =Y < =γ 6 =γ 6 =C1). To a solution of SO 2 Cl 2 (3 ml) and AJC1 3 (0 036 g, 0 5 eq), under reflux, was added dropwise, a mixture of 4,4'-biphenol (100 mg), S 2 C1 2 (95 mg, 1 3 eq) and SO 2 Cl 2 (5 ml). After the addition, the reaction was stirred under reflux for 7h The cooled solution was evaporated off to give a crude which was poured into AcOEt, washed with brine and dried over Na 2 SO 4 Evaporation of the organic layer gave a crude which was chromatographed on silica gel to afford 2,2',3,3',5,5'.6,6'-octachloro-4,4'-biphenol (A- VT) ( 40 mg, 16%) mp 94-96 °C. 13 C-NMR (CD3COCD3), δ (ppm) 92 69 (s), 132 22 (s), 146 18 (s), 168 48 (s) Example 7) 2,2',3,3',5,5',6,6'-Octafluoro-4,4'-biphenoI hydrate (A-VTT) (general formula A where X=nothing, Y 4 =Y ' =OH, and Y 2 =Y 2 =Y 3 =Y 3 =Y 5 =Y 5 =Y 6 =Y i =F). A-VH This compound is a commercial product (AJdrich Chemical Co., ref.37,876-3). PHARMACOLOGICAL ACTION OF THE COMPOUNDS OF THE PRESENT INVENTION. 1) Action of inhibiting Human Recombinant Aidose Reductase. Human recombinant aidose reductase was obtained and purified as previously described 21 with slight modifications. Briefly, Sf9 insect cells (Spodoptera frugiperda, from Pharmingen) were cultured in Grace's medium (Gibco) at 27°C. Then, cultures were infected with the purified recombinant baculovirus AcAR that was kindly provided by Dr. C. Nishimura (National Children's Medical Research Center, Tokyo, Japan). The enzyme released into the culture medium was purified by affinity chromatography (Matrex Gel Orange Amicon). This Aidose Reductase was kept at - 20°C in 50 mM sodium phosphate, pH 7.0, 5mM dithiotreitol and 50% glycerol. Recombinant Aidose Reductase activity was determined according to the method previously described 21 . The assay was carried out in a 96-well microtiter plate, at 37°C in 100 mM sodium phosphate buffer, pH 6.2, 400 mM (NH^SO^ 0.1 mM NADPH and 5 mU/ml recombinant aidose reductase (1 mU of activity was defined as a change in absorbance of 0.012 units per minute). The reaction was initiated by addition of 10 mM glyceraldehyde and the enzymatic activity measured as the NADPH disappearance at 340 nm in a plate reader (MR-5000, Dynatech). Compounds were dissolved in DMSO (1% final concentration). 2) Action of inhibiting the intracellular accumulation of sorbitol in rabbit cornea cells. For this assay, cells from rabbit cornea (ATCC CCL 60) were used as previously described 23 . In summary, 10x10° cells were incubated in 2.5 ml of Minimum Essential Medium (JRH Biosciences), 0.5% foetal calf serum and 50 mM glucose for 16 h at 37°C in presence of 5% CO 2 . Compounds under study were added in DMSO whose final concentration was 1%. The sorbitol accumulated in the cells was extracted by lysis with 8%> perchloric acid and neutralised with 2N KOH 24 . Sorbitol quantitation was carried out using a colorimetric test (D-Sorbitol/Xylitol, Boehringer Mannheim). Examples of the activity results are given in Table 1 Table 1 REFERENCES The following references provide background information related to the present invention 1) Kador, P F Med Res. Rev 1988, 8, 325-352 2) Tanimoto, T , Nishimura, C Peripheral Nerve 1993, 4, 149-158 3) Dvornik, D In Aidose Reductase Inhibition. An Approach to the Prevention of Diabetic Complications, Porte, D Ed , McGraw-Hill New York, 1987 4) Kotani, T , Nagaki, Y , Ishii, A , Konishi, Y , Yago, H , Suehiro, S , Okukado, N , Okamoto, K J. Med. Chem 1997, 40, 684-694, and references therein 5) Kador, P F , Kinoshita, J H , Sharpiess, N E. J. Med. Chem 1985, 28, 841-849 6) Kador, P F , Robinson, W G , Kinoshita, J H Annu. Rev. Pharmacol. Toxicol 1985, 25, 691-714 7) Pfeifer, M A , Schumer, M P , Gelber, D A Diabetes 1997, 46 (Suppl 2), S82-S89 8) Lee, Y S , Pearstein, R , Kados, P F J. MedChe 1994, 37, 787-792. 9) Kador, P F , Sharpiess, N E Mol. Pharmacol. 1983, 24, 521-531 10) Kador, P F , Nakayama, T , Sato, S Smar, M , Miller, D D Enzymology and Mol. Biol. ofCarb. Metabol. 2 1989, 237-250 1 l)Higa, T , Fujiyama, T , Scheuer, P j Comp. Bioche . Physiol 1980, 65B, 525 12)Endo, M , Nakagawa, M , Hamamoto, Y , Ishihama M Rwre &Appl. Chem 1986, 58, 387 13)Kunιyoshi, M , Yamada, K , Higa, T Expenentia 1985, 41, 523 14)Fu, X , Schmitz, F J , Govindan, M , Abbas, S A J. Nat. Prod 1995, 58, 1384- 1391 15) Sharma, G M , Vig, B Tetrahedron Lett 1972, 17, 1715-1718 16) Norton, R S , Croft, K D , Wells, R j Tetrahedron, 1981, 37, 2341-2349 17) Carte, B , Faulkner, D j Tetrahedron, 1981, 37, 2335-2339 18)Fu, X , Schmitz, F j J.Nat.Prod 1996, 59, 1 102-1 103 19)Kιme, D E , Norymberski, J K J Chem. Soc, Perkin Trans I 1977, 1048 20) Francesconι, K A , Ghisalberti, E L Aust. J. Chem 1985, 38, 1271-7 21) Nishimura, C , Yamaoka, T , Mizutani, M , Yamashita, K , Akera, T , Tanimoto, T Biochim Biophys Ada 1991, 7075, 171-178 22) Nishimura, C , Matsuura, Y , Kokai, Y , Akera, T , Caφer, D , Morjana, N , Lyons, C , Flynn, T G J. Biol. Chem 1990, 265, 9788-9792 23 ) Rink, H , Baumstark-Khan, C In "Manual of Oculotoxicity" Eds O Hockwin, K. Green , L F Rubin, Gustav Fischer Verlag, Stuttgart, Germany, 1992, pp 389-401. 24) Yaginuma, S , Asahi, A , Takada, M , Hayashi, M . Tsujino M & Mizuno, K. In: "Novel Microbial Products for Medicine and Agriculture", Eds A L Demain, G.A. Somkuti, J C Hunter-Cevera, H W Rossmore, Society for Industrial Microbiology, 1989, pp 127-133

Claims: CLAIMS 1) The use for the manufacture of a medicament for the treatment and/or prevention of diabetic complications of a compound represented by the following general formula (A) (A) wherein at least one of Y or Y' is OH and the others Y and Y' are independently selected from the group consisting of hydrogen, halogen, hydroxy, methoxy, and nitro; X is selected from the group consisting of O, S, and ketone, or both subtituted benzyl groups are directly linked as a subtituted biphenyl compound. In addition, these aidose reductase inhibitors can form salts with a pharmaceutically acceptable cation, all such salts are within the scope of this invention. In addition, some of the compounds of this invention can form hydrates or solvates and they are also within the scope of the invention. 2) The use of a compound represented by the general formula (A) for the manufacture of a medicament for the treatment and/or prevention of diabetic neuropathy, diabetic cataract and retinopathy, diabetic corneal keratopathy, diabetic nephropathy, diabetic dermopathy and other diabetic microangiopathies. 3) A compound according to the general formula (A) where X=O, Y 2 =Y 2 =OH, Y°=Y* =H, and Y 3 =Y 3 =Y =Y 4 =Y 5 =Y 5' =Br. 4) A compound according to the general formula (A) where X=O, Y 2 =Y 2 =Y 4 =OH, Y*=Y* =H. and Y 3 =Y 3 =Y 4 =Y 5 =Y 5 =Br. 5) A compound according to the general 1 7 formula (A), where X=O, Y 2 =Y V =OH, Y^Y 6 =H, and Y 3 =Y 3' =Y 4 =Y 4 =Y 5 =Y 5 =C1). 6) A compound according to the general formula (A), where X=CO, Y 2 =Y 2 =OH, Y =Y 4' =Y 6 =Y 6' =H, and Y 3 =Y 3' =Y 5 =Y 5' =Br. 7) A compound according to the general formula (A), where X=nothing, Y 4 =N* =OH, and Y 2 =Y ' =Y 3 =Y 3' =Y s =Y 3' =Y 6 =Y^ ' =Br. 8) A compound according to the general formula (A), where X=nothing, Y 4 =Y 4 =OH, and Y 2 =Y " =Y 3 =Y 3' =Y 5 =Y 5' =Y 6 =Y° ' =C1.

Inventors: DE LA FUENTE BLANCO JESUS A, GARCIA DE QUESADA FORT TERESA, MARTIN LOPEZ MA JESUS, REYMUNDO CUESTA ISABEL, DE LA FUENTE BLANCO, JESUS A., GARCIA DE QUESADA FORT, TERESA, MARTIN LOPEZ, MA JESUS, REYMUNDO CUESTA, ISABEL
Applicants: FUENTE BLANCO JESUS A DE, GARCIA DE QUESADA FORT TERESA, MARTIN LOPEZ MA JESUS, O N C E ORGANIZACION NACIONAL, REYMUNDO CUESTA ISABEL, RUFFLES GRAHAM KEITH, DE LA FUENTE BLANCO, JESUS A., GARCIA DE QUESADA FORT, TERESA, MARTIN LOPEZ, MA JESUS, O.N.C.E. - (ORGANIZACION NACIONAL DE CIEGOS), REYMUNDO CUESTA, ISABEL, RUFFLES, GRAHAM, KEITH
Application year: 1999
Main classification: C07C43
IPC codes: A61K31, A61P3, A61P9, A61P17, A61P27, A61P43, C07C39, C07C43, C07C45, C07C49