SALTS OF COMPOUNDS HAVING A BENZIMIDAZOLIC STRUCTURE, USES AND PROCESS FOR THE PREPARATION THEREOF

Abstract

The present invention relates to salts of anthelmintic compounds with a benzimidazolic structure, such as albendazole (ABZ), fenbendazole (FBZ), triclabendazole (TRBZ), or sulphoxides thereof, flubendazole (FLZ), mebendazole (MBZ), oxibendazole (OBZ), thiabendazole (TBZ), cambendazole (CBZ), parbendazole (PBZ), nocodazole (NCZ), the use thereof and a process for preparation thereof.

Claims

1) Salts of benzimidazolic compounds with metals selected in the group consisting of lithium, sodium, potassium, magnesium and calcium, said benzimidazolic compounds being selected in the group consisting of albendazole, fenbendazole, triclabendazole, flubendazole, mebendazole, oxibendazole, thiabendazole, cambendazole, parbendazole, nocodazole, albendazole sulphoxide, fenbendazole sulphoxide and triclabendazole sulphoxide, said sulphoxides being in racemic form or in the form of the R- or S-enantiometer.

2) Pharmaceutical composition comprising or consisting of at least one salt as defined in claim 1, as an active ingredient, together with one or more excipients and/or adjuvants.

3) Pharmaceutical composition according to claim 2, further comprising at least one drug selected of the group consisting in anthelmintics, antitumourals and proton pump inhibitors.

4) Pharmaceutical composition according to claim 3, wherein said at least one anthelmintic drug is selected in the group consisting of abamectin, praziquantel, diethylcarbamazine, niclosamide, ivermectin, suramin, pirantel, levamisole, octadepsipeptides such as emodepside, aminoacetonitrile derivatives such as monepantel, and spiroindoles such as derquantel.

5) Pharmaceutical composition according to claim 3, wherein said at least one antitumour drug is selected in the group consisting of taxanes such as paclitaxel, docetaxel and cabazitaxel, camptothecins such as irinotecan and topotecan, Vinca alkaloids, platinum complexes such as oxaliplatin, cisplatin and carboplatin, temozolomide, gemcitabine, capecitabine and bevacizumab.

6) Pharmaceutical composition according to claim 3, wherein said at least one proton pump inhibitor drug is selected in the group consisting of omeprazole, lansoprazole, rabeprazole, and pantoprazole, in a racemic or enantiomerically pure form, or salts thereof.

7) Salt as defined in claim 1, for use as a medication.

8) Salt as defined in claim 1, for use in the treatment of helminthiases.

9) Salt as defined in the claim 1, for use in the treatment of tumours.

10) Salt as defined in claim 9, wherein said tumour is selected in the group consisting of ovarian carcinoma, adrenocortical carcinoma, lung carcinoma, pancreatic tumours, breast tumours, colorectal cancer, kidney tumours, melanoma, glioblastoma multiforme, osteosarcoma, leukaemia and lymphomas.

11) Combination of at least one salt as defined in the claim 1 with at least one drug anthelmintic, for separate or sequential use in the treatment of helminthiases.

12) Combination according to claim 11, for use according to claim 11, wherein said at least one further anthelmintic drug is selected in the group consisting of abamectin, praziquantel, diethylcarbamazine, niclosamide, ivermectin, suramin, pirantel, levamisole, octadepsipeptides such as emodepside, aminoacetonitrile derivatives such as monepantel, and spiroindoles such as derquantel.

13) Combination of at least one salt as defined in claim 1 with at least one antitumour drug and/or proton pump inhibitor, for separate or sequential use in the treatment of tumours.

14) Combination according to claim 13, for use according to claim 13, wherein said at least one further antitumour drug is selected in the group consisting of taxanes such as paclitaxel, docetaxel and cabazitaxel, camptothecins such as, for example, irinotecan and topotecan, Vinca alkaloids, platinum complexes such as oxaliplatin, cisplatin and carboplatin, temozolomide, gemcitabin, capecitabine and bevacizumab.

15) Combination according to claim 13, wherein said tumour is selected in the group consisting of ovarian carcinoma, adrenocortical carcinoma, lung carcinoma, pancreatic tumours, breast tumours, colorectal cancer, kidney tumours, melanoma, glioblastoma multiforme, osteosarcoma, leukaemia and lymphomas.

16) Combination according to claim 13, for use according to claim 13, wherein said at least one proton pump inhibitor is selected in the group consisting of omeprazole, lansoprazole, rabeprazole, and pantoprazole, in a racemic or enantiomerically pure form, or salts thereof.

17) Process for the preparation of the salts as defined in claim 1, said process comprising or consisting of the following steps: a) mixing a benzimidazolic compound selected in the group consisting in albendazole, fenbendazole, triclabendazole, flubendazole, mebendazole, oxibendazole, thiabendazole, cambendazole, parbendazole, nocodazole, albendazole sulphoxide, fenbendazole sulphoxide or triclabendazole sulphoxide, said sulphoxides being in racemic form or in the form of an R- or S-enantiometer, with a base capable of releasing a cation selected in the group consisting in lithium, sodium, potassium, magnesium or calcium in a suitable solvent; b) allowing to react until the formation of the salt.

18) Process according to claim 17, wherein said suitable solvent is selected in the group consisting in ethanol, methanol, 2-propanol, 1-propanol, pure or in hydroalcoholic mixtures.

19) Process according to claim 17, wherein step b) is conducted at a temperature ranging from room temperature to the reflux temperature.

20) Process according to claim 17, wherein the base capable of releasing the cation is selected in the group consisting of LiOH, NaOH, KOH or LiOR, LiNH2, LiNR2, NaOR, NaNH2, NaNR2, KOR, KNH2 or KNR2, where R is an ethyl group.

21) Process according to claim 17, wherein, when the salts are the salts of albendazole sulphoxide, fenbendazole sulphoxide or triclabendazole sulphoxide, said process further comprises a step c) of separating the enantiopure forms of said salts.

22) Process according to claim 21, wherein the separation of the enantiopure forms of said salts is conducted by HPLC on polysaccharide-based chiral stationary phases.

Description

EXAMPLE 1: PREPARATION OF THE SALTS OF BENZAMIDAZOLIC COMPOUNDS ACCORDING TO THE PRESENT INVENTION

[0053] ABZ-Na Synthesis.

[0054] A weighed amount of sodium hydroxide (1.0 eq) was solubilised in 40 mL of ethanol. ABZ (1.0 eq) was then added to the ethanol solution. The reaction mixture was heated under reflux for 2 hours. At the end of the reaction the mixture was cooled and filtered. The solvent was evaporated under reduced pressure. ABZ sodium salt appeared as a pale pink-coloured solid; mp 269-270 C.; IR v.sub.max 3338 (v NH), 1708 (v CO), 1626 (v CN), 1583 (v CC), 1262 (v CN), 1085 (v SO), 733 ( C.sub.sp2H) cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 0.94-1.01 (m, 3H, CH.sub.3), 1.52-1.57 (m, 2H, CH.sub.2), 2.78-2.82 (m, 2H, CH.sub.2), 3.69 (s, 3H, OCH.sub.3), 6.95-6.97 (m, 1H, Ar), 7.27 (d, J=8.0 Hz, 1H, Ar), 7.45 (s, 1H, Ar), 12.80 (bs, 1H, NH, D.sub.2O exch.); .sup.13C NMR (101 MHz, DMSO-d.sub.6) 13.55 (CH.sub.3), 22.67 (CH.sub.3CH.sub.2), 38.12 (CH.sub.2S), 51.56 (OCH.sub.3), 112.98 (Ar), 117.24 (Ar), 123.20 (Ar), 123.60 (Ar), 139.00 (Ar), 140.45 (Ar), 158.97 (CO), 160.36 (CN).

[0055] A synthetic procedure identical to the one shown for obtaining ABZ-Na was applied for the other salts of the present invention.

[0056] ABZ-K.

[0057] White-coloured solid, yield=98%, mp 270-271 C.; IR v.sub.max 3239 (v NH), 1608 (v CN), 1561 (v CC), 1270 (v CN), 787 ( C.sub.sp2H) cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 0.95 (t, J=7.2 Hz, 3H, CH.sub.3), 1.50-1.55 (m, 2H, CH.sub.2), 2.77-2.80 (m, 2H, CH.sub.2), 3.57 (s, 3H, OCH.sub.3), 6.91 (d, J=8.0 Hz, 1H, Ar), 7.13 (d, J=8.0 Hz, 1H, Ar), 7.28 (s, 1H, Ar), 12.01 (bs, 1H, NH, D.sub.2O exch.); .sup.13C NMR (101 MHz, DMSO-d.sub.6) 13.54 (CH.sub.3), 22.64 (CH.sub.3CH.sub.2), 38.03 (CH.sub.2S), 51.64 (OCH.sub.3), 112.76 (Ar), 115.93 (Ar), 123.19 (Ar), 123.60 (Ar), 139.12 (Ar), 141.15 (Ar), 158.93 (CO), 161.36 (CN).

[0058] ABZ-SONa.

[0059] White-coloured solid, yield=97%, mp 271-274 C.; IR v.sub.max 3188 (v NH), 1704 (v CO), 1618 (v CN), 1581 (v CC), 1264 (v CN), 1194 (v CO), 1098 (v SO), 734 (5 C.sub.sp2H) cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.64 (s, 3H, OCH.sub.3), 7.06-7.12 (m, 4H, Ar), 7.25 (t, J=7.6 Hz, 2H, Ar), 7.40 (d, J=8.0 Hz, 1H, Ar), 7.58 (s, 1H, Ar), 12.93 (bs, 1H, NH, D.sub.2O exch.); .sup.13C NMR (101 MHz, DMSO-d.sub.6) 51.78 (OCH.sub.3), 114.10 (Ar), 120.00 (Ar), 125.57 (Ar), 126.01 (Ar), 127.07 (Ar), 129.41 (Ar), 140.52 (Ar), 157.55 (CO), 158.86 (CN).

[0060] ABZ-SOK.

[0061] White-coloured solid, yield=97%, mp 262-264 C.; IR v.sub.max 3228 (v NH), 1704 (v CO), 1610 (v CN), 1560 (v CO), 1263 (v CN), 1185 (v CO), 1097 (v SO), 734 ( C.sub.sp2H) cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.63 (s, 3H, OCH.sub.3), 7.09-7.14 (m, 4H, Ar), 7.25 (t, J=7.6 Hz, 2H, Ar), 7.39 (d, J=8.0 Hz, 1H, Ar), 7.52 (s, 1H, Ar), 12.84 (bs, 1H, NH, D.sub.2O exch.); .sup.13C NMR (101 MHz, DMSO-d.sub.6) 51.84 (OCH.sub.3), 114.13 (Ar), 119.22 (Ar), 120.71 (Ar), 123.61 (Ar), 125.72 (Ar), 126.29 (Ar), 127.29 (Ar), 129.46 (Ar), 139.64 (Ar), 140.18 (Ar), 156.40 (CO), 158.90 (CN).

[0062] FBZNa.

[0063] White-coloured solid, yield=96%, mp 270-272 C.; IR v.sub.max 3362 (v NH), 1726 (v CO), 1624 (v CN), 1507 (v CC), 1271 (v CN), 1192 (v CO), 1093 (v SO), 748 ( C.sub.sp2H) cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.71 (s, 3H, OCH.sub.3), 7.28 (d, J=8.0 Hz, 1H, Ar), 7.42-7.53 (m, 4H, Ar), 7.63-7.68 (m, 3H, Ar); .sup.13C NMR (101 MHz, CD.sub.3OD) 51.21 (OCH.sub.3), 110.75 (Ar), 113.20 (Ar), 117.39 (Ar), 124.31 (Ar), 128.93 (Ar), 130.50 (Ar), 133.30 (Ar), 140.01 (Ar), 143.18 (Ar), 145.09 (Ar), 159.74 (CO), 160.72 (CN).

[0064] FBZK.

[0065] White-coloured solid, yield=98%, mp 238-240 C.; 3336 (v NH), 1712 (v CO), 1621 (v CN), 1522 (v CC), 1269 (v CN), 1189 (v CO), 1083 (v SO), 746 ( C.sub.sp2H) cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.56 (s, 3H, OCH.sub.3), 7.11-7.14 (m, 1H, Ar), 7.25 (d, J=8.0 Hz, 1H, Ar), 7.44-7.52 (m, 4H, Ar), 7.61 (d, J=7.2 Hz, 2H, Ar), 11.83 (bs, 1H, NH, D.sub.2O exch.); .sup.13C NMR (101 MHz, DMSO-d.sub.6) 51.66 (OCH.sub.3), 109.34 (Ar), 112.86 (Ar), 116.21 (Ar), 124.43 (Ar), 129.54 (Ar), 130.62 (Ar), 134.26 (Ar), 139.69 (Ar), 143.11 (Ar), 147.76 (Ar), 160.58 (CO), 160.89 (CN).

[0066] TRBZ-Na.

[0067] Yellow-coloured solid, yield=96%, mp>250 C. (dec.); IR v.sub.max 3112 (v C.sub.sp2H), 1613 (v CN), 1573 (v CC), 1271 (v CN), 733 ( C.sub.sp2H) CM.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 2.91 (s, 3H, SCH.sub.3), 6.95 (s, 1H, Ar), 7.13-7.39 (m, 3H, Ar), 8.02 (s, 1H, Ar); .sup.13C NMR (101 MHz, DMSO-d.sub.6) 35.60 (SCH.sub.3), 106.32 (Ar), 116.33 (Ar), 118.21 (Ar), 120.56 (Ar), 122.02 (Ar), 126.77 (Ar), 135.11 (Ar), 137.41 (Ar), 137.98 (Ar), 141.00 (Ar), 154.01 (OAr), 154.09 (OAr), 160.95 (CN).

[0068] TRBZ-K.

[0069] Yellow-coloured solid, yield=98%, mp>250 C. (dec.); IR v.sub.max (3106 (v C.sub.sp2H), 1604 (v CN), 1571 (v CC), 1279 (v CN), 755 ( C.sub.sp2H) cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 2.89 (s, 3H, SCH.sub.3), 6.90 (s, 1H, Ar), 7.09-7.40 (m, 3H, Ar), 7.97 (s, 1H, Ar); .sup.13C NMR (101 MHz, DMSO-d.sub.6) 35.55 (SCH.sub.3), 105.14 (Ar), 115.55 (Ar), 118.68 (Ar), 120.33 (Ar), 123.32 (Ar), 126.56 (Ar), 135.69 (Ar), 136.11 (Ar), 137.34 (Ar), 140.76 (Ar), 153.45 (OAr), 153.67 (OAr), 161.11 (CN).

[0070] TRBZ-SONa.

[0071] Brown-coloured solid, yield 96%, mp>250 C. (dec.); IR v.sub.max 3105 (v C.sub.sp2H), 1634 (v CN), 1590 (v CC), 1248 (v CN), 1077 (v SO), 723 ( C.sub.sp2H) cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.11 (s, 3H, SOCH.sub.3), 7.12 (s, 1H, Ar), 7.29-7.45 (m, 3H, Ar), 8.27 (s, 1H, Ar); .sup.13C NMR (101 MHz, DMSO-d.sub.6) 54.86 (SCH.sub.3), 108.87 (Ar), 117.57 (Ar), 119.24 (Ar), 121.65 (Ar), 124.34 (Ar), 126.89 (Ar), 133.45 (Ar), 134.76 (Ar), 136.76 (Ar), 141.56 (Ar), 152.07 (OAr), 153.55 (OAr), 159.67 (CN).

[0072] TRBZ-SOK.

[0073] Brown-coloured solid, yield=99%, mp>250 C. (dec.); IR v.sub.max 3110 (v C.sub.sp2H), 1628 (v CN), 1577 (v CC), 1286 (v CN), 1088 (v SO), 727 ( C.sub.sp2H) cm.sup.1; .sup.1H NMR (400 MHz, DMSO-d.sub.6): 3.15 (s, 3H, SOCH.sub.3), 7.03 (s, 1H, Ar), 7.22-7.56 (m, 3H, Ar), 8.04 (s, 1H, Ar); .sup.13C NMR (101 MHz, DMSO-d.sub.6) 54.04 (SCH.sub.3), 107.98 (Ar), 116.43 (Ar), 118.12 (Ar), 120.54 (Ar), 124.55 (Ar), 127.13 (Ar), 136.08 (Ar), 136.87 (Ar), 137.52 (Ar), 141.33 (Ar), 153.12 (OAr), 153.79 (OAr), 160.76 (CN).

[0074] Thiabendazole-Na (TBZ-A).

[0075] White-coloured solid, yield=96%, nip 299-300 C.; IR v.sub.max 3085 (v C.sub.sp2H), 2985 (v C.sub.sp2H), 1405 (v CC), 1229 (v CN), 740 ( C.sub.sp2H) cm.sup.1; .sup.1H NMR (300 MHz, DMSO-d.sub.6): 7.17-7.20 (q, 2H, Ar), 7.54-7.57 (q, 2H, Ar), 8.42-8.43 (d, J=2.4 Hz, 1H, Ar), 9.31-9.32 (d, J=1.8 Hz, 1H, Ar); .sup.13C NMR (75 MHz, DMSO-d.sub.6) 119.85 (Ar), 122.58 (Ar), 147.50 (Ar), 147.57 (Ar), 156.06 (CN).

[0076] Mebenbendazole-Na (MBZ-A).

[0077] Yellow-coloured solid, yield=94%, mp 288-289 C. (dec.); IR v.sub.max 3199 (v NH), 1619 (v CN), 1563 (v CC), 1280 (v CN), 791 ( C.sub.sp2H) cm.sup.1; .sup.1H NMR (300 MHz, DMSO-d.sub.6): 3.44 (s, 3H, CH.sub.3), 6.97-6.99 (d, J=8.1 Hz, 1H, Ar), 7.10-7.13 (dd, 1H, Ar), 7.42-7.60 (m, 6H, Ar); .sup.13C NMR (75 MHz, DMSO-d.sub.6) 51.18 (OCH.sub.3), 111.16 (Ar), 115.37 (Ar), 120.28 (Ar), 123.21 (Ar), 128.17 (Ar), 129.27 (Ar), 130.31 (Ar), 141.82 (CN), 161.17 (NHCO), 195.60 (CO).

[0078] Oxibendazole-Na (OBZ-A).

[0079] Pink-coloured solid, yield=97%, mp 249-251 C. (dec.); IR v.sub.max 3388 (v NH), 2963 (v C.sub.sp3H), 1626 (v CN), 1268 (V CN), 1179 (V CO), 792 ( C.sub.sp2H) cm.sup.1; .sup.1H NMR (300 MHz, DMSO-d.sub.6): 0.93-0.98 (t, J=7.3 Hz, 3H, CH.sub.3), 1.65-1.72 (m, 2H, CH.sub.2), 3.63 (s, 3H, CH.sub.3), 3.82-3.87 (t, J=6.4 Hz, 2H, CH.sub.2), 6.54-6.57 (dd, 1H, Ar), 6.85-6.86 (d, J=2.4 Hz, 1H, Ar), 7.13-7.15 (d, J=8.1 Hz, 1H, Ar); .sup.13C NMR (75 MHz, DMSO-d.sub.6) 10.97 (CH.sub.3), 22.67 (CH.sub.2), 52.39 (OCH.sub.3), 69.84 (OCH.sub.2), 109.39 (Ar), 114.69 (Ar), 154.32 (CN).

[0080] Parbendazole-Na (PBZ-A).

[0081] Pink-coloured solid, yield=95%, mp 247-248 C. (dec.); IR v.sub.max 3327 (v NH), 2963 (v C.sub.sp3H), 1625 (v CN), 1594 (v CC), 1280 (v CN), 1195 (v CO), 790 ( C.sub.sp2H) cm.sup.1; .sup.1H NMR (300 MHz, DMSO-d.sub.6): 0.84-0.89 (t, J=7.3 Hz, 3H, CH.sub.3), 1.26-1.31 (m, 2H, CH.sub.2), 1.48-1.55 (m, 2H, CH.sub.2), 3.64 (s, 3H, CH.sub.3), 6.76-6.79 (dd, 1H, Ar), 7.10-7.18 (m, 2H, Ar); .sup.13C NMR (75 MHz, DMSO-d.sub.6) 14.30 (CH.sub.3), 22.18 (CH.sub.2), 35.58 (CH.sub.2), 39.07 (CH.sub.2), 52.39 (OCH.sub.3), 113.09 (Ar), 113.14 (Ar), 121.27 (Ar), 121.38 (Ar), 134.85 (Ar), 134.91 (Ar), 150.70 (CN), 157.27 (NHCO).

EXAMPLE 2: PREPARATION OF THE ENANTIOPURE FORMS OF THE SALT ABZ-SONA

[0082] Enantiomeric separation of ABZ-SONa by semi-preparative HPLC was conducted on 1-cm I.D. Chiralpak AD or Chiralpak IA columns, progressively increasing the amount of racemic mixture injected in a single phase. The mobile phase consisted of pure ethanol. The flow temperature and flow velocity were fixed at 25 C. and 4.5 ml/min.

[0083] The injection of 15 mg of ABZ-SONa dissolved in 1 mL of methanol resulted in a complete enantioseparation, without peak overlapping, in a run time of about 15 min. After the semipreparative separation, the collected fractions were pooled, subjected to evaporation and analyzed by means of a chiral analytical column in order to determine their enantiomeric excess (e.e.). Both collected fractions were enantiomerically pure and the quantitative yields were about 90%. Therefore, the productivity of the sample of enantiomers of ABZ-SONa was about 650 mg per day.