US 2004OO63677A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0063677 A1 Myhren et al. (43) Pub. Date: Apr. 1, 2004 (54) METHODS OF TREATING DSORDERS (30) Foreign Application Priority Data USING LIPOPHILIC DERVATIVES Jan. 24, 1997 (GB)......................................... 97O1441.9 (75) Inventors: Finn Myhren, Porsgrunn (NO); Bernt Borretzen, Heistad (NO); Are Dalen, Trondheim (NO); Marit Liland Publication Classification Sandvold, Porsgrunn (NO) (51) Int. Cl. ............................ A61K 31/573; CO7J 5/00 Correspondence Address: (52) U.S. Cl. ............................................ 514/179; 552/570 JONES DAY 51 Louisiana Aveue, N.W WASHINGTON, DC 20001-2113 (US) (57) ABSTRACT (73) Assignee: Norsk Hydro ASA The properties of biologically active compounds, for (21) Appl. No.: 10/662,441 example drugs and agrochemicals, which contain in their molecular structure one or more functional groupS. Selected (22) Filed: Sep. 16, 2003 from alcohol, ether, phenyl, amino, amido, thiol, carboxylic acid and carboxylic acid ester groups are modified by Related U.S. Application Data replacing one or more of these functional groups by a lipophilic group Selected from those of the formula: (63) Continuation of application No. 10/116,358, filed on RCOO-, RCONH-, RCOS-, RCH-O-, RCH-NH-, Apr. 5, 2002, which is a continuation of application -COOCHR,-CONHCHR and -SCHR, wherein R is No. 09/355,111, filed on Sep. 27, 1999, now aban a lipophilic moiety Selected from cis-8-heptadecenyl, trans doned, filed as 371 of international application No. 8-heptadecenyl, cis-10-nonadecenyl and trans-10-nonadece PCT/NO98/00021, filed on Jan. 23, 1998. nyl. Patent Application Publication Apr. 1, 2004 Sheet 1 of 13 US 2004/0063677 A1 Fig. 1. 7O 60 w 50 40 O) S 3O 2O O O Liposomes Naproxen Oley Oley Oley ether ester amide Patent Application Publication Apr. 1, 2004 Sheet 2 of 13 US 2004/0063677 A1 Fig. 2. 18 16 14 12 Liposomes Naproxen Oley Oley Oley ether ester amide Patent Application Publication Apr. 1, 2004 Sheet 3 of 13 US 2004/0063677 A1 Fig. 3. 550 500 450 400 350 g 3OO 250 200 150 1 OO 50 Ol Liposomes Naproxen Olevt Oleyester amideOley Patent Application Publication Apr. 1, 2004 Sheet 4 of 13 US 2004/0063677 A1 Fig. 4. 2OO R 100 Liposomes Naproxen Oleyi Oley Oley ether ester amide Patent Application Publication Apr. 1, 2004 Sheet 5 of 13 US 2004/0063677 A1 Fig. 5. 3 O 2 5 121 OO5 O 6 a- 24 48 72 Hours post injection OControl Prednisolone Prednisolone-elaidate Patent Application Publication Apr. 1, 2004 Sheet 6 of 13 US 2004/0063677 A1 O O. O. O. O. O. O. O. O. O O. O. O. O. O. O. O O O. O. O. O. O. O. O. O LO O O O O O LO v CO CO CN CN v u/\u) OoueoSeugunueuo Patent Application Publication Apr. 1, 2004 Sheet 7 of 13 US 2004/0063677 A1 Fig. 7. 22O5 1 5 1 O O 6 2 2. 48 t Hours post treatment OControl Prednisolone Prednisolone-elaidate Patent Application Publication Apr. 1, 2004 Sheet 8 of 13 US 2004/0063677 A1 Fig. 8. 25 12 5O 1 O O 6 2 24 48 72 Hours post treatment Control Prednisolone Prednisolone-elaidate US 2004/0063677 A1 uequunNSI?00goOL)dxa(9 IIIIIIIIIIIIIIIIIIIIIIIIIIIIIII|, Patent Application Publication Apr. 1, 2004 Sheet 10 of 13 US 2004/0063677 A1 Patent Application Publication Apr. 1, 2004 Sheet 11 of 13 US 2004/0063677 A1 Fig. 11. 250 200 150 O O 5 O O O 20 40 60 80 OO 120 Time (minutes) -0-DOX - P --DOX - CAT - P -O-DOX - R -O-DOx - CAT - R Patent Application Publication Apr. 1, 2004 Sheet 12 of 13 US 2004/0063677 A1 Fig. 12. 4OO 12OO 2 1000 2. s 800 c g 600 c) O 9. 9 400 200 2 O O 2O 40 60 80 100 120 Time (minutes) -- Daunorubicine-elaidic-amide CEM -- Daunorubicine-elaidate-amide VLB Daunorubicine-oleic-carbamate CEM -- Daunorubicine-oleyl-carbamate VLB Patent Application Publication Apr. 1, 2004 Sheet 13 of 13 US 2004/0063677 A1 Fig. 13. 6OOO 5OOO 4000 3 O O O 2OOO OOO O 2O 40 60 8O 1 OO 120 Time (minutes) -- Daunorubicine CEM --Daunorubicine VLB US 2004/OO63677 A1 Apr. 1, 2004 METHODS OF TREATING DSORDERS USING biological and therapeutic activity as anti-Viral agents as LIPOPHILIC DERIVATIVES ara-cytidine itself. The compound 2,2'-anhydro-5'-O-oleyl ara-cytidine is specially mentioned. I. FIELD OF THE INVENTION 0008 EP-A-56265 discloses esters of arabino-furanosyl 0001. This invention relates to biologically active com thymine (Ara T) with saturated acids having 1-17 C-atoms. pounds, and it is concerned with providing by means of 0009 From PCT/WO90/00555 there are known lipid chemical derivatisation, a technique whereby the behaviour derivatives linked, especially through a phosphate group, to of many biologically active compounds, Such as drugs and the 5'-position of the pentose group of a nucleoside. The agricultural chemicals, may be favourably modified. purpose of this derivatisation is to make the nucleosides more lipophilic So that they could be included into lipo II. BACKGROUND OF THE INVENTION Somes, which are preferentially taken up by macrophages 0002 There is a great interest in the medical community and monocytes, cells which are found to harbour the HIV to investigate and improve the transport efficiency of drugs Virus. It is Stated that a targeting effect is thereby achieved. to the site of action in the patient. The work has mainly been 0010. The anti-viral and anti-cancer activities of nucleo focused on resorption of a drug from the intestine to the Side analogues are directly linked to intra-cellular phospho blood Stream, although transport across other biological rylation of the administered drug. This biochemical trans barriers often plays an important role in obtaining the formation is normally effectuated by viral and/or cellular necessary therapeutic effect in the treatment of many dis enzymes. To improve the effect WO96/25421 discloses eases like cancer, infections, inflammations, CNS disorders phospholipid derivatives of nucleosides with relatively short etc. The transport acroSS the cell membrane is often a main impediment to achieve optimal effect with a therapeutic chain (C or less) Saturated or unsaturated fatty acids. compound. 0011. The art has also sought to improve the character istics of other classes of pharmaceutical Substance through 0.003 Over the last decades drug resistance in the treat ment of malignant and infectious diseases has become derivatisation with fatty acids. increasingly prevalent and is now regarded as a Serious 0012 For example, WO96/22303 teaches that the clinical problem. The development of drug resistance can be pharmokinetic profile and mode of delivery of Several due to a number of mechanisms, but quite often relates to a different categories of therapeutic compounds (corticoster triggering of the normal mechanisms whereby microorgan ones, opioids and opioid antagonists, anti-Viral nucleosides, isms and cells clear toxic compounds to Subtoxic levels. One cyclosporins and related cyclopeptides, folate antagonists, example is the development of multi-drug resistance (MDR) catecholamine precursors and catecholamines and alkylating in cancer cells. In this case MDR frequently relates to a agents containing a carboxylic acid group) can be altered by cellular membrane protein pump by which the cells achieve conjugating them to one to three acyl derivatives of fatty a very efficient efflux of toxic compounds. In a clinical acids through the use of a linker/Spacer group which Situation, i.e. the treatment of a tumour with a cytostatic includes a tromethamine or ethanolamine derivative. Palm drug, cells with the most potent protein pump can prefer itic acid is the preferred fatty acid. entially Survive, and these cells may proliferate to a new 0013 Lipophilic pro drugs of several NSAIDs are known tumour which may be resistant to treatment with a variety of from H. Bundgaard et al (International Journal of Pharma different drugs. Similar mechanisms of action may be ceutics, 43 101-110 1988) and V. R. Shanbhag et al (Journal responsible for the lack of effect Seen in other therapeutic of Pharmaceutical Sciences, 149 Vol. 81, No. 2, February areas, for instance with anti-malarial drugs. 1992). In addition to the pro drug aspect, reduced GI 0004 Several techniques to try to circumvent resistance irritation is reported. EP-A-0195570 suggests that the mechanisms in the clinic are known. For example, the administration of gamma-linolenic and dihomo-gamma-li co-administration of a Ca" channel blocker Such as Vera nolenic acid in conjunction with NSAIDs reduces the side pamil or an immunomodulating agent like cycloSporin, have effects shown by the NSAIDs when taken on a continuing been tried out. However, no significant improvements have basis. been reported So far. 0014 U.S. Pat. No. 5,284.876 teaches the use of docosa 0005 There have been several proposals in the literature hexaenoic acid amides of dopamine as per oral pro drugs in for improving the therapeutic index, bioavailability, mem the treatment of CNS disorders. brane passage, organ targeting, etc of therapeutic com 0015 Physical mixtures containing fatty acids/fatty acid pounds by combining the compounds with fatty acids So as derivatives used as So-called penetration enhancers both to form either chemically coupled derivatives or physical with dermal and per oral administration are known from mixtures. PCT/US94/02880 and PCT/SE96/00122. 0006 Thus, for example, EP-A-393920 discloses that 0016 AS indicated, many of these prior proposals con anti-viral nucleosides and nucleoside analogues which are cern fatty acid derivatives of anti-Viral nucleosides and derivatised with long chain (C upwards) acyl groups have nucleoside analogues.