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Cals (O) (5) (O) - (E)------O O Ocs) Iningas US 20090215895A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0215895 A1 Ferrante et al. (43) Pub. Date: Aug. 27, 2009 (54) THERAPEUTIC AND CARRIERMOLECULES A6IP 29/00 (2006.01) A6IP 25/6 (2006.01) (75) Inventors: Antonio Ferrante, South Australia A6IP 25/08 (2006.01) (AU); Deborah Ann Rathjen, A6IP 25/22 (2006.01) South Australia (AU) A6IP 25/24 (2006.01) A6IP 9/12 (2006.01) Correspondence Address: A6IP 9/10 (2006.01) SCULLY, SCOTT, MURPHY & PRESSER, P.C. A6IP3/04 (2006.01) 400 GARDEN CITY PLAZA, SUITE 300 A6IP 25/28 (2006.01) GARDEN CITY, NY 11530 (US) A6IP 25/30 (2006.01) A6IP 25/18 (2006.01) Newstead (AU) (52) U.S. Cl. ........................................................ 514/560 (21) Appl. No.: 10/588,094 (57) ABSTRACT (22) PCT Filed: Jan. 28, 2005 The present invention relates generally to compounds com (86). PCT No.: PCT/AUOS/OOO98 prising a hydrocarbon chain portion and more particular to compounds comprising chemical derivatizations of the S371 (c)(1), hydrocarbon chain which are useful therapeutic and prophy (2), (4) Date: May 7, 2009 lactic molecules. The present invention further provides com pounds where the hydrocarbon chain portion is a carrier mol Related U.S. Application Data ecule for functional groups, moieties or agents. The compounds of the present invention are particularly useful in (60) Provisional application No. 60/540,604, filed on Jan. the treatment and prophylaxis of a range of conditions includ 30, 2004. ing cancers, protein kinase c(PKC)- or NFkB-related- or -as O O Sociated conditions, cardiovascular conditions, pain, inflam Publication Classification matory conditions, Vascular or immunological conditions (51) Int. Cl. Such as diabetes, neurological conditions and infection by a A6 IK 3L/202 (2006.01) range of viruses or prokaryotic or eukaryotic organisms. The A6IP 25/06 (2006.01) present invention further provides pharmaceutical composi A6IP 25/00 (2006.01) tions and methods of medical treatment. White blog cals (O) (5) (O) - (e)----- - - o O OCs) iningas cott invading write O bod Cots Ya massengerprotesy Macrophage Synoviocyte N. r Neutrophis A SE Joint namination digt Patent Application Publication Aug. 27, 2009 Sheet 1 of 16 US 2009/0215895 A1 a eats invading write blood cotls Ya massengerprotes : Macrophage Neutrophis A E. on namination dits Figure 1 Patent Application Publication Aug. 27, 2009 Sheet 2 of 16 US 2009/0215895 A1 Effect of EPUFA on oxygen radical production 250 g 200 s 150 5 E 2 2 ) 100 S4 A 50 O Vehicle AA PT2 Treatment Figure 2 Patent Application Publication Aug. 27, 2009 Sheet 3 of 16 US 2009/0215895 A1 100 (6u??j?MDd) asuodsa,jouoponpay?% $& Treatment Figure 3 Patent Application Publication Aug. 27, 2009 Sheet 4 of 16 US 2009/0215895 A1 Zld (6X/6uuOOL) Treatment Figure 4 Patent Application Publication Aug. 27, 2009 Sheet 5 of 16 US 2009/0215895 A1 AR10-2=7-5-3-Sl E1616 NE119, 21,n1 23 . Figure 5 E-selectin 2. 2 o o 20 8 2 s 2. incubation time (h) Figure 6 Patent Application Publication Aug. 27, 2009 Sheet 6 of 16 US 2009/0215895 A1 100 100 9. s E 5 80 E 5 80 E 5 60 3 60 a ESS. 5 & 40 40 n 20 g 20 O 24h 72 B-oxa-23:4n-6 Neutrophills Mononuclear Cells Figure 7 Patent Application Publication Aug. 27, 2009 Sheet 7 of 16 US 2009/0215895 A1 a -r ... - crisis . ... i. 's .." :- ... " ul- - - ar... r " ... s. is: 3. -- ES-25E2... ..M. - - a h r. sail. - ifr * Sr * i. TNF - -- - -- -- Figure 8 Patent Application Publication Aug. 27, 2009 Sheet 8 of 16 US 2009/0215895 A1 low - High High Control Diabetic Diabetic Glucose Glucose Glucose Glucose rat rat rat HMP5 +MP5 --MP5 Figure 9 Patent Application Publication Aug. 27, 2009 Sheet 9 of 16 US 2009/0215895A1 140 120. 1OO 8 O 6 O 4 O 2 O Control B-oxa 23:4n-6 PMA 22:6n-3 Treatment Figure 10 Patent Application Publication Aug. 27, 2009 Sheet 10 of 16 US 2009/0215895 A1 140 Natural PUFA 120 100 B-oxa-PUFA B-thia-PUFA Figure 11 Patent Application Publication Aug. 27, 2009 Sheet 11 of 16 US 2009/0215895 A1 140 55 120 5 SS 100 3. 80 C 9. 60 C 40 is 20 9 O O 9. t O c5 O O St. CO CN co O (Y) t c S. O w 8 st t 8 & C 8 (Sv C (s s cy 8 8 s CA Ch. 3. Fatty acid or derivative Figure 12 Patent Application Publication Aug. 27, 2009 Sheet 12 of 16 US 2009/0215895 A1 140 E-Selectin 120 100 80 60 3 2 40 20 O control p-oxa-23:in-8 14 O. 120 100 80 60 40 20 140 120 1 OO 80 60 40 20 O 4 8 12 16 20 24 Incubation time (h) Figure 13 Patent Application Publication Aug. 27, 2009 Sheet 13 of 16 US 2009/0215895 A1 1OO A o 80 : - 60 : O 59 40 s O SS 20 O 24h 72 h, OTH :Neutrophis Mononuclear cells Footpad reaction : Peritoneal inflammation inflammatory response 100 B 80 5 60 (9 as 40 SS 20 B-oxa-23:4n-6 E-selectin in aortic endothelium Figure 14 Patent Application Publication Aug. 27, 2009 Sheet 14 of 16 US 2009/0215895 A1 B-oxa-23:4 (n-6) OH /= 1N 8-monohydro- fox-23:4n-6) 15 monohydro- fox-23:4n-6) Xy a ( - Xy a ( ~a OH 18 monohydro- fox-23:4 n-7) Figure 15 Patent Application Publication US 2009/0215895 A1 100 CO?NOOCD Patent Application Publication Aug. 27, 2009 Sheet 16 of 16 US 2009/0215895 A1 300 O O O) O TNF 2:5-6 B-os-23:4n-6 (b) NFkB-site. TNF - p-oxa-23:4n-6 - - - + (c) GST-xBa(5-55)- E. 2000 TNF - r 3-oxn-23:4n-6 . s al Figure 17 US 2009/0215895 A1 Aug. 27, 2009 THERAPEUTIC AND CARRIERMOLECULES reduced Susceptibility to breakdown and, hence, are far less likely to cause the production of oxygen radicals which is the BACKGROUND OF THE INVENTION consequence of the metabolism of the natural ()-3 fatty acids. PT Series' PUFAs also have this property of resisting break 0001 1. Field of the Invention down but in addition are more soluble. MP-PT hybrids are 0002 The present invention relates generally to com particularly useful anti-inflammatory agents. pounds comprising a hydrocarbon chain portion and more 0011. As indicated above, naturally occurring ()-3 fatty particular to compounds comprising chemical derivatizations acids have been found to be useful in treating a range of of the hydrocarbon chain which are useful therapeutic and conditions including rheumatoid arthritis, multiple Sclerosis, prophylactic molecules. The present invention further pro inflammatory bowel disease and systemic lupus. The PUFAs vides compounds where the hydrocarbon chain portion is a of the MP, PT, LX and MP-PT hybrid series have also been carrier molecule for functional groups, moieties or agents. proposed for the treatment of malaria, to stimulate or inhibit The compounds of the present invention are particularly use neutrophil activity, to treat T-cell diseases and in the treatment ful in the treatment and prophylaxis of a range of conditions of cancer. including cancers, protein kinase c(PKC)- or NFKB-related 0012. There is a need to determine the full range of activi or -associated conditions, cardiovascular conditions, pain, ties of the PUFAs and to identify naturally occurring mem inflammatory conditions, vascular or immunological condi bers or to generate synthetic derivatives which have therapeu tions such as diabetes, neurological conditions and infection tic potential. by a range of viruses or prokaryotic or eukaryotic organisms. SUMMARY OF THE INVENTION The present invention further provides pharmaceutical com positions and methods of medical treatment. 0013 Throughout this specification, unless the context 0003 2. Description of the Prior Art requires otherwise, the word “comprise', or variations such 0004 Bibliographic details of references in the subject as “comprises' or “comprising, will be understood to imply specification are also listed at the end of the specification. the inclusion of a stated element or integer or group of ele 0005 Reference to any prior art in this specification is not, ments or integers but not the exclusion of any other element or and should not be taken as, an acknowledgment or any form integer or group of elements or integers. of Suggestion that that prior art forms part of the common 0014. In accordance with the present invention, it is pro general knowledge in any country. posed that the PUFAs are useful in the treatment interalia of conditions associated with or involving protein kinase CB 0006 Fatty acids are one of the most extensively studied (PKCB) and/or NFKB and in the treatment of pain, inflam classes of compounds due to their important role in biological mation, vascular or immunological conditions such as diabe systems (Ferrante et al. In The Neutrophils: New outlook for tes, cardiovascular conditions, atherosclerosis, neurological the old cells Ed Garbilovich Imperial College Press 4:79 conditions and infection by a range of viruses, prokaryotes or 150, 1999: Sinclair and Gibson (Eds) Invited papers from the eukaryotes. Third International Congress, American Oil 0015. In particular, the present invention contemplates a Chemists Society, Champaign, Ill., 1-482, 1992). Fatty acids method for the treatment or prophylaxis of a condition consist of saturated, monosaturated and polyunsaturated fatty selected from the list consisting of an NFKB-related or -as acids having a chain length from 4 to 30 carbonatoms.
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