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(12) Patent Application Publication (10) Pub. No.: US 2004/0106589 A1 Webb Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2004/0106589 A1 Webb Et Al US 2004O106589A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0106589 A1 Webb et al. (43) Pub. Date: Jun. 3, 2004 (54) FATTY ACID-PHARMACEUTICAL AGENT (22) Filed: Jun. 5, 2003 CONJUGATES Related U.S. Application Data (75) Inventors: Nigel L. Webb, Bryn Mawr, PA (US); Matthews O. Bradley, Laytonsville, (63) Continuation of application No. 09/730,450, filed on MD (US); Charles S. Swindell, Dec. 5, 2000, now Pat. No. 6,576,636, which is a Merion, PA (US); Victor E. Shashoua, continuation of application No. 08/651,428, filed on Brookline, MA (US) May 22, 1996, now abandoned. Correspondence Address: Publication Classification Edward R. Gates Wolf, Greenfield & Sacks, P.C. (51) Int. Cl. ....................... A61K 31156; A61K 31/22 600 Atlantic Avenue (52) U.S. Cl. ............................................ 514/182; 514/549 Boston, MA 02210 (US) (57) ABSTRACT (73) Assignee: Protarga Pharmaceuticals, Inc., King The invention provides conjugates of fatty acids and phar of Prussia, PA maceutical agents useful in treating noncentral nervous System conditions. Methods for Selectively targeting phar (21) Appl. No.: 10/455,250 maceutical agents to desired tissues are provided. Patent Application Publication Jun. 3, 2004 Sheet 1 of 14 US 2004/0106589 A1 - S. O 1. CD l O Ll CD - 2. l O Y n -100 -9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) CCRF-CEM-O- SR. ----- RPM-8226-- o- - - K-562- - -A - - HL-60 (TB) -g- - MOLT-4 D . 100 5 O -5 OO -1 OO 9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) A549/ATCC-o- EKVX-0-- NCI-H322M-...-a- NC-H226-- O - - NC-H23---0-- HOP-92.....O..... NC-H522--O-- HOP-62--- a-- NCI-H460-------- Fig. 2 Patent Application Publication Jun. 3, 2004 Sheet 2 of 14 US 2004/0106589 A1 COLON CANCER 1 OO 5 O -5 OO - 1 OO w -9 -8 -7 -6 -5 -4 LOGO OF SAMPLE CONCENTRATION (MOLAR) COLO 205-O- HCT-1 16-- (- - HCT-15- - -a-- KM12-- O - - SW-620---0--- HT29.....O. Fig. 3 1 OO CNS CANCER 5 O -5 OO -1 O O 9 -8 -7 -6 -5 -4 LOGO OF SAMPLE CONCENTRATION (MOLAR) SF-268-O- SF-295 - -g- - SF-539 - A SNB-75 -- O - - U251 - '-0- - SNB-19. Fig. 4 Patent Application Publication Jun. 3, 2004 Sheet 3 of 14 US 2004/0106589 A1 MELANOMA 1 OO relaas - i. 5 O -5 OO - 1 OO -9 -8 -7 -6 -5 -4 LOG10 OF SAMPLE CONCENTRATION (MOLAR) LOX MV -o- UACC-257---4--- SK-MEL-2..... O. SK-MEL-5 - - O - - M14 --- a-- MALME-3M--Q-- UACC-62- : A - Fig. 5 1 OO OVARAN CANCER 5 O O LOGO OF SAMPLE CONCENTRATION (MOLAR) GROW 1 -Co- OWCAR-3--O - - OVCAR-4--a- - OCWAR-8 - - O - SK-OV-3---0- OVCAR-5 ro Fig. 6 Patent Application Publication Jun. 3, 2004 Sheet 4 of 14 US 2004/0106589 A1 1 OO O LOGo OF SAMPLE CONCENTRATION (MOLAR) 786-O-O- A498--(- - ACHN- - - A -- - CAK-1: ....O. RXF 393 - - O - - TK-1 O -- 0- - - - UO-31 - A - - - Fig. 7 1 OO PROSTRATE CANCER O - 1 O O 9 - 8 - 7 - 6 5 w 4. LOGO OF SAMPLE CONCENTRATION (MOLAR) PC-3-O- Fig. 8 Patent Application Publication Jun. 3, 2004 Sheet 5 of 14 US 2004/0106589 A1 1 OO 5 O -5 OO -1 O O -9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) MCF7 -O- MDA-N- - -0 - - - HS 578 ... O. MDA-MB-435--O-- MDA-MB-231/--a-- T-47D-...- MCF 7/ADR-RE--&- Fig.BT-549-A- 9 1 OO LEUKEMAal 5 O -5 OO - 1 OO -9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) CCRF-CEM-o- SR. --0--- RPM-8226--o- - - K-562- - -A - - HL-60 (TB) -g- -Fig. MOLT-4 10 O' Patent Application Publication Jun. 3, 2004 Sheet 6 of 14 US 2004/0106589 A1 NON-SMALL CEL UNG CANCER 1 OO Sea 5 O -5- OO -100 9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) A549/ATCC-O EKVX --O-- NC-H322M--- a--- NC-H226-- O -- NC-H23---0-- HOP-92-......... NCI-H522--O-- HOP-62---- NC-H460------- Fig. 11 1 OO 5 O O COLO 205-o- HCT-116--o-- HCT-15---a-- KM12- - O --Fig. SW-620---4--- 12 HT29.... O ... Patent Application Publication Jun. 3, 2004 Sheet 7 of 14 US 2004/0106589 A1 H s O 1. CD 1 O I (D H 2 LL O 1. l -100 -9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) SF-268-O- SF-295 - -g- - SF-539 - - - A - - - SNB-75-0-- Fig.251 - 139 - SNB-19 ror MELANOMA 1 OO s ... - Cs Sis s L s O 1. CD l O CD. CC H 2. | O LI) - 1 OO 9 -8 -7 -6 -5 -4 LOG10 OF SAMPLE CONCENTRATION (MOLAR) LOX MV-O - UACC–257- -0- - - SK-MEL-2.....O..... SK-MEL-5 - - O - - M14 - - - a-- MALME-3M--C-- UACC-62- - -A- Fig. 14 Patent Application Publication Jun. 3, 2004 Sheet 8 of 14 US 2004/0106589 A1 100 5 O -5 OO -1 O O a 9 -8 -7 -6 -5 -4 LOGo OF SAMPLE CONCENTRATION (MOLAR) GROV1 -O- OVCAR-3--K) -- OVCAR-4--A- - OCWAR-8 - - O- - SK-OV3Fig. --0 15 OVCAR-5'0' RENAL CANCER 1 OO O -9 -8 -7 -6 -5 -4 786-O-OLOGo - OF SAMPLEA498- -g- CONCENTRATION - ACHN- - - A - -(MOLAR) - CAKl-1 - O - RXF393-- o- - TK-10---0-- UO-31 - "A" Fig. 16 Patent Application Publication Jun. 3, 2004 Sheet 9 of 14 US 2004/0106589 A1 1 OO PROSTRATE CANCER O - 1 OO -9 -8 -7 -6 -5 -4 LOGO OF SAMPLE CONCENTRATION (MOLAR) PC-3-o- Fig. 17 - S O 1. (D 1 O CD - 2. L O (Y L O -100 -9 -8 -7 -6 -5 -4 LOGO OF SAMPLE CONCENTRATION (MOLAR) MCF 7-O- MDA-N- - -0--- HS 578T....... MDA-MB-435 - -o- - MDA-MB-231/ -- a-- T-47D----...- MCF 7/ADR-RE-- ()-- BT-549-...-A-...- Fig. 18 Patent Application Publication Jun. 3, 2004 Sheet 10 of 14 US 2004/0106589 A1 LEUKEMA H s O 1. CD L O L CD CC - Z I O Y. l Cl - 1 OO - 10 -9 -8 -7 -6 LOGo OF SAMPLE CONCENTRATION (MOLAR) CCRF-CEM-O- MOLT-4---a- - - K-562 - K)- - Fig.SR 19 . -o- . NON-SMALL CELL LUNG CANCER C 1 O -9 -8 - -6 LOGo OF SAMPLE CONCENTRATION (MOLAR) A549/ATCC-o- NC-H322M-...-. NCI-H226 .......O...... NC-H23--O-- HOP-62 --- a--- NC-H522 - - - - EKVX-- C -. NC-H460 -...-A-...- Fig. 20 Patent Application Publication Jun. 3, 2004 Sheet 11 of 14 US 2004/0106589 A1 COLON CANCER H & O CD 1 O CD H 2 5-502 l -100 - - 10 -9 -8 -7 -6 LOGO OF SAMPLE CONCENTRATION (MOLAR) COLOHT29--O-- 205-O- cy's.KM12-...-0--- HCT-15- - - . HCC-2995- - O-- SW-620-...--A-...-Fig. 21 CNS CANCER 1 OO - - - - f N. -. H is ar so CD L O LL CD CC Her 2 O I Ol 1 O -9 -8 -7 -6 LOGo OF SAMPLE CONCENTRATION (MOLAR) SF-268-O- SF-295- -g- - SF-539 - - -a- - - SNB-75 -- O - - U251 - - - - SNB-19..... O. Fig. 22 Patent Application Publication Jun. 3, 2004 Sheet 12 of 14 US 2004/0106589 A1 MEANOMA - s O Y (D LL O I CD < H 2 l O -5O Y l - 1 OO - 10 -9 -8 -7 -6 LOG-10 OF SAMPLE CONCENTRATION (MOLAR) LOX IMV. -o- SK-MEL-5- -0-- SK-MEL-2..... O. SK-MEL-28 - - O - - M14 --- a-- UACC-62 - - - - - - MALME-3M--Q-- UACC-257- - - -A - Fig. 23 OVARAN CANCER I H & O Y CD L O CD < - 2. 5-50Y l -1 O O -1 o g -8 -7 C 6 LOGO OF SAMPLE CONCENTRATION (MOLAR) IGROV1 -o- OVCAR-3--O--OVCAR-4--A-- OCVAR-8--o- SK-OV3Fig. - 248 OVCAR-5" or Patent Application Publication Jun. 3, 2004 Sheet 13 of 14 US 2004/0106589 A1 RENAL CANCER H S O 1. CD - O I CD 2. I O -50 Y I Ol - 1 OO - 1 O -9 -8 -7 -6 LOGO OF SAMPLE CONCENTRATION (MOLAR) 786-O-O- A498- -<>- - ACHN- - -a- - - CAK-1: ....O..... RXF 393 - - O - - SN12C -- 0--- TK-10--- A.- ... UO31-...- ... Fig. 25 PROSTRATE CANCER H s O 1. CD l O CD CC 2. Lll O li 1 O -9 -8 -7 -6 LOGo OF SAMPLE CONCENTRATION (MOLAR) PC-3-O- DU-145-Fig. -O-- 26 Patent Application Publication Jun. 3, 2004 Sheet 14 of 14 US 2004/0106589 A1 BREAST CANCER 1 OO C H s O Y CD |- O Ll CD CC - 2. II C) Y Cl - 1 O g - -7 T -6 LOGo OF SAMPLE CONCENTRATION (MOLAR) MCF 7 -O- MDA-N--0-- HS 578T.O. MDA-MB-435- - - - MDA-ME-231/- - A - - T-47D-...- MCF 7/ADR-RE--Q-- BT-549-...-A-...- Fig. 27 US 2004/0106589 A1 Jun. 3, 2004 FATTY ACID-PHARMACEUTICAL AGENT 0006 Taxol has the following formula: CONJUGATES AcO O OH BACKGROUND OF THE INVENTION R 0001 Improving drug selectivity for target tissue is an "YNH O established goal in the medical arts. In general, it is desirable to deliver a drug Selectively to its target, So that dosage and, -Nulls III IIH consequently, Side effects can be reduced. This is particu Pir Y. So i Nlo larly the case for toxic agents Such as anti-cancer agents OH HO s 5Ac because achieving therapeutic doses effective for treating the PhCO2 cancer is often limited by the toxic side effects of the anti-cancer agent on normal, healthy tissue.
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