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(12) United States Patent (10) Patent No.: US 7,148,352 B2 ROSS Et Al

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(12) United States Patent (10) Patent No.: US 7,148,352 B2 ROSS Et Al US007 148352B2 (12) United States Patent (10) Patent No.: US 7,148,352 B2 ROSS et al. (45) Date of Patent: Dec. 12, 2006 (54) METHOD OF INHIBITING WO WO 98,52919 11, 1998 NEUROTROPHIN-RECEPTOR BINDING WO WOOOOO472 1, 2000 (75) Inventors: Gregory M. Ross, Kingston (CA); Igor L. Shamovsky, Kingston (CA); Sandra Marone, Kingston (CA); Donald F. OTHER PUBLICATIONS Weaver, Kingston (CA); Richard J. Riopelle, Kingston (CA) Brana, M.F., et al. “Enediynes as Antitumor Compounds: Synthesis of Tetrahydropyridine Derivatives'. J. Org. Chem. 61: 1369-1374 (73) Assignee: Queen's University at Kingston, (1996). Kingston (CA) Brana, M.F., et al. “Synthesis and cytostatic activity of benz(de)isoquinolin-1,3-diones. Structure-activity relationships'. (*) Notice: Subject to any disclaimer, the term of this Eur, J. Med. Chem-Chimca. Therapeutica, 16(3): 207-212 (May-Jun. patent is extended or adjusted under 35 1981). U.S.C. 15 4(b) by 441 days. Arient, J. and Marhan J., Imidazolfarbstoffe VI. Synthese und Eigenschaften des 1.2-Naptholylenbenzimidazols. Collection (21) Appl. No.: 10/219.31 9 Czechoslov, Chem. Commun. 26: 2774-2780 (1961). Nishizaki, S., Infrared spectra of N-substituted naphthalimides, (22) Filed: Aug. 16, 2002 Nippon Kagaki Zasshi 86(7): 696-9 (1965) (Japan). (From Chem. Abstracts, 1966, 64 (3), Abstract No. 3321e). (65) Prior Publication Data Jaen, J.C. et al., “Kynurenic Acid Derivatives Inhibit the Binding of Nerve Growth Factor (NGF) to the Low-Affinity p75 NGF Recep US 2003/O186901 A1 Oct. 2, 2003 tor”. J. Med. Chem. 38: 4439-4445 (1995). Spiegel, K. et al., “PD 90780, A Non Peptide Inhibitor of Nerve Related U.S. Application Data Growth Factor's Binding to the p75 NGF Receptor'. Biochemical (62) Division of applicatioin No. 09/562,721, filed on May and Biophysical Research Communications 217(2): 488-494 (Dec. 2, 2000, now Pat. No. 6,468,990. 14, 1995). Owolabi, J.B. et al., “Characterization of Antiallodynic Actions of (60) Provisional applicatioin No. 60/134,578, filed on May ALE-0540, a Novel Nerve Growth Factor Receptor Antagonist, in 17, 1999. the Rat'. J. of Pharmacology and Experimental Therapeutics 289(3): 1271-1276 (1999). (51) Int. C. Bailleux. V. et al., “Synthesis and Anticonvulsant Activity of Some CO7D 22/04 (2006.01) N-Phenylphthalimides”, Chem. Pharm. Bull. 42(9): 1817-1821 A6 IK 3/44 (2006.01) (1994). (52) U.S. Cl. ......................................... 546/98: 514/296 Bailleux. V. et al., “Anticonvulsant activity of some 4-amino-N- (58) Field of Classification Search .................. 546/98: phenylphthalimides and N-(3-amino-2- 514/296 methylphenyl)phthalimides), Biomed & Pharmacother 48: 95-101 See application file for complete search history. (1994). (56) References Cited (Continued) U.S. PATENT DOCUMENTS Primary Examiner D. Margaret Seaman (74) Attorney, Agent, or Firm—Omar A. Nassif 3,821,383 A 6, 1974 Sestanj ....................... 423,258 4,204,063 A 5, 1980 Brana et al. .................. 546/99 (57) ABSTRACT 4,254,109 A 3, 1981 Sestanj ....................... 424,178 4,874,863. A 10, 1989 Brana et al. .................. 540/99 5, 183,821 A 2, 1993 Brana et al. ... 514,296 5,342,942 A 8, 1994 Jaen et al. ... ... 544,250 The present invention relates to compositions which inhibit 5,420,137 A 5, 1995 Brana et al. ... 514,296 the binding of nerve growth factor to the p75' common 5,552,544 A 9, 1996 Bra na et al. ... 544,126 neurotrophin receptor and methods of use thereof. In one 5,554,622 A 9, 1996 Brana ......................... 514,284 embodiment, the compound which inhibits binding of nerve 5,616,589 A 4, 1997 Keilhauer et al. .......... 514,296 growth factor to p75' comprises, particularly when bound 6,029, 114 A 2, 2000 Shamovsky et al. .......... 702/22 to nerve growth factor, at least two of the following: (1) a 6,291.247 1 9, 2001 Riopelle et al. ............... 436.2 first electronegative atom or functional group positioned to 6,300,331 B 1 10, 2001 Noguchi et al. .............. 31,473 interact with Lys of nerve growth factor; (2) a second electronegative atom or functional group positioned to inter FOREIGN PATENT DOCUMENTS act with Lys of nerve growth factor; (3) a third electrone AU 43963/09 1, 2000 gative atom or functional group positioned to interact with DE 2323555. A 8, 1974 Lys of nerve growth factor; (4) a fourth electronegative DE 3707652 A1 9, 1988 atom or functional group positioned to interact with Lys of EP O 206 322 A2 12, 1986 nerve growth factor; and (5) a hydrophobic moiety which EP O 268 093 A1 5, 1988 FR 2521 139 A 8, 1983 interacts with the hydrophobic region formed by Ile', WO WO 98,17278 4f1998 Phe' and Phe of nerve growth factor. WO WO 98.171278 * 4f1998 WO WO 98,34632 8, 1998 19 Claims, 5 Drawing Sheets US 7,148,352 B2 Page 2 OTHER PUBLICATIONS the Hypolipidemic Activity of N-Substituted Imides'. J. Pharma ceutical Sciences 72(11): 1344-1347 (1983). Shibata, Y. et al., “Phenylphthalimides with Tumor Necrosis Factor Chapman, J.M. Jr. et al., “Hypolipidemic Activity of Phthalimide Alpha Production-Enhancing Activity”, Chem. Pharm. Bull. 44(1): Derivatices V: Reduced and Hydrolytic Products of Simple Cyclic 156-162 (1996). Imides”. J. Pharmaceutical Sciences 73(10): 1482-1484 (1984). Chapman, J.M. Jr. et al., “Hypolipidemic Activity of Phthalimide Tyman J.H.P., “Fluorescent naphthalimide dyes', Chemical Derivatives. 2. N-Phenylphthalimide and Derivatives”. J. Med. Abstract 108: 7506 (1997). Chem. 26:237-243 (1983). Chemical Abstracts 88:1543.05. Chapman, J.M. Jr. et al., “Hypolipidermic Activity of Phthalimide Szadowski et al., “Przemysl Chemizny” 57(2): 70-74 (1978). Derivatives. 3. A Comparison of Phthalimide and 1.2- Bailleux. V. et al., “Comparative Anticonvulsant Activity and Benisothiazolin-3-one 1,1-Dioxide Derivatives to Phthalimidine Neurotoxicity of 4-Amino-N-(2,6-Dimethylphenyl)Phthalimide and 1.2-Benzisothiazoline 1,1-Dioxide Congeners”. J. Med. Chem. and Prototype Antiepileptic Drugs in Mice and Rats.” Epilepsia 26: 243-246 (1983). 36(6):559-565 (1995). Chapman, J.M. Jr. et al., “Hypolipidemic Activity of Phthalimide Derivatives IV: Further Chemical Modification and Investigation of * cited by examiner U.S. Patent Dec. 12, 2006 Sheet 1 of 5 US 7,148,352 B2 A 45-70 A B- 4.5-7.5. A (6 bonds) (6-8 bonds) \ 5,5-7.5. A B- 4.5-7.5A (7 bonds) (6-8 bonds) c A-C denote electronegative ators Fig. 1 n = 3 - 5 U.S. Patent Dec. 12, 2006 Sheet 2 of 5 US 7,148,352 B2 Q Q M Q A Horn-C Hics-C orN 'N A A A OH F SH A A N O o, t OH HN1 N ass U.S. Patent Dec. 12, 2006 Sheet 3 of 5 US 7,148,352 B2 O 2 C MeCO 2 C O MeCOCHCI S. Sn PhP (Wittig Reaction) Mego O O C Diels Alder N H C O C O OPg C C O O Deprotection2 N N Dehydration dur-a-a-a-al H H V (PPA) PPA=Poly Phosphoric Acid Fig. 3 U.S. Patent Dec. 12, 2006 Sheet S of 5 US 7,148,352 B2 t 8 8 t L O-E-O 3 O8 O8 CD O ---------- O o C SN \ / 3. ar if n? O 3E to - (-i or OC t 5 O 2. -O \ / O O 5 US 7,148,352 B2 1. 2 METHOD OF INHIBITING p75' has been demonstrated to participate in human NEUROTROPHIN-RECEPTOR BINDING melanoma progression (Herrmann et al., 1993; Marchetti et al., 1996). Furthermore, NGF and NT-3 increase the pro RELATED APPLICATION duction of heparin by 70 W melanoma cells, which is associated with their metastatic potential (Marchetti et al., This application is a divisional of U.S. patent application 1996). Although this effect has been shown to be mediated Ser. No. 09/562,721, filed May 2, 2000 now U.S. Pat. No. by the common neurotrophin receptor, neither BDNF nor 6.468,990, which claims the benefit under 35 U.S.C. S 119(e) NT-4/5 appeared to be active. to U.S. provisional patent application 60/134,578, filed May Due to the implication of NGF/p75' binding in various 17, 1999, the contents of each of which are hereby incor 10 disease states, a need exists for pharmaceutical agents and porated by reference. methods of use thereof for interfering with the binding of NGF to the p75' common neurotrophin receptor. BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION The neurotrophins are a family of structurally and func 15 tionally related proteins, including Nerve Growth Factor The present invention relates to the discovery of molecu (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neu lar structural features which contribute to the ability of a rotrophin-3 (NT-3), Neurotrophin-4/5 (NT-4/5) and Neu compound to inhibit the binding of NGF to the common rotrophin-6 (NT-6). These proteins promote the survival and neurotrophin receptor p75'. Compounds which have differentiation of diverse neuronal populations in both the these features are of use, for example, for inhibiting binding peripheral and central nervous systems (Hefti, 1986; Hefti of NGF to p75'. Such compounds can also be used to treat and Weiner, 1986; Levi-Montalcini, 1987; Barde, 1989: a patient having a condition which is mediated, at least in Leibrock et al., 1989; Maisonpierre et al., 1990; Rosenthal part, by the binding of NGF to ps'. et al., 1990; Hohnet al., 1990: Gotz et al., 1994; Maness et In one embodiment, the present invention relates to com al., 1994) and are involved in the pathogenesis of diverse 25 positions which inhibit the binding of nerve growth factor to neurological disorders.
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