US 20140121152A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0121152 A1 Jenkins et al. (43) Pub. Date: May 1, 2014 (54) ACTIVE AGENT PRODRUGS WITH Publication Classification HETEROCYCLIC LINKERS (51) Int. C. C07K5/06 (2006.01) (75) Inventors: Thomas E. Jenkins, Half Moon Bay, A638/05 (2006.01) CA (US); Craig O. Husfeld, San Mateo, A6II 45/06 (2006.01) CA (US) C07K5/08 (2006.01) A638/06 (2006.01) (73) Assignee: Signature Therapeutics, Inc., Palo Alto, (52) U.S. C. CA (US) CPC. C07K5/06 (2013.01); C07K5/08 (2013.01); A6 IK38/06 (2013.01); A61K 45/06 (2013.01); (21) Appl. No.: 14/000,594 A6 IK38/05 (2013.01) USPC 514/1.3: 530/331:546/44; 546/226,544/361 (22) PCT Fled: Mar. 8, 2012 (57) ABSTRACT (86) PCT NO.: PCT/US12/28367 The embodiments provide prodrug compounds of Formulae S371 (c)(1), I-XVII. The present disclosure also provides compositions, (2), (4) Date: Dec. 27, 2013 and their methods of use, where the compositions comprise a prodrug compound of Formulae I-XVII that provides con trolled release of an active agent. Such compositions can Related U.S. Application Data optionally provide a trypsin inhibitor that interacts with the (60) Provisional application No. 61/451,019, filed on Mar. enzyme that mediates the controlled release of an active agent 9, 2011, provisional application No. 61/583,523, filed from the prodrug so as to attenuate enzymatic cleavage of the on Jan. 5, 2012. prodrug. Patent Application Publication May 1, 2014 Sheet 1 of 26 US 2014/O121152 A1 Figure 1 A. ---. x N srax °, w y . %. '. '. thiitor Patent Application Publication May 1, 2014 Sheet 2 of 26 US 2014/O121152 A1 Figure 2 38ts s S. SSS Srs Patent Application Publication May 1, 2014 Sheet 3 of 26 US 2014/O121152 A1 Figure 2 (continued) 3S 8. Patent Application Publication May 1, 2014 Sheet 4 of 26 US 2014/O121152 A1 Figure 3 Site, - &FES fi & s s H H Fiss SSS $s ELS&S ISS & PSE { R&FE: s & ........ : s al s E. & & & s s 8 s *:::SF:SESS $3. Lists RSSS 8:S E ; F S s I 8. ESSESSS SSSSSSSS: Patent Application Publication May 1, 2014 Sheet 5 of 26 US 2014/O121152 A1 Figure 4 -O OC from Oxycodone (28 umol/kg) -be OC from Compound KC-9 (31 umol/kg) - OC from Compound KC-11 (34 umol/kg) 1OO OC from Compound KC-12 (29 umol/kg) - OC from Compound KC-13 (29 umol/kg) -- OC from Compound KC-14 (29 umol/kg) -0. OC from Compound KC-15 (29 umol/kg) 10 -- OC from Compound KC-16 (29 umol/kg) - OC from Compound KC-17 (28 umol/kg) S o C g : 1 e x 9. O.1 O.O1 Time, hr Patent Application Publication May 1, 2014 Sheet 6 of 26 US 2014/O121152 A1 Figure 5A -A OC from Oxycodone (5.7 umol/kg) -0- OC from 20 mg OxyContin Tablet -e OC from Compound KC-12 (5.7 umol/kg) -H OC from Compound KC-13 (5.7umol/kg) -e OC from Compound KC-14 (5.7 umol/kg) OC from Compound KC-15 (5.7 umol/kg) as OC from Compound KC-16 (5.8 umol/kg) cHe OC from Compound KC-17 (5.8 umol/kg) - S 2 10 o o S 1 5 0.1 OO1 Time, hr Figure 5B 1000 -o- OC from Compound KC-17 (5.8 umol/kg) -A OC from Oxycodone (5.7umol/kg) -0- OC from 20 mg OxyContin Tablet -H OC from Compound KC-3 (5.7 umol/kg) E o O s O ce g 9. Time, hr Patent Application Publication May 1, 2014 Sheet 7 of 26 US 2014/O121152 A1 Figure 6A -o- OC from Compound KC-12 (6.5 pmol/kg) 1OO -H OC from Compound KC-12 (29 umol/kg) - 10 S d 5 1 O ce X 9. O.1 0.01 O 6 12 18 24 Time, hr Figure 6B -o- OC from Compound KC-17 (6 umol/kg) 1OO -- OC from Compound KC-17 (28 umol/kg) -- OC from Compound KC-17 (60 umol/kg) 1O S O d 5 1 s O 9 e x O. O.1 O.O1 O 6 12 18 24 Time, hr Patent Application Publication May 1, 2014 Sheet 8 of 26 US 2014/O121152 A1 Figure 7A -O OC from Compound KC-12 (6.5umol/kg) -H OC from Compound KC-12 ((6.5umol/kg) ) + Compound 109 (0.2 umol/kg) site OC from Compound KC-12 (6.5umol/kg) + Compound 109 (0.9 umol/kg) -0. OC from Compound KC-12 ((6.5umol/kg) ) + Compound 109 (1.9 umol/kg) 4. S. d 5 2 "O O d 9. 24 Time, hr Figure 7B -O- OC from Compound KC-17 (6 umol/kg) -- OC from Compound KC-17 (6 umol/kg) + Compound 109 (0.2 umol/kg) -A- OC from Compound KC-17 (6 umol/kg) + Compound 109 (0.9 umol/kg) -0. OC from Compound KC-17 (6 umol/kg) + Compound 109 (1.9 umol/kg) Patent Application Publication May 1, 2014 Sheet 9 of 26 US 2014/O121152 A1 Figure 7C -O- OC from Compound KC-17 (60 umol/kg) -H OC from Compound KC-17 (60 umol/kg) + Compound 109 (1.9 umol/kg) -- OC from Compound KC-17 (60 umol/kg) + Compound 109 (9.3 umol/kg) -0- OC from Compound KC-17 (60 umol/kg) + Compound 109 (18.5umol/kg) 40 23 OO 1 O Patent Application Publication May 1, 2014 Sheet 10 of 26 US 2014/O121152 A1 Figure 8 -O Tapentadol from Compound TP-5 (34 umol/kg) H. Tapentadol from Compound TP-5 (34 umol/kg) + Compound 109 (55 umol/kg) 2. O. O 6 12 18 24 Time, hr Patent Application Publication May 1, 2014 Sheet 11 of 26 US 2014/O121152 A1 Figure 9 -- Hydrocodone from Compound KC-31 (28 umol/kg) 's. -o- Hydrocodone from Compound KC-31 (12 mol/kg) 's. -- Hydrocodone from Compound KC-31 (6 umol/kg) + Hydrocodone from HC (30 umol/kg) - 8s 3 O) C 2 2 1 W - Y TN - - - - - - *.. O Nix O 1 2 3 4. 5 66 9 12 15 18 21 24 Time, hr Patent Application Publication May 1, 2014 Sheet 12 of 26 US 2014/O121152 A1 Figure 10 6 -O- Hydrocodone from HC (30 pmol/kg) -- Hydrocodone from Compound KC-32 (28 umol/kg) -- Hydrocodone from Compound KC-35 (24 umol/kg) -- Hydrocodone from Compound KC-36 (27 umol/kg) . --- Hydrocodone from Compound KC-37 (28 umol/kg) 4. 3 O 2 4 6 8 Time, hr Patent Application Publication May 1, 2014 Sheet 13 of 26 US 2014/O121152 A1 Figure 11 -O- Hydrocodone from HC (30 umol/kg) -- Hydrocodone from Compound KC-38 (28 umol/kg) be Hydrocodone from Compound KC-39 (28 umol/kg) Time, hr Patent Application Publication May 1, 2014 Sheet 14 of 26 US 2014/O121152 A1 Figure 12 6 -O- Hydrocodone from HC (30 pmol/kg) -H Hydrocodone from Compound KC-40 (28 umol/kg) 5 -- Hydrocodone from Compound KC-47 (28 umol/kg) -X- Hydrocodone from Compound KC-50 (28 umol/kg) Time, hr Patent Application Publication May 1, 2014 Sheet 15 of 26 US 2014/O121152 A1 Figure 13A 1O -o- Hydrocodone (HC) from Compound KC-40 (6 umol/kg) -th HC from Compound KC-40 (6 umol/kg) + Compound 109 (0.2 umol/kg) 8 be HC from Compound KC-40 (6 umol/kg) + Compound 109 (0.44 umol/kg) -- HC from Compound KC-40 (6 umol/kg) + Compound 109 (0.9mol/kg) d E 6 -- HC from Compound KC-40 (6 umol/kg) + Compound 109 (1.7 umol/kg) Os d d 9 Os e E. Time, hr Patent Application Publication May 1, 2014 Sheet 16 of 26 US 2014/O121152 A1 Figure 13B -- Hydrocodone from HC (30 umol/kg normalized to 65umol/kg) -- HC from Compound KC-40 (62 mol/kg) + Compound 109 (1.7 umol/kg) -)- HC from Compound KC-40 (62 mol/kg) + Compound 109 (4.4 umol/kg) -- HC from Compound KC-40 (62 umol/kg) + Compound 109 (9.0 umol/kg) -- HC from Compound KC-40 (62( mol/kg)) + Compound 109 (17.4( umol/kg) Time, hr Patent Application Publication May 1, 2014 Sheet 17 of 26 US 2014/O121152 A1 Figure 13C s Hydrocodone (HC) from Compound KC-50 (6 umol/kg) 12 es HC from Compound KC-50 (6 umol/kg) + Compound 109 0.2 Lmol/kg) a) HC from Compound KC-50 (6( umol/kg)) + Compound 109 0.44 umol/kg) es HC from Compound KC-50 (6 umol/kg ) + Compound 109 0.9 umol/kg) O -- HC from Compound KC-50 (6( umol/kg)) + Compound 109 1.7 umol/kg) 4. Time, hr Patent Application Publication May 1, 2014 Sheet 18 of 26 US 2014/O121152 A1 Figure 13D Hydrocodone from HC (30pumol/kg normalized to 67 umol/kg) 12 HC from Compound KC-50 (64 umol/kg) + Compound 109 (1.7 umol/kg) HC from Compound KC-50 (64 umol/kg) + Compound 109 (4.4 umol/kg) HC from Compound KC-50 (64 umol/kg) + Compound 109 (9.0 umol/kg) Time, hr Patent Application Publication May 1, 2014 Sheet 19 of 26 US 2014/O121152 A1 Figure 14A 80 -H Hydrocodone from HC (0.5umol/kg) -o-, HC from Compound KC-40 (0.1 umol/kg) -- HC from Compound KC-40 (0.5umol/kg) 60 --- HC from Compound KC-40 (2.0 umol/kg) 40 Patent Application Publication May 1, 2014 Sheet 20 of 26 US 2014/O121152 A1 Figure 14B 150 -- Hydrocodone from HC (0.5umol/kg) -o-, HC from Compound KC-40 (0.5umol/kg) + Compound 109 (0.14 umol/kg) 100 5 O Figure 14C 150 -H Hydrocodone from HC (0.5umol/kg normalized to 2 umol/kg) -o-, HC from Compound KC-40 (2.0 umol/kg) + Compound 109 (0.56 umol/kg) Time, hr Patent Application Publication May 1, 2014 Sheet 21 of 26 US 2014/O121152 A1 Figure 14D -H Hydrocodone from HC (0.5umol/kg normalized to 5umol/kg) 'T -- HC from Compound KC-40 (4.7amol/kg) + Compound 109 (14 amol/kg) i Time, hr Patent Application Publication May 1, 2014 Sheet 22 of 26 US 2014/O121152 A1 Figure 15A H Hydrocodone from HC (0.5umol/kg) 60 -o-, HC from Compound KC-50 (0.1 umol/kg) -- HC from Compound KC-50 (0.5umol/kg) -be- HC from Compound KC-50 (2 umol/kg) 4O 20 Time, hr Patent Application Publication May 1, 2014 Sheet 23 of 26 US 2014/O121152 A1 Figure 15B 15 -H Hydrocodone from HC (0.5umol/kg) -o-, HC from Compound KC-50 (0.5 pmol/kg) - HC from Compound KC-50 (0.5 pmol/kg) + Compound 109 (0.14 umol/kg) -- HC from Compound KC-50 (0.5 pmol/kg) + Compound 109 (0.28 umol/kg) E o d O o 8C e E.