USOO7514464B2 (12) United States Patent (10) Patent No.: US 7.514.464 B2 Billen et al. (45) Date of Patent: *Apr. 7, 2009 (54) SUBSTITUTEDARYLPYRAZOLES EP O295227 5, 1988 EP O295,117 6, 1988 (75) Inventors: Denis Billen, Sandwich (GB); Nathan EP O295.118 12, 1988 Anthony Logan Chubb, Sandwich EP O273862 7, 1991 (GB); David Morris Gethin, Sandwich EP O57928O 1, 1994 EP O234119 8, 1994 (GB); Kim Thomas Hall, Sandwich EP O780378 6, 1997 (GB); Lee Richard Roberts, Sandwich EP O9333.63 8, 1999 (GB); Nigel Derek Arthur Walshe, EP O957094 11, 1999 Sandwich (GB) GB 1586258 3, 1981 GB 2O853O2 4f1982 (73) Assignee: Pfizer Limited, Sandwich, Kent (GB) WO WO93/06089 4f1993 WO WO94, 16732 8, 1994 (*) Notice: Subject to any disclaimer, the term of this WO WO95/242.19 9, 1995 patent is extended or adjusted under 35 WO WO97/O71O2 2, 1997 U.S.C. 154(b) by 334 days. WO WO97/O72O2 2, 1997 WO WO97,116O2 4f1997 WO WO97/12521 4f1997 This patent is Subject to a terminal dis- WO WO97,36483 10, 1997 Ca10. WO WO97,36484 10, 1997 WO WO97,36485 10, 1997 (21) Appl. No.: 11/153,103 WO WO97,36486 10, 1997 WO WO98,24767 6, 1998 (22) Filed: Jun. 15, 2005 OTHER PUBLICATIONS (65) Prior Publication Data Elkaschefet al., Chemical Abstracts, vol. 81, No. 1520695, 1974. US 2006/OO148O2A1 Jan. 19, 2006 Primary Examiner Kamal A Saeed (74) Attorney, Agent, or Firm—Lucy X. Yang; Paul M. Misiak Related U.S. Application Data (63) Continuation-in-part of application No. 11/013,176, (57) ABSTRACT filed on Dec. 15, 2004. This invention relates to a combination product comprising a (60) Provisional application No. 60/.571,337, filed on May compound of formula I 13, 2004. (30) Foreign Application Priority Data (I) Dec. 8, 2003 (GB) ................................. O3293.14.9 (51) Int. Cl. A6 IK 3/4439 (2006.01) CO7D 23 L/10 (2006.01) (52) U.S. Cl. .................................... 514/406; 548/377.1 (58) Field of Classification Search ................. 514/406; 548/377.1 See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS 5,232,940 A 8, 1993 Hatton et al. ............... 514,406 5,547,974 A 8, 1996 Hatton et al. ............... 514,407 wherein X, R', R. R. R. R. R. R7 and Rare as described FOREIGN PATENT DOCUMENTS herein, and one or more further biologically active com EP OOSO335 10, 1981 pounds as described herein, particularly anti-parasitic agents. EP O2494.09 12/1987 EP O280991 2, 1988 16 Claims, No Drawings US 7,514,464 B2 1. 2 SUBSTITUTED ARYLPYRAZOLES wherein: R" is CF, OCF, H, OCF, SCF, -SOCF, -SOCF, or CROSS-REFERENCE TO RELATED SFs: APPLICATIONS R’ is H, fluoro, or C, alkyl optionally substituted by 1 to 5 5 halogen atoms independently selected from chloro and This application is a Continuation-in-Part of application fluoro; Ser. No. 11/013,176, filed on Dec. 15, 2004, now pending, R. R. R. and R independently represent H, C alkyl which claims the benefit of U.S. provisional application Ser. optionally Substituted by 1 to 5 halogen groups indepen No. 60/.571,337, filed May 13, 2004, and claims the benefit of dently selected from chloro and fluoro, or a chloro or United Kingdom Application No. 03293.14.9, filed Dec. 18. 10 fluoro; 2003, which are incorporated herein by reference. R’ is C1 or fluoro; X is CR or N where R is C1 or fluoro; and FIELD OF THE INVENTION R is NRR): This invention relates to a combination product comprising R" is selected from hydrogen, Ce alkyl, Calkenyl, Cs a pyrazole derivative of formula (I) in combination with one 15 cycloalkyl, C(O)CC alkyl and C alkanoyl, wherein or more biologically active compounds as described herein, each of the above groups may include one or more optional particularly anti-parasitic agents. The compounds of interest substituents where chemically possible independently of formula (I) are cyclopropylarylpyrazoles and, more par selected from halo, het, phenyl, hydroxy, —C(O)OH, ticularly, the invention relates to 1-aryl-4-cyclopropylpyra —C(O)O C. alkyl, C. alkyl, C. haloalkyl, Cs Zoles in which there is at least one fluorine attached to the cycloalkyl, Calkoxy, Chaloalkoxy, amino, Calkyl cyclopropyl ring. amino and di C-alkyl amino; International Patent Application Publication No. (WO) R’ is selected from hydrogen, C, alkyl, Calkenyl, C. 9824767, European Patent Application Publication No. (EP) alkanoyl and C(O)CC alkyl, wherein each of the above 933363 and EP957094 describe 4-cyclopropylarypyrazoles groups may include one or more optional Substituents having parasiticidal activity for the control of arthropods. 25 where chemically possible independently selected from, The prior art compounds do not always demonstrate good halo, phenyl, hydroxy, —COOH, —C(O)OC-alkyl, C. activity or a long duration of action against parasites. Simi alkyl, Co haloalkyl, Css cycloalkyl, Co alkoxy, C. larly, some parasiticidal agents are useful only for a narrow haloalkoxy, amino, Ce alkyl amino and di C. alkyl spectrum of parasites. It is an aim of the present invention to amino; overcome various disadvantages of or improve on the prop 30 erties of prior art compounds. Thus it is an aim of the inven or R and R together with the Natom to which they are tion to provide an arylpyrazole which has improved activity attached may form a three to seven-membered heterocyclic relative to prior art compounds against parasites. The com ring containing one or more further N, O or S atoms and pounds of the present invention have especially good ability wherein said heterocyclic ring may bear one or more to control a broad spectrum of arthropods as shown by the optional Substituents selected from oxo, halo, het, phenyl, results of tests demonstrating their potency and efficacy. In 35 hydroxy, —COOH, -C(O)OC alkyl, Ce alkyl, C. particular, the compounds of the present invention are signifi haloalkyl, Cs cycloalkyl, C. alkoxy, Chaloalkoxy, cantly more active against fleas than similar prior art com amino, Calkyl amino and di Ce alkyl amino; and pounds. het represents a four- to seven-membered heterocyclic group, It is a further aim to provide compounds with a long dura which is aromatic or non-aromatic and which contains one tion of action. Most preferably, the compounds control infes 40 or more heteroatoms selected from nitrogen, oxygen, Sul tation by arthropods for a period of at least twenty-eight days. fur and mixtures thereof, and wherein said heterocyclic The extended duration of action is generally attributed to an ring is optionally substituted, where the Valence allows, extended half life of the compound in vivo in the host mam with one or more Substituents selected from halo, cyano, mal. nitro, Ce alkyl, Ce haloalkyl, Ce alkoxy, OC(O)Cl. It is also desirable that the compounds of the present inven 45 alkyl, C(O)Cl. alkyl, C(O)OC, alkyl and NRR", where tion should have an improved pharmacokinetic profile, RandR are independently selected from hydrogen, C. improved safety, improved persistence and improved solubil alkyl and Coalkenyl, wherein each of the above groups ity. may include one or more optional Substituents where Thus, according to the present invention, there is provided chemically possible independently selected from halo, a compound of formula (I): 50 phenyl, hydroxy, —COOH, C(O)OC alkyl, C. alkyl, Co haloalkyl, Css cycloalkyl, Co alkoxy, C. (I) R5 haloalkoxy, amino, Ce alkyl amino and di C. alkyl R6 R4 amino; or a pharmaceurtically acceptable salt or prodrug thereof 55 NC with the proviso that at least one of R. R. R. R. or R is R2 R3 fluoro. ( \ In the compounds of formula (I) within the scope of this YN R9 invention, the variables of said formula (I) (ie, R', R. R. R. 60 R. R. R. R. R. R. R', and X) may have any definition R provided herein for that specific variable. Formula I and For 21 mula (I) are used interchangeably. In the compounds according to formula (I), Chaloalky N or Chaloalkoxy means a Chalky or C. alkoxy Substi 65 tuted by 1 to 5 chloro or fluoro groups chosen independently. RI Also, halo means a group selected from fluoro, bromo, chloro, bromo or iodo. US 7,514,464 B2 5 6 5-amino-1-2,6-dichloro-4-pentafluorothiophenyl]-4-1-(di prodrugs.” Textbook of Drug Design and Discovery, (3" Edi fluoromethyl)-2,2,3,3-tetrafluorocyclopropyl)-1H-pyra tion), 2002, 410-458, (Taylor and Francis Ltd., London); and Zole-3-carbonitrile; references therein. Isopropyl 3-cyano-1-2,6-dichloro-4-(trifluoromethyl)phe Suitable prodrugs may have an N-containing group at the nyl-4-2,2-difluoro-1-(trifluoromethyl)cyclopropyl)-1H 5-position of the pyrazole ring /////of formula (I) and are pyrazol-5-ylcarbamate; bound to the ring through N. The 5-N group can be substituted pyridin-4-ylmethyl 3-cyano-1-2,6-dichloro-4-(trifluorom once or twice. Examples of substituents include: alkyl ethyl)phenyl]-4-2,2-difluoro-1-(trifluoromethyl)cyclo amines, aryl amines, amides, ureas, carbamates, cyclic car propyl)-1H-pyrazol-5-ylcarbamate; bamates, imines, enamines, imides, cyclic imides, Sulfena pyridin-3-ylmethyl 3-cyano-1-2,6-dichloro-4-(trifluorom mides, and sulfonamides. The hydrocarbon portion of these ethyl)phenyl]-4-2,2-difluoro-1-(trifluoromethyl)cyclo 10 groups contain Ce alkyl, phenyl, heteroaryl Such as pyridyl, propyl)-1H-pyrazol-5-yl-carbamate; Calkenyl, and Cs cycloalkyl, wherein each of the above pyridin-2-ylmethyl 3-cyano-1-2,6-dichloro-4-(trifluorom groups may include one or more optional Substituents where ethyl)phenyl]-4-2,2-difluoro-1-(trifluoromethyl)cyclo chemically possible independently selected from: halo: propyl)-1H-pyrazol-5-ylcarbamate; hydroxy, Calkyl and C alkoxy.