IP Library › Granted Patent US 9,133,172

Granted Patent B2

US 9,133,172 · App. 14/375,061 · Granted Sep 15, 2015

Dihydrofuran azetidine derivatives as antiparasitic agents

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,133,172
App. No.: 14/375,061
Granted: Sep 15, 2015
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

This invention recites dihydrofuran substituted azetidine derivatives of Formula (1) stereoisomers thereof, veterinarily acceptable salts thereof, compositions thereof, and their use as a parasiticide in mammals and birds. The substituents A, R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 6 , and n are as described herein.

Claims (91)

1. A compound of Formula (1)

wherein

A is phenyl, naphthyl, or heteroaryl where said heteroaryl contains 1 to 4 heteroatoms each independently selected from N, O and S;

R 1a , R 1b , and R 1c are each independently hydrogen, halo, hydroxyl, cyano, nitro, C 1- C 6 alkyl, C 1- C 6 haloalkyl, C 1- C 6 alkoxy, C 0- C 3 alkylC 3- C 6 cycloalkyl, C 1 -C 6 haloalkoxy, —C(O)NH 2 , —SF 5 , or —S(O) p R;

R 2 is halo, cyano, C 1- C 6 alkyl, C 1- C 6 haloalkyl, nitro, hydroxyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —S(O) p R, or —OR;

R 3 is hydrogen, halo, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 0 -C 3 alkylC 3 -C 6 cycloalkyl, —C(O)NH 2 , nitro, —SC(O)R, —C(O)NR a R b , C 0 -C 3 alkylNR a R 4 , —NR a NR b R 4 , —NR a OR b , —ONR a R b , N 3 , —NHR 4 , —OR, or —S(O) p R;

R 4 is hydrogen, C 1 -C 6 alkyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, —C(O)R 5 , —C(S)R 5 , —C(O)NR a R 5 , —C(O)C(O)NR a R 5 , —S(O) p R c , —S(O) 2 NR a R 5 , —C(NR 7 )R 5 , —C(NR 7 )NR a R 5 , C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle;

R 5 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkyl heterocycle;

R 6 is cyano, C 1 -C 6 haloalkyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkenyl, or C 2 -C 6 haloalkynyl;

R 7 is hydrogen, C 1 -C 6 alkyl, hydroxyl, cyano, nitro, —S(O) p R c , or C 1 -C 6 alkoxy;

R is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl each optionally substituted by at least one halo;

R a is hydrogen, C 1 -C 6 alkyl, or C 0 -C 3 alkylC 3 -C 6 cycloalkyl; wherein the alkyl and alkylcycloalkyl is optionally substituted by cyano or at least one halo substituent;

R b is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 0 -C 3 alkylphenyl, C 0 -C 3 alkylheteroaryl, or C 0 -C 3 alkylheterocycle, each optionally substituted, where chemically possible, with at least one substituent selected from hydroxyl, cyano, halo, or —S(O) p R;

R c is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkylC 3 -C 6 cycloalkyl, C 0 -C 3 alkylC 3 -C 6 cycloalkyl, C 0 -C 3 alkylphenyl, C 0 -C 3 alkylheteroaryl, or C 0 -C 3 alkylheterocycle each optionally substituted with at least one substituent selected from cyano, halo, hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, —S(O) p R, —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R b , —SCN, or —C(O)NR a R b ;

each of R 4 and R 5 C 1 -C 6 alkyl or C 0 -C 6 alkylC 3 -C 6 cycloalkyl can be optionally and independently substituted by at least one substituent selected from C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, cyano, halo, hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, —S(O) p R c , —SH, —S(O) p NR a R b , —NR a R b , —NR a C(O)R b , —SC(O)R b , —SCN, or —C(O)NR a R b ; and

wherein R 4 and R 5 C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle moiety can be further optionally substituted with at least one substituent selected from C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, cyano, halo, oxo, ═S, ═NR 7 , hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —SH, —S(O) p R, and C 1 -C 6 haloalkoxy;

n is the integer 0, 1, or 2, and when n is 2, each R 2 may be identical or different from each other; and

p is the integer 0, 1, or 2;

stereoisomers thereof, and pharmaceutically or veterinarily acceptable salts thereof.

2. The compound of claim 1 having Formula (2a), (2b), or (6a)

wherein

R 1a , R 1b , and R 1c are each independently selected from hydrogen, halo, hydroxyl, and C 1 -C 6 haloalkyl;

R 2 is halo, cyano, hydroxyl, —C(O)NR a R b , or —OR; and

R 3 is hydrogen, halo, hydroxyl, N 3 , or cyano;

stereoisomers thereof, and pharmaceutically or veterinarily acceptable salts thereof.

3. The compound of claim 2 having Formula (2a)

wherein

R 1a , R 1b , and R 1c are each independently selected from hydrogen, halo, and C 1 -C 6 haloalkyl; and

R 3 is hydrogen, halo, hydroxyl, or cyano;

stereoisomers thereof, and pharmaceutically or veterinarily acceptable salts thereof.

4. The compound of claim 3 wherein

R 4 is —C(O)R 5 , —C(O)NR a R 5 , —S(O) p R c , —C(S)R 5 , —S(O) 2 NR a R 5 , —C(NR 7 )R 5 ; or —C(NR 7 )NR a R 5 ;

stereoisomers thereof, and pharmaceutically or veterinarily acceptable salts thereof.

5. The compound of claim 4 wherein

R 1a , R 1b , and R 1c are each independently selected from hydrogen, chloro, fluoro, bromo, and C 1 -C 6 haloalkyl; and

R 4 is —C(O)R 5 , —C(O)NR a R 5 , or —C(NR 7 )R 5 ;

stereoisomers thereof, and pharmaceutically or veterinarily acceptable salts thereof.

6. The compound of claim 5 of Formula (2a) having Formula (2c)

wherein

R 1a , R 1b , and R 1c are each independently selected from hydrogen, chloro, fluoro, and C 1 -C 6 haloalkyl;

stereoisomers thereof, and pharmaceutically or veterinarily acceptable salts thereof.

7. A compound of claim 6 selected from the group selected from:

1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)phenyl)-3-fluoroazetidin-1-yl)-2-(methylsulfonyl)ethanone;

1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)phenyl)-3-fluoroazetidin-1-yl)-2-methylpropan-1-one;

1-(3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-2-methanesulfonyl-ethanone;

1-(3-Fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-di-hydro-furan-3-yl]-phenyl}-azetidin-1-yl)-2-methyl-propan-1-one;

1-(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-2-methanesulfonyl-ethanone; and

1-(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-furan-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-2-methyl-propan-1-one, stereoisomers thereof, and pharmaceutically or veterinarily acceptable salts thereof.

8. A pharmaceutical or veterinary composition comprising a therapeutic amount of a compound of Formula (1)

wherein

A is phenyl, naphthyl, or heteroaryl where said heteroaryl contains 1 to 4 heteroatoms each independently selected from N, O and S;

R 1a , R 1b , and R 1c are each independently hydrogen, halo, hydroxyl, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 0 -C 3 alkylC 3 -C 6 cycloalkyl, C 1 -C 6 haloalkoxy, —C(O)NH 2 , —SF 5 , or —S(O) p R;

R 2 is halo, cyano, C 1- C 6 alkyl, C 1 -C 6 haloalkyl, nitro, hydroxyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —S(O) p R, or —OR;

R 3 is hydrogen, halo, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 0 -C 3 alkylC 3 -C 6 cycloalkyl, —C(O)N H 2 , nitro, —SC(O)R, —C(O)NR a R b , C 0 -C 3 alkylNR a R 4 , —NR a NR b R 4 , —NR a OR b , —ONR a R b , N 3 , —NHR 4 , —OR, or —S(O) p R;

R 5 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 0 -C 6 alkylC 3 -C 6 cycloalkyl, C 0 -C 6 alkylphenyl, C 0 -C 6 alkylheteroaryl, or C 0 -C 6 alkylheterocycle;

R 6 is cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —C(O)NR a R b , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 haloalkenyl, or C 2 -C 6 haloalkynyl;

R 7 is hydrogen, C 1 -C 6 alkyl, hydroxyl, cyano, nitro, —S(O) p R c , or C 1 -C 6 alkoxy;

R is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl each optionally substituted by at least one halo;

R a is hydrogen, C 1 -C 6 alkyl, or C 0 -C 3 alkylC 3 -C 6 cycloalkyl; wherein the alkyl and alkylcycloalkyl is optionally substituted by cyano or at least one halo substituent;

n is the integer 0, 1, or 2, and when n is 2, each R 2 may be identical or different from each other; and

p is the integer 0, 1, or 2;

stereoisomers thereof, and pharmaceutically or veterinarily acceptable salts thereof.

9. The pharmaceutical or veterinary composition of claim 8 further comprising a pharmaceutically or veterinarily acceptable excipient, diluent, or carrier.

10. The pharmaceutical or veterinary composition of claim 9 further comprising at least one additional veterinary agent.

11. The pharmaceutical or veterinary composition of claim 10 wherein said additional veterinary agent is selected from the group consisting of abamectin, ivermectin, avermectin, moxidectin, emamectin, eprinomectin, selamectin, doramectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfenbendazole, oxibendazole, parbendazole, tetramisole, levamisole, pyrantel pamoate, oxantel, morantel, indoxacarb, closantel, triclabendazole, clorsulon, refoxanide, niclosamide, praziquantel, epsiprantel, 2-desoxoparaherquamide, pyripole, pyrafluprole, lufenuron, spiromesifen, tebufenozide, spinosad, spinetoram, imidacloprid, dinotefuran, metaflumizone, thibendiamide, chlorantraniliprole, indoxacarb, pyridalyl, pyrimidifen, pyrifluquinazon, milbemycin oxime, milbemycin, DEET, demiditraz, amitraz, fipronil, methoprene, hydroprene, novaluron, lufenuron, permethrin, and pyrethrin, or mixtures thereof.

12. The pharmaceutical or veterinary composition of claim 11 wherein said additional veterinary agent is milbemycin oxime or moxidectin.

13. A method for the treatment of an animal with a parasitic infection or infestation comprising administering to said animal in need thereof an effective amount of a compound of Formula (1)