IP Library › Granted Patent US 10,570,129

Granted Patent B2

US 10,570,129 · App. 15/735,686 · Granted Feb 25, 2020

Carboline antiparasitics

Inventors: Govindan Subramanian (Belle Mead, NJ); Michael P. Curtis (Portage, MI); Jinxia (Nancy) Deng (Portage, MI); Richard Andrew Ewin (Kalamazoo, MI); Christopher Scott Knauer (Kalamazoo, MI); Graham M. Kyne (Portage, MI); Tomasz Respondek (Kalamazoo, MI); Susan Mary Kult Sheehan (Galesburg, MI); John Adam Wendt (Mattawan, MI)

Assignee: Zoetis Services LLC

C07D471/04 A01N47/38

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Quick Facts

Patent No.: US 10,570,129
App. No.: 15/735,686
Granted: Feb 25, 2020
Kind: B2

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Abstract

The present invention provides Formula (1) compounds that are gamma-carbolines, Formula (1) wherein R1 a , R1 b , R1 c , R1 d , R2, R3, and “-” are as defined herein; veterinary acceptable salts thereof, and stereoisomers thereof, which act as parasiticides, in particular, endoparasiticides.

Claims (78)

1. A Formula (1) compound

wherein

R 1a , R 1b , R 1c , and R 1d are each independently selected from the group consisting of hydrogen, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, —C(O)NR a R b , cyano, —S(O) p R, phenyl, pyridinyl, saturated or partially saturated 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from the group consisting of N, S, and O, and wherein said heterocyclic ring, phenyl, or pyridinyl moiety are each optionally and independently substituted with at least one substituent selected from the group consisting of oxo, cyano, halo, and C 1 -C 6 alkyl; or R 1a and R 1b or R 1b and R 1c or R 1c and R 1d together form a tetrahydrofuran ring or phenyl ring;

R 2 is phenyl or a 5- or 6-membered heteroaryl ring containing at least one heteroatom selected from the group consisting of N, S, or O, and wherein said phenyl or heteroaryl ring is optionally and independently substituted with at least one R 5 substituent selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, hydroxyl, C 1 -C 6 alkoxy, and C 3 -C 6 cycloalkyl;

R 3 is C 1 -C 4 alkylaryl, C 1 -C 4 alkylheteroaryl, C 2 -C 6 alkenylaryl, or C 2 -C 6 alkenylheteroaryl; and wherein each aryl and heteroaryl moiety is optionally and independently substituted with at least one R 4 substituent selected from the group consisting of halo, cyano, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, and —S(O) p R; and wherein the alkenyl moiety is optionally substituted with halo;

R a and R b are each independently selected from the group consisting of H and C 1 -C 6 alkyl;

R is H or C 1 -C 6 alkyl;

p is the integer 0, 1, or 2; and wherein the solid line accompanied by the dotted line “- - - -” represents a single or double bond, and veterinary acceptable salts thereof, and stereoisomers thereof.

2. A veterinary composition comprising a Formula (1) compound of claim 1 , and further comprising a veterinary acceptable carrier, and optionally, at least one additional antiparasitic agent.

3. A method for treating an animal with a parasitic infection comprising administering a therapeutically effective amount of a Formula (1) compound of claim 1 to an animal in need thereof.

4. A Formula (1.1) or Formula (1.2) compound of Formula (1) of claim 1

wherein

Ring A is phenyl, pyridinyl, or thiophene;

Ring B is naphthyl, quinolinyl, or isoquinolinyl;

each of Ring A and Ring B moieties are optionally and independently substituted with at least one R 4 substituent selected from halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and —S(O) 2 CH 3 ;

R 2 is phenyl, pyridinyl, thiazolyl, pyridazinyl, or pyrrolyl, each optionally and independently substituted with at least one R 5 substituent selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxyl, and cyclopropyl;

n is the integer 0, 1, 2, 3, 4, or 5, and when n is 2 or more, then each R 4 can be the same or different from each other; and veterinary acceptable salts thereof, and stereoisomers thereof.

5. A Formula (1.1) compound of claim 4 wherein Ring A is phenyl optionally substituted with at least one R 4 substituent selected from halo, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, and —S(O) 2 CH 3 ; R 2 is pyridinyl or thiazolyl, each optionally and independently substituted with at least one R 5 substituent selected from the group consisting of halo, methyl, —CF 3 , —OCH 3 , —OCH 2 CH 3 , hydroxyl, and cyclopropyl, and veterinary acceptable salts thereof, and stereoisomers thereof.

6. A compound of claim 5 wherein R 2 is pyridinyl optionally substituted with at least one R 5 substituent selected from the group consisting of fluoro, chloro, bromo, methyl, hydroxyl, —CF 3 , —OCH 3 , —OCH 2 CH 3 , and cyclopropyl, and veterinary acceptable salts thereof, and stereoisomers thereof.

7. A Formula (1.2) compound of claim 4 wherein R 2 is pyridinyl optionally substituted with at least one R 5 substituent selected from the group consisting of fluoro, chloro, bromo, methyl, —CF 3 , —OCH 3 , —OCH 2 CH 3 , hydroxyl, and cyclopropyl, and veterinary acceptable salts thereof, and stereoisomers thereof.

8. A Formula (1.1a) compound of Formula (1.1) of claim 4

wherein

R 1a , R 1b , R 1c , and R 1d , are each independently selected from the group consisting of H, chloro, fluoro, bromo, cyano, methyl, —OCH 3 , —OCH 2 CH 3 , —OCF 3 ,

—CF 3 , —SCH 3 , —S(O) 2 CH 3 , —C(O)NH 2 , phenyl, pyridinyl, morpholinyl, azathienyl, and pyrrolidinyl; and wherein the phenyl and pyridinyl is optionally substituted with at least one substituent selected from halo, cyano, or oxo; or

R 1a and R 1b or R 1b and R 1c or R 1c and R 1d together form a phenyl ring or tetrahydrofuran ring;

R 4a , R 4b , R 4c , R 4d and R 4e are each independently selected from the group consisting of H, fluoro, chloro, bromo, methyl, —CF 3 , cyano, —OCF 3 , —OCH 3 , and —S(O) 2 CH 3 ; and

9. A Formula (1.1a) compound of claim 8 wherein at least two of R 1a , R 1b , R 1c , and R 1d are H; and wherein one of R 5a or R 5b is hydrogen and the other is chloro, fluoro, bromo, —CF 3 , methyl, hydroxyl, cyclopropyl, —OCH 3 or —OCH 2 CH 3 ; and veterinary acceptable salts thereof, and stereoisomers thereof.

10. A Formula (1.1a) compound of claim 8 selected from the group consisting of

(E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide;

(E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide;

(E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide;

(E)-2-(3-(4-chloro-2,3-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide;

(E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide

(E)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide

(E)-2-(3-(4-bromo-2,3-difluorophenyl)allyl)-8-cyano-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide

(E)-8-cyano-2-(3-(4-fluorophenyl)allyl)-N-((2-fluoropyridin-4-yl)methyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, and veterinary acceptable salts thereof, and stereoisomers thereof.

11. A veterinary composition comprising a Formula (1.1a) compound

wherein

R 1a , R 1b , R 1c , and R 1d , are each independently selected from the group consisting of H, chloro, fluoro, bromo, cyano, methyl, —OCH 3 , —OCH 2 CH 3 , —OCF 3 ,

R 1a and R 1b or R 1b and R 1c or R 1c and R 1d together form a phenyl ring or tetrahydrofuran ring;

R 4a , R 4b , R 4c , R 4d and R 4e are each independently selected from the group consisting of H, fluoro, chloro, bromo, methyl, —CF 3 , cyano, —OCF 3 , —OCH 3 , and —S(O) 2 CH 3 ; and

R 5a and R 5b are each independently selected from the group consisting of H, chloro, fluoro, bromo, —CF 3 , methyl, hydroxyl, cyclopropyl, —OCH 3 , and —OCH 2 CH 3 ; and veterinary acceptable salts thereof, and stereoisomers thereof; and further comprising a veterinary acceptable carrier, and optionally, at least one additional antiparasitic agent.

12. The veterinary composition of claim 11 further comprising at least one additional antiparasitic agent selected from the group consisting of pyrantel, praziquantel, moxidectin, milbemycin, milbemycin oxime, doramectin, abamectin, ivermectin, selamectin, eprinomectin, levamisole, spinosad, emodepside, albendazole, mebendazole, derquantel, or mixtures thereof.

13. A method of treating a parasitic infection in an animal comprising administering a therapeutically effective amount of a Formula (1.1a) compound

wherein

R 1a , R 1b , R 1c , and R 1d , are each independently selected from the group consisting of H, chloro, fluoro, bromo, cyano, methyl, —OCH 3 , —OCH 2 CH 3 , —OCF 3 ,

R 4a , R 4b , R 4c , R 4d and R 4e are each independently selected from the group consisting of H, fluoro, chloro, bromo, methyl, —CF 3 , cyano, —OCF 3 , —OCH 3 , and —S(O) 2 CH 3 ; and

14. The method of claim 13 , wherein the animal is a companion animal and said parasitic infection is an endoparasitic infection, and wherein the Formula (1.1a) compound is administered orally, topically, or parenterally.

15. A Formula (1.1a) compound of claim 10 selected from the group consisting of

(E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide;

(E)-2-(3-(4-chloro-3-fluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide;

(E)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-2-(3-(2,3,4-trifluorophenyl)allyl)-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; and

(E)-2-(3-(4-chloro-2,3-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide; and veterinary acceptable salts thereof, and stereoisomers thereof.

16. A Formula (1.1a) compound of claim 15 that is (E)-2-(3-(4-chloro-3,5-difluorophenyl)allyl)-N-((2-chloropyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydro-5H-pyrido[4,3-b]indole-5-carboxamide, and veterinary acceptable salts thereof, and stereoisomers thereof.

17. The veterinary composition of claim 11 comprising a Formula (1.1a) compound selected from the group consisting of