ANTHELMINTIC COMPOUNDS

• US 20180338972A1
• Filed: 08/03/2018
• Published: 11/29/2018
• Est. Priority Date: 05/19/2014
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim Animal Health USA, Inc. (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Merial Incorporated (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Long, Alan, Gurrala, Srinivas Reddy
• Granted Patent: US 10,463,661 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/06 the aromatic ring being substituted by nitro groups
• CPC Class Codes: A61K 31/423 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/10 Anthelmintics
• CPC Class Codes: A61P 33/14 Ectoparasiticides, e.g. scabicides
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 487/06 Peri-condensed systems
• CPC Class Codes: H05B 41/06 thermal only

Abstract

The present invention relates to novel anthelmintic compounds of formula (I) below:

wherein

• • Y and Z are independently a bicyclic carbocyclic or a bicyclic heterocyclic group, or one of Y or Z is a bicyclic carbocyclic or a bicyclic heterocyclic group and the other of Y or Z is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl, and variables X₁, X₆, X₈, Q₁, Q₂, Q₃, Q₄, Q₅, Q₆, Ring A, Ring B, W, W′, R₂, R₃, R, R′, m, n and q are as defined herein. The invention also provides for veterinary compositions comprising the anthelmintic compounds of the invention, and their uses for the treatment and prevention of parasitic infections in animals.

Claims

1. An anthelmintic compound of formula (IA-1):

6. The anthelminitic compound of claim 1, wherein:

X₁ is —

NH—

which is optionally substituted a substituent selected from the group consisting of hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, alkylcarbonyl, alkenylcarbonyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl, heterocyclyl, carbocyclylalkyl and heterocyclylalkyl, where each substituent may be further independently substituted by hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino or carboxy (—

COOH).

7. The compound of any one of claims 1 to 5, wherein at least one of Y and Z is optionally substituted naphthyl, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, dihydroquinazolinyl or tetrahydroquinolinyl.

8. The anthelminitic compound of claim 1 to 5, wherein one of Y and Z is optionally substituted naphthyl, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, dihydroquinazolinyl or tetrahydroquinolinyl;

and the other of Y and Z is optionally substituted phenyl.

9. The anthelminitic compound of claim 8, wherein one of Y and Z is benzothiazolyl or benzoxazolyl optionally substituted with one or more halogen, C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy, C₁-C₃halolakoxy, C₁-C₃alkylthio, C₁-C₃haloalkylthio, C₁-C₃alkylsulfinyl, C₁-C3haloalkylsulfinyl, C₁-C₃alkylsulfonyl or C₁-C3haloalkylsulfonyl;

and the other of Y and Z is phenyl optionally substituted with one or more CN, halogen, C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy, C₁-C₃halolakoxy, C₁-C₃alkylthio or C₁-C₃haloalkylthio.

8-1. The anthelminitic compound of claim 1 or 2, wherein one of Ring A and Ring B is L19, L20 or L21:

9-1. The anthelminitic compound of claim 1 or 2, wherein one of Ring A and Ring B is trans cyclohexylene, L1 or L4:

10. The anthelminitic compound of claim 1 or 2, wherein:

at least one of Y and Z is optionally substituted naphthyl, indolyl, benzothiazolyl, benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, dihydroquinazolinyl or tetrahydroquinolinyl, and the other of Y and Z is optionally substituted phenyl;

one of Ring A and Ring B is L19, L20 or L21;

11. The anthelminitic compound of claim 10, wherein:

one of Y and Z is benzothiazolyl or benzoxazolyl optionally substituted with one or more halogen, C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy, C₁-C₃halolakoxy, C₁-C₃alkylthio or C₁-C₃haloalkylthio; and

the other of Y and Z is phenyl optionally substituted with one or more CN, halogen, C₁-C₃alkyl, C₁-C₃haloalkyl, C₁-C₃alkoxy, C₁-C₃halolakoxy, C₁-C₃alkylthio or C₁-C₃haloalkylthio.

12. The anthelminitic compound of claim 11, wherein one of Y and Z is benzothiazolyl or benzoxazolyl substituted with one or more of CF₃, OCF₃, SCF₃;

and

the other of Y and Z is phenyl substituted with halogen, CN or CF₃.

13. The anthelminitic compound of claim any one of claims 1 to 12, wherein X₁ is a bond, —

NH—

or —

NMe-.

14. The anthelminitic compound of claim any one of claims 1 to 13, wherein X₈ is a bond, —

NH—

, —

NMe-, >

N(CH₂)₂NEt₂, >

NCO₂Et or >

NCO(CH₂)₂CO₂H.

15. A composition for the treatment and prevention of a parasitic infection or infestation in an animal, comprising an effective amount of at least one anthelmintic compound of any one of claims 1 to 14 in combination with a pharmaceutically acceptable carrier.

16. The composition of claim 15, wherein the composition comprises an additional parasiticidal active agent.

17. A method for the treatment and prevention of a parasitic infection or infestation in an animal, comprising administering an effective amount of the compound of any one of claims 1 to 13 to the animal.

18. Use of a compound of any one of claims 1 to 13 in the manufacture of a medicament for the treatment of a parasitic infestation or infection in an animal.

19. A compound of any one of claims 1 to 13 for use in the treatment or prevention of a parasitic infestation or infection in an animal.

2. An anthelmintic compound of formula (IA-2):

3. An anthelmintic compound of formula (IB-2):

4. An anthelmintic compound of formula (IB-4):

5. An anthelmintic compound of formula (IC-1):