IP Library › Granted Patent US 9,249,102

Granted Patent B2

US 9,249,102 · App. 14/083,879 · Granted Feb 2, 2016

Anthelmintic compounds and compositions and method of using thereof

Inventors: Charles Q. Meng (Johns Creek, GA); Alan Long (Hillsborough, NC); Srinivas Reddy Gurrala (Cary, NC); Douglas Edward Wilkinson (Wake Forest, NC)

Assignee: MERIAL, INC.

C07D215/38 A61K31/167 A61K31/4704 A61K31/495 A61K31/496 A61K31/4995 A61K45/06 C07C233/56 C07C235/16 C07D213/74 C07D215/42 C07D217/06 C07D241/04 C07D263/58 C07D277/64 C07D277/82 C07D295/15 C07D295/185 C07D295/215 C07D307/14 C07D307/81 C07D307/82 C07D333/66 C07D401/06 C07D401/12 C07D403/12 C07D405/12 C07D409/12 C07D413/12 C07D417/06 C07D417/12 C07D471/08 C07C2101/14

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Quick Facts

Patent No.: US 9,249,102
App. No.: 14/083,879
Granted: Feb 2, 2016
Kind: B2

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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 X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 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 (815)

1. An anthelmintic compound of formula (I):

wherein:

Y is a bicyclic carbocyclic or a bicyclic heterocyclic group optionally substituted by one or more of halogen, nitro, cyano, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl or phenyl; and Z is phenyl optionally substituted with one or more substituents independently selected from selected from the group consisting of halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 halothio, C 1 -C 4 haloalkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 haloalkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 haloalkylsulfonyl, phenyl, C 1 -C 4 alkylcarbonyl or C 1 -C 4 haloalkylcarbonyl;

X 1 is a bond, —C(O)—, or —CH 2 — wherein —(CH 2 ) n the —CH 2 — group is optionally substituted with alkyl;

X 2 is a 1,4-piperazinyl linker optionally substituted with one or two alkyl groups;

X 3 is a diradical group;

X 4 is —CH 2 —, wherein the —CH 2 — is optionally substituted with alkyl;

X 5 is a bond;

X 6 is —O—;

X 7 is 1,4-trans-cyclohexylenyl; and

X 8 is —NH— optionally substituted with alkyl.

2. The compound of claim 1 , wherein Y 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.

3. The compound of claim 1 , wherein

X 2 is L1, L13, L14 or L15:

wherein R 5 and R 6 are independently hydrogen or C 1 -C 3 -alkyl.

4. A composition for the treatment 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 3 in combination with a pharmaceutically acceptable carrier.

5. The composition of claim 4 , wherein the composition comprises an additional parasiticidal active agent.

6. A method for the treatment of a parasitic infection or infestation in an animal, comprising administering an effective amount of the compound of any one of claims 1 to 3 to the animal.

7. The compound of claim 3 , wherein X 2 is L1.

8. The compound of claim 3 , wherein X 8 is unsubstituted —NH—; and X 4 is unsubstituted —CH 2 —.

9. The compound of claim 7 , wherein:

X 1 is a bond or —CH 2 —;

X 4 is unsubstituted —CH 2 —;

X 8 is —NH— or —N(CH 3 )—;

Y is optionally substituted benzothiazolyl, benzoxazolyl or quinolinyl; and

Z is phenyl substituted with one or two C 1 -C 4 haloalkyl, halogen, nitro, cyano or C 1 -C 4 haloalkylsulfonyl.

10. The compound of claim 1 or 3 , wherein Y 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.

11. The compound of claim 10 , wherein Y is optionally substituted indolyl, benzothiazolyl, benzoxazolyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, indazolyl, dihydroisoindolyl, dihydroquinazolinyl or tetrahydroquinolinyl; and Z is phenyl optionally substituted with one or more of halogen, nitro, cyano, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, halothio, C 1 -C 4 alkylthio, C 1 -C 4 haloalkylthio or C 1 -C 4 haloalkylsulfonyl.

12. The compound of claim 11 , wherein Y is indolyl, benzothiazolyl, benzoxazolyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, indazolyl, dihydroisoindolyl, dihydroquinazolinyl or tetrahydroquinolinyl optionally substituted with one or more halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, halothio, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl and alkylsulfonyl.

13. The compound of claim 12 , wherein Y is indolyl, benzothiazolyl, benzoxazolyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, indazolyl, dihydroisoindolyl, dihydroquinazolinyl or tetrahydroquinolinyl optionally substituted with one or more halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio or SF 5 ; and Z is phenyl optionally substituted with one or more of halogen, nitro, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy.

14. The compound of claim 13 , wherein Y is indolyl, benzothiazolyl, benzoxazolyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, benzopyranyl, indazolyl, dihydroisoindolyl, dihydroquinazolinyl or tetrahydroquinolinyl optionally substituted with one or more F, Cl, Br, methyl, CF 3 , OCH 3 , OCF 3 , SF 5 or SCF 3 ; and Z is phenyl optionally substituted with one or more of F, Cl, Br, nitro, cyano, methyl, CF 3 , OCH 3 or OCF 3 .

15. The compound of claim 14 , wherein Y is benzothiazolyl, benzoxazolyl or quinolinyl substituted with one or more F, Cl, Br, CF 3 , OCF 3 , SF 5 or SCF 3 ; and Z is phenyl substituted with two to four substituents selected from the group consisting of F, Cl, Br, nitro, cyano, methyl, CF 3 , OCF 3 or SCF 3 .

16. The compound of claim 7 , wherein:

X 1 is a bond;

X4 is unsubstituted —CH 2 —;

X 8 is —NH— or —N(CH 3 )—.

17. The compound of claim 3 , wherein the compound is selected from the group consisting of:

X 1

X 2

X 4

X 8

bond

—CH 2 —

bond

—CH 2 —

bond

—CH 2 —

bond

—CH 2 —

bond

—CH 2 —

bond

—CH 2 —

bond

—CH 2 —

bond

—CH 2 —

bond

—CH 2 —

160

bond

—CH 2 —

161

bond

—CH 2 —

232

bond

—CH 2 —

233

bond

—CH 2 —

236

bond

—CH 2 —

237

bond

—CH 2 —

245

bond

—CH 2 —

NMe

246

bond

—CH 2 —

NMe

247

bond

—CH 2 —

NMe

248

bond

—CH 2 —

NMe

249

bond

—CH(CH 3 )—

250

bond

—CH(CH 3 )—

251

bond

—CH(CH 3 )—

252

bond

—CH(CH 3 )—

266

bond

—CH 2 —

267

bond

—CH 2 —

268

bond

—CH 2 —

269

bond

—CH 2 —

NMe

270

bond

—CH 2 —

271

bond

—CH 2 —

272

bond

—CH 2 —

273

bond

—CH 2 —

277

bond

—CH 2 —

278

bond

—CH 2 —

279

bond

—CH 2 —

281

bond

—CH 2 —

NMe

282

bond

—CH 2 —

NMe

283

bond

—CH 2 —

NMe

289

bond

—CH 2 —

290

bond

—CH 2 —

293

bond

—CH 2 —

NMe

314

bond

—CH 2 —

331

bond

—CH 2 —

335

bond

—CH 2 —

336

bond

—CH 2 —

342

bond

—CH 2 —

358

bond

—CH 2 —

364

bond

—CH 2 —

399

bond

—CH 2 —

400

bond

—CH 2 —

CH 2

—CH 2 —

CH 2

—CH 2 —

CH 2

—CH 2 —

CH 2

—CH 2 —

C(O)

—CH 2 —

C(O)

—CH 2 —

C(O)

—CH 2 —

CH 2

—CH 2 —

CH 2

—CH 2 —

CH 2

—CH 2 —

C(O)

—CH 2 —

C(O)

—CH 2 —

C(O)

—CH 2 —

260

CH 2

—CH 2 —

261

CH 2

—CH 2 —

NMe

262

—CH 2 —

NMe

280

CH 2

—CH 2 —

NMe

299

CH 2

—CH 2 —

310

CH 2

—CH 2 —

377

CH 2

—CH 2 —

378

CH 2

—CH 2 —

379

CH 2

—CH 2 —

380

CH 2

—CH 2 —

401

CH 2

—CH 2 —

307

CH 2

L13

—CH 2 —

308

CH 2

L13

—CH 2 —

309

bond

L15

—CH 2 —

178

CH 2

—CH 2 —

179

CH 2

—CH 2 —

180

CH 2

—CH 2 —

181

C(O)

—CH 2 —

182

C(O)

—CH 2 —

183

C(O)

—CH 2 —

234

CH 2

—CH 2 —

235

CH 2

—CH 2 —

253

CH 2

—CH 2 —

254

—CH 2 —

255

—CH 2 —

256

CH 2

—CH 2 —

NMe

257

—CH 2 —

NMe

258

CH 2

—CH 2 —

NMe

259

—CH 2 —

NMe

274

CH 2

—CH 2 —

275

CH 2

—CH 2 —

NMe

284

CH 2

—CH 2 —

NMe

285

CH 2

—CH 2 —

286

CH 2

—CH 2 —

287

CH 2

—CH 2 —

288

CH 2

—CH 2 —

291

CH 2

—CH 2 —

292

CH 2

—CH 2 —

294

CH 2

—CH 2 —

300

—CH 2 —

301

CH 2

—CH 2 —

302

CH 2

—CH 2 —

304

—CH 2 —

406

—CH 2 —

305

CH 2

—CH 2 —

306

CH 2

—CH 2 —

312

CH 2

—CH 2 —

313

CH 2

—CH 2 —

315

CH 2

—CH 2 —

316

CH 2

—CH 2 —

318

CH 2

—CH 2 —

319

CH 2

—CH 2 —

320

CH 2

—CH 2 —

321

CH 2

—CH 2 —

322

CH 2

—CH 2 —

323

CH 2

—CH 2 —

324

CH 2

—CH 2 —

325

CH 2

—CH 2 —

326

CH 2

—CH 2 —

338

C(O)

—CH 2 —

343

—CH 2 —

344

CH 2

—CH 2 —

375

CH 2

—CH 2 —

376

CH 2

—CH 2 —

365

CH 2

L13

—CH 2 —

370

CH 2

L13

—CH 2 —

371

CH 2

L14

—CH 2 —

297

CH 2

—CH 2 —

298

—CH 2 —

327

CH 2

—CH 2 —

328

CH 2

—CH 2 —

329

CH 2

—CH 2 —

332

CH 2

—CH 2 —

333

CH 2

—CH 2 —

334

CH 2

—CH 2 —

357

CH 2

L13

—CH 2 —

372

CH 2

L14

—CH 2 —

373

CH 2

L13

—CH 2 —

374

CH 2

L14

—CH 2 —

391

bond

—CH 2 —

392

bond

—CH 2 —

393

CH 2

—CH 2 —

394

bond

—CH 2 —

417

bond

—CH 2 —

418

bond

—CH 2 —

419

CH 2

—CH 2 —

420

CH 2

—CH 2 —

421

bond

—CH 2 —

422

bond

—CH 2 —

423

bond

—CH 2 —

424

CH 2

—CH 2 —

425

CH 2

—CH 2 —

426

CH 2

—CH 2 —

427

bond

L15

—CH 2 —

wherein Y, X 1 , X 2 , X 4 , X 8 and Z are as shown.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 4, 2015

From: MERIAL LIMITED

To: MERIAL, INC.

Reel/Frame 035554/0570 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 16, 2014

From: MENG, CHARLES Q.; LONG, ALAN; HUBER, SCOT; GURRALA, SRINIVAS REDDY; WILKINSON, DOUGLAS EDWARD; PACOFSKY, GREGORY

To: MERIAL LIMITED

Reel/Frame 033322/0813 →

Continuity (2)

Provisional Application 61728782 · Nov 20, 2012

Related Publication 20140142114A1 · May 22, 2014