IP Library › Granted Patent US 9,493,463

Granted Patent B2

US 9,493,463 · App. 14/713,423 · Granted Nov 15, 2016

Substituted xanthine derivatives

Inventors: Roger D. Tung (Lexington, MA); Julie F. Liu (Lexington, MA); Scott L. Harbeson (Cambridge, MA)

Assignee: Concert Pharmaceuticals, Inc.

C07D473/10 C07D473/04 C07B2200/05 C07B2200/07

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Quick Facts

Patent No.: US 9,493,463
App. No.: 14/713,423
Granted: Nov 15, 2016
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

This invention relates to novel compounds that are substituted xanthine derivatives and pharmaceutically acceptable salts thereof. For example, this invention relates to novel substituted xanthine derivatives that are derivatives of pentoxifylline. This invention also provides compositions comprising one or more compounds of this invention and a carrier and the use of the disclosed compounds and compositions in methods of treating diseases and conditions for which pentoxifylline and related compounds are beneficial.

Claims (670)

1. A compound of Formula B:

or a pharmaceutically acceptable salt thereof, wherein:

each of R 1 and R 2 is independently selected from —CH 3 and —CD 3 ;

R 5 is hydrogen or deuterium;

each Z 3 is hydrogen or deuterium;

each Z 4 is hydrogen or deuterium;

each Z 5 is hydrogen or deuterium;

either (a) Y 1 is OH, and Y 2 is hydrogen or deuterium, or (b) Y 1 and Y 2 are taken together with the carbon to which they are attached to form C═O; and

the deuterium incorporation at each designated deuterium atom is at least 90%.

2. The compound of claim 1 , wherein R 5 is deuterium.

3. The compound of claim 2 , wherein each Z 3 , Z 4 and Z 5 is hydrogen and R 1 is —CD 3 .

4. The compound of claim 1 , wherein each Z 3 , Z 4 and Z 5 is hydrogen.

5. The compound of claim 1 , wherein each Z 3 , Z 4 and Z 5 is deuterium.

6. The compound of claim 1 , wherein R 1 and R 2 are each —CD 3 .

7. The compound of claim 1 , wherein Y 1 and Y 2 are taken together with the carbon to which they are attached to form C═O.

8. The compound of claim 1 , wherein Y 1 and is OH, and Y 2 is hydrogen or deuterium.

9. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, selected from the following:

Compound

R 1

R 2

R 3

R 4

Y 1

Y 2

103

CD 3

(CD 2 ) 4

taken together as ═O

104

CH 3

CD 3

(CD 2 ) 4

taken together as ═O

105

CD 3

CH 3

CD 3

(CD 2 ) 4

taken together as ═O

106

CH 3

CD 3

(CD 2 ) 4

taken together as ═O

107

CH 3

CD 3

† CD 2 (CH 2 ) 3

taken together as ═O

108

CH 3

CD 3

† (CD 2 ) 3 CH 2

taken together as ═O

109

CD 3

CH 3

CD 3

† CD 2 (CH 2 ) 3

taken together as ═O

110

CD 3

CH 3

CD 3

† (CD 2 ) 3 CH 2

taken together as ═O

111

CH 3

CD 3

† CD 2 (CH 2 ) 3

taken together as ═O

112

CH 3

CD 3

† (CD 2 ) 3 CH 2

taken together as ═O

113

CD 3

† CD 2 (CH 2 ) 3

taken together as ═O

114

CD 3

† (CD 2 ) 3 CH 2

taken together as ═O

118

CD 3

† CD 2 (CH 2 ) 3

119

CD 3

CH 3

CD 3

† CD 2 (CH 2 ) 3

120

CH 3

CD 3

† CD 2 (CH 2 ) 3

121

CH 3

CD 3

† CD 2 (CH 2 ) 3

122

CD 3

(CD 2 ) 4

123

CD 3

CH 3

CD 3

(CD 2 ) 4

124

CH 3

CD 3

(CD 2 ) 4

125

CH 3

CD 3

(CD 2 ) 4

126

CD 3

† (CD 2 ) 3 CH 2

127

CD 3

CH 3

CD 3

† (CD 2 ) 3 CH 2

128

CH 3

CD 3

† (CD 2 ) 3 CH 2

129

CH 3

CD 3

† (CD 2 ) 3 CH 2

130

CD 3

CH 3

(CH 2 ) 4

131

CD 3

CH 3

(CH 2 ) 4

132

CH 3

CD 3

CH 3

(CH 2 ) 4

133

CH 3

(CH 2 ) 4

134

CD 3

† CD 2 (CH 2 ) 3

135

CD 3

CH 3

CD 3

† CD 2 (CH 2 ) 3

136

CH 3

CD 3

† CD 2 (CH 2 ) 3

137

CH 3

CD 3

† CD 2 (CH 2 ) 3

138

CD 3

(CD 2 ) 4

139

CD 3

CH 3

CD 3

(CD 2 ) 4

140

CH 3

CD 3

(CD 2 ) 4

141

CH 3

CD 3

(CD 2 ) 4

142

CD 3

† (CD 2 ) 3 CH 2

143

CD 3

CH 3

CD 3

† (CD 2 ) 3 CH 2

144

CH 3

CD 3

† (CD 2 ) 3 CH 2

145

CH 3

CD 3

† (CD 2 ) 3 CH 2

wherein the deuterium incorporation at each designated deuterium atom is at least 90%; and wherein “†” represents the portion of the R 4 moiety bound to C(Y 1 )(Y 2 ) in the compound.

10. A compound of Formula A:

or a pharmaceutically acceptable salt thereof, selected from the following:

Compound

R 1

R 2

R 3

R 4

R 5

Y 1

Y 2

400

CD 3

CH 3

(CH 2 ) 4

Taken together as ═O

401

CD 3

CH 3

(CH 2 ) 4

Taken together as ═O

402

CH 3

CD 3

CH 3

(CH 2 ) 4

Taken together as ═O

403

CD 3

(CD 2 ) 4

Taken together as ═O

404

CH 3

CD 3

(CD 2 ) 4

Taken together as ═O

405

CD 3

CH 3

CD 3

(CD 2 ) 4

Taken together as ═O

406

CH 3

CD 3

(CD 2 ) 4

Taken together as ═O

407

CH 3

CD 3

† CD 2 (CH 2 ) 3

Taken together as ═O

408

CH 3

CD 3

† (CD 2 ) 3 CH 2

Taken together as ═O

409

CD 3

CH 3

CD 3

† CD 2 (CH 2 ) 3

Taken together as ═O

410

CD 3

CH 3

CD 3

† (CD 2 ) 3 CH 2

Taken together as ═O

411

CH 3

CD 3

† CD 2 (CH 2 ) 3

Taken together as ═O

412

CH 3

CD 3

† (CD 2 ) 3 CH 2

Taken together as ═O

413

CD 3

† CD 2 (CH 2 ) 3

Taken together as ═O

414

CD 3

† (CD 2 ) 3 CH 2

Taken together as ═O

415

CD 3

CH 3

(CH 2 ) 4

416

CD 3

CH 3

(CH 2 ) 4

417

CH 3

CD 3

CH 3

(CH 2 ) 4

418

CD 3

† CD 2 (CH 2 ) 3

419

CD 3

CH 3

CD 3

† CD 2 (CH 2 ) 3

420

CH 3

CD 3

† CD 2 (CH 2 ) 3

421

CH 3

CD 3

† CD 2 (CH 2 ) 3

422

CD 3

(CD 2 ) 4

423

CD 3

CH 3

CD 3

(CD 2 ) 4

424

CH 3

CD 3

(CD 2 ) 4

425

CH 3

CD 3

(CD 2 ) 4

426

CD 3

† (CD 2 ) 3 CH 2

427

CD 3

CH 3

CD 3

† (CD 2 ) 3 CH 2

428

CH 3

CD 3

† (CD 2 ) 3 CH 2

429

CH 3

CD 3

† (CD 2 ) 3 CH 2

430

CD 3

CH 3

(CH 2 ) 4

431

CD 3

CH 3

(CH 2 ) 4

432

CH 3

CD 3

CH 3

(CH 2 ) 4

433

CH 3

(CH 2 ) 4

434

CD 3

† CD 2 (CH 2 ) 3

435

CD 3

CH 3

CD 3

† CD 2 (CH 2 ) 3

436

CH 3

CD 3

† CD 2 (CH 2 ) 3

437

CH 3

CD 3

† CD 2 (CH 2 ) 3

438

CD 3

(CD 2 ) 4

439

CD 3

CH 3

CD 3

(CD 2 ) 4

440

CH 3

CD 3

(CD 2 ) 4

441

CH 3

CD 3

(CD 2 ) 4

442

CD 3

† (CD 2 ) 3 CH 2

443

CD 3

CH 3

CD 3

† (CD 2 ) 3 CH 2

444

CH 3

CD 3

† (CD 2 ) 3 CH 2

445

CH 3

CD 3

† (CD 2 ) 3 CH 2

wherein the deuterium incorporation at each designated deuterium atom is at least 90%; and wherein “†” represents the portion of the R 4 moiety bound to C(Y 1 )(Y 2 ) in the compound.

11. A compound selected from any one of the following:

or a pharmaceutically acceptable salt of any of the foregoing; wherein the deuterium incorporation at each designated deuterium atom is at least 90%.

12. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

14. A method of treating a disease or condition in a patient in need thereof, comprising administering to the patient an effective amount of a composition of claim 13 , wherein the disease is selected from diabetic nephropathy, hypertensive nephropathy or intermittent claudication on the basis of chronic occlusive arterial disease of the limbs.

15. A method of treating chronic kidney disease in a patient in need thereof, comprising administering to the patient an effective amount of a composition of claim 13 .

16. The method of claim 15 wherein the chronic kidney disease is glomerulonephritis, focal segmental glomerulosclerosis, nephrotic syndrome, reflux uropathy, or polycystic kidney disease.

17. A method of treating chronic disease of the liver in a patient in need thereof, comprising administering to the patient an effective amount of a composition of claim 13 .

18. The method of claim 17 wherein the chronic disease of the liver is nonalcoholic steatohepatitis, fatty liver degeneration or other diet-induced high fat or alcohol-induced tissue-degenerative conditions, cirrhosis, liver failure, or alcoholic hepatitis.

19. A method of treating a diabetes-related disease or condition in a patient in need thereof, comprising administering to the patient an effective amount of a composition of claim 13 , wherein the disease or condition is selected from insulin resistance, retinopathy, diabetic ulcers, radiation-associated necrosis, acute kidney failure or drug-induced nephrotoxicity.

20. A method of treating intermittent claudication in a patient in need thereof, comprising administering to the patient an effective amount of a composition of claim 13 .

21. A method of treating a disease or condition in a patient in need thereof, wherein the disease or condition is selected from insulin dependent diabetes; non-insulin dependent diabetes; metabolic syndrome; obesity; insulin resistance; dyslipidemia; pathological glucose tolerance; hypertension; hyperlipidemia; hyperuricemia; gout; and hypercoagulability, comprising administering to the patient an effective amount of a composition of claim 13 .

Assignments (2)

MERGER Recorded Aug 2, 2023

From: CONCERT PHARMACEUTICALS, INC.

To: SUN PHARMACEUTICAL INDUSTRIES, INC.

Reel/Frame 064465/0383 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 18, 2015

From: TUNG, ROGER D.; LIU, JULIE F.; HARBESON, SCOTT L.

To: CONCERT PHARMACEUTICALS, INC.

Reel/Frame 035659/0072 →

Continuity (6)

Continuation 13949888 · Jul 24, 2013

Continuation 12380579 · Feb 27, 2009

Provisional Application 61198715 · Nov 7, 2008

Provisional Application 61134568 · Jul 11, 2008

Provisional Application 61067736 · Feb 29, 2008

Related Publication 20150322068A1 · Nov 12, 2015