US2009239886A1PendingUtilityA1
Substituted xanthine derivatives
Assignee: CONCERT PHARMACEUTICALS INCPriority: Feb 29, 2008Filed: Feb 27, 2009Published: Sep 24, 2009
Est. expiryFeb 29, 2028(~1.6 yrs left)· nominal 20-yr term from priority
A61P 9/00A61P 37/02A61P 9/12A61P 9/10A61P 7/02A61P 35/00A61P 3/10A61P 3/06A61P 27/02A61P 33/02A61P 31/18A61P 31/12A61P 3/00A61P 25/24A61P 25/00A61P 3/04A61P 13/02A61P 13/12A61P 1/04A61P 1/16A61P 21/04A61P 1/02A61P 19/06C07D 473/04C07B 2200/07C07B 2200/05C07D 473/10Y02A50/30
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Claims
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
exact text as granted — not AI-modified1 . A compound of Formula B:
or 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; and
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.
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
101
CD 3
CD 3
CH 3
(CH 2 ) 4
taken together as ═O
102
CH 3
CD 3
CH 3
(CH 2 ) 4
taken together as ═O
103
CD 3
CD 3
CD 3
(CD 2 ) 4
taken together as ═O
104
CH 3
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 3
(CD 2 ) 4
taken together as ═O
107
CH 3
CH 3
CD 3
† CD 2 (CH 2 ) 3
taken together as ═O
108
CH 3
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 3
† CD 2 (CH 2 ) 3
taken together as ═O
112
CH 3
CD 3
CD 3
† (CD 2 ) 3 CH 2
taken together as ═O
113
CD 3
CD 3
CD 3
† CD 2 (CH 2 ) 3
taken together as ═O
114
CD 3
CD 3
CD 3
† (CD 2 ) 3 CH 2
taken together as ═O
115
CD 3
CD 3
CH 3
(CH 2 ) 4
OH
H
117
CH 3
CD 3
CH 3
(CH 2 ) 4
OH
H
118
CD 3
CD 3
CD 3
† CD 2 (CH 2 ) 3
OH
H
119
CD 3
CH 3
CD 3
† CD 2 (CH 2 ) 3
OH
H
120
CH 3
CD 3
CD 3
† CD 2 (CH 2 ) 3
OH
H
121
CH 3
CH 3
CD 3
† CD 2 (CH 2 ) 3
OH
H
122
CD 3
CD 3
CD 3
(CD 2 ) 4
OH
H
123
CD 3
CH 3
CD 3
(CD 2 ) 4
OH
H
124
CH 3
CD 3
CD 3
(CD 2 ) 4
OH
H
125
CH 3
CH 3
CD 3
(CD 2 ) 4
OH
H
126
CD 3
CD 3
CD 3
† (CD 2 ) 3 CH 2
OH
H
127
CD 3
CH 3
CD 3
† (CD 2 ) 3 CH 2
OH
H
128
CH 3
CD 3
CD 3
† (CD 2 ) 3 CH 2
OH
H
129
CH 3
CH 3
CD 3
† (CD 2 ) 3 CH 2
OH
H
130
CD 3
CD 3
CH 3
(CH 2 ) 4
OH
D
131
CD 3
CH 3
CH 3
(CH 2 ) 4
OH
D
132
CH 3
CD 3
CH 3
(CH 2 ) 4
OH
D
133
CH 3
CH 3
CH 3
(CH 2 ) 4
OH
D
134
CD 3
CD 3
CD 3
† CD 2 (CH 2 ) 3
OH
D
135
CD 3
CH 3
CD 3
† CD 2 (CH 2 ) 3
OH
D
136
CH 3
CD 3
CD 3
† CD 2 (CH 2 ) 3
OH
D
137
CH 3
CH 3
CD 3
† CD 2 (CH 2 ) 3
OH
D
138
CD 3
CD 3
CD 3
(CD 2 ) 4
OH
D
139
CD 3
CH 3
CD 3
(CD 2 ) 4
OH
D
140
CH 3
CD 3
CD 3
(CD 2 ) 4
OH
D
141
CH 3
CH 3
CD 3
(CD 2 ) 4
OH
D
142
CD 3
CD 3
CD 3
† (CD 2 ) 3 CH 2
OH
D
143
CD 3
CH 3
CD 3
† (CD 2 ) 3 CH 2
OH
D
144
CH 3
CD 3
CD 3
† (CD 2 ) 3 CH 2
OH
D
and 145
CH 3
CH 3
CD 3
† (CD 2 ) 3 CH 2
OH
D.
10 . A compound of Formula A:
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 3
(CH 2 ) 4
D
Taken together as ═O
401
CD 3
CD 3
CH 3
(CH 2 ) 4
D
Taken together as ═O
402
CH 3
CD 3
CH 3
(CH 2 ) 4
D
Taken together as ═O
403
CD 3
CD 3
CD 3
(CD 2 ) 4
D
Taken together as ═O
404
CH 3
CH 3
CD 3
(CD 2 ) 4
D
Taken together as ═O
405
CD 3
CH 3
CD 3
(CD 2 ) 4
D
Taken together as ═O
406
CH 3
CD 3
CD 3
(CD 2 ) 4
D
Taken together as ═O
407
CH 3
CH 3
CD 3
† CD 2 (CH 2 ) 3
D
Taken together as ═O
408
CH 3
CH 3
CD 3
† (CD 2 ) 3 CH 2
D
Taken together as ═O
409
CD 3
CH 3
CD 3
† CD 2 (CH 2 ) 3
D
Taken together as ═O
410
CD 3
CH 3
CD 3
† (CD 2 ) 3 CH 2
D
Taken together as ═O
411
CH 3
CD 3
CD 3
† CD 2 (CH 2 ) 3
D
Taken together as ═O
412
CH 3
CD 3
CD 3
† (CD 2 ) 3 CH 2
D
Taken together as ═O
413
CD 3
CD 3
CD 3
† CD 2 (CH 2 ) 3
D
Taken together as ═O
414
CD 3
CD 3
CD 3
† (CD 2 ) 3 CH 2
D
Taken together as ═O
415
CD 3
CD 3
CH 3
(CH 2 ) 4
D
OH
H
416
CD 3
CH 3
CH 3
(CH 2 ) 4
D
OH
H
417
CH 3
CD 3
CH 3
(CH 2 ) 4
D
OH
H
418
CD 3
CD 3
CD 3
† CD 2 (CH 2 ) 3
D
OH
H
419
CD 3
CH 3
CD 3
† CD 2 (CH 2 ) 3
D
OH
H
420
CH 3
CD 3
CD 3
† CD 2 (CH 2 ) 3
D
OH
H
421
CH 3
CH 3
CD 3
† CD 2 (CH 2 ) 3
D
OH
H
422
CD 3
CD 3
CD 3
(CD 2 ) 4
D
OH
H
423
CD 3
CH 3
CD 3
(CD 2 ) 4
D
OH
H
424
CH 3
CD 3
CD 3
(CD 2 ) 4
D
OH
H
425
CH 3
CH 3
CD 3
(CD 2 ) 4
D
OH
H
426
CD 3
CD 3
CD 3
† (CD 2 ) 3 CH 2
D
OH
H
427
CD 3
CH 3
CD 3
† (CD 2 ) 3 CH 2
D
OH
H
428
CH 3
CD 3
CD 3
† (CD 2 ) 3 CH 2
D
OH
H
429
CH 3
CH 3
CD 3
† (CD 2 ) 3 CH 2
D
OH
H
430
CD 3
CD 3
CH 3
(CH 2 ) 4
D
OH
D
431
CD 3
CH 3
CH 3
(CH 2 ) 4
D
OH
D
432
CH 3
CD 3
CH 3
(CH 2 ) 4
D
OH
D
433
CH 3
CH 3
CH 3
(CH 2 ) 4
D
OH
D
434
CD 3
CD 3
CD 3
† CD 2 (CH 2 ) 3
D
OH
D
435
CD 3
CH 3
CD 3
† CD 2 (CH 2 ) 3
D
OH
D
436
CH 3
CD 3
CD 3
† CD 2 (CH 2 ) 3
D
OH
D
437
CH 3
CH 3
CD 3
† CD 2 (CH 2 ) 3
D
OH
D
438
CD 3
CD 3
CD 3
(CD 2 ) 4
D
OH
D
439
CD 3
CH 3
CD 3
(CD 2 ) 4
D
OH
D
440
CH 3
CD 3
CD 3
(CD 2 ) 4
D
OH
D
441
CH 3
CH 3
CD 3
(CD 2 ) 4
D
OH
D
442
CD 3
CD 3
CD 3
† (CD 2 ) 3 CH 2
D
OH
D
443
CD 3
CH 3
CD 3
† (CD 2 ) 3 CH 2
D
OH
D
444
CH 3
CD 3
CD 3
† (CD 2 ) 3 CH 2
D
OH
D
445
CH 3
CH 3
CD 3
† (CD 2 ) 3 CH 2
D
OH
D
or a pharmaceutically acceptable salt of any of the foregoing.
11 . A compound selected from any one of the following:
or a pharmaceutically acceptable salt of any of the foregoing.
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 chronic kidney disease in a patient in need thereof, comprising administering to the patient an effective amount of a composition of claim 13 .
22 . 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 .
23 . The compound of claim 4 , wherein R 5 is deuterium.
24 . The compound of 4 , wherein R 1 and R 2 are each —CD 3 .
25 . The compound of claim 24 , wherein R 5 is deuterium.
26 . The compound of claim 5 , wherein R 5 is deuterium.
27 . The compound of 5 , wherein R 1 and R 2 are each —CD 3 .
28 . The compound of claim 27 , wherein R 5 is deuterium.Cited by (0)
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