US2009042842A1PendingUtilityA1
Analogues of cilostazol
Assignee: CONCERT PHARMACEUTICALS INCPriority: Apr 25, 2007Filed: Apr 24, 2008Published: Feb 12, 2009
Est. expiryApr 25, 2027(~0.7 yrs left)· nominal 20-yr term from priority
A61P 7/02A61P 3/10A61P 9/00A61P 9/10A61P 7/00A61P 29/00A61P 3/04C07D 401/12A61P 15/00A61P 1/04A61P 11/06
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Claims
Abstract
This invention relates to novel compounds which are derivatives of the phosphodiesterase inhibitor, cilostazol and pharmaceutically acceptable salts thereof. This invention also provides pyrogen-free compositions comprising one or more compounds of the invention and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are treated by administration of an phosphodiesterase inhibitor, such as cilostazol. The invention also relates to the use of the disclosed compounds and compositions as reagents in analytical studies involving cilostazol.
Claims
exact text as granted — not AI-modified1 . A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a cyclohexyl ring having 0-11 deuterium;
Q is —CH 2 CH 2 — or —CH═CH— where one or more of the hydrogen in Q is optionally replaced by deuterium;
each Y variable is independently selected from hydrogen or deuterium; and
at least one Y variable is deuterium or there is at least one deuterium substituent in Q or Ring A, with the proviso that if the only sites of deuteration are on Ring A, Ring
A is not
2 . The compound of claim 1 , wherein:
Y 1 and Y 2 are the same; and Y 3 and Y 4 are the same.
3 . The compound of claim 2 , wherein each Y is hydrogen.
4 . The compound of claim 1 , wherein Ring A is selected from cyclohexyl, per-deuterocyclohexyl and 4,4-dideutero-cyclohexyl.
5 . The compound of claim 1 , wherein Q is selected from —CH 2 CH 2 —, -CD 2 CD 2 -, —CH═CH—, and -CD=CD-.
6 . The compound of claim 1 , wherein the compound is any one compound selected from the compounds set forth in the table below, wherein each Y is hydrogen:
Compound
Ring “A”
Q
100
per-deuterocyclohexyl
—CD 2 CD 2 —
101
4,4-dideuterocyclohexyl
—CD 2 CD 2 —
102
cyclohexyl
—CD 2 CD 2 —
103
per-deuterocyclohexyl
—CD 2 CH 2 —
104
4,4-dideuterocyclohexyl
—CD 2 CH 2 —
105
cyclohexyl
—CD 2 CH 2 —
106
per-deuterocyclohexyl
—CH 2 CH 2 —
107
4,4-dideuterocyclohexyl
—CH 2 CH 2 —
108
per-deuterocyclohexyl
—CD═CD—
109
4,4-dideuterocyclohexyl
—CD═CD—
110
per-deuterocyclohexyl
—CH═CH—
111
4,4-dideuterocyclohexyl
—CH═CH—
7 . The compound of claim 1 selected from:
8 . The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
9 . A pyrogen-free composition comprising a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a cyclohexyl ring having 0-11 deuterium;
Q is —CH 2 CH 2 — or —CH═CH— where one or more of the hydrogen in Q is optionally replaced by deuterium;
each Y variable is independently selected from hydrogen or deuterium; and
at least one Y variable is deuterium or there is at least one deuterium substituent in Q or Ring A, with the proviso that if the only sites of deuteration are on Ring A, Ring A is not
and an acceptable carrier.
10 . The composition of claim 9 , wherein the composition is suitable for pharmaceutical use and the carrier is a pharmaceutically acceptable carrier.
11 . The composition of claim 10 , further comprising a second therapeutic agent useful in treating a patient suffering from or susceptible to arterial occlusive disease, intermittent claudication or stroke.
12 . The composition of claim 11 , wherein the second therapeutic agent is selected from aspirin, clopidogrel and probucol
13 . A method of treating a disease selected from chronic arterial occlusive disease, diabetic mellitus complications, intermittent claudication, intimal proliferation, restenosis, intracranial arterial stenosis, recurrent strokes, cerebral infarction, cerebrovascular disorders, arthrosclerosis, atherothrombosis complications, peripheral vascular disease, Reynaud's Disease, sexual dysfunction, ulcers, cerebral circulation impairment, thrombolytic disorders, inflammation, hypotension, asthma, ischemic heart disease, coronary heart disease and acute coronary syndrome, in a patient in need thereof, comprising the step of administering to the patient a pharmaceutically acceptable composition comprising:
a) a compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a cyclohexyl ring having 0-11 deuterium;
Q is —CH 2 CH 2 — or —CH═CH— where one or more of the hydrogen in Q is optionally replaced by deuterium; each Y variable is independently selected from hydrogen or deuterium; and at least one Y variable is deuterium or there is at least one deuterium substituent in Q or Ring A; and
b) a pharmaceutically acceptable carrier.
14 . The method of claim 13 , wherein the disease is chronic arterial occlusive disease, intermittent claudication or stroke.
15 . The method of claim 13 , further comprising co-administering to the patient in need thereof a second therapeutic agent useful in treating arterial occlusive disease, intermittent claudication or stroke.
16 . The method of claim 15 , wherein the second therapeutic agent is selected from aspirin and clopidogrel.
17 . A method of preventing restenosis or stent thrombosis in a patient following implantation of a drug-eluting stent in the patient comprising the step of administering to the patient in need thereof and effective amount of:
a) a pharmaceutically acceptable composition comprising:
i) a compound represented by the following Structural Formula:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a cyclohexyl ring having 0-11 deuterium;
Q is —CH 2 CH 2 — or —CH═CH— where one or more of the hydrogen in Q is optionally replaced by deuterium; each Y variable is independently selected from hydrogen or deuterium; and at least one Y variable is deuterium or there is at least one deuterium substituent in Q or Ring A; and
ii) a pharmaceutically acceptable carrier; and
b) aspirin.
18 . The method of claim 17 , further comprising administering to the patient in need thereof clopidogrel.
19 . A method of treating type 2 diabetes or metabolic syndrome X in a patient in need thereof comprising the step of administering to the patient an effective amount of a pharmaceutically acceptable composition comprising:
a) a compound represented by Structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a cyclohexyl ring having 0-11 deuterium;
Q is —CH 2 CH 2 — or —CH═CH— where one or more of the hydrogen in Q is optionally replaced by deuterium; each Y variable is independently selected from hydrogen or deuterium; and at least one Y variable is deuterium or there is at least one deuterium substituent in Q or Ring A; and
b) a pharmaceutically acceptable carrier.
20 . The method of claim 19 , further comprising co-administering to the patient in need thereof probucol.
21 - 23 . (canceled)
24 . The composition of claim 9 , wherein:
Y 1 and Y 2 are the same; and Y 3 and Y 4 are the same.
25 . The composition of claim 24 , wherein each Y is hydrogen.
26 . The composition of claim 9 , wherein Ring A is selected from cyclohexyl, per-deuterocyclohexyl and 4,4-dideutero-cyclohexyl.
27 . The composition of claim 9 , wherein Q is selected from —CH 2 CH 2 —, -CD 2 CD 2 -, —CH═CH—, and -CD=CD-.
28 . The composition of claim 9 , wherein the compound is any one compound selected from the compound set forth in the table below, wherein each Y is hydrogen:
Compound
Ring “A”
Q
100
per-deuterocyclohexyl
—CD 2 CD 2 —
101
4,4-dideuterocyclohexyl
—CD 2 CD 2 —
102
cyclohexyl
—CD 2 CD 2 —
103
per-deuterocyclohexyl
—CD 2 CH 2 —
104
4,4-dideuterocyclohexyl
—CD 2 CH 2 —
105
cyclohexyl
—CD 2 CH 2 —
106
per-deuterocyclohexyl
—CH 2 CH 2 —
107
4,4-dideuterocyclohexyl
—CH 2 CH 2 —
108
per-deuterocyclohexyl
—CD═CD—
109
4,4-dideuterocyclohexyl
—CD═CD—
110
per-deuterocyclohexyl
—CH═CH—
111
4,4-dideuterocyclohexyl
—CH═CH—
29 . The composition of claim 9 , wherein the compound of the composition is selected from:Join the waitlist — get patent alerts
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