US2013217640A1PendingUtilityA1
Glycosylated acetaminophen pro-drug
Est. expiryJul 22, 2030(~4 yrs left)· nominal 20-yr term from priority
C07H 15/203A61P 25/04
44
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Claims
Abstract
The present invention relates to methods and compositions for the synthesis, production, and use of pro-drug analogs of the analgesic acetaminophen. This invention relates to a method for the production of a broad group of glycosides of acetaminophen derivatives.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of the formula:
wherein R 1 is an alkyl, alkyl alkanoate, alkenyl, alkynyl, acyl, alkanediyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl oximes (R═CH═NOH), alkyl hydrazones (R═CH═NHNHR), alkyl amines, or a substituted version of any of these groups or a protecting group, phosphates [R═OP(O)(OH) 2 ], sulfonates [R═OS(O) 2 OH], sugar, OH, or H; and R 2 is an alkyl, alkyl alkanoate, alkenyl, alkynyl, acyl, alkanediyl, aryl, aralkyl, heteroaryl, heteroaralkyl, allyl oximes (R═CH═NOH), alkyl hydrazones (R═CH═NHNHR), alkyl amines or a substituted version of any of these groups or a protecting group, phosphates [R═—OP(O)(OH) 2 ], sulfonates [R═OS(O) 2 OH], sugar, or H.
2 . The compound of claim 1 , further comprising a pharmaceutically effective carrier.
3 . The compound of claim 1 having the formula:
4 . The compound of claim 1 having the formula:
5 . The compound of claim 1 having the formula:
6 . The compound of claim 1 having the formula:
7 . The compound of claim 1 having the formula:
8 . The compound of claim 1 having the formula:
9 . The compound of claim 1 having the formula:
10 . The compound of claim 1 having the formula:
11 . The compound of claim 1 having the formula:
12 . A composition comprising a compound of the formula:
wherein R 1 is an alkyl, alkyl alkanoate, alkenyl, alkynyl, acyl, alkanediyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl oximes (R═CH═NOH), allyl hydrazones (R═CH═NHNHR), alkyl amines, or a substituted version of any of these groups or a protecting group, phosphates [R═—OP(O)(OH) 2 ], sulfonates [R═OS(O) 2 OH], sugar, OH, or H; and R 2 is an alkyl, alkyl alkanoate, alkenyl, alkynyl, acyl, alkanediyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkyl oximes (R═CH═NOH), alkyl hydrazones (R═CH═NHNHR), alkyl amines or a substituted version of any of these groups or a protecting group, phosphates [R═—OP(O)(OH) 2 ], sulfonates [R═OS(O) 2 OH], sugar, or H.
13 . The compound of claim 12 , further comprising a pharmaceutically effective carrier.
14 . The compound of claim 12 having the formula:
15 . The compound of claim 12 having the formula:
16 . The compound of claim 12 having the formula:
17 . The compound of claim 12 having the formula:
18 . The compound of claim 12 having the formula:
19 . The compound of claim 12 having the formula:
20 . The compound of claim 12 having the formula:
21 . The compound of claim 12 having the formula:
22 . The compound of claim 12 having the formula:
23 . A method of producing a 2,3-hydroxy-glycoside derivative of acetaminophen, comprising:
a) providing a glycoside derivative of acetaminophen wherein the glycoside has an olefin at the 2,3 position relative to the anomeric carbon bonded to the acetaminophen; b) treating said glycoside derivative of acetaminophen under conditions so as to hydroxylate the olefin and produce a 2,3-hydroxy-glycoside derivative of acetaminophen.
24 . The method of claim 23 wherein said hydroxylating conditions comprise using OsO 4 .
25 . The method of claim 23 , wherein said glycoside derivative of acetaminophen of step a) contains protecting groups.
26 . The method of claim 25 , wherein said protecting groups are removed before hydroxylation of the olefin.
27 . The method of claim 25 , wherein said protecting groups are removed after hydroxylation of the olefin.
28 . The method of claim 23 , wherein said 2,3-hydroxy-glycoside derivative of acetaminophen derivative has the formula:
29 . The method of claim 23 , wherein said 2,3-hydroxy-glycoside derivative of acetaminophen derivative has the formula:
30 . The method of claim 23 , wherein said 2,3-hydroxy-glycoside derivative of acetaminophen derivative has the formula:
31 . The method of claim 23 , wherein said 2,3-hydroxy-glycoside derivative of acetaminophen derivative has the formula:
32 . The method of claim 23 , wherein said 2,3-hydroxy-glycoside derivative of acetaminophen derivative has the formula:
33 . The method of claim 23 , wherein said 2,3-hydroxy-glycoside derivative of acetaminophen derivative has the formula:
34 . The method of claim 23 , wherein said 2,3-hydroxy-glycoside derivative of acetaminophen derivative has the formula:
35 . The method of claim 23 , wherein said 2,3-hydroxy-glycoside derivative of acetaminophen derivative has the formula:
36 . The method of claim 23 , wherein said 2,3-hydroxy-glycoside derivative of acetaminophen derivative has the formula:
37 . A method of synthesizing a 2,3-dideoxy-glycoside derivative of acetaminophen wherein the glycoside has methylene groups at the 2 and 3 positions relative to the anomeric carbon bonded to the acetaminophen, comprising:
a) providing a glycoside derivative of acetaminophen wherein the glycoside has an olefin at the 2,3 position relative to the anomeric carbon bonded to the acetaminophen; b) treating said glycoside derivative of acetaminophen under such reducing conditions so as to reduce the olefin and produce a 2,3-dideoxy-glycoside derivative of acetaminophen.
38 . The method of claim 37 , wherein said reducing conditions comprise using TsNHNH 2 .
39 . The method of claim 38 , wherein said glycoside derivative of acetaminophen of step a) contains protecting groups.
40 . The method of claim 39 , wherein said protecting groups are removed before reduction of the olefin.
41 . The method of claim 39 , wherein said protecting groups are removed after reduction of the olefin.
42 . The method of claim 37 , wherein said 2,3-dideoxy-glycoside derivative of acetaminophen has the formula:
43 . The method of claim 37 , wherein said 2,3-dideoxy-glycoside derivative of acetaminophen has the formula:
44 . The method of claim 37 , wherein said 2,3-dideoxy-glycoside derivative of acetaminophen has the formula:
45 . The method of claim 37 , wherein said 2,3-dideoxy-glycoside derivative of acetaminophen has the formula:
46 . The method of claim 37 , wherein said 2,3-dideoxy-glycoside derivative of acetaminophen has the formula:
47 . The method of claim 37 , wherein said 2,3-dideoxy-glycoside derivative of acetaminophen has the formula:
48 . The method of claim 37 , wherein said 2,3-dideoxy-glycoside derivative of acetaminophen has the formula:
49 . The method of claim 37 , wherein said 2,3-dideoxy-glycoside derivative of acetaminophen has the formula:
50 . The method of claim 37 , wherein said 2,3-dideoxy-glycoside derivative of acetaminophen has the formula:
51 . The method of treating a subject, comprising:
a) providing a subject; b) treating said subject with a 2,3-hydroxylated glycoside derivative of acetaminophen.
52 . The method of claim 51 , wherein said treatment reduces one or more symptoms of a diseased state.
53 . The method of treating a subject, comprising:
a) providing a subject; b) treating said subject with a 2,3-dideoxy-glycoside derivative of acetaminophen.
54 . The method of claim 53 , wherein said treatment reduces one or more symptoms of a diseased state.
55 . A method of synthesizing a glycosylated acetaminophen, comprising:
a) providing a 4-nitrophenol, a per-acylated carbohydrate, an acid catalyst, and solvent; b) glycosylating said 4-nitrophenol with said per-acylated carbohydrate with said acid catalyst in said solvent so as to produce a first product, said first product comprising a nitro group; c) treating said first product so as to reduce said nitro group to an amide and to concomitantly acylate said amide, thereby creating a second product, said second product comprising a plurality of acetate groups; d) treating said second product under conditions such that all of said acetate groups are hydrolyzed, thereby creating a third product, said third product comprising a plurality of hydroxyl groups, one of said hydroxyl groups at position C-6; and e) treating said third product under conditions such that said hydroxyl at position C-6 is selectively acylated, thereby synthesizing a glycosylated acetaminophen.
56 . The method of claim 55 , wherein said per-acylated carbohydrate is pentaacetyl mannose.
57 . The method of claim 55 , wherein said per-acylated carbohydrate is pentaacetyl glucsose.
58 . The method of claim 55 , wherein said per-acylated carbohydrate is pentaacetyl galactose.
59 . The method of claim 55 , wherein said per-acylated carbohydrate is tetraacetyl rhamnose.
60 . The method of claim 55 , wherein said per-acylated carbohydrate is octaacetyl maltose.
61 . The method of claim 55 , wherein said per-acylated carbohydrate is octaacetyl lactose.
62 . The method of claim 55 , wherein said acid catalyst is BF 3 OEt 2 .
63 . The method of claim 55 , wherein said solvent is CH 2 Cl 2 .
64 . The method of claim 56 , wherein the structure of said first product is:
65 . The method of claim 64 , wherein the structure of said second product is:
66 . The method of claim 65 , wherein the structure of said third product is:
67 . The method of claim 66 , wherein the structure of said glycosylated acetaminophen is:
68 . A method of synthesizing an amino hydroxyl glycosylated acetaminophen analog, comprising:
a) providing acetylated protecting group protected 2,3-olefin glycosylated acetaminophen analog, m-CPBA, and solvent; b) epoxidizing said acetylated protecting group protected 2,3-olefin glycosylated acetaminophen analog with said m-CPBA in said solvent so as to produce a first product, said first product comprising an 2,3-epoxide group; c) treating said first product so as to change said epoxide group to an azide and hydroxyl group, thereby creating a second product, said second product comprising an azide and hydroxyl group; d) treating said second product under conditions such that all of said azide groups are hydrogenated and reduced, thereby creating a third product, said third product comprising an amine and hydroxyl groups; and e) treating said third product under conditions such that said acetylated hydroxyl protecting groups are selectively removed, thereby synthesizing an amino hydroxyl glycosylated acetaminophen analog.
69 . The method of claim 68 , wherein the structure of said first product is:
70 . The method of claim 68 , wherein the structure of said second product is selected from the group:
71 . The method of claim 68 , wherein the structure of said third product is selected from the group:
72 . The method of claim 68 , wherein the structure of said amino hydroxyl glycosylated acetaminophen analog is selected from the group:
73 . A method of synthesizing 2,3-dideoxy-glycoside derivative of acetaminophen, comprising:
a) providing protecting group protected 2,3-olefin glycosylated acetaminophen analog, H 2 , and a metal which catalyzes hydrogenation; b) hydrogenating said protecting group protected 2,3-olefin glycosylated acetaminophen analog with said H 2 and metal so as to produce a first product, said first product comprising a protecting group protected 2,3-dideoxy-glycoside derivative of acetaminophen; c) treating said first product so as to remove the protecting group of said first product, thereby creating a 2,3-dideoxy-glycoside derivative of acetaminophen.
74 . The method of claim 73 , wherein the structure of said protecting group protected 2,3-olefin glycosylated acetaminophen analog is selected from the group:
wherein R is a protecting group, acetate, or H.
75 . The method of claim 73 , wherein the structure of said first product is selected from the group:
wherein R is a protecting group, acetate, or H.
76 . The method of claim 73 , wherein the structure of said 2,3-dideoxy-glycoside derivative of acetaminophen is selected from the group:
77 . The method of claim 73 , wherein said metal which catalyzes hydrogenation is selected from the group: nickel, platinum, palladium, rhodium, and ruthenium based metals.Cited by (0)
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