EP0074306A2
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EP
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Anti-viral guanine derivatives
Assignee: Merck and Co Inc
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Filing: 1982-08-24
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Granted: —
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Expires: 2002-08-24
Abstract
Abstract 9-(1,3-dihydroxy-2-propoxymethyl)guanine and 9-(2,3-dihydroxy-1-propoxymethyl)guanine have been found to have potent anti-viral activity against herpes viruses. These compounds, their acyl derivatives, their phosphate derivatives and their pharmaceutically acceptable salts, pharmaceutical formulations containing these compounds, the treatment of viral infections with these compounds, methods of preparing these compounds, and novel intermediates useful in their preparation are all disclosed. The compounds may be prepared by reaction of the appropriate acetoxymethyl ether with diacetylguanine, followed by deprotection. The acetoxymethyl ethers may be obtained by reaction of glycerol formal with acetic anhydride in the presence of a catalyst.
Inventors
- 👤 Wallace T. Ashton
- 👤 John D. Karkas
- 👤 Arthur K. Field
- 👤 Richard L. Tolman
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-29 11:40
CPC Classifications
C; C07; C07D; C07D473/00; A; A61; A61P; A61P31/00; A61P31/12; A61P31/20; A61P31/22; C07F; C07F9/00; C07F9/02; C07F9/547; C07F9/6561; C07F9/65616
Claims Analysis
Total Claims: 23
Claim 1
Independent Claim
85 words
A compound of the formula: wherein R and R 2 are independently H, or OR 1 and OR together are R 3 is H , alkyl of 1-20 carbon atoms which may be straight chain or branched, saturated or mono- or polyunsaturated, aryl, substituted aryl, heterocyclyl, aralkyl, alkoxyalkyl or aryloxyalkyl, R 4 and R 5 are independently H, a pharmaceutically acceptable cation, alkyl of 1-8 carbon atoms which may be straight chain or branched, aryl, aralkyl, phosphate or pyrophosphate, and R 8 is H or
Claim 2
Dependent Claim
85 words
A compound of the formula: wherein R and R 2 are independently H, or OR 1 and OR together are R 3 is H , alkyl of 1-20 carbon atoms which may be straight chain or branched, saturated or mono- or polyunsaturated, aryl, substituted aryl, heterocyclyl, aralkyl, alkoxyalkyl or aryloxyalkyl, R 4 and R 5 are independently H, a pharmaceutically acceptable cation, alkyl of 1-8 carbon atoms which may be straight chain or branched, aryl, aralkyl, phosphate or pyrophosphate, and R 8 is H or
Claim 3
Dependent Claim
18 words
A compound of Claim 1 wherein each of R 1 , R 2 and R 8 is H.
Claim 4
Dependent Claim
13 words
A compound of Claim 1 wherein OR 1 and OR 2 together are
Claim 5
Dependent Claim
29 words
An intermediate for a compound of formula I of Claim 1 of the formula wherein R is AcO or bromine, chlorine or iodine, and Ac is an acyl group.
Claim 6
Dependent Claim
29 words
An intermediate for a compound of formula II of Claim 1 of the formula wherein R is AcO or bromine, chlorine or iodine, and Ac is an acyl group.
Claim 7
Dependent Claim
49 words
A compound of Claim 1 having the formula wherein R 6 is -CH 2 OH or -CH 2 OCR 3 and R 7 is -CH 2 OCR 3 , or wherein R 6 is or and R 7 is H and R 8 is as defined in Claim 1.
Claim 8
Dependent Claim
57 words
A method of preparing a compound of Claim 1 wherein R 1 , R and R 8 are each H which comprises de- acylating a compound of the formula wherein R 6 is and R 7 is or wherein R 6 is and R 7 is H, and R8 is H or as defined in Claim 1.
Claim 9
Dependent Claim
134 words
A method of preparing a compound of Claim 6 which comprises reacting a compound of formula I or I I of Claim 1 wherein R l , R 2 and R 8 are each H with an acylating compound of the formula wherein X is a carboxyl activating group whereby a monoacylated derivative is formed when the reaction is allowed to proceed until 1 equivalent of the acylating compound is reacted with the compound of formula I or II, or whereby a diacylated derivative is formed when the reaction is allowed to proceed until 2 equivalents of the acylating compound are reacted with the compound of formula I or II or whereby a triacylated derivative is formed when 3 equivalents of the acylating agent are reacted with the compound of formula I or II.
Claim 10
Dependent Claim
19 words
A method according to Claim 8 wherein the carboxyl activating group is halide, acyloxy, 1-benzotriazolyloxy, N-succinimidvloxv or 1,3-disubstituted isoureido.
Claim 11
Dependent Claim
86 words
A method of preparing a compound of Claim 1 wherein R 1 and R 2 are H, or or OR 1 and OR 2 together are and R 8 is H, which comprises reacting a compound of formula I or II of Claim 1 wherein R 1 , R 2 and R are each H with a phosphorylating agent and treating the resultant intermediate with water or an alkanol of 1-8 carbon atoms and isolating at least one of the resultant acyclic or cyclic phosphate derivatives.
Claim 12
Dependent Claim
17 words
A method according to Claim 10 wherein the phosphorylating agent is POX 3 wherein X is halogen.
Claim 13
Dependent Claim
73 words
A method of preparing a compound of Claim 1 wherein one of R 1 and R 2 is H and the other is and R 8 is H and R 4 is as defined in Claim 1 and R 5 is either H or a pharmaceutically acceptable cation which comprises reacting a compound of formula I or II, in which OR 1 and OR 2 together are with an aqueous alkali metal hydroxide.
Claim 14
Dependent Claim
50 words
A method of preparing a monophosphate derivative of a compound of formula I or II of Claim 1 wherein R 1 , R 2 and R 8 are each H which comprises incubating said compound of formula I or II in the presence of HSV1 thymidine kinase and adenosine triphosphate.
Claim 15
Dependent Claim
54 words
A method for preparing a pvrophosphate derivative of a compound of formula I or II of Claim 1 wherein R 1 , R 2 and R 8 are each H which comprises incubating said compound of formula I or II in the presence of HSV1 thymidine kinase, adenosine triphosphate and q uanosine monophosphate kinase.
Claim 16
Dependent Claim
59 words
A method for preparing a linear tri- phosphate derivative of a compound of formula I or II of Claim 1 wherein R 1 , R 2 and R 8 are each H which comprises incubating said compound of formula I or II in the presence of HSV1 thymidine kinase, adenosine triphosphate, guanosine monophosphate kinase and extract of HSV1-infected cells.
Claim 17
Dependent Claim
72 words
A method for preparing a linear triphosphate derivative of a compound of formula I or II of Claim 1 wherein R 1 , R 2 and R 8 are each H which comprises incubating a compound of formula I or II wherein one of R 1 or R 2 is and the other is H and R 4 is phosphate, and R 8 is H, with 3'-phosphoglycerate kinase, 3-phosphoglyceraldehyde dehydrogenase and 3-phosphoglyceraldehyde.
Claim 18
Dependent Claim
31 words
A composition for treating a herpes virus infection in a mammalian or avian species, which contains a compound of Claim 1 in a quantity effective to impart an anti-herpes virus effect.
Claim 19
Dependent Claim
18 words
A composition according to Claim 17 for administering the compound at from about 0.01 to about 200 mg/kg.
Claim 20
Dependent Claim
26 words
A composition according to Claim 17 for topically administering the compound at a dosage level of from about 0.1 % to about 5 % by weight.
Claim 21
Dependent Claim
21 words
A composition according to Claim 19 wherein the dosage level is from about 0.25 % to about 3 % by weight.
Claim 22
Dependent Claim
25 words
A composition according to Claim 17 for orally or parenterally administering the compound, at a dosage level of from about 0.8 to about 100 mg/kg.
Claim 23
Dependent Claim
18 words
A composition according to Claim 21 wherein the dosage level is from about 5 to about 50 mg/kg.
References Cited (Backward Citations)
No citation records indexed.
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