EP0253412B1
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EP
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N-phosphonylmethoxyalkyl derivatives of pyrimidine and purine bases, methods for their preparation and pharmaceutical compositions therefrom with antiviral activity
Assignee: Rega Foundation institute Of Organic Chemistry And
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Filing: 1987-07-17
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Granted: 1990-10-31
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Expires: 2007-07-17
Abstract
Abstract This invention relates to new nucleotide analogues exhibiting antiviral activity which represent N-(2-phosphonylmethoxyethyl) and N-(3-hydroxy-2-phosphonylmethoxypropyl) derivatives of pyrimidine and purine bases and to methods for their preparation and to their use in pharmaceutical compositions. These compounds are easily accessible from heterocyclic bases and their N-(2-hydroxyethyl) or N-(2,3-dihydroxypropyl) derivatives. Some of the compounds according to this invention exhibit a marked antiviral activity or can be converted into such active compounds by chemical transformations.
Inventors
- 👤 Antonin Rndr Holy
- 👤 Ivan Rosenberg
- 👤 Erik Prof.Dr. De Clercq
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-29 22:48
CPC Classifications
C; C07; C07F; C07F9/00; C07F9/02; C07F9/547; C07F9/6561; C07F9/65616; A; A61; A61P; A61P31/00; A61P31/12; C07F9/645; C07F9/6509; C07F9/6512
Claims Analysis
Total Claims: 13
Claim 1
Independent Claim
58 words
N-Phosphonylmethoxyalkyl derivatives of pyrimidine and purine bases of the general formula I, wherein R is a hydrogen atom or a hydroxymethyl group, and B is an optionally substituted pyrimidin-1-yl, pyrimidin-3-yl, purin-3-yl, purin-7-yl or purin-9-yl residue, or an aza, deaza, deoxy or deanimo analogue thereof unsubstituted adenin-9-yl being excluded, and the salts thereof with alkali, metals, ammonia and amines.
Claim 2
Dependent Claim
58 words
N-Phosphonylmethoxyalkyl derivatives of pyrimidine and purine bases of the general formula I, wherein R is a hydrogen atom or a hydroxymethyl group, and B is an optionally substituted pyrimidin-1-yl, pyrimidin-3-yl, purin-3-yl, purin-7-yl or purin-9-yl residue, or an aza, deaza, deoxy or deanimo analogue thereof unsubstituted adenin-9-yl being excluded, and the salts thereof with alkali, metals, ammonia and amines.
Claim 3
Dependent Claim
29 words
N-Phosphonylmethoxyalkyl derivatives of formula I according to claim 1, wherein the residues B are aza, deaza, deoxy or deamino analogues of uracil, thymine, cytosine, guanine, adenine, hypoxanthine or xanthine.
Claim 4
Dependent Claim
22 words
N-Phosphonylmethoxyalkyl derivatives of formula I according to claim 1, wherein the residue B is 6-alkylpurin-3-yl, 6-alkylpurin-7-yl or 6-alkylpurin-9-yl or a derivative thereof.
Claim 5
Dependent Claim
30 words
N-Phosphonylmethoxyalkyl derivatives of formula I according to one of claims 1 to 3, wherein the substituent B is substituted with a methyl, amino, bromo, fluoro, hydroxy and/or a thio group.
Claim 6
Dependent Claim
38 words
N-Phosphonylmethoxyalkyl derivatives of formula I according to claim 1, wherein B is Uracil-1-yl, Thymin-1-yi, Cytosin-1-yl, 6-Methylpurin-9-yl, Guanin-9-yl, Hypoxanthin-9-yl, 2-Aminoadenin-9-yi, 8-Bromoadenin-9-yl, 2-Aminopurin-9-yl, 6-Hydrazinopurin-9-yl, 7-Deaza-8-azaadenin-9-yl, 7-Deaza-8-azahypoxanthin-9-yl, 5-Methylcytosin-1-yl, 5-Fluorouracil-1-yl, Guanin-7-yl, Adenin-3-yl, Hypoxanthin-9-yl, 2-Methyladenin-9-yl, 2-Methylthioadenin-9-yl, N6-Dimethyladenin-9-yl, 8-Hydroxyadenin-9-yl, 6-Hydroxylaminopurin-9-yl, 6-Thiopurin-9-yi, Purin-9-yl, or Xanthin-9-yl.
Claim 7
Dependent Claim
28 words
N-Phosphonylmethoxyalkyl derivatives of formula I according to one of claims 1 to 5 representing the following combinations of R and B and having the indicated C 2- configuration:
Claim 8
Dependent Claim
125 words
Methods for preparing the N-phosphonylmethoxyalkyl derivatives of formula I according to one of claims 1 to 6, wherein R is a hydrogen atom, characterized by (A) - reaction of N-(2-hydroxyethyl) derivatives of the corresponding heterocyclic bases having the formula II B CH2CH2-OH (II), wherein B is as in formula I of claim 1, with diesters of p-toluenesulfonyloxymethanephosphonic acid, and - cleavage with a trimethylhalogenosilane, or (B) - reaction of an alkali metal salt of the heterocyclic bases with diesters of 2-bromoethoxymethanephosphonic acid of the general formula III Br-CH 2 CH 2 OCH 2 P(O)(OC 2 H 5 ) 2 (III) to give intermediates of the general formula IV B-CH 2 CH 2 0CH 2 P(O)(OC 2 Hs) 2 (IV) and - treatment with a trimethylhalogenosilane.
Claim 9
Dependent Claim
135 words
Methods for preparing the N-phosphonylmethoxyalkyl derivatives of formula I according to one of claims 1 to 6, wherein R is a hydroxymethyl group, characterized by (A) - reaction of a protected N-(2,3-dihydroxypropyl) derivative of the heterocyclic bases of the general formula V, B-CH2CH(OH)CH2-OH (V), wherein B is as in formula I of claim 1, and having a free 2-hydroxy group with diesters of p-toluenesulfonyloxymethanephosphonic acid and - cleavage with a trimethylhalogenosilane, or (B) - reaction of unprotected compounds of formula V with chloromethanephosphonyl dichloride of the formula VI Cl-CH 2 P(O)Cl 2 (VI), -isomerization of the formed 2'-O-chloromethanephosphonyl esters of the compounds of formula V in a mineral acid or in water to the corresponding 3'-O-chloromethanephosphonyl esters of the general formula VII -treatment of the compounds of formula VII with an aqueous alkali metal hydroxide.
Claim 10
Dependent Claim
119 words
Methods for preparing N-phosphonylmethoxyalkyl derivatives of formula I according to one of claims 1 to 6, characterized in that - for preparing compounds of formula I wherein B is 5-halogenouracil-1-yl, an uracil-1-yl derivative of formula I is halogenated, preferably with bromine or iodine; - for preparing compounds of formula I wherein B is a hypoxanthin-9-yl moiety, a corresponding adenine derivative, particularly HPMPA or PMEA, is deaminated with nitrous acid or amyl nitrite; - for preparing compounds of formula I wherein B is a xanthin-9-yi moiety, a corresponding guanine derivative is deaminated with nitrous acid or amyl nitrite, and - for preparing compounds of formula I wherein B is an 8-halogenopurine, the corresponding purine base is halogenated, preferably with chlorine.
Claim 11
Dependent Claim
30 words
Pharmaceutical compositions exhibiting antiviral activity, characterized in that they comprise at least one N-phosphonylmethoxyalkyl derivative of formula I as active ingredient in a concentration of from 0.01 to 100 mass-%.
Claim 12
Dependent Claim
30 words
Pharmaceutical compositions exhibiting antiviral activity, characterized in that they comprise at least one N-phosphonylmethoxyalkyl derivative of formula I as active ingredient in a concentration of from 0.01 to 100 mass-%.
Claim 13
Dependent Claim
26 words
Use of the N-phosphonylmethoxyalkyl derivatives of formula I according to one of claims 1 to 6 for preparing pharmaceutical compositions for the treatment of virus diseases.
References Cited (Backward Citations)
No citation records indexed.
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