Claims
- 1. A compound having the formula ##STR101## or a pharmaceutically acceptable salt thereof wherein R.sub.1 is ##STR102## R.sub.4 is alkyl; R.sub.5 is hydrogen, alkyl, substituted alkyl, or aryl; and
- R.sub.6 and R.sub.7 are independently hydrogen, --PO.sub.3 H.sub.2, or ##STR103##
- 2. A compound according to claim 1 wherein R.sub.1 is ##STR104##
- 3. A compound according to claim 1 wherein R.sub.6 and R.sub.7 are independently hydrogen or ##STR105##
- 4. A compound according to claim 1 wherein R.sub.6 and R.sub.7 are independently hydrogen or --PO.sub.3 H.sub.2.
- 5. A compound according to claim 1 wherein R.sub.6 and R.sub.7 are hydrogen.
- 6. A compound according to claim 1 wherein ##STR106##
- 7. A compound according to claim 1 wherein R.sub.1 is ##STR107##
- 8. A compound according to claim 1, [1S-(1.alpha.,3.alpha.,4.beta.)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylene-cyclopentyl]-6H-purin-6-one.
- 9. A compound according to claim 1, [1R-(1.alpha.,3.alpha.,5.beta.)]-3-(6-amino-9H-purin-9-yl)-5-hydroxy-2-methylenecyclopentanemethanol.
- 10. An antiviral composition useful for treating herpes simplex virus 1 and 2, varicella zoster virus, and human cytomegalovirus comprising a pharmaceutically acceptable carrier and an effective amount of a compound of the formula ##STR108## wherein R.sub.1, R.sub.6 and R.sub.7 are as defined in claim 1.
- 11. A method of treating a herpes simples virus 1, a herpes simplex virus 2, a varicella zoster virus, or a human cytomegalovirus infection in a mammalian species comprising administering an effective amount of the composition of claim 10.
RELATED APPLICATION
This application is a continuation-in-part of Ser. No. 599,568 filed Oct. 18, 1990, now abandoned.
Antiviral activity is exhibited by compounds having the formula ##STR2## and its pharmaceutically acceptable salts. In formula I, and throughout the specification, the symbols are as defined below. ##STR3## wherein R.sub.2 is fluoro, chloro, bromo, iodo, hydrogen, methyl, trifluoromethyl, ethyl, n-propyl, 2-fluoroethyl, 2-chloroethyl, ethynyl, or ##STR4## wherein R.sub.3 is chloro, bromo, iodo, hydrogen, methyl or trifluoromethyl; R.sub.4 is alkyl; R.sub.5 is hydrogen, alkyl, substituted alkyl, or aryl; and R.sub.6 and R.sub.7 re independently hydrogen, --PO.sub.3 H.sub.2 or ##STR5##
Preferred compounds of formula 1 are when R.sub.1 is ##STR6##
Most preferred compounds of formula 1 are when R.sub.1 is ##STR7## The term "alkyl" refers to both straight and branched chain groups. Those groups having 1 to 10 carbons are preferred. The term "substituted alkyl" refers to alkyl groups having one or more, preferably one, substituents. Preferred substituents are halogen, amino, azido, hydroxy, cyano, trialkylammonium (wherein each alkyl group has 1 to 6 carbons), alkoxy of 1 to 6 carbons, aryl and carboxy. The term "aryl" refers to phenyl and phenyl substituted with one, two or three substituents, preferably one. Preferred substitutents are alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, halogen, trifluoromethyl, amino, alkylamino of 1 to 6 carbons, nitro, cyano, alkanoyloxy of 2 to 11 carbons, carboxy, carbamoyl and hydroxy.
The compounds of formula 1, and the pharmaceutically acceptable salts thereof, are antiviral agents that can be used to treat viral infection in mammalian species such as domesticated animals (e.g., dogs, cats, horses and the like) and humans, and avian species (e.g., chickens and turkeys). The compounds of formula 1 wherein R.sub.1 is ##STR8## are effective against one or more of the following viruses: herpes simplex virus 1 and 2, varicella-zoster virus, and cytomegalovirus. They are also believed to be active against a variety of other DNA and retroviruses. Exemplary DNA viruses in addition to those named above include other herpes viruses (e.g., Epstein-Barr virus, pseudorabies virus, human herpes virus 6, and the like), poxviruses (e.g. vaccinia virus, monkey pox, and myoma), papovaviruses (e.g., the papilloma viruses), hepatitis B virus, and adenoviruses. Exemplary retroviruses include those effecting man, such as human immunodeficiency virus (HIV), human T-cell lymphotropic viruses -I and -II and those effecting other animals, such as feline leukemia virus, murine leukemia virus and equine infectious anemia virus. All of the other compounds of formula 1 are believed to be active against one or more of the following viruses: herpes simplex virus 1 and 2, varicella-zoster virus, and cytomegalovirus.
The compounds of this invention may be administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), orally or topically.
The compounds may be administered orally or parenterally in an amount effective to treat the infection. The dosage will, of course, depend on the severity of the infection, but will likely be in the range of about 1.0 to 50 mg/kg of body weight. The desired dose may be administered several times daily at appropriate intervals.
For infections of the eye, or other external tissues, (e.g. mouth and skin), the compositions may be applied to the infected part of the body of the patient topically as an ointment, cream, aerosol, gel, powder, lotion, suspension or solution (e.g. as in eye drops). The concentration of the compound in the vehicle will, of course, depend on the severity of the infection, but will likely be in the range of about 0.1 to 7% by weight.
The compounds of this invention can be prepared from a compound of formula ##STR9## wherein "Bn" is ##STR10## and P is a protecting group such as a benzyl, trityl, substituted trityl (e.g. 4-monomethoxytrityl or 4,4'-dimethoxytrityl), or silyl group. The term silyl refers to silyl protecting groups well known in the art [e.g. t-butyldimethylsilyl, t-butyldiphenylsilyl, (triphenylmethyl)dimethylsilyl, methyldiisopropylsilyl, or triisopropylsilyl]. Protection of the hydroxyl group in the known compound of formula using benzyl bromide and sodium hydride affords the known compound of formula 2 wherein P is a benzyl group [see K. Biggadike et.al, J. Chem. Soc. Perkin Trans, 1 549 (1988)]. Protection with a trityl, substituted trityl or silyl group can be accomplished by methods known in the art.
A compound of formula 1 wherein R.sub.1 is ##STR11## and R.sub.6 and R.sub.7 are hydrogen can be prepared by reaction of a compound of formula 2 with a compound of formula ##STR12## in the presence of a base such as lithium hydride, sodium hydride, or potassium hydride in an aprotic polar solvent such as dimethylformamide, dimethyl sulfoxide, or sulfolane (tetramethylene sulfone).
This yields the corresponding compound of formula ##STR13##
Protection of the amino (--NH.sub.2) group in the compound of formula 5 affords a compound of formula ##STR14## wherein the protecting group P.sub.1 can be trityl or substituted trityl (e.g. 4-monomethoxytrityl or 4,4'-dimethoxytrityl). The protection can be accomplished by treatment of the compound of formula 5 with trityl chloride or a substituted trityl chloride in dichloromethane in the presence of triethylamine (and, optionally, in the presence of 4-N,N-dimethylaminopyridine). Oxidation of the hydroxyl group in this compound of formula 6 yields a compound of formula ##STR15##
The oxidation can be carried out by methods well know in the art (e.g. 1,3-dicyclohexylcarbodiimide/dimethyl sulfoxide/methylphosphonic acid in dichloromethane or pyridinium dichromate/molecular sieves in dichloromethane). Treatment of a compound of formula 7 with a methylenation reagent such as zinc/titanium tetrachloride/dibromomethane in dichloromethane/tetrahydrofuran or methylenetriphenylphosphorane yields a compound of formula ##STR16##
Removal of the protecting groups from a compound of formula 8 provides the compound of formula 1 wherein R.sub.1 is ##STR17## and R.sub.6 and R.sub.7 are hydrogen.
When the protecting groups P and P.sub.1 are trityl or substituted trityl, removal of the trityl groups P and P.sub.1 can be accomplished by treatment with aqueous alcoholic mineral acid (e.g. hydrochloric acid in aqueous methanol) or aqueous acetic acid. Subsequently, the benzyl group protecting the primary hydroxyl group can be removed by treatment with boron trichloride in dichloromethane. When the protecting group P is benzyl and the P.sub.1 protecting group is trityl or substituted trityl, the P.sub.1 protecting group can be removed by treatment with aqueous alcoholic mineral acid or aqueous acetic acid, and the benzyl protecting groups can be removed with boron trichloride. When the protecting group P is a silyl group and P.sub.1 is a trityl or substituted trityl group, the silyl group can be removed first by treatment with fluoride ion (e.g. tetrabutylammonium fluoride in tetrahydrofuran). Subsequently, the P.sub.1 protecting group can be removed by treatment with aqueous alcoholic mineral acid or aqueous acetic acid, and then the benzyl group protecting the primary alcohol group can be removed by treatment with boron trichloride. Alternatively, the P.sub.1 protecting group can be removed first, the silyl protecting group P second, and the benzyl group protecting the primary alcohol last.
The compound of formula 1 wherein R.sub.1 is ##STR18## and R.sub.6 and R.sub.7 are hydrogen can be prepared as follows:
Reaction of a compound of formula 2 with a compound of formula ##STR19## according to procedures analogous to those used in preparation of the compound of formula 5 affords a compound of formula ##STR20##
Protection of the amino group (--NH.sub.2) in the compound of formula 10 according to the procedures analogous to those used in the preparation of the compound of formula 6 yields a compound of formula ##STR21##
Oxidation of the alcohol group in the compound of formula 11 under conditions analogous to those used in the preparation of the compound of formula 7 provides a compound of formula ##STR22##
Methylenation of the ketone group in the compound of formula 12 under conditions analogous to those used in the preparation of the compound of formula 8 yields a compound of formula ##STR23##
Finally, removal of the protecting groups from the compound of formula 13 provides the compound of formula 1 wherein R.sub.1 is ##STR24## and R.sub.6 and R.sub.7 are hydrogen.
When the protecting groups P and P.sub.1 are trityl or substituted trityl, removal of the trityl groups and the purine O-benzyl protecting group can be accomplished by treatment with aqueous alcoholic mineral acid (e.g. hydrochloric acid in aqueous methanol). Subsequently, the benzyl group protecting the primary hydroxyl, can be removed by treatment with boron trichloride in dichloromethane. When the protecting group P is benzyl and the P.sub.1 protecting group is trityl or substituted trityl, the P.sub.1 protecting group and the purine O-benzyl protecting group can be removed first by treatment with aqueous alcoholic mineral acid. Subsequently, the benzyl groups protecting the alcohol groups can be removed by treatment with boron trichloride. When the protecting group P is a silyl group and P.sub.1 is a trityl or substituted trityl group, the silyl group can be removed first by treatment with fluoride ion (e.g. tetrabutylammonium fluoride in tetrahydrofuran). Subsequently, the P.sub.1 protecting group and the purine O-benzyl protecting group can be removed by treatment with aqueous alcoholic mineral acid. Finally, the benzyl group protecting the primary alcohol can be removed by treatment with boron trichloride. Alternatively, the P.sub.1 and purine O-benzyl protecting groups can be removed first, the silyl protecting group P second, and the benzyl group protecting the primary alcohol last.
Alternatively, this compound can be prepared from a compound of formula 1 wherein R.sub.1 is ##STR25## and R.sub.6 and R.sub.7 are hydrogen, by hydrolysis of the chloro group using aqueous acid (e.g. aqueous hydrochloric acid).
The compound of formula 1 wherein R.sub.1 is ##STR26## and R.sub.6 and R.sub.7 are hydrogen can be prepared from the compound of formula 5 wherein P is a silyl group (e.g. t-butyldiphenylsilyl). Hydrogenolysis of this compound (e.g. ammonium formate and palladium on carbon in methanol; palladium hydroxide on carbon and cyclohexene in ethanol; or palladium on carbon, hydrogen, and ethanol) results in reduction of the chloro group and removal of the benzyl protecting group on the primary hydroxyl to afford the compound of formula ##STR27##
Protection of the primary hydroxyl group and the amino (--NH.sub.2) group in the compound of formula 14 by reaction with trityl chloride or a substituted trityl chloride in dichloromethane in the presence of triethylamine and 4-N,N-dimethylaminopyridine affords the compound of formula ##STR28## where the P.sub.1 groups are trityl or substituted trityl. Sequential oxidation and methylenation of the compound of formula 15 under conditions analogous to those used in the preparation of the compounds of formulas 7 and 8,respectively, followed by removal of the protecting groups, affords the compound of formula 1 wherein R.sub.1 is ##STR29## and R.sub.6 and R.sub.7 are hydrogen.
The silyl protecting group P can be removed first by treatment with fluoride ion (e.g. tetrabutylammonium fluoride in tetrahydrofuran), and then the trityl protecting groups P.sub.1 can be removed by treatment with aqueous alcoholic mineral acid (e.g. hydrochloride acid in aqueous methanol) or aqueous acetic acid. Alternatively, the trityl protecting groups P.sub.1 can be removed first followed by removal of the silyl protecting group P.
Alternatively, reaction of the compound of formula ##STR30## wherein P.sub.1 is a trityl or substituted trityl group, with a compound of formula 2 under conditions analogous to those used in the preparation of the compound of formula 5 affords a compound of formula ##STR31##
Sequential oxidation and methylenation of the compound of formula 17 under conditions analogous to those used in the preparation of the compounds 7 and 8, respectively, followed by removal of the protecting groups affords the compound of formula 1 wherein R.sub.1 is ##STR32## and R.sub.6 and R.sub.7 are hydrogen.
Alternatively, reaction of a compound of formula ##STR33## with a compound of formula 2 affords a compound of formula ##STR34## Protection of the amino (--NH.sub.2) group with a trityl or substituted trityl group provides the compound of formula 17, which can then be converted (as described above) to the compound of formula 1 wherein R.sub.1 is ##STR35## and R.sub.6 and R.sub.7 are hydrogen.
The compound of formula 1 wherein R.sub.1 is ##STR36## and R.sub.6 and R.sub.7 are hydrogen can be prepared from a compound of formula 8 by methods known in the art. Thus, for example, when a compound of formula 8 (wherein P is a protecting group such as benzyl, silyl, trityl or substituted trityl, and P.sub.1 is trityl or substituted trityl) is treated with hot methanolic ammonia, displacement of the chloro group with an amino group will result. The protecting groups can then be removed according to procedures known in the art.
Alternatively, this compound of formula 1 can be prepared from a compound of formula 1 wherein R.sub.1 is ##STR37## and R.sub.6 and R.sub.7 are hydrogen by methods known in the art. (See, e.g., J.C. Martin, et al, J. Med. Chem. 28, 358 (1985)).
A compound of formula 1 wherein R.sub.1 is ##STR38## and R.sub.6 and R.sub.7 are hydrogen can be prepared by treatment of a compound of formula 5 with sodium alkoxide, which provides the compound of formula ##STR39## Protection of the amino group, oxidation and methylenation (according to procedures analogous to those used in the preparation of compounds 6, 7 and 8), followed by removal of protecting groups, provides the compound of formula 1 wherein R.sub.1 is ##STR40## and R.sub.6 and R.sub.7 are hydrogen.
Alternatively, this compound of formula 1 can be prepared from a compound of formula 1 wherein R.sub.1 is ##STR41## and R.sub.6 and R.sub.7 are hydrogen by methods known in the art. See, for example, J.F. Gerster, et al., J. Amer. Chem. Soc., 87, 3752 (1965); K.K. Ogilvie, et al., Can. J. Chem., 62, 2702 (1984); M.R. Harnden, et al., J. Med. Chem., 30, 1636 (1987).
Alternatively, this compound of formula 1 can be prepared from a compound of formula ##STR42## and a compound of formula 2 using procedures analogous to those used in the preparation of compounds 5, 6, 7 and 8, followed by removal of the protecting groups. A compound of formula 21 can be prepared from the compound of formula 4 by methods know in the art (See, e.g., W.A. Bowles, et al., J. Med. Chem., 6, 471 (1963); M.MacCoss, et al., Tetrahedron Lett., 26, 1815 (1985)).
The compound of formula 1 wherein R.sub.1 is ##STR43## and R.sub.6 and R.sub.7 are hydrogen can be prepared from a compound of formula 2 and a compound of formula ##STR44## according to procedures analogous to those used in preparation of compounds 10, 11, 12, and 13, followed by removal of the protecting groups.
The compound of formula 1 wherein R.sub.1 is ##STR45## and R.sub.6 and R.sub.7 are hydrogen can be prepared as follows:
Reaction of the compound of formula ##STR46## with a compound of formula 2 according to procedures analogous to those used in preparation of the compound of formula 5, affords a compound of formula
Selective protection of the amino (--NH.sub.2 ) group in the compound of formula 24 with an acyl group P.sub.2 (e.g., acetyl) gives the compound of formula ##STR47## See, for example, G. S. Ti et al., J. Amer. Chem Soc., 104, 1316 (1982)). Oxidation of the compound of formula 25 and subsequent treatment with zinc/titanium tetrachloride/dibromomethane according to procedures analogous to those used in the preparation of compounds 7 and 8 provides a compound of formula ##STR48##
Removal of the protecting groups from this compound yields the compound of formula 1 wherein R.sub.1 is ##STR49## and R.sub.6 and R.sub.7 are hydrogen.
Alternatively, oxidation of the compound of formula 25 and subsequent treatment with methylenetriphenylphosphorane according to procedures analogous to those used for the preparation of compounds 7 and 8 gives the compound of formula 26 wherein the amino (--NH.sub.2 ) group still possesses an acyl protecting group, P.sub.2. Removal of the protecting groups from this compound provides the compound of
formula 1 wherein R.sub.1 is ##STR50## and R.sub.6 and R.sub.7 are hydrogen. (Removal of the acyl protecting group P.sub.2 can be accomplished using sodium methoxide in methanol or methanolic ammonia).
Alternatively, this compound of formula 1 can be prepared by reaction of the compound of formula ##STR51## with a compound of formula 2 under conditions analogous to those used for the preparation of the compound of formula 5. Subsequent oxidation and methylenation according to procedures analogous to those used in the preparation of compounds 7 and 8 provides the compound of formula ##STR52##
Treatment of a compound of formula 28 with hot ammonia in an alcohol (such as methanol or ethanol) followed by removal of protecting groups yields the compound of formula 1 wherein R.sub.1 is ##STR53## and R.sub.6 and R.sub.7 are hydrogen.
In another alternative, this compound of formula 1 can be prepared from a compound of formula 1 wherein R.sub.1 is ##STR54## and R.sub.6 and R.sub.7 are hydrogen by methods known in the art. (See e.g. J.C. Martin et al., J. Med. Chem., 28, 358 (1985)).
The compound of formula 1 wherein R.sub.1 is ##STR55## and R.sub.6 and R.sub.7 are hydrogen can be prepared by removal of the protecting groups from the compound of formula 28.
The compound of formula 1 wherein R.sub.1 is ##STR56## and R.sub.6 and R.sub.7 are hydrogen can be prepared from the compound of formula 1 wherein R.sub.1 is ##STR57## and R.sub.6 and R.sub.7 are hydrogen by following known procedures. See, for example, J. A. Montgomery et al., "Synthetic Procedures in Nucleic Acid Chemistry", Vol. 1, W. W. Zorbach and R. S. Tipson, Eds., Interscience Publishers (John Wiley and Sons), N.Y. p. 205, 1968.
The compound of formula 1 wherein R.sub.1 is ##STR58## and R.sub.6 and R.sub.7 are hydrogen can be prepared from this compound of formula 1 wherein R.sub.1 is ##STR59## and R.sub.6 and R.sub.7 are hydrogen by acid hydrolysis (e.g. hot aqueous hydrochloric acid) or basic hydrolysis (e.g., aqueous methanolic sodium hydroxide).
Alternatively, this compound of formula 1 can be prepared by treatment of a compound of formula 1 wherein R.sub.1 is ##STR60## and R.sub.6 and R.sub.7 are hydrogen with adenosine deaminase or nitrous acid according to methods known in the art (e.g., M. J. Robins, et al., J. Med. Chem., 27, 1486 (1984); K.K. Ogilvie et al, Can. J. Chem., 62 241 (1984)); I. Iwai, et al., in "Synthetic Procedures in Nucleic Acid Chemistry", Vol. 1, W. W. Zorbach and R. S. Tipson, Eds., Interscience Publishers (John Wiley and Sons), N.Y., p. 135, 1968; R. E. Holmes et al., J. Amer. Chem. Soc., 86, 1242 (1964)).
The compound of formula ##STR61## wherein R.sub.2 is hydrogen, fluoro, methyl, ethyl, n-propyl, 2-chloroethyl, or 2-fluoroethyl can be prepared by reaction of the corresponding compound of formula ##STR62## with a compound of formula 2 in the presence of a base such as lithium hydride, sodium hydride, or potassium hydride in an aprotic polar solvent such as dimethylformamide, dimethyl sulfoxide or sulfolane to yield a compound of formula ##STR63##
Oxidation of the hydroxyl group in a compound of formula 31 using methods known in the art (e.g. 1,3-dicyclohexylcarbodiimde/dimethylsulfoxide/methylphosphonic acid in dichloromethane or pyridinium dichromate/molecular sieves in dichloromethane) provides the compound of formula ##STR64##
Treatment of the compound of formula 32 with a methylenation reagent such as zinc/titanium tetrachloride/dibromomethane in dichloromethane/tetrahydrofuran or methylenetriphenylphosphorane yields the compound of formula ##STR65##
Removal of the protecting groups from the compound of formula 33 provides the corresponding compound of formula 29. For example, when the protecting group P is benzyl, both benzyl groups can be removed by treatment with boron trichloride in dichloromethane. When the protecting group P is trityl or substituted trityl, the trityl protecting group can be removed by treatment with aqueous acetic acid or aqueous alcoholic mineral acid, (e.g., hydrochloric acid in aqueous methanol), and then the benzyl protecting group can be removed by treatment with boron trichloride. When the protecting group P is a silyl group, removal of the silyl protecting group can be accomplished with fluoride ion (e.g. tetrabutylammonium fluoride in tetrahydrofuran) and then the benzyl group can be removed by treatment with boron trichloride. Alternatively, the benzyl group can be removed first, followed by removal of the silyl group.
The compound of formula 30 wherein R.sub.2 is 2-chloroethyl or 2-fluoroethyl can be prepared by methods known in the art (H. Griengl et. al., J. Med., 30 1199 (1987); J. Med. Chem., 28 1679 (1985)).
The compound of formula 31 wherein R.sub.2 is fluoro can also be prepared from the corresponding compound 31 wherein R.sub.2 is hydrogen and the protecting group P is benzyl, trityl or substituted trityl by fluorination using trifluoromethyl hypofluorite following methodology known in the art. For example, see M.J. Robins, et al., J. Amer. Chem. Soc., 93 5277 (1971); Chem. Communs., 18 (1972); T.S. Lin et al., J. Med. Chem., 26, 1691 (1983).
The compounds of formula 29 wherein R.sub.2 is 2-chloroethyl and 2-fluoroethyl can also be prepared from a compound of formula ##STR66## wherein P.sub.3 is trityl, substituted trityl, or a silyl protecting group. Removal of the P.sub.3 protecting group yields a compound of formula 33 wherein P is benzyl and R.sub.2 is 2-hydroxyethyl. Treatment of this compound with triphenylphosphinecarbon tetrachloride, and subsequent removal of the benzyl protecting groups with boron trichloride, affords the compound of formula 29 wherein R.sub.2 is 2-chloroethyl. Similar treatment using triphenylphosphine/N-bromosuccinimide or triphenylphosphine/N-bromosuccinamide/tetrabutylammonium iodide in place of triphenylphosphine/carbon tetrachloride (e.g., see H. Griengl, et al., J. Med. Chem., 28, 1679 (1985)) affords compounds of formula 33 wherein P is benzyl and R.sub.2 is 2-bromoethyl or 2-iodoethyl, respectively. Subsequent treatment with fluoride ion, followed by removal of the benzyl protecting groups, provides the compound of formula 29 wherein R.sub.2 is 2-fluoroethyl. Alternatively, treatment of a compound of formula 33 wherein P is benzyl and R.sub.2 is 2-hydroxyethyl with diethylaminosulfur trifluoride provides, upon removal of the benzyl protecting groups, a compound of formula 29 wherein R.sub.2 is 2-fluoroethyl.
The compound of formula 34 can be prepared from a compound of formula ##STR67## and a compound of formula 2 by methods analogous to those used in the preparation of compounds 31, 32 and 33 wherein R.sub.2, for example, is hydrogen, methyl or ethyl, and P is benzyl. The compound of formula 35 can be prepared from the corresponding free alcohol by methods known in the art.
The compound of formula ##STR68## wherein R.sub.2 is hydrogen, fluoro, methyl, ethyl, n-propyl, 2-chloroethyl or 2-fluoroethyl can be prepared from the corresponding compound of formula 33 wherein the protecting group P is a benzyl, trityl, substituted trityl or silyl group. Treatment of this compound with, for example, 4-chlorophenyl dichlorophosphate and 1,2,4-triazole in a solvent such as pyridine and reaction of the resulting intermediate with ammonium hydroxide in a solvent such as dioxane provides the corresponding compound of formula See, for example, T. S. Lin et al., J. Med. Chem., 26, 1691 (1983); P. Herdewijn, et al., J. Med. Chem., 28, 550 (1985). Removal of the protecting groups from the compound of formula 37 yields the corresponding compound of formula 36. For example, if P is a benzyl group, both benzyl protecting groups can be removed by treatment with boron trichloride. If P is a trityl or substituted trityl protecting group, the P group can be removed with aqueous alcoholic mineral acid or aqueous acetic acid, and the benzyl group protecting the primary alcohol can be removed with boron trichloride. If P is a silyl protecting group, the P group can be removed with fluoride ion followed by removal of the benzyl protecting group. Alternatively, the benzyl protecting group can be removed with boron trichloride followed by removal of the silyl protecting group with fluoride ion.
Alternatively, the compound of formula 33 wherein R.sub.2 is hydrogen, fluoro, methyl, ethyl, n-propyl, 2-chloroethyl or 2-fluoroethyl and the protecting group P is a benzyl, trityl, substituted trityl or silyl group can be reacted with a sulfonyl chloride (e.g., p-toluenesulfonyl chloride) in an inert solvent (e.g., 1,2-dichloroethane or dioxane) in the presence of a base such as potassium carbonate. (For other sulfonyl chlorides and solvents, see, for example, European Patent Application EP 204,264). This affords the corresponding compound of formula ##STR69## which can be treated with ammonia gas in an inert solvent (e.g., 1,2-dichloroethane or dioxane) to afford the corresponding compound of formula 37 . Removal of the protecting groups from the compound of formula 37 yields the corresponding compound of formula 36.
Alternatively, the compound of formula 36 wherein R.sub.2 is fluoro, hydrogen, methyl, ethyl, n-propyl, 2-chloroethyl or 2-fluoroethyl can be prepared from the corresponding compound of formula 29 by methods known in the art. See, for example, T.S. Lin, et al., J. Med. Chem., 26, 1691 (1983); P. Herdewijn, et al., J. Med. Chem., 28, 550 (1985); European Patent Application EP 360018.
Alternatively, the compound of formula 36 wherein R.sub.2 is fluoro, hydrogen, methyl, ethyl, n-propyl, 2-chloroethyl or 2-fluoroethyl can be prepared by reaction of the corresponding compound of formula ##STR70## with a compound of formula 2 in the presence of a lithium hydride, sodium hydride or potassium hydride in an aprotic polar solvent such as dimethylformamide, dimethyl sulfoxide or sulfolane to yield a compound of formula ##STR71##
Selective protection of the amino group in the compound of formula 40 with an acyl group P.sub.2 (e.g. acetyl) yields a compound of formula ##STR72## (See, for example, G.S. Ti et al., J. Amer. Chem. Soc., 104, 1316 (1982)). Oxidation of the compound of formula 41,followed by methylenation with zinc/titanium tetrachloride/dibromomethane, with subsequent or simultaneous removal of the acyl protecting group Pz, gives a compound of formula 37. Removal of the protecting groups from this compound provides a compound of formula 36 wherein R.sub.2 is fluoro, hydrogen, methyl, ethyl, n-propyl, 2-chloroethyl or 2-fluoroethyl. When the protecting group P is benzyl, both benzyl groups can be removed by treatment with boron trichloride in dichloromethane. When the protecting group P is trityl or substituted trityl, the trityl protecting group can be removed by treatment with aqueous acetic acid or aqueous alcoholic mineral acid (e.g., hydrochloric acid in aqueous methanol), and then the benzyl protecting group can be removed by treatment with boron trichloride. When the protecting group P is a silyl group, removal of the silyl protecting group can be accomplished with fluoride ion (e.g., tetrabutylammonium fluoride in tetrahydrofuran) and then the benzyl group can be removed by treatment with boron trichloride. Alternatively, the benzyl group can be removed first followed by removal of the silyl group.
Alternatively, oxidation of the compound of formula 41 and subsequent treatment with methylenetriphenylphosphorane gives a compound of formula ##STR73## Removal of the protecting groups from this compound provides the compound of formula 36 wherein R.sub.2 is fluoro, hydrogen, methyl, ethyl, n-propyl, 2-chloroethyl or 2-fluroethyl. Removal of the acyl protecting group P.sub.2 can be accomplished using sodium methoxide in methanol or methanolic ammonia.
Alternatively, the compound of formula 40 wherein R.sub.2 is hydrogen, fluoro, methyl, ethyl, n-propyl, 2-chloroethyl or 2-fluoroethyl and the protecting group P is a benzyl, trityl, or silyl group can be prepared from the corresponding compound of formula 31 using methodology known in the art. See, for example, T.S. Lin et al., J. Med. Chem., 26, 1691 (1983); P. Herdewijn et al., J. Med. Chem., 28, 550 (1985); European Patent Applications EP 360018 and EP 204264.
Alternatively, the compound of formula 40 or 41 wherein R.sub.2 is fluoro can be prepared from the corresponding compound of formula 40 or 41 wherein R.sub.2 is hydrogen and the protecting group P is benzyl, trityl or substituted trityl by fluorination using trifluoromethyl hypofluorite following methodology known in the art. For example, see M.J. Robins, et al., J. Amer. Chem. Soc., 93, 5277 (1971) and Chem. Communs., 18 (1972); T.S. Lin et al., J. Med. Chem., 26, 1691 (1983).
The compound of formula 29 wherein R.sub.2 is chloro, bromo or iodo can be prepared from the compound of formula 31 wherein R.sub.2 is hydrogen and the protecting group P is a benzyl group. Halogenation of this compound of formula 31 by methods known in the art provides the corresponding compound of formula ##STR74## wherein R.sub.2 is chloro, bromo or iodo. (See, for example, P. Herdewijn et al., J. Med. Chem., 28, 550 (1985); M. J. Robins et al., J. Org. Chem., 48, 1854 (1983); T.S. Lin et al., J. Med. Chem., 26, 598 (1983); T. Ueda et al., Nucleotides and Nucleosides, 4, 401 (1985); "Synthetic Procedures in Nucleic Acid Chemistry", Vol. 1, W.W. Zorback and R.S. Tipson, Eds., John Wiley and Sons, NY, p. 491, 1968). Oxidation of the compound of formula 43 and subsequent methylenation with zinc/titanium tetrachloride/dibromomethane or methylenetriphenylphosphorane provides the compound of formula ##STR75## wherein R.sub.2 is chloro, bromo or iodo. (See, for example, European Patent Application EP 360018). Removal of the benzyl protecting groups in the compound of formula 44 by treatment with boron trichloride affords the compound of formula 29 wherein R.sub.2 is chloro, bromo, or iodo.
The compound of formula 36 wherein R.sub.2 is chloro, bromo or iodo can be prepared from the corresponding compound of formula 44 using methods known in the art (and analogous to those used in the conversion of compound 33 to compound 37 wherein, for example, R.sub.2 is hydrogen, methyl or ethyl), followed by removal of the benzyl protecting groups with boron trichloride.
Alternatively, the compound of formula 36 wherein R.sub.2 is chloro, bromo or iodo can be prepared from the corresponding compound of formula 29 by methods known in the art. See, for example, T.S. Lin, et al., J. Med. Chem., 26, 1691 (1983); P. Herdewijn, et al., J. Med. Chem., 28, 550 (1985); European Patent Applications EP 360018 and EP 204264).
The compound of formula 29 wherein R.sub.2 is trifluoromethyl can be prepared from the compound of formula 44 wherein R.sub.2 is iodo by treatment with trifluoromethyl iodide and copper followed by the removal of the benzyl protecting groups using boron trichloride. See, for example, Y. Kobayashi et al., J. Chem. Soc. Perkin 1, 2755 (1980); S. Lin et al., J. Med. Chem., 26, 1691 (1983).
The compound of formula 29 wherein R.sub.2 is trifluoromethyl can be prepared from a compound of formula 43 wherein R.sub.2 is iodo as follows: A compound of formula 43 wherein R.sub.2 is iodo can be converted to a compound of formula ##STR76## wherein R.sub.2 is iodo and the protecting group P.sub.4 is trityl, substituted trityl or acyl (e.g., acetyl). Treatment of this compound of formula 45 with trifluoromethyl iodide and copper according to procedures known in the art (see for example, Y. Kobayashi, et al., J. Chem. Soc. Perkin, 2755 (1980); S. Lin, et.al.; J. Med. Chem., 26 1691 (1983)) and subsequent removal of the P.sub.4 protecting group provides the compound of formula 43 wherein R.sub.2 is trifluoromethyl. Oxidation of the compound of formula 43 wherein R.sub.2 is trifluoromethyl and subsequent treatment with zinc/titanium tetrachloride/dibromomethane or methylenetriphenylphosphorane provides the compound of formula 44 wherein R.sub.2 is trifluoromethyl. Removal of the benzyl protecting groups from the compound of formula 44 by treatment with boron trichloride provides the compound of formula 29 wherein R.sub.2 is trifluoromethyl.
The compound of formula 36 wherein R.sub.2 is trifluoromethyl can be prepared from the corresponding compound of formula 44 using methods known in the art (and analogous to those used in the conversion of compound 33 to compound 37 wherein, for example, R.sub.2 is hydrogen, methyl, or ethyl), followed by removal of the benzyl protecting groups with boron trichloride.
Alternatively, the compound of formula 36 wherein R.sub.2 is trifluoromethyl can be prepared from the corresponding compound of formula 29 by methods known in the art. See for example, T.S. Lin et al., J. Med. Chem., 26, 1691 (1983); P. Herdewijn et al., J. Med. Chem., 28, 550; (1985); European Patent Applications EP 360018 and EP 204264.
The compound of formula 29 wherein R.sub.2 is ##STR77## and R.sub.3 is chloro, bromo, iodo, hydrogen, methyl or trifluoromethyl can be prepared from the compound of formula 43 wherein R.sub.2 is iodo or --HgCl. Reaction of the compound of formula 43 wherein R.sub.2 is iodo or --HgCl via organopalladium intermediates affords the compound of formula 43 wherein R.sub.2 is ##STR78## and R.sub.3 is chloro, bromo, iodo, hydrogen, methyl or trifluoromethyl. The compound of formula 43 wherein R.sub.2 is HgCl can be prepared from the compound of formula 31 wherein R.sub.2 is hydrogen and P is a benzyl protecting group. See, for example, references in E. DeClercq et al., Pharmac. Ther., 26, 1 (1984); M.E. Perlman et al., J. Med. Chem., 28, 741 (1985); P. Herdewijn et al., J. Med. Chem., 28, 550 (1985); D. E. Bergstrom et al., J. Med. Chem., 27, 279 (1984).
Oxidation of a compound of formula 43 wherein R.sub.2 is ##STR79## and R.sub.3 is chloro, bromo, iodo, hydrogen, methyl, or trifluoromethyl, and subsequent treatment with zinc/titanium tetrachloride/dibromomethane or methylenetriphenylphosphorane provides the corresponding compound of formula 44. Removal of the benzyl protecting groups from this compound using boron trichloride affords the compound of formula 29 wherein R.sub.2 is ##STR80## and R.sub.3 is chloro, bromo, iodo, hydrogen, methyl or trifluoromethyl.
The compound of formula 36 wherein R.sub.2 is ##STR81## and R.sub.3 is chloro, bromo, iodo, hydrogen, methyl or trifluromethyl can be prepared from the corresponding compound of formula 29 by methods known in the art. See for example, T.S. Lin, et al., J. Med. Chem., 26, 1691 (1983); P. Herdewijn, et al., J. Med. Chem., 28, 550 (1985); European Patent Applications EP 360018 and EP 204264.
Alternatively, the compound of formula 36 wherein R.sub.2 is ##STR82## and R.sub.3 is chloro, bromo, iodo, hydrogen, methyl or trifluoromethyl can be prepared from the corresponding compound of formula 44 using methods known in the art (and analogous to those used in the conversion of compound 33 to compound 37 wherein, for example, R.sub.2 is hydrogen, methyl or ethyl), followed by removal of the benzyl protecting groups with boron trichloride.
The compound of formula 29 wherein R.sub.2 is ethynyl can be prepared from a compound of formula 45 wherein R.sub.2 is iodo and the protecting P.sub.4 is acyl (e.g. acetyl), trityl, or substituted trityl as follows: Treatment of the compound of formula 45 wherein R.sub.2 is iodo and P.sub.4 is acyl with trimethylsilylacetylene/bis (triphenylphosphine) palladium (II) chloride/copper (I) iodide in triethylamine and, subsequently, with sodium methoxide in methanol according to procedures known in the art (see, for example, E. DeClercq et al., J. Med. Chem., 26, 661 (1983)) provides the compound of formula 43 wherein R.sub.2 is ethynyl. Alternatively, analogous treatment of the compound of formula 45 wherein R.sub.2 is iodo and P.sub.4 is trityl or substituted trityl, followed by removal of the trityl or substituted trityl protecting group P.sub.4, using, for example, aqueous acetic acid or aqueous alcoholic mineral acid, provides the compound of formula 43 wherein R.sub.2 is ethynyl. Oxidation of the compound of formula 43 followed by methylenation with zinc/titanium tetrachloride/dibromomethane or methylenetriphenylphosphorane yields the compound of formula 44 wherein R.sub.2 is ethynyl, and subsequent removal of the benzyl protecting groups with boron trichloride provides the compound of formula 29 wherein R.sub.2 is ethynyl.
The compound of formula 36 wherein R.sub.2 is ethynyl can be prepared from the corresponding compound of formula 44 using methods known in the art (and analogous to those used in the conversion of compound 33 to compound 37 wherein, for example, R.sub.2 is hydrogen, methyl, or ethyl), followed by removal of the benzyl protecting groups with boron trichloride.
Alternatively, the compound of formula 36 wherein R.sub.2 is ethynyl can be prepared from the corresponding compound of formula 29 by methods known in the art. See, for example, T.S. Lin, et al., J. Med. Chem., 26, 1691 (1983); P. Herdewijn et al., J. Med. Chem., 28, 550 (1985); European Patent Applications EP 360018 and EP 204264.
Compounds of formula 1 wherein R.sub.1 is ##STR83## can be prepared from the corresponding compounds of formula 1 wherein R.sub.1 is ##STR84## by methods known in the art.
Compounds of formula 1 wherein one or both R.sub.6 and R.sub.7 are ##STR85## can be prepared by methods known in the art from the corresponding compounds of formula 1 wherein R.sub.6 and R.sub.7 are hydrogen.
For examples of acylation procedures see: "Synthetic Procedures in Nucleic Acid Chemistry", Vol. 1, W. W. Zorbach and R. S. Tipson, Eds., John Wiley and Sons, 1968; "Nucleic Acid Chemistry," Part 1, L.B. Townsend and R. S. Tipson, Eds., John Wiley and Sons, 1978; Y. Ishido, et al., Nucleosides and Nucleotides, 5, 159 (1986); J.C. Martin, et al., J. Pharm. Sci., 76, 180 (1987); A. Matsuda, et al., Synthesis, 385 (1986).
Compounds of formula 1 wherein R.sub.1 is ##STR86## can be prepared from the corresponding compound of formula 1 wherein R.sub.1 is ##STR87## by procedures known in the art. See, for example, A Holy and J. Zemlicka, Collect. Czech. Chem. Commun., 32, 3159 (1967); K.K. Ogilvie, et al., Nucleosides and Nucletides, 4, 507 (1985); M.H. Caruthers, et al., J. Amer. Chem. Soc., 108, 2040 (1986).
Compounds of the formula 1 wherein R.sub.6 and/or R.sub.7 are --PO.sub.3 H.sub.2 can be prepared from the corresponding compounds of formula 1 wherein R.sub.6 and R.sub.7 are hydrogen by procedures known in the art. See, for example, H. Schaller, et al., J. Amer. Chem. Soc., 85, 3821 (1963); J. Beres, et al., J. Med. Chem., 29, 494 (1986); R. Noyori, et al., Tet. Lett., 28, 2259 (1987); W. Pfeiderer, et al., Helv. Chim. Acta., 70, 1286 (1987); "Nucleic Acid Chemistry". Part 2, L.B. Townsend and R.S. Tipson, Eds., John Wiley and Sons, 1978.
Unless otherwise stated, the stereochemistry shown for the compounds of this invention and intermediates leading to compounds of this invention is absolute. It is drawn to show that in the compounds of this invention, the base represented by R.sub.1 is cis to the --CH.sub.2 OR.sub.6 substituent and trans to the --OR.sub.7 substituent attached directly to the cyclopentyl ring. It is also drawn to show that the absolute stereochemistry of the cyclopentyl carbon attached to the base (R.sub.1) is "S".
For example, the 1S-enantiomer of the compound of formula 1 wherein R.sub.1 is ##STR88## and R.sub.6 and R.sub.7 are hydrogen, [1S-(1.alpha.,3.alpha.,4.beta.)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, can be prepared from the 1S-enantiomer of the compound of formula 2. The 1S-enantiomer of the compound of formula 2 can be prepared from the 1S-enantiomer of the compound of formula 3. By following the procedure described by K. Biggadike et al., J. Chem. Soc. Perkin Trans 1, 549 (1988), the 1S-enantiomer of the compound of formula 3 can be prepared from the 1S-enantiomer of the compound of formula and the 1S-enantiomer of the compound of formula 46 can be prepared by reaction of the compound of formula ##STR89## with the chiral hydroborating agent, (-)-diisopinocampheylborane i.e. (-)-diisopinan-3-ylborane].
The compounds of formula 1 wherein R.sub.1 is ##STR90## can form acid addition salts with inorganic or organic acids, Illustrative are the halide (e.g., chloride and bromide), alkylsulfonate, sulfate, phosphate and carboxylate salts.
The compounds of formula I wherein R.sub.1 is ##STR91## can form basic salts with inorganic and organic bases. Illustrative are alkali metal salts (e.g., sodium and potassium), alkaline earth metal salts (e.g. calcium and magnesium), ammonium and substituted ammonium salts.
The compounds of formula 1 wherein R.sub.6 and/or R.sub.7 are --PO.sub.3 H.sub.2 can form basic salts with inorganic and organic bases. Illustrative are the alkali metal salts (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), ammonium and substituted ammonium salts.
The following examples are specific embodiments of this invention. All temperatures are given in degrees Centigrade.
US Referenced Citations (6)
Foreign Referenced Citations (4)
| Number |
Date |
Country |
| 360018 |
Mar 1990 |
EPX |
| 365849 |
May 1990 |
EPX |
| 8807049 |
Jan 1988 |
WOX |
| 9101318 |
Feb 1991 |
WOX |
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Continuation in Parts (1)
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599568 |
Oct 1990 |
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Patent Grant
5206244
