4′-C-ethynyl pyrimidine nucleoside compounds and...

Details 4′-C-ethynyl pyrimidine nucleoside compounds and... 4′-C-ethynyl pyrimidine nucleoside compounds and...

2000-05-12

2001-09-18

Geist, Gary (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S028500, C536S028510, C536S028520, C536S026800, C514S049000, C514S051000

Reexamination Certificate

active

06291670

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to 4′-C-ethynyl nucleosides and the use thereof for producing pharmaceuticals, and more particularly to the use thereof in treating acquired immunodeficiency syndrome (AIDS).
2. Background Art
The clinical setting for AIDS has been dramatically changed by a multi-drug therapy called highly active antiretroviral therapy, or HAART. In this therapy, nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), and lamivudine (3TC) and protease inhibitors (PIs) are employed in combination. Application of this therapy has drastically decreased the number of deaths due to AIDS in many countries (Textbook of AIDS Medicine, p751 (Williams & Wilkins, Baltimore, 1999)).
In spite of the decrease in AIDS-related deaths due to HAART, there has emerged a multi-drug resistant HIV-1 (human immunodeficiency virus-1) mutant exhibiting cross-resistance to various drugs. For example, in the early 1990s patients infected with an HIV exhibiting resistance to both AZT and 3TC were very rare, whereas the percentage of AIDS patients infected with such an HIV was as high as 42% in 1995-1996 (
AIDS
, 11, 1184(1997)).
It has been reported that such multi-drug resistant viruses cause 30-60% of drug failure cases in which the viremia level drops once below the detection limit and then revives to exhibit lasting viremia (
AIDS
, 12, 1631(1998)). Thus, the present status of AIDS treatment is serious.
Conventionally, in terms of a compound which exhibits potent antiviral activities against multi-drug resistant viruses, there have been known only a few protease inhibitors; e.g., JE-2147, which have potent antiviral activity against a multi-PI resistant HIV-1 (
Proc. Natl. Acad. Sci. USA
, 96,8675(1999)). However, no nucleoside derivative having such potent activities has been reported yet.
Ohrui, one of the inventors of the present invention, has synthesized 1-(4-C-ethynyl-&bgr;-D-ribo-pentofuranosyl)thymine, 4′-C-ethynyluridine, and 4′-C-ethynylcytidine and assayed biological activities such as antiviral and antitumor activities thereof. However, no such biological activities have been observed for these compounds (
Biosci. Biotechnol. Biochem
., 63(4), 736-742, 1999).
Furthermore, Matsuda et al. have synthesized 4′-C-ethynylthymidine and assayed the anti-HIV activity thereof. The anti-HIV activity of the compound is weaker than that of AZT. However, the assay described by Matsuda et al. (
Bioorg. Med. Chem. Lett
., 9(1999), 385-388) is drawn to an ordinary assay for determining anti-HIV activity on the basis of MT-4 cells versus an HIV-1 III
b
strain, and does not use a multi-drug resistant virus strain.
SUMMARY OF THE INVENTION
In order to find a compound having more potent antiviral activity than AZT, the present inventors have synthesized a variety of 4′-C-ethynyl nucleosides and evaluated the antiviral activity thereof, and have found that: 1) a 4′-ethynyl nucleoside derviative having a specific structure exhibits potent anti-HIV activity equal to or greater than that of AZT; 2) the compound has potent antiviral activity against a multi-drug resistant virus strain exhibiting resistance to various anti-HIV drugs such as AZT, ddI, ddC, d4T, and 3TC; and 3) the compound exhibits no significant cytotoxicity. The present invention has been accomplished on the basis of these findings.
Accordingly, the present invention provides 4′-C-ethynyl nucleosides (other than 4′-C-ethynylthymidine) represented by formula [I]:
wherein B represents a base selected from the group consisting of pyrimidine, purine, and derivatives thereof; X represents a hydrogen atom or a hydroxyl group; and R represents a hydrogen atom or a phosphate residue.
The present invention also provides a pharmaceutical composition containing any one of the compounds and a pharmaceutically acceptable carrier.
Preferably, the composition is employed as an antiviral drug or a drug for treating AIDS.
The present invention also provides use, as pharmaceuticals, of compounds represented by formula [1].
The present invention also provides a method for treatment of AIDS, comprising administering a compound of formula [1] to a vertebrate, including human.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
(1) Compounds
The compounds of the present invention are represented by formula [I]. Examples of bases in formula [I] represented by B include pyrimidines; purines, including azapurines and deazapurines; and derivatives thereof.
Examples of substituents in the bases includes a halogen atom, an alkyl group, a haloalkyl group, an alkenyl group, a haloalkenyl group, an alkynyl group, an amino group, an alkylamino group, a hydroxyl group, a hydroxyamino group, an aminoxy group, an alkoxy group, a mercapto group, an alkylmercapto group, an aryl group, an aryloxy group, and a cyano group. The number and substitution site of these substituents are not particularly limited.
Examples of halogen atoms serving as substituents include chlorine, fluorine, iodine, and bromine. Examples of alkyl groups include C1-C7 alkyl group such as methyl, ethyl, and propyl. Examples of haloalkyl groups include C1-C7 haloalkyl groups such as fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, and bromoethyl. Examples of alkenyl groups include C2-C7 alkenyl groups such as vinyl and allyl. Examples of haloalkenyl groups include C2-C7 haloalkenyl groups such as bromovinyl and chlorovinyl. Examples of alkynyl groups include C2-C7 alkynyl groups such as ethynyl and propynyl. Examples of alkylamino groups include C1-C7 alkylamino groups such as methylamino and ethylamino.
Examples of alkoxy groups include C1-C7 alkoxy groups such as methoxy and ethoxy. Examples of alkylmercapto groups include C1-C7 alkylmercapto groups such as methylmercapto and ethylmercapto. Examples of aryl groups include a phenyl group; alkylphenyl groups having a C1-C5 alkyl such as methylphenyl and ethylphenyl; alkoxyphenyl groups having a C1-C5 alkoxy such as methoxyphenyl and ethoxyphenyl; alkylaminophenyl groups having a C1-C5 alkyl such as dimethylaminophenyl and diethylaminophenyl; and halogenophenyl groups such as chlorophenyl and bromophenyl.
Examples of pyrimidine bases and derivatives thereof include cytosine, uracil, 5-fluorocytosine, 5-fluorouracil, 5-chlorocytosine, 5-chlorouracil, 5-bromocytosine, 5-bromouracil, 5-iodocytosine, 5-iodouracil, 5-methylcytosine, 5-ethylcytosine, 5-methyluracil (thymine), 5-ethyluracil, 5-fluoromethylcytosine, 5-fluorouracil, 5-trifluorocytosine, 5-trifluorouracil, 5-vinyluracil, 5-bromovinyluracil, 5-chlorovinyluracil, 5-ethynylcytosine, 5-ethynyluracil, 5-propynyluracil, pyrimidin-2-one, 4-hydroxyaminopyrimidin-2-one, 4-aminoxypyrimidin-2-one, 4-methoxypyrimidin-2-one, 4-acetoxypyrimidin-2-one, 4-fluoropyrimidin-2-one, and 5-fluoropyrimidin-2-one.
Examples of purine bases and derivatives thereof include purine, 6-aminopurine (adenine), 6-hydroxypurine, 6-fluoropurine, 6-chloropurine, 6-methylaminopurine, 6-dimethylaminopurine, 6-trifluoromethylaminopurine, 6-benzoylaminopurine, 6-acethylaminopurine, 6-hydroxyaminopurine, 6-aminoxypurine, 6-methoxypurine, 6-acetoxypurine, 6-benzoyloxypurine, 6-methylpurine, 6-ethylpurine, 6-trifluoromethylpurine, 6-phenylpurine, 6-mercaputopurine, 6-methylmercaputopurine, 6-aminopurine-1-oxide, 6-hydroxypurine-1-oxide, 2-amino-6-hydroxypurine (guanine), 2,6-diaminopurine, 2-amino-6-chloropurine, 2-amino-6-iodepurine, 2-aminopurine, 2-amino-6-mercaptopurine, 2-amino-6-methylmercaptopurine, 2-amino-6-hydroxyaminopurine, 2-amino-6-methoxypurine, 2-amino-6-benzoyloxypurine, 2-amino-6-acetoxypurine, 2-amino-6-methylpurine, 2-amino-6-cyclopropylaminomethylpurine, 2-amino-6-phenylpurine, 2-amino-8-bromopurine, 6-cyanopurine, 6-amino-2-chloropurine (2-chloroadenine), 6-amino-2-fluoropurine (2-fluoroadenine), 6-amino-3-deazapurine, 6-amino-8-azapurine, 2-amino-6-hydroxy-8-azapurine, 6-amino-7-deaz

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