Antiviral phosphonomethoxy nucleotide analogs having...

Details Antiviral phosphonomethoxy nucleotide analogs having... Antiviral phosphonomethoxy nucleotide analogs having...

2002-05-29

2003-11-25

McKane, Joseph K. (Department: 1626)

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

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S244000, C546S023000

Reissue Patent

active

RE038333

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to intermediates for phosphonomethoxy nucleotide analogs, in particular intermediates suitable for use in the efficient oral delivery of such analogs.
Such analogs per se and various technologies for oral delivery of these and other therapeutic compounds are known. See WO 91/19721, WO 94/03476, WO 94/03466, WO 92/13869, U.S. Pat. No. 5,208,221, 5,124,051, DE 41 38 584 A1, WO 94/10539, WEJ7368583647920, WO 95 79/07919, WO 92/09611, WO 92/01698, WO 91/19721, WO 88/05438, EP 0 632 048, EP 0 481 214, EP 0 369 409, EP 0 269 947, U.S. Pat. Nos. 3,524,846 and 5,386,030, Engel, Chem. Rev. 77: 349-367 1997, Farquhar et al., J. Pharm. Sci. 72: 324-325 1983, Starrett et al., Antiviral Res. 19: 267-273 1992, Safadi et al., Pharmaceutical Research 10(9): 1350-1355 1993, Sakamoto et al., Chem. Pharm. Bull. 32(6): 2241-2248 1984, and Davidsen et al., J. Med. Chem. 37(26): 4423-4429 1994.
SUMMARY OF THE INVENTION
In accordance with this invention, compounds are provided having formula (1a)
wherein Z is independently —OC(R
2
)
2
OC(O)X(R)
a
, an ester, an amidate or —H, but at least one Z is —OC(R
2
)
2
OC(O)X(R)
a
;
A is the residue of an antiviral phosphonomethoxy nucleotide analog;
X is N or O;
R
2
independently is —H, C
1
-C
12
alkyl, C
5
-C
12
aryl, C
2
-C
12
alkenyl, C
2
-C
12
alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or —OR
3
in which R
3
is C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl or C
5
-C
12
aryl;
R independently is —H, C
1
-C
12
alkyl, C
5
-C
12
aryl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl, C
7
-C
12
alkyenylaryl, C
7
-C
12
alkynylaryl, or C
6
-C
12
alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, —N(R
4
)
2
or —OR
3
, where R
4
independently is —H or C
1
-C
8
alkyl, provided that at least one R is not H; and
a is 1 when X is 0 , or 1 or 2 when X is N;
with the proviso that when a is 2 and X is N, (a) two N-linked R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be —OR
3
or (c) both N-linked R groups can be —H;
and the salts, hydrates, tautomers and solvates thereof.
Further embodiments of the compounds of this invention are compounds of formula (1)
wherein B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl of their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl;
R is independently —H, C
1
-C
12
alkyl, C
5
-C
12
aryl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl, C
7
-C
12
alkenylaryl, C
7
-C
12
alkynylaryl, or C
6
-C
12
alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or —OR
3
in which R
3
is C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl or C
5
-C
12
aryl;
R
1
is hydrogen, —CH
3
, —CH
2
OH, —CH
2
F, —CH═CH
2
, or —CH
2
N
3
, or R
1
and R
8
are joined to form —CH
2
—;
R
2
independently is hydrogen or C
1
-C
6
alkyl; and
R
8
is hydrogen or —CHR
2
—O—C(O)—OR, or R
8
is joined with R
1
to form —CH
2
—;
and the salts, hydrates, tautomers and solvates thereof.
Other embodiments of this invention include a method for preparing a compound of formula (1a) which comprises reacting the diacid of a phosphonomethoxy nucleotide analog with LC(R
2
)
2
OC(O)X(R)
a
wherein L is a leaving group.
In particular embodiments of this invention, a method for preparing a compound of formula (1) is provided which comprises reacting a compound of formula (4)
with LC(R
2
)
2
OC(O)X(R)
a
.
DETAILED DESCRIPTION OF THE INVENTION
The abbreviations NMP, DMF and DMPU mean, respectively, N-methylpyrrolidinone, dimethylformamide and N,N′-dimethylpropyleneurea.
Heterocycle means aromatic and nonaromatic ringed moieties. Heterocyclic moieties typically comprise one ring or two fused rings, where the ring(s) is 5- or 6-membered and typically contains 1 or 2 noncarbon atoms such as oxygen, nitrogen or sulfur, usually oxygen or nitrogen.
“Alkyl” as used herein, unless stated to the contrary, is C
1
-C
12
hydrocarbon containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms in the form of normal, secondary, tertiary or cyclic structures. Examples are —CH
3
, —CH
2
CH
3
, —CH
2
CH
2
CH
3
, —CH(CH
3
)
2
, —CH
2
CH
2
CH
2
CH
3
, —CH
2
CH(CH
3
)
2
, —CH(CH
3
) CH
2
CH
3
, —C(CH
3
)
3
, —CH
2
CH
2
CH
2
CH
2
CH
3
, —CH (CH
3
)CH
2
CH
2
CH
3
, —CH(CH
2
CH
3
)
2
, —C(CH
3
2
CH
2
CH
3
, —CH(CH
3
)CH(CH
3
)
2
, —CH
2
CH
2
CH(CH
3
)
2
, —CH
2
CH (CH
3
)CH
2
CH
3
, —CH
2
C(CH
3
)
3
, —CH
2
CH
2
CH
2
CH
2
CH
2
CH
3
, —CH(CH
3
) CH
2
CH
2
CH
2
CH
3
, —CH(CH
2
CH
3
)(CH
2
CH
2
CH
3
) —C(CH
3
)
2
CH
2
CH
2
CH
3
, —CH(CH
3
)CH(CH
3
)CH
2
CH
3
, —CH(CH
3
)CH
2
CH(CH
3
)
2
, —C(CH
3
)(CH
2
CH
3
)
2
, —CH (CH
2
CH
3
)(CH(CH
3
)
2
, —C(CH
3
)
2
CH(CH
3
)
2
, —CH(CH
3
C (CH
3
)
3
, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclobutylmethyl, 1-cyclopropyl-1-ethyl, 2-cyclopropyl-1-ethyl, cyclohexyl, cyclopentylmethyl, 1-cyclobutyl-1-ethyl, 2-cyclobutyl-1-ethyl, 1-cyclopropyl-1-propyl, 2-cyclopropyl-1-propyl, 3-cyclopropyl-1-propyl, 2-cyclopropyl-2-propyl, and 1-cyclopropyl-2-propyl.
“Alkenyl” as used herein, unless stated to the contrary, is C
1
-C
12
hydrocarbon containing normal, secondary, tertiary or cyclic structures. Examples are —CH═CH
2
, —CH═CHCH
3
, —CH
2
CH═CH
2
, —C(═CH
2
)(CH
3
), —CH═CHCH
2
CH
3
, —CH
2
CH═CHCH
3
, —CH
2
CH
2
CH═CH
2
, —CH═C(CH
3
)
2
, —CH
2
C(═CH
2
) (CH
3
), —C(═CH
2
)CH
2
CH
3
, —C(CH
3
)
2
, —CH
2
C(═CH
2
) (CH
3
)CH═CH
2
, —C═CHCH
2
CH
2
CH
3
, —CHCH═CHCH
2
CH
3
, —CHCH
2
CH═CHCH
3
, —CHCH
2
CH
2
CH═CH
2
, —C(═CH
2
)CH
2
CH
2
CH
3
, —C(CH
3
)═CH
2
CH
2
CH
3
, —CH(CH
3
)CH═CHCH
3
, —CH(CH
3
)CH
2
CH═CH
2
, —CH
2
CH═C(CH
3
)
2
, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.
“Alkynyl” as used herein, unless stated to the contrary, is C
1
-C
12
hydrocarbon containing normal, secondary, tertiary, or cyclic structures. Examples are —CCH, —CCCH
3
, —CH
2
CCH, —CCCH
2
CH
3
, —CH
2
CCCH
3
, —CH
2
CH
2
CCH, CH(CH
3
)CCH, —CCCH
2
CH
2
CH
3
, —CH
2
CCCH
2
CH
3
, —CH
2
CH
2
CCCH
3
and —CH
2
CH
2
CH
2
CCH.
Salt(s) include those derived by combination of appropriate anions such as inorganic or organic acids. Suitable acids include those having sufficient acidity to form a stable salt, preferably acids of low toxicity. For example, one may form invention salts from acid addition of certain organic and inorganic acids, e.g., HF, CHl, HBr, HI, H
2
SO
4
, H
3
PO
4
, or from organic sulfonic acids, organic carboxylic acids to basic centers, typically a mines. Exemplary organic sulfonic acids include C
6
-C
16
aryl sulfonic acids, C
6
-C
16
heteroaryl sulfonic acids and C
1
-C
16
alkyl sulfonic acids such as phenyl &agr;-naphthyl, &bgr;-naphthyl, (S)-camphor, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pentyl and hexyl sulfonic acids. Exemplary organic carboxylic acids include C
1
-C
16
alkyl, C
6
-C
16
aryl carboxylic acids and C
4
-C
16
heteroaryl carboxylic acids such as acetic, glycolic, lactic, pyruvic, malonic, glutaric, tartaric, citric, fumaric, succinic, malic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic and 2-phenoxybenzoic. Salts also include the invention compound salts with one or more amino acids. Many amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically in one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine. Salts are usually biologically compatible or pharmaceutically acceptable or non-toxic, particularly for mammalian cells. Salts that are biologically toxic are generally used with synthetic intermediates of invention compounds. The salts of inventio

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