Nucleotide analogs

Details Nucleotide analogs Nucleotide analogs

1999-02-10

2001-05-01

Low, Christopher S. F. (Department: 1654)

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

Organic compounds

Carbohydrates or derivatives

C536S022100, C536S025340, C536S027140, C536S027210, C536S026100, C562S553000

Reexamination Certificate

active

06225460

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to novel nucleotide analog amidates and esters, their pharmaceutically acceptable acid addition salts, a process for their production, and to their use. The nucleotides of the present invention exhibit antitumor/antineoplastic activity, a broad spectrum of antimicrobial activity and certain other desirable activities.
Compounds related to the nucleotide analogs of the present invention may be found in: U.S. Pat. Nos. 5,043,339, 5,108,994 and 5,166,198; EP 206 459; EP 253 412; EP 269 947; EP 270 885; EP 319 228; EP 343 133; EP 398 231; EP 404 296; EP 465 297; EP 468 119; EP 468 866; EP 479 640; EP 481 214; EP 494 370; EP 531 597; PCT/GB91/01171; PCT/US92/01020; PCT/US92/05208; WO 91/19721; Bronson et al,
Bioorg Medicinal Chem Lett
(1992) 2:685-690; Bronson et al,
j Med Chem
, (1989) 32:1457-1463; Bronson et al,
Nucleotide Analogs as Antiviral Agents
, ACS Symposium Series 401, J. C. Martin, Ed., p. 72-87, American Chemical Society, Washington, D.C. (1989); Colla, et al,
J Med Chem
(1983) 26:602-604; Curley, et al,
Antiviral Res
(1990) 14:345-356; De Clercq, et al,
Nature
, (1986) 323:464-467; Farrow, et al,
J Med Chem
(1990) 33:1400-1406; Farquhar, et al,
J. Pharm Sci
(1983) 72:324-325; Freed, et al,
Biochem Pharmacol
(1989) 19:3193-3198; Freeman, et al,
J Med Chem
(1992) 35:3192-3196; Gabrielsen, B., et al,
Antiviral Res Suppl I
(1992) 17:149; Gumport, et al,
Proc Natl Acad Sci
(1971) 2559-2563; Juodka, et al,
Coll Czech Chem Commun
(1974) 39:963-968; Kim, et al,
Bioorg Medicinal Chem Lett
(1992) 2:367-370; Kim, et al,
Tet Lett
(1992) 33:25-28; Kim, et al,
J Med Chem
(1990) 33:1207-1213; Kumar, et al,
J Med Chem
(1990) 33:2368-2375; McGuigan, et al,
Antiviral Chem Chemother
(1993) 4:97-101; McGuigan, et al,
Antiviral Res
(1991) 15:255-263; Rosenberg, et al,
Coll Czech Chem Commun
(1988) 53:2753-2777; Rosenberg, et al,
Coll Czech Chem Commun
(1988) 52:2792-2800; Rosenberg, et al,
Coll Czech Chem Commun
(1988) 52:2801-2808; Starrett, et al,
Antiviral Res
(1992) 19:267-273; Yu, et al,
J Med Chem
(1992) 35:2958-2969; Wolff-Kugel, et al,
Tet Lett
(1991) 32:6341-6344.
A characteristic of nucleotide analogs or nucleotides having a phosphonate or a phosphate group is the presence of one or two negative charges associated with the phosphorus group at physiologic pH. The charge associated with moieties such as phosphate or phosphonate groups is believed to generally limit bioavailability by limiting cell membrane permeation via passive diffusion (Liebman, et al,
J. Biol. Chem
., (1955) 216:823-830; Roll, et al,
J Biol Chem
, (1956) 220:439-444; Srivastava, et al,
Bioorg Chem
(1984) 12:118-129; Palu, et al,
Antiviral Res
(1991) 16:115-119; Sastry, et al,
Mol Pharmacol
(1992) 41:441-445). These compounds are often, therefore, given parenterally in order to enhance bioavailability by increasing serum or intracellular levels.
Other characteristics of nucleotide analogs that can limit their efficacy include unfavorable pharmacokinetic or pharmacodynamic properties, insufficient potency and/or unfavorable toxicity characteristics.
Studies were conducted to ameliorate one or more of the above-mentioned problems associated with nucleotide analog drugs. The present invention includes novel nucleotide analogs that are hydrolyzable in vivo. The nucleotide analogs can have improved bioavailability, improved pharmacokinetic or pharmacodynamic properties, enhanced potency and/or improved toxicity characteristics compared to the corresponding unmodified nucleotide analog. Methods to synthesize and use the compounds and methods to obtain and use antibodies that recognize the compounds are also disclosed.
SUMMARY OF THE INVENTION
In a principal embodiment, the objects of this invention are accomplished by a nucleotide analog amidate comprising a phosphonate radical wherein the improvement comprises an amino acid residue or polypeptide radical in which an amino group of the amino acid or polypeptide is bonded to the phosphorus atom of the nucleotide analog by an amidate bond, a carboxyl group of the amino acid residue or polypeptide radical is positioned such that it is capable as the free acid of hydrolyzing the phosphoroamidate bond, and the carboxyl group is blocked (such as by moieties including esters or amides). The nucleotide analog amidates of this invention are hydrolyzed in vivo to the corresponding nucleotide analog and are thus precursors of the corresponding nucleotide analog.
In accordance with this invention the nucleotide analog amidates or a physiologically acceptable salt thereof, have the structure of formula I
wherein L
1
and L
2
are independently an amino acid or polypeptide residue bonded to the phosphorus atom of the nucleotide analog by an amidate bond, or L
1
or L
2
are an oxyester, thioester, a substituted or unsubstituted amine, or hydroxy, provided that one or both of L
1
and L
2
is an amino acid or polypeptide residue and any carboxyl group that is linked by less than about 5 atoms to the amidate N is esterified or amidated, the dotted lines represent facultative bonds and wherein, (i) P and Z are linked to form a compound of the formula Ib
or (ii) L
1
and Z are linked to form a compound of the formula Ic
wherein
substituents linked to carbon atoms designated # are in the R, S or RS configuration;
X
1
is O or S;
Z is —CHR
7
—R
11
—(CH
2
)
m1
—C
#
(R
8
) ((CH
2
)
m2
(R
9
))—(CH
2
)
m3
—R
10
—(CH
2
)
m4
—, —Q—C
6
H
4
—CH
2
—, —CHR
7
—O—CHR
7
—O—CHR
7
—, —CHR
7
—(CHR
13
)
m1
—CHR
14
—R
10
—,
or VIII
wherein
R
7
is H or C
1
-C
4
alkyl;
R
8
is H or C
1
-C
4
alkyl, C
2
-C
4
alkenyl, azidomethyl or azidoethyl;
R
9
is halogen (F, Cl, Br or I), H or OH;
R
10
is O, CH
2
or a chemical bond;
R
11
is O, S, CH
2
, CHF or CF
2
;
Q is —C(R
12
)
2
—CH
2
—, —C(R
12
)
2
—O—, —CR
12
═CR
12
—, or —C≡C—, wherein each R
12
is independently H, or halogen;
R
13
is H, halogen, OH, CH
3
, CH
2
OH, or C
3
-C
6
acyloxymethyl;
R
14
is H, halogen, OH, CH
3
, CH
2
OH, C
3
-C
6
acyloxymethyl, or C
2
-C
6
acyloxy;
R
25
is CH
2
, CHF or O;
R
26
is CH or S, provided that when R
25
is CH, R
26
is not S;
R
27
is H, OH, halogen, N
3
, C
1
-C
4
alkyl, C
1
-C
4
alkoxy or, when R
26
is S, R
27
is absent;
R
27a
is H, OH, halogen, N
3
, C
1
-C
4
alkyl, C
1
-C
4
alkoxy;
R
28
is H, OH, halogen, N
3
, C
1
-C
4
alkyl or C
1
-C
4
alkoxy;
R
29
is O, S, CH
2
, CHF, CF
2
;
R
32
is O;
m1 is an integer having a value from 0 to 4;
m2 is an integer having a value from 0 to 4;
m3 is an integer having a value from 0 to 4;
m4 is an integer having a value from 0 to 4;
B is a heterocyclic base; and
substituents linked to the carbon atom designated C
#
are in the R, S or RS configuration.
In a further embodiment the objects are accomplished by compounds of the formula II, IIa, IIb and IIc
wherein L
2
is OR, SR or
n is an integer having a value from 1 to 5 and if n>1, each —C(R
3
)(R
2
)— may be the same or different;
n1 is an integer;
substituents linked to the carbon atom designated # are in the R, S or RS configuration;
R is H, C
1
-C
20
alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen (F, Cl, Br, I), C
3
-C
20
aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen or R is C
4
-C
20
aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
1
-C
6
haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen, or R is C
3
-C
24
1-acyloxy-1-alkyl (C
1
-C
8
alkyl), or R is C
6
-C
24
1-acyloxy-1-aryl-1-alkyl (C
1
-C
6
aryl, C
1
-C
4
alkyl), or R is C
3
-C
24
1-acyloxy-2-alkoxy-1-alkyl (C
1
-C
8
alkyl), or R is C
3
-C
24
1-acyloxy-2-haloalkyl (C
1
-C
8
haloalkyl, 1 to 3

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