Immunoeffector compounds

Details Immunoeffector compounds Immunoeffector compounds

2002-02-04

2003-02-25

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S023000, C514S024000, C514S025000, C536S004100, C536S017200, C536S017300, C536S017500, C536S018700, C424S001730, C424S009430

Reexamination Certificate

active

06525028

ABSTRACT:

FIELD OF THE INVENTION
This invention relates generally to immunoeffector compounds, their use in pharmaceutical compositions, and methods for their production and their use in prophylactic and/or therapeutic vaccination. More particularly, the present invention relates to novel compounds comprising 2-deoxy-2-amino-&bgr;-D-glucopyranose (glucosamine) glycosidically linked to a cyclic aminoalkyl (aglycon) group, and their use in pharmaceutical adjuvant systems.
BACKGROUND OF THE INVENTION
Humoral immunity and cell-mediated immunity are the two major branches of the mammalian immune response. Humoral immunity involves the generation of antibodies to foreign antigens. Antibodies are produced by B-lymphocytes Cell-mediated immunity involves the activation of T-lymphocytes which either act upon infected cells bearing foreign antigens or stimulate other cells to act upon infected cells. Both branches of the mammalian immune system are important in fighting disease Humoral immunity is the major line of defense against bacterial pathogens. In the case of viral disease, the induction of cytotoxic T lymphocytes (CTLs) appears to be crucial for protective immunity. Thus, an effective vaccine preferably stimulates both branches of the immune system to protect against disease.
Vaccines present foreign antigens from disease causing agents to a host so that the host can mount a protective immune response. Often vaccine antigens are killed or attenuated forms of the microbes which cause the disease. The presence of non-essential components and antigens in these killed or attenuated vaccines has encouraged considerable efforts to refine vaccine components including developing well-defined synthetic antigens using chemical and recombinant techniques. The refinement and simplification of microbial vaccines, however, has led to a concomitant loss in potency. Low-molecular weight synthetic antigens, though devoid of potentially harmful contaminants, are often not sufficiently immunogenic by themselves. These observations have led investigators to add immune system stimulators known as adjuvants to vaccine compositions to potentiate the activity of the vaccine components.
Immune adjuvants are compounds which, when administered to an individual or tested in vitro, increase the immune response to an antigen in a subject to which the antigen is administered, or enhance certain activities of cells from the immune system. A number of compounds exhibiting varying degrees of adjuvant activity have been prepared and tested (see, for example, Shimizu et al. 1985, Bulusu et al. 1992, Ikeda et al. 1993, Shimizu et al. 1994, Shimizu et al. 1995, Miyajima et al. 1996). However, these and other prior adjuvant systems often display toxic properties, are unstable and/or have unacceptably low immunostimulatory effects.
Presently, the only adjuvant licensed for human use in the United States is alum, a group of aluminum salts (e.g., aluminum hydroxide, aluminum phosphate) in which vaccine antigens are formulated. Particulate carriers like alum reportedly promote the uptake, processing and presentation of soluble antigens by macrophages. Alum, however, is not without side-effects and is unfortunately limited to humoral (antibody) immunity only.
The discovery and development of effective adjuvant systems is essential for improving the efficacy and safety of existing and future vaccines. Thus, there is a continual need for new and improved adjuvant systems, particularly those that drive both effector arms of the immune system, to better facilitate the development of a next generation of synthetic vaccines. The present invention fulfills these and other needs.
SUMMARY OF THE INVENTION
The compounds of the present invention are immunoeffector molecules which enhance humoral and cell-mediated immune responses to vaccine antigens. The compounds can generally be descrbed as belonging to the class of cyclic AGP compounds, where AGP stands for aminoalkyl glucosaminide phosphates. The term “cyclic AGP” means an azacycloalkyl or (azacycloalkyl)alkyl glucosaminide phosphate, wherein a 2-deoxy-2-amino-b-D-glucopyranose (glucosamine) is glycosidically linked to an azacycloalkyl or (azacycloalkyl)alkyl (aglycon) group.
The compounds of this invention comprise a 2-deoxy-2-amino-&bgr;-D-glucopyranose (glucosamine) glycosidically linked to an cyclic aminoalkyl (aglycon) group. The compounds are phosphorylated at the 4 or 6-position of the glucosarine ring and acylated with alkanoyloxytetradecanoyl residues on the aglycon nitrogen and the 2 and 3-positions of the glucosamine ring, The compounds of the subject invention are described generally by formula (I):
and pharmaceutically acceptable salts thereof,
wherein X is —O— or —NH— and Y is —O— or —S—; R
1
, R
2
, and R
3
are each independently a ( C
9
-C
14
)acyl group, including saturated, unsaturated and branched acyl groups; R
4
is —H or —PO
3
R
7
R
8
, wherein R
7
and R
8
are each independently H or (C
1
-C
4
) aliphatic groups; R
5
is —H, —CH
3
or —PO
3
R
9
R
10
, where R
9
and R
10
are each independently selected from —H and (C
1
-C
4
)aliphatic groups; R
6
is independently selected from H, OH, (C
1
-C
4
) oxyaliphatic groups, —PO
3
R
11
R
12
, —OPO
3
R
11
R
12
, —SO
3
R
11, —OSO
3
R
11
, —NR
11
R
12
, —SR
11
, —CN, —NO
2
, —CHO, —CO
2
R
11
, and —CONR
11
R
12
, wherein R
11
and R
12
are each independently selected from H and (C
1
-C
4
)aliphatic groups; with the provisos that one of R
4
and R
5
is a phosphorus-containing group and that When R
4
is —PO
3
R
7
R
8
, R
5
is other than —PO
3
R
9
R
10
, wherein “*
1-3
” and “**” represent chiral centers;
wherein n, m, p and q are each independently an integer from 0 to 6, with the proviso that the sum of p and m is from 0 to 6.
In some embodiments of compounds of the present invention X and Y are each oxygen, R
4
is PO
3
R
7
R
8
, R
5
and R
6
are H, and n, m, p, and q are integers from to 0 to 3. In a more preferred embodiment, R
7
and R
8
are —H. In an even more preferred embodiment, n is 1, m is 2, and subscripts p and q are 0. In yet an even more preferred embodiment, R
1
, R
2
, and R
3
are C
9
-C
13
acyl groups, most preferably C
10
-C
12
acyl groups. In a still more preferred embodiment, *
1-3
are in the R configuration, Y is in the equatorial position, and ** is in the S configuration. Particularly preferred are (N-[(R)-3-tetradecanoyloxytetradecanoyl]-(S)-2-pyrrolidinylmethyl 2-deoxy-4-O-phosphono-2-[(R)-3-tetradecanoyloxytetradecanoylamino]-3-O-[(R)-3-tetradecanoyloxytetradecanoyl]-&bgr;-D-glucopyranoside, Formula (II),
(N-[(R)-3-dodecanoyloxytetradecanoyl]-(S)-2-pyrrolidinyhnethyl 2-deoxy-4-O-phosphono-2-[(R)-3-dodecanoyloxytetradecanoylamino]-3-O-[(R)-3-dodecanoyloxytetradecanoyl]-&bgr;-D-glucopyranoside, Formula (III),
and (N-[(R)-3-decanoyloxytetradecanoyl]-(S)-2-pyrrolidinylmethyl 2-deoxy-4-O-phosphono-2-[(R)-3-decanoyloxytetradecanoylamino]-3-O-[(R)-3-decanoyloxytetradecanoyl]-&bgr;-D-glucopoyranoside, Formula (IV),
and their pharmaceutically acceptable salts.
The present invention also provides pharmaceutical compositions containing compounds of the general and specific formulas above. The pharmaceutical compositions can be combined with a variety of antigens and in a variety of formulations known to those of skill in the art.
The compounds of the present invention are also useful in methods of inducing an immune response in a subject. The method entails administering to the subject a therapeutically effective amount of one or more compounds of the present invention, preferably in a pharmaceutical composition that also contains a pharmaceutically acceptable carrier.
The present invention also encompasses methods of treating a mammal suffering from or susceptible to a pathogenic infection, cancer or an autoimmune disorder. The method entails administering to the mammal a therapeutically effective amount of one or more compounds of the present invention, preferably in a pharmaceutical composition that also

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