Low molecular weight dendritic compounds as pharmaceutical...

Details Low molecular weight dendritic compounds as pharmaceutical... Low molecular weight dendritic compounds as pharmaceutical...

1999-02-04

2001-05-01

Aulakh, Charanjit S. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

C564S180000, C548S491000, C514S415000, C514S622000

Reexamination Certificate

active

06225352

ABSTRACT:

Natural biopolymers such as peptides, proteins, DNA, RNA, polysaccharides and conjugates thereof, and synthetic polymers such as polyethylene, polypropylene, and polyamides consist largely of long linear chains of covalently joined monomeric species.
Dendritic polymers are a special class of synthetic polymer that are characterized by a nonlinear array of monomeric species. Dendritic polymers may be viewed as having the structure of dendrites or trees (Greek dendron=tree).
Dendritic polymers have unique physical properties with a range of potential novel industrial applications (Review: Vögtle F., et al.,
Angew. Chem. Int. Ed.,
1994;33:2413-2420).
This invention relates to low molecular weight (<1000 daltons) dendritic compounds that offer a distinctly novel structural and chemical motif that can interact with a wide range of biologically important targets and hence have potential therapeutic utility.
SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION
The low molecular weight dendritic polymers of this instant invention (herein called “dendroids”) are of formula
or a pharmaceutically acceptable salt thereof wherein:
A is a “core” monomer such as 1,2,3,5-tetrasubstituted or 1,2,4- or 1,3,5-trisubstituted benzene; 2,3,4,5-tetrasubstituted or 2,3,5; or 2,4,5-trisubstituted thiophenes; 2,3,4,6- or 2,4,5,6-tetrasubstituted or 2,3,5; or 2,3,6-trisubstituted pyridine; 1,8,X-trisubstituted naphthalenes (perisubstituted naphthalene); or other such ortho- and metasubstituted aromatics or hydroaromatics.
A may also be a cyclic small hydrocarbon, such as cyclobutane, oxetane, thioxetane, azetidine, cyclopropane, or bicyclo [2.2.1]heptane, a “spiro” carbon atom, or a single nitrogen atom.
B, C, and D are covalently bonded to A, and may be identical or are independently taken from —Y—Z— when:
Y is exemplified by such “spacer” groups, but not limited to ═(CH
2
)
n
—O—(n=0-3); O—(CH
2
)
n
—; —NHCO (CH
2
)
n
; (CH
2
)
n
NHCO—; CONH—(CH
2
)
n
—; (CH
2
)
n
CONH—; —(CH
2
)
n
—; a bond.
Z=di-, tri-, or tetrasubstituted benzene or as defined for A above or is a substituted amine, amide, carbamate, or a bond.
E through M are defined as independently taken from B through D above.
X=defined below.
Preferred dendritic compounds are:
8-(4-Bromo-benzyloxy)-naphthalene-1-carboxylic acid dimethylamide;
8-(4-Methoxy-benzyloxy)-naphthalene-1-carboxylic acid dimethylamide;
8-(3,4-Dimethoxy-benzyloxy)-naphthalene-1-carboxylic acid dimethylamide;
8-(3,4,5-Trimethoxy-benzyloxy)-naphthalene-1-carboxylic acid dimethylamide;
Benzene, 4-[[2-[(3,5-dimethoxyphenyl)methoxy]phenoxy]methyl]-1,2-dimethoxy-;
1,2-Dimethoxy-4-[[3-[3,5-dimethoxyphenyl)methoxy]phenoxy]methyl]-benzene;
Benzene, 5-[[2-[3,4-dimethoxyphenyl)-methoxy]-6-[(3,5-dimethoxyphenyl)methoxy]phenoxy]methyl]-1,2,3-trimethoxy-;
8-(3,5-Dimethoxy-benzyloxy)-naphthalene-1-carboxylic acid dimethylamide;
8-(Biphenyl-4-ylmethoxy)-naphthalene-1-carboxylic acid dimethylamide;
8-(4-Benzyloxy-benzyloxy)-naphthalene-1-carboxylic acid dimethylamide;
8-(4-Styryl-benzyloxy)-naphthalene-1-carboxylic acid dimethylamide;
8-Hydroxy-naphthalene-1-carboxylic acid benzyl-phenethyl-amide;
8-(4-Benzyloxy-benzyloxy)-naphthalene-1-carboxylic acid benzyl-phenethyl-amide;
8-(4-Benzyloxy-benzyloxy)-naphthalene-1-carboxylic acid benzyl-ethyl-amide;
8-(4-Benzyloxy-benzyloxy)-naphthalene-1-carboxylic acid [1-(1H-indol-3-yl)-ethyl])-isopropyl-amide; and
8-(4-Benzyloxy-benzyloxy)-naphthalene-1-carboxylic acid [2-(2-methoxy-phenyl)-ethyl]-phenethyl-amide.
The minimum branching array of the dendroid is given in formula in which none of B through to I is a bond.
The Domain of A (I) is considered as the zero-order branching domain; Area II (to include B,C) is the first order domain, and Area III (to include E through I) is the second order domain.
Most compounds of MW<1000 daltons would likely fall within a second order array.
The “capping” moieties of the dendroid (B through M) essentially form a surface that is able to interact with the biological target. The nature of these capping moieties is important to determine the specificity and selectivity of the dendroid-receptor interaction.
Hence, a further embodiment of this invention is that B through M may also terminate in additional capping moieties taken from those known in the art of drug design that optimally bind to biological receptors. These include in a second order dendroid, that E, for example, may be further derivatized by P when P is taken from:
1. Side chains of the 20 genetically coded amino acids, e.g., E—CH
2
CO
2
H (Aspartic acid side-chain mimetic); E—(CH
2
)
3
NH
2
(Lysine side-chain mimetic). P may also be attached by spacers such as Y above.
2. Heterocyclic bases of nucleotide monomers also attached by spacers such as Y. Heterocyclic bases may include guanine, uracil, adenosine, cytosine, and thymine for delivery of the dendroid to RNA and DNA targets
3. Sugar residues such as glucose, sucrose, mannose, and ribose, attached by spacers such as Y for delivery to glycoprotein and carbohydrate targets.
4. Conjugate systems of 1 to 3 above to embody glycopeptides and peptide/oligonucleotides, attached by spacers such as Y.
The spacer group Y also conveys important structural and physical properties to the molecule to create “self assembly supra molecular” topologies. (Lehn J. M.,
Pure and Applied Chemistry
1994; 66:1961-1966).
For example, when two or more of the spacers Y are composed of hydrophobic moieties (e.g., methylene groups), they are able to undergo hydrophobic collapse and hence hold the dendritic Groups B through M together in 3-dimensional space. This enhances the ability of the capping groups to form a discrete surface to interact optimally with the biological target.
When two of the spacers are composed of hydrophilic moieties (e.g., amide/reverse amide groups), they may undergo hydrophilic collapse (e.g., to form a hydrogen bond in an antiparallel planer arrangement) which may also enhance a surface formation by B through M.
Additionally, if the capping groups B through M are required to be spaced apart (e.g., 2 polar groups such as an amine and carboxylic acid), then the potential for intramolecular hydrophilic collapse (to form an intramolecular salt-bridge) can be minimized by inserting a hydrophobic moiety between them (see Compound 1 as an example, below). Dendroids should be viewed as low molecular weight monomeric species and therefore distinct from dendritic compounds which are essentially polymeric species. Hence, dendroids represent a unique vehicle for controlling the 5 critical molecular design parameters, i.e., size, shape, topology, flexibility, and surface chemistry.
The dendroids are of particular interest in the ability of the “capped surfaces” to interact with biological receptor targets where the receptor determinants are spread over a large surface area, say 400 Å
2
.
Dendroids are expected to interact with large protein surfaces. Examples include those found between the ras/raf protein complex and other key protein/receptor complexes involved in regulation of cell growth such as Rb (retinoblastoma) and p-53 protein. the latter being a key element in the development of programmed cell death (apoptosis). Also included is the C-A-A-X motif of ras protein farnesylation, the FK-506/binding proteins complex, and cytokines such as IL-1, TNF, and IL-6, inhibition of &bgr;-amyloid protein fibrillogenesis/aggregation/deposition, and ion channels blocked by large peptides and proteins such as conotoxins, spider and snake venom.
FIG. III specifically claimed monomer precursors for A include:
Where X=H or (CH
2
)
n
CO
2
R(R=ester such as Me, Et); N=no bonds (i.e., a spiro carbon motif) or CH, N, S, or O. R
1
=Br, OBz. B defined as above. Where the OH groups can be derivatized to give B through M as described in the literature by the same moieties (see Vögtle F., above) with Example 1, FIG. III, or

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