Prodrugs for liver specific drug delivery

Details Prodrugs for liver specific drug delivery Prodrugs for liver specific drug delivery

2000-09-08

2004-06-22

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

C424S600000, C424S001110, C424S009200, C424S001650, C424S601000, C514S007600

Reexamination Certificate

active

06752981

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed towards novel prodrugs of alcohol, amine, and thiol-containing compounds, to their preparation, to their synthetic intermediates, and to their uses. Prodrugs of the invention may be used to deliver drugs to the liver with high tissue specificity.
BACKGROUND OF THE INVENTION
The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention. All cited publications are incorporated by reference in their entirety.
Drug induced toxicities and pharmacological side effects are often associated with interactions by the drug or drug metabolite in tissues not associated with the pharmacological benefits of the drug therapy. In other cases, the desired pharmacological effect is poorly achieved either because of dose-limiting toxicities or inadequate drug levels in the target tissues. Thus, there is a need to deliver drugs to specific tissues or organs. High organ specificity can be achieved by a variety of mechanisms including local administration to the target organ and drug-protein conjugates. Local administration to the target organ is an invasive procedure. Drug-protein conjugates exhibit poor oral bioavailability, limitations in carrier manufacturing and drug loading, a potential for diminished liver uptake due to down regulation of the receptor in diseased tissue, and a high incidence of antibody induction. A third approach entails use of prodrugs that are activated by enzymes highly enriched in the target organ.
There is particularly a need to deliver drugs to the liver to treat diseases such as hepatitis, cancer, malaria, and fibrosis which are poorly treated with current therapies. Many therapies for these conditions have narrow therapeutic indices. Other diseases such as hyperlipidemia where the liver is responsible for the overproduction of biochemical endproducts that directly contribute to the pathogenesis of disease can also be treated with liver specific drug delivery. Thus, there is still a need for prodrugs to enhance specificity.
SUMMARY OF THE INVENTION
The present invention is directed towards novel cyclic phosph(oramid)ate prodrugs of alcohol-, amine-, and thiol-containing drugs, their preparation, their synthetic intermediates, and their uses. Another aspect of the invention is the use of the prodrugs to treat diseases that benefit from enhanced drug distribution to the liver and like tissues and cells that express cytochrome P450, including hepatitis, cancer, liver fibrosis, malaria, other viral and parasitic infections, and metabolic diseases where the liver is responsible for the overproduction of the biochemical end product, e.g. glucose (diabetes); cholesterol, fatty acids and triglycerides (hyperlipidemia) (atherosclerosis) (obesity). In one aspect, the invention is directed towards the use of the prodrugs to enhance oral drug delivery. In another aspect, the prodrugs are used to prolong pharmacodynamic half-life of the drug. In addition, the prodrug methodology of the current invention is used to achieve sustained delivery of the parent drug. In another aspect, the prodrugs are used to increase the therapeutic index of the drug. In another aspect of the invention, a method of making these prodrugs is described. In another aspect, the prodrugs are also useful in the delivery of diagnostic imaging agents to the liver.
One aspect of the present invention concerns prodrugs of formula I
wherein:
V, W, and W′ are independently selected from the group consisting of —H, alkyl, aralkyl, alicyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, 1-alkenyl, and 1-alkynyl; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, optionally 1 heteroatom, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, optionally containing 1 heteroatom, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 additional carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said additional carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, optionally containing one heteroatom, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, optionally containing 0-2 heteroatoms, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from the group consisting of —CHR
2
OH, —CHR
2
OC(O)R
3
, —CHR
2
OC(S)R
3
, —CHR
2
OC(S)OR
3
, —CHR
2
OC(O)SR
3
, —CHR
2
OCO
2
R
3
, —OR
2
, —SR
2
, —CHR
2
N
3
, —CH
2
aryl, —CH(aryl)OH, —CH(CH═CR
2
2
)OH, —CH(C≡CR
2
)OH, —R
2
, —NR
2
2
, —OCOR
3
, —OCO
2
R
3
, —SCOR
3
, —SCO
2
R
3
, —NHCOR
2
, —NHCO
2
R
3
, —CH
2
NHaryl, —(CH
2
)
p
—OR
12
, and —(CH
2
)
p
—SR
12
;
p is an integer 2 or 3;
with the provisos that:
a) V, Z, W, W′ are not all —H; and
b) when Z is —R
2
OR
2
, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or alicyclic;
c) when Z is CHR
2
OH, then M is not —NH(lower alkyl), —N(lower alkyl)
2
, —NH(lower alkylhalide), —N(lower alkylhalide)
2
or —N(lower alkyl)(lower alkylhalide); and
d) when V is aryl or substituted aryl, then M is not —O(D) where D is hydrogen, a metal ion or an ammonium ion;
R
2
is selected from the group consisting of R
3
and —H;
R
3
is selected from the group consisting of alkyl, aryl, alicyclic, and aralkyl;
R
6
is selected from the group consisting of —H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;
R
12
is selected from the group consisting of —H, and lower acyl;
each Y is independently selected from the group consisting of —O—, and —NR
6
—;
M is selected from the group consisting of drugs MH containing an —OH, —NHR
2
, or —SH group, and that is attached to the phosphorus in formula I via O, N, or S of said OH, —NHR
2
, or SH group;
and pharmaceutically acceptable prodrugs and salts thereof.
Since these compounds have asymmetric centers, the present invention is directed not only to racemic and diastereomeric mixtures of these compounds, but also to individual stereoisomers. The present invention also includes pharmaceutically acceptable and/or useful salts of the compounds of formula I, including acid addition salts. The present inventions also encompass prodrugs of compounds of formula I.
Definitions
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term “aryl” refers to aromatic groups which have 5-14 ring atoms and at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. Suitable aryl groups include phenyl and furanyl.
Carbocyclic aryl groups are groups, wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
Heterocyclic aryl or heteroaryl groups are groups having from 1 to 4 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substit

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