Polymeric prodrugs of amino- and hydroxyl-containing...

Details Polymeric prodrugs of amino- and hydroxyl-containing... Polymeric prodrugs of amino- and hydroxyl-containing...

1998-10-30

2001-01-30

Russel, Jeffrey E. (Department: 1653)

Drug, bio-affecting and body treating compositions

Lymphokine

C424S085200, C424S085400, C424S094300, C435S188000, C514S002600, C514S013800, C514S018700, C514S034000, C514S049000, C514S247000, C514S345000, C514S351000, C514S352000, C514S424000, C514S425000, C514S426000, C514S432000, C514S445000, C514S447000, C514S459000, C514S460000, C514S471000, C514S472000, C514S473000, C514S480000, C514S512000, C514S547000, C530S326000, C530S330000, C530S345000, C530S351000, C530S408000, C530S409000, C530S410000, C536S006400, C536S028500

Reexamination Certificate

active

06180095

ABSTRACT:

TECHNICAL FIELD
The present invention relates to double prodrugs. In particular, the invention relates to polymeric-based double prodrugs having reversible linkages involving amino and hydroxyl moieties of chemical compounds and biologically active materials such as enzymes, proteins and the like.
BACKGROUND OF THE INVENTION
Over the years, several methods of administering biologically-effective materials to mammals have been proposed. Many medicinal agents are available as water-soluble salts and can be included in pharmaceutical formulations relatively easily. Problems arise when the desired medicinal agent is either insoluble in aqueous finds or is rapidly degraded in vivo. For example, alkaloids are often especially difficult to solubilize.
One way to solubilize medicinal agents is to include them as part of a soluble prodrug. Prodrugs include chemical derivatives of a biologically-active parent compound which, upon administration, eventually liberate the parent compound in vivo. Prodrugs allow the artisan to modify the onset and/or duration of action of an agent in vivo and can modify the transportation, distribution or solubility of a drug in the body. Furthermore, prodrug formulations often reduce the toxicity and/or otherwise overcome difficulties encountered when administering pharmaceutical preparations. Typical examples of prodrugs include organic phosphates or esters of alcohols or thioalcohols. See
Remington's Pharmaceutical Sciences,
16th Ed., A. Osol, Ed. (1980), the disclosure of which is incorporated by reference herein.
Prodrugs are often biologically inert, or substantially inactive, forms of the parent or active compound. The rate of release of the active drug, i.e. the rate of hydrolysis, is influenced by several factors but especially by the type of bond joining the parent drug to the modifier. Care must be taken to avoid preparing prodrugs which are eliminated through the kidney or reticular endothelial system, etc. before a sufficient amount of hydrolysis of the parent compound occurs. By incorporating a polymer as part of the prodrug system, one can increase the circulating half-life of the drug. However, in some situations such as with alkaloids, it has been determined that when only one or two polymers of less than about 10,000 daltons are conjugated thereto, the resulting conjugates are rapidly eliminated in vivo especially if a somewhat hydrolysis-resistant linkage is used. In fact, such conjugates are so rapidly cleared from the body that even if a hydrolysis-prone ester linkage is used, not enough of the parent molecule is regenerated in vivo. This is often not a concern with moieties such as proteins, enzymes and the like even when hydrolysis-resistant linkages are used. In those cases multiple polymer strands, each having a molecular weight of about 2-5 kDa, are used to further increase the molecular weight and circulating half-life.
Although the above-mentioned concept of prodrug-based delivery systems has proven to be useful in many instances, there are nonetheless situations where alternatives are desired. For example, Bundgaard in “The Double Prodrug Concept and Its Applications” in
Advanced Drug Delivery Reviews,
3 (1989) 39-65, (the contents of which are hereby incorporated by reference) pointed out that in many cases it is difficult to obtain a prodrug which has the proper combination of adequate stability in vitro and high susceptibility to regenerate the parent drug in vivo. As pointed out by Bundgaard, a promising means of overcoming some of the previously encountered shortcomings involves the use of cascade latentiation or “pro-prodrugs”. In such systems, the hydrolytic reaction sequence involves a first step which usually is an enzymatic cleavage and the second involves a non-enzymatic hydrolysis that occurs only after the first has taken place.
it is believed that in spite of the reported work in the field of double prodrugs, some specific problems were not addressed sufficiently. For example, the previously reported techniques do not sufficiently address the solubility problems of many parent compounds. In addition, the problem of designing in a sufficient increase in circulating half-life for the prodrug was also not sufficiently developed. Thus, there continues to be a need to provide additional technologies for forming prodrugs which would benefit from the double prodrug concept. For example, it would be advantageous to provide the artisan with alternative techniques for transport carrier attachment so as to regulate biological effect. Furthermore, it would be desirable to provide additional techniques to address problems associated with involving amino residues of parent compounds and thus avoid excessively fast or slow hydrolysis of the transport form from the parent compound at physiological pH.
SUMMARY OF THE INVENTION
The present invention addresses the shortcomings described above. In one aspect of the invention, compounds of Formula (I) are provided:
wherein:
L
1
is a bifunctional linking moiety such as
G is H or
where
B is H, a leaving group, a residue of an amine-containing moiety, or a residue of a hydroxyl-containing moiety;
Y
1-5
are independently O, S or NR
12
;
M is X or Q; wherein
X is an electron withdrawing group
Q is a moiety containing a free electron pair positioned three to six atoms from
R
1
, R
4
, R
7
, R
8
, R
9
, R
10
, R
12
, R
14
and R
15
are independently selected from the group consisting of hydrogen, C
1-6
alkyls, C
3-12
branched alkyls, C
3-8
cycloalkyls, C
1-6
substituted alkyls, C
3-8
substituted cycloalkyls, aryls, substituted aryls, aralkyls, C
1-6
heteroalkyls, substituted C
1-6
heteroalkyls;
R
2
, R
3
, R
5
and R
6
are independently selected from the group consisting of hydrogen, C
1-6
alkyls, C
1-6
alkoxy, phenoxy, C
1-8
heteroalkyls, C
1-8
heteroalkoxy, substituted C
1-6
alkyls, C
3-8
cycloalkyls, C
3-8
substituted cycloalkyls, aryls, substituted aryls, aralkyls, halo-, nitro- and cyano-, carboxy-, carboxyalkyl, alkylcarbonyl, etc.;
Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
(b), (m), (r), (s), (t), (u), and (v) are independently zero or one;
(a) and (n) are independently zero or a positive integer;
(p) is zero or a positive integer;
(q) is three or four; and
R
11
is a polymer such as a polyalkylene oxide.
In some preferred embodiments, (r) and (t) are one and R
2
and R
6
are independently selected from C
1-6
alkoxy or C
1-6
alkyl moieties and R
3
and R
5
are both hydrogen.
In other preferred embodiments, (v) is zero,
where B is hydrogen. This aldehyde derivative of Formula (I) provides useful intermediates for forming prodrug compositions.
In alternative preferred aspects of the invention, B is a leaving group such as N-hydroxy-benzotriazolyl, N-hydroxyphthalimidyl, halogen, p-nitrophenoxy, imidazolyl, N-hydroxysuccinimidyl, thiazolidyl thione, or other activating groups. Alternatively, B is a residue of any amino-containing or hydroxyl-containing compound for which one or more of improved aqueous solubility, decreased antigenicity, prodrug and/or controlled release delivery is desired. For example, B, can be a residue of an enzyme, protein, or organic compound such as daunorcubicin, doxorubicin, p-aminoaniline mustard, camptothecin, paclitaxel, Ara-C, melphalan, podophyllotoxin, etc.
For purposes of the present invention, the term “residue” shall be understood to mean that portion of a biologically active compound which remains after it has undergone a substitution reaction in which the prodrug carrier portion has been attached.
For purposes of the present invention, the term “alkyl” shall be understood to include straight, branched, substituted C
1-12
alkyls, C
3-8
cycloalkyls or substituted cycloalkyls, etc.
The double prodrugs of the present invention are thus unique delivery systems. Preferably the polymeric portion is first released by hydrolysis and then the result “second prodrug” moiety undergoes a 1,4 or 1,6-aryl or benzyl elimination reac

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