Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-08-21
2001-10-16
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C435S188000, C530S408000, C530S409000, C530S410000, C514S034000, C514S049000, C514S241000, C514S247000, C514S269000, C514S291000, C514S296000, C514S345000, C514S372000, C514S380000, C514S404000, C514S422000, C514S423000, C514S424000, C514S445000, C514S473000, C514S480000, C514S490000, C514S529000, C514S546000, C514S551000, C514S646000, C536S006400, C536S028500, C544S180000, C544S239000, C544S298000, C546S082000, C546S110000, C546S279100, C546S301000, C548S213000, C548S243000, C548S370400, C548S518000, C548S
Reexamination Certificate
active
06303569
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 or 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 fluids 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
Reminaton'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.
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. The use of polymeric-based transport systems as part of cascade latentiation technology was not disclosed.
The problems associated with preparing prodrugs of amine-containing drugs was recently highlighted by Shan, D. et al. in “Prodrug Strategies Based on Intramolecular Cyclization Reactions”
J. Pharm. Sci.
July 1997 Vol.86, No.7, 765-767, (the contents of which are hereby incorporated by reference). To avoid the relative stability of the amide bond, the authors disclose prodrugs which incorporate various moieties which are capable of undergoing intramolecular cyclization reactions to release the parent drug. The chemical or biological triggering mechanisms which initiate the cyclization reactions are independent of those which are required for releasing the original drug via hydrolysis of the amide bond. Again, non-polymeric-based systems are disclosed.
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 and/or hydroxyl 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:
B is H, OH, OSiR
13
, a residue of an amine-containing target moiety or a residue of a hydroxyl-containing moiety;
L
1
is a bifunctional linking moiety such as
L
2
is a bifunctional linking moiety such as
Y
1-2
are independently O or S;
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 C(═Y
2
);
R
1
, R
2
, and R
4
are independently one of C
1-6
alkyls, C
3-2
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, C
1-6
alkoxy, phenoxy, and C
1-6
heteroalkoxy;
R
7
, R
8
, R
9
, R
10
and R
13
are independently hydrogen or a member of the group which defines R
1
, R
2
, and R
4
;
Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group;
(m) is zero or one;
(n) is zero or a positive integer;
(p) is zero, one or two;
(q) is three or four; and
11
is a polymer residue, such as a water-soluble polyalkylene oxide.
In certain preferred aspects, Ar is a di-alkyl substituted phenyl such as a dimethylphenyl and/or B is a leaving group such as N-hydroxybenzotriazolyl, 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 daunorubicin, doxorubicin, p-aminoaniline mustard, camptothecin, paclitaxel, AraC, 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 reaction in which the prodrug carrier portion has been attached by modification of a hydroxyl or amino group.
For purposes of the present invention, the term “alkyl” shall be understood to include straight, branched, substituted C
1-12
alkyls, including alkoxy, 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 or esterase activity and then the resultant “second prodrug” moiety undergoes a cyclization reaction to regenerate the amine-or hydroxyl-containing parent (i.e. bioactive) compound in vivo.
Some of the chief advantages of the double prodrug compounds of the present invention are that they are capable of solubilizing amine-or hydroxyl-containing compounds and extending their half-life as compared to the native or even “second” prodrug counterparts. The polymeric portion can also impart an antigenicity-reducing effect on the parent c
Choe Yun H.
Greenwald Richard B.
Pendri Annapurna
Enzon Inc.
Roberts & Mercanti L.L.P.
Russel Jeffrey E.
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