Therapeutic azo-compounds for drug delivery

Details Therapeutic azo-compounds for drug delivery Therapeutic azo-compounds for drug delivery

2001-07-27

2003-08-05

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Designated organic nonactive ingredient containing other...

Aftertreated solid synthetic organic polymer

C424S078080

Reexamination Certificate

active

06602915

ABSTRACT:

BACKGROUND OF THE INVENTION
5-Aminosalicylic acid (5-ASA) is the active component of a commonly used treatment for inflammatory bowel disease (IBD) and Crohn's disease treatment. 5-ASA drug is typically linked via an azo bond to a carrier that allows for targeted drug release exclusively in the large intestine where the azo bond is cleaved by the indigenous bacteria. However, the carrier molecule for this component is associated with several side effects such as nausea and vomiting, rash, or other severe toxic reactions.
4-Aminosalicylic acid (4-ASA) has shown promise in the treatment of inflammatory bowel disease as well as tuberculosis. However, this drug causes several objectionable side effects. Some of the less common side effects are hepatitis, hypokalemia, acute renal failure, mild hypoprothrombinemia, hemolytic anaemia and thrombocytopenia. Patients can also develop hypersensitivity and hypothyroidism and goiter. The side effects that makes this drug intolerable to patients, however, are the gastrointestinal reactions. 4-ASA is a gastrointestinal irritant which frequently causes symptoms of anorexia, nausea, vomiting, and diarrhea. The diarrhea can be severe enough to cause steatorrhea, malabsorption, secondary folic acid deficiency and megaloblastic anemia.
Accordingly, attempts have been made to prepare formulations which alleviate these side effects. Several formulations have been created which include enteric-coated tablets and granules, solutions, and suspensions, as well as chemically modified forms such as complexes with resin and ascorbic acid, phenyl esters, and benzoyl amides. Several polymeric drugs incorporating 4-ASA based on either dialdehyde starch/oxidized cellulose, poly(vinyl alcohol), or polyacrylate backbones have also been prepared.
In the present invention, drugs are incorporated into polymeric systems to furnish a polyazo compound. Using these polymeric drug delivery systems, targeted and temporal drug delivery can be achieved, without unwanted side effects of the current formulations.
SUMMARY OF THE INVENTION
Polymeric polyazo compounds which degrade into useful biologically active compounds have now been developed. Accordingly, the invention provides a polymer of the invention which comprises a backbone, wherein the backbone has an azo linkage, and wherein the backbone has one or more groups that will yield a biologically active compound upon hydrolysis and cleavage of the azo-bond of the polymer.
The invention also provides a pharmaceutical composition comprising a polymer of the invention and a pharmaceutically acceptable carrier.
The invention also provides a therapeutic method for treating a disease in an animal comprising administering to an animal in need of such therapy, an effective amount of a polymer of the invention.
The invention also provides a method of delivering a biologically active compound to a host comprising administering to the host a biocompatible and biodegradable polymer of the invention, which degrades into the biologically active compound.
The invention provides a polymer of the invention for use in medical therapy, as well as the use of a polymer of the invention for the manufacture of a medicament useful for the treatment of a disease in a mammal, such as a human.
The invention also provides a therapeutic method for treating inflammatory bowel disease, cancer, or a brain tumor comprising administering to a mammal in need of such therapy, an effective amount of a polymer of any one of formula (III), (IV) or (V), as described herein.
The invention also provides a therapeutic method for producing an anti-infective effect in an animal comprising administering to an animal in need of such therapy, an effective amount of a polymer of any one of formula (III), (IV) or (V), as described herein.
The invention also provides a therapeutic method for treating cancer comprising administering to an animal in need of such therapy, an effective amount of a polymer of any one of formula (III), (IV) or (V), as described herein.
The invention also provides processes and intermediates disclosed herein that are useful for preparing a polymer of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The following definitions are used, unless otherwise described: halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as “isopropyl” being specifically referred to. Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (C
1
-C
6
)alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
The term anhydride linkage means —C(═O)—O—(O═)C—, term ester linkage means —OC(═O)— or —C(═O)O—; the term thioester linkage means —SC(═O)— or —C(═O)S—; and the term amide linkage means —N(R)C(═O)— or —C(═O)N(R)—, wherein each R is a suitable organic radical, such as, for example, hydrogen, (C
1
-
6
)alkyl, (C
3
-C
6
)cycloalkyl, (C
3
-C
6
)cycloalkyl(C
1
-C
6
)alkyl, aryl, heteroaryl, aryl(C
1
-C
6
)alkyl, or heteroaryl(C
1
-C
6
)alkyl.
The term “amino acid,” comprises the residues of the natural amino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as well as unnatural amino acids (e.g. phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, citruline, &agr;-methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). The term also comprises natural and unnatural amino acids bearing a conventional amino protecting group (e.g. acetyl or benzyloxycarbonyl), as well as natural and unnatural amino acids protected at the carboxy terminus (e.g. as a (C
1
-
6
)alkyl, phenyl or benzyl ester or amide; or as an &agr;-methylbenzyl amide). Other suitable amino and carboxy protecting groups are known to those skilled in the art (See for example, Greene, T. W.; Wutz, P. G. M. “Protecting Groups In Organic Synthesis” second edition, 1991, New York, John Wiley & sons, Inc., and references cited therein).
The term “host” includes animals and plants.
The term “peptide” describes a sequence of 2 to 35 amino acids (e.g. as defined hereinabove) or peptidyl residues. The sequence may be linear or cyclic. For example, a cyclic peptide can be prepared or may result from the formation of disulfide bridges between two cysteine residues in a sequence. Preferably a peptide comprises 3 to 20, or 5 to 15 amino acids. Peptide derivatives can be prepared as disclosed in U.S. Pat. Nos. 4,612,302; 4,853,371; and 4,684,620, or as described in the Examples hereinbelow. Peptide sequences specifically recited herein are written with the amino terminus on the left and the carboxy terminus on the right.
Polymers of the Invention
The biocompatible, biodegradable polyazo compounds of the invention are useful in a variety of applications where delivery of a biologically active compound (active agent) to the large intestine is desired.
The polymers of the invention may be prepared in accordance with methods commonly employed in the field of synthetic polymers to produce a variety of useful products with valuable physical and chemical properties. The polymers can be readily processed into tablets, coatings

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