Long-acting drugs and pharmaceutical compositions comprising...

Details Long-acting drugs and pharmaceutical compositions comprising... Long-acting drugs and pharmaceutical compositions comprising...

1999-02-05

2003-01-07

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Insulin; related peptides

C514S001000, C514S002600, C514S003100, C530S336000, C530S337000, C530S399000, C530S402000

Reexamination Certificate

active

06504005

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel long-acting prodrugs capable of undergoing chemical transformation in the body from an inactive into a bioactive form, said prodrugs bearing functional groups sensitive to mild basic conditions, more particularly fluorenylmethoxycarbonyl (Fmoc)- and fluorenylmethyl (Fm)-substituted prodrugs, and to pharmaceutical compositions comprising them.
BACKGROUND OF THE INVENTION
Therapeutical drugs currently being used both in human therapy and veterinary can be classified according to various criteria. For example, drugs may be categorized as molecules having a proteinaceous-peptidic, i.e. composed of amino acid building units, or non-peptidic character, or by a criterion unrelated to the structure such as drugs absorbed orally or administered by other modes, i.e. injection, intranasal or topical, in order to reach the blood circulation.
Orally absorbed compounds are, in general, low molecular weight, rather stable, lipophilic (“oily”) and of a non-peptidic nature. Virtually all peptidic and protein drugs, due to their intrinsic hydrophilic (non-lipophilic) and polar features and metabolical instability, do not obey these criteria and must be administered mostly by injection. Further, as these molecules are rapidly degraded in the body by diverse mechanisms, notably proteolysis, they are usually short-living species.
Non-peptidic drugs are very often sufficiently hydrophobic and can reach the blood circulation through the gastrointestinal pathway. Due to their relative chemical stability, the non-peptidic drugs are usually long-living species.
Protein and peptide drugs have major and numerous clinical applications. e.g. insulin in the treatment of diabetes, gonadotropin-releasing hormone (GnRH) analogs in the therapy of prostate cancer, calcitonin in the treatment of bone-related disorders. The potential for this most important family of molecules is vast, but has as yet been only partially, if not marginally, explored. This, to large extent, is due to their short life in the body and inconvenience of the mode of administration. Non-peptidic drugs, such as antibiotics, although relatively long-lived, have to be administered several times a day over a period of a week, or longer, to maintain the desired continuous circulating levels.
Oral absorption of drugs is a highly desirable goal in the treatment of human diseases, particularly in prolonged therapeutical treatments. Structural alteration of drugs may result in the augmentation of oral and topical absorption, biostability and, eventually, bioavailability. Major efforts are currently being directed toward these goals. Most approaches include drug modification in such way that its native architecture, i.e. bioactive structure, is preserved. This native structure is the one recognized specifically by the drug's target and is a prerequisite feature of the drug's potency. Unfortunately, however, in many cases, the native structure is also recognized by the ‘clearing machinery system’, which is capable of binding the drug, degrading or metabolizing it and thus accelerates its disposal. Thus, stabilization of the bioactive structure is often attempted concomitantly with the desire to enhance metabolic stability. Methods such as encapsulation, decreased solubility and chemical modification have been employed to achieve this goal.
It would be highly desirable to prolong the half-life of virtually many, if not all peptidic as well as non-peptidic drugs existing on the market or to be developed in the future, including antibiotics, antiviral, antihypertensive, antiinflammatory, analgesic, anticholesterolemia, anticarcinogenic, antidiabetic, growth-promoting, and other drugs. Prodrugs related to native drugs that are toxic above certain threshold concentrations might be particularly beneficial.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide novel prodrugs characterized by their high sensitivity to mild basic conditions and their capability of undergoing transformation from an inactive into a bioactive form under physiological conditions in the body.
It is another object of the present invention to provide prodrugs derived from drugs having free amino, carboxyl, hydroxyl and/or mercapto groups, said prodrugs being essentially non-active biologically but being capable of spontaneous and slow conversion to the original active drug molecule in the body, following administration.
It is still another object of the present invention to provide prodrugs that present higher metabolic stability and augmented bioavailability.
It is a further object of the present invention to provide prodrugs that represent alternative possibilities for drug administration, e.g. oral and transdermal, and are further capable of penetrating through physiological barriers, e.g. blood-brain-barrier.
It is still a further object of the present invention to provide prodrugs that permit specific drug targetting to inflicted locations in the body.
The present invention thus relates to novel prodrugs derivatized from a drug in which one or more groups of said drug molecule selected from the group comprising free amino, carboxyl, hydroxyl and/or mercapto, are substituted by functional groups sensitive to bases and removable under mild basic. e.g. physiological, conditions.
The new concept of the invention for slow-releasing drugs includes their derivatization into novel, generally more hydrophobic, drug derivatives. In this approach it is preferred to lose, rather than to preserve, the native conformation, the biological potency and the recognition identity of the drug by the degradative systems. An advantage of this approach, however, resides in the fact that the thus modified derivative can slowly and spontaneously hydrolyze back to the native active drug under the in vivo conditions.
In a particular embodiment, the prodrugs of the invention are of the formula:
X—Y
wherein
Y is a moiety of a drug bearing at least one functional group selected from free amino, carboxyl, hydroxyl and/or mercapto, and
X is a radical selected from radicals of the formulas (i) to (iv):
wherein R
1
and R
2
, the same or different, are each hydrogen, alkyl, alkoxy, alkoxyalkyl, aryl, alkaryl, aralkyl, halogen, nitro, sulfo, amino, ammonium, carboxyl, PO
3
H
2
, or OPO
3
H
2
; R
3
and R
4
, the same or different, are each hydrogen, alkyl or aryl; and A is a covalent bond when the radical is linked to a carboxyl or mercapto group of the drug Y, or A is OCO— when the radical is linked to an amino or hydroxyl group of Y.
According to the present invention, Y is a moiety of any drug for human and veterinary use bearing at least one functional group selected from free amino, carboxyl, hydroxyl and/or mercapto, such as, but not being limited to, antidiabetic drugs, e.g. insulin; growth promoters, e.g. human growth hormone, bovine growth hormone; antibiotics such as aminoglycosides, e.g. gentamicin, neomycin and streptomycin, &bgr;-lactams, such as penicillins, e.g. amoxicillin, ampicillin, piperacillin, and cephalosporins, e.g. cefaclor, cefminox and cephalexin, macrolides, e.g. carbomycin and erythromycin, and polypeptidic antibiotics. e.g. bacitracin, gramicidins and polymyxins; synthetic antibacterials, e.g. trimethoprim, piromidic acid, and sulfamethazine; analgesic and anti-inflammatory drugs. e.g. acetaminophen, aspirin, ibufenac, indomethacin; antiallergic and antiasthmatic drugs, e.g. amlexanox and cromolyn; antihypercholesterolemic drugs, e.g. clofibric acid, oxiniacic acid and triparanol; &bgr;-adrenergic blockers and antihypertensive drugs, e.g. bupranolol, captopril, indenolol, propranolol and 4-aminobutanoic acid; antineoplastic drugs, e.g. daunorubicin, azacitidine, 6-mercaptopurine, interferons, interleukin-2, methotrexate, taxol and vinblastine; antiviral drugs, e.g. acyclovir, ganciclovir, amantadine, interferons, AZT and ribavirin, etc. The term drug according to the invention is intended to encompass also pheromones.
The terms “alkyl”, “alkoxy”, “alkoxyalkyl”, “aryl”, “alkaryl

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