Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-04-05
2004-07-13
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S181000, C552S574000, C552S576000
Reexamination Certificate
active
06762175
ABSTRACT:
This invention relates to biologically active compounds, and it is concerned with providing by means of chemical derivatisation, a technique whereby the behaviour of many biologically active compounds, such as drugs and agricultural chemicals, may be favourably modified.
There is a great interest in the medical community to investigate and improve the transport efficiency of drugs to the site of action in the patient. The work has mainly been focused on resorption of a drug from the intestine to the blood stream, although transport across other biological barriers often plays an important role in obtaining the necessary therapeutic effect in the treatment of many diseases like cancer, infections, inflammations, CNS disorders etc. The transport across the cell membrane is often a main impediment to achieve optimal effect with a therapeutic compound.
Over the last decades drug resistance in the treatment of malignant and infectious diseases has become increasingly prevalent and is now regarded as a serious clinical problem. The development of drug resistance can be due to a number of mechanisms, but quite often relates to a triggering of the normal mechanisms whereby microorganisms and cells clear toxic compounds to subtoxic levels. One example is the development of multi-drug resistance (MDR) in cancer cells. In this case MDR frequently relates to a cellular membrane protein pump by which the cells-achieve a very efficient efflux of toxic compounds. In a clinical situation, the treatment of a tumour with a cytostatic drug, cells with the most potent protein pump can preferentially survive, and these cells may proliferate to a new tumour which may be resistant to treatment with a variety of different drugs. Similar mechanisms of action may be responsible for the lack of effect seen in other therapeutic areas, for instance with anti-malarial drugs.
Several techniques to try to circumvent resistance mechanisms in the clinic are known. For example, the co-administration of a Ca
2+
channel blocker such as verapamil or an immunomodulating agent like cyclosporin, have been tried out. However, no significant improvements have been reported so far.
There have been several proposals in the literature for improving the therapeutic index, bioavailability, membrane passage, organ targeting, etc of therapeutic compounds by combining the compounds with fatty acids so as to form either chemically coupled derivatives or physical mixtures.
Thus, for example, EP-A-393920 discloses that anti-viral nucleosides and nucleoside analogues which are derivatised with long chain (C
16
upwards) acyl groups have advantages as compared with the parent compound. It is stated that the fatty acid portion of these molecules preferably are made up of polyunsaturated fatty acids, such as &ggr;-linolenic or linoleic acid.
US-A-3920630 teaches that 2,2′-anhydro-aracytidine and its 5′-O-acylates have the same general biological and therapeutic activity as anti-viral agents as ara-cytidine itself. The compound 2,2′-anhydro-5′-O-oleyl-ara-cytidine is specially mentioned.
EP-A-56265 discloses esters of arabino-furanosyl-thymine (Ara T) with saturated acids having 1-17 C-atoms.
From PCT/WO90/00555 there are known lipid derivatives linked, especially through aphosphate group, to the 5′-position of the pentose group of a nucleoside. The purpose of this derivatisation is to make the nucleosides more lipophilic so that they could be included into liposomes, which are preferentially taken up by macrophages and monecytes, cells which are found to harbour the HIV virus. It is stated that a targeting effect is thereby achieved.
The anti-viral and anti-cancer activities of nucleoside analogues are directly linked to intra-cellular phosphorylation of the administered drug. This biochemical transformation is normally effectuated by viral and/or cellular enzymes. To improve the effect WO96/25421 discloses phospholipid derivatives of nucleosides with relatively short chain (C
14
or less) saturated or unsaturated fatty acids.
The art has also sought to improve the characteristics of other classes of pharmaceutical substance through derivatisation with fatty acids.
For example, WO96/22303 teaches that the pharmokinetic profile and mode of delivery of several different categories of therapeutic compounds (corticosterones, opioids and opioid antagonists, anti-viral nucleosides, cyclospprins and related cyclopeptides, folate antagonists, catecholamine precursors and catecholamines and alkylating agents containing a carboxylic acid group) can be altered by conjugating them to one to three acyl derivatives of fatty acids through the use of a linker/spacer group which includes a tromethamine or ethanolamine derivative. Palmitic acid is the preferred fatty acid.
Lipophilic pro drugs of several NSAIDs are known from H. Bundgaard et al (International Journal of Pharmaceutics, 43 101-110 1988) and V. R. Shanbhag et al (Journal of Pharmaceutical Sciences, 149 Vol 81, No 2, February 1992). In addition to the pro drug aspect, reduced GI irritation is reported. EP-A-0195570 suggests that the administration of gamma-linolenic and dihomo-gamma-linolenic acid in conjunction with NSAIDs reduces the side effects shown by the NSAIDs when taken on a continuing basis.
U.S. Pat. No. 5,284,876 teaches the use of docosahexaenoic acid amides of dopamine as per oral prodrugs in the treatment of CNS disorders.
Physical mixtures containing fatty acids/fatty acid derivatives used as so-called penetration enhancers both with dermal and per oral administration are known from PCT/US94/02880 and PCT/SE96/00122.
As indicated, many of these prior proposals concern fatty acid derivatives of anti-viral nucleosides and nucleoside analogues. It is indeed not surprising that this should be so as it has long been known that certain polyunsaturated fatty acids attack viruses. In EP-A-0642525 we ourselves taught that the anti-viral effect of nucleosides and nucleoside analogues can be highly potentiated through reaction with oleic acid (cis-9-octadecenoic acid), elaidic acid (trans-9-octadecenoic acid), cis-11-eicosenoic acid or trans-11-eicosenoic acid, to form the corresponding 5′—O-monoester. We have shown that the beneficial effects which can be obtained from these four specific monounsaturated, &ohgr;-9 C18 or C20 fatty acids are superior to those generally obtainable through fatty acid derivatisation.
We have now surprisingly found in accordance with the present invention that the properties of numerous different biologically active compounds may be favourably modified by derivatisation with an &ohgr;-9 C18 or C20 monounsaturated fatty acid. The present invention thus provides a widely utilisable but simple technique for enhancing the value of many drugs and agricultural chemicals, for instance.
Broadly, the present invention in one aspect provides a lipophilic derivative of a biologically active compound containing in its molecular structure one or more functional groups selected from alcohol, ether, phenyl, amino, amido, thiol, carboxylic acid and carboxylic acid ester groups, other than a nucleoside or nucleoside analogue, said lipophilic derivative being characterised by a molecular structure in whichthe or at least one said functional group of said biologically active compound is replaced by a lipophilic group selected from those of the formula: RCOO—, RCONH—, RCOS—, RCH
2
O—, RCH
2
NH—, —COOCH
2
R, —CONHCH
2
R and —SCH
2
R, wherein R is a lipophilic moiety selected from cis-8-heptadecenyl, trans-8-heptadecenyl, cis-10-nonadecenyl and trans-10-nonadecenyl.
In one preferred embodiment of the present invention, the biological effect of a therapeutic compound is improved by derivatising the compound with a n-9 C18 or C20 monounsaturated fatty acid. We present below a detailed discussion of the application of this invention to drugs selected from the following groups:
1. cancer drugs;
2. antiinflammatory drugs
NSAIDs
adrenocorticosteroids;
3. antibiotics and other antibacterial agents;
4. antiparasitic drugs;
5. CNS drugs;
6. c
Børretzen Bernt
Dalen Are
Myhren Finn
Sandvold Marit Liland
Badio Barbara P.
Fitzpatrick ,Cella, Harper & Scinto
Norsk Hydro ASA
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