Compounds with super-aspirin effects

Abstract

A compound having the structural formula (I) and pharmaceutically acceptable salt and / or hydrates thereof, (I) wherein Y is an arylester or an C1-C8 alkylaryl ester, selected from the group consisting of: benzene, toluene, xylene, benzoic acid, benzoate, nicotinate, isonicotinate and halobenzene, which can be unsubstituted or substituted with at least one nitric oxide releasing group; and / or at least one of hydroxide, —Cl, —Br, a C1-C8 alkyl, benzyl, a C1-C8 alkoxy, benzyloxy, —NHC(O)R, —NH2, —NO2—ONO2, —(CH2)nONO2, —OC(O)[(CH2)n]cyclicONO2, —OCOArONO2, —OCOAr(CH2)nONO2 or a C1-C5 haloalkyl ester, wherein R is a C1-C8 alkyl or a C1-C8 alkoxy group, n=1-8 and m=3-10, to produce a super-aspirin effect.

Description

FIELD OF THE INVENTION[0001]The invention relates to aspirin prodrug compounds that are capable of providing a super-aspirin effect which provides an additional antiplatelet effect over the antiplatelet effect of any aspirin released. In particular, the compounds are useful in conditions where aspirin has traditionally thought to be ineffective, such as conditions where inhibition of tumor cell induced platelet aggregation (TCIPA) is desired. The compounds may be used in cardiovascular and / or anticancer applications.DESCRIPTION OF RELATED ART[0002]Aspirin is an effective antiplatelet drug, reducing the risk of myocardial infarction (MI), stroke or death by approximately 25% in patients who are at increased risk of cardiovascular (CV) events. However, in some cases less than expected inhibition of platelets by aspirin has been referred to as aspirin resistance.a Aspirin resistance levels have been reported to range from 5 to 63% in various studies.bc [0003]A number of potential mecha...

AI Technical Summary

Benefits of technology

[0026]Thus the compounds of the invention thereby produce beneficial (i) cardio and chemo protective aspirin effects from the aspirin generated from the prodrug, and a (ii) unexpected additional antiplatelet aggregation effect.

[0047]In addition to aspirin release and additional antiplatelet effects produced, these compounds also release beneficial organic nitrates which release NO. NO protects the GI tract. This is desirable, since nitric oxide together with aspirin causes vasodilation and further inhibits platelet aggregation and monocyte adhesion. In other words, NO and aspirin function beneficially together. Thus these compounds are particularly protective towards the gastrointestinal tract. NO is gastroprotective through multiple mechanisms: by promoting blood flow, removing toxins, and stimulating mucus secretion and angiogenesis. Furthermore, nitric oxide is also a potent vasodilator and it inhibits platelet and monocyte adhesion and platelet aggregation.

[0050]In addition to aspirin release and additional antiplatelet aggregation effect produced, compound (ST0702) generates nicotinic acid. Advantageously, nicotinic acid increases high density lipoprotein cholesterol (HDL) and reduces low density lipoprotein cholesterol and triglycerides. The additional antiplatelet effect arising from this compound means this compound inhibits TCIPA, whereas aspirin itself does not.

[0054]This compound is desirable as it functions as a cancer preventative agent, with a dual effect through aspirin release and inhibition of TCIPA. It also benefits cardiovascular disease patients through aspirin and, nicotinic acid release. It will particularly benefit susbset of the population having CVD and active cancer metastasis.

[0063]Compound ST0702 concurrently produce an aspirin like effect and inhibit cancer cell metastasis through the inhibition of tumor cell induced platelet aggregation (TCIPA).

[0066]Thus either compound (II) or (III) (or mixtures thereof) can be advantageously used in the treatment of cancer metastasis by inhibition of tumor cell induced platelet aggregation (TCIPA). Suitably, either compound (II) or (III) (or mixtures thereof) can be used in the manufacture of a medicament for the treatment of cancer metastasis involving tumor cell induced platelet aggregation (TCIPA). Thus, the compound having structural formula (II) or structural formula (III) may be used as a platelet modulation drug for use in the treatment of or the prevention of a disease involving cancer metastasis mediated by tumor cell induced platelet aggregation (TCIPA). Such uses are particularly beneficial in patients having CVD due to the aspirin and nicotinate released in additional to the additional antiplatelet aggregation effect.

Problems solved by technology

In another chemoprevention trial, it was shown that despite using highly motivated, well educated patients, adherence was poor.j

Enteric coated aspirin does not solve the aspirin resistance problem.

Also, delayed enteral absorption of aspirin increases the potential for aspirin esterases in the GI mucosa to hydrolyse aspirin to salicylic acid before entering the portal circulation and thereby reduce the effect of the administered dose.a Another study showed that in patients prescribed aspirin within the previous 72 hours, with enteric coating, 65% of patients still had normal platelet function in comparison to 25% taking an uncoated preparation.

Therefore, aspirin resistance is a major public health problem affecting up to half of patients.

Of these, compliance appears to be the greatest issue.

A second major issue appears to be lack of efficacy of clinically popular enteric coated versions of low dose aspirin, which is not seen with immediate release aspirin and higher doses.

This is a complex problem that is partly due to poor compliance (which is linked to intestinal toxicity) but it is also a reflection of the multi-factorial nature of cardiovascular disease which demands multiple pharmacological responses.

Thrombosis is the most frequent complication and a major cause of death in cancer patients.

The presence of comorbidities including pulmonary disease, renal disease, infection, blood transfusion, chemotherapy and obesity are associated with a higher risk of arterial events.

In addition to the typical causes of arterial ischemia related to traditional cardiovascular conditions, patients with underlying malignancy or hematologic disorders have added risks for in situ thrombosis related to the inherent thrombophilia associated with their malignancy and its therapy.

Therefore, platelet aggregation inhibition may slow down the rate of tumor progression and metastasis.

However, clinical trials of the antiplatelet agent aspirin which inhibits platelet cyclooxygenase and thereby TXA2 production, have proven inconclusive in cancer patients.

Indeed some clinical studies have found that treatment with high doses of aspirin did not protect patients from metastasis.

In addition, aspirin has also failed in preventing TCIPA in vitro with different tumour cell lines (Alonso-Escolano et al., 2003; Jurasz et al., 2001; Medina et al., 2006).

Indeed, aspirin itself does not have intrinsic activity against cancer metastasis and has failed in preventing TCIPA in vitro with different tumour cell lines.

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