Patent Evaluation: Novel Piperidines as κ-opioid Agonists

Summary

Novelty: Novel derivatives of 2-amidomethylpiperidine and processes for their preparation are disclosed. The compounds are selective κ-opioid agonists. They are potentially useful as analgesics, sedatives and cerebroprotective agents.

Biology: Compounds were screened for binding to κ- and μ-opioid receptors in rat brain homogenates. The preferred compound had K_i values of 7 and 270nM, respectively. In the phenylquinone writhing test in mice, the same compound gave ED₅₀ of values 1.7 mg/kg (sc) and 10 mg/kg (po).

Chemistry: One hundred and eighty-five compounds are exemplified. 3.4-Dichloro-N-methyl-N-((1-(1-methyl)-2-piperidinyl)phenylmethyl))benzene acetamide is the preferred compound.

Structure:      

Patent Evaluation: κ-Opioids as Potent Analgesics

Summary

Novelty: A novel series of azacyclic k-agonists are claimed and are said to be of use in the treatment of pain and cerebral ischaemia.

Biology: Data are given for a number of compounds in two analgesic tests, the mouse writhing assay (ED₅₀ values in the range 0.005–0.299 mg/kg sc) and the mouse tail-flick (ED₅₀ values in the range 0.052–10 mg/kg sc).

Biology: Experimental and physical data are given on a number of examples, some of which are optically pure. Sixteen compounds are named within the claims, the most active in the tail-flick model is (2S)-1-(4-trifluoromethylphenyl)acetyl-2-[N-methyl-N-(2-fluoroethyl)]-aminomethyl piperidine hydrochloride.

Structure:     

Patent Evaluation: Arylethanolamine derivatives and their use as β3-adrenoceptor agonists

Summary

Novelty: Novel arylethanolamine derivatives are claimed to be β₃-adrenoreceptor agonists. They are stated to show good selectivity for β₃-rather than β1- or β2-adrenoreceptors. They are potentially useful for the treatment of hyperglycaemia and obesity.

Biology: Lipolysis stimulated by β-agonists was demonstrated in rat white adipocytes, according to the method of Rodbell (J. Biol. Chem. (1964) 239:375–380) and the modification of Honnor et al. (J. Biol. Chem. (1985) 260:15122–15129). The specified compound had an EC₅₀ of 41.7nM (intrinsic activity = 1.0). In vitro, β1- and β2- adrenoceptor agonist activity was studied using rat atrial preparations and rat uterine preparations, respectively. The specified compound demonstrated K_i values of 7610nM and 3656nM for β1- and β2- adrenoceptors, respectively.

Chemistry: Five compounds are disclosed and are exemplified by synthesis. Yields, mps, optical rotations and nmr data are given. Two compounds are specifically claimed including the (R)-4-[2-[N-[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxyacetic acid, sodium salt.     

Patent Evaluation: Optically pure (S)-metoproloI as an improved β-bIocker

The English Court of Appeal Judgment in Bristol-Myers Squibb Company vs. Baker Norton Pharmaceuticals and Napro Biotherapeutics² has restricted the scope of second medical use claims in England to inventions for distinctly different therapeutic applications, thereby excluding inventions for new modes of administration or ones with inherent therapeutically beneficial effects. The Court of Appeal’s decision cuts across a body of European and international decisions and limits ³ to second non-medical uses. In coming to their decision, the Court of Appeal considered in detail the European decisions of ⁴ and Mobil but declined to overrule them. How the Court of Appeal’s decision will impact on decisions by Courts in other jurisdictions, in particular in Europe, remains to be seen. However, the English Courts have recently considered two further ‘second medical use claim’ patents: the Court of Appeal in American Home Products vs. Novartis⁵ and the High Court in Lilly Icos ⁶. And although these cases do not turn on the fact that they are second medical use claim patents, the Courts do not appear to be deviating from the Court of Appeal decision in Bristol-Myers Squibb. Nevertheless, what is clear, is that the Court of Appeal in Bristol-Myers Squibb omitted to address the public policy issue regarding the extent to which valuable and costly research and development in new therapeutic applications of known medicines, exemplified by the Bristol-Myers Squibb case, should be rewarded by the grant of further patents. This issue is of concern to the pharmaceutical industry and is one that the English Courts will undoubtedly have to clearly address in the future.     

Novel coumarin–benzimidazole derivatives as antioxidants and safer anti-inflammatory agents

Inspired from occurrence of anti-inflammatory activity of 3-substituted coumarins and antiulcer activity of various 2-substituted benzimidazoles, novel compounds have been designed by coupling coumarin derivatives at 3-position directly or through amide linkage with benzimidazole nucleus at 2-position. The resultant compounds are expected to exhibit both anti-inflammatory and antioxidant activities along with less gastric toxicity profile. Two series of coumarin–benzimidazole derivatives (4a–e and 5a–e) were synthesized and evaluated for anti-inflammatory activity and antioxidant activity. Compounds 4c, 4d and 5a displayed good anti-inflammatory (45.45%, 46.75% and 42.85% inhibition, respectively, versus 54.54% inhibition by indomethacin) and antioxidant (IC₅₀ of 19.7, 13.9 and 1.2 µmol/L, respectively, versus 23.4 µmol/L for butylatedhydroxytoluene) activities. Evaluation of ulcer index and in vivo biochemical estimations for oxidative stress revealed that compounds 4d and 5a remain safe on gastric mucosa and did not induce oxidative stress in tissues. Calculation of various molecular properties suggests the compounds to be sufficiently bioavailable.KEY WORDS: Anti-inflammatory, Benzimidazoles, Coumarins, DPPH, Gastric toxicity     

Design and synthesis of 3′-fluoropenciclovir analogues as antiviral agents

Based on fluorine switch approach, a series of 3′-fluoropenciclovir analogues with different purine and pyrimidine bases were designed and synthesized. Direct reduction of β-fluoroester to the corresponding 3-fluoroalcohol provided an easy and new entry pathway towards the synthesis of 3′-fluoropenciclovir analogues. The synthesized 3′-fluoropenciclovir analogues were evaluated for their antiviral activities against the poliovirus, HSV-1, HSV-2 and HIV.     

Patent Evaluation: Diadenosine 5′, 5″- P1, P4-tetraphosphate as a Thrombolytic Agent

Summary

Novelty: Diadenosine 5′, 5″-P¹, P⁴-tetraphosphate (AP₄A) is disclosed as an inhibitor of platelet aggregation.

Biology: Three examples are given of in vivo tests on male New Zealand white rabbits which show that AP₄A produces a marked inhibitory effect on ADP-induced but not collagen-induced clotting. In vitro tests on human platelet-rich plasma are also described using twelve analogues of AP₄A. In the third example, the effect of S-containing analogues is given for three cases and compared with a previous one. Results are expressed in five tables and six figures.

Chemistry: Syntheses are not given. Fifteen analogues of AP₄A are mentioned and evaluated for ID₅₀ (μM).     

Use of 2,2′-Azobis(2-Amidinopropane) Dihydrochloride as a Reagent Tool for Evaluation of Oxidative Stability of Drugs

No HeadingPurpose. To study the oxidative degradation of drugs using a hydrophilic free radical initiator, 2,2-Azobis(-amidinopropane) dihydrochloride (AAPH).Methods. AAPH was used as the free radical initiator to study oxidation of three model compounds (A, B, and C), which represent different oxidizable moieties. In the solution model, the drugs and AAPH were dissolved in a mixture of acetonitrile and aqueous buffer and incubated at elevated temperatures to evaluate oxidative degradation. The effects of pH and drug-AAPH ratio on the kinetics of the reaction were evaluated for compound A. Commonly used antioxidants were also evaluated by addition to solutions of drug and AAPH. In the solid-state model, blends of drug with microcrystalline cellulose were treated with AAPH and placed at elevated temperature and humidity to evaluate solid state oxidation.Results. Use of AAPH resulted in selective oxidation of the model drugs by a free radical initiated process. The scope of the technique was further investigated in detail using compound A. The rate of oxidation of compound A varied directly with the concentration of AAPH. The pseudo first-order rate constants for the oxidative degradation were calculated from the kinetic data. The antioxidants were rank-ordered based on their quenching activity on the rates of AAPH initiated oxidation for compound A. The concept was extended to oxidation in solid state.Conclusions. The proposed AAPH model is useful in assessing oxidative stability of drug candidates in development.     

Metalloprotease inhibitors as anti-inflammatory agents: an evolving target?

The metalloproteases (MMPs) are a family of enzymes that are important for tissue remodeling. These enzymes have been implicated in a number of pathologies, including cancer, arthritis, atherosclerosis and chronic obstructive pulmonary disease. Thus, inhibitors of MMPs may have utility in the therapy of inflammatory diseases, particularly in arthritis where current therapies do not halt the progression of the disease. Many compounds have been identified as inhibitors of MMPs, and some have progressed to the clinic. However, no compound developed as an MMP inhibitor has been licensed for clinical use thus far. This review discusses this therapeutic area and compares inhibitors of MMPs with other novel therapeutic approaches in the treatment of inflammatory disease. Inhibitors of MMPs may find utility in disorders not currently targeted, but where MMPs are involved in the pathology.     

Patent focus on cancer chemotherapeutics. III Angiogenesis agents: October 2000 – March 2001

Angiogenesis refers to the formation of new blood vessels from existing blood vessels, a process that is believed to be a key requirement for tumour growth and metastasis. Angiogenesis inhibition represents a new approach to cancer chemotherapy and several agents and approaches are now entering late clinical development. This review summarises the key aspects of recent patent applications referring to cancer chemotherapy and cancer drug discovery that involve inhibition or reduction of angiogenesis. The review covers the main mechanism-based approaches such as MMPIs, inhibitors of the growth factor signalling pathways, integrin antagonists and urokinase inhibitors. Additional sections relating to vascular damaging agents, endogenous inhibitors and selected natural products are also included. The scope includes applications that published from October 2000 through March 2001.     

Patent focus on cancer chemotherapeutics V. Angiogenesis agents: September 2001 – August 2002

Angiogenesis refers to the formation of new capillaries from existing blood vessels and is believed to be a key process in tumour growth. Angiogenesis inhibition represents an active area of cancer drug discovery, with several agents and approaches now entering late stage clinical development. This review summarises the key aspects of recent patent applications relating to cancer chemotherapy and drug discovery that involve inhibition or modulation of angiogenesis. The review includes applications that have been published between September 2001 and August 2002. In particular, the review focuses on the approaches aimed at growth factor targets, such as angiopoietin, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF).     

Novel brominated quinoline and pyrimidoquinoline derivatives as potential cytotoxic agents with synergistic effects of γ-radiation

New quinoline derivatives 6, 7 and 19, pyrimidoquinoline derivatives 8-16 and triazolopyrimidoquinoline derivatives 17 and 18 bearing a bromo-substituent were synthesized starting from 3-(4-Bromophenylamino)-5,5-dimethylcyclohex-2-enone 3. All the newly synthesized compounds were evaluated for their in vitro anticancer activity against human breast cancer cell line (MCF7). Compounds 9, 11, 17 and 18 showed IC(50) values (36.4, 39.7, 39.02 and 36.4 μM, respectively) comparable to that of the reference drug doxorubicin (IC(50) = 32.02 μM). On the other hand, compound 6, 14 and 19 exhibited better activity than doxorubicin with IC(50) values of 8.5, 23.5 and 23.7 μM. Additionally, the most potent compounds 6, 14 and 19 were evaluated for their ability to enhance the cell killing effect of γ-radiation.     

Novel antifungal agents: a patent review (2011 – present)

Introduction: Invasive fungal infections (IFI) have increased significantly over the past decades. The mortality rate of IFI is alarming, and early and accurate diagnosis is difficult. Most used antifungal drugs are not completely effective due to the development of increasing resistance and undesirable side effects which limit their use. In this scenario, new effective broad spectrum and safer antifungal drugs are urgently needed.

Areas covered: This review summarizes the latest advances in the discovery of new antifungal compounds through the patents granted from 2011 to August 2013. In the 26 patents reviewed here, either derivatives of existing antifungal drugs or novel structures are included. New imidazoles, fluconazole analogs and adducts of azoles with 2,6-di-tert-butyl-4-methylphenol are described. The review also includes chitinases, β-1,3-D-glucan and chitin synthases inhibitors and novel structures.

Expert opinion: In the patents reviewed here, progress has been made to accomplish at least one of the necessary requirements for the development of novel antifungal agents, such as broad spectrum of activity, more favorable pharmacokinetic profile, good bioavailability and low adverse effects. However, in vivo activity, mechanisms of action, drug–drug interactions and other aspects that make a compound a good antifungal agent need further development.     

2,2′-Azo-bis-amidinopropane as a radical source for lipid peroxidation and enzyme inactivation studies

1. 2,2′-Azo-bis-amidinopropane (ABAP) thermal decomposition produces free radicals that initiate the lipid peroxidation of erythrocyte ghost membranes.

2. Addition of 6-n-propyl-2-thiouracil decreases the rate of the process, both by decreasing consumption of the natural antioxidants of the membranes and by direct interaction with the free radicals involved in the lipid peroxidation.

3. Peroxyl radicals produced in ABAP thermal decomposition inactivate lysozyme, horseradish peroxidase (HRP) and glucose oxidase, in that order. The number of enzyme molecules inactivated per radical introduced into the system increases with enzyme concentration.

4. Competitive studies employing mixtures of enzymes show that the order of reactivity of these enzymes towards the peroxyl radicals is the opposite to that obtained for the rate of enzyme inactivation. It is concluded that inactivation efficiency is determined mainly by the average number of free radicals that must react with an enzyme molecule to produce its inactivation, and that this number is directly related to the molecular weight of the enzyme.     

Synthesis and antiviral evaluation of novel 3′- and 4′-doubly branched carbocyclic nucleosides as potential antiviral agents

A series of 3'- and 4'-branched carbocyclic nucleosides 25, 26, 27, 28, 29 and 30 were synthesized starting from simple acyclic ketone derivatives. The construction of the required quaternary carbon was made using a [3,3]-sigmatropic rearrangement. In addition, the installation of a methyl group in the 3'-position was accomplished using a Horner-Wadsworth-Emmons (HWE) reaction with triethyl 2-phosphonopropionate. Bis-vinyl was successfully cyclized using a Grubbs' catalyst (II). Natural bases (adenine, cytosine, uracil) were efficiently coupled with the use of a Pd(0) catalyst.     

Evaluation in vitro of synthetic curcumins as agents promoting monocytic gene expression related to β-amyloid clearance

Accumulation of amyloid-beta (Aβ) is one of the hallmarks of Alzheimer's disease (AD), and efficient clearance of Aβ by cells of the innate immune system may be an important mechanism for controlling or preventing disease onset. It was reported that peripheral blood mononuclear cells (PBMCs) of most AD patients are defective in the phagocytosis of soluble Aβ. Natural curcumins were shown to restore Aβ phagocytosis by AD PBMCs and to up-regulate the expression of key genes including MGAT3 and those encoding Toll-like receptors (TLRs). Bisdemethoxycurcumin (BDC), a minor component of natural curcumin, was shown to have the greatest potency for stimulating AD PBMCs. Because natural curcumins have inherent limitations with regard to physicochemical properties, synthetic curcumin analogues were developed that showed improved solubility, stability, and bioavailability. An in vitro system using human monocytic cell lines (U-937, THP-1) was used to evaluate analogues for the potency of innate immune cell stimulation. These cell lines showed responses to curcuminoids and to 1α,25-dihydroxyvitamin D3 (VD3) resembling those seen in human PBMCs. From more than 45 curcuminoids analyzed, the most potent compounds possessing enhanced pharmaceutical properties were identified. The most promising candidates included prodrug versions containing water solubility-enhancing amino acids and stability-increasing modifications near the central diketone. In vivo studies showed compound (5) substantially increased bioavailability by combining several promising structural modifications. Studies examining ex vivo phagocytosis of Aβ and bead particles in mouse microglia showed that BDC and several water-soluble analogues were quite effective compared to curcumin or an unnatural analogue. In vitro studies using monocytic cell lines reported herein complement those using human PBMCs and represent a routinely accessible and uniform cellular resource allowing direct comparisons between compounds.     

Synthesis and Evaluation of Novel Erlotinib–NSAID Conjugates as More Comprehensive Anticancer Agents

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