Patent Evaluation: Novel N-hydroxyureas as 5-lipoxygenase Inhibitors

Summary

Novelty: Acetylenic N-hydroxyureas are disclosed and are stated to be 5-lipoxygenase inhibitors, which are potentially suitable for treating diseases such as asthma, rhinitis, rheumatoid arthritis, psoriasis, ARCs and inflammatory bowel disease.

Biology: In vitro 5-LPO inhibition was determined using an RBL supernatant assay; IC₅₀ values are given for fifty-five compounds. In vivo activity was determined in a rat peritoneal anaphylaxis model with results given for thirty-seven compounds. N-hydroxy-N-[4-[5-(4-fluorophenyl)-2-furyl]-3-butyn-2-yl]urea has an IC₅₀ of 0.2 μM and showed 83% inhibition at 30 μmol/kg po

Chemistry: The syntheses of 157 examples and eighteen intermediates are described in full. One hundred and forty-six compounds are explicitly claimed with N-hydroxy-N-[4-[5-(4-fluorophenoxy)-2-furyl-3-butyn-2-yl]urea and its enantiomers.

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Patent Evaluation: Novel Sulphonamide 5-Lipoxygenase Inhibitors

Summary

Novelty: Novel sulphonamide derivatives which are inhibitors of the enzyme 5-lipoxygenase (5-LPO) are disclosed. Processes for their manufacture and pharmaceutical compositions containing them are given. The compounds are potentially useful in the treatment of inflammatory and allergic diseases.

Biology: The effect of 5-LPO inhibition was evaluated using three procedures. Test (a) was an in vitro assay which involved incubating the compound with heparinized human blood. Test (b) was an ex vivo assay, and test (c) an in vivo system involving the measurement of the effects of a test compound administered orally against the liberation of LTB₄. The exemplified compound has an IC₅₀ of 0.09 μM against LTB₄ in test (a) and an oral ED₅₀ of 1 mg/kg versus LTB₄ in test (c).

Chemistry: Eight compounds are exemplified including N-(3-chloro-4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl)-N-methylmethanesulphonamide.

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Patent Evaluation: Thioxoheterocycles as 5-lipoxygenase Inhibitors

Summary

Novelty: Novel thioxoheterocycles and their preparation are disclosed. Also described are pharmaceutical compositions containing the novel compounds and their use in the production of medicaments for use in a leukotriene mediated disease or medical condition.

Biology: The thioxoheterocycles are inhibitors of the enzyme 5-LPO. The effects of this inhibition are demonstrated by standard procedures. No other biological data are provided.

Chemistry: Three specifically claimed compounds illustrate the preparation of novel compounds and intermediates. A preferred class of novel compounds are specifically claimed including 4-[5-fluoro-3-(1-methyl-2-thioxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-4-meth-oxytetrahydropyran.

Chemistry: Three specifically claimed compounds illustrate the preparation of novel compounds and intermediates. A preferred class of novel compounds are specifically claimed including 4-[5-fluoro-3-(1-methyl-2-thioxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-4-meth-oxytetrahydropyran.

Structure:      

Patent Evaluation: Hydroxyurea Anti-Inflammatory Agents

Summary

Novelty: N-hydroxyureas are disclosed which are inhibitors of 5-lipoxygenase (5-LPO) and are potentially useful for the treatment of inflammatory disorders, such as asthma.

Biology: The ability of the compounds to inhibit 5-LPO was demonstrated using a rat peritoneal macrophage assay. IC₅₀ values are said to be between 0.01-30μM; no specific data are presented.

Chemistry: The compounds of the invention were prepared from the appropriate oxazole (thiazole) carboxaldehyde. Seven examples are given, all of which are specifically claimed, including N-hydroxy-N-[(2-phenyloxazol-4-yl)methyl]urea.     

Patent Evaluation: Benzanilide derivatives as 5-HT1D antagonists

Summary

Novelty: Novel benzanilide derivatives are claimed to be 5-HT₁₀ antagonists. They are potentially useful for the treatment of depression, Parkinson's disease and a variety of CNS disorders including anxiety, panic and memory disorders.

Biology: No biological data are disclosed.

Chemistry: A total of forty-six final compounds and fifty-one intermediates are disclosed. Syntheses are given in all cases. Yields, mps and some ¹H nmr data are given. Twenty-five compounds are specifically claimed including 4′-cyano-N4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-[1,1′-biphenyl]-4-carboxamide.     

Patent Evaluation: Benzo-isoquinoline derivatives as 5-HT1A agonists and their potential use in therapeutics

Summary

Novelty: Novel benzo-isoquinoline derivatives are claimed to be 5-HT_1A agonists and dopamine antagonists. They are potentially useful as antidepressants and antipsychotics. They may also have utility in the treatment of hypertension and congestive heart failure.

Biology: Behavioural, psychological and biochemical tests were performed. In a CNS receptor binding assay 5-HT_1A inhibition was 15-99%, dopamine D₁ inhibition was 0-57% and dopamine D2 inhibition was 2-74%. In a dopamine cell firing assay, one compound demonstrated an ED50 value of 0.065 mg/kg. Data for sympathetic nerve discharge, metabolism and hypothermia are also given.

Chemistry: Over a hundred compounds are disclosed and are exemplified by synthesis. Preparations of intermediates are also given. Detailed reaction schemes are provided. Twenty-four compounds are specifically claimed, including (-)-10-cyano-1,2,3,4,4a,5,6,10b-octahydro-trans-3-N-propylbenzo[f]isoquinoline.     

Patent Evaluation: Quinoline 5-Lipoxygenase Inhibitors

Summary

Novelty: 2-Substituted quinolines are disclosed which are active as inhibitors of 5-lipoxygenase (5-LPO). These compounds are potentially useful as inhibitors of inflammation, allergic responses and airways hyper-reactivity, as well having potential use for the prevention of thromboembolism and ischaemic damage.

Biology: Inhibition of 5-LPO was demonstrated by suppression of leukotriene LTB₄ production by Ca²⁺-ionophore-stimulated polymorphonuclear lymphocytes; IC₅₀ values for selected compounds were between 0.56-2.50 μM.

Chemistry: Synthesis of the compounds comprises reaction of a 2-halogenomethylquinoline with an appropriately substituted phenol derivative. Forty-three preparative examples are given, together with seventy-nine final compounds. Synthesis of the compounds forms a subsidiary part of the claim. No compounds are specifically claimed. 2-[3-Fluoro-4-(quinolin-2-methoxy)phenyl]-2-cyclopentylacetic acid methyl ester is an active and exemplified compound.

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Patent Evaluation: Indole leukotriene biosynthesis antagonists

Summary

Novelty: Novel indole derivatives are disclosed as leukotriene antagonists in these four related patents. These are: azaarylmethoxy (AG7604 and AG7610), bicyclic-heteroarylmethoxy (AG7612) and heteroarylmethoxy (AG7913) indoles. All are potentially useful as anti-inflammatory, anti-allergic and anti-asthmatic agents. They are also stated to be cytoprotective and to be useful for the treatment of a variety of disorders including hypertension, angina, cerebral spasm and migraine.

Biology: Protocols for an LTB₄ inhibitory assay and an asthmatic rat assay are given. However, no specific biological data are disclosed.

Chemistry: In AG7604 a total of sixteen final compounds are disclosed. Syntheses are given in four examples. All are specifically claimed including 3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(isoquinolin-3-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid.

In AG7610 eighteen final compounds are described. Syntheses are given in five examples. Preparation of intermediates is also given. All eighteen compounds are specifically claimed including 3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(pyridin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid.

Twenty-seven final compounds are disclosed in AG7612. Syntheses are given in three examples. The twenty-seven compounds are specifically claimed including 3-[1-(4-chlorobenzyl)-3-methyl-5-(benzothiazol-2-ylmethoxy)indol-2-yl]2,2-dimethyl propanoic acid.

Finally, in AG7613 a total of twenty-one final compounds are disclosed. Syntheses are given in three examples. Twenty-one compounds are specifically claimed including 3-[1-(4-chlorobenzyl)-3-methyl-5-(4-prop-2-ylthiazol-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid.     

Patent Evaluation: Potent dual Acting PAF/Histamine Antagonists

Summary

Novelty: Novel thazolidine carboxylic acid amide derivatives are disclosed. They are PAF antagonists and are potentially useful as anti-allergic and anti-asthmatic agents.

Biology: The compounds are evaluated for PCA inhibition in rats. At a dose of 6.4 mg/kg po, 56% inhibition is observed. The compounds are also evaluated in vitro for inhibition of PAF-induced, blood platelet aggregation (IC₅₀ = 1.8×10-⁶g/ml) and PAF-receptor binding (IC₅₀ = 6.7 × 10–7 g/ml).

Chemistry: 3-[4-(Diphenylmethylene)-1-piperidyl]propylcarbamoyl-2-(3-pyridyl)thiazolidine is one of fourteen specifically claimed compounds.     

5-Lipoxygenase inhibitors

Ether containing compounds are claimed as inhibitors of 5-lipoxygenase (5-LO), useful in treating allergic and inflammatory diseases. Data are given for 11 compounds in an in vitro assay of inhibition of calcium ionophore-induced LTB₄ biosynthesis in human whole blood. In US5268379 (101] the syntheses of 22 compounds are described as examples, and the structure of an additional 24 compounds are described in a table. Two particularly preferred and specifically claimed compounds are 4-methoxy-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)methoxy)-trans-prop-1-enyi]tetra hydropyran (1) and 3-(4-methoxytetrahydropyran-4-yl)-N-[(1,2-dihydro-1-methyl-2-oxoquinolin-6-yl)met hyll-trans-propenyl amide (2).     

Patent Evaluation: Novel cholinesterase inhibitors

Summary

Novelty: The use of [[(aminocarbonyloxy)-1-indanon]-2-yl]methylpiperidines and 6-(aminocarbonyloxy)-2-[(pyridin-4-yl)methylenyl]-1-indanones for the treatment of memory dysfunctions is claimed. They are stated to have acetylcholinesterase inhibitory activity and to be useful for the treatment of Alzheimer's disease.

Biology: Acetylcholinesterase inhibition was measured using rat brain preparations. The specified compound gave an IC₅₀ value of 1.34mM.

Chemistry: A process for the preparation of the compounds is claimed and exemplified in five cases. Four compounds are specifically claimed including 1-benzyl-4-[[6-(methylaminocarbonylxoy))-1-indanon]-2-yl]methylpiperidine.     

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: Spirononane Derivatives as PAF Antagonists

Summary

Novelty: Novel 1-oxa-2,9-diphenyl-spiro[4.4]nonane derivatives are claimed as PAF antagonists. They are potentially useful for the treatment of inflammatory disorders.

Biology: The inhibition of [³H]-PAF binding to human platelet plasma membrane was determined by isotopic labelling and filtration techniques. Results were given for eight compounds; IC₅₀ values were in the range 1.0-12.0μM. In vivo, the ability of the compounds to reverse hypotension caused by an infusion of PAF in male Sprague Dawley rats was demonstrated. 1-Oxa-6-oxo-7-(3-pyridyl)methylene-2,9-di(3,4-dimethoxyphenyl)spiro[4.4]nonane had an ED₅₀ value of 800 μg/kg iv.

Chemistry: Nineteen compounds are specifically claimed and are exemplified by synthesis; yields, mp, elemental analyses, IR and ¹H nmr data are reported. One of the specifically claimed compounds is 1-oxa-6-oxo-2,9-di(3,4-dimethoxyphenyl)spirone[4.4]nonane.

Structure:      

Patent Evaluation: Bridged Cyclic Ketal Derivatives as Squalene Synthetase Inhibitors

Summary

Novelty: Bridged cyclic ketals are described which are claimed to inhibit squalene synthase, thereby having potential in the treatment of fungal diseases, hypercholesterolaemia and hyperlipoproteinaemia.

Biology: Squalene synthase inhibitory activity was determined by incubation of the compound with [2-¹⁴C]-farnesylpyrophosphate and homogenized rat liver, and measurement of the concentration of [¹⁴C] squalene produced. IC₅₀ (50% inhibition) values were < 100 nM for forty-four compounds. In vitro activity against Candida albicans was also included.

Chemistry: Several cyclic ketals, obtained by fermentation, were chemically modified to produce novel derivatives. Over sixty intermediates and sixty-eight compounds are fully exemplified. Over twenty compounds are specifically claimed, including [1S-[1α(4S*,5S*),3α,4β,5α,6α(2E,4R*,6R*)7β]] 1-(4-hydroxy-5-methyl-3-methylene-6-phenylhexyl)- 4,6,7-trihydxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid-6-(4,6-dimethyl-2-octenoate).

Structure:      

Patent Evaluation: Benzamidazole Excitatory Amino Acid Antagonists

Summary

Novelty: Novel benzimidazole phosphonoamino acids, which are competitive NMDA antagonsits, are disclosed. They are potentially useful in the treamtent of convulsions, cerebral ischaemia, stroke and CNS disorders.

Biology: The NMDA competitive activity of the compounds was assayed by means of in vitro inhibition of [³H]CCP binding in rat brain tissue and in vivo antagonism of NMDA induced convulsions in mice. The assays are fully described. One compound gave an IC₅₀ of 7 nM and an ED₅₀ of 0.13 mg/kg (reference diazepam has ED₅₀ of 1.91 mg/kg).

Chemistry: The syntheses of the compounds are described in nine examples. R-α-amino-5-Chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid is one of five specifically claimed examples.     

Patent Evaluation: Benzodioxan Antipsychotic Agents

Summary

Novelty: Novel aminophenoxyalkyl derivatives of benzodioxan are disclosed and are claimed to be antipsychotic, antidepressant and anxiolytic agents. They are useful in the treatment of multi-CNS disease states.

Biology: The effect of the compounds on the synthesis of dopamine was determined using the method of Walters (Naunyn-Schmiedeberg's Arch. Pharmacol. (1976) 296:5-14). The antipsychotic activity of these compounds was determined using the method of Martin (J. Pharmacol. Exp. Therap. (1984) 229:706-711). The affinity for the dopamine D₂ receptor was also assayed for the compounds using the method of Fields (Brain Res. (1977) 136:578). Affinity for the 5HT_1A receptor was determined by the method of Hall et al. (J. Neurochem. (1985) 44:1685). The specified compound gave 64% (limbic) and 66% (striatal) inhibition of 0.15 mg ip and receptor affinities (IC₅₀) of 51 nM (D₂) and 8 nM (5HT_1A). Results for nineteen compounds are presented in a table.

Chemistry: Synthesis of the compounds are described in nineteen examples. N-[3-(3-aminophenoxy)propyl]-2,3-dihydro-7-hydroxy-1,4-benzodioxin-2-metanamine is one of fifteen specifically claimed compounds.     

Patent Evaluation: Novel Squalene Synthetase Inhibitors

Summary

Novelty: 1,2,4-Oxadiazole-derivatives, bearing a 5-linked 1-azabicyclo-[2.2.2]octane moiety are disclosed. The compounds are active as inhibitors of squalene synthetase and are potentially useful as antihypercholesterolaemic and anti-arteriosclerotic agents.

Biology: Inhibition of squalene synthetase was demonstrated in rat liver microsomes provided with tritiated substrate in the assay procedure; IC₅₀ values ranged between 11-58nM for selected compounds. No in vivo trials are reported.

Chemistry: Preparation of the compounds was previously disclosed in US4952587 and EP-323864-A. Several compounds are specifically claimed including 3-[3-(phenylmethyl)-1,2,4-oxadiazol-5-yl]-1-azabicyclo[2.2.2]octane.     

Patent Evaluation: Novel Piperidines as PAF Antagonists

Summary

Novelty: Imidazobenzazepines or imidazopyridoazepines, which bear an optionally N-substituted piperidine moiety, are disclosed. The compounds are claimed to be potent antagonists of platelet aggregating factor (PAF) and are potentially useful for the treatment of asthma, bronchitis and other chronic obstructive airways disease. The compounds may also have more general potential use as anti-allergic and anti-inflammatory agents.

Biology: The PAF antagonism of the compounds was demonstrated by inhibition of PAF-induced platelet aggregation in human platelet-rich plasma; IC₅₀ values for selected compounds were in the range 5-35 μM. In vivo utility of the compounds was assayed by the suppression of PAF-induced bronchospasm in guinea pigs. However, no specific data are provided.

Chemistry: Synthesis of the compounds was by conventional ring-closure and derivatization methods, which are exemplified in four cases, and form a subsidiary part of the claim. Four compounds are specifically claimed, including the preferred compound 4-(5,6-dihydro-¹11H-imidazo[2,1-b] [3]benzazepin-11-ylidene)-1-(4-pyridinylcarbonyl)piperidine-N′-oxide.

Structure:     

Antibacterial/β-Lactam Derivatives: Novel Covalently Bound Quinolone-β-Lactams as Broad-Spectrum Antibacterials

Summary

Novelty: β-Lactam derivatives exhibiting antibacterial activity are disclosed. They are useful in the treatment and/or prophylaxis of infectious diseases. The compound combine an antibacterially active quinoline antibiotic with 6-aminopenicillanic acid, (S)-3-amino-2-oxo-azetidine-1-sulphonic acid or a 7-ACA derivative.

Biology: In vitro antibacterial activity data against twenty-six different bacteria are provided (MIC - 0.063 - 500 μg/ml).

Chemistry: The compounds are synthesized in a multistep process and experimental details are given. [2S-(2α,5α,6β)]-6[[[4-[1-ethyl-6-fluoro-1,4-dihydro-3-(methoxycarbonyl)-4-oxo-7- quinolinyl]-1-piperazinyl]-methylene]amino]-3,3-dimethyl-6-oxo-4-thia-1- aza-bicyclo[3.2.0]heptane-2-carboxylic acid (below) is one of the eleven compounds which are specifically claimed.     

Patent Evaluation: Camphor derivatives as oxytocin antagonists

Novelty: Novel piperazinyl(su1phon)amide derivatives of camphor are claimed as oxytocin antagonists. They are potentially useful for preventing preterm labour and for stopping labour prior to caesarian delivery.

Biology: A radioligand binding assay using a crude membrane preparation of uteri from DES-treated rats is described. The specified compound gave an IC₅₀ value of 5.4nM.

Chemistry: Over one hundred compounds are exemplified. Two compounds are specifically claimed including 1 -((7,7-dimethyl-2-endo-(2S-(dimethylamino)-4-(methylsulphonyl)butyr-ido)-bicyclo [2.2.1] heptan- 1 - yl)-methanesulphony1)-4-(2-methyl-pheny1)piperazine.