Patent Evaluation: Novel 2,2′-alkylenediindoles as anti-ulcer agents

Summary

Novelty: Novel 2,2′-alkylenediindole derivatives are claimed to be H⁺/K⁺ ATPase inhibitors. They are potentially useful as anti-ulcer agents.

Biology: An H⁺/K⁺ ATPase inhibitory activity assay was performed in vitro using a pig stomach preparation. Inhibition was determined colorimetrically. Results are given for twelve compounds. ATPase inhibition was 5-100% (dose 5–20 μg/ml).

Chemistry: A total of twenty-three compounds are disclosed. Syntheses are given in five examples. Characterization is by ¹H nmr and ms. None of the compounds are specifically claimed. 3-(2-Phenylethylaminoethyl)-2,2′-tetramethylenediindole is typical of the claim.     

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: 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: An Improved Method for the Preparation of Ticlopidine

Summary

Novelty: A process for the preparation of the known antithrombotic platelet aggregation inhibitor ticlopidine is disclosed, together with novel N-2-chlorobenzyl-(2-oxo/2,2-dioxo)-1,2,3-oxathiazolidines useful as intermediates in the process. Prior methods for the preparation of ticlopidine were dangerous and showed low yield and high cost; the new process potentially circumvents these problems.

Biology: No biological data are presented.

Chemistry: Preparation of the novel intermediate N-2-chlorobenzyl-(2-oxo/2,2-dioxo)-1,2,3-oxathiazolidines, and the synthesis of ticlopidine by the action of thienyl lithium followed by cyclization are exemplified in four cases and are specifically claimed. Ticlopidine is 5-[(2- chlorophenyl)-methyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine. A specifically claimed intermediate is N-(2-chlorobenzyl)-2,2-dioxo-1, 2,3-oxathiazolidine.     

Patent Evaluation: Indole Derivatives as Anti-Allergic and Anti-Inflammatory Agents

Summary

Novelty: Novel indoles with lipoxygenase inhibitory activity are disclosed.

Biology: No detailed biological data are provided. The compounds are stated to have IC₅₀ values in the range 0.1-30μM.

Chemistry: Syntheses are described in twenty-nine examples and ten specifically claimed compounds are illustrated, one of which is 1-(3-methoxybenzyl)-5-(2-quinolylmethoxy)-indole.     

Patent Evaluation: Hydroxylamine derivatives as lipoxygenase inhibitors

Summary

Novelty: Novel substituted heteroaryl hydroxylamine derivatives are claimed to be lipoxygenase (LPO) inhibitors. They are said to be particularly effective against 5-LPO. They are potentially useful for the treatment of inflammatory and allergic disorders, asthma, dermatitis, ischaemia and endotoxin shock.

Biology: 5-LPO inhibition was determined by measuring the inhibition of the synthesis of 5-HETE and LTB₄ in guinea-pig polymorphonuclear leukocytes. Methods to measure antiinflammatory and anti-asthmatic activity are also described. However, no specific biological data are presented.

Chemistry: A total of eighty-six compounds are disclosed. Syntheses are given in thirteen examples. Nine compounds are specifically claimed including 2-[3-(4-fluorophenyl)propyl]-6-[2-(N-aminocarbonyl-N-hydroxyamino)ethoxy]-1-oxo-1,2,3,4-tetrahydroisoquinoline.     

Patent Evaluation: Heterocyclic Cholinesterase Inhibitors

Summary

Novelty: Novel condensed heterocyclic compounds are disclosed, which are potentially useful as cholinesterase inhibitors and hence as therapeutic and prophylactic agents for senile dementia and Alzheimer's disease.

Biology: In an in vitro rat cerebral cortex assay for AChE inhibition, the most effective compound had an IC₅₀ = 6.5 nM.

Chemistry: Syntheses of the compounds are described in thirty-three examples. 3-Methyl-7-[1-oxo-3-[1-(phenylmethyl)piperidin-4-yl]propyl]-2,3,4,5-tetrahydro-1H-3-benzazepine is one of ten specifically claimed examples.

Structure:     

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: Bisphosphonic Acids as Effective Anti-Arthritic Drugs

Summary

Novelty: Acyclic bisphosphonates are disclosed and are claimed to be effective anti-arthritic agents. These compounds are said to display reduced side-effects compared to NSAIDs, because they do not inhibit cyclooxygenase.

Biology: No biological data are disclosed.

Chemistry: One hundred and six compounds are disclosed; the preparation of thirty-four are fully described and physical data are given for another forty-eight compounds. The majority of the compounds were prepared by condensation of (simple) bisphosphonates with appropriate reagents under basic contions. Ninety-three are explicitly claimed, including (+)[2,(3,4-dihydro-4-oxo-2-phenyl-2H-1-benzopyran-3-yl)ethylidene-bisphosphonic acid tetraethyl ester.

Structure:      

Patent Evaluation: Indole Derivatives which Inhibit Leukotriene Biosynthesis

Summary

Novelty: Substituted indolyl compounds are claimed. They are said to be potent inhibitors of the lipoxygenase enzymes. These compounds may be useful for the treatment or amelioration of inflammatory disease states, in which leukotrienes play a role.

Biology: Inhibition of leukotriene biosynthesis was evaluated in vitro. Calcium ionophore-induced LTB₄ biosynthesis which is expressed by human polymorphonuclear leukocytes (PMNL) or whole human blood was also assayed. Inhibition of in vivo leukotriene biosynthesis, after oral administration of the compound, was determined using a rat peritoneal anaphylaxis model. These compounds were found to be orally effective in preventing in vivo leukotriene biosynthesis.

Chemistry: The syntheses of the compounds are described in several reaction schemes. All compounds are prepared using conventional methods. Two-hundred and seventy-eight examples are given. Twenty-four compounds are specifically claimed, including N′-hydroxy-N′-methyl-N-2-[2-methyl-3-(1-(4-chlorophenylmethyl)-3-(1,1-dimethyl-ethylthio)-5-(1-methylethyl)indol-2-yl)]propyl urea.

Structure:      

Patent Evaluation: Fluoroquinolone Antibacterial Agents

Summary

Novelty: Novel quinoline, naphthyridine and pyridobezoxazine derivatives are disclosed. The compounds are potentially useful against microbial pathogens.

Biology: The antibacterial activity of the compounds is demonstrated against a wide variety of bacteria including Staphylococcus aureus, Micrococcus leuteus and Pseudomonas aeruginosa. Additionally, the in vivo antibacterial activity of a specific compound is determined by studying the protection of CF-1 female mice from bacterial challenge (Staphylococcus aureus). An oral ED₅₀ of 6.0 mg/kg/day and a subcutaneous ED50 of 5.0mg/kg/day is obtained.

Chemistry: Thirty-three compounds are specifically claimed. Two of the specifically claimed compounds are 1-cyclopropyl-6,8-difluoro-7-(9-amino-1,4-dioxa-7-azaspiro [4,4]non-7-yl)-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid and 7-(2-didimethylaminomethyl-1,4-dioxa-7-azaspiro[4.4]non-7-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,8-napthyridine-3-carboxylic acid. The preparation of 552 compounds is either directly or indirectly exemplified. The preparative process is not claimed.     

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: Dual acting TxA Synthase Inhibitors/TxA Antagonists

Summary

Novelty: Novel pyridyl derivatives are disclosed and are claimed to be useful for the treatment and the prophylaxis of thromboembolic diseases, arteriosclerosis, ischaemia and asthma.

Biology: The antithrombotic and thromboxane antagonism effects of the compounds were assayed. The acute toxicity and the ability of the compounds to inhibit thromboxane synthetase (IC₅₀ = 4 nM) were also determined. In an assay of the inhibition of collagen-induced platelet aggregation, a specified compound exhibited an EC₅₀ = 0.5 μM.

Chemistry: Syntheses of the compounds are described in twelve examples using conventional methods. (-)-5E-6[4-(Z-2-(4-chlorophenyl)-cyclopropyl-l-carboxamido)-phenyl]-6-(3-pyridyl)-hex-5-enoic acid is one of four specifically claimed examples.

Structure:      

Patent Evaluation : EP-539977-A: GD Searle & Co: Substituted dibenzoxapines and their use as analgesic agents and prostaglandin antagonists

Novelty: Novel dibenzoxazepine derivatives are claimed to be analgesics and prostaglandin E₂ antagonists. They are potentially useful for the treatment of pain and inflammation.

Biology: Analgesic activity was demonstrated in a writhing assay in mice. Test compounds were administered to the mice and the number of writhes during a ten minute period counted. The specified compound had an ED₅₀ value of 11.2mg/kg (sc). Prostaglandin E₂ antagonism was demonstrated using guinea-pig ileum preparations. Prostaglandin E₂ response curves were generated for the test compounds. pA₂ values were in the range 5.6 to 8.0.

Chemistry: A total of nine final compounds are disclosed. Detailed, stepwise syntheses are given for all examples. Nineteen reaction schemes are detailed. All nine compounds are specifically claimed including N-[2-(8-chloro-10, 11-dihydrodibenz[b,f][1,4]oxa-zepin-10-yl)-2-oxoethyl]-3-(ethylsulfonyl)propanamide.     

Patent Evaluation: Psychotropic Benzodioxan Derivatives

Summary

Novelty: Novel benzodioxan derivatives useful as antipsychotic and anxiolytic agents are disclosed. The compounds are useful in the treatment of a variety of CNS disorders, such as depression, schizophrenia and paranoia.

Biology: The affinity of the compounds for the dopamine D₂ receptor and the serotonin 5-HT_1A receptor were determined according to the methods of Fields (Brain Res. (1977) 136:578) and Hall (J. Neurochem. (1985) 44:1685). One compound gave 83% inhibition for D₂ binding and 100% inhibition for 5-HT_1A binding at 0.1 μM.

Chemistry: Syntheses of the compounds are described in nine examples. N-Methyl-[2-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-amino]ethyltricyclo[3 .3.1.1 (3,7)]-decane-1-carboxamide is one of nine specifically claimed compounds.

Structure:      

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.

Structure:      

Patent Evaluation: Imidazotriazine TNF Inhibitors

Summary

Novelty: Imidazotriazines are disclosed which inhibit the production of IL-I and TNF. Accordingly they are potentially useful for the treatment of a number of inflammatory diseases in which these cytokines are involved.

Biology: Inhibition of IL-I or TNF production was demonstrated by incubating test compounds with lipopolysaccharide-stimulated peripheal blood monocytes for two days. Commercial ELISAs were used to quantify the cytokines. Data are given for three compounds, e.g. the compound shown had a IC₅₀ of 1.3 × 10^?7M against IL-I production.

Chemistry: Eleven illustrative preparations of intermediate imidazotriazines, prepared from condensation of aminotriazines with acetophenones, are described; physical data are given for many more compounds. Twenty detailed synthetic examples are given, with a further seventy compounds prepared in analogous manner e.g. 6-(4-chlorophenyl)-7-(pyrid-4-yl)-1,2,3,4-tetrahydroimidazo[1,2-b][1,2,4]triazine. None is specifically claimed.     

Patent Evaluation: Novel Imidazole Antihistamines

Summary

Novelty: Novel imidazole derivatives are disclosed which have agonistic and antagonistic activity at the histamine (H₃) receptor. The compounds are potentially useful as antihistamines and a process for their synthesis is claimed.

Biology: The agonistic and antagonistic activities were measured using the method described by Van der Werf et al. (Agents and Actions (1987) 20:34) and Menkveld et al. (Eur. J. Pharm. (1990) 86:343-347). The pA₂ values of the antagonists range from 5.8 to 9.9; pA₂ values of the agonists were in the range 7.3 to 9.3.

Chemistry: Syntheses are described in twenty-one examples. S-[Z-(imidazoyl-4-yl)ethyl]-N-(2-phenylethyl)-isothiourea is one of nine preferred compounds showing antagonistic activity. One agonist is preferred.

Structure:      

Patent Evaluation: Highly selective LTB4 antagonists

Summary

Novelty: Substituted phenyl-(2-hydroxy)ethylpyridine compounds and their ketone and alkyl analogues are claimed in WO948880 (AG2453). Very similar compounds are claimed in AG2454 (WO9118879). AG2446 (WO9118601) claims amine, ether or thioether linked pyridyl-benzoic acids derivatives. These compounds are potentially useful for diseases attributed to hydroxyleukotrienes, especially LTB₄ and LTB₄ agonists.

Biology: The biological data presented in all three patents is essentially the same. Antagonist activity is demonstrated by low levels of antagonism towards agonists such as potassium chloride, carbachol, histamine and PGF₂. The receptor binding affinity of the compounds is assessed on [³H]-LTB₄ binding to human U937 cell membranes. LTB₄ antagonist activity is measured by the ability to antagonize the LTB₄ elicited calcium transient, measured with fura-2 fluorescent calcium probe.

Chemistry: The syntheses are described using reaction flow diagrams. Four compounds are specifically claimed in AG2453 including 2-(E-2-carboxyethenyl)-3-decyloxy-6-[2-(3-carboxyphenyl)-2-hydroxy]ethylpyridine, dilithium salt. 3-[1-Oxythia-2-[2-(E-2-Carboxyethenyl)-3-dodecyloxy-6-pyridyl]ethyl]-benzoic acid is claimed in AG2446 along with thirteen related compounds.

Structure:     

Patent Evaluation: Halopropargylated cyclic quaternary ammonium compounds as antimicrobial agents

Novelty: Novel halopropargylated cyclic quaternary ammonium compounds are disclosed which are useful as antimicrobial agents and possess activity against a broad spectrum of fungi and bacteria, as well as low toxicity and favourable environmental profiles.

Biology: The compounds were assaycd for their bacterial and fungicidal ability using MIC tests against P. aeruginosa, S. aureus, E. coli and A. niger. Results are given in four tables. The compounds show excellent activity again3 Gram-negative bacteria such as E. coli.

Chemistry: Syntheses of the compounds are described in five examples, including that of 1 -tetradecyl- 1 -(3-iodopropargyl)pyrrolidinium 4-methylbenzenesulphonate.